Name: 714269-57-5|(2S,3R,4S,5S,6R)-2-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol|95%
Brand: Ambeed
SKU: A411294
Price: 14.0 USD
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1
[ 714269-57-5 ]
[ 461432-26-8 ]

Yield	Reaction Conditions	Operation in experiment
87.6%	With triethylsilane; boron trifluoride diethyl etherate; at 5℃; for 0.00416667h;	Accurately prepare a mixture of 300 ml of methanol and methanesulfonic acid (V methanol / methanesulfonic acid = 4:1),It is pumped into the third reaction unit of the microreactor at a flow rate of 3.5 ml/min, and mixed with the reaction liquid flowing out from the second reaction unit.The residence time of the reaction in this step is 19 seconds, and the reaction temperature controlled by the reaction unit is 5 C. After the reaction liquid flows out from the third reaction unit,At the same time, the prepared mixture of boron trifluoride diethyl ether and triethylsilane was pumped into the fourth reaction unit at a flow rate of 3.5 ml/min.The residence time of the reaction unit is 15 seconds, the temperature of the fourth reaction unit is controlled to be 5 C, and the liquid discharged from the fourth reaction unit is continuously collected 100 ml.Finally, it was added to 200 ml of n-heptane, stirred and crystallized, and kept at 0 C for 1 hour, and filtered to obtain a crude product of dapagliflozin. Take a small amount of dapagliflozin for liquid chromatography analysis.The conversion ratio of the raw material A was 99.9%, and the total yield was 87.6%.
76%	With triethylsilane; aluminum (III) chloride; In dichloromethane; acetonitrile; at -5 - 10℃; for 3.5h;Large scale;	Take 1-chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4-ethoxybenzyl)-benzene 44kg,Dichloromethane 50kg and acetonitrile 150kg added to the 500L reactor, stir;The reaction solution was cooled to -5 DEG C, 2 kg of anhydrous aluminum trichloride was added, stirred for 30 minutes, and 13 kg of Et3SiH was added dropwise at this temperature. After the dropwise addition, the temperature was gradually raised to 10 DEG C and the reaction was carried out for 3 hours.The reaction is completed, cooled to -5 C, saturated sodium bicarbonate solution was added dropwise, adjusting the pH to 6-7;Extract with ethyl acetate (50kg×2), wash the organic phase with saturated sodium chloride solution, wash with water to neutrality, then dry over anhydrous sodium sulfate, filter and evaporate the filtrate to recover the ethyl acetate.A mixed solution of 40 kg of methanol and dichloromethane (1:1) was added, stirred, and a large amount of solids were precipitated, and the mixture was cooled and stirred for 1 h.;Filter and wash the solid with cold ethanol and vacuum dry overnight at 50 C. to obtain 31 kg of a white solid with a yield of 76% and a purity of 99.37%.
76%		Take 1-chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4-ethoxybenzyl)-benzene, 44kg,Dichloromethane (50kg) and acetonitrile (150kg) were added to the 500L autoclave and stirred well; the reaction solution was cooled to -5C, 2kg of anhydrous aluminum trichloride was added, stirred for 30min, and 13kg of Et3SiH was added dropwise at this temperature. After the dropwise addition, the temperature was gradually increased to 10 C, reaction 3h. After the reaction is completed, cool down to -5C, add saturated sodium bicarbonate solution dropwise, adjust the pH to 6-7, extract with ethyl acetate (50kg × 2), wash the organic phase with saturated sodium chloride solution, and wash with water to neutrality. Then, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was recovered under reduced pressure. Ethyl acetate was added to a mixed solution of 40 kg of methanol and methylene chloride (1:1), stirred, and a large amount of solids precipitated, and the mixture was cooled and stirred for 1 h. Filtration, washing the solid with cold ethanol, vacuum drying at 50 C. overnight, yielded 31 kg of a white solid, yield 76%. Purity 99.37%.

76%		Take 1-chloro-4-(1-methoxy-D-glucopyran-1-yl)-2-(4-ethoxybenzyl)-benzene 44kg, dichloromethane 50kg and acetonitrile 150kg to add 500L reaction Stir well in the kettle. The reaction solution was cooled to -5 C, 2 kg of zinc chloride was added, and stirred for 30 min. 13 kg of Et 3 SiH was added dropwise thereto at this temperature, and the temperature was slowly raised to 10 C for 3 h.After the reaction was completed, the temperature was lowered to -5 C, and a saturated sodium hydrogencarbonate solution was added dropwise to adjust the pH to 6 to 7. Extracted with ethyl acetate (50 kg × 2), the organic phase was washed successively with saturated sodium chloride solution, water, then neutralized, then dried over anhydrous sodium sulfate, filtered, and filtrated to recover ethyl acetate under reduced pressure, 40 kg of methanol and two A mixed solution of methyl chloride (1:1) was stirred, and a large amount of solid was precipitated, and the mixture was cooled and stirred for 1 hour. Filtration, washing the solid with cold ethanol, and drying under vacuum at 50 C overnight to give a white solid 31 kg, yield 76%. The purity is 99.37%.
72.1%	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -20 - 0℃;	To 100mL three-necked flask was added 4.23g of intermediate -1,20ml methylene chloride, 15ml of acetonitrile, stirred to dissolve, cooled to -15 to -20 deg.] C, was added 6.84g of triethylsilane was added dropwise 6.09g three boron trifluoride diethyl, dropping the reaction temperature is kept at -10 deg.] C, then warmed to completion of the dropwise addition -5 -0 insulation mixing the reaction, the HPLC monitoring of the reaction is complete, add saturated sodium bicarbonate ph adjusted to about 7, Save pressure distillation, liquor added ethyl acetate, dried over anhydrous sodium sulfate to afford 2.84g Dag column net yield of 72.1%.
	With triethylsilane; boron trifluoride diethyl etherate; water; In acetonitrile; at 5 - 10℃; for 2h;Product distribution / selectivity;	Example 6; To acetonitrile (12 mL), at batch temperature of 8-10 C. under nitrogen atmosphere, was charged borontrifluoride diethyletherate (2.3 mL, 18.4 mmol) and water (0.82 mL, 4.6 mmol). After holding the above mixture for about 1 hour, triethylsilane (3 mL, 18.4 mmol) was added. The resulting mixture was held for about 1 hour, and then compound B (prepared as described in Example 17) in 10 mL acetonitrile was added. The batch was held at 5 to 10 C. On completion of the reaction as determined by HPLC, the reaction mixture was quenched with aqueous ammonium acetate (24 mL; 85 g) in 200 mL water. The phases were separated and product rich organic phase was dried over sodium sulfate. The product rich organic phase was concentrated under reduced pressure. Water (13 mg, 0.7 mmol, based on 0.3 g crude compound B input), (S)-propylene glycol (56 mg, 0.7 mmol), t-butylmethyl ether (5 mL, 17 mL/g compound B input), compound Ia seeds (20 mg) were mixed and held for 1 hr., to form a crystal slurry. Cyclohexane (10 mL, 33 mL/g compound B (input)) was added. The crystalline product (Ia) was isolated by filtration (4-5%) and dried in vacuo at 20-25 C.
	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -45 - -10℃;	Example 1C (282 g, 0.643 mol) was dissolved in anhydrous acetonitrile /dichloromethane (3.4 L, 1 :1 (v/v)) at -45 0C stirred solution of in was added triethylsilane (299 g, 2.57 mol) followed by addition of boron trifluoride etherate (245 mL, 1.93 mol). After the addition, the mixture was stirred for another 2 h at -10 0C. The reaction was quenched with saturated aqueous bicarbonate to pH 7.5. The volatiles were removed under reduced pressure and the residues were extracted with ethyl acetate (2 x 3.0 L). The combined organic layers were washed with brine (2 x 2.0 L), dried over sodium sulfate and concentrated to give the crude product as a white solid (250 g). Purity (HPLC): 82.8% (UV).[0132] A 5 L 4-necked flask was charged with the above crude product (203 g, 82% purity) and followed by Z-proline (114 g, 0.995 mol), ethanol(1.46 L) and water (162 mL). The mixture was heated to reflux for 30 min with rapid mechanical stirring. n-Hexane (200 mL) was added dropwise to the above solution. After the addition was complete, the reaction was cooled slowly to room temperature and then further to -5C. After stirring for 3 h at -5 0C, the mixture was filtered and the filter cake was washed with cold ethano I/water (90: 10 (v/v), 2 x 100 mL) and n-hexane (2 x 500 mL), and dried under vacuum at 65C to give the desired product as a white solid (186 g). A portion of this crude product (140 g) was dissolved in ethano I/water (90:10 (v/v), 700 mL) at 75 0C with mechanical stirring. After the solution became clear, it was cooled slowly to room temperature and stirred for another 5 h. The mixture was filtered and the filter cake was washed with cold ethanol (2 x 50 mL), n-hexane (2 x 100 mL) , dried under vacuum at 65 0C to get the desired product as a white solid (130 g, yield 66%). Purity (HPLC) 99.5% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, IH), 4.06-3.95 (m, 6H), 3.88-3.85 (m, IH), 3.72-3.68 (m, IH), 3.47-3.37 (m, 5H), 3.32-3.20 (m, 3H), 2.33-2.26 (m, 2H), 2.16-2.08 (m, 2H), 2.01-1.95 (m, 4H), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+ 1]+
	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -30 - -10℃; for 1.5h;Inert atmosphere;	Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol A solution of <strong>[714269-57-5](2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol</strong> (7.87 g, crude, ?17.9 mmol) in dichloromethane (59 mL) and acetonitrile (59 mL) was cooled to -30 C. under argon. Triethylsilane (11.5 mL, 71.6 mmole) was added to the reaction solution followed by addition of boron trifluoride etherate (6.8 mL, 53.7 mmole) so that the temperature didn't exceed -10 C. After the addition was complete the reaction solution was stirred for additional 1.5 h and then quenched with 5% sodium bicarbonate until the pH reached 7.5. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (280 mL). The combined organic phases were washed with brine (280 mL) and dried over anhydrous sodium sulfate. The sample was concentrated under reduced pressure to provide 6.8 g of the title compound as a pale solid which was used for the next step without purification. Yield: 93%. Purity (LCMS-0013) 2.9 min, 82% (UV); MS ESI (m/z) 409[M+1]+, calc. 408.
	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -20 - 20℃; for 0.333333h;Inert atmosphere;	[0280] To a 100 mL 3-neck flask equipped with magnetic stirrer and under argon atmosphere was added dichloromethane (7.0 mL), acetonitrile (7.0 mL) and triethylsilane (5.09 mL, 31.9 mmol) successively at room temperature. The above mixture was cooled to -20 to -25 C and BF3-Et20 (3.03 mL, 23.9 mmol) was added in one portion. Another 100 mL flask was charged with crude (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)- 6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (3.5 g, 7.97 mmol), dichloromethane (7.0 mL) and acetonitrile (7.0 mL), and the resulting mixture was shaking for 20 min at ambient temperature until a clear solution was obtained. Under an atmosphere of nitrogen, the (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution in dichloromethane and acetonitrile was transferred to an addition funnel and was slowly added to the solution of BF3-Et20 and triethylsilane over a period of 1 h while keeping the internal temperature between -15 to -20 C. After the addition was completed, the mixture was stirred at a temperature between -15 to -20 C. [0281] The reaction was quenched by addition of an aqueous solution of sodium bicarbonate (7.4% w/w, 25 g) via an addition funnel while keeping the internal temperature below -5 C. Additional solid sodium bicarbonate (1.7 g) was added to adjust the pH to -7.5. The volatile solvents were removed under reduced pressure at a temperature below 40 C. After cooling below room temperature, the residues were partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (2 x 15 mL). The combined organic layers were washed with 10% brine (2 x 20 mL). The combined extracts were concentrated under reduced pressure at a temperature below 40 C until the condensation rate slow down and almost distillation stop (not foaming). The residue was dried under oil pump (P=0.1 mm Hg) to give 3.25 g of off-white solid (99.7% yield, 89.3% pure by HPLC Method EGT-M-0001).
		Dichloromethane (1250 ml) followed by acetonitrile (1250 ml) were added to (2S ,3R,4 S,5 S ,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxy tetrahydro-2H-pyran-3,4,5-triol compound of formula-6 (250 gms) at 25-30 C. Cooled the reaction mixture to -20 to -25 C. under nitrogen atmosphere and stirred for 15 mins at the same temperature. Triethylsilane (132.35 gms) was slowly added to the reaction mixture at -20 to -25 C. and stirred for 15 mins. BF3-etherate (193.5 gms) was added to the reaction mixture at -25 to -20 C. and stirred for 15 mins at the same temperature. The temperature of the reaction mixture was slowly raised to -5 to 0 C. and stirred for 1 hr at the same temperature. The pH of the reaction mixture was neutralized by using 10% aqueous sodium bicarbonate solution. Ethyl acetate was added to the reaction mixture and stirred for 15 mins. Separated the both organic and aqueous layers, washed the organic layer with aqueous sodium chloride solution (50 gms of sodium chloride in 1250 ml of water) and then distilled off the solvent completely from the organic layer under reduced pressure.
90 g	With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -5℃; for 5h;	To a solution of Compound IV (100 gm, 0.22 mol.) in dichloromethane, acetonitrile (1 : 1, 1000 ml) mixture at -5eC was added B F3.OEt2 (0.35 mol.) and Tri ethyl si lane (0.47 mol) sequenti al ly at -5eC . T he reacti on mi xture was sti rred at the same temperature for 5 h. A f ter 5 h, reaction mixture was quenched with 10% NaHC03 solution. Reaction mass was concentrated to remove vol ati I es and added 1000ml of ethyl acetate. Layers were separated (0119) 3a and organic layer was washed with water (500 ml) followed by brine solution (500 ml). (0120) Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude Compound V (90 g, 0.22 mol) as foamy solid.

Reference： [1]Patent: CN109400561,2019,A .Location in patent: Paragraph 0083; 0085-0087; 0089-0091; 0093-0095; 0097; 0098
[2]Patent: CN107540648,2018,A .Location in patent: Paragraph 0041; 0042; 0054; 0055
[3]Patent: CN107573311,2018,A .Location in patent: Paragraph 0015; 0022
[4]Patent: CN108084130,2019,B .Location in patent: Paragraph 0050; 0072-0074
[5]Patent: CN105481915,2016,A .Location in patent: Paragraph 0023; 0024
[6]Patent: US2008/4336,2008,A1 .Location in patent: Page/Page column 21-22
[7]Patent: WO2010/22313,2010,A2 .Location in patent: Page/Page column 35; 38-39
[8]Patent: US2013/267694,2013,A1 .Location in patent: Page/Page column 0316
[9]Patent: WO2013/152476,2013,A1 .Location in patent: Paragraph 0260
[10]Patent: WO2013/152476,2013,A1
[11]Patent: US2017/29398,2017,A1 .Location in patent: Paragraph 0082-0083
[12]Patent: WO2017/221211,2017,A1 .Location in patent: Page/Page column 18

2
[ 67-56-1 ]
[ 714269-57-5 ]
2CH₄O*C₂₂H₂₇ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.5%	In n-heptane; toluene; at 20℃;Product distribution / selectivity;	Example 9; Preparation of Crystalline Di-MeOh Solvate Ig from Unpurified Compound B in Methanol/Toluene/Heptane using Seeds; 2.5 g of compound B (91.5%) was added to a scintillation vial with a magnetic stir-bar. 4 mL toluene was added to dissolve the compound Ia. 2 mL methanol was added. Next, seeds of compound Ig crystals (about 1%) were added. 4 mL heptane was added over 30 minutes and the mixture was stirred for 12 hours. Wet cake was isolated on a Buchner funnel. The wet cake was found to be crystalline methanol solvate Ig. It was dried under vacuum at 30 C. The resultant powder lost crystallinity. Yield=1.7 g=74.5% (corrected). Characterization XRD pattern of crystals: FIG. 10. The so formed crystalline MeOH solvate Ig may be used in place of compound B in the preparation of crystalline compound Ia as described in Example 6.
	at 20℃;Product distribution / selectivity;	Example 7; Crystals of methanol solvate Ig were obtained by dissolving pure compound B in methanol and stirring at room temperature. A white slurry formed after a few days, and was found to be crystalline methanol solvate Ig. The so formed crystalline di-MeOH solvate Ig may be used in place of compound B in the preparation of crystalline compound Ia as described in Example 6.
	In toluene; at 20℃;Product distribution / selectivity;	Example 8; Preparation of Crystalline Di-MeOh Solvate Ig from Unpurified Compound B in 80/20 Methanol/Toluene using Seeds; 6 g of compound B (HPLC AP approximately 80%) was dissolved in 15 mL of 80/20 methanol/toluene. Seeds (about 1% of starting compound B) of compound Ig crystals were added and the mixture was cooled to form a slurry containing crystals. The slurry was stirred for 6 hours before isolating. The wet cake was found to be crystalline methanol solvate If but loses crystallinity if left open for a few hours.

Reference： [1]Patent: US2008/4336,2008,A1 .Location in patent: Page/Page column 22
[2]Patent: US2008/4336,2008,A1 .Location in patent: Page/Page column 22
[3]Patent: US2008/4336,2008,A1 .Location in patent: Page/Page column 22

3
[ 110-65-6 ]
[ 714269-57-5 ]
[ 960404-59-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	In ethyl acetate; toluene; at 25 - 60℃; for 10h;Product distribution / selectivity;	Example 10; Preparation of Crystalline 1,4-Butyne-diol Solvate If from Compound B in Toluene/Ethyl Acetate using Seeds; 1,4-Butyne-diol solvate can be crystallized in an alkyl acetate (e.g. ethyl, propyl or butyl acetate), alcohol (e.g. isopropanol, butanol) or even water. Toluene and heptane act as anti-solvents when crystallized in alkyl acetate. 50 g (90.3 weight %) Compound B was dissolved in 675 mL toluene. The solution was heated to 60 C. and 75 mL ethyl acetate added. 1.5 eq 2-butyne-1,4-diol (=13.3 g) was added and the mixture held at 60 C. until the butyne diol dissolved. The solution was cooled to 55 C. and 0.1% seeds (50 mg) of 1,4-butyne-diol compound If was added. The mixture was held for 1 hour at 55 C. Compound If started crystallizing. The mixture was cooled to 25 C. over 6 hours. The resulting slurry was stirred for 3 hours before isolating (mother liquor conc was <3 mg/mL), filtered and washed with 180 mL toluene+20 mL ethyl acetate, and dried under vacuum at 45 C. to yield crystals of 1,4-butyne-diol solvate If. HPLC AP=99.5%. Potency=80.7 weight % (Expected potency=83.6% for 1:1 solvate). Yield=95%.; Example 16; A reaction scheme similar to that shown in Scheme IVA and FIG. 22 was employed. A -30 C. chiller for the lithiation reactor 5 jacketed static mixer 5) was set up. A -30 C. chiller for the coupling reactor 22 jacketed static mixer 22) and a pre-cooling heat exchanger (not shown in FIG. 22) for the compound D/toluene feed was set up.; Continuous Lithiation; The two feeds of E/THF/toluene (2.74 ml/min) and Q, namely, n-BuLi in hexane (0.41 ml/min), were mixed and combined through jacketed static mixer 5 (-30 C.). Before pumping the D/toluene feed, toluene (2.96 ml/min) was sent into the system as a make-up flow to maintain the overall flow constant at 6.1 ml/min. Samples at the outlet of the lithiation static mixer 5 for HPLC analysis were collected. Samples were taken before (a) the onset of the coupling reaction, and (b) after the collection of the reaction mixture into the MSA-MeOH reactor.; Continuous Coupling Reaction; The D/toluene feed (2.96 ml/min) was pre-cooled via a heat exchanger before mixing with the lithiation stream. The two streams namely G and D were mixed and combined through a jacketed static mixer 22 (between -24 C. and -30 C.). The reaction stream appeared yellowish in color. Samples were collected at the outlet of the mixer 22 for HPLC analysis. Samples were taken before and after the collection into the MSA-MeOH reactor 25.; Methyl Glycosidation; The coupling reaction stream 24 was fed to a 500-ml reactor 25 containing MSA and methanol or HCl/MeOH at <-10 C. with stirring. After the collection were finished, the reaction mixture was kept at <-10 C. with stirring for another hour. The reaction mixture was heated up to 35 C. The reaction was deemed complete (about 6 hrs) until HPLC analysis indicated that desilylated hemiketal H' RAP<0.3%. The reaction was cooled to room temperature (20 C.) and the reaction mixture was held for 16 hrs to form compound B.; Formation of Crystals of If; B was crystallized with 2-butyne-1,4-diol (J) in toluene/EtOAc to yield crystals of If.
90%	In n-heptane; acetic acid butyl ester; at 20 - 60℃; for 12h;Product distribution / selectivity;	Example 11; Preparation of Crystalline 1,4-Butyne-diol Solvate If from Compound B in Butyl Acetate/Heptane; 0.5 g Compound B (91 weight %) was dissolved in 3.5 mL butyl acetate+3.5 mL heptane at 60 C. 1.5 eq 2-Butyne-1,4-diol was added and the mixture cooled to room temperature. The resulting slurry was stirred for 12 hours, filtered and washed with 1 mL 1:1 butyl acetate: heptane, and dried under vacuum at 50 C. to yield crystals of 1,4-butyne-diol solvate If. Potency=85.1%. Yield=90%. The 1,4-butyne-diol solvate If may be employed in place of compound B and employing the Lewis acid BF3.2CH3COOH in place of BF3OEt2 to form the crystalline compound Ia.

Reference： [1]Patent: US2008/4336,2008,A1 .Location in patent: Page/Page column 23; 25-26
[2]Patent: US2008/4336,2008,A1 .Location in patent: Page/Page column 23

4
[ 67-56-1 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example 16; A reaction scheme similar to that shown in Scheme IVA and FIG. 22 was employed. A -30 C. chiller for the lithiation reactor 5 jacketed static mixer 5) was set up. A -30 C. chiller for the coupling reactor 22 jacketed static mixer 22) and a pre-cooling heat exchanger (not shown in FIG. 22) for the compound D/toluene feed was set up.; Continuous Lithiation; The two feeds of E/THF/toluene (2.74 ml/min) and Q, namely, n-BuLi in hexane (0.41 ml/min), were mixed and combined through jacketed static mixer 5 (-30 C.). Before pumping the D/toluene feed, toluene (2.96 ml/min) was sent into the system as a make-up flow to maintain the overall flow constant at 6.1 ml/min. Samples at the outlet of the lithiation static mixer 5 for HPLC analysis were collected. Samples were taken before (a) the onset of the coupling reaction, and (b) after the collection of the reaction mixture into the MSA-MeOH reactor.; Continuous Coupling Reaction; The D/toluene feed (2.96 ml/min) was pre-cooled via a heat exchanger before mixing with the lithiation stream. The two streams namely G and D were mixed and combined through a jacketed static mixer 22 (between -24 C. and -30 C.). The reaction stream appeared yellowish in color. Samples were collected at the outlet of the mixer 22 for HPLC analysis. Samples were taken before and after the collection into the MSA-MeOH reactor 25.; Methyl Glycosidation; The coupling reaction stream 24 was fed to a 500-ml reactor 25 containing MSA and methanol or HCl/MeOH at <-10 C. with stirring. After the collection were finished, the reaction mixture was kept at <-10 C. with stirring for another hour. The reaction mixture was heated up to 35 C. The reaction was deemed complete (about 6 hrs) until HPLC analysis indicated that desilylated hemiketal H' RAP<0.3%. The reaction was cooled to room temperature (20 C.) and the reaction mixture was held for 16 hrs to form compound B.; Formation of Crystals of If; B was crystallized with 2-butyne-1,4-diol (J) in toluene/EtOAc to yield crystals of If.

Reference： [1]Patent: US2008/4336,2008,A1 .Location in patent: Page/Page column 25-26

5
[ 714269-57-5 ]
[ 108-24-7 ]
methyl-2,3,4,6-tetra-O-acetyl-1-C-(2-chloro-4'ethoxydiphenylmethan-3yl)-α-D-glucopyranose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.6%	With N-ethyl-N,N-diisopropylamine;dmap; In tetrahydrofuran; at -5 - 5℃;	6.0 Kg methyl-1-C-(2-chloro-4?-ethoxydiphenylmethane-3-yl)-?-D-glucopyranoside were dissolved in 30 L THF and 13.04 kg DIPEA and 0.06 kg DMAP added. A sample was taken for HPLC. The mixture was cooled to 0-5 C. and 9.14 kg acetic anhydride added at such a rate that the temperature did not exceed +5 C. After complete addition the mixture was agitated at 0-5 C. for 1.5 h, then a sample taken for HPLC. The agitation was continued at 0-5 C. for another 1.5 h, then take a sample for HPLC. 30 L precooled (5 C.) MTBE were added and the mixture washed with 30 L ice-water then agitated for about 30 min at 5 C. The layers were separated and the aqueous layer extracted with 12 L MTBE. The combined organic phases were washed consecutively with 12 L 10% aqueous phosphoric acid, then twice with 12 L sat. Na-bicarbonate solution and with 8L brine. The solvent was evaporated at 40 C. in vacuum and the oily residue degassed carefully to obtain the title compound: Yield 7.52 kg (12.39 mol, 90.6%).

Reference： [1]Patent: US2004/138439,2004,A1 .Location in patent: Page 19; 20

6
[ 32469-28-6 ]
[ 714269-57-5 ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: CN106674245,2017,A

7
[ 461432-23-5 ]
[ 32469-28-6 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
78.3%		A solution of 11.97 kg 2-Chloro-5-bromo-4?-ethoxy-diphenylmethane was charged to a first reactor containing 120 L THF. A sample was taken for HPLC and then the solution was cooled to ?78 C. In a second reactor 17.16 kg of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone were dissolved in 87 L of heptane and the solution cooled to ?78 C. To the first reactor was added 23.15 kg s-BuLi (12% in cyclohexane) at such a rate that the reaction temperature did not exceed ?68 C. After complete addition the mixture was agitated at ?78 C. for 1 h, then a sample was taken for HPLC. Care was taken to avoid contact with humidity during sampling. (At this point, if the content of starting materials is determined to be less than 3 AP, the reaction may be continued to the next step; or if not, additional s-BuLi may be necessary.) The content of reactor one was added via a cooled line (?78 C.) to the cooled second reactor (?78 C.) at such a rate that the temperature did not exceed ?68 C. After complete addition, the mixture in the second reactor was agitated at ?78 C. for 30 min, then a sample taken for HPLC. Sampling was repeated every hour until completeness. The reaction was considered complete if no changes in AP were observed in two consecutively taken samples. The mixture was warmed to ?40 C., then 100 L water added very carefully. The mixture was agitated vigorously for 10 min and then the phases separated, and the aqueous phase extracted with 35 L MTBE. The combined organic phases were washed with 35 L brine. The organic phase was then concentrated to an oily residue and degassed carefully at 40 C. in vacuum to remove all volatiles. The oily residue was dissolved in 100 L methanol and 1.72 kg methanesulfonic acid slowly added. (At this stage, the reaction temperature may increase to 30 C.). The reaction mixture was agitated at 20-25 C. for about 12 h, then heated to 40 C. for 3 h, and a sample taken for HPLC. In the HPLC chromatogram 2 peaks were observed in 95:5 to 90:10 ratio. The major compound so identified corresponded with the product. 2.49 Kg triethylamine were added and the mixture concentrated in vacuum to an oily residue. This residue was dissolved in 150 L ethyl acetate and the solution washed twice with 50 L water. The organic phase was concentrated in vacuum to an oily residue and degassed carefully to remove all volatiles. The oily residue was dissolved in 37 L toluene and the toluene solution slowly added to 300 L heptane. The product precipitated; the suspension was agitated for 3 min. The precipitate was collected and the cake washed with very little heptane. It was then dried in circulating air to constant weight. Yield: 12.63 kg of the title compound (28.78 mol; 78.3%)
78%		Take 32kg of 5-bromo-2-chloro-4'-ethoxydiphenylmethane and 100kg of dry THF/toluene (1:4) mixed solvent into a nitrogen-dried 500 litre reactor.The liquid nitrogen was cooled to -78C, and 34L of a 1.6 mol·L-1 n-butyllithium hexane solution was slowly added dropwise, and the mixture was stirred at this temperature for 1 hour.Then, 100 kg of a toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucuronide (26 kg) cooled to -78C was slowly added dropwise to the above reaction solution.-78 C reaction 3h, the reaction is complete, at this temperature was added 50kg of methanol solution of methanesulfonic acid (methanesulfonic acid 23kg + methanol 27kg);The reaction was stirred at 0 C for 4h, and then warmed to 40 C stirred reaction 7h;5mol · L-1 sodium hydroxide aqueous solution was added to the reaction solution, adjusted to pH 7-8;Stir for 30 min, extract with ethyl acetate (50 kg x 2), and wash the organic phase with saturated aqueous sodium chloride until neutral,Then, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 34.6 kg of light yellow viscous oil in a yield of 78%.
78%		Take 32 kg of 5-bromo-2-chloro-4'-ethoxydiphenylmethane, add 100 kg (1:4) of anhydrous THF/toluene to the 500 liter reactor under nitrogen, and cool the liquid nitrogen to - 78 C,34 L of a 1.6 mol·L-1 n-butyllithium hexane solution was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. Will be cold to -78 C2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone100 kg of a toluene solution (26 kg) was slowly added dropwise to the above reaction liquid, and reacted at -78 C for 3 hours. After the completion of the reaction, 50 kg of a methanol solution of methanesulfonic acid (23 kg of methanesulfonic acid + 27 kg of methanol) was added thereto. The reaction was stirred at 0 C for 4 h, then warmed to 40 C and stirred for 7 h. A 5 mol·L-1 aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 7-8. After stirring for 30 min, it was extracted with ethyl acetate (50 kg×2). The organic phase was washed with saturated aqueous sodium chloride to neutral, then dried over anhydrous sodium sulfateA yellowish viscous oil was obtained in an amount of 34.6 kg, yield 78%.

Reference： [1]Patent: US2004/138439,2004,A1 .Location in patent: Page 19
[2]Patent: CN107540648,2018,A .Location in patent: Paragraph 0039; 0040; 0052; 0053
[3]Patent: CN108084130,2019,B .Location in patent: Paragraph 0050; 0069-0071
[4]Patent: CN111040000,2020,A

8
[ 67-56-1 ]
[ 461432-23-5 ]
[ 32469-28-6 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of Example IB (200 g, 0.614 mol) in anhydrous toluene/TEtaF (1.2 L, 2:1 (v/v)) was added n-BuLi (2.5 M in hexane, 295 mL) dropwise at -65 0C. The reaction was stirred at -65 0C for 30 min. Then the mixture was transferred by a cannula to a solution of (5i?,^5i?,(5i?)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2/f- pyran-2-one) (373 g, 0.798 mol) in toluene (1.2 L ) at -65 0C. The mixture was stirred at -65 0C until starting material was consumed (2 h). The reaction was quenched with hydrochloric acid (36-38percent, 113 mL, 1.35 mol) in methanol (800 mL), and stirred at room temperature overnight. The reaction was neutralized with saturated sodium bicarbonate to pEta 7.5 and the organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 3.0 L). The combined organic layers were washed with brine (2 x 2.0 L), dried over sodium sulfate and concentrated. The residue was dissolved in hot toluene (600 mL) and poured into n-hexane (2.0 L) with vigorous stirring. After stirring for Ih, the mixture was filtered and the filter cake was dried under vacuum to give the desired product as a white solid. This solid was used without further purification in the next step. MS ESI (m/z) 439[M+1]+
		A mixture of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene compound of formula-4 (83.33 gms) and toluene (420 ml) was heated to reflux temperature and stirred for 2 hrs under azeotropic conditions. Distilled off the solvent completely under reduced pressure. Cooled the obtained compound to 25-30° C. under nitrogen atmosphere. Tetrahydrofuran (665 ml) followed by the compound obtained in step-(a) were added to the reaction mixture at 25-30° C. under nitrogen atmosphere. Cooled the reaction mixture to -85 to -80° C. and stirred for 20 mins at the same temperature. n-butyl lithium (238.3 ml) was slowly added to the reaction mixture at -85 to -80° C. under nitrogen atmosphere. Raised the temperature of the reaction mixture to -75 to -70° C. and stirred for 2 hrs at the same temperature. A solution of methane sulfonic acid (91.4 ml) in methanol (500 ml) was slowly added to the reaction mixture at -75 to -70° C. The temperature of the reaction mixture was slowly raised to 0-5° C. and then to 10-15° C. The reaction mixture was stirred for 18 hrs at 10-15° C. 10percent aqueous sodium bicarbonate solution was added to the reaction mixture at 10-15° C. The temperature of the reaction mixture was raised to 25-30° C. and stirred for 15 mins. Separated the both organic and aqueous layers, the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined, washed with 10percent aqueous sodium chloride solution and then distilled off the solvent completely from the organic layer under reduced pressure. Cooled the obtained compound to 40-45° C. and then co-distilled with toluene. Toluene (100 ml) was added to the obtained compound at 25-30° C. and stirred for 20 mins at the same temperature. Diisopropyl ether (500 ml) was added to the reaction mixture at 25-30° C. Cooled the reaction mixture to 15-20° C. and stirred for 2 hrs at the same temperature. Settled the reaction mixture and decanted the upper organic layer. Distilled off the solvent from the bottom to get title compound. Yield: 135 gms; Purity by HPLC: 89.02percent.
	With n-butyllithium; methanesulfonic acid; In tetrahydrofuran; toluene; at -15 - 5℃; for 0.0113889h;	Accurately weigh 65.12g (0.2Mol) of raw material A, then add toluene / tetrahydrofuran mixture (V toluene / tetrahydrofuran = 2:1), dilute to 500ml, mix and pump into the microreactor at a flow rate of 14ml / min a reaction unit,At the same time, the concentration of 2.0mol / L n-butyl lithium solution was pumped into the first reaction unit at a flow rate of 3.4ml / min for thorough mixing to produce lithium halide exchange reaction, the residence time was 27 seconds, and the reaction temperature was controlled at -15 ° C. After the reaction solution flows out of the first reaction unit,At the same time, the raw material C was flowed into the second reaction unit of the microreactor at a flow rate of 2.2 ml/min to carry out a lactone condensation reaction.The residence time of the reaction in this step was 22 seconds, and the reaction temperature of the second reaction unit was controlled to be -15 °C. Accurately prepare a mixture of 300 ml of methanol and methanesulfonic acid (V methanol / methanesulfonic acid = 4:1),It is pumped into the third reaction unit of the microreactor at a flow rate of 3.5 ml/min, and mixed with the reaction liquid flowing out from the second reaction unit.The residence time of the reaction in this step is 19 seconds, and the reaction temperature controlled by the reaction unit is 5 ° C. After the reaction liquid flows out from the third reaction unit,At the same time, the prepared mixture of boron trifluoride diethyl ether and triethylsilane was pumped into the fourth reaction unit at a flow rate of 3.5 ml/min.The residence time of the reaction unit is 15 seconds, the temperature of the fourth reaction unit is controlled to be 5 ° C, and the liquid discharged from the fourth reaction unit is continuously collected 100 ml.Finally, it was added to 200 ml of n-heptane, stirred and crystallized, and kept at 0 ° C for 1 hour, and filtered to obtain a crude product of dapagliflozin.

Reference： [1]Patent: WO2010/22313,2010,A2 .Location in patent: Page/Page column 35; 37-38
[2]Patent: US2017/29398,2017,A1 .Location in patent: Paragraph 0081
[3]Patent: CN109400561,2019,A .Location in patent: Paragraph 0083-0085; 0087-0089; 0091-0093; 0095-0097

9
[ 281652-58-2 ]
[ 714269-57-5 ]

Reference： [1]Patent: WO2013/152476,2013,A1
[2]Patent: WO2013/152654,2013,A1

10
[ 103-73-1 ]
[ 714269-57-5 ]

Reference： [1]Patent: US2017/342100,2017,A1

11
[ 90-80-2 ]
[ 714269-57-5 ]

Reference： [1]Patent: WO2013/152654,2013,A1
[2]Patent: WO2015/43473,2015,A1
[3]Patent: WO2015/43511,2015,A1
[4]Patent: CN106674245,2017,A

12
[ 19094-56-5 ]
[ 714269-57-5 ]

Reference： [1]Patent: WO2013/152476,2013,A1
[2]Patent: WO2013/152654,2013,A1

13
[ 67-56-1 ]
[ 960404-86-8 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In tetrahydrofuran; at -10 - 15℃; for 18h;	Ketal Formation from the Hemiketal. [0331] The residue was dissolved in methanol (34 mL) and tetrahydrofuran (17 mL) with mechanical stirring (240 RPM). The above mixture was cooled to -10 C. over 40 min. A pre-cooled (0 C.) solution of concentrated hydrochloric acid (1.0 mL) was added dropwise to the reaction mixture while keeping the temperature between -10 and 0 C. The mixture was then allowed to warm to 10 to 15 C. and was stirred for 18 h. [0332] The reaction was slowly quenched by adding purified water (25 mL) while maintaining the temperature below 20 C. The mixture was charged with n-heptane (15 mL). After stirring for 30 min (240 RPM) and settling for 15 min, the lower aqueous layer was transferred to the flask. The upper organic layer was transferred to another one suitable separating funnel and extracted with water-methanol (1:1, 10 mL). The aqueous layers were combined and cautiously quenched with aqueous sodium bicarbonate suspension (20 g) to pH weakly basic (pH was about 7.5 to 8). The volatile organic were removed under reduced pressure (0.01 MPa) at the external temperature 30 C. The residue was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with deionized water (40 mL), saturated brine (40 mL) and deionized water (40 mL). The organic layer was dried over sodium sulfate (15 g). The suspension was filtered over the filtration paper and the filter cake was wash with ethyl acetate (10 mL). The organic layer was concentrated in a rotary evaporator under vacuum (0.01 MPa) at a temperature 30 C. until the rate of solvent condensation almost stopped. The organic layer was concentrated (20 to 30 C., 0.01 MPa) to give crude (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-trio 6 (3.56 g, yield: 81.1%, 77.1% pure by HPLC-0001) as a light yellow glassy solid. This crude product was directly used in the next step.
	With methanesulfonic acid; In neat (no solvent); at 20℃; for 6h;Inert atmosphere;	Compound III (100 gm, 0.23 mol.) solution in methanol (1000 ml) under nitrogen atmosphere at room temperature was added Methanesulfonic acid (0.11 mol.) at room temperature and continue stirring for 6 h. After 6 h, reaction mass was concentrated to get the syrup which was dissolved in dichloromethane (1000 ml) and 10% NaHC03 (500 ml) was added to it and stirred for 20 min and separated the layers. Organic layer was washed with brine solution (500 ml), dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude C ompound IV .

Reference： [1]Patent: US2013/267694,2013,A1 .Location in patent: Paragraph 0330-0332
[2]Patent: WO2017/221211,2017,A1 .Location in patent: Page/Page column 17-18

14
[ 67-56-1 ]
[ 1103738-29-9 ]
[ 32469-28-6 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
		[0258] Arylmagnesium Formation: A three-necked round-bottom flask equipped with thermometer and jacketed addition funnel was charged with a solution of l-chloro-2-(4- ethoxybenzyl)-4-iodobenzene (7.45 g, 20 mmol) and THF (15 mL) and the mixture was magnetically stirred and kept under an argon atmosphere. To the solution was added zPrMgCl-LiCl (17.7 mL, 1.3 M in THF, 23 mmol) dropwise over 30 min between -5 to 0 C. The mixture was stirred for an additional 1.5 h at -5 to 0 C. [0259] Gluconolactone Solution: A 100 mL round-bottom flask was charged with (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydropyran-2- one (12.1 g, 26 mmol) and n-heptane (18.5 mL) and the mixture was cooled to -5 C under argon. z'PrMgCl-LiCl (0.8 mL, 1.3 M in THF, 1 mmol) was added dropwise and the mixture was stirred for 30 min at -5 to 0 C. The cooled gluconolactone solution was added dropwise to the arylmagnesium over 30 min at a temperature between -5 and 0 C. After the addition was completed, the mixture was stirred for 2 h at -5 C. A pre-cooled (0 C) solution of concentrated hydrochloric acid (6.7 mL, 80 mmol) in methanol (35 mL) was added dropwise to the reaction mixture while keeping the temperature below 0 C. The mixture was allowed to warm to 15 to 20 C and stirred for additional 16 h. The mixture was cautiously quenched with saturated aqueous sodium bicarbonate (-20 mL) to pH weakly basic and the mixture was extracted with ethyl acetate (2 x 80 mL). The combined organic layers were washed with deionized water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentration under vacuum to give 7.87 g of product as a light yellow glassy solid. Yield: -90%. Purity (LC-MS Method EGT-M-0013) 3.0 min, 80% (UV); MS ESI (m/z) 439[M+1]+, calc. 438.
		0286] Gluconolactone Solution. A 100 mL flask was charged with (3R,4S,5R,6R)-3,4,5- tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (6.54 g) and n-heptane (10.2 mL), and stirred for 10 min under argon sparging. The mixture was cooled to -30 C to -20 C under nitrogen atmosphere. The solution was added to a suitable cooled addition funnel and was kept ready for addition to the aryl magnesium. [0287] Aryl magnesium Formation. A 4-neck 100 mL flask bottle equipped with a thermometer, mechanical stirrer, condenser and addition funnel was purged with nitrogen and was charged with anhydrous THF (7 mL) and l-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (3.73 g, 10 mmol). After stirring and sparging with nitrogen for 30 min at ambient temperature, the mixture was cooled to -60 C under nitrogen atmosphere. To the solution was added iPrMgCl-LiCl (Aldrich, titrated concentration 12.9% wt/wt, 7.58 g) (0.95 eq. by titration) via a suitable addition funnel at such a rate that the temperature was maintained between -50 C and -60 C in 30 min under nitrogen atmosphere. The mixture was stirred for an additional 10 min at -60 to -50 C. The conversion of l-chloro-2-(4-ethoxybenzyl)-4- iodobenzene to the aryl magnesium was monitored by quenching an aliquot with saturated ammonium chloride aqueous solution and the aliquot was extracted with ethyl acetate and was analyzed via HPLC-0001. [0288] Aryl Magnesium Coupling to Give an Anomeric Hemiketal. The cold gluconolactone solution in a cooled (-25 C) addition funnel was added dropwise to the aryl magnesium solution at such a rate as to maintain the temperature between -50 C and -60 C for over 40 min. After the addition was completed, the mixture was stirred for 5 h at -50 to -60 C. [0289] The reaction was slowly quenched with nitrogen-sparged (10 min) saturated ammonium chloride aqueous solution (30 g) at -15 C to 0 C via an addition funnel over 20 min. The mixture was allowed to warm to 10 to 15 C over 2.5 h and stirred for over 10 h. The upper organic layer was separated. Deionized water (10 g) was added to the aqueous layer. The aqueous phases were extracted with ethyl acetate (3 x 15 mL). The organic layers were combined and washed with deionized water (20 mL) and brine (16.7% w/w, 20 g). The ethyl acetate layer was treated with activated charcoal (1.32 g, 30% w/w based on the weight of expected (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol, CX-700 from Zhuxi Co.) for 1 h at 20 C followed by filtration over filter paper. The organic layer was concentrated at a temperature 35 C under vacuum (0.01 MPa) until the rate of solvent condensation almost stopped. Methanol (10 mL) was added and the mixture was re-concentrated at 35 C under vacuum (0.01 MPa) until the rate of solvent condensation almost stopped. [0290] Ketal Formation from the Hemiketal. The residue was dissolved in methanol (34 mL) and tetrahydrofuran (17 mL) with mechanical stirring (240 RPM). The above mixture was cooled to -10 C over 40 min. A pre-cooled (0 C) solution of concentrated hydrochloric acid (1.0 mL) was added dropwise to the reaction mixture while keeping the temperature between -10 and 0 C. The mixture was then allowed to warm to 10 to 15 C and was stirred for 18 h. [0291] The reaction was slowly quenched by adding purified water (25 mL) while maintaining the temperature below 20 C. The mixture was charged with n-heptane (15 mL). After stirring for 30 min (240 RPM) and settling for 15 min, the lower aqueous layer was transferred to the flask. The upper organic layer was transferred to another one suitable separating funnel and extracted with water-methanol (1 : 1, 10 mL). The aqueous layers were combined and cautiously quenched with aqueous sodium bicarbonate suspension (20 g) to pH weakly basic (pH was about 7.5 to 8). The volatile organic were removed under reduced pressure (0.01 MPa) at the external temperature 30 C. The residue was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with deionized water (40 mL), saturated brine (40 mL) and deionized water (40 mL). The organic layer was dried over sodium sulfate (15 g). The suspension was filtered over the filtration paper and the filter cake was wash with ethyl acetate (10 mL). The organic layer was concentrated in a rotary evaporator under vacuum (0.01 MPa) at a temperature 30 C until the rate of solvent condensation almost stopped. The organic layer was concentrated (20 to 30 C, 0.01 MPa) to give crude (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (3.65 g, yield: 83.1%, 90.4% pure by HPLC-0001) as a light yellow glassy solid. This crude product was directly used in the next step.

Reference： [1]Patent: WO2013/152476,2013,A1 .Location in patent: Paragraph 0258; 0259
[2]Patent: WO2013/152654,2013,A1 .Location in patent: Paragraph 0286-0291

15
[ 714269-57-5 ]
[ 147-85-3 ]
(2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol bis(L-proline) cocrystal [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; for 0.5h;Reflux;	[0261] A 500 mL 4-necked flask was charged with the above crude product (6.8 g, 82% purity) followed by L-proline (3.8 g, 33.2 mmol), ethanol (57.4 mL) and water (3.8 mL). The mixture was heated to reflux for 30 min with rapid mechanical stirring. -Hexane (102 mL) was added dropwise to the above solution over 30 min. After the addition was complete, the reaction was cooled slowly to room temperature and stirred for additional 16 h. The mixture was filtered and the filter cake was washed with cold 95% ethanol/water (0 C, 2 x 3.4 mL) and n-hexane (2 x 13.6 mL), and dried under vacuum at 65C to give the desired product as a white solid (4.5 g). This crude product (4.5 g) was dissolved in ethanol/water (95%, 22.5 mL) at 75 C with mechanical stirring. The mixture was heated to reflux for 30 min with rapid mechanical stirring. -Hexane (45 mL) was added dropwise to the above solution over 30 min. After the addition was complete, the reaction was cooled slowly to room temperature and stirred for additional 16 h. The mixture was filtered and the filter cake was washed with n-hexane (2 ^ 9 mL), and dried under vacuum at 65C to give 3.8 g of the desired product as a white solid. Purity (HPLC Method EGT-M-0001) 99.0% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, 1H), 4.06-3.95 (m, 6H), 3.88-3.85 (m, 1H), 3.72-3.68 (m, 1H), 3.47-3.37 (m, 5H), 3.32-3.20 (m, 3H), 2.33-2.26 (m, 2H), 2.16-2.08 (m, 2H), 2.01-1.95 (m, 4H), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+l]+.

Reference： [1]Patent: WO2013/152476,2013,A1 .Location in patent: Paragraph 0261

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[ 1528636-28-3 ]
[ 714269-57-5 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 57 - 65

17
[ 714269-57-5 ]
[ 1528636-29-4 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 57 - 65

18
[ 714269-57-5 ]
[ 1528636-33-0 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 57 - 65

19
[ 714269-57-5 ]
[ 1528636-39-6 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 57 - 65
[2]Patent: CN109970822,2019,A

20
[ 714269-57-5 ]
[ 1210344-57-2 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 57 - 65
[2]Patent: US2017/342100,2017,A1
[3]Patent: US2017/342100,2017,A1

21
[ 714269-57-5 ]
[ 75-77-4 ]
[ 1528636-28-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole; In dichloromethane; at 5 - 20℃; for 4h;	100g of compound A and 91.5g of imidazole were added to 500mL of dichloromethane, stirred, cooled to 5 C, 141.1g of TMSCl was slowly added dropwise, after the completion of the dropwise addition, naturally warmed to room temperature and stirred for 4h, added to 500mL of water and stirred for 20min, allowed to stand layering, collected The organic phase is concentrated under reduced pressure to give Compound III as an oil.It was used in the next step without further purification.Compound III was dissolved in 500 mL of acetonitrile, 127 g of IBX was added, the temperature was raised to reflux, stirred for 4 hours, cooled to room temperature, filtered, and the filtrate was concentrated to give Compound VI.It was used in the next step without purification.Compound VI was dissolved in 500 mL of ethanol, and 136 g of paraformaldehyde was added to obtain a suspension. The temperature was raised to 55 C, and 154 g of a 20% ethanol sodium ethanol solution was slowly added dropwise thereto, and the reaction was kept for 4 hours.Add 2120g of 20% sodium hydrogen sulfite solution, stir for 30min, concentrate and remove most of the ethanol, add once with 1.5L methyl tert-butyl ether, let stand for layering, collect the organic phase, use 750mL methyl t-butyl in water phase. The ether was extracted once, and the layers were separated, and the organic phase was combined and concentrated under reduced pressure to give Compound I. The oily compound I is added to 300 mL of methanol to dissolve, 0.1-g seed crystals are added, stirred for 8 to 10 hours, and the temperature is lowered to 0 to 5 C, and the mixture is further stirred for 2-4 hours, filtered, and the filter cake is added with 200 mL of methanol, and the temperature is raised to 55-60 C. The mixture was stirred for 1 hour, and the system was slowly cooled to -15 to -10 C. The mixture was further stirred for 2 hours, filtered, and dried to obtain 37 g of a white solid compound I in a yield of 35.0%.

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 57 - 65
[2]Patent: CN109970822,2019,A .Location in patent: Paragraph 0025; 0026; 0030-0064

22
[ 67-56-1 ]
(2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol [ No CAS ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
71.6%	With toluene-4-sulfonic acid; at 20℃; for 12h;Inert atmosphere;	[00115] Toa solution of(2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol1c (65.7 g, 92.13 mmol) in methanol (300mL) wasadded p-toluenesulfonic acid monohydrate (8.76 g, 46.06 mmol). The mixture wasstirred at roomtemperaturefor 12 hours, and neutralized with saturated aqueous sodium bicarbonate till pHbecomes 7, andthenconcentrated in vacuo. To the residue was added water (100 mL). The resultingmixture was extractedwith ethylacetate (200 mL X 3). The combined organic layers were washed with saturatedaqueous sodiumchloride(200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purifiedbyre-crystallization from toluene/n-hexane(v/v) = 1/1 to give the title compound1d as a white solid (29.0 g,71.6%). Thecompound was characterized by the following spectroscopic data: 1H NMR (400MHz, DMSO-d6) (ppm):7.52 (s, 1H), 7.39 (m, 2H), 7.08 (m, 2H), 6.83 (m, 2H), 4.96 (d, 1H), 4.73 (m,2H), 4.52 (t, 1H),4.09-3.94(m, 4H), 3.76-3.72 (m, 1H), 3.61-3.51 (m, 2H), 3.38 (m, 1H), 3.23 (m, 1H), 2.92(s, 3H), 2.89 (m,1H), 1.29(t, 3H).
141.5 g	With n-butyllithium; toluene-4-sulfonic acid; at 20℃; for 12h;	A solution of p-toluenesulfonic acid monohydrate (43.8 g, 230.3 mmol) was added to a solution of (2S, 3R, 4S, 5R, 6R) -2- (4-chloro-3 - [(4-ethoxyphenyl) methyl] phenyl] -3,4,5-tris (trimethylsiloxy) -6- (trimethylsiloxy Base armorYl) tetrahydropyran-2-ol lc (328.5 g, 460.65 mmol) in methanol (1.5 L) was stirred at room temperature for 12 hours. With saturationSodium bicarbonate solution to adjust the solution pH = 7, vacuum concentration to remove most of the solvent. The residue was added to 500 mL of water, washed with ethyl acetateExtraction (1 L x 3), combined with organic phase. The organic phase was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered,The residue was recrystallized [toluene / n-hexane (v / v) = 1/1] to give the title compound 1d (141.5.0 g, white solidBody), yield: 70.6%.

Reference： [1]Patent: WO2015/43473,2015,A1 .Location in patent: Paragraph 00115
[2]Patent: CN106674245,2017,A .Location in patent: Paragraph 0082; 0090; 0091; 0092; 0093

23
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-ethynyl-6,8-dioxabicyclo[3.2.1]octane [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

24
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-ethynyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

25
[ 714269-57-5 ]
(1S,2S,3S,4R,S₅)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

26
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

27
[ 714269-57-5 ]
[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1
[3]Patent: CN106674245,2017,A
[4]Patent: US2017/342100,2017,A1

28
[ 714269-57-5 ]
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1
[3]Patent: CN106674245,2017,A
[4]Patent: US2017/342100,2017,A1

29
[ 714269-57-5 ]
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1
[3]Patent: US2017/342100,2017,A1
[4]Patent: US2017/342100,2017,A1

30
[ 714269-57-5 ]
[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1
[3]Patent: US2017/342100,2017,A1
[4]Patent: US2017/342100,2017,A1

31
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1

32
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1

33
[ 714269-57-5 ]
methyl (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1

34
[ 714269-57-5 ]
methyl (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

35
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

36
[ 714269-57-5 ]
ethyl (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo [3.2.1]octane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

37
[ 714269-57-5 ]
ethyl (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

38
[ 714269-57-5 ]
isopropyl (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

39
[ 714269-57-5 ]
isopropyl (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

40
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

41
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

42
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-N-methyl-6,8-dioxabicyclo[3.2.1]octane-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

43
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-N-methyl-6,8-dioxabicyclo[3.2.1]octane-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

44
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-N,N-dimethyl-6,8-dioxabicyclo[3.2.1]octane-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

45
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-N,N-dimethyl-6,8-dioxabicyclo[3.2.1]octane-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

46
[ 714269-57-5 ]
2,2-dimethylpropanoyloxymethyl (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

47
[ 714269-57-5 ]
2,2-dimethylpropanoyloxymethyl (1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

48
[ 714269-57-5 ]
1-[(1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: WO2015/43511,2015,A1

49
[ 714269-57-5 ]
1-[(1R,2S,3S,4R,5S)-2,3,4-tris(benzyloxy)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanone [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

50
[ 714269-57-5 ]
1-[(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanone [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

51
[ 714269-57-5 ]
1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanone oxime [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

52
[ 714269-57-5 ]
1-[(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanone oxime [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

53
[ 714269-57-5 ]
(1E)-(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde oxime [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

54
[ 714269-57-5 ]
(1E)-(1S,2S,3S,4R,5S)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo [3.2.1]octane-1-carbaldehyde oxime [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

55
[ 714269-57-5 ]
N-methoxy-1-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanimine [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

56
[ 714269-57-5 ]
(E)-(1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde O-methyl oxime [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

57
[ 714269-57-5 ]
2-[(E)-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methyleneamino]oxyethanol [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

58
[ 714269-57-5 ]
(E)-(1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde O-(2-hydroxyethyl)oxime [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1

59
[ 714269-57-5 ]
[ 18162-48-6 ]
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole; In dichloromethane; at 0℃; for 2h;	[00116] Toa solution of<strong>[714269-57-5](2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol</strong>1d (82.2 g, 187.4 mmol) in dichloromethane (800 mL) was addedimidazole(25.5 g, 374.7 mmol) at room temperature. The mixture was stirred at 0 C andthentert-butyldimethylsilylchloride (56.7g, 374.7 mmol) was added. The resulting mixture was further stirred at0 C for 2hours. The mixture was adjusted to pH 7 with saturated aqueous sodiumbicarbonate at 0 C,. Theorganiclayer was washed with water (100 mL X 2) and saturated aqueous sodium chloride(100 mL X 2), driedoveranhydrous sodium sulfate and concentrated in vacuo to give the title compound1e as yellow oil (119 g,100%). Thecrude product was used without further purification. The compound wascharacterized by thefollowingspectroscopic data: 1H NMR (400 MHz, CDClg) 8 (ppm): 7.37 (m, 2H), 7.30 (m,1H), 6.08 (m, 2H),6.80 (m,2H), 4.02 - 3.88 (m, 7H), 3.67 (m, 2H), 3.22 (m, 1H), 3.08 (s, 3H), 1.40 (t,3H), 0.90(s, 9H), 0.12(s,3H),0.09(s, 3H).
	With 1H-imidazole; In dichloromethane; at 0 - 20℃; for 2h;	in room temperature,Imidazole(51 g, 749.4 mmol)Was added to a solution of (2S, 3R, 4S, 5S, 6R) -2- [4-chloro-3 - [(4-Oxo) methyl] phenyl] -6-hydroxymethyl) -2-methoxy-tetrahydropyran-3,4,5-triol 1d (164.5 g, 374.9 mmol)In methylene chloride (1.6 L), the resulting mixture was reduced to 0 C,Tert-Butyldimethylchlorosilane (113.5 g,749.5 mmol),Stirring was continued at 0 & lt; 0 & gt; C for 2 hours.At 0 & lt; 0 & gt;Add saturated sodium bicarbonate to adjust the reaction solution pH = 7, liquid separation,The organic phase was washed with water (200 mL x 2), saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressureTo give the title compound 1e (223 g, yellow oil) in a yield of 93.7%. The crude product is used directly in the next step.
	With triethylamine; In dichloromethane; at 10 - 30℃;	Methyl-1-C-[4-chloro-3-(4-ethoxybenzyl)phenyl]-alpha-D-glucopyrano side (75 g, Formula II, Example 4) was dissolved in dichloromethane (750 mL) to obtain a solution. Triethylamine (86.43 g) was added to the solution, and then the mixture was cooled to 10 C. to 15 C. tert-Butyldimethylsilyl chloride (30.9 g) was added to the mixture at 10 C. to 15 C., and then the mixture was stirred for 12 hours to 15 hours at 25 C. to 30 C. An aqueous ammonium chloride solution (20%, 750 mL) was added to the mixture, the mixture was stirred for 10 minutes to 15 minutes, and then the layers were separated. The organic layer was washed with deionized water (375 mL) and an aqueous sodium chloride solution (20%, 375 mL), successively. The organic layer was concentrated under reduced pressure at 40 C. to 45 C. and the residue was as such used for the next step. 1H NMR (400 MHz, CDCl3): delta ppm 0.09 (s, 3H), 0.11 (s, 3H), 0.91 (s, 12H), 1.39 (t, J=8 Hz, 3H), 3.06 (s, 3H), 3.20-3.22 (m, 1H), 3.63-3.66 (m, 2H), 3.87-3.96 (m, 7H), 6.80 (d, J=11.6 Hz, 2H), 7.07 (d, J=8.64, 2H), 7.30 (dd, J1=8.32 Hz, J2=2.1 Hz, 1H), 7.34 (s, 1H), 7.37 (t, J=2.04 Hz, 1H) Mass (m/z): 570.4 (M+NH4)+

Reference： [1]Patent: WO2015/43473,2015,A1 .Location in patent: Paragraph 00116
[2]Patent: CN106674245,2017,A .Location in patent: Paragraph 0082; 0094; 0095; 0096; 0097
[3]Patent: US2017/342100,2017,A1 .Location in patent: Paragraph 0132; 0133; 0134

60
[ 714269-57-5 ]
[ 18162-48-6 ]
tert-butyl-dimethyl-[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxyl]silane [ No CAS ]

Reference： [1]Patent: WO2015/43473,2015,A1
[2]Patent: US2017/342100,2017,A1

61
(3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one [ No CAS ]
[ 714269-57-5 ]

Reference： [1]Patent: WO2015/43511,2015,A1

62
(2S,3R,4S,5R,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-ol [ No CAS ]
[ 714269-57-5 ]

Reference： [1]Patent: WO2015/43511,2015,A1 .Location in patent: Paragraph 00135

63
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-7-methyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

64
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-1-(2-amino-1-hydroxyethyl)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

65
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(1-hydroxy-2-(methylamino)ethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

66
[ 714269-57-5 ]
1-((1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl)ethyl ethylcarbonate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

67
[ 714269-57-5 ]
1-((1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl)ethyl isopropylcarbonate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

68
[ 714269-57-5 ]
1-((1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl)ethyl pivalate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

69
[ 714269-57-5 ]
5-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]oxazolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

70
[ 714269-57-5 ]
[(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

71
[ 714269-57-5 ]
[(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[3-[bromo-(4-ethoxyphenyl)methyl]-4-chlorophenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

72
[ 714269-57-5 ]
[(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[4-chloro-3-(4-ethoxybenzoyl)phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

73
[ 714269-57-5 ]
[(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[4-chloro-3-[(4-ethoxyphenyl)hydroxymethyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

74
[ 714269-57-5 ]
[(1R,2S,3S,4R,5S)-2,4-diacetoxy-1-(1-acetoxyethyl)-5-[4-chloro-3-[(4-hydroxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-3-yl]acetate [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

75
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-5-[4-chloro-3-[(4-hydroxyphenyl)methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

76
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-5-[4-chloro-3-[[4-(1,1,2,2,2-pentadeuterioethoxy)phenyl]methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

77
[ 714269-57-5 ]
(1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(oxiran-2-yl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

78
[ 714269-57-5 ]
5-((1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]octan-1-yl)oxazolidin-2-one [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

79
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-5-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

80
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-5-(4-chloro-3-((4-ethoxyphenyl)(hydroxy)methyl)phenyl)-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

81
[ 714269-57-5 ]
(1R,2S,3S,4R,5S)-5-(3-(4-ethoxybenzyl)phenyl)-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1

82
[ 714269-57-5 ]
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol [ No CAS ]

Reference： [1]Patent: WO2015/43511,2015,A1 .Location in patent: Paragraph 00136

83
[ 461432-23-5 ]
[ 318967-97-4 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
77.3%	With n-butyllithium; In tetrahydrofuran; hexane; toluene; at -78 - -65℃; for 2h;Inert atmosphere;	Under nitrogen, to a 50mL three-necked flask were added sequentially 3.99g2- chloro-5-bromo-ethoxy -4`- - diphenylmethane, 10ml of tetrahydrofuran and 30ml of toluene, followed by stirring to dissolve, cooled to -78 deg.] C, was added dropwise 2.4M n-hexane solution of n-butyllithium in 5.48ml, dropping the temperature was kept below -70 deg.] C, after the addition was complete the reaction was complete to give 2-chloro-5-ethoxy-lithium -4`- - diphenyl methane solution. Under nitrogen atmosphere, into a three-necked 250mL flask was added 8.43g Compound B-2 and 40ml of toluene, followed by stirring to dissolve, cooled to -78 deg.] C, the lithium-chloro-5-ethoxy -4`- - diphenylmethane was added dropwise, the dropping rate to keep the temperature below -65 deg.] C, after the addition was complete the reaction was kept 2 hours, 17.63g of tetrabutyl ammonium fluoride was added dropwise, the reaction was stirred for 1 hour at room temperature, methanol was added dropwise a solution of 7.45g of sulfuric acid ( containing 2.56 g of sulfuric acid), after the completion of the dropwise addition, the reaction mixture was stirred at room temperature, the HPLC monitoring of the reaction is complete, add saturated NaHCO3 solution to a pH of about 7.5, the organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined organic phases were washed with saturated brine washed with water, vacuum distillation, additional 20ml toluene, evaporated under reduced pressure rotary evaporation to give 4.16g of intermediate -1, yield: 77.3percent.

Reference： [1]Patent: CN105481915,2016,A .Location in patent: Paragraph 0025; 0026

84
[ 461432-23-5 ]
C₁₈H₄₂O₆Si₄ [ No CAS ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
78.6%	With n-butyllithium; In tetrahydrofuran; hexane; toluene; at -78 - -65℃; for 2h;Inert atmosphere;	Under nitrogen, to a 50mL three-necked flask were added sequentially 3.99g2- chloro-5-bromo-ethoxy -4`- - diphenylmethane, 10ml of tetrahydrofuran and 20ml of toluene, followed by stirring to dissolve, cooled to -78 deg.] C, was added dropwise 2.4M n-hexane solution of n-butyllithium in 5.36ml, dropping the temperature was kept below -70 deg.] C, after the addition was complete the reaction was complete to give 2-chloro-5-ethoxy-lithium -4`- - diphenyl methane solution. Under nitrogen atmosphere, into a three-necked 250mL flask was added 6.25g Compound B-1 and 30ml of toluene, followed by stirring to dissolve, cooled to -78 deg.] C, the lithium-chloro-5-ethoxy -4`- - diphenylmethane was added dropwise, the dropping rate to keep the temperature below -65 deg.] C, after the addition was complete the reaction was kept 2 hours, methanol was added dropwise a solution of 5.82g of hydrochloric acid (containing 1.82 g of hydrochloric acid), after the completion of the dropwise addition, the reaction mixture was stirred at room temperature, the HPLC monitor completion of the reaction, added saturated NaHCO3 solution until a pH of about 7.5, the organic layer was separated and the aqueous layer extracted with ethyl acetate, the combined organic phase was washed with saturated brine, evaporated under reduced pressure, additional 20ml toluene was distilled off under reduced pressure by rotary evaporation dryness to give 4.23g of intermediate -1, yield: 78.6percent.

Reference： [1]Patent: CN105481915,2016,A .Location in patent: Paragraph 0022; 0023

85
[ 461432-23-5 ]
[ 75-75-2 ]
[ 32469-28-6 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
78%		Take 5-bromo-2-chloro-4'-ethoxydiphenylmethane 32kg,Anhydrous THF/toluene 100kg (1:4) is added to the nitrogen-dried 500 litre reactor.The liquid nitrogen was cooled to -78°C and hexane solution of 1. 6 mol·L-1 n-butyllithium was slowly added dropwise.Keep stirring at this temperature for 1h;Then it will cool to -78°CA 100kg toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-lactone (26kg) was slowly added dropwise to the above reaction solution, and the reaction was carried out at -78°C for 3 hours after the reaction was completed. Add 50kg of methane sulfonic acid in methanol solution (23g of methanesulfonic acid + 27kg of methanol) at this temperature; stir the reaction again at 0°C for 4h, then raise the temperature to 40°C and stir the reaction for 7h; 5mol?L-1 NaOH aqueous solution Into the reaction solution, adjusted to pH 7-8; stirred for 30min, extracted with ethyl acetate (50kg × 2), the organic phase was washed with saturated aqueous sodium chloride to neutral, then dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated to dryness to give 34.6 kg of light yellow viscous oil in a yield of 78percent.

Reference： [1]Patent: CN107573311,2018,A .Location in patent: Paragraph 0015; 0021

86
[ 1103738-29-9 ]
[ 32469-28-6 ]
[ 714269-57-5 ]
C₂₁H₂₇ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		500 ml of clean anhydrous reactor was charged with 30 g of 4-iodo-1-chloro-2- (4-ethoxybenzyl) benzene (compound 3) and 120 ml of anhydrous tetrahydrofuran. Argon is protected and cooled to T <0 C. While maintaining T <0 C, dropping 1.3.5 isopropyl magnesium chloride lithium chloride 92.5mL, after the drop to maintain -5 ~ 0 C reaction 1h. T ? 5 C50 g was added dropwise2,3,4,5-trimethylsiloxy gluconolactone (compound 4),And maintained at a temperature of 5 ± 1 C for 3 h.To the reaction solution was added 150 ml of a 20% methanolic hydrochloric acid solution,Stirred at room temperature for 10 h. To obtain a reaction solution containing the compound 1.

Reference： [1]Patent: CN106748674,2017,A .Location in patent: Paragraph 0026-0041

87
[ 189628-37-3 ]
[ 714269-57-5 ]

Reference： [1]Patent: CN107540648,2018,A

88
[ 1103738-29-9 ]
[ 32469-28-6 ]
[ 714269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
81.8%		Add 100mL of tetrahydrofuran to a 1L reaction flask and add 50g1-chloro-2- (4-ethoxybenzyl) -4-iodobenzene and81.4g2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone,Turn on stirring and cool down to -30 -20 under the protection of nitrogen.134 mL of a 1.3 mol / L tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride was added dropwise,Control the temperature from -30 C to -20 C. After holding the reaction for 1 hour, increase the temperature to -10 C.200 mL of 15 mL of a methanol solution of methanesulfonic acid was added dropwise.The reaction was performed at 20 C to 30 C for 2 hours. The reaction was quenched by the dropwise addition of saturated NaHCO3,Adjust the pH to neutral, concentrate the organic solvent under reduced pressure, add 100 mL of n-heptane for extraction,The aqueous layer was separated, and the aqueous layer was extracted twice with ethyl acetate, each time with 100 mL of ethyl acetate.The organic phases were combined and washed once with saturated brine.Concentrated under reduced pressure to give the product as a pale yellow oil with a purity of 82.8%.Add 50 mL of ethyl acetate to the concentrate, turn on the stirring, and lower the temperature to -55 C to -65 C.After precipitation of a large amount of white solid, stirred for 0.5 h, and 250 mL of n-heptane was added dropwise to the reaction.Stir for 0.5h, filter with suction, and place the filter cake in a hot air circulation drying box for 15h.48.2 g of the title compound was obtained, with a molar yield of 81.8% and a purity of 89.6%.

Reference： [1]Patent: CN110407891,2019,A .Location in patent: Paragraph 0049-0054

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	714269-57-5	MDL No. :	MFCD27923102
Formula :	C₂₂H₂₇ClO₇	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GKTWLVVOULBRDU-BDHVOXNPSA-N
M.W :	438.90	Pubchem ID :	24807437
Synonyms :

Num. heavy atoms :	30
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.45
Num. rotatable bonds :	7
Num. H-bond acceptors :	7.0
Num. H-bond donors :	4.0
Molar Refractivity :	110.6
TPSA :	108.61 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.47 cm/s

Log Po/w (iLOGP) :	3.49
Log Po/w (XLOGP3) :	2.12
Log Po/w (WLOGP) :	1.49
Log Po/w (MLOGP) :	1.16
Log Po/w (SILICOS-IT) :	2.82
Consensus Log Po/w :	2.22

[ CAS No. 714269-57-5 ] {[proInfo.proName]}

Quality Control of [ 714269-57-5 ]

Related Doc. of [ 714269-57-5 ]

Product Details of [ 714269-57-5 ]

Calculated chemistry of [ 714269-57-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 714269-57-5 ]

Application In Synthesis of [ 714269-57-5 ]

[ 714269-57-5 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-3.73
Solubility :	0.0816 mg/ml ; 0.000186 mol/l
Class :	Soluble
Log S (Ali) :	-4.03
Solubility :	0.0408 mg/ml ; 0.0000929 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.78
Solubility :	0.00725 mg/ml ; 0.0000165 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.87

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed