Structure of 32469-28-6
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CAS No. : | 32469-28-6 |
Formula : | C18H42O6Si4 |
M.W : | 466.86 |
SMILES Code : | O=C1O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C |
MDL No. : | MFCD22665922 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
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). |
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. |
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. |
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). |
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. |
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 |
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. |
Yield | Reaction Conditions | Operation in experiment |
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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. |
Yield | Reaction Conditions | Operation in experiment |
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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. |
Yield | Reaction Conditions | Operation in experiment |
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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%. |
Yield | Reaction Conditions | Operation in experiment |
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(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: |
Yield | Reaction Conditions | Operation in experiment |
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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%. |
Yield | Reaction Conditions | Operation in experiment |
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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% |
Yield | Reaction Conditions | Operation in experiment |
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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 |
Yield | Reaction Conditions | Operation in experiment |
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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 |
Yield | Reaction Conditions | Operation in experiment |
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(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. |