* 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.
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -25 - -20℃; for 4 h; Inert atmosphere; Large scale
Example 5 Preparation of ((2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6-(Hydroxymethyl)Tetrahydro-2H-Pyran-3,4,5-triol [0236] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by reduction of the anomeric OMe and/or OH. (3R,4S,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6-(Hydroxymethyl)-2-Methoxytetrahydro-2H-Pyran-3,4,5-Triol Solution [0237] A 30 L glass reactor equipped with a thermometer was charged with crude (3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (2.7 kg), DCM (5.4 kg) and acetonitrile (3.2 kg), and the mixture was magnetically stirred until all the solids dissolved under nitrogen sparging. [0238] Triethylsilane Solution: [0239] BF3.Et2O (2.34 kg) was added to a cold (−21 to −15° C.) solution of triethysilane (2.55 kg) dichloromethane (5.4 kg) and acetonitrile (3.2 kg) under nitrogen. [0240] The (3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution was added to the cold triethylsilane solution at such a rate to maintain the temperature between −20 and −25° C. (3 h). [0241] The reaction mixture was stirred for another 4 h at −22 to −25° C. and then quenched by addition of an aqueous solution of sodium bicarbonate (7.4percent w/w, 18.3 kg) while keeping the internal temperature below −10° C. Solid sodium bicarbonate (1.35 kg) was added to adjust the pH to 7.5. The solvents were removed under reduced pressure (temperature below 40° C.). The residue was partitioned between ethyl acetate (18 kg) and water (9.2 kg). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×9 kg). The combined organic layers were washed with brine (2×9 kg) and the solvents were removed under reduced pressure at the temperature below 40° C. until the condensation almost stop Anhydrous ethanol (9 kg) was added and concentrated to give the crude product of the title compound (2.5 kg, 90percent yield, 90.8percent HPLC purity, HPLC-0001) as foamy solid.
70%
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane; acetonitrile at -25 - -20℃; Inert atmosphere
General procedure: To a solution of 16b (2.1 g, 4.2 mmol) in dichloromethane (10.5 mL) and acetonitrile (10.5 mL) at –25 °C under argon was added triethylsilane (2.7 mL, 16.8 mmol). Then boron trifluoride etherate (1.6 mL, 12.6 mmol) was added while maintaining the reaction temperature below –20 °C, and the reaction mixture was stirred for another 4 h at –25 to –20 °C. The reaction was quenched by addition of 5percent sodium bicarbonate until a pH of 7.5 was obtained. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The sample was concentrated under reduced pressure to give product crude 7b as a light yellow solid (1.82 g, 92percent yield; HPLC purity: 88.3percent).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12.0h;
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (30 mg, 0.08 mmol) in anhydrous DMF (1 mL) were added 2-cyclopropoxyethyl 4-methylbenzenesulfonate (intermediate BP) (20 mg, 0.08 mmol) and Cs2CO3 (52 mg, 0.16 mmol). The mixture was stirred at room temperature for 12 h. Then the reaction mixture was poured into water, extracted with EA, washed with brine, dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative HPLC to obtain compound BQ (11 mg) as a colorless oil. 1H NMR (CD3OD): delta 7.30 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.82 (d, J= 8.8 Hz, 2H), 4.13 (m, 5H), 3.85 (m, 3H), 3.81 (m, IH), 3.40 (m, 4H), 3.30 (m, IH), 0.52 (m, 4H); MS ESI (m/z) 465 (M+H)+, calc. 464.
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
In ethanol; for 1.0h;Reflux; Large scale;
Example 13 Preparation of <strong>[1118567-05-7](2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol</strong>, bis(L-proline) complex [0279] This example describes preparation of <strong>[1118567-05-7](2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol</strong>, bis(L-proline) complex by co-crystallization of (<strong>[1118567-05-7](2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol</strong> with L-proline in ethanol/water/n-heptane solvent mixture. [0280] The crude <strong>[1118567-05-7](2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol</strong> (1.09 kg) was added to a glass reactor containing ethanol (95%, 7 kg) and L-proline (0.54 kg) and the mixture was refluxed for 1 h. While keeping the temperature between 55 to 60 C., n-heptane (3.7 kg) was added over 1.5 h. The mixture was stirred for 2 h at 60 to 70 C. and slowly cooled (over 12 h, 10 C./h) to -5 C. and stirred at this temperature for 5 h. The mixture was filtered and the solids were washed with cold (-5 C.) ethanol (95%, 2×0.9 kg) and n-heptane (2×1.5 kg) and the solids were dried under reduced pressure at 55 to 65 C. for 20 h to give a white solid (1.34 kg, 82% yield, 98.2% pure by HPLC-0001).
In ethanol; water; at 80℃; for 1.0h;
To stirred solution of Example 5E in CH2CyCH3CN (650 mL:650 mL) at -5 0C was added triethylsilane (28.2 mL, 563 mmol), and followed by BF3-Et2O (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm to room temperature gradually. The reaction was quenched with aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give the crude product (230 g, purity 82.3%). This product and L-proline (113.7 g) in EtOH/H2O (15:1 v/v, 2.09 L) was stirred at 80 0C for 1 h when it became a clear solution. Hexane (3.0 L) was added dropwise into the above hot solution over 50 min, with the temperature being kept at about 60 0C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/ H2O (15:1 (v/v), 2 x 300 mL), hexane (2 x 900 mL), and dried at 45 0C under vacuum for 10 h to give the pure title compound as a white solid (209 g).Purity (HPLC) 99.2% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.25 ~ 7.34 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, IH), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H)
In ethanol; water; at 80℃; for 1.0h;
To stirred solution of Example IE in CH2C12/CH3CN (650 mL:650 mL) at -5 C was added triethylsilane (28.2 mL, 563 mmol), and followed by BF3-Et20 (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm to room temperature gradually. The reaction was quenched with aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na2S04 and concentrated to give the crude product 6 (230 g, purity 82.3%). This product and L-proline (113.7 g) in EtOH/H20 (15:1 v/v, 2.09 L) was stirred at 80 C for 1 h when it became a clear solution. Hexane (3.0 L) was added dropwise into the above hot solution over 50 min, with the temperature being kept at about 60 C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/ H20 (15:1 (v/v), 2x300 mL), hexane (2x900 mL), and dried at 45 C under vacuum for 10 h to give the pure title compound 7 as a white solid (209 g). Purity (HPLC) 99.2% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.25-7.34 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, 1H), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H).
Preparation of (25,5R, R,55,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(Z-proline) complex (7)[0104] To stirred solution of Example IE in CH2C12/CH3CN (650 mL:650 mL) at -5 C was added triethylsilane (28.2 mL, 563 mmol), and followed by BF3-Et20 (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm to room temperature gradually. The reaction was quenched with aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na2S04 and concentrated to give the crude product 6 (230 g, purity 82.3%). This product and L-proline (113.7 g) in EtOH/H20 (15:1 v/v, 2.09 L) was stirred at 80 C for 1 h when it became a clear solution. Hexane (3.0 L) was added dropwise into the above hot solution over 50 min, with the temperature being kept at about 60 C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/ H20 (15:1 (v/v), 2x300 mL), hexane (2x900 mL), and dried at 45 C under vacuum for 10 h to give the pure title compound 7 as a white solid (209 g).Purity (HPLC) 99.2% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.25-7.34 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, 1H), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H)
In ethanol; for 1.0h;Reflux;
[0211] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex by co-crystallization of ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol with L-proline in ethanol/water/n-heptane solvent mixture. [0212] The crude (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2.5 kg) was added to a glass reactor containing ethanol (95%, 16 kg) and L-proline (1.24 kg) and the mixture was refluxed for 1 h. While keeping the temperature above 60 C, n-heptane (8.5 kg) was added over 40 min. The mixture was slowly cooled to 25 to 20 C and stirred at this temperature for 10 h. The mixture was filtered and the solids were washed with cold (-5 C) ethanol (95%o, 2 x 2.5 L) and n-heptane (2 x 5 L) and the solids were dried under reduced pressure at 55 to 65 C for 20 h to give a white solid (3.03 kg, 81 % yield, 99.4% pure by HPLC Method EGT-M-0001).
3.03 kg
In ethanol; n-heptane; water; at 20℃; for 11.6667h;Reflux; Large scale;
[0231] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex by co-crystallization of ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol with L-proline in ethanol/water/n-heptane solvent mixture. [0232] The crude (2S,3R,4R,5S, R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2.5 kg) was added to a glass reactor containing ethanol (95%, 16 kg) and L-proline (1.24 kg) and the mixture was refluxed for 1 h. While keeping the temperature above 60 C, n-heptane (8.5 kg) was added over 40 min. The mixture was slowly cooled to 25 to 20 C and stirred at this temperature for 10 h. The mixture was filtered and the solids were washed with cold (-5 C) ethanol (95%o, 2 x 2.5 L) and n-heptane (2 x 5 L) and the solids were dried under reduced pressure at 55 to 65 C for 20 h to give a white solid (3.03 kg, 81% yield, 99.4% pure by HPLC-0001).
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -5 - 20℃; for 16.0h;
To stirred solution of Example 5E in CH2CyCH3CN (650 mL:650 mL) at -5 0C was added triethylsilane (28.2 mL, 563 mmol), and followed by BF3-Et2O (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm to room temperature gradually. The reaction was quenched with aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give the crude product (230 g, purity 82.3%). This product and L-proline (113.7 g) in EtOH/H2O (15:1 v/v, 2.09 L) was stirred at 80 0C for 1 h when it became a clear solution. Hexane (3.0 L) was added dropwise into the above hot solution over 50 min, with the temperature being kept at about 60 0C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/ H2O (15:1 (v/v), 2 x 300 mL), hexane (2 x 900 mL), and dried at 45 0C under vacuum for 10 h to give the pure title compound as a white solid (209 g).Purity (HPLC) 99.2% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.25 ~ 7.34 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, IH), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H).
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -5 - 20℃; for 16.0h;
To stirred solution of Example IE in CH2C12/CH3CN (650 mL:650 mL) at -5 C was added triethylsilane (28.2 mL, 563 mmol), and followed by BF3-Et20 (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm to room temperature gradually. The reaction was quenched with aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na2S04 and concentrated to give the crude product 6 (230 g, purity 82.3%). This product and L-proline (113.7 g) in EtOH/H20 (15:1 v/v, 2.09 L) was stirred at 80 C for 1 h when it became a clear solution. Hexane (3.0 L) was added dropwise into the above hot solution over 50 min, with the temperature being kept at about 60 C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/ H20 (15:1 (v/v), 2x300 mL), hexane (2x900 mL), and dried at 45 C under vacuum for 10 h to give the pure title compound 7 as a white solid (209 g). Purity (HPLC) 99.2% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.25-7.34 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, 1H), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H).
Preparation of (25,5R, R,55,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(Z-proline) complex (7)[0104] To stirred solution of Example IE in CH2C12/CH3CN (650 mL:650 mL) at -5 C was added triethylsilane (28.2 mL, 563 mmol), and followed by BF3-Et20 (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm to room temperature gradually. The reaction was quenched with aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na2S04 and concentrated to give the crude product 6 (230 g, purity 82.3%). This product and L-proline (113.7 g) in EtOH/H20 (15:1 v/v, 2.09 L) was stirred at 80 C for 1 h when it became a clear solution. Hexane (3.0 L) was added dropwise into the above hot solution over 50 min, with the temperature being kept at about 60 C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/ H20 (15:1 (v/v), 2x300 mL), hexane (2x900 mL), and dried at 45 C under vacuum for 10 h to give the pure title compound 7 as a white solid (209 g).Purity (HPLC) 99.2% (UV). 1H NMR (CD3OD, 400 MHz): delta 7.25-7.34 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, 1H), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H)
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex[ No CAS ]
[ 1118567-05-7 ]
Yield
Reaction Conditions
Operation in experiment
93.9%
In methanol; water; at 20℃; for 5.0h;Product distribution / selectivity;
To a 5.0 L 4-necked flask equipped with a mechanical stirrer was added the starting co-crystal (150.0 g) and methanol (300 mL). The mixture was stirred at room temperature with mechanical stirring (anchor agitator, 2-blades 9 cm) until a cloudy solution/suspension formed, to which distilled water (1500 mL) was added dropwise at a rate of -12.5 mL/min. As the mixture warmed from the exotherm of adding water to methanol, the mixture became clear after adding about 1/5 to 1/3 of the water. After the addition was completed the reaction was stirred continuously at 80 rpm for another 5 h. The reaction mixture was filtered over medium-speed filter paper and the filter cake was washed with distilled water (450 mL and then 300 mL) and dried under vacuum using an oil pump (~6 mmHg) at 45 C for 48 hours to give the target product as a white crystalline solid (94.2 g, 93.9% yield, purity (HPLC):99.3%).
93.9%
With methanol; In water; at 20℃;Product distribution / selectivity;
This example illustrates the preparation of a crystalline form of (2S, 3R, 4R, 5S, 6R)-2- (4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol.[0106] To a 5.0 L 4-necked flask equipped with a mechanical stirrer was added the starting co-crystal (150.0 g) and methanol (300 mL). The mixture was stirred at room temperature with mechanical stirring (anchor agitator, 2-blades 9 cm) until a cloudy solution/suspension formed, to which distilled water (1500 mL) was added dropwise at a rate of -12.5 mL/min. As the mixture warmed from the exotherm of adding water to methanol, the mixture became clear after adding about 1/5 to 1/3 of the water. After the addition was completed the reaction was stirred continuously at 80 rpm for another 5 h. The reaction mixture was filtered over medium-speed filter paper and the filter cake was washed with distilled water (450 mL and then 300 mL) and dried under vacuum using an oil pump (~6 mm Hg) at 45 C for 48 hours to give the target product as a white crystalline solid (94.2 g, 93.9% yield, purity (HPLC): 99.3%)
92%
With water; In methanol; for 0.5h;Reflux; Large scale;
Example 14 Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol crystals [0281] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by crystallization of ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(442-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol bis(L-proline) complex in methanol/water solvent mixture. [0282] (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1.3 kg) was added to a propylene drum (25 L) and methanol (3.6 kg) and water (1.3 kg) and the mixture was stirred until the solids dissolved. The solution was filtered through filter membrane (Millipore, 0.45 mum) into a clean glass reactor (50 L). The mixture was refluxed for 30 min and water (7.2 kg) was added over 1.0 h while maintaining the temperature between 50 and 65 C. The mixture was slowly cooled to 42 C. over 2 h. A suspension of seed crystal (26 g) in cold (-5 C.) mixture of methanol/water (78 mL, 2.8/6.5 (w/w)) and the slow cooling was continued to -5 C. over 12 h. The suspension was stirred for another 5 h and was filtered. The solid was slurried with cold water and filtered (0 to 5 C., 3×2.6 kg). The filter cake was dried under reduced pressure for 24 h until the loss on drying was no more than 0.5% to give a white solid (825 g, 92% yield, 99.3% pure by HPLC-0001).
88.3%
With methanol; water; at 50 - 65℃; for 2.0h;Reflux;
[0213] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by crystallization of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)- 6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex in methanol/water solvent mixture. [0214] (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) (1.05 kg) was added to a propylene drum (25 L) and methanol (3.3 kg) and water (1.05 kg) and the mixture was stirred until the solids dissolved. The solution was filtered through filter membrane (Millipore, 0.45 muiotaeta) into a clean glass reactor (20 L). The mixture was refluxed for 30 min and water (4.83 kg) was added over 1.5 h while maintaining the temperature between 50 and 65 C. The mixture was slowly cooled to ~20 C and stirred for another 5 h. The solid was filtered and the filter cake was slurried with water and filtered (3 x 2.1 kg). The filter cake was dried under reduced pressure for 24 h until the loss on drying was no more than 0.5% to give a white solid (620 g, 88.3% yield, 99.8% pure by HPLC Method EGT-M-0001).
88.3%
With water; In methanol; at 20℃;Reflux; Large scale;
[0234] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by crystallization of ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol bis(L-proline) complex in methanol/water solvent mixture. [0235] (2S, 3R, 4R, 5S,
In water; ethyl acetate; at 60℃; for 3.0h;
Example 5F (40 g, purity 99.8%) in water (400 rnL) was stirred and heated to 60 0C for 1 h. Ethyl acetate (1.0 L) was added dropwise at 60 0C over 1 h. The mixture was stirred for another 1 h. After cooling, the organic layer was separated, washed with water (3x), dried over Na2SO4 and concentrated to give the title compound as a glassy solid (24.0 g, purity 99.8%). 1H NMR (CD3OD, 400 MHz): delta 7.25-7.34 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.84(d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, IH), 3.36 - 3.46 (m,4H), 3.21-3.30 (m, 3H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H).
In methanol; water; at 20 - 60℃;Purification / work up;
A 5 L 4-neck flask was charged with 8 (amorphous), 116 g, and methanol (580 mL). The reaction mixture was heated to 60 C with mechanical stirring and the solution became clear. Water (2320 mL) was added dropwise to the reaction solution at 40 mL/min at 50 C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filter cake was washed with water (2x200 mL), dried under vacuum at 55 C for 12 hours, to afford white crystalline 8. Yield is 112.8 g (97.2%).
13
[ 1459754-30-3 ]
[ 1118567-05-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -25 - -20℃; for 4.0h;Inert atmosphere; Large scale;
Example 5 Preparation of ((2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6-(Hydroxymethyl)Tetrahydro-2H-Pyran-3,4,5-triol [0236] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by reduction of the anomeric OMe and/or OH. (3R,4S,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6-(Hydroxymethyl)-2-Methoxytetrahydro-2H-Pyran-3,4,5-Triol Solution [0237] A 30 L glass reactor equipped with a thermometer was charged with crude (3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (2.7 kg), DCM (5.4 kg) and acetonitrile (3.2 kg), and the mixture was magnetically stirred until all the solids dissolved under nitrogen sparging. [0238] Triethylsilane Solution: [0239] BF3.Et2O (2.34 kg) was added to a cold (-21 to -15 C.) solution of triethysilane (2.55 kg) dichloromethane (5.4 kg) and acetonitrile (3.2 kg) under nitrogen. [0240] The (3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution was added to the cold triethylsilane solution at such a rate to maintain the temperature between -20 and -25 C. (3 h). [0241] The reaction mixture was stirred for another 4 h at -22 to -25 C. and then quenched by addition of an aqueous solution of sodium bicarbonate (7.4% w/w, 18.3 kg) while keeping the internal temperature below -10 C. Solid sodium bicarbonate (1.35 kg) was added to adjust the pH to 7.5. The solvents were removed under reduced pressure (temperature below 40 C.). The residue was partitioned between ethyl acetate (18 kg) and water (9.2 kg). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×9 kg). The combined organic layers were washed with brine (2×9 kg) and the solvents were removed under reduced pressure at the temperature below 40 C. until the condensation almost stop Anhydrous ethanol (9 kg) was added and concentrated to give the crude product of the title compound (2.5 kg, 90% yield, 90.8% HPLC purity, HPLC-0001) as foamy solid.
70%
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -25 - -20℃;Inert atmosphere;
General procedure: To a solution of 16b (2.1 g, 4.2 mmol) in dichloromethane (10.5 mL) and acetonitrile (10.5 mL) at -25 C under argon was added triethylsilane (2.7 mL, 16.8 mmol). Then boron trifluoride etherate (1.6 mL, 12.6 mmol) was added while maintaining the reaction temperature below -20 C, and the reaction mixture was stirred for another 4 h at -25 to -20 C. The reaction was quenched by addition of 5% sodium bicarbonate until a pH of 7.5 was obtained. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate. The sample was concentrated under reduced pressure to give product crude 7b as a light yellow solid (1.82 g, 92% yield; HPLC purity: 88.3%).
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -25 - -20℃; for 7.0h;Inert atmosphere;
[0206] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by reduction of the anomeric OMe and/or OH. R = H or Me [0207] (3R,4S,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6- (Hydroxymethyl)-2-Methoxytetrahydro-2H-Pyran-3,4,5-Triol Solution: A 30 L glass reactor equipped with a thermometer was charged with crude (3R,4S,5S,6R)-2-(4-chloro-3- (4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H- pyran-3,4,5-triol (2.7 kg), DCM (5.4 kg) and acetonitrile (3.2 kg), and the mixture was magnetically stirred until all the solids dissolved under nitrogen sparging. [0208] Triethylsilane Solution: BF3-Et20 (2.34 kg) was added to a cold (-21 to -15 C) solution of triethysilane (2.55 kg) dichloromethane (5.4 kg) and acetonitrile (3.2 kg) under nitrogen. [0209] The (3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution was added to the cold triethylsilane solution at such a rate to maintain the temperature between -20 and -25 C (3 h). [0210] The reaction mixture was stirred for another 4 h at -22 to -25 C and then quenched by addition of an aqueous solution of sodium bicarbonate (7.4% w/w, 18.3 kg) while keeping the internal temperature below -10 C. Solid sodium bicarbonate (1.35 kg) was added to adjust the pH to -7.5. The solvents were removed under reduced pressure (temperature below 40 C). The residue was partitioned between ethyl acetate (18 kg) and water (9.2 kg). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 9 kg). The combined organic layers were washed with brine (2 x 9 kg) and the solvents were removed under reduced pressure at the temperature below 40 C until the condensation almost stop. Anhydrous ethanol (9 kg) was added and concentrated to give the crude product of the title compound (2.5 kg, 90% yield, 90.8% pure by HPLC Method EGT-M-0001) as foamy solid. An analogous procedure is used for reduction of the anomeric OH group.
With triethylsilane; boron trifluoride diethyl etherate; In dichloromethane; acetonitrile; at -25 - -20℃; for 7.0h;Inert atmosphere; Large scale;
[0212] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by reduction of the anomeric OMe and/or OH. R = H or Me [0213] (3R,4S,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6- (Hydroxymethyl)-2-Methoxytetrahydro-2H-Pyran-3,4,5-Triol Solution: A 30 L glass reactor equipped with a thermometer was charged with crude (3R,4S,5S,6R)-2-(4-chloro-3- (4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H- pyran-3,4,5-triol (2.7 kg), DCM (5.4 kg) and acetonitrile (3.2 kg), and the mixture was magnetically stirred until all the solids dissolved under nitrogen sparging. [0214] Triethylsilane Solution: BF3-Et20 (2.34 kg) was added to a cold (-21 to -15 C) solution of triethysilane (2.55 kg) dichloromethane (5.4 kg) and acetonitrile (3.2 kg) under nitrogen. [0215] The (3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6- (hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution was added to the cold triethylsilane solution at such a rate to maintain the temperature between -20 and -25 C (3 h). [0216] The reaction mixture was stirred for another 4 h at -22 to -25 C and then quenched by addition of an aqueous solution of sodium bicarbonate (7.4% w/w, 18.3 kg) while keeping the internal temperature below -10 C. Solid sodium bicarbonate (1.35 kg) was added to adjust the pH to -7.5. The solvents were removed under reduced pressure (temperature below 40 C). The residue was partitioned between ethyl acetate (18 kg) and water (9.2 kg). The layers were separated and the aqueous layer was extracted with ethyl acetate (2x9 kg). The combined organic layers were washed with brine (2 x 9 kg) and the solvents were removed under reduced pressure at the temperature below 40 C until the condensation almost stop. Anhydrous ethanol (9 kg) was added and concentrated to give the crude product of the title compound (2.5 kg, 90% yield, 90.8% HPLC purity, HPLC-0001) as foamy solid.
Take 46.5 mg of the <strong>[1118567-05-7]THR1442</strong> solid sample obtained in Preparation Example 1, and add 2.0 mL of methanol to dissolve.Take 13.3 mg of L-aspartic acid and add 3 mL of water to form a clear solution.The L-aspartic acid aqueous solution was added to a methanol solution of <strong>[1118567-05-7]THR1442</strong>, and the resulting solution was allowed to volatilize at 10 C.57.0 mg of <strong>[1118567-05-7]THR1442</strong> L-aspartic acid cocrystal was obtained in a yield of 95%.