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[ CAS No. 461432-26-8 ]

{[proInfo.proName]} (Synonyms:BMS-512148) ,{[proInfo.pro_purity]}
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Chemical Structure| 461432-26-8
Chemical Structure| 461432-26-8
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CAS No. :461432-26-8 MDL No. :MFCD13182359
Formula : C21H25ClO6 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :408.87 g/mol Pubchem ID :9887712
Synonyms :

Safety of [ 461432-26-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
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Application In Synthesis of [ 461432-26-8 ]

  • Downstream synthetic route of [ 461432-26-8 ]

[ 461432-26-8 ] Synthesis Path-Downstream   1~24

  • 1
  • [ 461432-26-8 ]
  • [ 4254-15-3 ]
  • dapagliflozin (S) propylene glycol hydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
4% With water In tert-butyl methyl ether; cyclohexane for 1h; 6 Example 6; To acetonitrile (12 mL), at batch temperature of 8-10° C. under nitrogen atmosphere, was charged borontrifluoride diethyletherate (2.3 mL, 18.4 mmol) and water (0.82 mL, 4.6 mmol). After holding the above mixture for about 1 hour, triethylsilane (3 mL, 18.4 mmol) was added. The resulting mixture was held for about 1 hour, and then compound B (prepared as described in Example 17) in 10 mL acetonitrile was added. The batch was held at 5 to 10° C. On completion of the reaction as determined by HPLC, the reaction mixture was quenched with aqueous ammonium acetate (24 mL; 85 g) in 200 mL water. The phases were separated and product rich organic phase was dried over sodium sulfate. The product rich organic phase was concentrated under reduced pressure. Water (13 mg, 0.7 mmol, based on 0.3 g crude compound B input), (S)-propylene glycol (56 mg, 0.7 mmol), t-butylmethyl ether (5 mL, 17 mL/g compound B input), compound Ia seeds (20 mg) were mixed and held for 1 hr., to form a crystal slurry. Cyclohexane (10 mL, 33 mL/g compound B (input)) was added. The crystalline product (Ia) was isolated by filtration (4-5%) and dried in vacuo at 20-25° C.
With water In methanol; Isopropyl acetate; cyclohexane at 5 - 20℃; for 1 - 22.1667h; 1; 1A Example 1; Compound A can be prepared as described in Example 1, Part E of U.S. Pat. No. 6,515,117. A 10-L glass reactor equipped with a thermocouple and a nitrogen inlet was charged with MeOH (1.25 L), deionized water (3.6 L) followed by 50% aqueous NaOH (205.9 ml, 3.899 mol). The residual solution of NaOH in the measuring cylinder was transferred with water (94 ml) to the reaction vessel. Compound A (503.11 g, 0.872 mol) was added and the mixture was stirred and heated to 68° C. over 1.5 h. After 1 h, the circulation bath temperature was lowered from 80 to 70° C.; internal temperature became 65° C. After a total of 3 h HPLC1 indicated completion of reaction, Compound I AP 99.5. After the mixture was cooled to 25° C., isopropyl acetate (2.5 L) was added. The mixture was stirred for 10 minutes and then the aqueous layer was separated (pH=12.5) and organic layer was washed with water (1 L). During this wash the pH of the biphasic system was adjusted to 6.0 with conc. HCl (5.0 ml) and then the aqueous layer was separated.2 The organic layer was collected in a separate vessel. The reactor was washed with water (2 L), MeOH (2 L) and flushed with nitrogen gas. The wet solution of compound B was recharged into the reactor and (S)-propylene glycol ((S)-PG) (67.03 g, 0.872 mole) was introduced. Optionally, seed crystals of (S)-PG Ia may be added at this stage. Instantaneous crystallization produced a thick slurry. After stirring for 1 h, cyclohexane (2.5 L) was added rapidly over 10 minutes and the stirring was continued for 21 h. The product was filtered through a filter paper (Whatman No.5, Buchner funnel 24 diameter). The filtration was rapid and took about 15 minutes. The filter cake was washed with a mixture (1:1) of MTBE/cyclohexane (2×1 L) and dried under suction for 0.5 h. The solid was transferred to a pyrex tray and dried under vacuum (25 mm Hg) in an oven at 25-30° C. for two days till water analysis by KF corresponded to monohydrate (3.6 wt. %). The (S)-PG product Ia was obtained (0.425 kg, yield 97%) as a snow white solid, HPLC3 AP 99.7. Seed crystals may be prepared by dissolving compound I in a solvent such as MTBE and treating the resulting solution with (S)-propylene glycol and proceeding as described above without the use of seeding. 1HPLC: Column: YMC ODS-A (C-18) S3, 4.6×50 mm. Solvent A: 0.2% aq. H3PO4. Solvent B: 90% CH3CN/10% H2O Start % B=0, final % B=100 Gradient time 8 min; hold time 3 min. Integration stop time 11.0 min. Flow rate 2.5 ml/min. UV wave length 220 nm. 2Neutralization before phase split was done to prevent contamination of the product with NaOH. (S)-PG structure prepared without neutralization was slightly basic [pH 8.3 of a suspension sonicated in water (20 mg/ml)]. 3HPLC method: Mobile Phase A: 0.05% TFA in H2O Mobile Phase B: 0.05% TFA in CAN. Column: YMC Hydrosphere 4.6×150 (3μ). Gradient: 30-90% B over 45 minutes, hold 5 minutes; back to 30% B and re-equilibrate for 10 min. Wavelength: 220 nm. Injection Volume: 10 μl. Temperature: Ambient; Example 1A; Procedure; 20 g of compound A was charged to a reactor at ambient temperature and pressure. 30 mL Methanol and 49.75 mL 3N NaOH were added to the reactor and the reaction mixture was heated to 80° C. or reflux, and held about 2-3 hours for reaction completion<0.5 AP. The batch was cooled to 20° C. and neutralized to pH 6.0-7.5 using con. HCl or 1N acetic acid (requires 1 mL/gm input).; Extraction; The product was extracted from the reaction mixture into 100 mL isopropyl acetate, the aqueous phase was split away and the organic phase washed with water until conductivity<10 mS (4 mL/gm input). The aqueous phase was split away.; Crystallization; 2.8 g (1.05 eq) (S)-(+)-1,2 Propanediol was added to the reaction mixture. The batch was seeded with 0.1 g compound I seed. 160 mL Cyclohexane was added and the batch cooled to from room temperature to 5° C. The batch was allowed to stir at from room temperature to 5° C. at least 1 hour before isolation.; Isolation and Drying; Each load of isolated cake was washed with 50/50 by volume isopropyl acetate/cyclohexane mixture. The cake was dried at 30° C. in a vacuum oven under full vacuum. (Cake is dry when KF=3.6%-4.1%). Yield=84% (uncorrected) Typical purity=99.81 AP Typical PG content=15.1-15.8% by GC
With water In methanol; Isopropyl acetate; cyclohexane at 5℃; for 1 - 22h; 2.A; 2.B Example 2APreparation of Dapagliflozin (S)-Propylene Glycol Hydrate (Ia)The preparation of structure Ia is described and depicted schematically below. Compound A can be prepared as described in Example 1, Part E of U.S. Pat. No. 6,515,117.A 10-L glass reactor equipped with a thermocouple and a nitrogen inlet was charged with MeOH (1.25 L), deionized water (3.6 L) followed by 50% aqueous NaOH (205.9 ml, 3.899 mol). The residual solution of NaOH in the measuring cylinder was transferred with water (94 ml) to the reaction vessel. Compound A (503.11 g, 0.872 mol) was added and the mixture was stirred and heated to 68° C. over 1.5 hour. After 1 hour, the circulation bath temperature was lowered from 80° C. to 70° C.; internal temperature became 65° C. After a total of 3 hours, HPLC indicated completion of reaction, Compound I AP 99.5. (HPLC: Column: YMC ODS-A (C-18) S3, 4.6×50 mm. Solvent A: 0.2% aq. H3PO4. Solvent B: 90% CH3CN/10% H2O Start % B=0, final % B=100 Gradient time 8 min; hold time 3 minutes. Integration stop time 11.0 minutes. Flow rate 2.5 ml/minute. UV wave length 220 nm.)After the mixture was cooled to 25° C., isopropyl acetate (2.5 L) was added. The mixture was stirred for 10 minutes and then the aqueous layer was separated (pH=12.5) and organic layer was washed with water (1 L). During this wash the pH of the biphasic system was adjusted to 6.0 with concentrated HCl (5.0 ml) and then the aqueous layer was separated. Neutralization before phase split was done to prevent contamination of the product with NaOH. The (S)-propylene glycol structure prepared without neutralization was slightly basic [pH 8.3 of a suspension sonicated in water (20 mg/ml)].The organic layer was collected in a separate vessel. The reactor was washed with water (2 L), MeOH (2 L) and flushed with nitrogen gas. The wet solution of compound B was recharged into the reactor and (S)-propylene glycol ((S)-PG) (67.03 g, 0.872 mole) was introduced. Optionally, seed crystals of (S)-PG Ia can be added at this stage. Seed crystals can be prepared by dissolving compound I in a solvent such as MTBE and treating the resulting solution with (S)-propylene glycol and proceeding as described above without the use of seeding.Instantaneous crystallization produced a thick slurry. After stirring for 1 hour, cyclohexane (2.5 L) was added rapidly over 10 minutes and the stirring was continued for 21 hours. The product was filtered through a filter paper (Whatman No.5, Buchner funnel 24 diameter). The filtration was rapid and took about 15 minutes. The filter cake was washed with a mixture (1:1) of MTBE/cyclohexane (2×1 L) and dried under suction for 0.5 hour. The solid was transferred to a pyrex tray and dried under vacuum (25 mm Hg) in an oven at 25-30° C. for two days till water analysis by K.F. corresponded to monohydrate (3.6 wt. %). The (S)-PG product Ia was obtained (0.425 kg, yield 97%) as a snow white solid, mp 71° C., HPLC AP 99.7. (HPLC method: Mobile Phase A: 0.05% TFA in H2O. Mobile Phase B: 0.05% TFA in CAN. Column: YMC Hydrosphere 4.6×150 (3μ). Gradient: 30-90% B over 45 minutes, hold 5 minutes; back to 30% B and re-equilibrate for 10 min. Wavelength: 220 nm. Injection Volume: 10 μl. Temperature: Ambient).The (R) form of dapagliflozin can be prepared using these methods and substituting (S)-propylene glycol with (R)-propylene glycol.; Example 2BPreparation of Dapagliflozin (S)-Propylene Glycol Hydrate (Compound Ia)The structure Ia can alternatively be prepared as described and depicted schematically below. 20 g of compound A was charged to a reactor at ambient temperature and pressure. 30 mL Methanol and 49.75 mL 3N NaOH were added to the reactor and the reaction mixture was heated to 80° C. or reflux, and held about 2-3 hours for reaction completion <0.5 AP. The batch was cooled to 20° C. and neutralized to pH 6.0-7.5 using 1N acetic acid (requires 1 mL/gm input).Extraction: The product was extracted from the reaction mixture into 100 mL isopropyl acetate, the aqueous phase was split away and the organic phase washed with water until conductivity <10 mS (4 mL/gm input). The aqueous phase was split away.Crystallization: 2.8 g (1.05 eq) (S)-(+)-1,2 Propanediol 96%+ was added to the reaction mixture. The batch was seeded with 0.1 g compound I seed. 160 mL Cyclohexane was added and the batch cooled to 5° C. The batch was allowed to stir at 5° C. at least 1 hour before isolation.Isolation and Drying: Each load of isolated cake was washed with 50/50 by volume isopropyl acetate/cyclohexane mixture. The cake was dried at 30° C. in a vacuum oven under full vacuum. (Cake is dry when KF=3.6%-4.1%).Yield=84% (uncorrected) Typical purity=99.81AP Typical PG content=15.1-15.8% by GC Capsules containing the SGLT2 inhibitor of Formula I (dapagliflozin) or Formula Ia (dapagliflozin (S)-Propylene glycol hydrate) were prepared in strengths of 2.5 mg (Example 3), 10 mg (Example 4) and 100 mg (Example 5) as two-piece, gray opaque size No.0 (2.5 mg and 10 mg) and size No.00 (for 100 mg) hard gelatin capsules.
  • 2
  • [ 714269-57-5 ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
87.6% With triethylsilane; boron trifluoride diethyl etherate; at 5℃; for 0.00416667h; Accurately prepare a mixture of 300 ml of methanol and methanesulfonic acid (V methanol / methanesulfonic acid = 4:1),It is pumped into the third reaction unit of the microreactor at a flow rate of 3.5 ml/min, and mixed with the reaction liquid flowing out from the second reaction unit.The residence time of the reaction in this step is 19 seconds, and the reaction temperature controlled by the reaction unit is 5 C. After the reaction liquid flows out from the third reaction unit,At the same time, the prepared mixture of boron trifluoride diethyl ether and triethylsilane was pumped into the fourth reaction unit at a flow rate of 3.5 ml/min.The residence time of the reaction unit is 15 seconds, the temperature of the fourth reaction unit is controlled to be 5 C, and the liquid discharged from the fourth reaction unit is continuously collected 100 ml.Finally, it was added to 200 ml of n-heptane, stirred and crystallized, and kept at 0 C for 1 hour, and filtered to obtain a crude product of dapagliflozin. Take a small amount of dapagliflozin for liquid chromatography analysis.The conversion ratio of the raw material A was 99.9%, and the total yield was 87.6%.
76% With triethylsilane; aluminum (III) chloride; In dichloromethane; acetonitrile; at -5 - 10℃; for 3.5h;Large scale; Take 1-chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4-ethoxybenzyl)-benzene 44kg,Dichloromethane 50kg and acetonitrile 150kg added to the 500L reactor, stir;The reaction solution was cooled to -5 DEG C, 2 kg of anhydrous aluminum trichloride was added, stirred for 30 minutes, and 13 kg of Et3SiH was added dropwise at this temperature. After the dropwise addition, the temperature was gradually raised to 10 DEG C and the reaction was carried out for 3 hours.The reaction is completed, cooled to -5 C, saturated sodium bicarbonate solution was added dropwise, adjusting the pH to 6-7;Extract with ethyl acetate (50kg×2), wash the organic phase with saturated sodium chloride solution, wash with water to neutrality, then dry over anhydrous sodium sulfate, filter and evaporate the filtrate to recover the ethyl acetate.A mixed solution of 40 kg of methanol and dichloromethane (1:1) was added, stirred, and a large amount of solids were precipitated, and the mixture was cooled and stirred for 1 h.;Filter and wash the solid with cold ethanol and vacuum dry overnight at 50 C. to obtain 31 kg of a white solid with a yield of 76% and a purity of 99.37%.
76% Take 1-chloro-4-(1-methoxy-D-glucopyranose-1-yl)-2-(4-ethoxybenzyl)-benzene, 44kg,Dichloromethane (50kg) and acetonitrile (150kg) were added to the 500L autoclave and stirred well; the reaction solution was cooled to -5C, 2kg of anhydrous aluminum trichloride was added, stirred for 30min, and 13kg of Et3SiH was added dropwise at this temperature. After the dropwise addition, the temperature was gradually increased to 10 C, reaction 3h. After the reaction is completed, cool down to -5C, add saturated sodium bicarbonate solution dropwise, adjust the pH to 6-7, extract with ethyl acetate (50kg × 2), wash the organic phase with saturated sodium chloride solution, and wash with water to neutrality. Then, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was recovered under reduced pressure. Ethyl acetate was added to a mixed solution of 40 kg of methanol and methylene chloride (1:1), stirred, and a large amount of solids precipitated, and the mixture was cooled and stirred for 1 h. Filtration, washing the solid with cold ethanol, vacuum drying at 50 C. overnight, yielded 31 kg of a white solid, yield 76%. Purity 99.37%.
76% Take 1-chloro-4-(1-methoxy-D-glucopyran-1-yl)-2-(4-ethoxybenzyl)-benzene 44kg, dichloromethane 50kg and acetonitrile 150kg to add 500L reaction Stir well in the kettle. The reaction solution was cooled to -5 C, 2 kg of zinc chloride was added, and stirred for 30 min. 13 kg of Et 3 SiH was added dropwise thereto at this temperature, and the temperature was slowly raised to 10 C for 3 h.After the reaction was completed, the temperature was lowered to -5 C, and a saturated sodium hydrogencarbonate solution was added dropwise to adjust the pH to 6 to 7. Extracted with ethyl acetate (50 kg × 2), the organic phase was washed successively with saturated sodium chloride solution, water, then neutralized, then dried over anhydrous sodium sulfate, filtered, and filtrated to recover ethyl acetate under reduced pressure, 40 kg of methanol and two A mixed solution of methyl chloride (1:1) was stirred, and a large amount of solid was precipitated, and the mixture was cooled and stirred for 1 hour. Filtration, washing the solid with cold ethanol, and drying under vacuum at 50 C overnight to give a white solid 31 kg, yield 76%. The purity is 99.37%.
72.1% With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -20 - 0℃; To 100mL three-necked flask was added 4.23g of intermediate -1,20ml methylene chloride, 15ml of acetonitrile, stirred to dissolve, cooled to -15 to -20 deg.] C, was added 6.84g of triethylsilane was added dropwise 6.09g three boron trifluoride diethyl, dropping the reaction temperature is kept at -10 deg.] C, then warmed to completion of the dropwise addition -5 -0 insulation mixing the reaction, the HPLC monitoring of the reaction is complete, add saturated sodium bicarbonate ph adjusted to about 7, Save pressure distillation, liquor added ethyl acetate, dried over anhydrous sodium sulfate to afford 2.84g Dag column net yield of 72.1%.
With triethylsilane; boron trifluoride diethyl etherate; water; In acetonitrile; at 5 - 10℃; for 2h;Product distribution / selectivity; Example 6; To acetonitrile (12 mL), at batch temperature of 8-10 C. under nitrogen atmosphere, was charged borontrifluoride diethyletherate (2.3 mL, 18.4 mmol) and water (0.82 mL, 4.6 mmol). After holding the above mixture for about 1 hour, triethylsilane (3 mL, 18.4 mmol) was added. The resulting mixture was held for about 1 hour, and then compound B (prepared as described in Example 17) in 10 mL acetonitrile was added. The batch was held at 5 to 10 C. On completion of the reaction as determined by HPLC, the reaction mixture was quenched with aqueous ammonium acetate (24 mL; 85 g) in 200 mL water. The phases were separated and product rich organic phase was dried over sodium sulfate. The product rich organic phase was concentrated under reduced pressure. Water (13 mg, 0.7 mmol, based on 0.3 g crude compound B input), (S)-propylene glycol (56 mg, 0.7 mmol), t-butylmethyl ether (5 mL, 17 mL/g compound B input), compound Ia seeds (20 mg) were mixed and held for 1 hr., to form a crystal slurry. Cyclohexane (10 mL, 33 mL/g compound B (input)) was added. The crystalline product (Ia) was isolated by filtration (4-5%) and dried in vacuo at 20-25 C.
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -45 - -10℃; Example 1C (282 g, 0.643 mol) was dissolved in anhydrous acetonitrile /dichloromethane (3.4 L, 1 :1 (v/v)) at -45 0C stirred solution of in was added triethylsilane (299 g, 2.57 mol) followed by addition of boron trifluoride etherate (245 mL, 1.93 mol). After the addition, the mixture was stirred for another 2 h at -10 0C. The reaction was quenched with saturated aqueous bicarbonate to pH 7.5. The volatiles were removed under reduced pressure and the residues were extracted with ethyl acetate (2 x 3.0 L). The combined organic layers were washed with brine (2 x 2.0 L), dried over sodium sulfate and concentrated to give the crude product as a white solid (250 g). Purity (HPLC): 82.8% (UV).[0132] A 5 L 4-necked flask was charged with the above crude product (203 g, 82% purity) and followed by Z-proline (114 g, 0.995 mol), ethanol(1.46 L) and water (162 mL). The mixture was heated to reflux for 30 min with rapid mechanical stirring. n-Hexane (200 mL) was added dropwise to the above solution. After the addition was complete, the reaction was cooled slowly to room temperature and then further to -5C. After stirring for 3 h at -5 0C, the mixture was filtered and the filter cake was washed with cold ethano I/water (90: 10 (v/v), 2 x 100 mL) and n-hexane (2 x 500 mL), and dried under vacuum at 65C to give the desired product as a white solid (186 g). A portion of this crude product (140 g) was dissolved in ethano I/water (90:10 (v/v), 700 mL) at 75 0C with mechanical stirring. After the solution became clear, it was cooled slowly to room temperature and stirred for another 5 h. The mixture was filtered and the filter cake was washed with cold ethanol (2 x 50 mL), n-hexane (2 x 100 mL) , dried under vacuum at 65 0C to get the desired product as a white solid (130 g, yield 66%). Purity (HPLC) 99.5% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, IH), 4.06-3.95 (m, 6H), 3.88-3.85 (m, IH), 3.72-3.68 (m, IH), 3.47-3.37 (m, 5H), 3.32-3.20 (m, 3H), 2.33-2.26 (m, 2H), 2.16-2.08 (m, 2H), 2.01-1.95 (m, 4H), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+ 1]+
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -30 - -10℃; for 1.5h;Inert atmosphere; Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol A solution of <strong>[714269-57-5](2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol</strong> (7.87 g, crude, ?17.9 mmol) in dichloromethane (59 mL) and acetonitrile (59 mL) was cooled to -30 C. under argon. Triethylsilane (11.5 mL, 71.6 mmole) was added to the reaction solution followed by addition of boron trifluoride etherate (6.8 mL, 53.7 mmole) so that the temperature didn't exceed -10 C. After the addition was complete the reaction solution was stirred for additional 1.5 h and then quenched with 5% sodium bicarbonate until the pH reached 7.5. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2*80 mL). The combined organic phases were washed with brine (2*80 mL) and dried over anhydrous sodium sulfate. The sample was concentrated under reduced pressure to provide 6.8 g of the title compound as a pale solid which was used for the next step without purification. Yield: 93%. Purity (LCMS-0013) 2.9 min, 82% (UV); MS ESI (m/z) 409[M+1]+, calc. 408.
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -20 - 20℃; for 0.333333h;Inert atmosphere; [0280] To a 100 mL 3-neck flask equipped with magnetic stirrer and under argon atmosphere was added dichloromethane (7.0 mL), acetonitrile (7.0 mL) and triethylsilane (5.09 mL, 31.9 mmol) successively at room temperature. The above mixture was cooled to -20 to -25 C and BF3-Et20 (3.03 mL, 23.9 mmol) was added in one portion. Another 100 mL flask was charged with crude (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)- 6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (3.5 g, 7.97 mmol), dichloromethane (7.0 mL) and acetonitrile (7.0 mL), and the resulting mixture was shaking for 20 min at ambient temperature until a clear solution was obtained. Under an atmosphere of nitrogen, the (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution in dichloromethane and acetonitrile was transferred to an addition funnel and was slowly added to the solution of BF3-Et20 and triethylsilane over a period of 1 h while keeping the internal temperature between -15 to -20 C. After the addition was completed, the mixture was stirred at a temperature between -15 to -20 C. [0281] The reaction was quenched by addition of an aqueous solution of sodium bicarbonate (7.4% w/w, 25 g) via an addition funnel while keeping the internal temperature below -5 C. Additional solid sodium bicarbonate (1.7 g) was added to adjust the pH to -7.5. The volatile solvents were removed under reduced pressure at a temperature below 40 C. After cooling below room temperature, the residues were partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (2 x 15 mL). The combined organic layers were washed with 10% brine (2 x 20 mL). The combined extracts were concentrated under reduced pressure at a temperature below 40 C until the condensation rate slow down and almost distillation stop (not foaming). The residue was dried under oil pump (P=0.1 mm Hg) to give 3.25 g of off-white solid (99.7% yield, 89.3% pure by HPLC Method EGT-M-0001).
Dichloromethane (1250 ml) followed by acetonitrile (1250 ml) were added to (2S ,3R,4 S,5 S ,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxy tetrahydro-2H-pyran-3,4,5-triol compound of formula-6 (250 gms) at 25-30 C. Cooled the reaction mixture to -20 to -25 C. under nitrogen atmosphere and stirred for 15 mins at the same temperature. Triethylsilane (132.35 gms) was slowly added to the reaction mixture at -20 to -25 C. and stirred for 15 mins. BF3-etherate (193.5 gms) was added to the reaction mixture at -25 to -20 C. and stirred for 15 mins at the same temperature. The temperature of the reaction mixture was slowly raised to -5 to 0 C. and stirred for 1 hr at the same temperature. The pH of the reaction mixture was neutralized by using 10% aqueous sodium bicarbonate solution. Ethyl acetate was added to the reaction mixture and stirred for 15 mins. Separated the both organic and aqueous layers, washed the organic layer with aqueous sodium chloride solution (50 gms of sodium chloride in 1250 ml of water) and then distilled off the solvent completely from the organic layer under reduced pressure.
90 g With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -5℃; for 5h; To a solution of Compound IV (100 gm, 0.22 mol.) in dichloromethane, acetonitrile (1 : 1, 1000 ml) mixture at -5eC was added B F3.OEt2 (0.35 mol.) and Tri ethyl si lane (0.47 mol) sequenti al ly at -5eC . T he reacti on mi xture was sti rred at the same temperature for 5 h. A f ter 5 h, reaction mixture was quenched with 10% NaHC03 solution. Reaction mass was concentrated to remove vol ati I es and added 1000ml of ethyl acetate. Layers were separated (0119) 3a and organic layer was washed with water (500 ml) followed by brine solution (500 ml). (0120) Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude Compound V (90 g, 0.22 mol) as foamy solid.

  • 3
  • [ 461432-26-8 ]
  • [ 147-85-3 ]
  • (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 [ No CAS ]
YieldReaction ConditionsOperation in experiment
66% In ethanol; water; for 0.5h;Reflux; Example 1C (282 g, 0.643 mol) was dissolved in anhydrous acetonitrile /dichloromethane (3.4 L, 1 :1 (v/v)) at -45 0C stirred solution of in was added triethylsilane (299 g, 2.57 mol) followed by addition of boron trifluoride etherate (245 mL, 1.93 mol). After the addition, the mixture was stirred for another 2 h at -10 0C. The reaction was quenched with saturated aqueous bicarbonate to pH 7.5. The volatiles were removed under reduced pressure and the residues were extracted with ethyl acetate (2 x 3.0 L). The combined organic layers were washed with brine (2 x 2.0 L), dried over sodium sulfate and concentrated to give the crude product as a white solid (250 g). Purity (HPLC): 82.8% (UV).[0132] A 5 L 4-necked flask was charged with the above crude product (203 g, 82% purity) and followed by Z-proline (114 g, 0.995 mol), ethanol(1.46 L) and water (162 mL). The mixture was heated to reflux for 30 min with rapid mechanical stirring. n-Hexane (200 mL) was added dropwise to the above solution. After the addition was complete, the reaction was cooled slowly to room temperature and then further to -5C. After stirring for 3 h at -5 0C, the mixture was filtered and the filter cake was washed with cold ethano I/water (90: 10 (v/v), 2 x 100 mL) and n-hexane (2 x 500 mL), and dried under vacuum at 65C to give the desired product as a white solid (186 g). A portion of this crude product (140 g) was dissolved in ethano I/water (90:10 (v/v), 700 mL) at 75 0C with mechanical stirring. After the solution became clear, it was cooled slowly to room temperature and stirred for another 5 h. The mixture was filtered and the filter cake was washed with cold ethanol (2 x 50 mL), n-hexane (2 x 100 mL) , dried under vacuum at 65 0C to get the desired product as a white solid (130 g, yield 66%). Purity (HPLC) 99.5% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, IH), 4.06-3.95 (m, 6H), 3.88-3.85 (m, IH), 3.72-3.68 (m, IH), 3.47-3.37 (m, 5H), 3.32-3.20 (m, 3H), 2.33-2.26 (m, 2H), 2.16-2.08 (m, 2H), 2.01-1.95 (m, 4H), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+ 1]+
In water; isopropyl alcohol; at 20 - 80℃; Example 12; A solution of L-proline (11.5 g, 100 mmol) in 10 mL of water was heated to 80 C. and 100 mL and isopropanol was added. To the rapidly stirred solution of L-proline was added a room temperature solution of compound I (21.4 g, 50 mmol) in 100 mL of isopropanol. Solids formed, and the solution was cooled slowly to room temperature. The solution was filtered and the resulting solids were washed with isopropanol followed by hexanes. The solids were dried under vacuum oven to give 30.4 g of a white solid containing compound I as a 1:2 crystalline complex with L-proline (structure Ih, form 3).
3.8 g In ethanol; water; for 0.5h;Reflux; Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyMetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) cocrystal A 500 mL 4-necked flask was charged with the above crude product (6.8 g, 82% purity) followed by L-proline (3.8 g, 33.2 mmol), ethanol (57.4 mL) and water (3.8 mL). The mixture was heated to reflux for 30 min with rapid mechanical stirring. n-Hexane (102 mL) was added dropwise to the above solution over 30 min. After the addition was complete, the reaction was cooled slowly to room temperature and stirred for additional 16 h. The mixture was filtered and the filter cake was washed with cold 95% ethanol/water (0 C., 2*3.4 mL) and n-hexane (2*13.6 mL), and dried under vacuum at 65 C. to give the desired product as a white solid (4.5 g). This crude product (4.5 g) was dissolved in ethanol/water (95%, 22.5 mL) at 75 C. with mechanical stirring. The mixture was heated to reflux for 30 min with rapid mechanical stirring. n-Hexane (45 mL) was added dropwise to the above solution over 30 min. After the addition was complete, the reaction was cooled slowly to room temperature and stirred for additional 16 h. The mixture was filtered and the filter cake was washed with n-hexane (2*9 mL), and dried under vacuum at 65 C. to give 3.8 g of the desired product as a white solid. Purity (HPLC-0001) 99.0% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.34?7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, 1H), 4.06?3.95 (m, 6H), 3.88?3.85 (m, 1H), 3.72?3.68 (m, 1H), 3.47?3.37 (m, 5H), 3.32?3.20 (m, 3H), 2.33?2.26 (m, 2H), 2.16?2.08 (m, 2H), 2.01?1.95 (m, 4H), 1.35 (t, J=7.2 Hz, 3H); MS ESI (m/z): 409 [M+1]+.
3.8 g In ethanol; hexane; water; at 20℃; for 17h;Reflux; [0273] A 500 mL 4-necked flask was charged with the above crude product (6.8 g, 82% purity) followed by L-proline (3.8 g, 33.2 mmol), ethanol (57.4 mL) and water (3.8 mL). The mixture was heated to reflux for 30 min with rapid mechanical stirring. -Hexane (102 mL) was added dropwise to the above solution over 30 min. After the addition was complete, the reaction was cooled slowly to room temperature and stirred for additional 16 h. The mixture was filtered and the filter cake was washed with cold 95% ethanol/water (0 C, 2 x 3.4 mL) and n-hexane (2 x 13.6 mL), and dried under vacuum at 65 C to give the desired product as a white solid (4.5 g). This crude product (4.5 g) was dissolved in ethanol/water (95%, 22.5 mL) at 75 C with mechanical stirring. The mixture was heated to reflux for 30 min with rapid mechanical stirring. -Hexane (45 mL) was added dropwise to the above solution over 30 min. After the addition was complete, the reaction was cooled slowly to room temperature and stirred for additional 16 h. The mixture was filtered and the filter cake was washed with n-hexane (2 x 9 mL), and dried under vacuum at 65C to give 3.8 g of the desired product as a white solid. Purity (HPLC-0001) 99.0% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, 1H), 4.06-3.95 (m, 6H), 3.88-3.85 (m, 1H), 3.72-3.68 (m, 1H), 3.47-3.37 (m, 5H), 3.32-3.20 (m, 3H), 2.33-2.26 (m, 2H), 2.16-2.08 (m, 2H), 2.01-1.95 (m, 4H), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+l]+.

  • 4
  • [ 461432-26-8 ]
  • [ 147-85-3 ]
  • [ 960404-66-4 ]
YieldReaction ConditionsOperation in experiment
In ethanol; water; at -20 - 20℃; for 50h;Heating / reflux; Example 13; A solution of L-proline (0.23 g, 0.2 mmol) in 1.1 mL of 90% ethanol/water was briefly heated to boiling and a solution of compound I (0.4 g, 1 mmol) in 4 mL of ethanol was added. The resulting solution was cooled to -20 C. for 2 h during which time solids formed. The solution was stored at room temperature for 2 days. The vessel was centrifuged and the supernatant was removed. The remaining solids were washed in 1 mL of MTBE, and the solids were dried under vacuum to give 0.025 g of a white solid containing compound I in a 1:1 crystalline complex with L-proline (structure Ii, form 6).
In n-heptane; acetone; at 20 - 65℃;Inert atmosphere; To the 10 cc of acetone charged 1.0 mole (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4- ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol under argon atmosphere at ambient temperature and stirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 - 65C and stirred for 1 hr. Slowly added" proline at 60 - 65C and maintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 - 65C and stirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs. Filtered the mass under argon atmosphere. Washed the cake with 10 cc n-Heptane. Dried the cake at 50-55C under reduced pressure to get 93-95% titled compound. HPLC purity: 98-99%
75 g In ethyl acetate; at 55℃; for 2h; <strong>[461432-26-8]Dapagliflozin</strong> residue (48.11 g in 50 mL of ethyl acetate) and ethyl acetate (350 mL) were charged into a round bottom flask at 28C. The reaction mass temperature raised to 55C. L-proline (20.25 g) was added to the reaction mass at 55C. L-proline (6.75 g) was added to the reaction mass at 55C. Flushed the funnel with ethyl acetate (25 mL). The reaction mass was stirred for 2 hours at 55C. L-proline (6.75 g) was added to the reaction mass at 55C. Flushed the funnel with ethyl acetate (25 mL). ). The reaction mass was stirred for 2 hours at 55C. The reaction mass temperature cooled to 28C. The reaction mass was stirred for 5 hours at 28C. The resulting slurry was filtered and washed with ethyl acetate (150 mL). The solid was dried with suction at 28C. Product weight: 75 g; purity by HPLC: 99.2%.
  • 5
  • [ 461432-26-8 ]
  • [ 147-85-3 ]
  • C5H9NO2*C21H25ClO6*0.5H2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
With water; In ethanol; at -20 - 70℃; for 72h; Example 14; A solution of L-proline (0.23 g, 2 mmol) and compound I (4.34 g, 10 mmol) in 31 mL of 97% ethanol/water was briefly heated to 70 C. to give a clear solution. The resulting solution was cooled to -20 C. and seed crystals of compound I 1:1 complex with L-proline structure Ii form 6 were added. After 3 days at -20 C., solids were collected via filtration, and the filter cake was washed with cold (-20 C.) ethanol. The resulting solids were suspended in 5 mL of heptane, followed by filtration and washing with heptane to give 0.3 g of a white solid. The material (0.02 g) was further crystallized from 20/1 EtOH/H2O with slow evaporation of solvent and slight heating/cooling to grow larger X-ray quality crystals containing a ratio of 4 molecules of compound I, 4 molecules of L-proline and 2 molecules of water per unit cell, hemihydrate of 1:1 complex with L-proline (structure Ij form H.5-2).
  • 6
  • [ 461432-25-7 ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
96.18% With water; sodium carbonate; In methanol; at 25 - 50℃; for 6h; A mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3 -(4-ethoxybenzyl) phenyptetrahydro-2H-pyran-3,4,5-triyl triacetate compound of formula-7 (10 gms), methanol (90 ml) and water (10 ml) was stirred for 30 mins at 25-30 C. Sodium carbonate (16.53 gms) was added to the reaction mixture, heated to 45-50 C. and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30 C. and stirred for 15 mins at the same temperature. Filtered the reaction mixture, washed with methanol and distilled off the solvent completely from the filtrate under reduced pressure. Ethyl acetate followed by water were added to the obtained compound at 25-30 C. and stirred for 15 mins at the same temperature. Separated the both organic and aqueous layers, the organic layer was washed with 2% aqueous sodium bicarbonate solution, followed by 10% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compound of formula-1. Yield: 6.8 gms; % yield: 96.18%; Purity by HPLC: 99.08%.
95% With lithium hydroxide; In tetrahydrofuran; methanol; water; at 0 - 20℃; Take a 1000mL three-necked flask, add compound 2 crystal 58g (100mmol), methanol 300mL and tetrahydrofuran 200mL, mechanical stirring, keep the reaction temperature 0 C ~ 5 C, dropping lithium hydroxide solution 100mL (containing 2.4g hydroxide Lithium, 200 mmol). After dripping up to room temperature to react overnight. After completion of the reaction, the solvent was concentrated under reduced pressure to remove most of the solvent and extracted with ethyl acetate. The combined organic phases were washed with saturated brine and concentrated under reduced pressure to give 38.8 g of a white solid (95% yield).
91% With water; lithium hydroxide; In ethanol; at 40 - 45℃; A mixture of compound 8 (57.70 g, 100 mmol) was added to the three-Anhydrous ethanol (288 mL) was added,After stirring, 20% aqueous lithium hydroxide solution (96 g, 800 mmol) was added,Plus heating after heating to 40 ~ 45 reaction 2 to 3 hours.The reaction was quenched by the removal of some of the ethanol and cooling to room temperature by adding water (288 mL)Isopropyl acetate (288 mL) was added twice,The organic phase saturated brine was washed twice (288 mL)Dried over sodium sulfate, filtered, concentrated and recrystallized from ethyl acetate petroleum ether to separate the product Daggerine net 9 (37.21 g, 91%)
81% With sodium hydroxide; In tetrahydrofuran; at 20℃; Dapagliflozin intermediate tetrahydrofuran solution (concentration 0.3kg/L, 50L)Pump 5 mm inside straight at 20 mL/minIn the first stainless steel reaction tube with a length of 10 meters,Temperature control to 20 degrees,Sodium hydroxide solution (0.5kg/L)Pump 5 mm inside straight through at 10 mL/minIn the 90-meter long stainless steel reaction tube,When the temperature is controlled to 20 degrees, the reaction liquid flows into the vertical storage tank and is stationary.The organic phase was separated and the organic layer was washed once with a 5% aqueous potassium hydrogensulfate solution.After the activated carbon is bleached and filtered,The filtrate is concentrated to a large amount of solids,8.77 kg of dapagliflozin product was obtained by filtration, with a yield of 81.0%.
With methanol; sodium hydroxide; water; at 20 - 80℃; under 760.051 Torr; for 2 - 3h;Heating / reflux;Product distribution / selectivity; Example 1; Compound A can be prepared as described in Example 1, Part E of U.S. Pat. No. 6,515,117. A 10-L glass reactor equipped with a thermocouple and a nitrogen inlet was charged with MeOH (1.25 L), deionized water (3.6 L) followed by 50% aqueous NaOH (205.9 ml, 3.899 mol). The residual solution of NaOH in the measuring cylinder was transferred with water (94 ml) to the reaction vessel. Compound A (503.11 g, 0.872 mol) was added and the mixture was stirred and heated to 68 C. over 1.5 h. After 1 h, the circulation bath temperature was lowered from 80 to 70 C.; internal temperature became 65 C. After a total of 3 h HPLC1 indicated completion of reaction, Compound I AP 99.5. After the mixture was cooled to 25 C., isopropyl acetate (2.5 L) was added. The mixture was stirred for 10 minutes and then the aqueous layer was separated (pH=12.5) and organic layer was washed with water (1 L). During this wash the pH of the biphasic system was adjusted to 6.0 with conc. HCl (5.0 ml) and then the aqueous layer was separated.2 The organic layer was collected in a separate vessel. The reactor was washed with water (2 L), MeOH (2 L) and flushed with nitrogen gas. The wet solution of compound B was recharged into the reactor and (S)-propylene glycol ((S)-PG) (67.03 g, 0.872 mole) was introduced. Optionally, seed crystals of (S)-PG Ia may be added at this stage. Instantaneous crystallization produced a thick slurry. After stirring for 1 h, cyclohexane (2.5 L) was added rapidly over 10 minutes and the stirring was continued for 21 h. The product was filtered through a filter paper (Whatman No.5, Buchner funnel 24 diameter). The filtration was rapid and took about 15 minutes. The filter cake was washed with a mixture (1:1) of MTBE/cyclohexane (2×1 L) and dried under suction for 0.5 h. The solid was transferred to a pyrex tray and dried under vacuum (25 mm Hg) in an oven at 25-30 C. for two days till water analysis by KF corresponded to monohydrate (3.6 wt. %). The (S)-PG product Ia was obtained (0.425 kg, yield 97%) as a snow white solid, HPLC3 AP 99.7. Seed crystals may be prepared by dissolving compound I in a solvent such as MTBE and treating the resulting solution with (S)-propylene glycol and proceeding as described above without the use of seeding. 1HPLC: Column: YMC ODS-A (C-18) S3, 4.6×50 mm. Solvent A: 0.2% aq. H3PO4. Solvent B: 90% CH3CN/10% H2O Start % B=0, final % B=100 Gradient time 8 min; hold time 3 min. Integration stop time 11.0 min. Flow rate 2.5 ml/min. UV wave length 220 nm. 2Neutralization before phase split was done to prevent contamination of the product with NaOH. (S)-PG structure prepared without neutralization was slightly basic [pH 8.3 of a suspension sonicated in water (20 mg/ml)]. 3HPLC method: Mobile Phase A: 0.05% TFA in H2O Mobile Phase B: 0.05% TFA in CAN. Column: YMC Hydrosphere 4.6×150 (3mu). Gradient: 30-90% B over 45 minutes, hold 5 minutes; back to 30% B and re-equilibrate for 10 min. Wavelength: 220 nm. Injection Volume: 10 mul. Temperature: Ambient; Example 1A; Procedure; 20 g of compound A was charged to a reactor at ambient temperature and pressure. 30 mL Methanol and 49.75 mL 3N NaOH were added to the reactor and the reaction mixture was heated to 80 C. or reflux, and held about 2-3 hours for reaction completion<0.5 AP. The batch was cooled to 20 C. and neutralized to pH 6.0-7.5 using con. HCl or 1N acetic acid (requires 1 mL/gm input).; Extraction; The product was extracted from the reaction mixture into 100 mL isopropyl acetate, the aqueous phase was split away and the organic phase washed with water until conductivity<10 mS (4 mL/gm input). The aqueous phase was split away.; Crystallization; 2.8 g (1.05 eq) (S)-(+)-1,2 Propanediol was added to the reaction mixture. The batch was seeded with 0.1 g compound I seed. 160 mL Cyclohexane was added and the batch cooled to from room temperature to 5 C. The batch was allowed to stir at from room temperature to 5 C. at least 1 hour before isolation.; Isolation and Drying; Each load of isolated cake was washed with 50/50 by volume isopropyl acetate/cyclohexane mixture. The cake was dried at 30 C. in a vacuum oven under full vacuum. (Cake is dry when KF=3.6%-4.1%). Yield=84% (uncorrected) Typical purity=99.81 AP Typical PG content=15.1-15.8% by GC
The preparation of structure Ia is described and depicted schematically below. Compound A can be prepared as described in Example 1, Part E of U.S. Pat. No. 6,515,117.A 10-L glass reactor equipped with a thermocouple and a nitrogen inlet was charged with MeOH (1.25 L), deionized water (3.6 L) followed by 50% aqueous NaOH (205.9 ml, 3.899 mol). The residual solution of NaOH in the measuring cylinder was transferred with water (94 ml) to the reaction vessel. Compound A (503.11 g, 0.872 mol) was added and the mixture was stirred and heated to 68 C. over 1.5 hour. After 1 hour, the circulation bath temperature was lowered from 80 C. to 70 C.; internal temperature became 65 C. After a total of 3 hours, HPLC indicated completion of reaction, Compound I AP 99.5. (HPLC: Column: YMC ODS-A (C-18) S3, 4.6×50 mm. Solvent A: 0.2% aq. H3PO4. Solvent B: 90% CH3CN/10% H2O Start % B=0, final % B=100 Gradient time 8 min; hold time 3 minutes. Integration stop time 11.0 minutes. Flow rate 2.5 ml/minute. UV wave length 220 nm.)After the mixture was cooled to 25 C., isopropyl acetate (2.5 L) was added. The mixture was stirred for 10 minutes and then the aqueous layer was separated (pH=12.5) and organic layer was washed with water (1 L). During this wash the pH of the biphasic system was adjusted to 6.0 with concentrated HCl (5.0 ml) and then the aqueous layer was separated. Neutralization before phase split was done to prevent contamination of the product with NaOH. The (S)-propylene glycol structure prepared without neutralization was slightly basic [pH 8.3 of a suspension sonicated in water (20 mg/ml)].The organic layer was collected in a separate vessel. The reactor was washed with water (2 L), MeOH (2 L) and flushed with nitrogen gas. The wet solution of compound B was recharged into the reactor and (S)-propylene glycol ((S)-PG) (67.03 g, 0.872 mole) was introduced. Optionally, seed crystals of (S)-PG Ia can be added at this stage. Seed crystals can be prepared by dissolving compound I in a solvent such as MTBE and treating the resulting solution with (S)-propylene glycol and proceeding as described above without the use of seeding.Instantaneous crystallization produced a thick slurry. After stirring for 1 hour, cyclohexane (2.5 L) was added rapidly over 10 minutes and the stirring was continued for 21 hours. The product was filtered through a filter paper (Whatman No.5, Buchner funnel 24 diameter). The filtration was rapid and took about 15 minutes. The filter cake was washed with a mixture (1:1) of MTBE/cyclohexane (2×1 L) and dried under suction for 0.5 hour. The solid was transferred to a pyrex tray and dried under vacuum (25 mm Hg) in an oven at 25-30 C. for two days till water analysis by K.F. corresponded to monohydrate (3.6 wt. %). The (S)-PG product Ia was obtained (0.425 kg, yield 97%) as a snow white solid, mp 71 C., HPLC AP 99.7. (HPLC method: Mobile Phase A: 0.05% TFA in H2O. Mobile Phase B: 0.05% TFA in CAN. Column: YMC Hydrosphere 4.6×150 (3mu). Gradient: 30-90% B over 45 minutes, hold 5 minutes; back to 30% B and re-equilibrate for 10 min. Wavelength: 220 nm. Injection Volume: 10 mul. Temperature: Ambient).The (R) form of dapagliflozin can be prepared using these methods and substituting (S)-propylene glycol with (R)-propylene glycol.
The structure Ia can alternatively be prepared as described and depicted schematically below. 20 g of compound A was charged to a reactor at ambient temperature and pressure. 30 mL Methanol and 49.75 mL 3N NaOH were added to the reactor and the reaction mixture was heated to 80 C. or reflux, and held about 2-3 hours for reaction completion <0.5 AP. The batch was cooled to 20 C. and neutralized to pH 6.0-7.5 using 1N acetic acid (requires 1 mL/gm input).Extraction: The product was extracted from the reaction mixture into 100 mL isopropyl acetate, the aqueous phase was split away and the organic phase washed with water until conductivity <10 mS (4 mL/gm input). The aqueous phase was split away.Crystallization: 2.8 g (1.05 eq) (S)-(+)-1,2 Propanediol 96%+ was added to the reaction mixture. The batch was seeded with 0.1 g compound I seed. 160 mL Cyclohexane was added and the batch cooled to 5 C. The batch was allowed to stir at 5 C. at least 1 hour before isolation.Isolation and Drying: Each load of isolated cake was washed with 50/50 by volume isopropyl acetate/cyclohexane mixture. The cake was dried at 30 C. in a vacuum oven under full vacuum. (Cake is dry when KF=3.6%-4.1%).Yield=84% (uncorrected) Typical purity=99.81AP Typical PG content=15.1-15.8% by GC Capsules containing the SGLT2 inhibitor of Formula I (dapagliflozin) or Formula Ia (dapagliflozin (S)-Propylene glycol hydrate) were prepared in strengths of 2.5 mg (Example 3), 10 mg (Example 4) and 100 mg (Example 5) as two-piece, gray opaque size No.0 (2.5 mg and 10 mg) and size No.00 (for 100 mg) hard gelatin capsules.
With lithium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; To a stirred solution of tetraacetylated ?-C-glucoside (27.2 g, 49 mmol) prepared e.g. according to Example 19, in 480 mL of 2:3:1 THF/MeOH/H2O was added LiOH monohydrate (2.3 g, 57 mmol) at 20 C. After stirring overnight, the volatiles were removed using a rotary evaporator. The residue, after being dissolved in EtOAc (300 mL), was washed 1? with brine (150 mL), 1? with brine (50 mL) containing 10 mL of 5% aq KHSO4 and finally with brine (50 mL) prior to drying over Na2SO4. The volatiles were removed using a rotary evaporator and the resultant oil was reevaporated from a minimum amount of CH2Cl2 to yield 20.4 g of desired title C-arylglucoside as a glassy off white solid
With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20 - 25℃; for 4h; Lithium hydroxide (0.25 g) was added to a solution of(1C)-2,3,4,6-tetra-O-acetyl- 1,5-anhydro-1-[4-chloro-3-(4-ethoxybenzyl)phenylj-D-glucitol (Formula III; 2.5 g) inmethanol (12 mL), tetrahydrofuran (8 mL), and water (4 mL) at 20C to 25C and stirred for about 4 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum at 40C to 45C. The residue was dissolved in ethyl acetate (25 mL) and washed with an aqueous solution of sodium chloride (10%; 2 x 25 mL). The layers were separated and the organic layer was concentrated under vacuum at 40C to 45C to obtainan oily residue. Dichloromethane (10 mL) was added to the oily residue and concentrated under vacuum at 40C to 45C to obtain dapagliflozin.
7.5 g With water; sodium hydroxide; In tetrahydrofuran; methanol; for 24h; To a stirred solution of D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4- ethoxyphenyl)methyl] phenyl] -? 2,3,4, 6-tetraacetate, (15)-, (1 Og) in tetrahydrofuran:methanol: water mixture, was added sodium hydroxide and the reaction mixture was stirred for 24h . The solvents were distilled out under vacuum and the residue obtained was treated with methylene dichloride, water and neutralized by using dilute hydrochloricacid. The two layers were separated and the organic layer washed with brine solution. The organic layer was concentrated and isopropyl alcohol was added to it. Polyethylene glycol (PEG) was added to the reaction mixture which was stirred for about 3h. The reaction mixture was concentrated, degassed. The solid obtained stirred with cyclohexane, filtered and dried to give amorphous dapagliflozin containing less than 1%of PEG (7.5g).
With lithium hydroxide; In tetrahydrofuran; methanol; water; at 0 - 20℃; 53.1 g (90.3 mmol) of the solid of Compound 1 was placed in a 1 L round bottom flask,To a flask was treated with 300 mL of THF,200 mL of methanol (MeOH),The solution was made to be turbid, and then 100 mL (LiOH 1.1 g, 46 mmol) of an aqueous solution of LiOH was added dropwise to the reaction system. The temperature of the control system was between 0 and 5 C during the dropwise addition. As the solution of LiOH was gradually added To clarify, room temperature reaction overnight.With the addition of LiOH solution gradually become clear, with HPLC detection of raw material reaction, when the raw material consumption is completeAnd the acetyl group was completely removed, the reaction was stopped, and most of the organic solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed successively with saturated NH4Cl and brine, dried over anhydrous sodium sulfate,And concentrated under reduced pressure to give 35.9 g of a yellow foamy solid (Compound 2: dapagliflozin crude) in a yield of 97%.
With water; sodium hydroxide; In butan-1-ol; at 80℃; for 12h; To a solution of compound V I (60 g, 0.1039 mol) in n-butanol (300 mL) was added 10% NaOH aq. solution (120 mL) at room temperature, heated to 80eC and stirred for 6 h. After 6h, 10 % NaOH aq. Solution (120 mL) was added and stirred at 80eC for additional 6 h. After completion of the reaction (by H PLC), temperature brought to 25e5eC. Organic layer (0125) 3a was separated, added water (300 mL) and adjusted the pH to 6.0-7.0 using 1.5N HC I solution. Organic layer separated and washed with 0.15 % NH4CI solution. Organic layer was separated and filtered through celite bed followed by concentration to get syrupy mass (crude V II). To this syrupy mass gave toluene ( 120 mL X 3) followed by ethyl acetate (180 mL) chasings to get syrupy mass. Ethyl acetate (78 mL) was added to above mass and (0126) stirred for 10min to dissolve. To this solution 1,2-butanediol (9.84 g) followed by water (1.87 mL) were added and stirred for 30 min at 25e5eC. Reaction mass was cooled to 15e2eC, Cyclohexane(180 mL) was added to reaction mass and sti rred at same temperature for 30min. Another lot of cyclohexane (90 mL) was added to reaction mass and continued stirring for 3hrs at 15e2 eC. After 3 h, filtered the mass and washed with pre-cooled (10- iti 15eC) ethyl acetate and cyclohexane mixture. Dried the material f or 12 h to get C ompound V III as a off white solid. (46.8 g, 0.09 mol, Purity: 99.80%).

  • 7
  • (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 [ No CAS ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
95% In water; ethyl acetate; at 80℃; A suspension of Example ID (23.0 g, 45.6 mmol) in ethyl acetate (230 niL) and water (230 rnL) was heated to 80 0C until the solution became clear. The solution was transferred to a separator funnel immediately. The ethyl acetate layer was separated. Water layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the desired product as a white solid (14 g, yield 95%). Purity (HPLC), 99.1% (UV); 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, IH), 4.06-3.95 (m, 4H), 3.88-3.85 (m, IH), 3.69-3.65 (m, IH), 3.47-3.37 (m, 3H), 3.27 (m, IH), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+l]+
94% With water; In methanol; at 20 - 25℃; for 16h; Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (pure) [0319] [0320] A three-neck round-bottom flask equipped with a thermometer, condenser and addition funnel was charged with (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex (3.8 g, 5.96 mmol) and methanol (15.2 mL). After refluxing for 20 min with magnetic stirring (100 RPM), water (76 mL) was added dropwise over 40 min. After the addition was completed, the mixture was cooled to 2025 C. and stirred for another 16 h. The mixture was filtered, and the filter cake was washed with water (2×7.6 mL), dried under vacuum at 45 to 50 C. for 12 h to give 2.3 g product as a white solid. Yield: 94%. Purity (HPLC-0001), 99.3% (UV); 1H NMR (CD3OD, 400 MHz): delta 7.347.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, 1H), 4.063.95 (m, 4H), 3.883.85 (m, 1H), 3.693.65 (m, 1H), 3.473.37 (m, 3H), 3.27 (m, 1H), 1.35 (t, J=7.2 Hz, 3H); MS ESI (m/z): 409 [M+1]+.
94% With water; In methanol; at 20 - 25℃; for 17h;Reflux; [0274] A three-neck round-bottom flask equipped with a thermometer, condenser and addition funnel was charged with (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex (3.8 g, 5.96 mmoand methanol (15.2 mL). After refluxing for 20 min with magnetic stirring (100 RPM), water (76 mL) was added dropwise over 40 min. After the addition was completed, the mixture was cooled to 20-25 C and stirred for another 16 h. The mixture was filtered, and the filter cake was washed with water (2 x 7.6 mL), dried under vacuum at 45 to 50 C for 12 h to give 2.3 g product as a white solid. Yield: 94%. Purity (HPLC-0001), 99.3% (UV); 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, 1H), 4.06-3.95 (m, 4H), 3.88-3.85 (m, 1H), 3.69-3.65 (m, 1H), 3.47-3.37 (m, 3H), 3.27 (m, 1H), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+l]+.
  • 8
  • [ 461432-26-8 ]
  • [ 98-59-9 ]
  • [ 1219000-33-5 ]
YieldReaction ConditionsOperation in experiment
88% With pyridine; at 0℃; for 2h; Step 1: ( (2R, 3S, 4R, 5R, 6S) -6- (4-chloro-3- (4-ethoxybenzyl) phenyl) -3, 4, 5-trihydroxytetrahydro-2H-pyran-2-yl) methyl 4-methylbenzenesulfonate (6a) At 0, to a well stirred solution of <strong>[461432-26-8]dapagliflozin</strong>, 24 (0.54 g, 1.32 mmol) in anhydrous pyridine (10 mL) was added p-toluenesulfonyl chloride (0.63 g, 3.3 mmol) . The obtained system was stirred for another 2h. The reaction was quenched with H2O, and then concentrated the pyridine under vacuo. The obtained residue was dissolved in EtOAc (15 mL) and 1N HCl (5 mL) , separated the organic layer, and the water layer was extracted with EtOAc (3 × 10 mL) , combined the organic phase and concentrated. Purification by flash column chromatography (silica gel, EtOAc:PE 1:1EtOAc) gave 0.65 g of the 6a as colorless oil, yield: 88.1H NMR (400 MHz, CDCl3) delta 7.72-7.68 (m, 2H) , 7.31-7.26 (m, 2H) , 7.22-7.17 (m, 3H) , 7.13 (dd, J 1.6, 8.0 Hz, 1H) , 7.06-7.04 (m, 2H) , 6.78-6.75 (m, 2H) , 4.36 (dd, J 4.4, 11.2 Hz, 1H) , 4.21 (d, J 9.6 Hz, 1H) , 4.04-3.99 (m, 2H) , 3.96-3.91 (m, 3H) , 3.65 (t, J 9.2 Hz, 1H) , 3.58 (t, J 9.2 Hz, 1H) , 3.52-3.49 (m, 1H) , 3.38 (t, J 9.2 Hz, 1H) , 3.20 (br, 3H) , 2.37 (s, 3H) , 1.35 (t, J 6.8 Hz, 3H) LC-MS (ESI) m/z: calcd for [C28H31ClO8SNH4+] , 580.18, found 580.4.
With 2,6-dimethylpyridine; at 0 - 20℃; Step I: To a solution of (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3- (4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol (1.Og, 2.45 mmole) (prepared according to procedure described in J. Med. Chem. 2008; 51 , 5, 1145-1149), in 2, 6-lutidine (10 ml.) was added tosylchloride (2.3g, 12.25 mmole) at 0 0C and stirred at room temperature for 6 h. The reaction mixture was diluted with water (50 ml_), extracted with EtOAc (2X50 ml_), and washed with 2N HCI and brine. The crude product obtained after the removal of solvent was purified on silica gel column (1 % MeOH in DCM) to furnish toluene-4- sulfonic acid (2R, 3S, 4R, 5R, 6S)-6-[4-chloro-3- (4-ethoxy-benzyl)-phenyl]-3, 4, 5- trihydroxy-tetrahydro-pyran-2-ylmethyl ester (1.15 g).
With 2,6-dimethylpyridine; at 0 - 20℃; for 6h; To a solution of (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.0g, 2.45 mmole) (prepared according to procedure described in J. Med. Chem. 2008; 51, 5, 1145-1149), in 2,6-lutidine (10 mL) was added tosylchloride (2.3 g, 12.25 mmole) at 0 C. and stirred at room temperature for 6 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (2*50 mL), and washed with 2N HCl and brine. The crude product obtained after the removal of solvent was purified on silica gel column (1% MeOH in DCM) to furnish toluene-4-sulfonic acid (2R, 3S, 4R, 5R, 65)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester (1.15 g).
  • 9
  • [ 461432-26-8 ]
  • [ 1219000-66-4 ]
YieldReaction ConditionsOperation in experiment
Step I. To a solution of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3,4,5-triol (2 g, 4.9 mmole), prepared according to procedure described in J. Med. Chem. 2008; 51 , 5, 1145-1149, in a mixture of THF (50 ml.) and saturated aq. NaHCO3 (50 ml.) was added 2,2,6,6-tetramethylpiperidine-1-oxyl 52822radical (TEMPO) (153 mg, 0.97 mmole) and KBr (116 mg, 0.97 mmole) at 0 0C followed by addition of sodium hypochlorite (50 ml.) drop-wise during 15 min. and then stirred for1 h. at the same temperature. The reaction mixture was diluted with water (50 ml_), and pH was adjusted to 2-3 using 2N HCI and extracted with EtOAc (2X200ml_), washed with brine. The crude product obtained after the removal of solvent to furnish(2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro- pyran-2-carboxylic acid.
To a solution of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (2 g, 4.9 mmole), prepared according to procedure described in J. Med. Chem. 2008; 51, 5, 1145-1149, in a mixture of THF (50 mL) and saturated aq.NaHCO3 (50 mL) was added 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO) (153 mg, 0.97 mmole) and KBr (116 mg, 0.97 mmole) at 0 C. followed by addition of sodium hypochlorite (50 mL) drop-wise during 15 min. and then stirred for 1 h. at the same temperature. The reaction mixture was diluted with water (50 mL), and pH was adjusted to 2-3 using 2N HCl and extracted with EtOAc (2×200mL), washed with brine. The crude product obtained after the removal of solvent to furnish (2S,3S,4R,5R,6S)-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid.
  • 10
  • [ 461432-26-8 ]
  • [ 1219000-72-2 ]
YieldReaction ConditionsOperation in experiment
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃;Reflux; Step I. To a mixture of (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol (500 mg, 0.98 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), PPh3 (450 mg, 1.6 mmole) and imidazole (101 mg, 1.5 mmole) in dichloromethane (20 ml.) was added52 52822iodine (400 mg, 1.5 mmole) at 0 0C and the mixture was refluxed for 18 hours. The reaction mixture was diluted with water (50 ml.) and extracted with dichloromethane (2 X 200 ml_). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in dichloromethane) to furnish 480 mg of (2S, 3R, 4R, 5S, 6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tetrahydro- pyran-3, 4, 5-triol.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃;Reflux; To a mixture of (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol (500 mg, 0.98mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), PPh3 (450 mg, 1.6 mmole) and imidazole (101mg, 1.5mmole) in dichloromethane (DCM, 20 mL) was added iodine (400 mg, 1.5 mmole) at 00C and refluxed for 18 hrs. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2X200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 480 mg of (2S, 3R, 4R, 5S, 6S)-2- [4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tetrahydro-pyran-3, 4, 5-triol .
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃; for 18h;Reflux; To a mixture of (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol (500 mg, 0.98 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), PPh3 (3.0 g, 7.3 mmole) and imidazole (650 mg, 9.5 mmole) in 50 mL of dichloromethane (DCM) was added iodine (2.4 g, 9.5 mmole) at 0 C and refluxed for 18 hrs. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2X200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 3.5 g of (2S, 3R, 4R, 5S, 6S)-2-[4- chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tetrahydro-pyran-3, 4, 5-triol.
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0℃;Reflux; To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (500 mg, 0.98 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), PPh3 (3.0 g, 7.3 mmole) and imidazole (650 mg, 9.5 mmole) in 50 mL of dichloromethane (DCM) was added iodine (2.4 g, 9.5 mmole) at 0 C. and refluxed for 18 hrs. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 3.5 g of (2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-iodomethyl-tetrahydro-pyran-3,4,5-triol.

  • 11
  • [ 461432-24-6 ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
83.1% With triethylsilane; boron trifluoride diethyl etherate; In methanol; dichloromethane; ethyl acetate; at -20 - 20℃; for 5h; Compound 4a' (10.0 g, 22.1 mmol, 1.0 eq, purity 90.2%) was dissolved in dichloromethane (50 mL) and EtOAc (50 mL).The above solution was added to the reaction flask, and triethylsilane (7.7 g, 66.2 mmol, 3.0 eq) was added under nitrogen atmosphere, and the temperature was lowered to -20 C to -10 C, and boron trifluoride etherate (6.3 g, 44.2) was added dropwise. Methanol, 2.0 eq), after completion of the dropwise addition, the mixture was stirred for 4 hours, and then further stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate solution (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the mixture was separated, and the aqueous phase was extracted again with ethyl acetate (50 mL). The organic phase was combined and washed with water (50 mL) The aqueous sodium sulfate was dried, filtered and concentrated to dryness to give 7.4 g of the compound of formula I, yield 83.1%, purity 85.0%.
44% (2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6- (hydroxymethyl)-tetrahydro-2H-pyran-3A5-triol: At about -10 0C, triethylsilane (343 mg, 2.96 mmol, 3.00 equiv) and boron trifluoride diethyl etherate (420 mg, 2.96 mmol, 3.00 equiv) were added dropwise to a stirred solution of (3R,4S,5S,6R)-2-(3-(4- <n="34"/>ethoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxy-tetrahydro-2H-pyran- 3,4,5-triol (300 mg, 0.68 mmol, 1.00 equiv) and acetonitrile / dichloromethane (50 niL). After stirring at ambient temperature for about 16 hours, the reaction was quenched by adding a saturated solution of sodium bicarbonate (50 mL). Standard extractive workup with ethyl acetate (3 x 200 mL) gave a crude residue which was first purified by silica gel column chromatography (eluted with dichloromethane / methanol (20 : 1) and then purified by preparative EtaPLC to remove the (2R,3R,4R,5S,6R)-2-(3-(4- ethoxybenzyl)-4-chlorophenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol isomer. The title product was isolated as a white solid (130 mg; yield = 44%). 1H NMR (300 MHz, CDC13), delta: 7.37 (d, J = 8.1 Hz, IH), 7.32 (d, J = 1.8 Hz, IH), 7.24 (dd, J= 8.1, 1.8 Hz, IH), 7.09 (d, J= 8.4 Hz, IH), 6.82 (d, J= 8.4 Hz, IH), 4.83-5.00 (br m, 3H), 4.44 (s, IH), 3.93-4.03 (m, 5H), 3.67-3.71 (m, IH), 3.10-3.47 (m, 6H), 1.30 (t, J= 7.2 Hz, 3H); LC-MS : m/z= 453 (M+HCOO) ".
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -10℃; for 1.5h;Inert atmosphere; [0272] A solution of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl) phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (7.87 g, crude, -17.9 mmol) in dichloromethane (59 mL) and acetonitrile (59 mL) was cooled to -30 C under argon. Triethylsilane (11.5 mL, 71.6 mmole) was added to the reaction solution followed by addition of boron trifluoride etherate (6.8 mL, 53.7 mmole) so that the temperature didn't exceed -10 C. After the addition was complete the reaction solution was stirred for additional 1.5 h and then quenched with 5% sodium bicarbonate until the pH reached 7.5. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 80 mL). The combined organic phases were washed with brine (2 x 80 mL) and dried over anhydrous sodium sulfate. The sample was concentrated under reduced pressure to provide 6.8 g of the title compound as a pale solid which was used for the next step without purification. Yield: 93%. Purity (LCMS-0013) 2.9 min, 82% (UV); MS ESI (m/z) 409[M+1]+, calc. 408.
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; at -40 - -5℃; for 6h; (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxy methyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol solution (51.5 g in 50 mL of dichloromethane) was charged into a round bottom flask. The solution was cooled to -35C. Triethylsilane (34.1 g) was added to the reaction mass at -35C. Boron trifluoride etherate (37.5 g) was added to the reaction mass at -40C. The reaction mass was stirred for 2 hours at -38C. The reaction mass temperature raised to -5C. The reaction mass was stirred for 4 hours at -5C. Water (500 mL) was slowly added to the reaction mass. The reaction mass temperature raised to 28C. The organic and aqueous layers were separated. The organic layer was washed with water (500 mL). 5% NaHC03 solution (250 mL) was added to the reaction mass. The reaction mass was stirred for 20 minutes at 28C. Methanol (500 mL) and 20% NaCl solution (250 mL) were added to the reaction mass at 28C. The organic and aqueous layers were separated. The organic layer was washed with 10% NaCl solution (250 mL). The reaction mass was evaporated under vacuum at 45C. The residue product was obtained as dapagliflozin. Ethyl acetate (150 mL) was added to the reaction mass. The reaction mass was evaporated under vacuum at 55C.

  • 12
  • [ 461432-26-8 ]
  • [ 76-83-5 ]
  • [ 1290629-77-4 ]
YieldReaction ConditionsOperation in experiment
With pyridine; at 20℃; for 18h;Reflux; To a mixture of (2S, 3R, 4R, 5S, 6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyl-tetrahydro-pyran-3, 4, 5-triol (7.0 g, 17.1 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), trityl chloride (5.2 g, 18.8 mmole) in pyridine ( 50 mL) was added at room temperature and refluxed for 18 hrs. The excess pyridine was evaporated; reaction mixture was diluted with water (250 mL) and washed with 1 N dil. HCI (50 mL) extracted with dichloromethane (2X200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 9.8 g of (2S,3R,4R>5S,6R)- 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol.
With pyridine; for 18h;Reflux; To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.0 g, 17.1 mmole) (prepared according to procedure as described in J. Med. Chem. 2008; 51 (5); 1145-1149), trityl chloride (5.2 g, 18.8 mmole) in pyridine (50 mL) was added at room temperature and refluxed for 18 hrs. The excess pyridine was evaporated; reaction mixture was diluted with water (250 mL) and washed with 1N dil. HCl (50 mL) extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 9.8 g of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol.
  • 13
  • [ 461432-26-8 ]
  • [ 864070-37-1 ]
YieldReaction ConditionsOperation in experiment
1.6 g With hydrogen bromide; In water; for 16h;Reflux; A mixture of <strong>[461432-26-8]dapagliflozin</strong> (1) (5 g, 0.012 mol) and aqueousHBr (12.6 g, 0.073 mol, 48% w/w) were warmed and stirredunder a gentle reflux for 16 h. The reaction mass was cooledto an ambient temperature and partitioned between MTBE(50 mL) and H2O (50 mL). Following extraction of aqueouslayer with MTBE (50 mL), the combined organic layerswere neutralized with aqueous NaOH solution. The organiclayer was separated, washed with H2O (50 mL) and concentrated. The residue was then treated with EtOH(20 mL) and the precipitated salts were removed by celitebed filtration. The filtrate was concentrated under reducedpressure and the residue was purified by column chromatographyto afford pure desethyl <strong>[461432-26-8]dapagliflozin</strong> (4) (1.6 g)as a glassy off-white amorphous solid. [alpha]D20: +5.5 (c = 0.2in methanol); 1H NMR (D2O) (500 MHz): 3.46-3.59 (m,4H), 3.73 & 3.84 (2dd, 2H), 3.95 (s, 2H), 4.15-4.18 (d, 1H,J = 9.3Hz), 6.74-6.76 (d, 2H, J = 6Hz), 7.05-7.07 (d, 2H, J =6Hz), 7.22-7.23 (d, 1H, J = 3Hz), 7.26 (s, 1H), 7.30(s, 1H), 7.37-7.40 (d, 1H, J = 9Hz); HRMS (ESI) calculatedfor C19H21ClO6 (M- H)+: 379.0948, found: 379.0936;
  • 14
  • [ 461432-26-8 ]
  • [ 108-24-7 ]
  • [ 18162-48-6 ]
  • C33H45ClO8Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% Step 1. Synthesis of Compound d [0132] To a stirred solution of Compound c (639.4 mg, 1.6 mmol) in pyridine (1.6 mL) was added DMAP (87.7 mg, 0.8 mmol) at room temperature. The reaction flask was cooled in an ice bath; a solution of TBDMSCl (353.6 mg, 2.4 mmol) in pyridine (1.6 mL) was added. The reaction was gradually warmed up to room temperature and stirred overnight. After the reaction was complete, Ac2O (1.5 mL, 15.6 mmol) was added. The obtained mixture was stirred at room temperature for another 3 h. The reaction flask was cooled in an ice bath, and H2O was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic phase was sequentially washed with 1 N HCl, H2O, and saturated NaHCO3 (aq). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/Hexane=1/10) to give Compound d (926.8 mg, 92%).
  • 15
  • [ 281652-58-2 ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / -3 - 5 °C 1.2: 12 h / 0 - 25 °C 1.3: polymethylhydrosiloxane (PMHS) / 16 h / 30 °C 2.1: TurboGrignard / tetrahydrofuran / 1.5 h / -5 - 0 °C / Inert atmosphere 2.2: 1 h / -5 - 0 °C 2.3: 16 h / -10 - 20 °C 3.1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane; acetonitrile / 0.33 h / -20 - 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / -3 - 5 °C 1.2: 12 h / 0 - 25 °C 1.3: polymethylhydrosiloxane (PMHS) / 16 h / 30 °C 2.1: TurboGrignard / tetrahydrofuran / 1.5 h / -5 - 0 °C / Inert atmosphere 2.2: 1 h / -5 - 0 °C 2.3: 16 h / -10 - 20 °C 3.1: water; ethanol / 0.5 h / Reflux 4.1: methanol / 0.33 h / Reflux 4.2: 16.67 h / 20 - 25 °C
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride / dichloromethane / 1 h / -3 °C / Inert atmosphere 2.1: triethylsilane; boron trifluoride diethyl etherate / acetonitrile / 5 h / 0 - 20 °C / Inert atmosphere 3.1: bis(η3-allyl-μ-chloropalladium(II)) / N,N-dimethyl-formamide / 16 h / 20 °C / Inert atmosphere 4.1: borane-THF / tetrahydrofuran / 16 h / 0 - 20 °C / Inert atmosphere 4.2: 0.33 h / 0 - 20 °C / Inert atmosphere
  • 16
  • [ 19094-56-5 ]
  • [ 461432-26-8 ]
  • 17
  • [ 1103738-29-9 ]
  • [ 461432-26-8 ]
  • 18
  • (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol bis(L-proline) cocrystal [ No CAS ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
94% [0262] A three-neck round-bottom flask equipped with a thermometer, condenser and addition funnel was charged with (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)- 6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex (3.8 g, 5.96 mmol) and methanol (15.2 mL). After refluxing for 20 min with magnetic stirring (100 RPM), water (76 mL) was added dropwise over 40 min. After the addition was completed, the mixture was cooled to 20-25 C and stirred for another 16 h. The mixture was filtered, and the filter cake was washed with water (2 x 7.6 mL), dried under vacuum at 45 to 50 C for 12 h to give 2.3 g product as a white solid. Yield: 94%. Purity (HPLC Method EGT-M-0001), 99.3% (UV); 1H NMR (CD3OD, 400 MHz): delta 7.34-7.25 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 4.10 (d, J=9.2 Hz, 1H), 4.06-3.95 (m, 4H), 3.88-3.85 (m, 1H), 3.69-3.65 (m, 1H), 3.47-3.37 (m, 3H), 3.27 (m, 1H), 1.35 (t, J=7.2Hz, 3H); MS ESI (m/z): 409 [M+l]+.
  • 19
  • [ 864070-37-1 ]
  • [ 80-40-0 ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
75% With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 12h; Inert atmosphere;
  • 20
  • [ 1432591-86-0 ]
  • [ 461432-26-8 ]
YieldReaction ConditionsOperation in experiment
30 mg With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 15h; A solution of the 2,4-di-O-tert-butyldiphenylsilyl-1-C-(4-chloro-3-(4-ethoxybenzyl)phenyl)-beta-D-glucopyranoside (60 mg, 0.068 mmol) in THF (3.0 mL) and TBAF (3.0 mL, 3.0 mmol, 1.0 M in THF) was stirred at ambient temperature for 15 hours. CaCO3 (0.62 g), Dowex 50WX8-400 ion exchange resin (1.86 g) and MeOH (5 mL) were added to the product mixture and the suspension was stirred at ambient temperature for 1 hour and then the mixture was filtrated through a pad of diatomaceous earth. The filter cake was rinsed with MeOH and the combined filtrates was evaporated under vacuum and the resulting residue was purified by column chromatography (eluting with 1:10 MeOH/DCM) affording dapagliflozin (30 mg). [0281] 1H NMR (400 MHz, CD3OD) delta 7.37-7.34 (m, 2H), 7.29 (dd, J=8.2, 2.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.82-6.80 (m, 2H), 4.10 (d, J=9.6 Hz, 2H), 4.04 (d, J=9.2 Hz, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.91-3.87 (m, 1H), 3.73-3.67 (m, 1H), 3.47-3.40 (m, 3H), 3.31-3.23 (m, 2H), 1.37 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CD3OD) delta 157.4 (C), 138.6 (C), 138.5 (C), 133.1 (C), 131.5 (C), 130.5 (CH), 129.4 (CH×2), 128.7 (CH), 126.8 (CH), 114.0 (CH×2), 80.5 (CH), 80.8 (CH), 78.3 (CH), 75.0 (CH), 70.4 (CH), 63.0 (CH2), 61.7 (CH2), 37.8 (CH2), 13.8 (CH3); LCMS (ESI) m/z 426 (100, [M+NH4]+), 428 (36, [M+NH4+2]+), 447 (33, [M+K]+).
  • 21
  • [ 461432-26-8 ]
  • [ 108-24-7 ]
  • [ 461432-25-7 ]
YieldReaction ConditionsOperation in experiment
6.4g With dmap; In acetone; at 20 - 30℃; for 3h; Acetic anhydride (11.6 mL) was added to dapagliflozin (10 g) in acetone (50 mL) at about 25C. The reaction mixture was cooled to about 20C and dimethylaminopyridine (0.15 g) was added to it at 20C to 25C. The reaction mixture was stirred for about 3 hours at 25C to 30C. After completion of the reaction, thereaction mixture was concentrated under vacuum at 40C to 45C to obtain a residue. The residue was dissolved in dichloromethane (50 mL) and washed with water (50 mL). The organic layer was separated and concentrated under vacuum to obtain a residue. The residue was dissolved in ethanol (20 mL) and again concentrated at 50C to 55C to obtain a residue. The residue was dissolved in ethanol (100 mL) and heated to 70C to 75C toobtain a clear solution. The solution was slowly cooled to about 20C and stirred for one hour at 15C to 20C to obtain a solid. The solid was filtered, washed with ethanol (10 mL), and dried under vacuum at 40C to 45C for about 16 hours to obtain (1C)-2,3,4,6- tetra-O-acetyl- 1,5 -anhydro- 1 -[4-chloro-3 -(4-ethoxybenzyl)phenylj -D-glucitol.
128 g Dichloromethane (1000 ml) was added to the obtained compound in step-a) at 25-30 C. and stirred for 15 mins at the same temperature. Dimethylaminopyridine (11.94 gms) was added to the reaction mixture at 25-30 C. and stirred for 20 mins at the same temperature. Acetic anhydride (249.46 gms) was added to the reaction mixture at 25-30 C. and stirred for 4 hrs at the same temperature. Water was slowly added to the reaction mixture at 25-30 C. and stirred for 15 mins. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous 10% aqueous hydrochloric acid solution, followed by with 10% aqueous sodium bicarbonate solution and then with 10% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (1000 ml) was added to the obtained compound at 35-40 C., heated the reaction mixture to 60-65 C. and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 25-30 C. and stirred for 30 mins. The reaction mixture was further cooled to 0-5 C. and stirred for 1 hr 30 mins at the same temperature. Filtered the solid, washed with methanol. Methanol (1200 ml) was added to the obtained solid, heated to reflux temperature and stirred for 45 mins. Cooled the reaction mixture to 0-5 C. and stirred for 1 hr 30 mins. Filtered the solid, washed with methanol and then dried to get the title compound. Yield: 128 gms; MR: 125-128 C.; Purity by HPLC: 99.53%.
  • 22
  • [ 461432-26-8 ]
  • C21H21ClI4O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane;Reflux; Inert atmosphere; 12.69 g (50 mmol) of iodine is dissolved in 50 mL of dry dichloromethane, stirred under cooling with an icewaterbath, 13.11 g (50 mmol) of triphenylphosphine is added slowly, after the addition, the reaction compounds arestirred for another 10 min. 13.62 g (200 mmol) of imidazole is then added slowly, and stirred for another hour after theaddition. To the above resulting system, 0.98 g (2 mmol) of compound 1 is added, after the addition the reactioncompounds are stirred at reflux overnight under nitrogen atmosphere. The reaction mixture is diluted with 100 mL ofdichloromethane, washed with saturated salt water, and dried with anhydrous sodium sulfate. The drying agent isremoved by filtration, the solvent in the filtrate is removed on the rotary evaporator, the resulting residue is purified bysilica gel column chromatography to obtain the pure product 65, a white, foam-like solid. ESI-MS, m/z = 870 ([M+Na]+).
  • 23
  • [ 461432-26-8 ]
  • [ 18162-48-6 ]
  • (2R,3S,4R,5R,6S)-2-((tert-butyldimethylsilyloxy)methyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triol [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.15h; 4.09 g (10 mmol) of compound 1 is dissolved in 30 mL of dry DMF, stirred under cooling with an ice-water bath, 2.72 g (40 mmol) of imidazole is added, and then 1.66 g (11 mmol) of TBDMSCl (tert-butyldimethylsilyl chloride) is added dropwise slowly over 15 min. After the addition, the reaction compounds is stirred for another 3 hours at room temperature. The reaction mixture is diluted with 150 mL of dichloromethane, washed with 50 mL x 3 of saturated salt water, and dried with anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent in the filtrate is removed on the rotary evaporator, the resulting residue is purified by silica gel column chromatography to obtain the pure product 2, a white foam-like solid. 1H NMR (DMSO-d6, 400 MHz), delta 7.35 (d, 1H, J = 8.0 Hz), 7.28 (d, 1H, J = 2.0 Hz), 7.17 (dd, 1H, J = 2.0 Hz and 8.4 Hz), 7.05 (d, 2H, J = 8.8 Hz), 6.79 (d, 2H, J = 8.8 Hz), 4.92-4.95 (m, 2H), 4.81 (d, 1H, J = 6.0 Hz), 3.93-3.99 (m, 5H), 3.85 (d, 1H, J = 10.4 Hz), 3.66 (dd, 1H, J = 5.2 Hz and 11.6 Hz), 3.17-3.28 (m, 3H), 3.02-3.08 (m, 1H), 1.28 (t, 3H, J = 7.0 Hz), 0.80 (s, 9H), -0.05 (s, 3H), -0.09 (s, 3H).
With dmap; In pyridine; at 0 - 20℃; for 18h;Inert atmosphere; A solution of TBSCl (724 mg, 4.8 mmol) in pyridine (3.7 mL) was added to a mixture of 6 (1.51 g, 3.7 mmol) and DMAP (207 mg, 1.8 mmol) in pyridine (3.7 mL) at 0 C under N2(g). The reaction mixture was allowed to warm to room temperature and left overnight, with stirring. After the reaction was complete, Ac2O (3.5 mL, 36.9 mmol) was added and the solution stirred at room temperature for another 3 h. The reaction was quenched with H2O at 0 C, and the resulting mixture was extracted with CH2Cl2. The organic layer was sequentially washed with 1 N HCl(aq), H2O, and saturated NaHCO3(aq), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/n-Hexane = 1/5) to provide 7 (1.48 g, 62%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.33 (d, J = 8.4 Hz, 1H, ArH), 7.16 (dd, J = 8.0, 2.0 Hz, 1H, ArH), 7.10 (d, J = 2.0 Hz, 1H, ArH), 7.07-7.03 (m, 2H, ArH), 6.82-6.79 (m, 2H, ArH), 5.27 (dd, J = 9.6, 9.2 Hz, 1H, Glc H3), 5.20 (t, J = 9.6 Hz, 1H, Glc H4), 4.99 (dd, J = 9.6, 9.2 Hz, 1H, Glc H2), 4.28 (d, J = 10.0 Hz, 1H, Glc H1), 4.08-3.93 (m, 4H, 2 x CH2), 3.78-3.68 (m, 2H, Glc H6a, H6b), 3.63 (ddd, J = 9.6, 4.8, 2.4 Hz, 1H, Glc H5), 2.04 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.71 (s, 3H, CH3), 1.39 (t, J = 7.2 Hz, 3H, CH3), 0.86 (s, 9H, 3 x CH3), 0.01 (s, 3H, CH3), -0.03 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) delta 170.51, 169.33, 168.80, 157.39, 138.90, 135.58, 134.30, 131.08, 129.73, 129.56, 126.03, 114.41, 79.31, 78.92, 74.46, 72.85, 68.81, 63.30, 62.44, 38.25, 25.74, 20.69, 20.67, 20.31, 18.26, 14.83, -5.37; MS (ESI) m/z: 671 (MNa+).
  • 24
  • [ 461432-26-8 ]
  • [ 1125-88-8 ]
  • [ 1181680-65-8 ]
YieldReaction ConditionsOperation in experiment
83% With camphor-10-sulfonic acid; In N,N-dimethyl-formamide; at 60℃; A 250 ml round bottom flask is added 20.44g (50mmol) compound II - 1, 22.83g (150mmol) benzene formaldehyde dimethyl acetal, 3g camphor sulfonic acid (CSA) and 120 ml dry DMF, then heating at 60 C under stirring overnight, TLC shows the reaction is complete.The reaction mixture is cooled to room temperature to be dumped after to the 400 ml ice water, stirring, for 200 ml × 3 methylene chloride extraction. The combined organic phase, are saturated NaHCO3Solution and salt water washing, drying with anhydrous sodium sulfate, the solvent on the rotary evaporator, the residue obtained after column chromatography purification, to obtain the product III - 1.
With camphor-10-sulfonic acid; In N,N-dimethyl-formamide; at 110℃; for 3h;Inert atmosphere; 4.09 g (10 mmol) of compound 1, 1.83 g (12 mmol) of benzaldehyde dimethyl acetal and 0.1 gram of CAS (camphorsulfonic acid) is dissolved in 30 mL of dry DMF, heated and stirred for 3 hours at 110C under nitrogen atmosphere. After cooling the reaction mixture is diluted with 150 mL of dichloromethane, washed successively with 20 mL of 5% sodium carbonate solution and saturated salt water, and dried with anhydrous sodium sulfate. The drying agent is removed by filtration, the solvent in the filtrate is removed on the rotary evaporator, and the resulting residue is purified by silica gel column chromatography to obtain the pure product 7, a white solid. Melting point 176-178C. 1H NMR (DMSO-d6, 400 MHz), delta 7.45-7.47 (m, 2H), 7.36-7.40 (m, 4H), 7.28 (d, 1H, J = 1.6 Hz), 7.21 (dd, 1H, J = 2.0 Hz and 8.4 Hz), 7.08 (d, 2H, J = 8.8 Hz), 6.83 (d, 2H, J = 8.4 Hz), 5.60 (s, 1H), 5.31 (d, 1H, J = 3.6 Hz), 5.13 (d, 1H, J = 5.6 Hz), 4.16-4.22 (m, 2H), 3.94-3.99 (m, 4H), 3.65-3.70 (m, 1H), 3.50-3.51 (m, 3H), 3.24-3.28 (m, 1H), 1.29 (t, 3H, J = 6.8 Hz).
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