32469-28-6| (3S,4S,5R,6R)-3,4,5-Tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one| Ambeed

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Yield	Reaction Conditions	Operation in experiment
86.4%	Stage #1: With n-butyllithium; butyl magnesium bromide In tetrahydrofuran; hexane; toluene at -16 - -12℃; for 1 h; Stage #2: at -15 - -12℃; for 3 h; Stage #3: With methanesulfonic acid In tetrahydrofuran; hexane; toluene at 20℃; for 16 h;	A solution of 0.9M n-butyl magnesium chloride in tetrahydrofuran (0.9M, 7.3mL) was added to toluene (18.0mL) at -16 ° C and a solution of n-butyl lithium in n-hexane was added dropwise at -12~-16 ° C (2.66 M, 4.9 mL) and stirred at -12 to -15 ° C for 16 minutes.2- (5-bromo-2-fluorobenzyl) -1-benzothiophene (Compound I, 2.000 g) at -12 to -15 ° C,Of a toluene solution (10.0 mL)The reaction solution was dropped,At -12 to -16 ° CStir for one hour.A solution of 2,3,4,6-di-O- (trimethylsilyl) -D-glucono-1,5-lactone (Compound II, 3.197g) in toluene (10.0 ML) was added dropwise to the reaction solution, and the mixture was stirred at -12 to -15 ° C for 3 hours.The reaction mixture was poured into a methanol solution (10.0 mL) of methanesulfonic acid (3.0 mL) at 0 ° C or less, and the mixture was stirred at room temperature for 16 hours and 36 minutes. The reaction mixture was quenched by the addition of an aqueous sodium carbonate solution at a pH of about 8.The organic layer was washed with saturated brine (10 mL, once) and dried over anhydrous sodium sulfate, and extracted with ethyl acetate (50 mL, twice). After filtration, the filtrate was distilled off under reduced pressure, and the title compound (2.336 g, yield 86.4percent) was isolated from the obtained residue by silica gel column chromatography.

1
[ 67-56-1 ]
[ 5433-01-2 ]
[ 32469-28-6 ]
C₁₆H₂₄O₆ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 9746 - 9749

2
[ 32469-28-6 ]
[ 714269-57-5 ]

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

3
[ 461432-23-5 ]
[ 32469-28-6 ]
[ 461432-24-6 ]

Yield	Reaction Conditions	Operation in experiment
> 99%		A 2.0M isopropyl magnesium chloride solution in tetrahydrofuran and 100 mL of toluene were added to a 1000 mL reaction flask, cooled to -30 ° C., and 123 mL of a n-hexane solution of n-butyllithium was added dropwise thereto. After the reaction for 0.5 hour, 4-bromo- Chloro-2-2- (4-ethoxybenzyl) -benzene (Formula I)(50 g, 153.5 mmol)Diluted with 100mL toluene slowly added dropwise to the system, maintaining the system temperature -30 ,The reaction was continued for 1 hour after the addition was completed.Then 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone was added to 100 mLToluene diluted, slowly added dropwise to the system, the dropwise addition is completed, stirring was continued for 1 hour.Dropping and dissolving 45mL concentrated hydrochloric acid in methanol solution 150mL, after the addition was completed,The reaction was carried out at 25 ° C for 5 hours at room temperature. The reaction is completed,The reaction was quenched by dropwise addition of saturated sodium bicarbonate solution until the pH reached 7-8, liquid separation,Evaporation of the organic layer under reduced pressure gave Formula II. The compound was a light yellow oil weighing 70g and yield greater than 99percent and was used directly in the next step reaction.

Reference： [1]Patent: CN107304194,2017,A .Location in patent: Paragraph 0036; 0037
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 1145 - 1149

4
[ 1030825-20-7 ]
[ 32469-28-6 ]
[ 1030825-21-8 ]

Yield	Reaction Conditions	Operation in experiment
93.7%		This embodiment is a method for preparing a cardinol intermediate, and the preparation method comprises the following steps:1) Under the protection of nitrogen,100 g (0.245 mol) of <strong>[1030825-20-7]2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene</strong> was sufficiently dissolved in 300 mL of tetrahydrofuran.At a temperature of -25 ° C to -20 ° C,100 g (0.245 mol) of sec-butylmagnesium chloride. Lithium chloride was added dropwise.After the addition was completed, the reaction was continued for 1 hour;Maintain temperature,Further, 171.6 g (0.368 mol) of 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone was added dropwise.After the addition is completed,Continue to react for 2 hours;Wherein 2,3,4,6-tetra-O-(trimethylsilyl)-D-gluconolactone is previously dissolved in 200 mL of tetrahydrofuran;2) in the reaction liquid after the reaction in the step 1),51.8 g (0.539 mol) of methanesulfonic acid in methanol was added dropwise.Stir,After natural temperature reaction for 18 hours, at a temperature of -5 ° C to 5 ° C,The reaction was quenched with saturated aqueous sodium bicarbonate;3) adjusting the pH of the reaction solution after the reaction in step 2) with a saturated aqueous solution of sodium hydrogencarbonate to 7-8, and after removing the solvent under reduced pressure,Extracted with methyl n-butyl ether twice,Combine the organic phase,Dissolve the solvent under reduced pressure,Obtaining a yellow viscous solid crude;Add the crude product to 300 mL of methyl n-butyl ether.After fully dissolving, add 600 mL of n-heptane, stir, and precipitate a solid.The solvent was removed and dried under vacuum to obtain the intermediate of cagliflozin; 108.9 g of pale yellow solid was obtained, purity 87.9percent.The yield was 93.7percent.
		(1) To a solution of <strong>[1030825-20-7]5-bromo-1-[5-(4-fluorophenyl)-2-thienylmethyl]-2-methylbenzene</strong> (1, 28.9 g) in tetrahydrofuran (480 ml) and toluene (480 ml) was added n-butyllithium (1.6M hexane solution, 50.0 ml) dropwise at -67 to -70 C. under argon atmosphere, and the mixture was stirred for 20 minutes at the same temperature. Thereto was added a solution of 2 (34.0 g) in toluene (240 ml) dropwise at the same temperature, and the mixture was further stirred for 1 hour at the same temperature. Subsequently, thereto was added a solution of methanesulfonic acid (21.0 g) in methanol (480 ml) dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 17 hours. The mixture was cooled under ice-water cooling, and thereto was added a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The insoluble was filtered off and the solvent was evaporated under reduced pressure. The residue was triturated with toluene (100 ml)-hexane (400 ml) to give 1-(1-methoxyglucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]-benzene (3) (31.6 g). APCI-Mass m/Z 492 (M+NH4).

Reference： [1]Patent: CN109553649,2019,A .Location in patent: Paragraph 0062-0079
[2]Patent: US2008/146515,2008,A1 .Location in patent: Page/Page column 3-4

5
[ 461432-23-5 ]
[ 32469-28-6 ]
[ 960494-15-9 ]

Yield	Reaction Conditions	Operation in experiment
		(3RLambdaS,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-(hvdroxymethyl)- 2-methoxy-tetrahydro-2H-pyran-3A5-triol: At about -78 0C, n-butyl lithium (1.1 niL, 1.10 equiv, 2.5M) was added dropwise to a stirred solution of 2-(4-ethoxybenzyl)-4- bromo-1-chlorobenzene (50 mg, 0.15 mmol, 1.00 equiv) and tetrahydrofuran (50 rnL). After stirring at about -78 0C for about 1 hour, a solution of (3R,4S,5S,6R)-3,4,5- tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)-tetrahydropyran-2-one (87 mg, 0.19 mmol, 1.00 equiv) and toluene (10 mL) was added dropwise. The resulting solution was stirred at about -78 0C for about 3 hours and then a solution of methanesulfonic acid (50 mg, 0.52 mmol, 3.00 equiv) and methanol (10 mL) was added dropwise. The mixture was stirred for about 16 hours, and then a saturated sodium bicarbonate solution (20 mL) was added. Standard extractive workup with ethyl acetate, gave a crude product which was then purified by silica gel column chromotagraphy (eluted with dichloromethane / methanol (30 : I)) to obtain the title product as a white solid (30 mg; yield = 45percent). LC-MS : m/z = 439 (MH)+.
	With n-butyllithium; In tetrahydrofuran; hexane; at -88 - -75℃;Inert atmosphere;	To a mixture of 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucono-1,5-lactone (25g) and 5- bromo-2-chloro-4?-ethoxydiphenylmethane (8.7g) in tetrahydrofuran (174mL), cooled to about -75°C to about -88 °C under nitrogen atmosphere, n-butyl lithium in hexane (50mL) was slowly added. The reaction mixture was stirred at about the same temperature and then mixture of methanol and methanesulphonic acid was added to it.The reaction mixture was quenched into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated sodium chloride solution and concentrated under vacuum to obtain a residue. The residue was purified with a mixture of toluene and cyclohexane. Yield: 1 lg as thick mass with 80-85percent HPLC purity.
		To a stirred?78 °C solution of 5a (5.0 g, 15.4 mmol) in 60 mL of 1:2 anhydrous THF/toluene under N2 was added n-BuLi (10.6 mL, 1.6 M) in hexane dropwise to insure the temperature remained below ?70 °C. After stirring for 30 min following the addition, this solution was transferred by cannula to a stirred ?78 °C solution of 2,3,4,6-tetra-O-Trimethylsilyl-beta-D-glucolactone (7.9 g, 16.9 mmol) in 20 mL of toluene at a rate that maintained the reaction below ?70 °C. The solution was stirred for 30 min at ?78 °C prior to quenching by addition of 10 mL of MeOH containing methanesulfonic acid (3.0 mL, 46.2 mmol). The reaction stirred overnight as the temperature rose to 20 °C. The reaction, once complete, was quenched by the addition of aqueous NaHCO3 until the pH was weakly basic. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration using a rotary evaporator, the residue was dissolved in hot toluene (50 mL). The resulting solution was poured into 250 mL of stirred hexane. The precipitate was collected by vacuum filtration, the resulting filter cake was washed with hexane and then air dried to give a crude product, which was used for the next reaction without further purification.

Reference： [1]Patent: WO2010/48358,2010,A2 .Location in patent: Page/Page column 32
[2]Patent: WO2016/178148,2016,A1 .Location in patent: Paragraph 0192
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3947 - 3952

6
[ 67-56-1 ]
[ 1034305-17-3 ]
[ 32469-28-6 ]
[ 1034305-23-1 ]

Yield	Reaction Conditions	Operation in experiment
86.4%		A solution of 0.9M n-butyl magnesium chloride in tetrahydrofuran (0.9M, 7.3mL) was added to toluene (18.0mL) at -16 C and a solution of n-butyl lithium in n-hexane was added dropwise at -12~-16 C (2.66 M, 4.9 mL) and stirred at -12 to -15 C for 16 minutes.2- (5-bromo-2-fluorobenzyl) -1-benzothiophene (Compound I, 2.000 g) at -12 to -15 C,Of a toluene solution (10.0 mL)The reaction solution was dropped,At -12 to -16 CStir for one hour.A solution of 2,3,4,6-di-O- (trimethylsilyl) -D-glucono-1,5-lactone (Compound II, 3.197g) in toluene (10.0 ML) was added dropwise to the reaction solution, and the mixture was stirred at -12 to -15 C for 3 hours.The reaction mixture was poured into a methanol solution (10.0 mL) of methanesulfonic acid (3.0 mL) at 0 C or less, and the mixture was stirred at room temperature for 16 hours and 36 minutes. The reaction mixture was quenched by the addition of an aqueous sodium carbonate solution at a pH of about 8.The organic layer was washed with saturated brine (10 mL, once) and dried over anhydrous sodium sulfate, and extracted with ethyl acetate (50 mL, twice). After filtration, the filtrate was distilled off under reduced pressure, and the title compound (2.336 g, yield 86.4%) was isolated from the obtained residue by silica gel column chromatography.
		Forth step: Synthesis of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]glucitol; To a toluene (32.5 ml)-diisopropyl ether (25 ml) solution of <strong>[1034305-17-3]2-(5-bromo-2-fluorobenzyl)-1-benzothiophene</strong> (5.0 g) was dropwise added a n-hexane solution (10 ml) of n-butyl lithium (1.6 M) at -43.5 to -33.3C, followed by stirring for 10 minutes. To the reaction mixture was added, at -72.6 to -65.0C, a toluene (17.5 ml) solution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucono-1,5-lactone (8.0 g), followed by stirring for 6 hours. The reaction mixture was added to a methanol (25 ml) solution of an ethyl acetate solution (7.8 ml) of hydrogen chloride (4 M) at a temperature of 0C or lower, followed by stirring at 0C for 17 hours. The reaction mixture was added to a water (35 ml) solution of potassium carbonate (1.29 g). Thereto was added ethyl acetate, followed by extraction. The aqueous layer was extracted with toluene (20 ml)-ethyl acetate (10 ml). The organic layers obtained by extraction were combined and subjected to vacuum distillation to distil off the solvent until the reside became 40 ml. Toluene (25 ml) was added to the residue and the mixture was subjected to vacuum distillation to distil off the solvent until the residue became 40 ml. This operation of adding toluene to the residue and subjecting the mixture to vacuum distillation to distil off the solvent, was repeated twice to obtain methyl 1-C-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-alpha-glucopyranoside as a toluene solution. 1H-NMR (CD3OD): delta 3.08 (3H, s), 3.10 (1H, m), 3.42 (1H, dd), 3.58 (1H, m), 3.75 (1H, dd), 3.82 (1H, m), 3.92 (1H, dd), 4.23 (1H, d), 4.32 (1H, d), 7.05 (1H, s), 7.09 (1H, dd), 7.22 (1H, m), 7.27 (1H, m), 7.54 (1H, m), 7.64-7.65 (2H, m), 7.72 (1H, d)

Reference： [1]Patent: TW2016/2128,2016,A .Location in patent: Paragraph 0024; 0025
[2]Patent: EP2105442,2009,A1 .Location in patent: Page/Page column 14

7
[ 67-56-1 ]
[ 461432-23-5 ]
[ 32469-28-6 ]
[ 461432-24-6 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 6 5.0g (15.4mmol) was dissolved in 20mL tetrahydrofuran and 40mL of dry toluene was dried in nitrogen atmosphere, cooled to -78 °C, n-butyllithium was slowly dropwise added 10.6mL (16.94mmol, 1.6M), was added after -78 °C the reaction 0.5 h, then 5mL of dry toluene was slowly added dropwise trimethylchlorosilane dissolved glucose protected lactone, addition was complete the reaction at -78 °C 1h, then 10mL of methanesulfonic acid was added 3.0mL (46.2mmol dissolved in methanol ), after the addition the reaction warmed to room temperature for 16 h, after completion of the reaction, the reaction solution was added dropwise with saturated sodium bicarbonate, ethyl acetate (50mL × 3). the combined organic phases with saturated sodium bicarbonate × 2, saturated sodium chloride × 2, dried over anhydrous Na2SO4 dry. Suction filtration to give a yellow oil, toluene / petroleum ether (1:5) was recrystallized to give a pale yellow solid was separated by column chromatography (dichloromethane: methanol = 20) to give 7 as a white solid.
		Hexyl lithium (1.71 L, 6.14 mol) was slowly added to a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (1 kg, 3.07 mol) in THF (4 L) and toluene (4L) at -100°C to -80°C. After stirring for 60 to 90 minutes at same temperature, solution of 2,3,4,6-tetra-O-trimethylsilyl-3-D-glucolactone (1.93 kg, 4.14 mol) in toluene was slowly added by maintaining the reaction at -105°C to -80°C and mixture was stirred for 2-3 hours at same temperature. Subsequently, a solution of methane sulphonic acid (0.885Kg) in methanol (3 L) was added to the reaction mixture at -100°C to -50°C and stirred for 1 hour at same temperature. The reaction mixture was further stirred for 2 hours at room temperature. Water was added to the resultant mixture followed by addition of aqueous Na2CO3. After phase separation, the organic layer was washed with brine solution, and after concentration to yield oily mass. The obtained oily mass added in todichloromethane (4.5 L) and acetonitrile; and resultant mass was stirred under nitrogen atmosphere at room temperature. The reaction mixture was cooled at -35°C to -25°C. To this stirred solution was added triethylsilane (1.07 kg, 9.21 mol) followed by addition of BF3Et2O (1 L). Approximately 30 minutes after addition was complete; the resulting mixture was stirred at room temperature. After completion of reaction, the mixture was cooled at 0-10°C and further quenched by the addition of aqueous NaHCO3 solution. After phase separation, L-proline (1.41 kg) in isopropanol (5 L) was added into theorganic layer containing product. The reaction mixture was heated at 35-40°C for 1-2hours. The reaction mixture was cooled at room temperature and further stirred for 1hour. The resultant precipitate was filtered and dried to obtain title compound (yield: 2.0Kg).
		To a stirred solution of 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene (intermediate B) (8 g, 24 mmol) in 30 mL of dry THF:toluene (1 :2) under Ar was added n-BuLi (2.5 M, 0.7 mL) dropwise at -780C. After stirring for an additional 30 min, the solution was transferred to <n="40"/>a stirred solution of 2,3,4,6-tetra-O-trimethylsilyl-beta-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H- pyran-2-one) (0.28 g, 0.60 mmol) in 30 mL of toluene. The solution was stirred for 1 h at -780C prior to quenching by addition of 50 mL of methanol containing MeSO3H (1.5 mL, 24 mmol). The mixture was stirred overnight, then quenched by the addition of aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. After concentration, the residue was dissolved in hot (5O0C) toluene (20 mL). The resulting solution was poured into 100 mL of stirred hexane. The precipitate was collected by filtration and concentrated to give the crude intermediate, which was used without further purification. The crude intermediate (6 g, 13.6 mmol) was dissolved in 40 mL of DCM:MeCN (1 :1) and Et3SiH (4.4 mL, 27.3 mmol) was added, followed by addition of BF3-Et2O (2.0 mL, 20.5 mmol) at a rate to insure the temperature remained under O0C. The stirred solution was allowed to warm to O0C over 5 h. When TLC showed it was complete, the reaction was quenched by addition of saturated aqueous NaHCO3. The mixture was removed and the residue was extracted with EtOAc. The organic layer was washed with water and brine and dried over Na2SO4. The product was concentrated to give intermediate C, which was used without further purification.

Preparation of (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (4)To 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene (10 g, 0.031 mol) in anhydrous toluene/TEtaF (78 mL, v/v = 2:1) was added dropwise n-BuLi (2.5 M in hexane, 13.5 mL) at -65 °C and stirred for 30 minutes at -65 °C. The mixture was transferred to a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6- ((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (15.7 g, 0.034 mol) in toluene (78 mL) at -65 0C. The mixture was stirred at -65 0C for 2 hours until starting material was consumed. The reaction was quenched with methanesulfonic acid (4.18 mL, 0.065 mol) in methanol (70 mL), and the mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated bicarbonate, then with water, then with brine, and were dried over sodium sulfate. After removal of the volatiles, the residue was slurried in toluene/hexane (120 mL, 1 :5), filtered, and dried under vacuum to give compound 4 as a white solid (12.5 g). The crude product was used in the next step without further purification.

Reference： [1]Patent: CN103739581,2016,B .Location in patent: Paragraph 0236
[2]Patent: WO2017/118945,2017,A1 .Location in patent: Page/Page column 34; 35
[3]Patent: WO2009/26537,2009,A1 .Location in patent: Page/Page column 37-38
[4]Patent: WO2010/9243,2010,A1 .Location in patent: Page/Page column 91; 92

8
[ 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

9
[ 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

10
[ 75-77-4 ]
[ 1240304-54-4 ]
[ 24078-12-4 ]
[ 32469-28-6 ]
[ 1359948-56-3 ]

Yield	Reaction Conditions	Operation in experiment
		(11) Reference Example 1-11: Intermediate (A)[0088] To a solution of compound (A9) (210 g, 0.621 mol) in THF (3.1 L), 2.76 M n- butyllithium in hexane (236 mL, 0.652 mol) was added dropwise over 20 minutes at -86C to -74C under an argon atmosphere, and stirred at the same temperature for 35 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-l,5-lactone (305 g, 0.652 mol) in THF (890 mL) was added dropwise over 38 minutes and stirred at the same temperature for 50 minutes. Further, trimethylchlorosilane (82.8 mL, 0.652 mmol) was added dropwise over 4 minutes and stirred at the same temperature for 3 hours. Then, 2.76 M n-butyllithium in hexane (326 mL, 0.901 mol) was added dropwise over 23 minutes and stirred at the same temperature for 40 minutes. Finally, a solution of 4-bromo-2- methylbenzaldehyde (136 g, 0.683 mmol) in THF (890 mL) was added dropwise over 43 minutes and stirred at the same temperature for 35 minutes. The reaction mixture was diluted with water (3.1 L) and warmed to room temperature. After addition of toluene (3.1 L), the organic layer was separated and the solvent was distilled off under reduced pressure.[0089] The resulting residue (633 g) was dissolved in methanol (3.1 L), and methanesulfonic acid (4.03 mL, 0.0621 mol) was added thereto, followed by heating under reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with triethylamine (17.3 mL, 0.124 mol) and then concentrated. The concentrated product (413 g) was dissolved in toluene (1.1 L) and washed three times with water (1.65 L). The organic layer was diluted with toluene (0.55 L) and extracted with 1 M aqueous sodium hydroxide (0.55 L). The aqueous layer was washed with toluene (1.65 L) and acidified by addition of 2 M aqueous hydrochloric acid (0.43 L). The resulting aqueous layer was extracted with toluene (1.1 L). The organic layer was washed with 10% aqueous sodium chloride (1.1 L), followed by distilling off the solvent under reduced pressure. [0090] The resulting residue (273 g) was dissolved in THF (1.01 L). To this solution, diisopropylethylamine (776 mL, 4.53 mol), acetic anhydride (381 mL, 4.03 mol) and 4-dimethylaminopyridine (615 mg, 5.04 mmol) were added and stirred at room temperature for 21 hours. The reaction mixture was cooled on ice, and water (1.0 L) and toluene (1.0 L) were added thereto. The organic layer was separated and washed with saturated aqueous sodium bicarbonate (1.0 L), followed by distilling off the solvent under reduced pressure. [0091] The resulting residue (390 g) was dissolved in acetonitrile (3.85 L). To this solution, water (9.07 mL, 0.504 mol) and t-BuMe2SiH (334 mL, 2.02 mol) were added and cooled on ice, followed by dropwise addition of TMSOTf (392 mL, 2.17 mol) over 30 minutes. After stirring at the same temperature for 1 hour, acetic anhydride (95.2 mL, 1.01 mol) was added dropwise over 10 minutes and stirred at the same temperature for an additional 15 minutes. To the reaction mixture, toluene (3.85 mL) and 3% aqueous sodium bicarbonate (1.92 L) were added. The organic layer was separated and washed with 3% aqueous sodium bicarbonate (1.92 L) and 10% aqueous sodium chloride (1.92 L), and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was crystallized from 2-propanol (1.42 L). The resulting precipitate was filtered to give intermediate (A) (201 g, 47%; 4 steps) as a colorless powder.

Reference： [1]Patent: WO2010/95768,2010,A1 .Location in patent: Page/Page column 28-29

11
[ 1240304-64-6 ]
[ 32469-28-6 ]
C₂₈H₅₆O₇Si₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of compound (A1) (24.5 g, 88.6 mmol) in THF (100 mL), a solution of 2.6M n-butyllithium in hexane (34 mL, 88.6 mmol) was added dropwise at -78 C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 5 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (37.6 g, 80.5 mmol) in THF (60 mL) was added dropwise over 25 minutes, and the mixture was stirred at the same temperature for 10 minutes. Ice and water were added to the reaction mixture, and the resulting mixture was warmed to room temperature and then extracted with ethyl acetate. The organic layer combined was washed with brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. [0110] The resulting residue was dissolved in a solution containing methanesulfonic acid (1.55 g, 16.1 mmol) in methanol (380 mL), and the solution was stirred at room temperature for 2 hours. Then, the solution was neutralized with triethylamine (11.2 mL, 80.5 mmol), and the reaction mixture was concentrated. [0111] The resulting residue (30.2 g) was dissolved in pyridine (100 mL), and acetic anhydride (100 mL) was added, followed by stirring the mixture for 14 hours at room temperature. Iced water (400 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The organic layer combined was washed with 1M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane?hexane:ethyl acetate=6:4) to give light yellow oily compound (A2) (32.8 g, 80%; 3 steps). [0112] 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.23 (d, J=6.92 Hz, 6H) 1.84 (s, 3H) 1.97 (s, 3H) 2.06 (s, 3H) 2.10 (s, 3H) 2.87 (sept, J=6.92 Hz, 1H) 3.32 (s, 3H) 3.87 (s, 3H) 4.04 (ddd, J=10.18, 4.74, 2.41 Hz, 1H) 4.17-4.23 (m, 1H) 4.28-4.36 (m, 1H) 5.25 (dd, J=10.18, 9.40 Hz, 1H) 5.36 (d, J=10.18 Hz, 1H) 5.60 (dd, J=10.18, 9.40 Hz, 1H) 6.74 (d, J=1.55 Hz, 1H) 6.79 (dd, J=8.08, 1.55 Hz, 1H) 7.26-7.33 (m, 1H). [0113] MS ESI/APCI Dual posi: 533[M+Na]+.
		(2) Reference Example 2-2: Compound (B2) (B2)[0094] To a solution of compound (Bl) (24.5 g, 88.6 mmol) in THF (100 mL), 2.6 M n-butyllithium in hexane (34 mL, 88.6 mmol) was added dropwise at -78C under a nitrogen atmosphere and stirred at the same temperature for 5 minutes. Then, a solution of 2,3,4,6- tetra-O-trimethylsilyl-D-glucono-l,5-lactone (37.6 g, 80.5 mmol) in THF (60 mL) was added dropwise over 25 minutes and stirred at the same temperature for 10 minutes. To the reaction mixture, ice and water were added, and the mixture was warmed to room temperature and then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure.[0095] The resulting residue was dissolved in a solution containing methanesulfonic acid (1.55 g, 16.1 mmol) in methanol (380 mL) and stirred at room temperature for 2 hours. After neutralization with triethylamine (11.2 mL, 80.5 mmol), the reaction mixture was concentrated.[0096] The resulting residue (30.2 g) was dissolved in pyridine (100 mL). To this solution, acetic anhydride (100 mL) was added and stirred at room temperature for 14 hours. After addition of ice-cold water (400 mL), the mixture was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane ? hexane:ethyl acetate = 6:4) to give compound (B2) (32.8 g, 80%; 3 steps) as a light-yellow oil. [0097] 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.23 (d, J=6.92 Hz, 6 H) 1.84 (s, 3 H) 1.97 (s, 3 H) 2.06 (s, 3 H) 2.10 (s, 3 H) 2.87 (sept, J=6.92 Hz, 1 H) 3.32 (s, 3 H) 3.87 (s, 3 H) 4.04 (ddd, J=10.18, 4.74, 2.41 Hz, 1 H) 4.17-4.23 (m, 1 H) 4.28-4.36 (m, 1 H) 5.25 (dd, J=10.18, 9.40 Hz, 1 H) 5.36 (d, J=10.18 Hz, 1 H) 5.60 (dd, J=10.18, 9.40 Hz, 1 H) 6.74 (d, J=1.55 Hz, 1 H) 6.79 (dd, J=8.08, 1.55 Hz, 1 H) 7.26-7.33 (m, 1 H).MS ESI/APCI Dual posi: 533[M+Na]+.

Reference： [1]Patent: US2013/165645,2013,A1 .Location in patent: Paragraph 0109
[2]Patent: WO2010/95768,2010,A1 .Location in patent: Page/Page column 30-31

12
[ 1030825-20-7 ]
[ 32469-28-6 ]
C₃₆H₅₇FO₆SSi₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 6355 - 6360

13
[ 915095-89-5 ]
[ 32469-28-6 ]
C₃₅H₅₉ClO₇Si₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 5.5 mL 2.0 M BuMgCl in THF in 30 mL of tetrahydrofuran is added 12 mL of 2.5 M BuLi in hexane at -15 to -5 C. and stirred at -10 C. for 20 minutes. 10.00 g of (S)-3-4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 10 mL of THF is added at -23 to -20 C. and stirred at -22 C. for 20 min. 20.32 g of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 7 mL of THF is added at -20 to -18 C. The reaction is then stirred at -20 C. for 1 hour and warmed to -12 C. in another hour. 60 mL of 25 weight-% aqueous NH4Cl solution is added to quench the reaction. 40 mL of MTBE is added and the organic layer is separated. The aqueous layer is extracted with 30 mL of EtOAc. The combined organic phases are dried over MgSO4 and concentrated.
		To a solution of 5.5 mL 2.0 M BuMgCl in THF in 30 mL of tetrahydrofuran is added 12 mL of 2.5 M BuLi in hexane at -15 to -5 C. and stirred at -10 C. for 20 minutes. 10.00 g of (S)-3-4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 10 mL of THF is added at -23 to -20 C. and stirred at -22 C. for 20 min. 20.32 g of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 7 mL of THF is added at -20 to -18 C. The reaction is then stirred at -20 C. for 1 hour and warmed to -12 C. in another hour. 60 mL of 25 weight-% aqueous NH4Cl solution is added to quench the reaction. 40 mL of MTBE is added and the organic layer is separated. The aqueous layer is extracted with 30 mL of EtOAc. The combined organic phases are dried over MgSO4 and concentrated.
		To a solution of 5.5 mL 2.0 M BuMgCl in THF in 30 mL of tetrahydrofuran is added 12 mL of 2.5 M BuLi in hexane at -15 to -5 C. and stirred at -10 C. for 20 minutes. 10.00 g of (S)-3-4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 10 mL of THF is added at -23 to -20 C. and stirred at -22 C. for 20 min. 20.32 g of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 7 mL of THF is added at -20 to -18 C. The reaction is then stirred at -20 C. for 1 hour and warmed to -12 C. in another hour. 60 mL of 25 weight-% aqueous NH4Cl solution is added to quench the reaction. 40 mL of MTBE is added and the organic layer is separated. The aqueous layer is extracted with 30 mL of EtOAc. The combined organic phases are dried over MgSO4 and concentrated.

To a solution of 2.90 g (S)-3-[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 4 mL of THF at 0 to 20 C. (or alternatively at 20 C.), is slowly charged 8.4 mL of 1.0 M i-PrMgCl/LiCl in THF. The reaction is stirred at 20 C. for 16 hours and cooled to -23 C. 4.3 g of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 2 mL of THF is added dropwise. The reaction is then stirred at -20 C. for 2 h. Aqueous NH4Cl solution (25 weight-%, 12 mL) is added to quench the reaction. MTBE (8 mL) is added and the organic layer is separated. The aqueous layer is extracted with EtOAc (30 mL). The combined organic phases are dried over MgSO4 and concentrated.

Reference： [1]Patent: US2006/258749,2006,A1 .Location in patent: Page/Page column 29
[2]Patent: US2006/258749,2006,A1 .Location in patent: Page/Page column 29
[3]Patent: US2006/258749,2006,A1 .Location in patent: Page/Page column 29
[4]Patent: US2006/258749,2006,A1 .Location in patent: Page/Page column 29

14
[ 915095-94-2 ]
[ 32469-28-6 ]
C₃₅H₅₉ClO₇Si₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 2.90 g (S)-3-[4-(5-iodo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran in 4 mL of THF at -23 C., is slowly charged 8.4 mL of 1.0 M i-PrMgCl/LiCl in THF. The reaction is stirred at -22 C. for 20 minutes. 4.3 g of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in 2 mL of THF is added dropwise. The reaction is then stirred at -20 C. for 2 h. Aqueous NH4Cl solution (25 weight-%, 12 mL) is added to quench the reaction. MTBE (8 mL) is added and the organic layer is separated. The aqueous layer is extracted with EtOAc (30 mL). The combined organic phases are dried over MgSO4 and concentrated.

Reference： [1]Patent: US2006/258749,2006,A1 .Location in patent: Page/Page column 29

15
[ 915095-94-2 ]
[ 32469-28-6 ]
[ 864070-44-0 ]

Yield	Reaction Conditions	Operation in experiment
73%		To a solution of the iodide V.1 (267 kg) in tetrahydrofuran (429 kg) is added Turbogrignard solution (isopropylmagnesium chloride/lithium chloride solution, 14 weight-% iPrMgCl in THF, molar ratio LiCl:iPrMgCl=0.9-1.1 mol/mol) (472 kg) at -21 to -15 C. temperature within 1 hr 50 min. On completion of the addition the conversion is determined via HPLC analysis. The reaction is regarded as completed when the area of the peak corresponding to the iodide V.1 is smaller than 5.0% of the total area of both peaks, iodide V.1 and the corresponding desiodo compound of iodide V.1. If the reaction is not completed, additional Turbogrignard solution is added until the criterion is met. In this particular case the result is 3.45%. Then the lactone IV.1 (320 kg) is added at -25 to -18 C. temperature within 1 hr 25 min. The resulting mixture is stirred for further 1 hr 30 min at -13 to -18 C. On completion the conversion is determined via HPLC analysis (for information). On completion, a solution of citric acid in water (938 L; concentration: 10%-weight) is added to the reaction mixture of a volume of about 2500 L at -13 to 19 C. within 1 hr 25 min.The solvent is partially distilled off from the reaction mixture (residual volume: 1816-1905 L) at 20 to 30 C. under reduced pressure and 2-methyltetrahydrofuran (532 kg) is added. Then the stirrer is switched off and the phases are separated at 29 C. After phase separation the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel). The measured pH value is 2 to 3. Then solvent is distilled off from the organic phase at 30 to 33 C. under reduced pressure and methanol (1202 kg) is added followed by the addition of a solution of 1.25N HCl in methanol (75 kg) at 20 C. (pH=0). Full conversion to the acetale III.1 is achieved by subsequent distillation at 20 to 32 C. under reduced pressure and addition of methanol (409 kg).Completion of the reaction is obtained when two criteria are fulfilled:1) The ratio of the sum of the HPLC-area of the alpha-form+beta-form of intermediate III.1 relative to the area of intermediate IIIa.1 is greater or equal to 96.0%:4.0%. 2) The ratio of the HPLC-area of the alpha-form of intermediate III.1 to the beta-form of III.1 is greater or equal to 97.0% to 3.0%. In this particular case both criteria are met. Triethylamin (14 kg) is added (pH=7.4) and solvent is distilled off under reduced pressure, acetonitrile (835 kg) is added and further distilled under reduced pressure. This procedure is repeated (addition of acetonitrile: 694 kg) and methylene chloride (640 kg) is added to the resulting mixture to yield a mixture of the acetale III.1 in acetonitrile and methylene chloride. The water content of the mixture is determined via Karl Fischer titration (result: 0.27%).The reaction mixture is then added within 1 hr 40 min at 10 to 19 C. to a preformed mixture of AlCl3 (176 kg), methylene chloride (474 kg), acetonitrile (340 kg), and triethylsilane (205 kg). The resulting mixture is stirred at 18 to 20 C. for 70 min. After completion of the reaction, water (1263 L) is added at 20 to 30 C. within 1 hr 30 min and the mixture is partially distilled at 30 to 53 C. under atmospheric pressure and the phases are separated. Toluene (698 kg) is added to the organic phase and solvent is distilled off under reduced pressure at 22 to 33 C. The product is then crystallized by addition of seeding crystals (0.5 kg) at 31 C. and water (267 kg) added after cooling to 20 C. The reaction mixture is cooled to 5 C. within 55 min and stirred at 3 to 5 C. for 12 hrs. Finally the product is collected on a centrifuge as colourless, crystalline solid, washed with toluene (348 kg) and dried at 22 to 58 C. 211 kg (73%) of product are obtained. The identity of the product is determined via the HPLC retention time.
73%		To a solution of the iodide V.1 (267 kg) in tetrahydrofuran (429 kg) is added Turbogrignard solution (isopropylmagnesium chloride/lithium chloride solution, 14 weight-% iPrMgCl in THF, molar ratio LiCl:iPrMgCl=0.9-1.1 mol/mol) (472 kg) at -21 to -15 C. temperature within 1 hr 50 min. On completion of the addition the conversion is determined via HPLC analysis. The reaction is regarded as completed when the area of the peak corresponding to the iodide V.1 is smaller than 5.0% of the total area of both peaks, iodide V.1 and the corresponding desiodo compound of iodide V.1. If the reaction is not completed, additional Turbogrignard solution is added until the criterion is met. In this particular case the result is 3.45%. Then the lactone IV.1 (320 kg) is added at -25 to -18 C. temperature within 1 hr 25 min. The resulting mixture is stirred for further 1 hr 30 min at -13 to -18 C. On completion of the addition the conversion is determined via HPLC analysis (for information). On completion, a solution of citric acid in water (938 L; concentration:10%-weight) is added to the reaction mixture of a volume of about 2500 L at -13 to 19 C. within 1 hr 25 min. The solvent is partially distilled off from the reaction mixture (residual volume: 1816-1905 L) at 20 to 30 C. under reduced pressure and 2-methyltetrahydrofuran (532 kg) is added. Then the stirrer is switched off and the phases are separated at 29 C. After phase separation the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel). The measured pH value is 2 to 3. Then solvent is distilled off from the organic phase at 30 to 33 C. under reduced pressure and methanol (1202 kg) is added followed by the addition of a solution of 1.25N HCl in methanol (75 kg) at 20 C. (pH=0). Full conversion to the acetale III.1 is achieved by subsequent distillation at 20 to 32 C. under reduced pressure and addition of methanol (409 kg).Completion of the reaction is obtained when two criteria are fulfilled:1) The ratio of the sum of the HPLC-area of the alpha-form+beta-form of intermediate III.1 relative to the area of intermediate IIIa.1 is greater or equal to 96.0%:4.0%.2) The ratio of the HPLC-area of the alpha-form of intermediate III.1 to the beta-form of III.1 is greater or equal to 97.0% to 3.0%.In this particular case both criteria are met. Triethylamin (14 kg) is added (pH=7.4) and solvent is distilled off under reduced pressure, acetonitrile (835 kg) is added and further distilled under reduced pressure. This procedure is repeated (addition of acetonitrile: 694 kg) and methylene chloride (640 kg) is added to the resulting mixture to yield a mixture of the acetale III.1 in acetonitrile and methylene chloride. The water content of the mixture is determined via Karl Fischer titration (result: 0.27%). The reaction mixture is then added within 1 hr 40 min at 10 to 19 C. to a preformed mixture of AlCl3 (176 kg), methylene chloride (474 kg), acetonitrile (340 kg), and triethylsilane (205 kg). The resulting mixture is stirred at 18 to 20 C. for 70 min. After completion of the reaction, water (1263 L) is added at 20 to 30 C. within 1 hr 30 min and the mixture is partially distilled at 30 to 53 C. under atmospheric pressure and the phases are separated. Toluene (698 kg) is added to the organic phase and solvent is distilled off under reduced pressure at 22 to 33 C. The product is then crystallized by addition of seeding crystals (0.5 kg) at 31 C. and water (267 kg) added after cooling to 20 C. The reaction mixture is cooled to 5 C. within 55 min and stirred at 3 to 5 C. for 12 hrs. Finally the product is collected on a centrifuge as colourless, crystalline solid, washed with toluene (348 kg) and dried at 22 to 58 C. 211 kg (73%) of product are obtained. The identity of the product is determined via the HPLC retention time.

Reference： [1]Patent: US2011/237789,2011,A1 .Location in patent: Page/Page column 12
[2]Patent: US2011/237526,2011,A1 .Location in patent: Page/Page column 8

16
[ 1103738-29-9 ]
[ 32469-28-6 ]
[ 461432-24-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		Preparation of (3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol Arylmagnesium Formation: A three-necked round-bottom flask equipped with thermometer and jacketed addition funnel was charged with a solution of <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (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 iPrMgCl.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. 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. iPrMgCl.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*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 (LCMS-0013) 3.0 min, 80% (UV); MS ESI (m/z) 439[M+1]+, calc. 438.

Reference： [1]Patent: US2013/267694,2013,A1 .Location in patent: Page/Page column 0311-0315

17
[ 1103738-29-9 ]
[ 32469-28-6 ]
[ 960404-86-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 24 Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; bis(L-Proline) cocrystal [0338] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; L-Proline; L-Proline. RRN 148Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol [0339] (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. [0342] Aryl Magnesium Formation. [0343] 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 <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (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 <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> 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. [0344] Aryl Magnesium Coupling to Give an Anomeric Hemiketal. [0345] 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. [0346] 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 (3×15 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.

Reference： [1]Patent: US2013/267694,2013,A1 .Location in patent: Page/Page column 0338-0346

18
[ 1103738-29-9 ]
[ 32469-28-6 ]
[ 960404-86-8 ]
C₂₁H₂₇ClO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 23 Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; bis(L-Proline) cocrystal [0321] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; L-Proline; L-Proline via Grignard reaction. Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol [0322] [0323] Gluconolactone Solution. [0324] 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 -20 C. to -30 C. under nitrogen atmosphere. The solution was added to a suitable cooled addition funnel and was kept ready for addition to the aryl magnesium. [0325] Aryl Magnesium Formation. [0326] 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 <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (3.73 g, 10 mmol). After stirring and sparging with nitrogen for 30 min at ambient temperature, the mixture was cooled to -20 C. under nitrogen atmosphere. To the solution was added iPrMgCl.LiCl (Aldrich, titrated concentration 12.9% wt/wt, 9.58 g) (depending on the titer of the reagent, 1.2 eq.) via a suitable addition funnel at such a rate that the temperature was maintained between -20 C. and -10 C. in 30 min under nitrogen atmosphere. The mixture was stirred for an additional 10 min at -20 to -10 C. The conversion of starting material 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 with the HPLC-0001. [0327] Aryl Magnesium Coupling to Give an Anomeric Hemiketal. [0328] The cold gluconolactone solution in a cooled (-15 C.) addition funnel was added dropwise to the aryl magnesium solution at such a rate as to maintain the temperature between -20 C. and -10 C. for over 40 min. After the addition was completed, the mixture was stirred for 5 h at -20 to -10 C. [0329] 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 (3×15 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 product, 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.

Reference： [1]Patent: US2013/267694,2013,A1 .Location in patent: Page/Page column 0321-0329

19
[ 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

20
[ 67-56-1 ]
[ 1103738-29-9 ]
[ 32469-28-6 ]
[ 461432-24-6 ]

Yield	Reaction Conditions	Operation in experiment
		[0270] 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 z'PrMgCl-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. [0271] 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 (LCMS-0013) 3.0 min, 80% (UV); MS ESI (m/z) 439[M+1]+, calc. 438.

Reference： [1]Patent: WO2013/152654,2013,A1 .Location in patent: Paragraph 0270; 0271

21
[ 1240304-54-4 ]
[ 24078-12-4 ]
[ 108-24-7 ]
[ 32469-28-6 ]
C₃₁H₃₇BrO₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
392 g		To a solution of 1,5-dibromo-2-isopropyl-4-(methoxymethoxy)benzene (200 g, 0.592 mol) in tetrahydrofuran (2.84 L), a solution of 2.69M n-butyllithium in hexane (231 mL, 0.621 mol) was then added dropwise over 20 minutes at -80 C. to -76 C. under an argon atmosphere, followed by stirring the mixture at the same temperature for 35 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (290 g, 0.621 mol) in tetrahydrofuran (800 mL) was added dropwise over 55 minutes, and the mixture was stirred at the same temperature for 50 minutes. Further, trimethylchlorosilane (75.7 mL, 0.621 mol) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 2 hours. Then, a solution of 2.69M n-butyllithium in hexane (319 mL, 0.858 mol) was added dropwise over 29 minutes, and the mixture was stirred at the same temperature for 40 minutes. Finally, a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (130 g, 0.651 mol) in tetrahydrofuran (800 mL) was added dropwise over 54 minutes, and the mixture was stirred at the same temperature for 30 minutes. Water (2.85 L) was added to the reaction mixture, and the resulting mixture was warmed to room temperature. Toluene (2.0 L) was added to separate the organic layer, and the solvent was distilled off under reduced pressure. [0144] The resulting residue (546 g) was dissolved in methanol (3.0 L), and methanesulfonic acid (3.84 mL, 0.0592 mol) was added, followed by heating under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and then neutralized with triethylamine (25 mL, 0.179 mol), and the reaction mixture was concentrated. The concentrate was dissolved in toluene (1.0 L), and washed with water (0.5 L, 1.0 L). To the organic layer, a 1M aqueous solution of sodium hydroxide (0.6 L) and toluene (1.0 L) were added for extraction, to separate the aqueous layer. The aqueous layer was washed with toluene (0.5 L). To the aqueous layer, 10% hydrochloric acid (0.7 L) was added, and the mixture was extracted with toluene (1.0 L). The organic layer was washed with a 10% aqueous solution of sodium chloride (1.0 L) and water (0.5 L), and the solvent was distilled off under reduced pressure. [0145] The resulting residue (314 g) was dissolved in pyridine (1.0 L), and acetic anhydride (0.8 L, 8.51 mol) was added, followed by stirring the mixture for 18 hours at room temperature. The reaction mixture was cooled on ice, and ice (1.5 L) and toluene (1.0 L) were added, and the mixture was stirred for 3 hours. The organic layer was separated, and then the aqueous layer was extracted with toluene (1.0 L). The organic layer combined was washed with 2M hydrochloric acid (1.5 L) twice, and further with a 5% aqueous solution of sodium hydrogen carbonate (1.0 L), and a 10% aqueous solution of sodium chloride (1.0 L), whereafter the solvent was distilled off under reduced pressure. [0146] The resulting residue (350 g) was dissolved in acetonitrile (3.4 L), and water (9.1 mL, 0.506 mol) and Et3SiH (328 mL, 2.05 mol) were added to the solution. Under ice cooling of the mixture, TMSOTf (403 mL, 2.23 mol) was added dropwise over 85 minutes. The mixture was stirred at the same temperature for 2 hours, and then a 3% aqueous solution of sodium hydrogen carbonate (1.92 L) was added dropwise over 40 minutes. The reaction mixture was diluted with toluene (1.0 L) and stirred for 15 minutes, whereafter the organic layer was separated. The aqueous layer was extracted with toluene (1.5 L). The organic layer combined was washed with a saturated aqueous solution of sodium hydrogen carbonate (1.50 L), and the solvent was distilled off under reduced pressure to give colorless liquid compound (A7) (392 g). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.09-1.19 (m, 6H) 1.69 (s, 3H) 1.99 (s, 3H) 2.05 (s, 3H) 2.12 (s, 3H) 2.25 (s, 3H) 2.80-2.97 (m, 1H) 3.66-3.96 (m, 3H) 4.08-4.35 (m, 2H) 4.42-4.57 (m, 1H) 5.19-5.37 (m, 3H) 6.52 (s, 1H) 6.57 (d, J=8.1 Hz, 1H) 6.87 (s, 1H) 7.12-7.20 (m, 1H) 7.30-7.33 (m, 1H).
		To a solution of 1,5-dibromo-2-isopropyl-4-(methoxymethoxy)benzene (200 g, 0.592 mol) in tetrahydrofuran (2.84 L), a solution of 2.69M n-butyllithium in hexane (231 mL, 0.621 mol) was then added dropwise over 20 minutes at -80C to -76C under an argon atmosphere, followed by stirring the mixture at the same temperature for 35 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (290 g, 0.621 mol) in tetrahydrofuran (800 mL) was added dropwise over 55 minutes, and the mixture was stirred at the same temperature for 50 minutes. Further, trimethylchlorosilane (75.7 mL, 0.621 mol) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 2 hours. Then, a solution of 2.69M n-butyllithium in hexane (319 mL, 0.858 mol) was added dropwise over 29 minutes, and the mixture was stirred at the same temperature for 40 minutes. Finally, a solution of <strong>[24078-12-4]4-bromo-2-methylbenzaldehyde</strong> (130 g, 0.651 mol) in tetrahydrofuran (800 mL) was added dropwise over 54 minutes, and the mixture was stirred at the same temperature for 30 minutes. Water (2.85 L) was added to the reaction mixture, and the resulting mixture was warmed to room temperature. Toluene (2.0 L) was added to separate the organic layer, and the solvent was distilled off under reduced pressure. (0078) The resulting residue (546 g) was dissolved in methanol (3.0 L), and methanesulfonic acid (3.84 mL, 0.0592 mol) was added, followed by heating under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and then neutralized with triethylamine (25 mL, 0.179 mol), and the reaction mixture was concentrated. The concentrate was dissolved in toluene (1.0 L), and washed with water (0.5 L, 1.0 L). To the organic layer, a 1M aqueous solution of sodium hydroxide (0.6 L) and toluene (1.0 L) were added for extraction, to separate the aqueous layer. The aqueous layer was washed with toluene (0.5 L). To the aqueous layer, 10% hydrochloric acid (0.7 L) was added, and the mixture was extracted with toluene (1.0 L). The organic layer was washed with a 10% aqueous solution of sodium chloride (1.0 L) and water (0.5 L), and the solvent was distilled off under reduced pressure. (0079) The resulting residue (314 g) was dissolved in pyridine (1.0 L), and acetic anhydride (0.8 L, 8.51 mol) was added, followed by stirring the mixture for 18 hours at room temperature. The reaction mixture was cooled on ice, and ice (1.5 L) and toluene (1.0 L) were added, and the mixture was stirred for 3 hours. The organic layer was separated, and then the aqueous layer was extracted with toluene (1.0 L). The organic layer combined was washed with 2M hydrochloric acid (1.5 L) twice, and further with a 5% aqueous solution of sodium hydrogen carbonate (1.0 L), and a 10% aqueous solution of sodium chloride (1.0 L), whereafter the solvent was distilled off under reduced pressure. (0080) The resulting residue (350 g) was dissolved in acetonitrile (3.4 L), and water (9.1 mL, 0.506 mol) and Et3SiH (328 mL, 2.05 mol) were added to the solution. Under ice cooling of the mixture, TMSOTf (403 mL, 2.23 mol) was added dropwise over 85 minutes. The mixture was stirred at the same temperature for 2 hours, and then a 3% aqueous solution of sodium hydrogen carbonate (1.92 L) was added dropwise over 40 minutes. The reaction mixture was diluted with toluene (1.0 L) and stirred for 15 minutes, whereafter the organic layer was separated. The aqueous layer was extracted with toluene (1.5 L). The organic layer combined was washed with a saturated aqueous solution of sodium hydrogen carbonate (1.50 L), and the solvent was distilled off under reduced pressure to give colorless liquid compound (A7) (392 g). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.09 - 1.19 (m, 6 H) 1.69 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.25 (s, 3 H) 2.80 - 2.97 (m, 1 H) 3.66 - 3.96 (m, 3 H) 4.08 - 4.35 (m, 2 H) 4.42 - 4.57 (m, 1 H) 5.19 - 5.37 (m, 3 H) 6.52 (s, 1 H) 6.57 (d, J=8.1 Hz, 1 H) 6.87 (s, 1 H) 7.12 - 7.20 (m, 1 H) 7.30 - 7.33 (m, 1 H).

Reference： [1]Patent: US2013/165645,2013,A1 .Location in patent: Paragraph 0143; 0144; 0145; 0146; 0147
[2]Patent: EP2607360,2015,B1 .Location in patent: Paragraph 0077

22
[ 32469-28-6 ]
[ 1210344-57-2 ]

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

23
[ 461432-23-5 ]
[ 32469-28-6 ]
(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 ]

Yield	Reaction Conditions	Operation in experiment
100%		[00114] To asolution of <strong>[461432-23-5]4-bromo-1-chloro-2-(4-ethoxyphenyl)methyl-benzene</strong> (30 g, 92.1 mmol,purchasedfromShanghai Kinsey pharmaceutical company) in anhydrous tetrahydrofuran (250 mL)was addedn-butyllithium(40.3 mL, 96.7 mmol, 2.4 M in hexane) dropwise at -78 oC. The mixture wasstirred at -78 °Cfor 40minutes, and then a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-onelb (47.3 g, 101.3 mmol) in anhydrous tetrahydrofuran (50 mL) was addeddropwise.After, themixture was further stirred at -78 °C for 5 hours and quenched with 100 mL ofsaturated aqueousammoniumchloride. The mixture was allowed to warm up to room temperature andconcentrated in vacuo. Tothe residuewas added 150 mL of water. The resulting mixture was extracted with ethylacetate (150 mL X 3).Thecombined organic layers were washed with saturated aqueous sodium chloride (200mL), dried overanhydroussodium sulfate and concentrated in vacuo to give the title compound 1c as paleyellow oil (69.7 g,100percent). Thecrude product was used without further purification.
		[00140] To a solution of <strong>[461432-23-5]4-bromo-1-chloro-2-(4-ethoxyphenyl)methyl-benzene</strong> I-c (30 g, 92.1 mmol, bought from Shanghai Kinsey pharmaceutical company) in anhydrous tetrahydrofuran (250 mL) was added n-butyllithium (40.3 mL, 96.7 mmol, 2.4 M in n-hexane) dropwise underN2 at ?78 °C. The mixture was stirred at ?78 °C for 40 mm and a solution of (3R,4S, 5R,6R)-3 ,4, 5-tn s(trimethyl silyloxy)-6-(trimethylsilyloxymethyl)tetrahydropyran-2-oneI-b (47.3 g, 101.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After the addition, the mixture was stirred at ?78 °C for 5 hours, and then quenched with 100 mL of saturated aqueous ammonium chloride at ?78 °C. The mixture was allowed to warm up to roomtemperature and concentrated in vacuo to remove most of the solvent. To the residue was added150 mL of water. The resulting mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 1-d as pale yellow oil (69.7 g, 100percent). This crude product was used in next step without further purification.
		At -78 & lt; 0 & gt; C,A solution of n-butyllithium in n-hexane(120.9 mL, 290 mmol, 7.2 M) was added dropwise2- (4-ethoxyphenyl) methyl-4-bromo-1-chlorobenzene(90 g, 276.3 mmol,Purchased in Shanghai Jinsai Pharmaceutical Company)Of anhydrous tetrahydrofuran(750 mL)After stirring at -78 & lt; 0 & gt; C for 40 min,(3R, 4S, 5R, 6R) -3,4,5-tris (trimethylsiloxy) -6 - [(trimethylsiloxy) methyl] -tetrahydropyran-2-one 1b (141.9 g, 304 mmol)ofAnhydrous tetrahydrofuran(150 mL)The solution was added dropwise to the reaction system.Drop finished,Stirring was continued at -78 & lt; 0 & gt; C for 5 hours.At -78 & lt; 0 & gt; C,The reaction was quenched by the slow addition of 300 mL of saturated ammonium chloride solution, warmed to room temperature and concentrated in vacuo to remove most of the solvent. The residue was added to 450 mLWater, extracted with ethyl acetate (450 mL x 3). The organic phases were combined and washed with saturated brine (600 mL) and dried over anhydrous sodium sulfateThe filtrate was concentrated under reduced pressure to give the title compound lc (208.9 g, pale yellow oil) in 100percent yield. Crude productDirectly for the next step.

Reference： [1]Patent: WO2015/43473,2015,A1 .Location in patent: Paragraph 00114
[2]Organic Process Research and Development,2014,vol. 18,p. 57 - 65
[3]Patent: WO2016/173425,2016,A1 .Location in patent: Paragraph 00138; 00140
[4]Patent: CN106674245,2017,A .Location in patent: Paragraph 0082; 0087; 0088; 0089

24
[ 915095-94-2 ]
[ 32469-28-6 ]
C₃₅H₅₉ClO₈Si₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Pre-Treatment of Griqnard solution (GriS; /-PrMqCI / LiCI in THF):In a glass flask, to a 1.3 mol/L solution of /'-PrMgCI / LiCI in THF (100 mL) the respective pre- treated metal test piece was added and the resulting mixture was stirred at room temperature for 7 days under argon atmosphere. Then, a sample was taken and analyzed for the iron ion content with analytical method A.Description of the Experiment:In a glass flask, a solution of compound I, wherein X denotes I and R1denotes (S)-tetra- hydrofuran-3-yl, (0.072 mol) in THF (54 mL) was cooled to -15 C to -40 C under argon atmosphere. 55 mL of the pre-treated Grignard solution (1.0 eq) was added at -15 C to -40 C within 60-65 min. A sample was taken and analyzed for compound I and oligomers with analytical method B and C, respectively. To this solution, compound II, wherein R2denotes trimethylsilyl, (1.1 eq) was added at -5 C to -25 C. After completion of the addition, the resulting mixture was stirred at -5 C to -15 C for additional 60-120 min. A sample was taken and analyzed for the hemiacetal intermediate of formula III (R' = H) with analytical method D.
	With n-butyllithium; In tetrahydrofuran; hexane; at -40℃;Flow reactor;	13.3 g of the initial reactant (EM1) and 16.43 g of TMS-lactone were taken and dissolved in 40 mL of tetrahydrofuran (THF) and connected to pump 1.1.6M n-butyllithium (in hexane) was connected to pump 2.The reactor was made of Sus material having a diameter of 3.175 mm x 4 m in length and 1.5875 mm in diameter x 1 m in length, and was kept in a low temperature reactor at -40 C to maintain the temperature.The flow rate of pump 1 started at 0.25 / 0.5 / 1.0 mL / min, and the flow rate of pump 2 started at 0.3 / 0.6 / 1.2 mL / min simultaneously.The product was formed after about 39/20/10 minutes, and the product was collected, worked-up, and analyzed from about 42/23/13 minutes.

Reference： [1]Organic Letters,2014,vol. 16,p. 4090 - 4093
[2]Patent: WO2018/69243,2018,A1 .Location in patent: Page/Page column 15; 16
[3]Patent: KR2019/129416,2019,A .Location in patent: Paragraph 0072-0083; 0088-0092

25
[ 915095-94-2 ]
[ 32469-28-6 ]
(1R,2S,3R,4R,5S)-1-(4-chloro-3-(4-(((S)-tetrahydrofuran-3-yl)oxy)benzyl)phenyl)hexane-1,2,3,4,5,6-hexaol [ No CAS ]

Reference： [1]Organic Letters,2014,vol. 16,p. 4090 - 4093

26
[ 75-75-2 ]
[ 1240304-64-6 ]
[ 108-24-7 ]
[ 32469-28-6 ]
[ 1240304-66-8 ]

Yield	Reaction Conditions	Operation in experiment
80%		To a solution of compound (A1) (24.5 g, 88.6 mmol) in THF (100 mL), a solution of 2.6M n-butyllithium in hexane (34 mL, 88.6 mmol) was added dropwise at -78C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 5 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (37.6 g, 80.5 mmol) in THF (60 mL) was added dropwise over 25 minutes, and the mixture was stirred at the same temperature for 10 minutes. Ice and water were added to the reaction mixture, and the resulting mixture was warmed to room temperature and then extracted with ethyl acetate. The organic layer combined was washed with brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. (0060) The resulting residue was dissolved in a solution containing methanesulfonic acid (1.55 g, 16.1 mmol) in methanol (380 mL), and the solution was stirred at room temperature for 2 hours. Then, the solution was neutralized with triethylamine (11.2 mL, 80.5 mmol), and the reaction mixture was concentrated. (0061) The resulting residue (30.2 g) was dissolved in pyridine (100 mL), and acetic anhydride (100 mL) was added, followed by stirring the mixture for 14 hours at room temperature. Iced water (400 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The organic layer combined was washed with 1M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane?hexane:ethyl acetate = 6:4) to give light yellow oily compound (A2) (32.8 g, 80%; 3 steps). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.23 (d, J=6.92 Hz, 6 H) 1.84 (s, 3 H) 1.97 (s, 3 H) 2.06 (s, 3 H) 2.10 (s, 3 H) 2.87 (sept, J=6.92 Hz, 1 H) 3.32 (s, 3 H) 3.87 (s, 3 H) 4.04 (ddd, J=10.18, 4.74, 2.41 Hz, 1 H) 4.17 - 4.23 (m, 1 H) 4.28 - 4.36 (m, 1 H) 5.25 (dd, J=10.18, 9.40 Hz, 1 H) 5.36 (d, J=10.18 Hz, 1 H) 5.60 (dd, J=10.18, 9.40 Hz, 1 H) 6.74 (d, J=1.55 Hz, 1 H) 6.79 (dd, J=8.08, 1.55 Hz, 1 H) 7.26 - 7.33 (m, 1 H). MS ESI/APCI Dual posi : 533[M+Na]+.

Reference： [1]Patent: EP2607360,2015,B1 .Location in patent: Paragraph 0059; 0060; 0061

27
[ 32469-28-6 ]
[ 842133-18-0 ]

Reference： [1]Patent: WO2015/181692,2015,A1
[2]Patent: WO2016/142950,2016,A1
[3]Patent: CN106866645,2017,A
[4]Patent: CN107286143,2017,A
[5]Patent: CN110698468,2020,A

28
[ 67-56-1 ]
[ 1030825-20-7 ]
[ 32469-28-6 ]
[ 1030825-21-8 ]

Yield	Reaction Conditions	Operation in experiment
92.1%		Magnesium powder (12.0g, 500mmol), iodine (1.3g, 10.0mmol) was added to a dry reaction flask,The dried under nitrogen in tetrahydrofuran (50mL) was added to the reaction flask was cooled to 0 ,2 - [(5-bromo-2-methylphenyl) methyl] -5- (4-fluorophenyl) thiophene (II) (36.1g, 100mmol)In tetrahydrofuran (100mL) was slowly added dropwise to the reaction flask, plus complete warmed to 25 ,The reaction was stirred for 5 ~ 8h, cooled to 0 ,The above reaction solution at 0 ,Was added dropwise to 2,3,4,6-tetra (trimethylsilyl) -D- -O- gluconolactone (III) (55.9g,120mmol) in anhydrous tetrahydrofuran (100 mL) solution was added dropwise, and the reaction mixture was stirred for 2 ~ 3h,And under cooling with containing methanesulfonic acid (26.4g, 275mmol) in methanol (150 mL) was added dropwise to the reaction solution in the above,Bi dropwise slowly warmed to room temperature and stirred overnight.After completion of the reaction, the temperature dropped to 0 ,About 300mL saturated sodium bicarbonate solution was added to about pH 7, separated and the aqueous layer was extracted once with 200mL ethylThe combined organic layers with saturated brine (200 mL), washed once, dried over anhydrous magnesium sulfate, suction filtered,The filtrate was distilled under reduced pressure to give a paleYellow solid powder-methyl-1-C- (3 - ((5- (4- fluorophenyl) -2-thienyl) methyl) -4-methyl-phenyl) -D- glucopyranoside (I) 42.0g, yield 92.1percent, HPLC content of 95.9percent.
		A solution of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (100 g; Example 3) in tetrahydrofuran (200 mL) and toluene (300 mL) was added to a solution of -butyl lithium in hexane (3.2M; 76.8 g) and tetrahydrofuran (200 mL) at -75°C to -65°C under nitrogen atmosphere. The reaction mixture was stirred for 20 minutes to 40 minutes at the same temperature. A solution of 2,3,4,6-tetrakis-0-trimethylsilyl-D-glucono-l,5- lactone (194 g) in toluene (500 mL) was added to the reaction mixture at -70°C to -75°C, and then the mixture was stirred for 60 minutes to 90 minutes at the same temperature. A solution of methanesulphonic acid (66 g) in methanol (700 mL) was slowly added to the reaction mixture at -70°C to -75 °C. The reaction mixture was allowed to reach a temperature of 25°C to 30°C, and was then stirred at the same temperature for 12 hours. After completion of the reaction, the reaction mixture was washed with an aqueous solution of sodium bicarbonate (25 g of sodium bicarbonate in 500 mL of de-ionized water) at 25°C to 30°C. Ethyl acetate (500 mL) was added to the organic layer, and then the mixture was stirred for 10 minutes to 15 minutes. The reaction mixture was allowed to settle for 15 minutes, and then the layers were separated. The aqueous layer was washed twice with ethyl acetate (500 mL) and the layers were separated. The organic layers were combined, and then washed with an aqueous solution of sodium chloride (10 g of sodium chloride in 200 mL of de-ionized water). The organic layer was concentrated under reduced pressure at 45°C to obtain an oily residue. The oily residue was dissolved in toluene (300 mL) at 40°C to 45°C to obtain a solution. Hexane (1000 mL) was slowly added to the solution at 25 °C to 30°C under a nitrogen atmosphere. The mixture was stirred at the same temperature for 15 minutes to 20 minutes to obtain a solid. The solid was filtered under reduced pressure under nitrogen atmosphere, and then dried for 20 minutes to 30 minutes under nitrogen atmosphere to obtain l-(l-methoxyglucopyranosyl)- 4-methyl-3-[5-(4-flourophenyl)-2-thienylmethyl]benzene.

Reference： [1]Patent: CN105753910,2016,A .Location in patent: Paragraph 0032; 0033
[2]Patent: WO2016/16852,2016,A1 .Location in patent: Page/Page column 8; 9

29
[ 32469-28-6 ]
[ 1118567-05-7 ]
C₂₄H₂₉ClO₇ [ No CAS ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 4684 - 4687

30
[ 32469-28-6 ]
[ 1118567-05-7 ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 4684 - 4687

31
[ 1030825-20-7 ]
[ 32469-28-6 ]
[ 107-18-6 ]
2-allyloxy-2-{3-[5-(4-fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To the mixture of 10 ccTHF and 10 cc Toluene added 0.138 mole 2-(5-Bromo-2-methyl- benzyl>-5-(4-fluoro-phenyl)-thiopheneatambient temperature. The reaction mass was stirred for 15 mm. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 mm. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6- trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction,thereaction mass was quenched with Methane suiphonic acid and Ally alcohol mixture at -70 to -80°C.Temperature was raised to ambient temperature and stirred over night. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 mm. Layers separated and aqueous was extracted with 10 cc of Toluene. Organic layer was combined and washed with water 30cc and sat. brine solution 50 cc. Organic layer was distilled under reduced pressure to recover the toluene. Solid compound thus obtainedwas dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75-79percent the titled compound as crystalline solid.HPLC purity:88-94 percent. JR dataAromatic C- F stretching: 832 cm? Lactones C ? 0 stretching: 1045 ? 1092 cm1 Allylic C- 0 stretching: 1161 cm1Anomeric C-O stretching: 1231 cm1Aromatic C=C stretching: 1510, 1548, 1603, 1703 cm Alkane C ? H stretching: 2892 , 2950 cmAllylic C-H stretching: 2990?3120 cm?Aromatic C ? H stretching: 3050 - 3090 cm Lactones 0 ? H stretching: 3240 ? 3380 cm Dip?Mass(M+Na) 523.28 m/z (M+K) 539.38 m/z

Reference： [1]Patent: WO2016/142950,2016,A1 .Location in patent: Page/Page column 15; 16

32
[ 1034305-17-3 ]
[ 32469-28-6 ]
C₂₁H₂₁FO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Under nitrogen atmosphere, a three-necked round bottom flask was dried THF (20ml), cooled to -10 deg.] C with stirring, sec-butyl magnesium chloride was added a solution of lithium chloride in THF (3.1ml, 3.1mmol) and n-hexane solution of n-BuLi (2.0ml, 4.96mmol), stirred for 10min.At -10 conditions, the 2- (5-bromo-2-yl) benzothiophene (1.0g, 3.1mmol) was dissolved in dry THF (10ml) was slowly added dropwise to the round bottom flask, the reaction 3h .At -10 condition, added trimethylsilyl protected gluconolactone (1.45g, 3.1mmol) in THF (10ml) solution, the reaction 3h.Was added 6NHCl (2ml) in water (10ml) was added dropwise.Saturated sodium bicarbonate solution (10ml), (100ml × 2) and extracted with ethyl acetate, the combined organic phase was washed with water (100ml) and saturated sodium chloride solution (100ml), dried over anhydrous sodium sulfate and filtered, The filtrate solvent was removed by rotary evaporation to give a pale yellow solid 1-C- [3- (benzo [B] thiophen-2-yl-methyl) -4-fluorophenyl] -ALPHA-D- glucopyranosyl-ol (yield 70%)Nitrogen blanket 1-C- [3- (benzo [B] thiophen-2-yl-methyl) -4-fluorophenyl] -ALPHA-D- glucopyranose crude alcohol (1.27g, 3.02mmol) was dissolved in acetonitrile: dichloromethane (1: 1, 20 ml), cooled to -10 .Was added triethylsilane (1.45ml, 9.06mmol), then added dropwise boron trifluoride etherate (1.14ml, 9.06mmol), warmed to 0 stirred for 4h.Saturated sodium bicarbonate solution (10ml) The reaction was quenched with water (50ml), (50ml × 2) and extracted with ethyl acetate, the combined organic phase was successively spent water (50ml) and saturated sodium chloride solution (50ml) and washed , dried over anhydrous sodium sulfate and filtered, spin solvent was evaporated to give a pale yellow solid Ignatius column net crude (1.07g).

Reference： [1]Patent: CN105541816,2016,A .Location in patent: Paragraph 0022; 0023; 0024

33
[ 32469-28-6 ]
[ 761423-87-4 ]
(1R)-1,5-anhydro-1-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol [ No CAS ]

Reference： [1]Patent: CN105541816,2016,A

34
[ 32469-28-6 ]
[ 461432-25-7 ]

Reference： [1]Patent: WO2016/178148,2016,A1
[2]Patent: CN103739581,2016,B
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3947 - 3952

35
[ 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

36
[ 1030825-20-7 ]
[ 32469-28-6 ]
C₃₆H₅₆FO₆SSi₄^(1-)*Li⁽¹⁺⁾ [ No CAS ]

Reference： [1]Patent: WO2017/71813,2017,A1 .Location in patent: Page/Page column 11

37
[ 915095-94-2 ]
[ 32469-28-6 ]
[ 1417573-74-0 ]

Yield	Reaction Conditions	Operation in experiment
96%		Step 2 Synthesis of 1-C_ [4-chloro-3 - [[4 - [[(3S) _tetrahydro-3-furanyl] oxy] phenyl] methyl] phenyl] -D-glucopyranoside Glycosides,Specific steps are as follows:(1) To the dry and clean reaction flask at room temperature, 125 ml of tetrahydrofuran was added,50 g of the compound 2 ((3S) -3- [4 - [(2-chloro-5-iodophenyl) methyl] phenoxy] tetrahydrofuran)Nitrogen protection environment,Began to drop isopropyl magnesium chloride lithium chloride 150 ml,After the dropwise reaction,Half an hour later,Sampling.(2) the reaction system temperature down to -25 C or so,(2, 3, 4, 6-tetra-trimethylsilyl-D-gluconolactone) was added dropwise.1 hour after the start of sampling,Quenching the reaction with a hydrogen chloride methanol solution,Stir,Dropping saturated sodium carbonate solution,Adjust the pH to 7 ~ 8.(3) Concentrate to remove methanol and tetrahydrofuran from the product.(4) the residue was added to the ethyl acetate and stirred to separate,Separate the lower layer of water.(5) To the next layer of water was added ethyl acetate,Layered,The ethyl acetate phase was combined,Washed,The ethyl acetate was dried over anhydrous sodium sulfate,Filtered, the filtrate was concentrated to no fractions,Weigh the oil1-C- [4-chloro-3- [[4- [[(3S) -tetrahydro-3-furanyl] oxy] phenyl] methyl] phenyl]D-glucopyranoside 56 g.The crude yield was 96%The crude purity was 84%The product has high purity,Can be used directly in the next step without purification.

Reference： [1]Patent: CN106317035,2017,A .Location in patent: Paragraph 0047-0052

38
[ 1030825-20-7 ]
[ 32469-28-6 ]
[ 1132832-76-8 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In toluene; at -18 - -5℃;	500 ml of a toluene solution of 85 g / L of the main raw material M1 was prepared in a 1 L three-necked flask and flowed into the A unit of the microreactor at a flow rate of 110 ml / min, and a solution of 1.8 mol / L n-butyllithium at a concentration of 20 ml / min The flow rate was simultaneously introduced into the A unit, the residence time of the reaction was 7.4 seconds, and the reaction temperature was controlled at -18 ° C. After the reaction solution flows out of the A unit, the configured 320 g / L of the M3 feed liquid flows into the B unit at a flow rate of 60 ml / min at the same time. The residence time of the reaction unit is 22.1 seconds, and the reaction temperature controlled by the reaction unit is - 5 ° C.

Reference： [1]Patent: CN106866645,2017,A .Location in patent: Paragraph 0025; 0052; 0053

39
[ 67-56-1 ]
[ 915095-89-5 ]
[ 32469-28-6 ]
[ 915095-96-4 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 50 gm of (S)-4-bromo-l-chloro-2-(4-tetrahydrofuran-3-yloxy-benzyl)- benzene in tetrahydrofuran 300 mL and toluene 100 mL was cooled to -90 C to -100 C, 90 mL of n-hexyl Lithium (33% in tetrahydrofuran) was gradually added and the solution was stirred for 15 to 30 min. Then a solution of 2, 3, 4, 6 -tetrakis-0-(trimethylsilyl)-D- glucopyranone in toluene was added at -90 C to -100 C and the reaction mixture was stirred for 2 to 5 hrs. Thereafter 200 mL solution of methanesulphonic acid in methanol was added to the reaction mixture at -70 C to -90 C, the temperature of the reaction mixture was raised to 0 C to 15 C and the reaction mixture was stirred for 10 to 15 hrs at ambient temperature. The solution was then quenched with 8% aq. sodium bicarbonate solution followed by layer separation. The aqueous layer was extracted with ethylacetate (2 X 250 mL).The combined organic layer was washed with 250 mL 10% brine solution. The combined organic layer was concentrated under vacuum followed by stripping with acetonitrile 50mL to afford 95 gm of crude intermediate compound of formula (IV) as an oily mass. 200 mL of dichloromethane and 100 mL of acetonitrile was added to the oily mass at -30 C to -40 C followed by addition of trimethylsilane and borontrifluoride etherate. The reaction mixture was stirred for 2 to 3 hrs followed by addition of 550 mL of 8% aq. sodium bicarbonate solution at 5 C to 20 C. The organic layer was separated and extracted with dichloromethane (I X 250 mL and 1 X 100 mL). The combined organic layer was concentrated to get an oily mass of compound of formula (V). A solution of compound of formula (V) in 200 mL dichloromethane was added to slurry of 50 gm L-proline in 200 mL isopropanol and heated at 40 oC to 50 C for 7-10 hrs. The reaction mixture was filtered and washed with 25 mL dichloromethane and dried under vacuum to afford 53 gm of crystalline Form A of Empagliflozin L-proline complex.

Reference： [1]Patent: WO2017/141202,2017,A1 .Location in patent: Page/Page column 11-12

40
[ 67-56-1 ]
[ 1103738-26-6 ]
[ 32469-28-6 ]
[ 1318794-58-9 ]

Yield	Reaction Conditions	Operation in experiment
57%		Example 5 Preparation of methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl) methoxymethyl] phenyl] D-glucopyranoside To a solution of (2-chloro-5-iodo-phenyl)-(4-ethoxyphenyl) methanone (9.1 g, 24 mmol, 1.1 equiv.) in 2-MeTHF (100 mL) was cooled to 0-5 C. and followed by dropwise addition of DIBAL-H (26 mL, 26 mmol, 1.2 equiv). After the reaction was complete, the reaction mixture was cooled to -78 C. and added 2,3,4,6-tetrakis-O-trimethylsilyl-D-gluconolactone (10 g, 21.4 mmol, 1.0 equiv.) followed by dropwise addition of 2.1 M n-butyllithium/hexane (13 mL, 27 mmol, 1.3 equiv). After stiffing at -78 C. for 2 h, a solution of methane sulfonic acid (15.3 mL, 236 mmol, 11.0 equiv.) in methanol (30 mL) was added. The cooling bath was then removed, and the resultants were stirred at ambient temperature for 16 h. After the reaction was complete, the reaction mixture was quenched by sat'd aq NaHCO3. The resultants were concentrated to remove the organic solvents prior to being extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration the crude oil was purified by column chromatography to yield 5.7 g (57%) of the title compound as a white solid.

Reference： [1]Patent: US2017/240520,2017,A1 .Location in patent: Paragraph 0109-0110

41
[ 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

42
[ 915095-94-2 ]
[ 32469-28-6 ]
[ 915095-96-4 ]

Yield	Reaction Conditions	Operation in experiment
		To 100L is added in the reaction kettle 15L tetrahydrofuran, 15L of the toluene and the 4.8 kg (S)-3 - (4 - (5 - iodo -2 - benzylic) phenoxy) tetrahydrofuran, stirring and dissolving, under the protection of nitrogen the reaction liquid cooling to - 80 - - 70 C, dropwise 7L 2.5M butyl lithium-hexane solution, dropped temperature control reaction 1 - 1.5 hour. Control temperature - 80 - - 70 C dropwise 2, 3, 4, 6 - trimethyl silicon-based - D - four - O - - delta - lactone of the gluconic acid a toluene solution (9.5 kg, 10L), dropped temperature control reaction 2 - 2.5 hour. Slowly added methanol solution of the mesylate (5 kg, 40L), after adding up to 20 - 30 C reaction 16 - 18 hours.The reaction liquid transfer to 300L in the reactor, adding 50L 8% aqueous solution of sodium bicarbonate and 50L ethyl acetate, collecting the organic phase, the aqueous phase extracted two times then ethyl acetate (40L × 2), combined with the organic phase. The use of the organic phase sequentially 50L purified water washing, 50L 20% sodium chloride aqueous solution washing, drying of the organic phase with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure to about 20L, adding 8L toluene stirring, slowly adding to the 200L in normal heptane, stirring 0.5 - 1 hours then adding, collecting the solid title compound directly cast to a step.

Reference： [1]Patent: CN106336403,2017,A .Location in patent: Paragraph 0038-0041

43
[ 75-75-2 ]
[ 1030825-20-7 ]
[ 32469-28-6 ]
[ 1358581-37-9 ]

Yield	Reaction Conditions	Operation in experiment
77%		Into a 3L 4 necked RB Flask, were added 2-[(5-bromo-2-methyl-phenyl) methylj-5-(4- fluorophenyl) thiophene of formula (4) (100 g, 0.27 moles), THF (600 ml) and toluene (600m1). Resulting solution was cooled to -100 ° C, and was added 1 .6M N-BuLi in hexane solution (208 ml, 0.33 moles) at -90 to -100°C followed by 2, 3, 4, 6-tetra-o-Trimethylsilyl-f3-D- Gluconolactone of formula (3) (142.3 g, 0.30 mole) in toluene (142 ml) under nitrogen atmosphere. After addition, the reaction mixture was stirred for 60 mm and was added methane sulfonic acid (72.7 g 0.75 moles) in methanol (600 ml) at -90 to - 100°C. Later the reaction mixture was allowed to ambient temperature, stirred for overnight and was quenched with satd. NaHCO3 solution (1.OL). Organic layer separated and washed with aqueous saturated sodium chloride solution and dried over Na2SO4. Excess solvent was recovered under reduced pressure to afford thick oily liquid and product was isolated from toluene (300 ml) - n-heptane (1200 ml) mixture. Resulting solid was filtered off and dried under reduced pressure to afford compound of formula (5) (101 g, 77percent) as off-white solid.

Reference： [1]Patent: WO2018/20506,2018,A1 .Location in patent: Page/Page column 12; 13

44
[ 1034305-17-3 ]
[ 32469-28-6 ]
C₃₃H₅₃FO₆SSi₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(1) Add 22 mL of tetrahydrofuran and 220 mL of toluene to the reaction flask, and stir.22.0 g of <strong>[1034305-17-3]2-(5-bromo-2-fluorobenzyl)benzothiophene</strong> (Compound 1) was added.Cool the reaction solution to -60C,A solution of n-butyl lithium in n-hexane (2.5 mol/L) 31.5 mL was added dropwise under nitrogen protection.Control the temperature of the reaction liquid is not higher than -60 C, dropping rate 3 drops / second,After about 5 minutes, the solution was incubated at -60C for 1 hour.2,3,4,6-Tetra-O-trimethylsilyl-D-gluconolactone (Compound 2)36.8g dissolved in toluene 20mL, dropsAdded to the above system, control the temperature of the reaction solution is not higher than -60 C,After about 10 minutes, the reaction was continued at -60C for 5 hours to obtain compound 3.

Reference： [1]Patent: CN107540706,2018,A .Location in patent: Page/Page column 8-11

45
[ 67-56-1 ]
[ 915095-89-5 ]
[ 32469-28-6 ]
[ 1279691-36-9 ]

Yield	Reaction Conditions	Operation in experiment
87%		Take (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran 183kg,400kg anhydrous THF/toluene (1:4) was added to the nitrogen-dried 3000 litre reactor.The liquid nitrogen was cooled to -78, and hexane solution of 1. 6 mol·L-1 n-butyllithium was slowly added dropwise.Stirring was continued at this temperature for 1 h; 600 kg of a 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-lactone (256 kg) in toluene solution cooled to -78C was slowly added dropwise to the above 600 kg. In the reaction solution,-78 reaction for 3 h, after the basic reaction of TLC detection is completed,At this temperature is added 500kg of methanesulfonic acid in methanol solution (methanesulfonic acid 225kg + methanol 275kg);The reaction was stirred at 0 C 4h, and then warmed to 40 C stirred reaction 6h;5 mol?L-1 sodium hydroxide aqueous solution was added to the reaction solution, and the pH was adjusted to 7-8; stirring for 30 min,Extract with ethyl acetate (300kg×2)The organic phase is washed with saturated aqueous sodium chloride solution until neutral, then dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 208 kg of a light yellow viscous oil with a yield of 87%.
84%		Take (5)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy) tetrahydrofuran (91 kg), anhydrous tetrahydrofuran/toluene (200 kg (1:4)), and add it to a nitrogen-dried 2000-liter reactor. , Liquid nitrogen was cooled to -78 C, was slowly added dropwise 1. 6 mol-L" 1 n-butyllithium hexane solution 120L, maintaining the temperature stirred for 1h;A 300 kg toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono lactone (130 kg) cooled to -78C was slowly added dropwise to the above reaction solution, -78 C reaction 3 h, TLC test after the completion of the basic reaction, at this temperature was added 300kg of methanol solution of methanesulfonic acid (methanesulfonic acid 115kg + methanol 185kg); stirred at 0 C reaction 4.0h, and then heated to 40 C The reaction was stirred for 6 h. After the reaction was completed, 5 mol.I/1 aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 7 - 8; stirred for 30 min, extracted with ethyl acetate (200 kg X 2), and the organic phase was washed with a saturated aqueous solution of sodium chloride. Neutral, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 100 kg of pale yellow viscous oil in a yield of 84%.

Reference： [1]Patent: CN107652278,2018,A .Location in patent: Paragraph 0021
[2]Patent: CN107652276,2018,A .Location in patent: Paragraph 0015; 0020

46
[ 461432-23-5 ]
[ 75-75-2 ]
[ 32469-28-6 ]
[ 461432-24-6 ]

Yield	Reaction Conditions	Operation in experiment
64.3%		Under nitrogen protection, in a 250 ml three-necked flask (numbered bottle A) was added 5-bromo-2-chloro-4'-ethoxydiphenylmethane (III-1) (12.5, 0.038 mol), 40 ml of dry tetrahydrofuran. And 80 ml of toluene (dried by chlorination of hydrazine), and the dried ice acetone was cooled to -72 ° C with stirring, and a 2.5 Mu n-BuLi n-hexane solution (18.4 ml, 0.046 mol) was added dropwise to ensure that the temperature was not higher than -60 °C, stir for 30 min. Prepare a 500ml three-neck bottle (No. B), nitrogen protection, add 2,3,4,6-tetra-O-trimethylsilyl-FD-gluconolactone (19.7g, 0.042mol) and 110ml toluene (dried by chlorination of hydrazine), dry ice acetone was cooled to -72V. After the reaction time in the bottle A was reached, the solution in the bottle A was introduced into the bottle B, the reaction was continued for 2 hours at a low temperature, methanesulfonic acid (14.8 g, 0.154 mol) and 110 ml of methanol were added, and the dry ice bath was removed, and the temperature was naturally raised to room temperature. The reaction was overnight. After completion of the reaction, a saturated sodium hydrogencarbonate solution was added to adjust the pH to neutrality. After separation, the aqueous phase was extracted with ethyl acetate. The organic phase was washed once with saturated sodium chloride and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated, and after chromatography, 10.8 g (64.3percent) of white foam solids were obtained.

Reference： [1]Patent: CN108218928,2018,A .Location in patent: Paragraph 0185; 0186; 0187

47
[ 75-75-2 ]
[ 915095-94-2 ]
[ 32469-28-6 ]
C₂₄H₂₉ClO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.1%		Under nitrogen protection, in a 250 ml three-necked flask (numbered bottle A) was added (5)-5-iodo-2-chloro-4'-(tetrahydro-3-furanyl)oxydiphenylmethane (ma-2) ( 10.0g, 0.024mol), 40ml of dry tetrahydrofuran and 80ml of toluene (dried with calcium chloride), dry ice acetone with stirring to _72 C, 2.5 Mu n-BuLi n-hexane solution (11.6ml, 0.029mol) ), ensure that the temperature is not higher than -60 C, stir for 30 min. Prepare a 500ml three-neck bottle (No. B), nitrogen protection, and add 2,3,4,6-tetra--0-trimethylsilyl-f3-D-gluconolactone (12.4g, 0.027mol) and 110 ml of toluene (dried with calcium chloride), dry ice acetone was cooled to _72 C. After the reaction time in the bottle A was reached, the solution in the bottle A was introduced into the bottle B, the reaction was continued for 2 hours at a low temperature, methanesulfonic acid (14.8 g, 0.154 mol) and 110 ml of methanol were added, and the dry ice bath was removed, and the temperature was naturally raised to room temperature. The reaction was overnight. After completion of the reaction, a saturated sodium hydrogencarbonate solution was added to adjust the pH to neutrality. After separation, the aqueous phase was extracted with ethyl acetate. The organic phase was washed once with saturated sodium chloride and dried over anhydrous sodium sulfate. Filtering,Dry the solvent,After column chromatography, 7.0 g (60.1%) of a white foamy solid was obtained.

Reference： [1]Patent: CN108218928,2018,A .Location in patent: Paragraph 0205; 0206; 0207

48
[ 75-75-2 ]
[ 1030825-20-7 ]
[ 32469-28-6 ]
[ 1030825-21-8 ]

Yield	Reaction Conditions	Operation in experiment
		(1) replacing the reaction flask three times under inert gas N2,Add 300g of toluene, cool down to -70 ° C,97 g of n-butyllithium n-hexane solution (1.6 M, 1.08 eq) was added dropwise over 1 hour;Continue to add 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene (68g) in a mixture of tetrahydrofuran (137g) and toluene (137g) within 1 hour The addition is completed;After reacting for 30 minutes, a mixed solution of 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucono-delta-lactone (98 g) and toluene (279 g) was added dropwise.The addition was completed within 2 hours, and the reaction was kept for 3 hours after the completion of the dropwise addition;A mixed solution of methanesulfonic acid (48 g) and methanol (280 g) was added dropwise.After the completion of the dropwise addition, the temperature was raised to 10 ° C and the reaction was completed for 5 hours;Add saturated sodium bicarbonate solution to adjust pH 7-8, and separate the water layer.Extracting twice with ethyl acetate, washing with saturated brine and organic phase;The organic oil is removed by distillation under reduced pressure to a yellow oil, ie, an intermediate of formula I:

Reference： [1]Patent: CN108191841,2018,A .Location in patent: Paragraph 0042; 0044; 0045; 0051; 0057

49
[ 915095-89-5 ]
[ 32469-28-6 ]
[ 1279691-36-9 ]

Yield	Reaction Conditions	Operation in experiment
84%		Take <strong>[915095-89-5](S)-<strong>[915095-89-5]3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran</strong></strong> 91kg,Anhydrous tetrahydrofuran/toluene 200 kg (1:4) mixed solvent was added to a nitrogen-dried 2000 liter reactor, liquid nitrogen was cooled to -78 C, and 1. 6 mol?L-1 n-butyl lithium was slowly added dropwise. 120L of the alkane solution, stirring at this temperature for 1h;300 kg of a toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (130 kg) cooled to -78 C was slowly added dropwise to the above reaction solution, -78 C Reaction for 3 h,After the basic reaction of TLC was detected, 300 kg of methanesulfonic acid in methanol (methanolsulfonic acid 115 kg + methanol) was added at this temperature.185 kg); The reaction was stirred at 0 C for 4. 0 h, then the temperature was raised to 40 C and the reaction was stirred for 6 h.After the reaction, 5 mol?L-1 sodium hydroxide aqueous solution was added to the reaction solution.Adjust to pH 7 - 8; stir for 30 min, extract with ethyl acetate (200 kg×2).The organic phase is washed with a saturated aqueous solution of sodium chloride until neutral, then dried over anhydrous sodium sulfate.Filtration and concentration of the filtrate to dryness afforded a pale yellow viscous oil, 100 g, yield 84%.

Reference： [1]Patent: CN107652277,2018,A .Location in patent: Paragraph 0021

50
[ 461432-23-5 ]
[ 32469-28-6 ]
(3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.4%		Add compound 3a (180g, 0.55mol), tetrahydrofuran (360ml), toluene (720ml) to a 5L three-necked flask, stir until dissolved, nitrogen protection, dry ice-acetone bath to -80 ~ -70 C, add n-butyl Lithium-based solution (287 ml, 0.715 mol, 1.3 eq), the dropwise addition process control temperature was -80 to -70 C, and the reaction was stirred at -80 to -70 C for 0.5 h after the completion of the dropwise addition. A solution of Compound 2a (400 g, 0.86 mol) in toluene (360 ml) was added dropwise, and the dropwise addition process was carried out at -80 to -70 C, and the reaction was stirred at -80 to -70 C for 1 hour after the dropwise addition.A solution of trifluoroacetic acid (126 g, 1.10 mol) dissolved in water (600 mL) was added dropwise to the reaction solution, and the temperature was controlled to be less than -20 C. After the completion of the dropwise addition, the temperature was naturally raised to 10 to 20 C, and the reaction was carried out for 2 to 3 hours.After completion of the reaction, water (180 ml) and ethyl acetate (180 ml) were added, and the mixture was stirred for 30 min. Wash with saturated aqueous sodium hydrogencarbonate (720 ml) and water (720 ml), dry over anhydrous sodium sulfate (400 g)Concentrated under reduced pressure at 42 C to dryness to give compound 4a (230 g).The yield was 98.4%.

Reference： [1]Patent: CN108610316,2018,A .Location in patent: Paragraph 0028-0039
[2]Organic Process Research and Development,2019,vol. 23,p. 1458 - 1461

51
[ 915095-89-5 ]
[ 108-24-7 ]
[ 32469-28-6 ]
C₃₁H₃₅ClO₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 58%		To the solution of <strong>[915095-89-5](S)-<strong>[915095-89-5]3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran</strong></strong> in tetrahydrofuran n-BuLi (2.5 mol) in hexane added at a rate that maintained the reaction temperature below -90C followed by addition of 2,3,4,6-tetra-0-trimethylsilyl-P-D- glucolactone in toluene at a rate that maintained the reaction temperature below -90C. The solution was stirred for 30 min at -95C prior to quenching by addition of methanol containing methanesulfonic acid. The reaction mixture was stirred overnight as the temperature raise to 20C. After completion of reaction, the reaction was quenched by the addition of triethylamine and distilled it out under vacuum. To the obtained residue water was added and extracted thrice with ethylacetate. The combined ethylacetate fractions were washed with brine and dried over sodium sulfate. The reaction mixture was concentrated to provide formula C in the form oil. To the methylenechloride solvent, aluminum chloride was added in one lot and cooled the mass to the temperature 0C to 10C. To the prepared solution acetonitrile was added followed by addition of triethyl silane at a rate such that the temperature was maintained between 0C to 10C. Mixed the above prepared complex with oil of formula C and stirred for 2 h. When HPLC analysis revealed that the reaction was completed, the reaction was quenched by addition of 50% aqueous hydrochloric acid solution. Aqueous layer was extracted with methylenechloride. Combined organic layer washed with 5% aqueous hydrochloric acid solution followed by water and brine. The organic layer was distilled and the obtained residue was added methylenechloride, acetic anhydride and dimethylaminopyridine, pyridine and stirred for 5-6 h. Water was added to the reaction mixture and layers were separated. The methylenechloride layer was distilled and ethanol was added to it followed by heating to 55-60C. The reaction mixture was cooled, filtered and dried to obtain acetylated empagliflozin of formula F.Yield: ~ 58%. Purity (by HPLC): >99.8%

Reference： [1]Patent: WO2018/207111,2018,A1 .Location in patent: Page/Page column 13; 14

52
[ 1030825-20-7 ]
[ 32469-28-6 ]
(2R,3S,4S,5S)-1-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)hexane-1,2,3,4,5,6-hexaol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		To a 500 mL three-necked flask under nitrogen, 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene (18.0 g, 0.05 mol) was added in sequence, 140 g of tetrahydrofuran, and stirred 10 Minutes later,Cool to -80 ° C, add n-butyl lithium (22 mL, 0.055 mol) dropwise, stir for 30 minutes.2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (28.0 g,0.06mol),After stirring for 60 minutes, a solution of trifluoroacetic acid (17.1 g, 0.15 mol) and 200 g of water was added dropwise, and after completion of the dropwise addition, the temperature was raised to 20 to 30 ° C and stirred for 12 hours. Saturated sodium bicarbonate solution was added dropwise to neutral, extracted with ethyl acetate (200 mL) and evaporated. The obtained solid was placed in a 500 mL three-necked flask, 200 mL of acetonitrile was added, stirred for 10 minutes, sodium borohydride (2.8 g, 0.075 mol) was added, and the mixture was heated to 50-60 ° C for 2 hours, cooled to 20 ° C, and 200 mL of water was added dropwise. Evaporate acetonitrile, filter, use trueThe filter cake was dried in an empty drying oven to obtain 18.7 g of a white solid, HPLC purity: 98percent, yield 81percent

Reference： [1]Patent: CN108912092,2018,A .Location in patent: Paragraph 0029-0031

53
[ 615-87-2 ]
[ 32469-28-6 ]
C₂₆H₅₁BrO₅Si₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 2.8-M n-butyllithium solution in hexane (26.8mL, 74.2mmol) was added dropwise to a THF (100mL) solution of <strong>[615-87-2]1,5-dibromo-2,4-dimethylbenzene</strong> (4) (17.6g, 74.2mmol) at -78C in a nitrogen atmosphere, and the mixture was stirred for 15 min at the same temperature. Then, a THF (60mL) solution of 2,3,4,6-tetra-O-trimethylsilyl-d-glucono-1,5-lactone (5) (38.1g, 81.7mmol) was added dropwise over 25min, and the mixture was stirred for 15min at the same temperature. Ice water was added to the reaction solution, and the resulting mixture was warmed to room temperature and then extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a methanol (370mL) solution containing 79 methanesulfonic acid (0.48mL, 7.42mmol), and the solution was stirred for 16h at room temperature. Then, the solution was neutralized with triethylamine (1.4mL, 10.3mmol), and the reaction mixture was concentrated. The resulting residue was purified using neutral silica gel column chromatography (chloroform:methanol ratio=9:1 to 8:1) to obtain the title compound as a light-yellow gummy substance (17.8g, 64% in 2 steps).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 394 - 409

54
[ 1240304-64-6 ]
[ 32469-28-6 ]
C₂₈H₅₆O₆Si₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 2.6-M n-butyllithium solution in hexane (34 mL, 88.6 mmol) was added dropwise to a THF (100 mL) solution of compound 22b (24.5 g,88.6 mmol) at -78 C in a nitrogen atmosphere, and the mixture was stirred for 5 min at the same temperature. Then, a THF (60 mL) solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (5) (37.6 g,80.5 mmol) was added dropwise over 25 min, and the mixture wasstirred for 10 min at the same temperature. Ice water was added to the reaction solution, and the resulting mixture was warmed to room temperature and then extracted twice with ethyl acetate. The combined organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a methanol (380 mL) solution containing methanesulfonic acid (1.55 g, 16.1 mmol), and the solution was stirred for 2 h at room temperature. Then, the solution was neutralized with triethylamine (11.2 mL, 80.5 mmol), and the reaction mixture was concentrated. The resulting residue (30.2 g) was dissolved in pyridine (100 mL), and acetic anhydride (100 mL) was then added; the mixture was then stirred for 14 h at room temperature. Ice water (400 mL) wasadded, and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic layer was washed with 1-M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution and then dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purifiedusing neutral silica gel column chromatography (hexane?hexane:ethyl acetate ratio=6:4). The obtained organic layer was distilled off under reduced pressure. Et3SiH (21 mL, 128 mmol) and BF3·OEt2(49 mL, 385 mmol) were added to a solution of the resulting residue (32.8 g) in chloroform (150 mL) and acetonitrile (150 mL) at 4 C in a nitrogen atmosphere, and the mixture was stirred for 1 h at the same temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with chloroform. Then, the organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and the solvent was distilled off under reducedpressure. The resulting residue was purified using neutral silica gel column chromatography (hexane:ethyl acetate ratio=2:1) to obtain the title compound as light-yellow gummy substance (22.9 g, 59% in 4steps).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 394 - 409

55
[ 67-56-1 ]
[ 1030825-20-7 ]
[ 32469-28-6 ]
[ 1358581-37-9 ]

Yield	Reaction Conditions	Operation in experiment
83%		34.2 g of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, anhydrous tetrahydrofuran/toluene 100 g (1:4) mixed solvent was added to 500 ml of nitrogen-dried reaction flask, liquid nitrogen was cooled to -78 ° C, and 17 ml 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. 150 g of a toluene solution of 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone (50 g) cooled to -78 ° C was slowly added dropwise to the above reaction solutionin -78 ° C and reaction for 3h, After the basic reaction of TLC was detected, 100 g of methanesulfonic acid in methanol (methanesulfonic acid 45 g + methanol 55 g) was added at this temperature; the reaction was stirred at 0 ° C for 4 h, then the temperature was raised to 40 ° C and stirred for 6 h; 5 mol·L-1 sodium hydroxide aqueous solution was added to the reaction solution, adjusted to pH 7-8; stirred for 30 min, Extracted with ethyl acetate (200 ml × 2),The organic phase is washed with a saturated aqueous solution of sodium chloride until neutral, then dried over anhydrous sodium sulfate.Filtration, the filtrate was concentrated to dryness to give a pale yellow viscous oil 38 g, yield 83percent

Reference： [1]Patent: CN109336874,2019,A .Location in patent: Paragraph 0018

56
[ 915095-94-2 ]
[ 32469-28-6 ]
[ 1279691-35-8 ]

Yield	Reaction Conditions	Operation in experiment
82.2%		Add 100mL of tetrahydrofuran to a 1L reaction flask,50.0g(S) -3- (4- (5-iodo-2-chlorobenzyl) phenoxy) tetrahydrofuran and 73.6 g 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, start stirring,Under nitrogen protection,Cool down to -30 -20 ,Drop 120mLIsopropylmagnesium chloride-lithium chloride1.3mol / L tetrahydrofuran solution,Control temperature: -30 -20 , after holding for 1h,Add 150mL10%Aqueous citric acid monohydrate solution, stirred for 30min, and allowed to stand and separate.The layers were separated and the organic phase was collected and concentrated under reduced pressure to give a pale yellow oil with a purity of 88.7%.Add 50 mL of ethyl acetate to the concentrate, turn on the stirring, and lower the temperature to -55 C to -65 C.After precipitating a large amount of white solid, stir for 0.5h,To the reaction was added 250 mL of n-heptane dropwise, stirred for 0.5 h, and filtered with suction.The filter cake was dried in a hot air circulation drying oven at 40 C for 15 hours to obtain 46.3 g of the title compound.The molar yield was 82.2%, and the purity was 94.0%.
		Compound V1 (10 kg, 24 mol),LiCl (1.28kg, 30mol) was added to 25L acetonitrile.Cool to -20 C, add 1.3M format reagent iPrMgCl solution (25L, 30mol),The temperature is controlled at -20 to -15 C, and the mixture is kept at -20 C for 1 hour.Add V2 (24kg, 50mol),The temperature was controlled at -10 to 0 C, and the reaction was stirred at 0 C for 8 hours.The reaction was quenched by dropwise addition of a saturated aqueous solution of citric acid (10 L).Add 50 L of dichloromethane and 40 L of water to extract the layers, and separate the organic layer.After concentration, 20 kg of crude oil was used directly for the next reaction.

Reference： [1]Patent: CN110407891,2019,A .Location in patent: Paragraph 0031-0036
[2]Patent: CN109988161,2019,A .Location in patent: Paragraph 0050-0059

57
[ 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

58
[ 67-56-1 ]
[ 915095-94-2 ]
[ 32469-28-6 ]
[ 1279691-36-9 ]

Yield	Reaction Conditions	Operation in experiment
		In a dry 20L four-necked flask, add SM1 (2000g) and THF (3575ml) under the protection of nitrogen, install an exhaust gas absorption device, stir it at 20-25 C and completely dissolve it, and then cool the internal temperature to -16 C.4410 ml of (1.3N) isopropylmagnesium chloride-lithium chloride THF solution was added dropwise. During the dropwise addition, the internal temperature was controlled at -14 ± 2 C. After 1.5 hours of dripping, the reaction was continued for 0.5 hours. 2251.5g SM2 was added dropwise, and the addition was completed after 50 minutes.The reaction was almost complete by TLC (developing solvent: petroleum ether / ethyl acetate = 3/1).Control the internal temperature below 5 C and add 6000ml of 10% citric acid aqueous solution dropwise. After 20min, the stirring is continued for 5min.The upper organic phase was separated, and the aqueous phase was extracted once more with 2000 ml of tetrahydrofuran. The combined organic phases were concentrated under reduced pressure to an oil at 30-32 C.Add 9000ml of methanol to the residue, stir to dissolve, and put it into a 20L four-necked flask.270 g of 2.5N HCl / methanol solution was added under stirring, and the temperature was controlled at 13 to 17 C. and the reaction was stirred for 15 hours.Adjust the pH to about 8 ~ 9 with triethylamine between 5 10 , then control the temperature to 32 ± 2 and concentrate to dryness under reduced pressure.The residue was dissolved by stirring with 3925 ml of acetonitrile and 2190 ml of dichloromethane (to be used in the next step).

Reference： [1]Patent: CN110655511,2020,A .Location in patent: Paragraph 0068-0071

59
[ 915095-89-5 ]
[ 32469-28-6 ]
C₃₅H₅₈ClO₈Si₄^(1-)*Li⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(3S) -3- [4-[(2-chloro-5-iodophenyl) methyl] phenoxy] tetrahydrofuran (1.0 g, 2.72 mmol), tetrahydrofuran (16 mL),PMDTA (1.2mL, 1.5equiv) was added to a 250mL three-necked bottle in sequence, and after replacing the air in the reaction bottle with nitrogen,The temperature of the cold trap is controlled at about -78 C, and 2.5M n-butyllithium (1.6mL, 1.5equiv) is slowly added dropwise and stirred for about 1h.TMS-protected gluconolactone 4 (1.5 g, 1.3 equiv) and toluene (16 mL) were added to another 50 mL round bottom flask and mixed well, and the temperature of the cold trap was controlled at about -78 C.The toluene solution of 4 was slowly dropped into a three-necked flask, keeping the temperature unchanged, and stirred for 2h.Keeping the temperature unchanged, methanol (10 mL) was slowly dropped into a three-necked flask and stirred for 20 min.Then the temperature rose to about -20 C, and a 15% citric acid aqueous solution (50 mL) was slowly dropped into the three-necked flask. After the drop was completed, the temperature was raised to room temperature and stirred for 2 hours.Then, a saturated sodium bicarbonate aqueous solution (100 mL) was slowly dropped into a three-necked flask, and the drop was completed, and stirred for 20 min.Transfer the reaction solution to a 250mL separatory funnel, let stand for layer separation, separate the organic phase, and extract the aqueous phase with ethyl acetate,The organic phases were combined and washed three times with brine, and the organic phase was dried over anhydrous magnesium sulfate.After filtering off the desiccant, the solvent was removed by rotary evaporation to obtain a yellow oil.

Reference： [1]Patent: CN111040000,2020,A .Location in patent: Paragraph 0055-0057

CAS No. :	32469-28-6	MDL No. :	MFCD22665922
Formula :	C₁₈H₄₂O₆Si₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	466.86	Pubchem ID :	-
Synonyms :

Signal Word:		Class:
Precautionary Statements:		UN#:
Hazard Statements:		Packing Group:

Precautionary Statements-General
Code	Phrase
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Code	Phrase
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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.
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P240	Ground/bond container and receiving equipment.
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P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
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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.
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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.
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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
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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
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 32469-28-6 ] {[proInfo.proName]}

Quality Control of [ 32469-28-6 ]

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[ 32469-28-6 ] Synthesis Path-Upstream 1~5

[ 32469-28-6 ] Synthesis Path-Downstream 1~59

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