Name: 864070-37-1|(2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol|95%
Brand: Ambeed
SKU: A1231619
Rating: 97 (40 reviews)

1
[ 864070-37-1 ]
[ 37595-74-7 ]
[ 864070-38-2 ]

Yield	Reaction Conditions	Operation in experiment
64%	With dmap; triethylamine In dichloromethane at 20℃; for 4h;	XVII 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzene EXAMPLE XVII 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzene 10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml triethylamine and 0.39 g N,N-bis-(trifluoromethanesulphonyl)-aniline in 10 ml dry dichloromethane. The solution is stirred for 4 h at ambient temperature and then combined with aqueous sodium chloride solution. It is extracted with ethyl acetate, the organic extracts are dried over sodium sulphate, and the solvent is removed. The residue is chromatographed through silica gel (dichloromethane/methanol 1:0->4:1). Yield: 0.33 g (64% of theory) Mass spectrum (ESI+): m/z=530/532 (Cl) [M+NH4]+
64%	With dmap; triethylamine In dichloromethane at 20℃; for 4h;
64%	With triethylamine In dichloromethane at 20℃; for 4h;	XIX 10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml triethylamine and 0.39 g N,N-bis-(trifluoromethanesulfonyl)-aniline in 10 ml dry dichloromethane. The solution is stirred for 4 h at ambient temperature and then combined with aqueous sodium chloride solution. It is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->4:1). Yield: 0.33 g (64% of theory) Mass spectrum (ESI+): m/z=530/532 (Cl) [M+NH4]+

64%	With dmap; triethylamine In dichloromethane at 20℃; for 4h;	XV Example XV; 1-Chloro-4-(β-D-glucopyranos-1-yl)-2-r4-(trifluoromethylsulfonyloxy)-benzyll-benzene; 10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g 1-chloro-4-(β-D- glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml triethylamine and 0.39 g N,N-bis- (trifluoromethanesulfonyl)-aniline in 10 ml dry dichloromethane. The solution is stirred for 4 h at ambient temperature and then combined with brine. The resulting mixture is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1 :0->4:1 ). Yield: 0.33 g (64% of theory ) Mass spectrum (ESI+): m/z = 530/532 (Cl) [M+NH4]+
64%	With triethylamine In dichloromethane at 20℃; for 4h;	X 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzene 10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml triethylamine and 0.39 g N,N-bis-(trifluoromethanesulphonyl)-aniline in 10 ml dry dichloromethane. The solution is stirred for 4 h at ambient temperature and then combined with aqueous sodium chloride solution. It is extracted with ethyl acetate, the organic extracts are dried over sodium sulphate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0->4:1). Yield: 0.33 g (64% of theory) Mass spectrum (ESI+): m/z=530/532 (Cl) [M+NH4]+
64%	With dmap; triethylamine In dichloromethane at 20℃; for 4h;	XIII 10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml triethylamine and 0.39 g N,N-bis-(trifluoromethanesulfonyl)-aniline in 10 mL dry dichloromethane. The solution is stirred for 4 h at ambient temperature and then combined with aqueous sodium chloride solution. It is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed through silica gel (dichloromethane/methanol 1:0->4:1). Yield: 0.33 g (64% of theory) Mass spectrum (ESI+): m/z=530/532 (Cl) [M+NH4]+
64%	With triethylamine In dichloromethane at 20℃; for 4h;	XXI 10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml triethylamine and 0.39 g N,N-bis-(trifluoromethanesulphonyl)-aniline in 10 ml dry dichloromethane. The solution is stirred for 4 h at ambient temperature and then combined with aqueous sodium chloride solution. It is extracted with ethyl acetate, the organic extracts are dried over sodium sulphate, and the solvent is removed. The residue is chromatographed through silica gel (dichloromethane/methanol 1:0->4:1). Yield: 0.33 g (64% of theory) Mass spectrum (ESI+): m/z=530/532 (CI) [M+NH4]+
64%	With dmap; triethylamine In dichloromethane at 20℃; for 4h;	VII EXAMPLE VII; 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trifluoromethylsulphonyloxy)-benzyl]-benzene; 10 mg 4-dimethylaminopyridine are added to a solution of 0.38 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 mL triethylamine and 0.39 g N,N-bis-(trifluoromethanesulfonyl)-aniline in 10 mL dry dichloromethane. The solution is stirred for 4 h at ambient temperature and then combined with brine. The resultant solution is extracted with ethyl acetate, the organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed through silica gel (dichloromethane/methanol 1:0->4:1). Yield: 0.33 g (64% of theory) Mass spectrum (ESI+): m/z=530/532 (Cl) [M+NH4]+
63%	With dmap; triethylamine In dichloromethane

Reference： [1]Current Patent Assignee: SRI INTERNATIONAL INC - US2005/209166, 2005, A1 Location in patent: Page/Page column 26
[2]Current Patent Assignee: SRI INTERNATIONAL INC - WO2005/92877, 2005, A1 Location in patent: Page/Page column 62
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/189548, 2006, A1 Location in patent: Page/Page column 26
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2007/93610, 2007, A1 Location in patent: Page/Page column 39
[5]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/9400, 2006, A1 Location in patent: Page/Page column 16
[6]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/4648, 2007, A1 Location in patent: Page/Page column 17
[7]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/27092, 2007, A1 Location in patent: Page/Page column 25
[8]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/54867, 2007, A1 Location in patent: Page/Page column 8
[9]Location in patent: scheme or table Lansdell, Mark I.; Burring, Denise J.; Hepworth, David; Strawbridge, Matthew; Graham, Emily; Guyot, Thierry; Betson, Mark S.; Hart, James D. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 4944 - 4947]

2
[ 864070-37-1 ]
[ 1556-18-9 ]
1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-cyclopentyloxy-benzyl)-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With caesium carbonate In N,N-dimethyl-formamide at 45℃; for 18h;	1 1-chloro-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranos-1-yl)-benzene EXAMPLE 1 1-chloro-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranos-1-yl)-benzene 0.16 ml iodocyclopentane are added to a mixture of 0.25 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.4 g caesium carbonate in 2.5 ml of dimethylformamide. The mixture is stirred for 4 h at 45° C., before another 0.1 g caesium carbonate and 0.05 ml iodocyclopentane are added. After another 14 h stirring at 45° C. aqueous sodium chloride solution is added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is removed and the residue is purified using silica gel (dichloromethane/methanol 1:0->5:1). Yield: 0.23 g (78% of theory) Mass spectrum (ESI+): m/z=466/468 (Cl) [M+NH4]+
78%	With caesium carbonate In DMF (N,N-dimethyl-formamide) at 45℃; for 18h;
78%	With caesium carbonate In N,N-dimethyl-formamide at 45℃; for 18h;	XIV Example XIV; 1-Chloro-2-(4-cvclopentyloxybenzyl)-4-(β-D-qlucopyranos-1-yl)-benzene; 0.16 mL lodocyclopentane are added to a mixture of 0.25 g 1-chloro-4-(β-D-glucopyranos-1- yl)-2-(4-hydroxybenzyl)-benzene and 0.4 g caesium carbonate in 2.5 mL of dimethylformamide. The mixture is stirred for 4 h at 45°C, before another 0.1 g caesium carbonate and 0.05 ml iodocyclopentane are added. After another 14 h stirring at 45 °C aqueous sodium chloride solution is added and the resulting mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel (dichloromethane/methanol 1 :0->5:1 ). Yield: 0.23 g (78% of theory) Mass spectrum (ESI+): m/z = 466/468 (Cl) [M+NH4]+

Reference： [1]Current Patent Assignee: SRI INTERNATIONAL INC - US2005/209166, 2005, A1 Location in patent: Page/Page column 28
[2]Current Patent Assignee: SRI INTERNATIONAL INC - WO2005/92877, 2005, A1 Location in patent: Page/Page column 67
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2007/93610, 2007, A1 Location in patent: Page/Page column 36-37

3
C₁₉H₂₁ClO₇ [ No CAS ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
46%	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10 - -5℃; for 5h;	XVI A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80° C. under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution and extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the solution is cooled to -10° C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition has ended the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulphate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by total acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallising the product in ethanol. The product thus obtained is converted into the title compound by reacting in methanol with 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+H]+
	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10 - -5℃; for 5h;	VI EXAMPLE VI 1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 mL dry diethyl ether is cooled to -80° C. under argon. 11.6 mL of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 mL diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 mL methanesulfonic acid in 35 mL of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution and the resultant mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated down. The residue is dissolved in 30 mL acetonitrile and 30 mL dichloromethane and the resulting solution is cooled to -10° C. After the addition of 4.4 mL triethylsilane 2.6 mL boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx.

Reference： [1]Current Patent Assignee: SRI INTERNATIONAL INC - US2005/209166, 2005, A1 Location in patent: Page/Page column 25
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/49537, 2007, A1 Location in patent: Page/Page column 15-16

4
[ 912917-85-2 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: (2S,3S,4R,5R,6R)-2-(3-(4-acetoxybenzyl)-4-chlorophenyl)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate With methanol; potassium hydroxide; water at 20℃; for 1h; Stage #2: With hydrogenchloride In methanol; water	XII To a solution of 7.9 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-acetoxy-benzyl)-benzene in 150 mL methanol is added 25 mL 4 M aqueous potassium hydroxide solution. The solution is stirred at room temperature for 1 h and then adjusted to pH 5 with 4 M hydrochloric acid. Most of the methanol is evaporated and the remaining solution is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is removed in vacuo. Yield: 5.1 g (100% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+NH4]+
100%	Stage #1: (2S,3S,4R,5R,6R)-2-(3-(4-acetoxybenzyl)-4-chlorophenyl)-6-(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate With methanol; potassium hydroxide; water at 20℃; for 1h; Stage #2: With hydrogenchloride In water	XII To a solution of 7.9 g 1-cloro4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-acetoxy-benzyl)-benzene in 150 mL methanol is added 25 mL 4 M aqueous potassium hydroxide solution. The solution is stirred at room temperature for 1 h and then adjusted to pH 5 with 4 M hydrochloric acid. Most of the methanol is evaporated, and the remaining solution is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate, and the solvent is removed in vacuo. Yield: 5.1 g (100% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+NH4]+
93%	With water; lithium hydroxide In tetrahydrofuran; methanol at 10 - 40℃;	4 Example-4: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl) phenyl)-6- (hydroxy-methyl) tetrahydro-2H-pyran-3,4,5-triol (VI) A mixture of (2S,3S,4R,5R,6R)-2-(3-(4-acetoxybenzyl)-4-chlorophenyl)-6- (acetoxymethyl) tetrahydro-2/-/-pyran-3,4,5-triyl triacetate (195 g), methanol (1755 ml), tetrahydrofuran (1170 ml) and water (585 ml) was cooled at 10-20°C. Lithium hydroxide (20.8 g) was added lot wise at 10-20°C. The reaction mixture was heated to 30-40°C and stirred for 4-5 h. After completion of reaction, organic solvent was distilled out from the reaction mixture under vacuum below 55°C. Aqueous sodium chloride solution (10%, 1000 ml) was added to the reaction mixture, stirred for 5-10 min. and then extracted with ethyl acetate (3x1000 ml). Combine the organic layers and washed with brine solution (1000 ml). Organic layer was distilled out under vacuum at 50-60°C. The obtained residue was stirred with methyl ethyl ketone (1000 ml) at 75-85°C for lh. Reaction mixture was cooled to 10-20°C and stirred for lh. The solid material was filtered and washed with methyl ethyl ketone (2x100 ml). The solid was dried at 45-55°C for 6-8 h to give the title compound as white solid (117 g). Yield: 93%. HPLC Purity: 98.28%

	With methanol; potassium hydroxide
	With methanol; potassium hydroxide; water	VI A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80° C. under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralized with solid sodium hydrogen carbonate, ethyl acetate is added, and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution, and the resulting mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane, and the solution is cooled to -10° C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition is complete the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/a which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product from ethanol. The product thus obtained is converted into the title compound by deacetylation in methanol with aqueous 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+H]+.
	With potassium hydroxide; water In methanol	VI Example Vl1-chloro-4-(β-D-qlucopyranos-1-yl)-2-(4-hvdroxybenzyl)-benzeneA solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-te/Tf-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80 0C under argon. 11.6 ml of a 1.7 M solution of te/if-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80 0C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to - 80 0C. The resulting solution is stirred for 3 h at -78 0C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution, and the resulting mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the solution is cooled to -10 0C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5 0C. After the addition is complete the solution is stirred for another 5 h at -5 to -10 0C and then quenched by the addition of aqueous sodium hydrogen carbonate solution. EPO The organic phase is separated, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed, and the residue is purified by chromatography on silica gel (dichoromethane/methanol 1 :0->3:1 ). The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product from ethanol. The product thus obtained is converted into the title compound by deacetylation in methanol with aqueous 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory)Mass spectrum (ESI+): m/z = 398/400 (Cl) [M+H]+
	With methanol; potassium hydroxide; water	XVIII A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80° C. under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution that is extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the resulting solution is cooled to -10° C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition has ended the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulphate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by total acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallising the product in ethanol. The product thus obtained is converted into the title compound by reacting in methanol with 4 M potassium hydroxide solution.
	With methanol; potassium hydroxide; water	VI EXAMPLE VI; 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene; A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 mL dry diethyl ether is cooled to -80° C. under argon. 11.6 mL of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 mL diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 mL methanesulfonic acid in 35 mL methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralized with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution that is extracted then four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated down. The residue is dissolved in 30 mL acetonitrile and 30 mL dichloromethane and the solution is cooled to -10° C. After the addition of 4.4 mL triethylsilane 2.6 mL boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallizing the product from ethanol. The product thus obtained is converted into the title compound by reacting in methanol with 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+H]+
	With water; lithium hydroxide In tetrahydrofuran; methanol at 15 - 20℃; for 1h;	8 Preparation of Compound of Formula (II) In a round bottom flask, 30.8 mL methanol, 3.5 gm compound of Formula (III), 19.25 ml THF and 10.25 ml water were taken and stirred for 15-20 minutes at 25° C. to 35° C. The reaction mixture was cooled to 15° C. to 20° C. 0.29 gm lithium hydroxide and 2 mL water were added into the reaction mixture and stirred for an hour. After completion of the reaction, 40 mL water and 40 mL ethyl acetate were added and stirred for half an hour. The organic and aqueous layers were separated. Organic layer was dried over sodium sulfate. The solvent was distilled out under vacuum to obtain compound of Formula (II).

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/234953, 2006, A1 Location in patent: Page/Page column 16
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/4648, 2007, A1 Location in patent: Page/Page column 16
[3]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2018/29264, 2018, A1 Location in patent: Page/Page column 25-26
[4]Current Patent Assignee: SRI INTERNATIONAL INC - WO2005/92877, 2005, A1 Location in patent: Page/Page column 61-62
[5]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/251728, 2006, A1 Location in patent: Page/Page column 7
[6]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2006/117359, 2006, A1 Location in patent: Page/Page column 16-17
[7]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/27092, 2007, A1 Location in patent: Page/Page column 24
[8]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/54867, 2007, A1 Location in patent: Page/Page column 7-8
[9]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1 Location in patent: Paragraph 0170; 0191; 0192

5
[ 1079083-63-8 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; potassium hydroxide; water	IX 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80° C. under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle cooled with dry ice to a solution of 4.78 g of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether, cooled to -80° C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution and the mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the solution is cooled to -10° C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise such that the temperature does not exceed -5° C. After all the solution has been added the resulting solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulphate, the solvent is removed and the residue is purified on silica gel. The product thus obtained is a roughly 6:1 mixture of β/a, which can be converted into the pure β-anomer by total acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallisation of the product from ethanol. The product thus obtained is converted into the title compound by reaction with 4 M potassium hydroxide solution in methanol. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+H]+
196 g	With lithium hydroxide monohydrate; water In tetrahydrofuran; methanol at 20 - 25℃; for 16h;	3 step 3 In a 10L reaction flask, add the crude product obtained in the previous step (theoretical value 0.52mol),Add tetrahydrofuran (1.3L), methanol (2L), water (665mL), stir for 30min,Add lithium hydroxide monohydrate (109.2g, 2.6mol), stir at 2025 for 16h, HPLC monitors the completion of the reaction, the reaction solution is concentrated under reduced pressure to remove part of the solvent (about 1L remaining),Add dilute hydrochloric acid (1mol/L) to the residue to adjust the pH to 6-7, add ethyl acetate to the aqueous phase and extract three times, 1.5L each time, combine the organic phases, and wash once with saturated sodium chloride solution (3L).The organic phase was concentrated under reduced pressure to remove the solvent, added 2L n-heptane slurry, washed for 2h, filtered,After drying, 196 g of the compound represented by formula IV was obtained, the yield of the two-step reaction was 99.0%, and the purity: 97.3%.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/9400, 2006, A1 Location in patent: Page/Page column 15-16
[2]Current Patent Assignee: BEIJING HUIZHIHENG BIOLOGICAL TECH; JILIN HUISHENG BIOLOGICAL PHARMACEUTICAL - CN112047915, 2020, A Location in patent: Paragraph 0104-0106

6
[ 912917-83-0 ]
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3R,4S,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10 - -5℃; for 5h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; acetonitrile	XVIII A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80° C. under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 ml methanesulfonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution which is extracted four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the solution is cooled to -10° C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition is complete the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallising the product in ethanol. The product thus obtained is converted into the title compound by reacting in methanol with 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+H]+
	Stage #1: (3R,4S,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; cyclohexane; ethyl acetate; acetonitrile at -10 - -5℃; for 1h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; acetonitrile	X 1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzene EXAMPLE X 1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzene A solution of 25.0 g 1-chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzene and 20.0 mL triethylsilane in 120 mL dichloromethane and 360 mL acetonitrile is cooled to -5--10° C. 10.0 mL Boron trifluoride etherate are added dropwise and the solution is stirred in the cooling bath for 1 h. Aqueous sodium hydrogen carbonate solution is added, the organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is removed in vacuo. The residue is washed with diisopropylether and dissolved in as little ethyl acetate as needed. The resulting solution is treated with cyclohexane and the precipitate is separated by filtration and dried at 50° C. Yield: 23.0 g (99% of theory, ca. 7:1 mixture with α-anomer) Mass spectrum (ESI-): m/z=425/427 (Cl) [M+HCOO]-

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/189548, 2006, A1 Location in patent: Page/Page column 25
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/234953, 2006, A1 Location in patent: Page/Page column 15-16

7
[ 864070-37-1 ]
[ 108-24-7 ]
[ 912917-85-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With pyridine; dmap In dichloromethane at 20℃; for 0.5h;	5 1-Chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glycopyranose-1-yl)-2-(4-acetoxy-benzyl)benzene EXAMPLE 5 1-Chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glycopyranose-1-yl)-2-(4-acetoxy-benzyl)benzene A solution of 1-chloro-4-(β-D-glycopyranose-1-yl)-2-(4-hydroxy-benzyl)benzene (0.38 g, 1 mmol) in dichloromethane (10 mL) was cooled to 0° C., pyridine (790 mg, 10 mmol) was added, sequence followed by the addition of acetyl anhydride (1.02 g, 10 mmol) and DMAP (12 mg, 0.1 mmol). After stirred at room temperature for 30 minutes, the organic phase was washed in turn with water, hydrochloric acid (1 N), saturated aqueous sodium bicarbonate and saturated brine. The organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give white powder, which was used for the next step without further purification. Yield: 0.56 g (95% of theoretical value). 1HNMR (500 MHz, CDCl3) δ: 7.29 (d, J=8.5 Hz, 1H), 7.13 (dd, J=2.0 Hz, 8.0 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.05 (d, J=2.0 Hz, 1H), 6.93 (dd, J=2.0 Hz, 6.5 Hz, 2H), 5.22 (t, J=9.5 Hz, 1H), 5.13 (t, J=9.5 Hz, 1H), 4.99 (t, J=9.5 Hz, 1H), 4.26 (d, J=10.0 Hz, 1H), 4.18-4.22 (m, 2H), 4.07 (dd, J=2.5 Hz, 12.5 Hz, 1H), 4.01 (q, J=15.5 Hz, 2H), 2.21 (s, 3H), 2.01 (s, 3H), 1.97 (s, 3H), 1.92 (s, 3H), 1.62 (s, 3H). LC-MS (ESI): m/z=613/615 (Cl) [M+Na]+.
95%	With pyridine; dmap In dichloromethane at 0 - 20℃; for 0.5h;	5 Example 5: 1-Chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glycopyranose-1-yl)-2-(4-acetoxy-benzyl)benzene[0089] Example 5 1-Chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glycopyranose-1-yl)-2-(4-acetoxy-benzyl)benzene A solution of 1-chloro-4-(β-D-glycopyranose-1-yl)-2-(4-hydroxy-benzyl) benzene (0.38 g, 1 mmol) in dichloromethane (10 mL) was cooled to 0°C, pyridine (790 mg, 10 mmol) was added, sequence followed by the addition of acetyl anhydride (1.02 g, 10 mmol) and DMAP (12 mg, 0.1 mmol). After stirred at room temperature for 30 minutes, the organic phase was washed in turn with water, hydrochloric acid (1 N), saturated aqueous sodium bicarbonate and saturated brine. The organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give white powder, which was used for the next step without further purification. Yield: 0.56 g (95% of theoretical value). 1HNMR (500 MHz, CDCl3) δ: 7.29(d, J=8.5Hz, 1H), 7.13(dd, J=2.0Hz, 8.0Hz, 1H), 7.08(d, J=8.5Hz, 2H), 7.05(d, J=2.0Hz, 1H), 6.93(dd, J=2.0Hz, 6.5Hz, 2H), 5.22(t, J=9.5Hz, 1H), 5.13(t, J=9.5Hz, 1H), 4.99(t, J=9.5Hz, 1H), 4.26(d, J=10.0Hz, 1H), 4.18-4.22(m, 2H), 4.07(dd, J=2.5Hz, 12.5Hz, 1H), 4.01(q, J=15.5Hz, 2H), 2.21(s, 3H), 2.01(s, 3H), 1.97(s, 3H), 1.92(s, 3H), 1.62(s, 3H). LC-MS (ESI): m/z = 613/615(Cl) [M+Na]+.
22%	With pyridine; dmap In dichloromethane at 20℃; for 1h;	XI 1-Chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-acetoxy-benzyl)-benzene EXAMPLE XI 1-Chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-acetoxy-benzyl)-benzene To a solution of 23.0 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzene and 55 mL pyridine in 200 mL dichloromethane is added 60 mL acetic acid anhydride followed by 0.1 g 4-dimethylaminopyridine. The solution is stirred for 1 h at ambient temperature. Then, the solution is diluted with dichloromethane and washed with 2 M aqueous hydrochloric acid. The organic phase is dried over sodium sulfate and the solvent is evaporated. The residue is recrystallized from ethanol to give the pure β-anomer as a white solid. Yield: 7.8 g (22% of theory) Mass spectrum (ESI+): m/z=608/610 (Cl) [M+NH4]+

22%

With pyridine; dmap In dichloromethane at 20℃; for 1h;

XI To a solution of 23.0 g 1-chloro4-(β-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzene and 55 mL pyridine in 200 mL dichloromethane is added 60 mL acetic acid anhydride followed by 0.1 g 4-dimethylaminopyridine. The solution is stirred for 1 h at ambient temperature. Then, the solution is diluted with dichloromethane and washed with 2 M aqueous hydrochloric acid. The organic phase is dried over sodium sulfate, and the solvent is evaporated. The residue is recrystallized from ethanol to give the pure β-anomer as a white solid. Yield: 7.8 g (22% of theory) Mass spectrum (ESI+): m/z=608/610 (Cl) [M+NH4]+

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0126-0130
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0042; 0089; 0090
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/234953, 2006, A1 Location in patent: Page/Page column 16
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/4648, 2007, A1 Location in patent: Page/Page column 16

8
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]
[ 108-24-7 ]
[ 912917-85-2 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In dichloromethane Resolution of racemate;	VI Example Vl1-chloro-4-(β-D-qlucopyranos-1-yl)-2-(4-hvdroxybenzyl)-benzeneA solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-te/Tf-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80 0C under argon. 11.6 ml of a 1.7 M solution of te/if-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80 0C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to - 80 0C. The resulting solution is stirred for 3 h at -78 0C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution, and the resulting mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the solution is cooled to -10 0C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5 0C. After the addition is complete the solution is stirred for another 5 h at -5 to -10 0C and then quenched by the addition of aqueous sodium hydrogen carbonate solution. EPO The organic phase is separated, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed, and the residue is purified by chromatography on silica gel (dichoromethane/methanol 1 :0->3:1 ). The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product from ethanol. The product thus obtained is converted into the title compound by deacetylation in methanol with aqueous 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory)Mass spectrum (ESI+): m/z = 398/400 (Cl) [M+H]+
	With pyridine In dichloromethane	VI EXAMPLE VI; 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene; A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 mL dry diethyl ether is cooled to -80° C. under argon. 11.6 mL of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 mL diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 mL methanesulfonic acid in 35 mL methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralized with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution that is extracted then four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated down. The residue is dissolved in 30 mL acetonitrile and 30 mL dichloromethane and the solution is cooled to -10° C. After the addition of 4.4 mL triethylsilane 2.6 mL boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallizing the product from ethanol. The product thus obtained is converted into the title compound by reacting in methanol with 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2006/117359, 2006, A1 Location in patent: Page/Page column 17
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/54867, 2007, A1 Location in patent: Page/Page column 7-8

9
(3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one [ No CAS ]
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane With n-butyllithium In diethyl ether; pentane at -80℃; for 0.5h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In diethyl ether; pentane at -80 - -78℃; for 3h; Stage #3: With methanol; triethylsilane; methanesulfonic acid; boron trifluoride diethyl etherate; water; sodium hydrogencarbonate more than 3 stages;	XIII Example XIII; 1-Chloro-4-(β-D-qlucopyranos-1-yl)-2-(4-hvdroxybenzyl)-benzene; A solution of 4.0 g [4-(5-Bromo-2-chloro-benzyl)-phenoxy]-terf-butyl-dimethyl-silane in 42 mL dry diethyl ether is cooled to -80 °C under argon. 11.6 mL of a chilled (ca. -50 °C) 1.7 M solution of tert-butyllithium in pentane are slowly added to the cooled solution and then the solution is stirred for 30 min at -80 °C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone in 38 mL diethyl ether chilled to -80 °C. The resulting solution is stirred for 3 h at -78 °C. Then a solution of 1.1 mL methanesulfonic acid in 35 mL methanol is added and the resultant reaction solution is stirred for another 16 h at ambient temperature. The solution is then neutralized with solid sodium hydrogen carbonate, ethyl acetate is added and the resultant solution is concentrated under reduced pressure. Aqueous sodium hydrogen carbonate solution is added to the remaining solution that is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated. The residue is dissolved in 30 mL acetonitrile and 30 mL dichloromethane and the resulting solution is cooled to -10 °C. After the addition of 4.4 mL triethylsilane, 2.6 mL boron trifluoride etherate are added dropwise so that the temperature does not exceed -5 °C. After the addition is complete, the reaction solution is stirred for another 5 h at -5 to -10 °C and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol). The product then obtained is an approx. 6:1 mixture of β/α which can be separated by global acetylation of the hydroxyl groups with acetic anhydride, pyridine and 4-dimethylaminopyridine in dichloromethane and recrystallisation of the resulting acetylated product from ethanol. The pure acetylated β-product thus obtained is converted into the title compound by removal of the acetyl groups in methanol with 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z = 398/400 (Cl) [IVH-NH4] +

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2007/93610, 2007, A1 Location in patent: Page/Page column 35-36

10
[ 864070-37-1 ]
[ 112052-11-6 ]
(2S,3R,4R,5S,6R)-2-{4-chloro-3-[4-(tetrahydrofuran-3(R)-yloxy)benzyl]phenyl}-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h;	0.19 g (S)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75° C. for 4 h, before another 0.29 g caesium carbonate and 0.19 g (S)-3-(4-methylphenyl-sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75° C. the mixture is cooled to ambient temperature, and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->5:1). Yield: 0.11 g (44% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/251728, 2006, A1 Location in patent: Page/Page column 7

11
[ 864070-37-1 ]
[ 219823-47-9 ]
[ 864070-44-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 21h;	Preparation example 1 preparation of according to handkerchief row only Reference Patent document WO2006/117359 A1 preparation prepared by the method of the embodiment of the net according to handkerchief row. In particular to: heating 2.85g the (R) - 3 - (4-methyl phenyl sulfonyl oxy)-tetrahydrofuran to 3.00g of 1-chloro-4 - (β-D-pyran glucose-1-yl) - 2 - (4-hydroxy-benzyl)-benzene and 4.36g cesium carbonate in 38 ml in a mixture of dimethyl formamide. The mixture for 75 °C stirring under 5 hours, then further adding 4.40g of and cesium carbonate 2.87g the (R) - 3 - (4-methyl phenyl sulfonyl oxy)-tetrahydrofuran. In the 75 °C in addition stirring 16 hours after cooling to room temperature after the mixture by adding saline. The obtained mixture is extracted with ethyl acetate, the combined organic extract is dried with anhydrous sodium sulfate. crosses the column purification of the residue (methylene chloride/methanol 1:0 → 5:1). Production of 2.1g, yield 57%. Mass spectrometric (ESI+): m/z=451/453 (Cl) [M+H]+, the net according to handkerchief row.
49%	With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h;	Preparation of the compound A:1-chloro-4-(β-D-qlucopyranos-1-yl)-2-r4-(<fS)-tetrahvdrofuran-3-yloxy)-benzyll- benzene0.19 g (f?)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75 0C for 4 h, before another 0.29 g caesium carbonate and 0.19 g (f?)-3-(4-methylphenyl- sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75 0C the mixture is cooled to ambient temperature and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1 :0 -> 5:1 ). Yield: 0.12 g (49% of theory) Mass spectrum (ESI+): m/z = 451/453 (Cl) [M+H] + EPO Preparation of the crystalline form:Variant 1 :30 mg 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene (obtained as described above) are dissolved in 0.8 ml of ethyl acetate (containing 0.5-3% water) upon heating up to about 50 0C. The solution is allowed to cool slowly (about 1 to 3 h) to about 20 0C. After 48 h the crystalline form is isolated as white crystals by filtration. An excess of the solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 3 to 4 h at reduced pressure.Variant 2:1 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 5 ml of water/ethanol mixture (2 : 3 volume ratio) upon heating up to about 50 0C. 8 ml of water are added and the solution is allowed to cool to about 20 0C in 1 to 3 h. After 16 h the crystalline form is isolated as white crystals by filtration. Excess solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 4 to 6 h.Variant 3:1 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 11 ml of isopropanol upon heating up to about 50 0C. The solution is allowed to cool to about 20 0C in 1 to 3 h. After 16 h the crystalline form is isolated as white crystals by filtration. Residual solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 4 to 6 h.Variant 4:8,9 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((Sj-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 60 ml of water/ethanol mixture (2 : 3 volume ratio) upon heating up to about 50 0C. The solution is allowed to cool to about 20 0C in 3 h and the crystalline compound is isolated by filtration. The separated white solid is dried at 40 0C for 16 h to yield about 6 g of the crystalline form.
49%	With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h;	VI 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene 0.19 g (R)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75° C. for 4 h, before another 0.29 g caesium carbonate and 0.19 g (R)-3-(4-methylphenyl-sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75° C. the mixture is cooled to ambient temperature and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→5:1). Yield: 0.12 g (49% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+

	With caesium carbonate at 25 - 40℃;	9 Preparation of Compound of Formula (I) In a round bottom flask, 1.2 g compound of Formula (II), 1.2 g cesium carbonate, 0.81 (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate and 18 mL DMF or DMSO were added at 25° C. to 35° C. The reaction mixture was heated to 35 to 40° C. and stirred for 24-36 hrs. The reaction mixture then cooled to 25° C. to 35° C. 40 mL water and 20 ml toluene were added stirred for 15-20 minutes. Layers were separated. The aqueous layer was extracted with dichloromethane, dried over sodium sulfate. The solvent was distilled out under vacuum. 10 mL ethanol was added and stirred for 30 minutes. The reaction mixture was stirred at 0-5° C. for an hour. The product was filtered and washed with pre-cooled ethanol and dried to obtain empagliflozin.
0.55 kg	With caesium carbonate In N,N-dimethyl-formamide at 30 - 45℃; for 24h;	36.d Preparation of Empagliflozin Tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane (1 .0 Kg), tetrahydrofuran (6.0 L) and (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl) tetrahydro-2H-pyran-2-one (1 .221 Kg) were charged into a 20 L flask under Nitrogen atmosphere. Toluene (6.0 L) was charged into the flask and the resulted mixture was cooled to -80 °C. n-Butyl Lithium in hexane (1 .6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 °C. The reaction mixture was maintained for 1 hour at -80 °C. A solution of methanesulfonic acid (1 .46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 °C. The reaction mass was heated to -10 °C and stirred for 30 minutes and heated to 30 °C and stirred for 12 hours at 30 °C. The reaction mass was cooled to 5 °C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly. The reaction mass was stirred for 30 minutes at 30 °C. The reaction mass was washed with Toluene (6.0 Lx 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask. The reaction mass was extracted with ethylacetate (10.0 Lx5) and the ethylacetate layer was washed with water (3.0 L). The ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor. The concentrated ethylacetate layer was stripped off with acetonitrile (3.0 Lx 3) then dichloromethane (7.0 L) and acetonitrile (1 .2 L) were charged into the reactor and the reaction mass was cooled to -30 °C. Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1 .307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 °C. Temperature was raised to -5 °C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 °C. The reaction mass was heated to 30 °C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor. The mass was washed with toluene (4.0 L) and extracted with ethylacetate (8.0 Lx2 and 4.0 Lx4) and the ethylacetate layer washed with water (2.0 Lx2) The organic layer was concentrated under vacuum until 2 volumes remained in the reactor then the crude mass was stripped off with ethylacetate (3.0 l_x2) and with DMF (1 .4 L). Tosyl-THF (0.634 Kg) and DMF (0.20 L) were charged into the reactor and the resulted mass was stirred for 30 minutes at 30 °C. Cesium carbonate lot 1 (0.57 Kg) was added to the reaction mass. Reaction mass was heated to 45 °C and stirred for 2 hours at 45 °C. Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours. Cesium carbonate lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 °C. The reaction mass was cooled to 30 °C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 °C under vacuum until 1 .0 volume remained in the reactor. The concentrated mass was cooled to 30 °C and water (10.0 L) and acetonitrile 1 .0 L) were charged into the reactor at 30 °C and the resulted mixture was heated to 45 °C and the mixture was stirred for 6 hours at 45 °C. The suspension was cooled to 25 °C and stirred for 7 hours at 25 °C. The precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried. The wet compound and DMF (1 .0 L) were charged into another reactor and the solution was heated to 45 °C. Acetonitrile (1 .0 L) charged followed by water (10.0 L) into the reactor at 45 °C and stirred for 6 hours. The suspension was cooled to 25 °C and stirred for 6 hours. The precipitation was fileted and the wet cake was washed with water. The wet material was suck dried. The wet material was dried under vacuum at 60 °C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC 99%.

Reference： [1]Current Patent Assignee: HANGZHOU PUSHAI PHARMACEUTICAL TECHNOLOGY CO LTD (unclear) - CN105384730, 2016, A Location in patent: Paragraph 0075; 0076
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2006/117359, 2006, A1 Location in patent: Page/Page column 17
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/249544, 2007, A1 Location in patent: Page/Page column 6
[4]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1 Location in patent: Paragraph 0170; 0193; 0194
[5]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2017/203457, 2017, A1 Location in patent: Page/Page column 42-44

12
[ 1120-90-7 ]
[ 864070-37-1 ]
1-Chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(pyridin-3-yloxy)-benzyl]-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate In 1-methyl-pyrrolidin-2-one at 120℃;	1 To an argon-purged flask charged with 0.43 g cesium carbonate and 1 mL N-methylpyrrolidinone are added 0.28 g 3-iodopyridine, 12 mg 2,2,6,6-tetramethylhepta-3,5-dione and 34 mg copper(I) chloride. The flask is tightly sealed and the mixture is stirred at 120° C over night. After cooling the reaction mixture to room temperature, the solvent is evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol 1:0→5:1). Yield: 82 mg (14% of theory) Mass spectrum (ESI+): m/z=458/460 (Cl) [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/234953, 2006, A1 Location in patent: Page/Page column 17

13
C₁₉H₂₁ClO₇ [ No CAS ]
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₁₉H₂₁ClO₇ With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10 - -5℃; for 5h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; acetonitrile	VI Example Vl1-chloro-4-(β-D-qlucopyranos-1-yl)-2-(4-hvdroxybenzyl)-benzeneA solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-te/Tf-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80 0C under argon. 11.6 ml of a 1.7 M solution of te/if-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80 0C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to - 80 0C. The resulting solution is stirred for 3 h at -78 0C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution, and the resulting mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the solution is cooled to -10 0C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5 0C. After the addition is complete the solution is stirred for another 5 h at -5 to -10 0C and then quenched by the addition of aqueous sodium hydrogen carbonate solution. EPO The organic phase is separated, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed, and the residue is purified by chromatography on silica gel (dichoromethane/methanol 1 :0->3:1 ). The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product from ethanol. The product thus obtained is converted into the title compound by deacetylation in methanol with aqueous 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory)Mass spectrum (ESI+): m/z = 398/400 (Cl) [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2006/117359, 2006, A1 Location in patent: Page/Page column 16-17

14
[ 864070-37-1 ]
[ 1638-75-1 ]
1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(dimethylphosphinoylmethoxy)-benzyl]-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 80℃;	XV To a stirred mixture of 1.0 g 1-chloro4-(β-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzene and 1.0 g potassium carbonate in 10 mL dimethylformamide is added 0.6 g chloro-(dimethylphosphanoyl)-methane. The mixture is stirred over night at 80° C. After cooling to ambient temperature, the reaction mixture is neutralized with 1 M hydrochloric acid, and the solvent is evaporated. The residue is taken up in 10 mL dichloromethane, and to the resultant suspension are added 2.1 mL pyridine, 2.4 mL acetic anhydride, and 50 mg 4-dimethylaminopyridine. The solution is stirred for 1 h at ambient temperature. 50 mL water is added, and the resulting solution stirred for an additional 5 min. The aqueous layer is separated, and the organic phase is washed with 1 M hydrochloric acid and aqueous sodium hydrogencarbonate solution and dried over magnesium sulfate. After removal of the solvent in vacuo, the residue is purified by chromatography on silica gel (dichloromethane/methanol 9: 1->2:1) to furnish the product as a white solid. Yield: 0.65 g (39% of theory) Mass spectrum (ESI+): m/z=639/641 (Cl) [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/4648, 2007, A1 Location in patent: Page/Page column 17

15
[ 912917-83-0 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; cyclohexane; ethyl acetate; acetonitrile at -10 - -5℃; for 1h;	X A solution of 25.0 g 1-chloro4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-hydroxy-benzyl)-benzene and 20.0 mL triethylsilane in 120 mL dichloromethane and 360 mL acetonitrile is cooled to -5--10° C. 10.0 mL Boron trifluoride etherate are added dropwise, and the solution is stirred in the cooling bath for 1 h. Aqueous sodium hydrogen carbonate solution is added, the organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed in vacuo. The residue is washed with diisopropylether and dissolved in as little ethyl acetate as needed. The resulting solution is treated with cyclohexane, and the precipitate is separated by filtration and dried at 50° C. Yield: 23.0 g (99% of theory, ca. 7:1 mixture with α-anomer) Mass spectrum (ESI-): m/z=425/427 (Cl) [M+HCOO]-
87.1%	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10℃; for 5h;	8 Synthesis of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxy-benzyl)-benzene (10) 45.3 g (0.11 mol) of 7 was dissolved in 300 mL of dichloromethane acetonitrile (1:1) mixture, and the reaction was stirred. Slowly add 29 mL (0.17 mol) of triethylsilane to the mixture while cooling to -10 °C. Then, 16 mL (0.13 mol) of boron trifluoride etherate solution was slowly added dropwise, and the reaction was carried out for 5 hours under ice bath conditions. The reaction was quenched by the addition of 150 mL of saturated sodium bicarbonate solution, and the reaction was stirred for 15 min, and the organic phase was separated. The solvent was evaporated under reduced pressure. The aqueous phase was extracted with ethyl acetate (2×). 10, 36.4 g, yield 87.1%.
64.33%	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at 0 - 10℃; for 4h;	5 Example-5: Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl) phenyl)-6- (hydroxy methyl) tetrahydro-2H-pyran-3,4,5-triol (VI) A mixture of (3R,4S,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2/-/-pyran-3,4,5-triol (136 g), acetonitrile (272 ml) and dichloromethane (1088 ml) was cooled to 0-10°C. Triethylsilane (76.98 g) followed by boron trifluoride diethyl etherate solution (156 g) was added to the reaction mixture at 0-10°C. The reaction was stirred at 0-10°C for 4 h. The pH of reaction mixture was adjusted to 7-8 by 20% aq. potassium bicarbonate solution. Organic solvent was distilled out from the reaction mixture under vacuum at 50-60°C. Reaction mixture was extracted with ethyl acetate (3 X 680 ml). Combine ethyl acetate layers; washed with brine solution (680 ml) and distilled out under vacuum at 50-60°C. Residue was concentrated under vacuum to remove remaining water azeotropically with methyl ethyl ketone (136 ml). Methyl ethyl ketone (680 ml) was added to the residue and stirred for 30 min. at 40- 50°C. Reaction mixture was cooled to 0-10°C, seeded with (2S,3R,4R,5S,6R)-2-(4-chloro- 3-(4-hydroxybenzyl)phenyl)-6-(hydroxy methyl) tetrahydro-2H-pyran-3,4,5-triol (0.68 g) and stirred for 1 h. The solid material was filtered and washed with chilled methyl ethyl ketone (2 x 68 ml). The solid was dried at 45-55°C for 6-8 h to give the title compound as white solid (80.5 g). Yield: 64.33 %. HPLC Purity: 97.07%

38%	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10 - 0℃; for 4h;	4 Example 4: 1-Chloro-4-(β-D-glycopyranose-1-yl)-2-(4-hydroxy-benzyl) benzene Example 4 1-Chloro-4-(β-D-glycopyranose-1-yl)-2-(4-hydroxy-benzyl) benzene A solution of the 1-chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4- hydroxybenzyl)benzene (1.06 g, 2.83 mmol) in CH2Cl2/CH3CN (1:1, 24 mL) gained above was cooled to -10°C. After addition of triethylsilane (660 mg, 5.66 mmol), BF3·Et2O (1.1 mL, 3.98 mmol) was added dropwise to the mixture at a rate that the reaction temperature was maintained below -5°C. When the addition finished, the mixture was stirred for 4 hours at 0°C. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate (50 mL). The organic phase was seperated and the aqueous phase was extracted for 3 times with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane/methanol, 15:1) to afford the target compound. Yield: 0.37 g (38% of theoretical value). 1HNMR (500 MHz, CD3OD) δ: 7.16-7.25 (m, 3H), 6.91 (d, J = 8.5 HZ, 2H), 6.58 (d, J = 8.5HZ, 2H), 3.97-4.01 (m, 1H), 3.89 (dd, J = 15 Hz, 13 Hz, 2H), 3.77 (d, J = 11 Hz , 1H), 3.57-3.60 (m, 1H), 3.28-3.35 (m, 3H), 3.17-3.21 (m, 1H). LC-MS (ESI): m/z = 403/405(Cl) [M+Na]+.
	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at -70 - 35℃;	10 Preparation of Compound of Formula (II-SH-A) In a round bottom flask, 100 g compound of Formula (V), 1000 mL acetonitrile and 1000 mL methylene dichloride were taken and stirred at 25-35° C. 84.92 g triethylsilane was added at 25 to 35° C. The reaction mixture was cooled to -60 to -70° C. 103.65 g boron trifluoride etherate was added using addition funnel in 2-3 hours at -60 to -70° C. and stirred for one hour. The temperature was raised to -10 to 0° C. The reaction mixture was stirred at 0 to -10° C. for 4-5 hours. After completion of the reaction, the pH was adjusted to 7 using sodium bicarbonate solution. The reaction mixture was stirred at 25 to 35° C. for 30-40 minutes. The layers were separated The aqueous layer was washed two-three times with ethyl acetate. The organic layers was combined and dried over sodium sulphate. The solvent was removed by distillation under vacuum. 100 mL ethyl methyl ketone was added and distilled out under vacuum at 40-50° C. then again 800 mL ethyl methyl ketone was added and the reaction mixture was heated to 75-80° C. The reaction mixture was cooled to 10-20° C. and stirred for 2 hours. The solid was filtered and washed with 100 mL ethyl methyl ketone at 25-30° C. and then dried under vacuum to obtain the Formula (II-SH-A). M.P.: 87.3-91° C. 1H NMR (400 MHz, DMSO d6) δ 9.23 (s, 1H), 7.35-7.37 (d, 1H), 7.29-7.30 (d, 1H), 7.21-7.24 (dd, 1H), 6.98-7.00 (d, 2H), 6.66-6.68 (m, 2H), 4.97-4.99 (t, 2H), 4.84-4.85 (d, 1H), 4.45-4.48 (t, 1H), 3.88-4.0 (m, 3H), 3.68-3.72 (m, 1H), 3.42-3.48 (m, 1H), 3.08-3.28 (m, 4H), 2.43-2.49 (q, 1H), 2.1 (s, 1.5H), 0.9 (t, 1.5H).
	Multi-step reaction with 3 steps 1.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 1.2: 0.5 h / -40 - -5 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 3.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C
	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -30 - -5℃; for 9h;	36.d Preparation of Empagliflozin Tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane (1 .0 Kg), tetrahydrofuran (6.0 L) and (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl) tetrahydro-2H-pyran-2-one (1 .221 Kg) were charged into a 20 L flask under Nitrogen atmosphere. Toluene (6.0 L) was charged into the flask and the resulted mixture was cooled to -80 °C. n-Butyl Lithium in hexane (1 .6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 °C. The reaction mixture was maintained for 1 hour at -80 °C. A solution of methanesulfonic acid (1 .46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 °C. The reaction mass was heated to -10 °C and stirred for 30 minutes and heated to 30 °C and stirred for 12 hours at 30 °C. The reaction mass was cooled to 5 °C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly. The reaction mass was stirred for 30 minutes at 30 °C. The reaction mass was washed with Toluene (6.0 Lx 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask. The reaction mass was extracted with ethylacetate (10.0 Lx5) and the ethylacetate layer was washed with water (3.0 L). The ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor. The concentrated ethylacetate layer was stripped off with acetonitrile (3.0 Lx 3) then dichloromethane (7.0 L) and acetonitrile (1 .2 L) were charged into the reactor and the reaction mass was cooled to -30 °C. Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1 .307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 °C. Temperature was raised to -5 °C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 °C. The reaction mass was heated to 30 °C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor. The mass was washed with toluene (4.0 L) and extracted with ethylacetate (8.0 Lx2 and 4.0 Lx4) and the ethylacetate layer washed with water (2.0 Lx2) The organic layer was concentrated under vacuum until 2 volumes remained in the reactor then the crude mass was stripped off with ethylacetate (3.0 l_x2) and with DMF (1 .4 L). Tosyl-THF (0.634 Kg) and DMF (0.20 L) were charged into the reactor and the resulted mass was stirred for 30 minutes at 30 °C. Cesium carbonate lot 1 (0.57 Kg) was added to the reaction mass. Reaction mass was heated to 45 °C and stirred for 2 hours at 45 °C. Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours. Cesium carbonate lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 °C. The reaction mass was cooled to 30 °C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 °C under vacuum until 1 .0 volume remained in the reactor. The concentrated mass was cooled to 30 °C and water (10.0 L) and acetonitrile 1 .0 L) were charged into the reactor at 30 °C and the resulted mixture was heated to 45 °C and the mixture was stirred for 6 hours at 45 °C. The suspension was cooled to 25 °C and stirred for 7 hours at 25 °C. The precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried. The wet compound and DMF (1 .0 L) were charged into another reactor and the solution was heated to 45 °C. Acetonitrile (1 .0 L) charged followed by water (10.0 L) into the reactor at 45 °C and stirred for 6 hours. The suspension was cooled to 25 °C and stirred for 6 hours. The precipitation was fileted and the wet cake was washed with water. The wet material was suck dried. The wet material was dried under vacuum at 60 °C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC 99%.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/4648, 2007, A1 Location in patent: Page/Page column 15-16
[2]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A Location in patent: Paragraph 0038; 0112-0114
[3]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2018/29264, 2018, A1 Location in patent: Page/Page column 26
[4]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0042; 0087; 0088
[5]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1 Location in patent: Paragraph 0170; 0195; 0196
[6]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[7]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2017/203457, 2017, A1 Location in patent: Page/Page column 42-44

16
(3R,4S,5S,6R)-2-(3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol [ No CAS ]
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10 - -5℃; for 5h;	XVIII A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80° C. under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralised with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution that is extracted four times with ethyl acetate. The organic phases are dried over sodium sulphate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane and the resulting solution is cooled to -10° C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition has ended the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulphate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by total acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallising the product in ethanol. The product thus obtained is converted into the title compound by reacting in methanol with 4 M potassium hydroxide solution.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/27092, 2007, A1 Location in patent: Page/Page column 24

17
[ 285-67-6 ]
[ 864070-37-1 ]
1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((1R,2R)-2-hydroxy-cyclopent-1-yloxy)-benzyl]-benzene [ No CAS ]
1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((1S,2S)-2-hydroxy-cyclopent-1-yloxy)-benzyl]-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In ethanol at 100℃; for 1.25h; Microwave irradiation;	1 EXAMPLE 1 1-Chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(trans-2-hydroxy-cyclopent-1-yloxy)-benzyl]-benzene A mixture of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.50 g), cyclopentene oxide (1.50 g) and potassium carbonate (0.45 g) in ethanol (1.5 mL) is stirred for 75 min at 100° C. in a microwave oven. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. After drying the combined organic phases over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 9:1->1:1). Yield: 300 mg (49% of theory) Mass spectrum (ESI+): m/z=465/467 (Cl) [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/49537, 2007, A1 Location in patent: Page/Page column 18

18
[ 864070-37-1 ]
[ 51572-54-4 ]
[ 927880-25-9 ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium carbonate; potassium iodide In methanol for 16h; Heating / reflux;	5 EXAMPLE 5 1-Chloro-4-(β-glucopyranos-1-yl)-2-[4-(1-methoxycarbonyl-cyclopent-1-yloxy)-benzyl]-benzene A mixture of 1-chloro-4-(β-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.46 g), 1-bromo-1-methoxycarbonylcyclopentane (0.87 g), potassium iodide (0.1 g) and potassium carbonate (0.5 g) in methanol (5 mL) is stirred at reflux for 16 h. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->4:1). Yield: 180 mg (30% of theory) Mass spectrum (ESI+): m/z=524/526 (Cl) [M+NH4]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/49537, 2007, A1 Location in patent: Page/Page column 19

19
[ 864070-37-1 ]
[ 874650-39-2 ]
1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(3-hydroxy-cyclopent-1-yloxy)-benzyl]-benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 16h;	2 A mixture of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.25 g), 3-hydroxy-cyclopent-1-yl p-tolylsulfonate (0.19 g) and cesium carbonate (0.33 g) in dimethylformamide (1.5 mL) is stirred at 70° C. for 16 h. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0->4:1). Yield: 90 mg (29% of theory) Mass spectrum (ESI+): m/z=482/484 (Cl) [M+NH4]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/49537, 2007, A1 Location in patent: Page/Page column 18

20
(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With pyridine; dmap; acetic anhydride In dichloromethane Stage #2: With methanol; potassium hydroxide	XIII Example XIII; 1-Chloro-4-(β-D-qlucopyranos-1-yl)-2-(4-hvdroxybenzyl)-benzene; A solution of 4.0 g [4-(5-Bromo-2-chloro-benzyl)-phenoxy]-terf-butyl-dimethyl-silane in 42 mL dry diethyl ether is cooled to -80 °C under argon. 11.6 mL of a chilled (ca. -50 °C) 1.7 M solution of tert-butyllithium in pentane are slowly added to the cooled solution and then the solution is stirred for 30 min at -80 °C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O- (trimethylsilyl)-D-glucopyranone in 38 mL diethyl ether chilled to -80 °C. The resulting solution is stirred for 3 h at -78 °C. Then a solution of 1.1 mL methanesulfonic acid in 35 mL methanol is added and the resultant reaction solution is stirred for another 16 h at ambient temperature. The solution is then neutralized with solid sodium hydrogen carbonate, ethyl acetate is added and the resultant solution is concentrated under reduced pressure. Aqueous sodium hydrogen carbonate solution is added to the remaining solution that is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated. The residue is dissolved in 30 mL acetonitrile and 30 mL dichloromethane and the resulting solution is cooled to -10 °C. After the addition of 4.4 mL triethylsilane, 2.6 mL boron trifluoride etherate are added dropwise so that the temperature does not exceed -5 °C. After the addition is complete, the reaction solution is stirred for another 5 h at -5 to -10 °C and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol). The product then obtained is an approx. 6:1 mixture of β/α which can be separated by global acetylation of the hydroxyl groups with acetic anhydride, pyridine and 4-dimethylaminopyridine in dichloromethane and recrystallisation of the resulting acetylated product from ethanol. The pure acetylated β-product thus obtained is converted into the title compound by removal of the acetyl groups in methanol with 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z = 398/400 (Cl) [IVH-NH4] +
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 2: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2007/93610, 2007, A1 Location in patent: Page/Page column 35-36
[2]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1

21
[ 110-91-8 ]
[ 5414-19-7 ]
[ 864070-37-1 ]
[ 1118566-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 80℃;	3 To a solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D) (50 mg, 0.13 mmol) in DMF (3.0 niL) were added l-bromo-2-(2-bromoethoxy)ethane (91 mg, 0.39 mmol), Cs2CO3 (127 mg, 0.39 mmol) and morpholine (68 mg, 0.79 mmol). After being vigorously stirred at an external temperature of 8O0C overnight, the solution was purified by preparative HPLC to give compound G (35 mg). 1H NMR (CD3OD): δ 7.60-7.40 (m, 3H), 7.12-7.09 (m, 2H), 6.85 (d , 2H, J= 8.4Hz), 4.60 (d, IH, J= 3.2Hz), 4.24-4.11 (m, 4H), 4.09-3.90 (m, 4H), 3.83-3.78 (m, 9H), 3.72-3.70 (m, 4H), 3.65-3.64 (m, 2H), 3.04-2.98 (m, 5H); MS ESI (m/z) 538 (M+H)+, calc. 537.

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 41

22
[ 864070-37-1 ]
[ 302331-20-0 ]
[ 1118567-51-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	9 3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3 ,4,5-triol (intermediate D) (30 mg, 78.7 mmol), 2-(2-(tert- butoxycarbonylamino)ethoxy)ethyl methanesulfonate (26.8 mg, 94.5 mmol) and CS2CO3 (30.8 mg, 94.5 mmol) were dissolved in DMF (3 ml) at room temperature and stirred overnight. The mixture was then extracted with EtOAc, washed with NH4Cl and NaCl, dried over Na2SO4, and evaporated to get the crude product, tert-butyl 2-(2-(4-(2-chloro-5- ((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)benzyl)phenoxy)ethoxy)ethylcarbamate (intermediate U) (40 mg), which was used for the next step without further purification. The crude intermediate U was dissolved in MeOH (0.5 mL), MeSOsH (6 μL) was added, and the mixture was stirred overnight at room temperature. Then the reaction was quenched with NaHCO3, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, concentrated, and separated by preparative HPLC to obtain compound V (11.6 mg). 1H NMR (CD3OD): δ 7.40-7.27 (m, 3H), 7.14-7.10 (m, 2 H), 6.87-6.85 (m, 2 H), 4.54 (d, J= 16, IH), 4.19-4.18 (m, IH ), 4.16-4.14 (m, 2H), 4.05-4.01 (m, 4 H), 3.94-3.93 (m, IH), 3.88-3.86 (m, 2H), 3.83-3.76 (m, 3H), 3.67-3.57 (m, IH ), 3.16-3.13 (m, 2 H); MS ESI (m/z): 468 (M+H)+, calc. 467.

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 48

23
[ 5414-19-7 ]
[ 864070-37-1 ]
[ 1118567-15-9 ]

Yield	Reaction Conditions	Operation in experiment
21%	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	25 To a stirred suspension of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (100 mg, 0.26 mmol) in λ/,λ/-dimethylformamide (3 mL) and cesium carbonate (162 mg, 0.52 mmol) was added l-bromo-2-(2-bromoethoxy)ethane (182 mg, 0.79 mmol). The mixture was stirred overnight at room temperature. The solution was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC to give 30 mg of yellow oil (21 % yield), which was used in the next step without purification.

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 80

24
[ 864070-37-1 ]
[ 252947-90-3 ]
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-(2,2,2-trifluoroethoxy)ethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	20 To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (200 mg) in anhydrous DMF were added 2-(2,2,2-trifluoroethoxy)ethyl 4-methylbenzenesulfonate (intermediate BS) (1.5 eq) and Cs2CO3 (2 eq). The mixture was stirred at room temperature for 12 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative-HPLC to obtain compound BT (117 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.62 (s, 2H), 4.08 ~ 4.12 (m, 3H), 4.02 ~ 4.05 (m, 3H), 4.00 ~ 3.94 (m, 2H), 3.90 ~ 3.87 (m, IH), 3.72 ~ 3.68 (m, IH), 3.46 ~ 3.39 (m, 3H), 3.30 ~ 3.27 (m, IH); MS ESI (m/z) 507 (M+H)+, calc. 506.

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 73-74

25
3-cyclopropylprop-2-ynyl 4-methylbenzenesulfonate [ No CAS ]
[ 864070-37-1 ]
[ 1118566-88-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	16 To a stirred solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)- 6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (20 mg, 0.0526 mmol) in 1 mL of DMF was added Cs2COs (21 ng, 0.063 mmol) and 3-cyclopropylprop-2-ynyl A- methylbenzenesulfonate (intermediate AU) (20 mg, 0.079 mmol) at room temperature. After stirring for 2 h, the reaction was quenched with 1 mL of ice water. The mixture was extracted 3X with ethyl acetate (5 mL each). The combined organic layers were washed 2X with water (5 mL each) and brine prior to drying over Na2SO4. Concentration of the solution and purification of the crude product by preparative LC-MS afforded compound AV (10 mg). 1H NMR (CD3OD): δ 7.37-7.34 (2H, m), 7.30-7.28 (IH, dd, J= 8.8, 2 Hz), 7.13-7.11 (2H, d, J = 8.8 Hz), 6.87-6.83 (2H, d, J= 8.8 Hz), 4.61 (2H, d, J= 2 Hz), 4.11 (IH, d, J= 9.2 Hz), 4.10-4.04 (2H, dd, J= 23.6, 14.8 Hz), 3.90-3.87 (IH, m), 3.72-3.68 (IH, m), 3.49-3.39 (3H, m), 3.31-3.28 (IH, m), 1.31-1.24 (IH, m), 0.79-0.75 (2H, m), 0.62-0.59 (2H, m).

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 61-62

26
[ 864070-37-1 ]
[ 2917-96-6 ]
[ 1118566-63-4 ]

Yield	Reaction Conditions	Operation in experiment
51.3%	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	10 To a solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D) (30 mg) and but-2-yne-l,4- diyl dimethanesulfonate (16.9 mg) in anhydrous DMF (10 mL) was added Cs2CO3 (51.5 mg). The mixture was stirred overnight at room temperature, whereupon LC-MS showed that intermediate D was exhausted. Then the mixture was poured into water and extracted with EtOAc, washed with water and brine, and dried with anhydrous Na2SO4. The solvent was then evaporated under reduced pressure, and the crude product was purified by preparative HPLC to obtain compound W (21.36 mg, yield 51.3%). 1H NMR (CD3OD): δ 7.32 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.88 (d, J= 8.8 Hz, 2H), 4.93 (t, J= 1.2 Hz, 2H), 4.81 (t, J= 1.2 Hz, 2H), 4.59 (d, J= 3.2 Hz, IH), 4.18 (m, IH), 4.02 (m, 4H), 3.94 (m, IH), 3.83 (m, IH), 3.67 (m, IH), 2.99 (s, 3H); MS ESI (m/z): 527 (M+H)+, calc. 526.

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 48-49

27
[ 864070-37-1 ]
[ 786686-61-1 ]
[ 1118567-23-9 ]

Yield	Reaction Conditions	Operation in experiment
31%	With caesium carbonate In N,N-dimethyl-formamide at 50℃;	28 To a stirred suspension of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (140 mg, 0.26 mmol) in λ/,λ/-dimethylformamide (2 mL) and cesium carbonate (130 mg, 0.4 mmol) was added 2-(l-methylcyclopropoxy)ethyl 4-methylbenzenesulfonate (54 mg, 0.20 mmol). The mixture was stirred overnight at 500C. The solution was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure, and the residue was purified by preparative HPLC-MS to give 30 mg of white solid (31% yield; HPLC purity 97.5 %). HPLC retention time: 3.27 min; Waters 2695 Separations Module equipped with a Waters 2996 Photodiode Array Detector and a Waters Micromass ZQ Detector; Waters XTerra C18 5 μm, 50 mm x 2.1 mm column; 1.0 niL/min, detection at 190-400 nm; 6 min gradient 10-95% A, hold 8 min at 95% A; solvent A: 0.045 % formic acid in acetonitrile, solvent B: 0.1 % formic acid in Milli-Q water. 1H NMR (CD3OD, 400 MHz): δ 7.28-7.36 (m, 3H), 7.12-7.14(d, J= 8.8 Hz, 2H), 6.83-6.86 (d, J= 8.8 Hz, 2H), 4.64 (s, IH), 4.02-4.12 (m, 5H), 3.81-3.91 (m, 3H), 3.71-3.73 (m, IH), 3.28-3.48 (m, 5H), 1.42 (s, 3H), .0.81-0.83 (d, J= 5.6 Hz, 2H), 0.44-0.46 (m, 2H); MS ES" (m/z): 523 (M + 45)".

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 85-86

28
[ 864070-37-1 ]
[ 862728-59-4 ]
[ 1118567-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12.0h;	To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (30 mg, 0.08 mmol) in anhydrous DMF (1 mL) were added 2-cyclopropoxyethyl 4-methylbenzenesulfonate (intermediate BP) (20 mg, 0.08 mmol) and Cs2CO3 (52 mg, 0.16 mmol). The mixture was stirred at room temperature for 12 h. Then the reaction mixture was poured into water, extracted with EA, washed with brine, dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative HPLC to obtain compound BQ (11 mg) as a colorless oil. 1H NMR (CD3OD): delta 7.30 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.82 (d, J= 8.8 Hz, 2H), 4.13 (m, 5H), 3.85 (m, 3H), 3.81 (m, IH), 3.40 (m, 4H), 3.30 (m, IH), 0.52 (m, 4H); MS ESI (m/z) 465 (M+H)+, calc. 464.

Reference： [1]Patent: WO2009/26537,2009,A1 .Location in patent: Page/Page column 72

29
[ 864070-37-1 ]
[ 211365-70-7 ]
[ 1118567-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;	21 To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (30 mg) in anhydrous DMF were added 2-(cyclohex-2-enyloxy)ethyl 4-methylbenzenesulfonate (intermediate BV) (1.5 eq) and CS2CO3 (2 eq). The mixture was stirred at room temperature for 16 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The crude oil was purified by preparative -HPLC to obtain compound BW (17.1 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.86 (d, J= 8.8 Hz, 2H), 5.87 ~ 5.76 (s, 2H), 4.59 (s, IH), 4.11 ~ 3.89 (m, 6H), 3.89 ~ 3.76 (m, 3H), 3.72 ~ 3.68 (m, IH), 3.49 ~ 3.40 (m, 3H), 2.03 ~ 1.98 (m,2H), 1.89 ~ 1.84 (m, IH), 1.80 ~ 1.62 (m, 2H), 1.79 - 1.51 (m, IH); MS ESI (m/z) 506 (M+H)+, calc. 505.

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 75

30
[ 908120-51-4 ]
[ 864070-37-1 ]
[ 1210040-71-3 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	22 To a stirred solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)- 6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (37 mg, 0.097 mmol) in 1.5 ml of DMF was added CS2CO3 (48 mg, 0.146 mmol) and (E)-(3-bromoprop-l- enyl)cyclopropane (intermediate BY) (50 mg) at room temperature. After stirring for 3 h, the reaction was quenched with 2 ml of ice water. The mixture was extracted 3X with ethyl acetate (5 ml), and the combined organic layers were washed 2X with water (5 ml) and brine, dried over Na2SO4, concentrated, and purified by preparative LC-MS to obtain compound BZ (8.6 mg). 1H NMR (CD3OD, 400 MHz): δ 7.37 ~ 7.33 (2H, m), 7.30 ~ 7.27 (IH, dd, J= 8.2, 2 Hz), 7.11 ~ 7.09 (2H, d, J= 8.8 Hz), 6.82 ~ 6.79 (2H, d, J= 8.8 Hz), 5.77 ~ 5.70 (IH, dt, J = 15.2, 6 Hz), 5.39 ~ 5.33 (IH, dd, J= 15.2, 8.8 Hz), 4.43 ~ 4.41 (2H, dd, J= 6.4, 1.0 Hz), 4.10 (IH, d, J= 9.6 Hz), 4.08 ~ 3.98 (2H, dd, J= 23.6, 15.2 Hz), 3.90 ~ 3.87 (IH, m), 3.72 ~ 3.67 (IH, m), 3.49 ~ 3.39 (3H, m), 3.31 ~ 3.27 (IH, m), 1.47 ~ 1.45 (IH, m), 0.76 ~ 0.71 (2H, m), 0.41 ~ 0.37 (2H, m); MS ESI (m/z) 461 (M+H)+, calc. 460.

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 76

31
[ 864070-37-1 ]
[ 1118567-11-5 ]
[ 1118567-12-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 48h;	23 2-(2-fluoroethoxy)ethyl 4-methylbenzenesulfonate (52 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (0.12 g, 0.36 mmol) was added to the flask, and the resulting mixture was stirred at room temperature for 48 hr. The reaction mixture was diluted with diethyl ether (50 mL) and the organic layer was washed with aqueous solutions of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 mL), followed by drying over sodium sulfate. The organic layer was concentrated in vacuo, followed by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.5 mg, 5.0%). 1H NMR (CDCl3, 300 MHz): δ 7.30 (d, IH, J= 11.6 Hz), 7.17-7.12 (br m, 2H), 7.04 (d, 2H, J=I 1.6 Hz), 6.78 (d, 2H, J= 11.6 Hz), 4.52 (dt, 2H, Jl = 5.6 Hz, J2 = 63.6 Hz), 4.33 (br s, IH), 4.13 (br s, IH), 4.04-3.96 (m, 4H), 3.81-3.67 (m, 5H), 3.63-3.49 (m, 2H), 3.38-3.21 (m, 3H), 2.78 (br s, IH), 1.77 (br s, 2H); LC/MS: theoretical mass = 470.15; observed M+l = 471.6, M+ Na = 493.4).

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 77

32
[ 864070-37-1 ]
[ 1118567-13-7 ]
[ 1118567-14-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 48h;	24 2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (53 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a reaction flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (intermediate Dl) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (98 mg, 0.30 mmol) was added to the flask, and the resulting mixture was stirred for 48 hr at room temperature. The reaction was diluted with diethyl ether (50 mL) and the organic layer was washed with an aqueous solution of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 ml), after which it was dried over sodium sulfate, filtered and concentrated en vacuo. The residue was purified by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.6 mg, 5.0%). 1H NMR (CDCl3, 300 MHz); δ 7.33 (d, IH, J=I 1.2 Hz), 7.15 (d, IH, J=I 1.2 Hz), 7.14 (s, IH), 7.06 (d, 2H, J=I 1.6 Hz), 6.79 (d, 2H, J=I 1.6 Hz), 5.86 (tt, IH, Jl = 5.2 Hz, J2 = 66.4 Hz), 4.07-3.98 (m, 3H), 3.87-3.84 (m, 3 H), 3.84-3.71 (m, 2H), 3.74 (td, 2H, Jl = 5.6 Hz, J2 = 18.4 Hz), 3.66-3.54 (m, 3 H), 3.30-3.36 (m, 2H), 2.78 (br s, IH), 2.42 (br s, IH), 1.65 (s, 2H); LC/MS: theoretical mass = 488.14; observed M+l = 489.2, M+ Na = 511.4).

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 79

33
[ 864070-37-1 ]
[ 1003852-75-2 ]
[ 1118566-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With caesium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: 2-(prop-2-ynyloxy)-1-methylethyl methanesulfonate In N,N-dimethyl-formamide at 40℃;	8 To a stirred solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D) (50 mg, 0.13 mmol) in DMF (10 mL) was added CS2CO3 (64 mg, 0.20 mmol) and the mixture was stirred for 0.5 h. Then l-(prop-2-ynyloxy)propan-2-yl methanesulfonate (38 mg, 0.20 mmol) was added, and the mixture was stirred at 400C overnight. The mixture then was filtered, evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound T (8.9 mg) as a white powder. 1H NMR (CD3OD): δ 7.25-7.34 (m, 3H), 7.08 (d, 2H, J= 8.8 Hz), 6.82 (d, 2H, J= 8.8 Hz), 4.56 (S, IH), 4.18 (m, IH), 5.28-5.33 (m, 2H), 4.07 (m, 2H), 4.01 (d, IH, J= 8.0 Hz), 3.87 (d, IH, J= 1.2Hz), 3.85 (m, IH), 3.60 (m, 3H), 3.38 (m, 3H), 3.28 (m,lH), 2.82 (m, IH), 1.24 (d, 2H).

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 47

34
[ 1118566-45-2 ]
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol With boron tribromide In dichloromethane at -78 - 0℃; Stage #2: With water	1 To a stirred solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Intermediate C) (2 g, 5.9 mmol) in dichloromethane was added BBr3 (14.6 mL, 1 M) dropwise at -780C. After the addition was complete, the mixture was allowed to warm to O0C and held at this temperature for 2 h. When LC-MS showed that no starting material remained, the mixture was cooled to -780C again, and quenched with water. When the temperature was stable, saturated NaHCO3 solution was added. The mixture was evaporated under reduced pressure, and the residue was extracted with EtOAc. The organic layer was washed with NaHCO3 and brine, dried over Na2SO4, evaporated and purified to obtain intermediate D (0.7 g).[0165] In addition, for use in the synthesis of certain compounds of the invention, the 2S isomer (intermediate Dl) and the 2R isomer (intermediate D2) of intermediate D were separated by preparative LC-MS. Intermediate Dl: 1H NMR (CD3OD): δ 7.30 (m, 3H), 6.97 (d, 2H, J= 6.8 Hz), 6.68 (d, 2H, J= 6.8 Hz), 4.56 (s, IH), 4.16 (s, IH), 3.91-4.02 (m, 5H), 3.79 (m, IH), 3.64 (m, IH). Intermediate D2: 1H NMR (CD3OD): δ 7.29~7.33(m, 3H), 7.00 (d, 2H, J= 6.8 Hz), 6.70 (d, 2H, J= 6.8 Hz), 4.58 (d, IH, J= 4.0 Hz), 3.96-4.02 (m, 4H), 3.93-3.95 (m, IH), 3.81-3.85 (m, IH), 3.64-3.69 (m, IH).

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1 Location in patent: Page/Page column 39

35
[ 864070-19-9 ]
(3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one [ No CAS ]
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane With tert.-butyl lithium In diethyl ether; pentane at -80℃; for 0.5h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In diethyl ether; pentane at -80 - -78℃; for 3h; Cooling with dry ice; Stage #3: With triethylsilane; methanesulfonic acid; boron trifluoride diethyl etherate more than 3 stages;	VI A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 ml dry diethyl ether is cooled to -80° C. under argon. 11.6 ml of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 ml diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 ml methanesulphonic acid in 35 ml of methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralized with solid sodium hydrogen carbonate, ethyl acetate is added, and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution, and the resulting mixture is extracted four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated down. The residue is dissolved in 30 ml acetonitrile and 30 ml dichloromethane, and the solution is cooled to -10° C. After the addition of 4.4 ml triethylsilane 2.6 ml boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition is complete the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/a which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallization of the product from ethanol. The product thus obtained is converted into the title compound by deacetylation in methanol with aqueous 4 M potassium hydroxide solution. Yield: 1.6 g (46% of theory) Mass spectrum (ESI+): m/z=398/400 (Cl) [M+H]+.
	Stage #1: [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane With tert.-butyl lithium In diethyl ether; pentane at -80℃; for 0.5h; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In diethyl ether; pentane at -80 - -78℃; for 3h; Stage #3: With methanol; triethylsilane; boron trifluoride etherate; methanesulfonic acid; sodium hydrogencarbonate more than 3 stages;	VI EXAMPLE VI 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene A solution of 4.0 g [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 mL dry diethyl ether is cooled to -80° C. under argon. 11.6 mL of a 1.7 M solution of tert-butyllithium in pentane are slowly added dropwise to the cooled solution, and then the solution is stirred for 30 min at -80° C. This solution is then added dropwise through a transfer needle, which is cooled with dry ice, to a solution of 4.78 g 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 38 mL diethyl ether chilled to -80° C. The resulting solution is stirred for 3 h at -78° C. Then a solution of 1.1 mL methanesulfonic acid in 35 mL methanol is added and the solution is stirred for 16 h at ambient temperature. The solution is then neutralized with solid sodium hydrogen carbonate, ethyl acetate is added and the methanol is removed together with the ether. Aqueous sodium hydrogen carbonate solution is added to the remaining solution that is extracted then four times with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated down. The residue is dissolved in 30 mL acetonitrile and 30 mL dichloromethane and the solution is cooled to -10° C. After the addition of 4.4 mL triethylsilane 2.6 mL boron trifluoride etherate are added dropwise so that the temperature does not exceed -5° C. After the addition the solution is stirred for another 5 h at -5 to -10° C. and then quenched by the addition of aqueous sodium hydrogen carbonate solution. The organic phase is separated off and the aqueous phase is extracted four times with ethyl acetate. The combined organic phase are dried over sodium sulfate, the solvent is removed and the residue is purified using silica gel. The product then obtained is an approx. 6:1 mixture of β/α which can be converted into the pure β-anomer by global acetylation of the hydroxy groups with acetic anhydride and pyridine in dichloromethane and recrystallizing the product from ethanol. The product thus obtained is converted into the title compound by reacting in methanol with 4 M potassium hydroxide solution.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2006/251728, 2006, A1 Location in patent: Page/Page column 7
[2]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2007/54867, 2007, A1 Location in patent: Page/Page column 7-8

36
[ 461432-26-8 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
1.6 g	With hydrogen bromide; In water; for 16h;Reflux;	A mixture of <strong>[461432-26-8]dapagliflozin</strong> (1) (5 g, 0.012 mol) and aqueousHBr (12.6 g, 0.073 mol, 48% w/w) were warmed and stirredunder a gentle reflux for 16 h. The reaction mass was cooledto an ambient temperature and partitioned between MTBE(50 mL) and H2O (50 mL). Following extraction of aqueouslayer with MTBE (50 mL), the combined organic layerswere neutralized with aqueous NaOH solution. The organiclayer was separated, washed with H2O (50 mL) and concentrated. The residue was then treated with EtOH(20 mL) and the precipitated salts were removed by celitebed filtration. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatographyto afford pure desethyl <strong>[461432-26-8]dapagliflozin</strong> (4) (1.6 g)as a glassy off-white amorphous solid. [alpha]D20: +5.5 (c = 0.2in methanol); 1H NMR (D2O) (500 MHz): 3.46-3.59 (m,4H), 3.73 & 3.84 (2dd, 2H), 3.95 (s, 2H), 4.15-4.18 (d, 1H,J = 9.3Hz), 6.74-6.76 (d, 2H, J = 6Hz), 7.05-7.07 (d, 2H, J =6Hz), 7.22-7.23 (d, 1H, J = 3Hz), 7.26 (s, 1H), 7.30(s, 1H), 7.37-7.40 (d, 1H, J = 9Hz); HRMS (ESI) calculatedfor C19H21ClO6 (M- H)+: 379.0948, found: 379.0936;

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4465 - 4470
[2]Journal of Chemical Sciences,2020,vol. 132

37
[ 864070-37-1 ]
4-methylbenzenesulfonic acid[(3-fluorooxetan-3-yl)methyl] ester [ No CAS ]
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-((3-fluorooxetan-3-yl)methoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 4h;	51 Preparation of Compound 12 The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)-benzene (122 mg, 0.32 mmol), compound Id″-12 (83 mg, 0.32 mmol) and cesium carbonate (209 mg, 0.64 mmol) in 5 mL of dimethylformamide was heated to 50° C. and stirred for 4 hours. The reaction mixture was cooled down to room temperature, filtered. The solvent was evaporated and the residue was purified by silical gel chromatography (AcOEt:MeOH=20:1) to afford compound 12 (69 mg, 46%). [0264] 1H-NMR (500 MHz, CD3OD) δ: 7.30-7.37 (2H, m), 7.28 (1H, dd, J=2.0, 8.0 Hz), 7.14 (2H, d, J=8.5 Hz), 6.89 (2H, d, J=8.5 Hz), 4.78 (2H, dd, J=8.5, 28.0 Hz), 4.74 (2H, dd, J=8.5, 27.5 Hz), 4.32 (2H, d, J=20.0 Hz), 4.09 (1H, d, J=9.5 Hz), 4.07 (1H, d, J=15.0 Hz), 4.02 (1H, d, J=15.0 Hz), 3.87 (1H, dd, J=2.0, 12.0 Hz), 3.69 (1H, dd, J=5.5, 12.0 Hz), 3.45 (1H, t, J=8.5 Hz), 3.34-3.42 (2H, m), 3.24-3.29 (1H, m). [0265] LC-MS (ESI): m/z=491[M+Na]+.
46%	With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 4h;	51 Example 51: Preparation of compound 12 Example 51: Preparation of compound 12: [0160] The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl) -benzene (122 mg, 0.32 mmol), compoundId"-12 (83 mg, 0.32 mmol) and cesium carbonate (209 mg, 0.64 mmol) in 5 mL of dimethylformamide was heatedto 50°C and stirred for 4 hours. The reaction mixture was cooled down to room temperature, filtered. The solvent wasevaporated and the residue was purified by silical gel chromatography (AcOEt:MeOH = 20:1) to afford compound 12(69 mg, 46%).1H-NMR (500 MHz, CD3OD) δ: 7.30-7.37 (2H, m), 7.28 (1H, dd, J= 2.0, 8.0 Hz), 7.14 (2H, d, J = 8.5 Hz), 6.89 (2H, d,J = 8.5 Hz), 4.78 (2H, dd, J = 8.5, 28.0 Hz), 4.74 (2H, dd, J = 8.5, 27.5 Hz), 4.32 (2H, d, J = 20.0 Hz), 4.09 (1H, d, J =9.5 Hz), 4.07 (1H, d, J = 15.0 Hz), 4.02 (1H, d, J = 15.0 Hz), 3.87 (1H, dd, J = 2.0, 12.0 Hz), 3.69 (1H, dd, J = 5.5, 12.0Hz), 3.45 (1H, t, J = 8.5 Hz), 3.34-3.42 (2H, m), 3.24-3.29 (1H, m).LC-MS (ESI): m/z = 491 [M+Na]+

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0262-0265
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0159; 0160

38
[ 864070-37-1 ]
C₁₂H₁₅FO₄S [ No CAS ]
C₂₄H₂₈ClFO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With caesium carbonate In N,N-dimethyl-formamide at 60℃;	59 Preparation of Compound 20 The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)-benzene (35 mg, 0.091 mmol), compound Ib″-20 (25 mg, 0.091 mmol) and cesium carbonate (36 mg, 0.11 mmol) in dimethylformamide (2.5 mL) was heated to 60° C. and stirred overnight. The reaction mixture was cooled down to room temperature, filtered. The solvent was evaporated and the residue was purified by HPLC-MS to afford compound 20 (25 mg, 57%). [0316] 1H-NMR (500 MHz, CD3OD) δ: 7.31-7.34 (m, 2H), 7.27 (dd, J=2.0 Hz, 8.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 4.75 (s, 1H), 4.66 (s, 1H), 4.57-4.61 (m, 4H), 4.16 (s, 2H), 3.98-4.08 (m, 3H), 3.87 (dd, J=1.5 Hz, 12.0 Hz, 1H), 3.69 (dd, J=5.0 Hz, 12.0 Hz, 1H), 3.37-3.46 (m, 2H), 3.26-3.30 (m, 2H). LC-MS (ESI): m/z=505[M+Na]+.
57%	With caesium carbonate In N,N-dimethyl-formamide at 60℃;	59 Preparation of compound 20 Preparation of compound 20[0181] The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl) -benzene (35 mg, 0.091 mmol), compoundIb"-20 (25 mg, 0.091 mmol) and cesium carbonate (36 mg, 0.11 mmol) in dimethylformamide (2.5 mL) was heatedto 60°C and stirred overnight. The reaction mixture was cooled down to room temperature, filtered. The solvent wasevaporated and the residue was purified by HPLC-MS to afford compound 20 (25 mg, 57%).1H-NMR (500 MHz, CD3OD) δ:7.31-7.34 (m, 2H), 7.27 (dd, J=2.0Hz, 8.5Hz, 1H), 7.12 (d, J=8.5Hz, 2H), 6.87 (d, J=8.5Hz,2H), 4.75 (s, 1H), 4.66 (s, 1H), 4.57-4.61 (m, 4H), 4.16 (s, 2H), 3.98-4.08 (m, 3H), 3.87 (dd, J=1.5Hz, 12.0Hz, 1H), 3.69(dd, J=5.0Hz, 12.0Hz, 1H), 3.37-3.46 (m, 2H), 3.26-3.30 (m, 2H). LC-MS (ESI): m/z = 505[M+Na

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0314-0316
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0175; 0181

39
[ 864070-37-1 ]
C₁₂H₁₄F₂O₄S [ No CAS ]
C₂₄H₂₇ClF₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With caesium carbonate In N,N-dimethyl-formamide at 65℃;	60 Preparation of compound 21 Preparation of compound 21[0187] The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl) -benzene (56 mg, 0.147 mmol), compoundIb"-21 (43 mg, 0.147 mmol) and cesium carbonate (58 mg, 0.177 mmol) in dimethylformamide (3 mL) was heatedto 65°C and stirred overnight. The reaction mixture was cooled down to room temperature, filtered. The solvent wasevaporated and the residue was purified by preparative HPLC to afford compound 21 (57 mg, 77%).1H-NMR (500 MHz, CD3OD) δ:7.30-7.38 (m, 2H), 7.28 (dd, J=1.5Hz, 8.5Hz, 1H), 7.14 (d, J=8.5Hz, 2H), 6.90 (d, J=8.5Hz,2H), 6.21 (t, J=56.0Hz, 1H), 4.76 (d, J=6.5Hz, 2H), 4.61 (d, J=6.5Hz, 2H), 4.28 (s, 2H), 3.96-4.13 (m, 3H), 3.81-3.92 (m,1H), 3.69 (dd, J=5.0Hz, 12.0Hz, 1H), 3.42-3.49 (m, 1H), 3.35-3.42 (m, 2H), 3.24-3.29 (m, 1H). LC-MS (ESI): m/z = 523[M+Na]+
	With caesium carbonate In N,N-dimethyl-formamide

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0182; 0187
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0317

40
[ 864070-37-1 ]
C₁₃H₁₇FO₄S [ No CAS ]
C₂₅H₃₀ClFO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With caesium carbonate In N,N-dimethyl-formamide at 80℃;	60 Preparation of Compound 23 The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)-benzene (2.90 g, 7.64 mmol), compound Ib″-23 (2.20 g, 7.64 mmol) and cesium carbonate (7.47 g, 22.92 mmol) in dimethylformamide (50 mL) was heated to 80° C. and stirred overnight. When starting materials were consumed (monitor by LC/MS), the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulphate, filtered, concentrated. The residue was purified by preparative HPLC to afford compound 23 (1.5 g 40%). [0330] 1H-NMR (500 MHz, CD3OD) δ: 7.30-7.38 (m, 2H), 7.28 (dd, J=2.0 Hz, 8.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 4.73 (dd, J=8.0 Hz, 20.0 Hz, 2H), 4.59 (dd, J=8.0 Hz, 20.0 Hz, 2H), 4.00-4.17 (m, 3H), 3.97 (t, J=6.5 Hz, 2H), 3.83-3.91 (m, 1H), 3.69 (dd, J=5.0 Hz, 10.5 Hz, 1H), 3.42-3.49 (m, 1H), 3.36-3.42 (m, 2H), 3.25-3.30 (m, 1H), 2.05-2.19 (m, 2H), 1.78-1.91 (m, 2H)0 LC-MS (ESI): m/z =519[M+Na]+.
40%	With caesium carbonate In N,N-dimethyl-formamide at 80℃;	62 Preparation of compound 23 Preparation of compound 23[0198] The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl) -benzene (2.90 g, 7.64 mmol), compoundIb"-23 (2.20 g, 7.64 mmol) and cesium carbonate (7.47 g, 22.92 mmol) in dimethylformamide (50 mL) was heatedto 80°C and stirred overnight. When starting materials were consumed (monitor by LC/MS), the solvent was evaporatedunder vacuum. The residue was dissolved in ethyl acetate. The organic phase was washed with water, dried overanhydrous sodium sulphate, filtered, concentrated. The residue was purified by preparative HPLC to afford compound23 (1.5 g 40%).1H-NMR (500 MHz, CD3OD) δ: 7.30-7.38 (m, 2H), 7.28 (dd, J=2.0Hz, 8.0Hz, 1H), 7.10 (d, J=8.5Hz, 2H), 6.82 (d, J=8.5Hz,2H), 4.73 (dd, J=8.0Hz, 20.0Hz, 2H), 4.59 (dd, J=8.0Hz, 20.0Hz, 2H), 4.00-4.17 (m, 3H), 3.97 (t, J=6.5Hz, 2H), 3.83-3.91(m, 1H), 3.69 (dd, J=5.0Hz, 10.5Hz, 1H), 3.42-3.49 (m, 1H), 3.36-3.42 (m, 2H), 3.25-3.30 (m, 1H), 2.05-2.19 (m, 2H),1.78-1.91 (m, 2H). LC-MS (ESI): m/z = 519[M+Na]+.

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0328-0330
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0191; 0198

41
[ 461432-23-5 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: boron tribromide / dichloromethane / 1.5 h / -78 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 3 h / 20 °C 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C / Inert atmosphere 3.2: 2 h / -78 - -70 °C / Inert atmosphere 3.3: 16 h / -78 - 20 °C / Inert atmosphere 4.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 4 h / -10 - 0 °C
	Multi-step reaction with 4 steps 1.1: boron tribromide / dichloromethane / 1.5 h / -78 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 3 h / 20 °C 3.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C / Inert atmosphere 3.2: 2 h / -78 - -70 °C 3.3: 16 h / -78 - 20 °C 4.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 4 h / -10 - 0 °C
	Multi-step reaction with 4 steps 1.1: boron tribromide / dichloromethane / 0 - 5 °C 2.1: triethylamine / dichloromethane / 0 - 5 °C 3.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 3.2: 12 h / -75 - 35 °C / Inert atmosphere 4.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C

Multi-step reaction with 6 steps 1.1: boron tribromide / dichloromethane / 0 - 5 °C 2.1: triethylamine / dichloromethane / 0 - 5 °C 3.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 3.2: 12 h / -75 - 35 °C / Inert atmosphere 4.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 4.2: 0.5 h / -40 - -5 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 6.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1
[3]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[4]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1

42
[ 864070-18-8 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C / Inert atmosphere 2.2: 2 h / -78 - -70 °C / Inert atmosphere 2.3: 16 h / -78 - 20 °C / Inert atmosphere 3.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 4 h / -10 - 0 °C
	Multi-step reaction with 3 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 3 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C / Inert atmosphere 2.2: 2 h / -78 - -70 °C 2.3: 16 h / -78 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 4 h / -10 - 0 °C
	Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / 2 h / 5 - 15 °C 2.1: n-butyllithium / tetrahydrofuran; hexane; toluene / 0.5 h / -65 °C / Inert atmosphere 2.2: 3 h / -65 - -55 °C 2.3: 16 h / 20 - 25 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 2 h / -30 - -10 °C / Inert atmosphere

	Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 2.2: 12 h / -75 - 35 °C / Inert atmosphere 3.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 2.2: 12 h / -75 - 35 °C / Inert atmosphere 3.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 3.2: 0.5 h / -40 - -5 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 5.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C
	Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 15 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 2.2: 1.5 h / -78 °C / Inert atmosphere 2.3: 18 h / 20 °C / Inert atmosphere 3.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / 5 h / -10 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1
[3]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]
[4]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[5]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[6]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A

43
4-bromo-1-chloro-2-(4-(methoxymethoxy)benzyl)-benzene [ No CAS ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 - -70 °C / Inert atmosphere 1.3: 16 h / -78 - 20 °C / Inert atmosphere 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 4 h / -10 - 0 °C
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; toluene; hexane / 0.5 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 - -70 °C 1.3: 16 h / -78 - 20 °C 2.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 4 h / -10 - 0 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

44
[ 1204220-63-2 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -30 - -10℃; for 2h; Inert atmosphere;
38%	With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -10 - 0℃; for 4h;	4 1-Chloro-4-(β-D-glycopyranose-1-yl)-2-(4-hydroxy-benzyl)benzene EXAMPLE 4 1-Chloro-4-(β-D-glycopyranose-1-yl)-2-(4-hydroxy-benzyl)benzene A solution of the 1-chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)benzene (1.06 g, 2.83 mmol) in CH2Cl2/CH3CN (1:1, 24 mL) gained above was cooled to -10° C. After addition of triethylsilane (660 mg, 5.66 mmol), BF3.Et2O (1.1 mL, 3.98 mmol) was added dropwise to the mixture at a rate that the reaction temperature was maintained below -5° C. When the addition finished, the mixture was stirred for 4 hours at 0° C. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate (50 mL). The organic phase was seperated and the aqueous phase was extracted for 3 times with ethyl acetate. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (dichloromethane/methanol, 15:1) to afford the target compound. Yield: 0.37 g (38% of theoretical value). 1HNMR (500 MHz, CD3OD) δ: 7.16-7.25 (m, 3H), 6.91 (d, J=8.5 HZ, 2H), 6.58 (d, J=8.5 HZ, 2H), 3.97-4.01 (m, 1H), 3.89 (dd, J=15 Hz, 13 Hz, 2H), 3.77 (d, J=11 Hz, 1H), 3.57-3.60 (m, 1H), 3.28-3.35 (m, 3H), 3.17-3.21 (m, 1H). LC-MS (ESI): m/z=403/405 (Cl) [M+Na]+.
2.67 g	With triethylsilane; aluminum (III) chloride In dichloromethane; acetonitrile at 5℃; for 1h; Cooling with ice;	4; 7; 8 The methyl glycoside intermediate was dissolved in a mixed solvent of 10 mL of acetonitrile and 10 mL of dichloromethane, and anhydrous aluminum trichloride (2.67 g, 20.0 mmol, 2.0 eq.) was added. Slowly add triethylsilane (Et3SiH) under ice water bath conditions (3.56g, 30.0mmol, 3.0eq.), The reaction system temperature is below 5 ° C, after the dropwise addition was completed, the reaction was stirred for 1 hour while the ice-water mixture was cooled. TLC monitoring showed that the indole intermediate was basically converted. Carefully quench the reaction with 10 mL of deionized water, dispense, The aqueous phase was extracted with dichloromethane (20 mL×3) and the organic phases were combined.Wash with saturated brine (20 mL), dry over anhydrous sodium The filtrate was evaporated under reduced pressure to remove the solvent. Obtaining a yellow oily product, Separation and purification by column chromatography gave a white solid white solid. That is, empagliflozin dehydrotetramethane impurity 2.67 g (7.0 mmol, yield 70.0%).

Reference： [1]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0121-0125
[3]Current Patent Assignee: ZHEJIANG MEDICINE CO., LTD. - CN109867648, 2019, A Location in patent: Paragraph 0048; 0059; 0060; 0062; 0070; 0072; 0073; 0076

45
[ 864070-37-1 ]
C₃₂H₃₆ClFO₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 20 °C / Cooling with ice
	Multi-step reaction with 3 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 0 - 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: 1,1'-azodicarbonyl-dipiperidine; tributylphosphine / tetrahydrofuran / 20 °C / Cooling with ice

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

46
[ 864070-37-1 ]
C₃₂H₃₇ClO₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 20 °C / Cooling with ice
	Multi-step reaction with 3 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 0 - 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: 1,1'-azodicarbonyl-dipiperidine; tributylphosphine / tetrahydrofuran / 20 °C / Cooling with ice

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

47
[ 864070-37-1 ]
C₂₄H₂₈ClFO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 20 °C / Cooling with ice 4: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 2 h / 20 °C
	Multi-step reaction with 4 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 0 - 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: 1,1'-azodicarbonyl-dipiperidine; tributylphosphine / tetrahydrofuran / 20 °C / Cooling with ice 4: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 2 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

48
[ 864070-37-1 ]
C₂₄H₂₉ClO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 20 °C / Cooling with ice 4: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 2 h / 20 °C
	Multi-step reaction with 4 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 0 - 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: 1,1'-azodicarbonyl-dipiperidine; tributylphosphine / tetrahydrofuran / 20 °C / Cooling with ice 4: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 2 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

49
[ 864070-37-1 ]
C₂₄H₂₉ClO₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 20 °C / Cooling with ice 4: lithium hydroxide monohydrate / tetrahydrofuran; methanol / 2 h / 20 °C 5: dihydrogen peroxide / water; acetic acid / 0.5 h / 20 °C
	Multi-step reaction with 5 steps 1: pyridine; dmap / dichloromethane / 0.5 h / 0 - 20 °C 2: ammonium acetate / tetrahydrofuran; methanol; water / 70 °C 3: 1,1'-azodicarbonyl-dipiperidine; tributylphosphine / tetrahydrofuran / 20 °C / Cooling with ice 4: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 2 h / 20 °C 5: dihydrogen peroxide / water; acetic acid / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

50
[ 864070-37-1 ]
C₂₃H₂₈ClNO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2: hydrogenchloride / methanol; water / 1.5 h / 20 °C
	Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2: hydrogenchloride / methanol; water / 1.5 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

51
[ 864070-37-1 ]
C₂₄H₃₀ClNO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2.1: hydrogenchloride / methanol; water / 1.5 h / 20 °C 3.1: acetic acid / ethanol / 20 °C 3.2: 20 °C
	Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2: hydrogenchloride / methanol; water / 1.5 h / 20 °C 3: sodium cyanoborohydride; acetic acid / ethanol / 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

52
[ 864070-37-1 ]
C₂₅H₃₀ClNO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2.1: hydrogenchloride / methanol; water / 1.5 h / 20 °C 3.1: triethylamine; dmap / dichloromethane / 20 °C 3.2: 0.5 h / 20 °C
	Multi-step reaction with 3 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2.1: hydrogenchloride / methanol; water / 1.5 h / 20 °C 3.1: triethylamine; dmap / dichloromethane / 20 °C 3.2: 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

53
[ 864070-37-1 ]
C₂₆H₃₂ClNO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2: hydrogenchloride / methanol; water / 1.5 h / 20 °C 3: sodium cyanoborohydride; acetic acid / ethanol / 20 °C
	Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C 2: hydrogenchloride / methanol; water / 1.5 h / 20 °C 3: sodium cyanoborohydride; acetic acid / ethanol / 20 °C

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1

54
[ 864070-37-1 ]
[ 115845-51-7 ]
C₂₃H₂₇ClO₇ [ No CAS ]
C₂₃H₂₇ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Overall yield = 63.2 %; Overall yield = 60 mg;	43 Preparation of Compounds 2, 3 and 4 The mixture of 1-chloro-4-(β-D-glucopyranose-1yl)-2-(4-hydroxy benzyl)benzene (80 mg, 0.21 mmol), 4-methylbenzenesulfonate 2-oxetane methyl ester (65.3 mg, 0.27 mmol) and Cs2CO3 (171 mg, 0.52 mmol) in 3 mL of DMF was heated to 80° C. and stirred for 2 hours. The mixture was cooled down to room temperature, and filtered. The solvent was evaporated, and the residue was purified by silica gel column chromatography (AcOEt/MeOH, 10:1) to afford compound 2. Compound 2 was then resolved via preparative HPLC [chiral column, CHIRALCEL OJ-H, mobile phase: n-Hexane:EtOH (0.1% NH(C2H5OH)2)=7:3; speed: 1 mL/1 min. Temp: 40° C. injection volume: 10 μL] to provide isomer 3 (retention time: 12.84 min) which has a shorter retention time and isomer 4 (retention time: 20.35 min). [0224] Compound 2: [0225] Yield: 60 mg (63.2% of theoretical value). [0226] 1HNMR (500 MHz, CD3OD) δ: 7.28-7.37 (m, 3H), 7.14 (d, J=9 HZ, 2H), 6.89-6.91 (m, 2H), 5.12-5.17 (m, 1H), 4.63-4.75 (m, 2H), 4.01-4.16 (m, 5H), 3.88-3.90 (m, 1H), 3.69-3.72 (m, 1H), 3.37-3.48 (m, 4H), 2.67-2.82 (m, 2H). [0227] LC-MS (ESI): m/z=473/475 (Cl) [M+Na]+. [0228] Compound 3: [0229] 1HNMR (500 MHz, CD3OD) δ: 7.34-7.37 (m, 2H), 7.28-7.30 (m, 1H), 7.14 (d, J=8.5 HZ, 2H), 6.89 (d, J=8.5 HZ, 2H), 5.14 (brs, 1H), 4.83-4.74 (m, 2H), 4.01-4.15 (m, 5H), 3.88-3.90 (m, 1H), 3.69-3.72 (m, 1H), 3.37-3.48 (m, 3H), 3.29-3.32 (m, 1H), 2.68-2.80 (m, 2H). [0230] LC-MS (ESI): m/z=473/475 (Cl) [M+Na]+. [0231] Compound 4: [0232] 1HNMR (500 MHz, CD3OD) δ: 7.23-7.25 (m, 2H), 7.17-7.19 (m, 1H), 7.02 (d, J=8.5 HZ, 2H), 6.78 (d, J=8.5 HZ, 2H), 5.02 (brs, 1H), 4.51-4.61 (m, 2H), 3.89-4.04 (m, 5H), 3.76-3.78 (m, 1H), 3.57-3.60 (m, 1H), 3.28-3.36 (m, 3H), 3.17-3.21 (m, 1H), 2.58-2.66 (m, 2H). [0233] LC-MS (ESI): m/z=473/475 (Cl) [M+Na]+.

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0223-0233

55
[ 864070-37-1 ]
[ 99314-44-0 ]
C₂₄H₂₉ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;	A mixture of 1-chloro-4-(beta-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)-benzene (80 mg, 0.21 mmol), 3-methyl-3-oxetanyl butane methyl 4-methyl benzenesulfonate (69.1 mg, 0.27 mmol) and cesium carbonate (171 mg, 0.52 mmol) in 3 mL of dimethylformamide was heated to 80 C. and stirred for 2 hours. The mixture was cooled down to room temperature, and filtered. The solvent was evaporated, and the residue was purified by silica gel column chromatography (AcOEt/MeOH, 10:1) to afford compound 5 (58 mg, yield; 59.4%). [0236] 1HNMR (500 MHz, CD3OD) delta: 7.29-7.37 (m, 3H), 7.14 (d, J=8.5 HZ, 2H), 6.89 (d, J=6.5 HZ, 2H), 4.66 (d, J=6 HZ, 2H), 4.45 (d, J=6 HZ, 2H), 4.01-4.11 (m, 5H), 3.88-3.90 (q, 1H), 3.69-3.72 (q, 1H), 3.39-3.47 (m, 3H), 3.29-3.31 (m, 1H), 1.43 (s, 3H). [0237] LC-MS (ESI): m/z=487/489 (Cl) [M+Na]+.
59.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;	Example 44: Preparation of compound 5: [0146] A mixture of 1-chloro-4-(beta-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)- benzene (80 mg, 0.21 mmol), 3-methyl-3-oxetanyl butane methyl 4-methyl benzenesulfonate (69.1 mg, 0.27 mmol) and cesium carbonate (171 mg, 0.52 mmol)in 3 mL of dimethylformamide was heated to 80C and stirred for 2 hours. The mixture was cooled down to roomtemperature, and filtered. The solvent was evaporated, and the residue was purified by silica gel column chromatography(AcOEt/MeOH, 10:1) to afford compound 5 (58 mg, yield; 59.4%).1HNMR (500 MHz, CD3OD) delta: 7.29-7.37(m, 3H), 7.14(d, J=8.5HZ, 2H), 6.89(d, J=6.5HZ, 2H), 4.66(d, J=6HZ, 2H), 4.45(d, J=6HZ, 2H), 4.01-4.11(m, 5H), 3.88-3.90(q, 1H), 3.69-3.72(q, 1H), 3.39-3.47(m, 3H), 3.29-3.31(m, 1H), 1.43(s, 3H).LC-MS (ESI): m/z = 487/489(Cl) [M+Na]+

Reference： [1]Patent: US2013/324464,2013,A1 .Location in patent: Paragraph 0234-0237
[2]Patent: EP2676965,2013,A1 .Location in patent: Paragraph 0145; 0146

56
[ 864070-37-1 ]
[ 1135039-66-5 ]
C₂₄H₂₉ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	47 Preparation of Compound 8 The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)-benzene (80 mg, 0.21 mmol), 2-(3-oxetane)ethyl 4-methylbenzene sulfonate (75 mg, 0.29 mmol) and cesium carbonate (137 mg, 0.42 mmol) in 3 mL of dimethylformamide was heated to 80° C. for 2 hours, and cooled down to room temperature, filtered. The solvent was evaporated and the residue was purified by silical gel chromatography (AcOEt/MeOH 20:1) to afford compound 8 (51 mg, yield; 52%). [0248] 1HNMR (500 MHz, CD3OD) δ: 7.37-7.28 (m, 3H), 7.11 (d, J=9.0 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 4.84 (dd, 1=8 Hz, 6 Hz, 2H), 4.53 (t, J=6.0 Hz, 2H), 4.11-3.88 (m, 6H), 3.72-3.69 (m, 1H), 3.48-3.22 (m, 5H), 2.17-2.13 (m, 2H). [0249] LC-MS (ESI): m/z=465/467 (Cl) [M+H]+
52%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	47 Example 47: Preparation of compound 8 Example 47: Preparation of compound 8: [0152] The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)-benzene (80 mg, 0.21 mmol), 2-(3-oxetane)ethyl 4- methylbenzene sulfonate (75 mg, 0.29 mmol) and cesium carbonate (137 mg, 0.42 mmol) in 3 mL ofdimethylformamide was heated to 80°C for 2 hours, and cooled down to room temperature, filtered. The solvent wasevaporated and the residue was purified by silical gel chromatography (AcOEt/MeOH 20:1) to afford compound 8 (51mg, yield; 52%).1HNMR (500 MHz, CD3OD) δ: 7.37-7.28 (m, 3H), 7.11 (d, J= 9.0 Hz, 2H), 6.79 (d, J= 8.5 Hz, 2H), 4.84 (dd, J = 8 Hz, 6Hz, 2H), 4.53 (t, J = 6.0 Hz, 2H), 4.11-3.88 (m, 6H), 3.72-3.69 (m, 1H), 3.48-3.22 (m, 5H), 2.17-2.13 (m, 2H).LC-MS (ESI): m/z = 465/467(Cl) [M+H]+

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0246-0249
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0151; 0152

57
[ 864070-37-1 ]
[ 892408-42-3 ]
C₂₈H₃₆ClNO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.5%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	52 Preparation of Compound 13 The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)-benzene (256.6 mg, 0.75 mmol), 4-methylbenzenesulfonate 1-carboxylic t-butyl-azetidine-3-methyl ester (220 mg, 0.58 mmol) and cesium carbonate (470 mg, 1.45 mmol) in 3 mL of dimethylformamide was heated to 80° C. for 2 hours, and cooled down to room temperature, filtered. The solvent was evaporated and the residue was purified by silical gel chromatography (10:1 CH2Cl2/MeOH). [0268] Yield: 170 mg (53.5% of theoretical value). [0269] 1H NMR (500 MHz, CD3OD) δ: 7.28-7.37 (m, 3H), 7.13 (d, J=7.5 HZ, 2H), 6.86 (d, J=7.5 HZ, 2H), 4.04-4.11 (m, 7H), 3.89 (d, J=12 HZ, 2H), 3.80 (s, 2H), 3.71-3.72 (m, 1H), 3.40-3.47 (m, 3H), 3.28-3.32 (m, 2H), 1.46 (s, 9H). [0270] LC-MS (ESI): m/z=572/574 (Cl) [M+Na]+.
53.5%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	52 Example 52: Preparation of compound Example 52: Preparation of compound: [0162] The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl)- benzene (256.6 mg, 0.75 mmol), 4-methylbenzenesulfonate 1-carboxylic t-butyl-azetidine-3-methyl ester (220 mg, 0.58 mmol) and cesium carbonate (470mg, 1.45 mmol) in 3 mL of dimethylformamide was heated to 80°C for 2 hours, and cooled down to room temperature,filtered. The solvent was evaporated and the residue was purified by silical gel chromatography (10:1 CH2Cl2 / MeOH).Yield: 170 mg (53.5% of theoretical value).1H NMR (500 MHz, CD3OD) δ: 7.28-7.37(m, 3H), 7.13(d, J=7.5HZ, 2H), 6.86(d, J=7.5HZ, 2H), 4.04-4.11(m, 7H), 3.89(d, J=12HZ, 2H), 3.80(s, 2H), 3.71-3.72(m, 1H), 3.40-3.47(m, 3H), 3.28-3.32(m, 2H), 1.46(s, 9H).LC-MS (ESI): m/z = 572/574(Cl) [M+Na]+

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - US2013/324464, 2013, A1 Location in patent: Paragraph 0266-0270
[2]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0161; 0162

58
[ 864070-37-1 ]
C₁₃H₁₈O₄S [ No CAS ]
C₂₅H₃₁ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With caesium carbonate In N,N-dimethyl-formamide at 80℃;	61 Synthesis of copmound 22 Synthesis of copmound 22[0190] The mixture of 1-chloro-4-(β-D-glucopyranosyl-1-yl)-2-(4-hydroxybenzyl) -benzene (224 mg, 0.59 mmol), compoundIb"-22 (159 mg, 0.599 mmol) and cesium carbonate (577 mg, 1.77 mmol) in dimethylformamide (5 mL) washeated to 80°C and stirred overnight. The reaction mixture was cooled down to room temperature. The solvent wasevaporated under vacuum and the residue was washed with water, extracted with ethyl acetate. The organic phase wasdried over anhydrous sodium sulphate, concentrated. The residue was purified by preparative HPLC to afford compound22 (70 mg, 25%). 1H-NMR (500 MHz, CD3OD) δ: 7.31-7.35 (m, 2H), 7.27 (dd, J=2.0Hz, 8.0Hz, 1H), 7.10 (d, J=8.5Hz,2H), 6.80 (d, J=8.0Hz, 2H), 4.82 (dd, J=6.0Hz, 8.0Hz, 2H), 4.38 (t, J=5.5Hz, 2H), 4.09 (d, J=9.5Hz, 1H), 4.03 (q, J=15.0Hz,2H), 3.92 (t, J=6.5Hz, 2H), 3.87 (d, J=12.5Hz, 1H), 3.69 (dd, J=5.5Hz, 12.0Hz, 1H), 3.43-3.46 (m, 1H), 3.35-3.41 (m,2H), 3.26-3.30 (m, 1H), 3.03-3.08 (m, 1H), 1.83-1.88 (m, 2H), 1.66-1.72 (m, 2H). LC-MS (ESI): m/z = 479[M+H]+.

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0188; 0190

59
[ 864070-37-1 ]
[ 115845-51-7 ]
C₂₃H₂₇ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.2%	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	43 Example 43: Preparation of compounds 2, 3 and 4 Example 43: Preparation of compounds 2, 3 and 4: [0141] The mixture of 1-chloro-4-(β-D-glucopyranose-1yl)-2-(4-hydroxy benzyl) benzene (80 mg, 0.21 mmol), 4-methylbenzenesulfonate2- oxetane methyl ester (65.3 mg, 0.27 mmol) and Cs2CO3 (171 mg, 0.52 mmol) in 3 mL of DMFwas heated to 80°C and stirred for 2 hours. The mixture was cooled down to room temperature, and filtered. The solventwas evaporated, and the residue was purified by silica gel column chromatography (AcOEt/MeOH, 10:1) to affordcompound 2

Reference： [1]Current Patent Assignee: SHANGPHARMA VENTURE DEVELOPMENT JIANGSU - EP2676965, 2013, A1 Location in patent: Paragraph 0141; 0142

60
[ 864070-37-1 ]
[ 80-40-0 ]
[ 461432-26-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Inert atmosphere;

Reference： [1]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]

61
[ 864070-37-1 ]
[ 59034-23-0 ]
[ 1204219-80-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Inert atmosphere;

Reference： [1]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]

62
[ 864070-37-1 ]
[ 60835-92-9 ]
[ 1204219-68-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Inert atmosphere;

Reference： [1]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]

63
[ 864070-37-1 ]
[ 80-48-8 ]
[ 333359-90-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Inert atmosphere;

Reference： [1]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]

64
[ 864070-37-1 ]
[ 7575-93-1 ]
[ 1204219-88-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1236 - 1251

65
[ 21739-92-4 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 10 h / 20 °C 2.1: aluminum (III) chloride / dichloromethane / 1 h / -5 - 20 °C / Inert atmosphere 2.2: 2 h / -5 - 0 °C / Inert atmosphere 3.1: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 18 h / 5 - 20 °C / Inert atmosphere 4.1: boron tribromide / dichloromethane / -10 - 0 °C / Inert atmosphere 5.1: triethylamine / acetonitrile / 2 h / 5 - 15 °C 6.1: n-butyllithium / tetrahydrofuran; hexane; toluene / 0.5 h / -65 °C / Inert atmosphere 6.2: 3 h / -65 - -55 °C 6.3: 16 h / 20 - 25 °C 7.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 2 h / -30 - -10 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 10 - 45 °C / Inert atmosphere 2.1: aluminum (III) chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 2.2: 1 h / 0 - 5 °C / Inert atmosphere 3.1: triethylsilane / acetonitrile / 10 - 15 °C 3.2: 10 - 45 °C 4.1: boron tribromide / dichloromethane / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0 - 5 °C 6.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 6.2: 12 h / -75 - 35 °C / Inert atmosphere 7.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C
	Multi-step reaction with 9 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 10 - 45 °C / Inert atmosphere 2.1: aluminum (III) chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 2.2: 1 h / 0 - 5 °C / Inert atmosphere 3.1: triethylsilane / acetonitrile / 10 - 15 °C 3.2: 10 - 45 °C 4.1: boron tribromide / dichloromethane / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0 - 5 °C 6.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 6.2: 12 h / -75 - 35 °C / Inert atmosphere 7.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 7.2: 0.5 h / -40 - -5 °C / Inert atmosphere 8.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 9.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C

Multi-step reaction with 6 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / 0 - 5 °C 1.2: 10 h / 0 - 5 °C 2.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / 4 h / 10 °C 3.1: boron tribromide / dichloromethane / 3.5 h / 0 - 20 °C / pH 7 - 8 4.1: triethylamine / dichloromethane / 15 h / 20 °C 5.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 5.2: 1.5 h / -78 °C / Inert atmosphere 5.3: 18 h / 20 °C / Inert atmosphere 6.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / 5 h / -10 °C

Reference： [1]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]
[2]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[3]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[4]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A

66
[ 21900-52-7 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: aluminum (III) chloride / dichloromethane / 1 h / -5 - 20 °C / Inert atmosphere 1.2: 2 h / -5 - 0 °C / Inert atmosphere 2.1: aluminum (III) chloride; sodium tetrahydroborate / tetrahydrofuran / 18 h / 5 - 20 °C / Inert atmosphere 3.1: boron tribromide / dichloromethane / -10 - 0 °C / Inert atmosphere 4.1: triethylamine / acetonitrile / 2 h / 5 - 15 °C 5.1: n-butyllithium / tetrahydrofuran; hexane; toluene / 0.5 h / -65 °C / Inert atmosphere 5.2: 3 h / -65 - -55 °C 5.3: 16 h / 20 - 25 °C 6.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 2 h / -30 - -10 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: aluminum (III) chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 1.2: 1 h / 0 - 5 °C / Inert atmosphere 2.1: triethylsilane / acetonitrile / 10 - 15 °C 2.2: 10 - 45 °C 3.1: boron tribromide / dichloromethane / 0 - 5 °C 4.1: triethylamine / dichloromethane / 0 - 5 °C 5.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 5.2: 12 h / -75 - 35 °C / Inert atmosphere 6.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / -70 - 35 °C
	Multi-step reaction with 8 steps 1.1: aluminum (III) chloride / dichloromethane / 0 - 5 °C / Inert atmosphere 1.2: 1 h / 0 - 5 °C / Inert atmosphere 2.1: triethylsilane / acetonitrile / 10 - 15 °C 2.2: 10 - 45 °C 3.1: boron tribromide / dichloromethane / 0 - 5 °C 4.1: triethylamine / dichloromethane / 0 - 5 °C 5.1: n-butyllithium / tetrahydrofuran / -75 - -70 °C / Inert atmosphere 5.2: 12 h / -75 - 35 °C / Inert atmosphere 6.1: triethylsilane / dichloromethane; acetonitrile / 1 h / 25 - 35 °C / Inert atmosphere 6.2: 0.5 h / -40 - -5 °C / Inert atmosphere 7.1: N-ethyl-N,N-diisopropylamine; dmap / tetrahydrofuran / 0 - 35 °C 8.1: lithium hydroxide; water / tetrahydrofuran; methanol / 1 h / 15 - 20 °C

Multi-step reaction with 7 steps 1.1: oxalyl dichloride; N,N-dimethyl-formamide / 12 h / 0 - 20 °C 2.1: aluminum (III) chloride / dichloromethane / 0.5 h / 0 - 5 °C 2.2: 10 h / 0 - 5 °C 3.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / 4 h / 10 °C 4.1: boron tribromide / dichloromethane / 3.5 h / 0 - 20 °C / pH 7 - 8 5.1: triethylamine / dichloromethane / 15 h / 20 °C 6.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 6.2: 1.5 h / -78 °C / Inert atmosphere 6.3: 18 h / 20 °C / Inert atmosphere 7.1: boron trifluoride diethyl etherate; triethylsilane / dichloromethane; acetonitrile / 5 h / -10 °C

Reference： [1]Xu, Ge; Lv, Binhua; Roberge, Jacques Y.; Xu, Baihua; Du, Jiyan; Dong, Jiajia; Chen, Yuanwei; Peng, Kun; Zhang, Lili; Tang, Xinxing; Feng, Yan; Xu, Min; Fu, Wei; Zhang, Wenbin; Zhu, Liangcheng; Deng, Zhongping; Sheng, Zelin; Welihinda, Ajith; Sun, Xun [Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1236 - 1251]
[2]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[3]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1
[4]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A

67
[ 864070-37-1 ]
[ 864070-44-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 0 - 50 °C 2: potassium carbonate / acetonitrile / 25 - 80 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2017/130217, 2017, A1

68
[ 75-77-4 ]
[ 864070-37-1 ]
(((2S,3S,4R,SR,6R)-2-(4-chloro-3-(4-((trimethylsilyl)oxy)benzyl)phenyl)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(trimethylsilane) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17.8 g	With 4-methyl-morpholine In tetrahydrofuran at 0 - 50℃;	14 Preparation of (((2S,3S,4R,SR,6R)-2-(4-chloro-3-(4-((trimethylsilyl)oxy)benzyl)phenyl)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl)tris(oxy))tris(trimethylsilane) of formula-14a Add (2S,3 R,4R,58,6R)-2-(4-chloro-3 -(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (10 gms) to tetrahydrofuran (100 ml) at 25-30°C and stirred for 10 mm. at the same temperature. N-Methylmorpholine (15.99/17.57 gr/ml, 6 moles) was added to the above reaction mixture and cooled to 0-5°C and added trimethylchlorosilane(11.40/1342 gms/ml, 4 moles) at same temperature. Heated the reaction mixture to 45-50°C and stirred for 10-11 hrs at the same temperature. Cooled the reaction mixture temperature to 0-5°C and quenched with chilled water. Ethyl acetate (500 ml) was added to the reaction mixture and separate the organic and aqueous layers. Extract the aqueous layer using ethyl acetate. Combined the organic layers followed by washed with 10% sodium dihydrogenphosphate dehydrate (NaH2PO4).2H20 and then with 10% NaG solution successively and dried over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. (Yield: 17.8 gms).

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2017/130217, 2017, A1 Location in patent: Page/Page column 36-37; 57

69
[ 864070-37-1 ]
[ 147-85-3 ]
[ 219823-47-9 ]
1-chloro-4-(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzyl]benzene di-L-proline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate With caesium carbonate at 25 - 50℃; Stage #2: <i>L</i>-proline In water at 75 - 80℃; for 0.5h;	11 Preparation of Co-Crystal of Empagliflozin and L-Proline from Compound of Formula (II-SH-A) In a round bottom flask, 15 g compound of Formula (II-SH-A), 17.96 g cesium carbonate, 11.45 g (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate and 150 mL DMSO or DMF were added at 25° C. to 35° C. The reaction mixture was heated to 35 to 40° C. and stirred for 4-5 hours. 2.86 g (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate and 6.41 g cesium carbonate were added and the reaction mixture was stirred at 40-50° C. for 24-36 hours. The reaction mixture then cooled to 25° C. to 35° C. 300 mL water was taken in another flask and cooled to 0-10° C. The reaction mixture was added into the water at 0-10° C. The reaction mixture was stirred at 25° C.-35° C. 75 mL toluene was added into the reaction mixture stirred for 30 minutes. The layers were separated and the aqueous layer was washed 2 to 3 times with toluene. In another flask, the aqueous layer and 450 mL methylene dichloride were taken and stirred for 30 minutes. Layers were separated. Organic layer was treated with 75 mL of 5% NaOH solution for 30 minutes and the layers were separated. The organic layer then treated with brine solution and then dried over sodium sulphate. The solvent was distilled out under vacuum to get a residue. 150 mL ethanol, 8 gm L-proline and 0.75 mL water were added into the flask having the residue and the reaction mixture was stirred for 30 minutes at 75-80° C. The reaction mixture then cooled and 75 mL toluene was added and stirred for 2 hours at 25-30° C. The solid was filtered and washed with ethanol and then dried to obtain co-crystal of empagliflozin and L-proline.

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - US2017/247356, 2017, A1 Location in patent: Paragraph 0197; 0198

70
[ 19094-56-5 ]
[ 864070-37-1 ]

Reference： [1]Patent: WO2017/203457,2017,A1

71
[ 1459754-40-5 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 1,1,3,3-tetramethyldisilazane / chlorobenzene / 5.5 h / 5 - 25 °C 2: dmap; triethylamine / dichloromethane / 3 h / 5 - 28 °C 3: n-butyllithium / tetrahydrofuran; toluene; hexane / 4 h / -80 °C / Inert atmosphere; Large scale 4: methanesulfonic acid / tetrahydrofuran; toluene; hexane / 12.5 h / -70 - 30 °C / Inert atmosphere 5: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 9 h / -30 - -5 °C
	Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; aluminum (III) chloride / tetrahydrofuran / 10 h / Reflux 2.1: 1H-imidazole; dmap / tetrahydrofuran / 12 h / 30 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / -20 - -10 °C 3.2: 1 h / -10 - 10 °C 3.3: 2 h / 40 °C / pH 2 4.1: aluminum (III) chloride; triethylsilane / acetonitrile; dichloromethane / 1 h / 5 °C / Cooling with ice
	Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; aluminum (III) chloride / tetrahydrofuran / 10 h / Reflux 2.1: dmap; 4-methyl-morpholine / 2-methyltetrahydrofuran / 12 h / 30 °C 3.1: TurboGrignard / tetrahydrofuran / 1 h / -20 - -10 °C 3.2: 1 h / -10 - 10 °C 3.3: 2 h / 40 °C 4.1: aluminum (III) chloride; triethylsilane / acetonitrile; dichloromethane / 1 h / 5 °C / Cooling with ice

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2017/203457, 2017, A1
[2]Current Patent Assignee: ZHEJIANG MEDICINE CO., LTD. - CN109867648, 2019, A
[3]Current Patent Assignee: ZHEJIANG MEDICINE CO., LTD. - CN109867648, 2019, A

72
[ 1459754-32-5 ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: dmap; triethylamine / dichloromethane / 3 h / 5 - 28 °C 2: n-butyllithium / tetrahydrofuran; toluene; hexane / 4 h / -80 °C / Inert atmosphere; Large scale 3: methanesulfonic acid / tetrahydrofuran; toluene; hexane / 12.5 h / -70 - 30 °C / Inert atmosphere 4: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 9 h / -30 - -5 °C
	Multi-step reaction with 3 steps 1.1: 1H-imidazole; dmap / tetrahydrofuran / 12 h / 30 °C 2.1: TurboGrignard / tetrahydrofuran / 1 h / -20 - -10 °C 2.2: 1 h / -10 - 10 °C 2.3: 2 h / 40 °C / pH 2 3.1: aluminum (III) chloride; triethylsilane / acetonitrile; dichloromethane / 1 h / 5 °C / Cooling with ice
	Multi-step reaction with 3 steps 1.1: dmap; 4-methyl-morpholine / 2-methyltetrahydrofuran / 12 h / 30 °C 2.1: TurboGrignard / tetrahydrofuran / 1 h / -20 - -10 °C 2.2: 1 h / -10 - 10 °C 2.3: 2 h / 40 °C 3.1: aluminum (III) chloride; triethylsilane / acetonitrile; dichloromethane / 1 h / 5 °C / Cooling with ice

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2017/203457, 2017, A1
[2]Current Patent Assignee: ZHEJIANG MEDICINE CO., LTD. - CN109867648, 2019, A
[3]Current Patent Assignee: ZHEJIANG MEDICINE CO., LTD. - CN109867648, 2019, A

73
[ 864070-37-1 ]
[ 1125-88-8 ]
(4aR,6S,7R,8R,8aS)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-7,8-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.45%	With toluene-4-sulfonic acid In water; butanone at 0 - 50℃;	14 Example-14: Preparation of (4aR,6S,7R,8R,8aS)-6-(4-chloro-3-(4-hydroxybenzyl) phenyl)-2-phenyl-hexahydropyrano[3,2-d][l,3]dioxine-7,8-diol (VII) A mixture of (2S,3 ,4 ,5S,6 )-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl) tetrahydro-2/-/-pyran-3,4,5-triol (10 g), p-toluenesulphonic acid monohydrate (1.6 g) and methyl ethyl ketone (80 ml) was stirred at 0-10°C. A solution of benzaldehyde dimethylacetal (9.7 g) in methyl ethyl ketone (20 ml) was slowly added to the reaction mixture at 0-10°C. The reaction mixture was stirred at 0-10°C for 4-5 h. After completion of reaction, reaction mixture was filtered and washed with methyl ethyl ketone (2x10 ml). The solid was dried at 50-60°C in air tray drier for 2 h to give the title compound as white solid (10.4 g). Yield: 84.45%

Reference： [1]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2018/29264, 2018, A1 Location in patent: Page/Page column 30

74
[ 864070-37-1 ]
[ 75-03-6 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 25 - 40℃;	11 Example-11: Preparation of (2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6- (hydroxy-methyl)tetrahydro-2H-pyran-3,4,5-triol (Dapagliflozin crude) A solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (20 g) in N,N-dimethylformamide (60 ml) was mixed with cesium carbonate (20.52 g) at 25-35°C. Ethyl iodide (9.8 g) was added drop wise and then the reaction mixture was heated to 30-40°C for 4-5 h. After completion of reaction, reaction mixture was dumped into water (300 ml) and product was extracted with ethyl acetate (3x200 ml). Organic layers were combined and washed with brine solution (100 ml). Organic layer was dried over sodium sulphate and distilled out under vacuum below 55°C to give title compound as brown colour syrup (21.6 g). Yield: 98.5%. HPLC Purity: 88.07%.

Reference： [1]Current Patent Assignee: AMNEAL PHARMACEUTICALS LLC - WO2018/29264, 2018, A1 Location in patent: Page/Page column 29

75
[ 864070-37-1 ]
[ 778-28-9 ]
(3R,4R,5S,6R)-2-((3-4-n-butoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.6%		1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL under an oil bath at 55 C. Stirring reaction in N,N-dimethylformamide for 13 min, oil bath 60 C Add 1.35g (5.9mmol) under the conditions The n-butyl p-toluenesulfonate was stirred for 15 h, added with saturated brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate (MgSO4) Obtained 2.08g of a colorless viscous solid 13c, The yield is 80.6%.

Reference： [1]Patent: CN108285439,2018,A .Location in patent: Paragraph 0038; 0115-0117

76
[ 864070-37-1 ]
[ 3839-35-8 ]
(3R,4R,5S,6R)-2-(3-(4-n-hexyloxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.3%		1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL of N,N-dimethylformamide under an oil bath of 55 C for 13 min.1.51 g (5.9 mmol) of n-hexyl p-toluenesulfonate was added in an oil bath at 60 C.The reaction was stirred for 15 h, then brine was added and ethyl acetate was evaporated.The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated.The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1) to give 2.23 g of colorless viscous solid 13d, yield 81.3%.

Reference： [1]Patent: CN108285439,2018,A .Location in patent: Paragraph 0038; 0118-0120

77
[ 864070-37-1 ]
[ 6165-76-0 ]
(3R,4R,5S,6R)-2-(3-(4-prop-2-ynyloxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.4%	Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With caesium carbonate In N,N-dimethyl-formamide at 55℃; for 0.216667h; Stage #2: propargyl p-toluenesulfonate In N,N-dimethyl-formamide at 60℃; for 15h;	11 Synthesis of (3R,4R,5S,6R)-2-(3-(4-prop-2-ynyloxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (13e) 1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL of N,N-dimethylformamide under an oil bath of 55 ° C for 13 min.Add 1.24g (5.9mmol) to the oil bath at 60 ° CPropyl p-toluenesulfonate 1 and stirred for 15 h,Add saturated brine, extract with ethyl acetate, and dry over anhydrous sodium sulfate.Filter and distill off the solvent under reduced pressure.The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1) to yield 1.89 g of colorless viscous solid 13e, yield 76.4%.

Reference： [1]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A Location in patent: Paragraph 0038; 0121-0123

78
[ 864070-37-1 ]
[ 640-60-8 ]
(3R,4R,5S,6R)-2-(3-(4-phenoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.7%	Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With caesium carbonate In N,N-dimethyl-formamide at 55℃; for 0.216667h; Stage #2: toluene-4-sulfonic acid phenyl ester In N,N-dimethyl-formamide at 60℃; for 15h;	12` Synthesis of (3R,4R,5S,6R)-2-(3-(4-phenoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (13f) 1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL of N,N-dimethylformamide under an oil bath of 55 ° C for 13 min.1.46 g (5.9 mmol) of phenyl p-toluenesulfonate was added in an oil bath at 60 ° C.The reaction was stirred for 15 h, then brine was added and ethyl acetate was evaporated.The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated.The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1)1.91g of colorless viscous solid 13f, yield 70.7%.

Reference： [1]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A Location in patent: Paragraph 0038; 0124-0126

79
[ 864070-37-1 ]
[ 1024-41-5 ]
(3R,4R,5S,6R)-2-(3-(4-benzyloxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.9%	Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With caesium carbonate In N,N-dimethyl-formamide at 55℃; for 0.216667h; Stage #2: benzyl tosylate In N,N-dimethyl-formamide at 60℃; for 15h;	13 Synthesis of (3R,4R,5S,6R)-2-(3-(4-benzyloxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (13g) 7.0 g (37 mmol) of p-toluenesulfonyl chloride and 5.0 mL (37 mmol) of triethylamine were added to 40 mL of dichloromethane solution under ice bath.After 10 min, benzyl alcohol .5 mL (23 mmol) was slowly added to the mixture.Control temperature does not exceed 8 ° C, after 5 h reaction, TLC detection (petroleum ether:Ethyl acetate = 25:1) until the reaction was complete, 10 mL of dichloromethane was added.The reaction solution was poured into ice water (10 mL × 2), and the reaction was stirred for 15 min.Wash with 10% hydrochloric acid solution, saturated sodium bicarbonate, and saturated brine.The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure.The residue is passed through a silica gel column to give the compound benzyl 4-methylbenzenesulfonate (G13). For the preparation of 13g.1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL of N,N-dimethylformamide under an oil bath of 55 ° C for 13 min.1.55 g (5.9 mmol) of (G13) was added in an oil bath at 60 ° C.The reaction was stirred for 15 h, then brine was added and ethyl acetate was evaporated.The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated.The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1)2.16 g of colorless viscous solid 13 g, yield 77.9%.

Reference： [1]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A Location in patent: Paragraph 0038; 0127-0130

80
[ 864070-37-1 ]
[ 4455-09-8 ]
(3R,4R,5S,6R)-2-(3-(4-benzylmethoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.4%		7.0 g (37 mmol) of p-toluenesulfonyl chloride and 5.0 mL (37 mmol) of triethylamine were added to 40 mL of dichloromethane solution under ice bath.After 10 min, 2.35 mL (23 mmol) of phenylethyl alcohol was slowly added to the mixture.Control temperature does not exceed 8 C, after 5 h reaction, TLC detection (petroleum ether:Ethyl acetate = 25:1) until the reaction was complete, 10 mL of dichloromethane was added.The reaction solution was poured into ice water (10 mL × 2), and the reaction was stirred for 15 min.Wash with 10% hydrochloric acid solution, saturated sodium bicarbonate, and saturated brine.The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure.The residue is passed through a silica gel column.Phenylethyl p-toluenesulfonate(H13),For the preparation of 13h.1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL of N,N-dimethylformamide under an oil bath of 55 C for 13 min.1.63 g (5.9 mmol) of (H13) was added in an oil bath at 60 C.The reaction was stirred for 15 h, then brine was added and ethyl acetate was evaporated.The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated.The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1)2.24g of colorless viscous solid 13h, yield 78.4%.

Reference： [1]Patent: CN108285439,2018,A .Location in patent: Paragraph 0038; 0131-0134

81
[ 864070-37-1 ]
[ 16200-57-0 ]
(3R,4R,5S,6R)-2-(3-(4-adamantyloxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.5%	Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With caesium carbonate In N,N-dimethyl-formamide at 55℃; for 0.216667h; Stage #2: Toluene-4-sulfonic acid adamantan-1-yl ester In N,N-dimethyl-formamide at 60℃; for 15h;	15 Synthesis of (3R,4R,5S,6R)-2-(3-(4-adamantyloxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (13i) 7.0 g (37 mmol) of p-toluenesulfonyl chloride and 5.0 mL (37 mmol) of triethylamine were added to 40 mL of dichloromethane solution under ice bath.10minAdamantanol3.50g (23mmol)Slowly added to the mixture,The control temperature does not exceed 8 ° C, after 5 h of reaction,TLC detection (petroleum ether: ethyl acetate = 25:1) until the reaction is complete,10 mL of dichloromethane was added, and the reaction solution was poured into ice water (10 mL × 2).Stir the reaction for 15 min, sequentially using 10% hydrochloric acid solution, saturated sodium bicarbonate,Wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, and filter.The filtrate was evaporated under reduced pressure and the residue was applied to silica gel column.The compound adamantyl p-toluenesulfonate (I13) was obtained for the preparation of 13i.1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL of N,N-dimethylformamide under an oil bath of 55 ° C for 13 min.Add 1.81 g (5.9 mmol) of (I13) in an oil bath at 60 °C.Stir the reaction for 15 h, add saturated brine,Extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered.Evaporate the solvent under reduced pressure.The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1)2.20g of colorless viscous solid 13i, yield 72.5%.

Reference： [1]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A Location in patent: Paragraph 0038; 0135-0138

82
[ 864070-37-1 ]
[ 26831-48-1 ]
(3R,4R,5S,6R)-2-(3-(4-adamantylethoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.2%	Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol With caesium carbonate In N,N-dimethyl-formamide at 55℃; for 0.216667h; Stage #2: 2-(adamantan-1-yl)ethyl-4-methylbenzenesulfonate In N,N-dimethyl-formamide at 60℃; for 15h;	16 Synthesis of (3R,4R,5S,6R)-2-(3-(4-adamantylethoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (13j) Under ice bath, 7.0 g (37 mmol) of p-toluenesulfonyl chloride and 5.0 mL (37 mmol) of triethylamine were added to 40 mL of dichloromethane solution.After 10 min, 4.15 g (23 mmol) of adamantane ethanol was slowly added to the mixture.The temperature was controlled to not exceed 8 ° C. After 5 h of reaction, TLC was detected (petroleum ether: ethyl acetate = 25:1) until the reaction was completed, and 10 mL of dichloromethane was added.The reaction solution was poured into ice water (10 mL × 2), and the reaction was stirred for 15 min.Wash with 10% hydrochloric acid solution, saturated sodium bicarbonate, and saturated brine.The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure.The residue is passed through a silica gel column.Compound adamantyl ethyl p-toluenesulfonate(J13),For the preparation of 13j.1.7 g (4.5 mmol) of 10 and 2.1 g (6.8 mmol) of cesium carbonate were added to 9 mL of N,N-dimethylformamide under an oil bath of 55 ° C for 13 min.1.97 g (5.9 mmol) of (J13) was added in an oil bath at 60 ° C.The reaction was stirred for 15 h, then brine was added and ethyl acetate was evaporated.The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated.The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1)2.34g of colorless viscous solid 13j, yield 73.2%.

Reference： [1]Current Patent Assignee: TIANJIN TASLY GROUP COMPANY., LTD. - CN108285439, 2018, A Location in patent: Paragraph 0038; 0139-0142

83
[ 864070-37-1 ]
(R)-tetrahydrofuran-3-yl 4-nitrobenzenesulfonate [ No CAS ]
[ 864070-44-0 ]

Yield	Reaction Conditions	Operation in experiment
55 g	With potassium carbonate In butan-1-ol at 25 - 80℃; for 2h;	6 £xample-6: D-glucitol, 1 ,5-anhydro-i -C-14-chloro-3-I 14-I (3S)-tetrahydro-3furanylI oxyl phenylJmethylphenylJ-, (18) (Empagliflozin (Formula-i)) (2R ,3 R,4R,58,6S)-2-(Acttoxymethyi)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetra hydro-2H-pyran-3 ,4,5-triyl triacetate (100 gms), (R)-tetrahydrofuran-3 -yl 4-nitrobenzene sulfonate (54.7 gms) and n-butanol (1000 ml) were mixed in a clean and dry round bottom flask at 25-30°C. To this reaction mixture, potassium carbonate (125.8 gms) was added and heated the reaction mixture to 80°C and stirred for 2 hrs. Filtered the reaction mixture and washed with n-butanol and distilled off the solvent completely from the filtrate under reduced pressure. Cooled the reaction mixture to 25-30°C and then added ethyl acetate and water. Heated the reaction mixture to 45-50°C and stirred for 45 mins at same temperature. Separated the organic and aqueous layers. Extracted the aqueous layer with ethyL acetate and combined the total organic layers. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (500 ml) was added to the above obtained residue compound at 25-30°C. Heated the reaction mixture to 70°C and stirred for 60 mm at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at same temperature. Filtered the obtained material and washed with ethyl acetate and then dried to get the solid compound. Dissolved the obtained solid in the mixture of methanol (100 ml) and toluene (100 ml) at 65-70°C. Cooled the reaction mixture to 25-30°C and fUrther to 0-5°C and stirred for 2 hrs at 0-5°C. Filtered the obtained solid, washed with methanol and toluene mixture and then dried to get title compound. (Yield: 55 gms, M.R: 165-170)

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2018/163194, 2018, A1 Location in patent: Page/Page column 20; 22; 23

84
[ 21739-92-4 ]
[ 864070-37-1 ]
(2R,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 20 °C 2.1: aluminum (III) chloride / dichloromethane / -5 - 4 °C 3.1: triethylsilane; trifluorormethanesulfonic acid; trifluoroacetic acid / 20 °C / Reflux 4.1: n-butyllithium / tetrahydrofuran; toluene / -78 °C / Inert atmosphere 4.2: 1 h / -78 °C 5.1: triethylsilane; boron trifluoride diethyl etherate / methanol; dichloromethane / 0 °C 6.1: boron tribromide / dichloromethane / -78 - 0 °C

Reference： [1]Current Patent Assignee: THERACOS INC - WO2009/26537, 2009, A1

85
[ 864070-37-1 ]
(R)-3-tosyl tetrahydrofuran [ No CAS ]
(2S,3R,4R,5S,6R)-2-{4-chloro-3-[4-(tetrahydrofuran-3(R)-yloxy)benzyl]phenyl}-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 25 - 50℃;	6 EXAMPLE 6: Preparation of empagliflozin of formula I The residue of compound of Formula III was dissolved in N,N-Dimethylformamide (210ml) at 25-35°C. Cesium carbonate (74.5 gr) and R-Tosyl tetrahydrofuran (26.8 gr) was added. Raised the temperature of the reaction mass to 45°C to 50°C and maintained for 12- 24 hrs. Water and dichloromethane (525ml) were added to the reaction mass and adjust the pH of the reaction mass to 7.0 to 8.0 using 5% hydrochloric acid solution. Separate the layers and extract the aqueous layer with dichloromethane. Organic layers were combined and washed with water, 10% sodium chloride, and dried over sodium sulphate. Filtered the solid and dried over vacuum to obtain empagliflozin as a residue.

Reference： [1]Current Patent Assignee: LAURUS LABS LIMITED - WO2018/224957, 2018, A1 Location in patent: Page/Page column 40

86
C₂₂H₃₂BrClO₂Si₂ [ No CAS ]
(3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one [ No CAS ]
[ 864070-37-1 ]

Yield	Reaction Conditions	Operation in experiment
40 g	Stage #1: C₂₂H₃₂BrClO₂Si₂ With n-butyllithium In tetrahydrofuran at -85 - -68℃; Stage #2: (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one In tetrahydrofuran at -85 - -68℃; Further stages;	4; 5 The residue of compound of Formula VI was dissolved in toluene (500 ml) at 25-35°C. Raised the temperature of the reaction mass to 70-75°C and distilled off the solvent completely under vacuum at below 75°C. Tetrahydrofuran (500 ml) was added and the reaction mass was cooled to -68 to -85°C, n-butyl lithium (33.2gms) was added at -68 to- 85°C and stirred for 2-3 hrs at -68 to -85°C. Silylated sugar solution (93.3 gms in 500 ml toluene) was added at -68 to -85°C and stirred for 1-2 hrs at -68 to -85°C. After completion of the reaction, a solution of methanesulphonic acid in methanol (68 gms in 300 ml of methanol, which was pre-cooled to -30 to -40°C) was added to the reaction mass at a temperature of -68 to -85°C. The temperature of the reaction mass was raised to 25-35°C, and water was added, and the layers were separated. The aqueous layer was extracted with 2-methyltetrahydrofuran or ethyl acetate, combined the organic layers and washed with water, 10% sodium chloride solution and dried over sodium sulphate. The organic layer was distilled completely under vacuum at below 60°C and ee-distilled cyclohexane or n-heptane to obtain the title compound. (0435) Yield: 75 gms (0436) EXAMPLE 5: Preparation of compound of Formula III (0437) The residue of compound of Formula IV was dissolved in a mixture of acetonitrile (300ml) and dichloromethane (300ml) at 25-35°C. Triethylsilane (129.2 gr) was added at 25-35°C and the temperature of the reaction mass was cooled to -25 to -35°C. Borontrifluoride- diethyletherate (158.1 gr) was added to the reaction mass at -40 to -30° C and stirred for 15 to 20 min. Temperature of the reaction mass was raised to 0°C and further maintained with stirring for 3 to 4hrs. Water was added, and the layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran or ethyl acetate, combined the organic layers and washed with water, 8% sodium bicarbonate solution and further with 10% brine solution and dried over sodium sulphate. The organic layer was distilled completely under vacuum at below 45°C and co-distilled with n-heptane and purified by ethyl acetate to obtain the title compound as a solid. (0438) Yield: 40 gms

Reference： [1]Current Patent Assignee: LAURUS LABS LIMITED - WO2018/224957, 2018, A1 Location in patent: Page/Page column 39-40

87
[ 915095-86-2 ]
[ 864070-37-1 ]

Reference： [1]Patent: CN109867648,2019,A
[2]Patent: CN109867648,2019,A

88
[ 864070-37-1 ]
[ 1335139-58-6 ]
(2S,3R,4R,5S,6R)‑2‑(3‑(4‑(((1R,3s,5S)‑bicyclo[3.1.0]hexane‑3‑yl)oxy)benzyl) ‑4‑chlorophenyl)‑6‑(hydroxymethyl)tetrahydro‑2H‑pyran‑3,4,5‑triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-benzyl-N,N,N-triethylammonium chloride; caesium carbonate In 1-methyl-pyrrolidin-2-one at 70℃; for 16h;	4 step 4 In a 2L reaction flask, add N-methylpyrrolidone (1.4L), and then add the compound of formula IV (140g, 0.37mol) and the compound of formula V (93.5g, 0.53mol) in sequence,Benzyl triethylammonium chloride (4.2g, 0.018mol), cesium carbonate (319.3g, 0.98mol),Under mechanical stirring, the temperature was raised to 70°C and the reaction continued for 16 hours. The reaction was monitored by HPLC.After the reaction is complete, cool to 25°C, pour into 2L of water, extract the aqueous phase with ethyl acetate (2L×3), combine the organic phases, wash with water (1.5L), and wash with saturated sodium chloride solution (1.5L).The organic phase was concentrated under reduced pressure to obtain the compound represented by formula VI, which was directly used in the next step without purification.

Reference： [1]Current Patent Assignee: BEIJING HUIZHIHENG BIOLOGICAL TECH; JILIN HUISHENG BIOLOGICAL PHARMACEUTICAL - CN112047915, 2020, A Location in patent: Paragraph 0107-0109

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	864070-37-1	MDL No. :	MFCD28387374
Formula :	C₁₉H₂₁ClO₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ODQAIMBPQWETBE-FQBWVUSXSA-N
M.W :	380.81	Pubchem ID :	44580555
Synonyms :		Chemical Name :	(2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

Num. heavy atoms :	26
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.37
Num. rotatable bonds :	4
Num. H-bond acceptors :	6.0
Num. H-bond donors :	5.0
Molar Refractivity :	95.55
TPSA :	110.38 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.45 cm/s

[ CAS No. 864070-37-1 ] {[proInfo.proName]}

Quality Control of [ 864070-37-1 ]

Related Doc. of [ 864070-37-1 ]

Product Details of [ 864070-37-1 ]

Calculated chemistry of [ 864070-37-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 864070-37-1 ]

Application In Synthesis of [ 864070-37-1 ]

[ 864070-37-1 ] Synthesis Path-Upstream 1~1

[ 864070-37-1 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

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Disposal

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Inquiry

Log Po/w (iLOGP) :	2.01
Log Po/w (XLOGP3) :	1.65
Log Po/w (WLOGP) :	0.83
Log Po/w (MLOGP) :	0.63
Log Po/w (SILICOS-IT) :	1.84
Consensus Log Po/w :	1.39

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-3.32
Solubility :	0.183 mg/ml ; 0.000481 mol/l
Class :	Soluble
Log S (Ali) :	-3.58
Solubility :	0.0998 mg/ml ; 0.000262 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.38
Solubility :	0.159 mg/ml ; 0.000418 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.33

Signal Word:	Danger	Class:	9
Precautionary Statements:	P501-P273-P260-P270-P264-P280-P391-P314-P337+P313-P305+P351+P338-P301+P312+P330	UN#:	3077
Hazard Statements:	H302-H319-H372-H410	Packing Group:	Ⅲ
GHS Pictogram:

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