* 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.
Stage #1: With potassium hydroxide In water; toluene at 100℃; for 15.25 h; Stage #2: With hydrogen bromide In water; toluene
This Example illustrates a process for preparing a compound of formula (IV). [0045] 3-(S)-(I -carbamoyl- l,l-diphenylmethyl)pvrrolidine L-(+)-tartrate (1.0 g, 2.33 mmol), potassium hydroxide (0.45 g, 7.04 mmol), methyltriethylammonium chloride (0.05 g, 0.32 mmol), 2 mL of water and 10 mL of toluene were charged into the bottom flask; a yellowish solution was formed. A solution of 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.6 g, 2.64 mmol) in 7 mL of toluene was added dropwise in 15 minutes. The reaction mixture was heated to 100 0C and stirred for 15 hours. Then the reaction mixture was cooled down to 20 °C. After that, 15 mL of toluene and 10 mL of water were added, the mixture was stirred for 20 minutes at atmospheric pressure and the layers were separated. The aqueous layer was extracted and the organic layer was dried with Na2SO4. Then 1 mL of concentrated hydrobromic acid solution was charged and the mixture was concentrated by distillation under vacuum. Then 10 mL of acetone and 10 mL of diisopropylether were charged and then the solvent was evaporated by distillation under vacuum to give 1.1 g (93.2percent molar yield) of a yellowish solid. (HPLC purity (method A): 92.19percent). [0046] The results demonstrate the improved yield of a compound of formula (IV) prepared by reacting the L-(+)-tartrate salt of 3 -(S)-(I -carbamoyl- 1,1- diphenylmethyl)pyrrolidine of formula (V) with 5-(2-bromoethyl)-2,3-dihydrobenzofuran of <n="14"/>formula (VI), methyltriethylammonium chloride, and potassium hydroxide, in the presence of toluene and water.
90.67%
Stage #1: With potassium hydroxide In 2-methyltetrahydrofuran; water at 60 - 70℃; Stage #2: for 16 h; Heating / reflux Stage #3: With hydrogen bromide In 2-methyltetrahydrofuran; water at 0 - 20℃; for 2 h;
This Example illustrates a process for preparing a compound of formula (IV). This Example also illustrates the conversion of a compound of formula (IV) to the hydrobromide salt.[0048] Into a reaction vessel were charged 2,2-diphenyl-2-[(35)-pyrrolidin-3- yl]acetamide L-(+)-tartrate (90.00 g, 0.21 mol), methyltriethylammonium chloride (4.82 g, 0.03 mol) and 2-methyltetrahydrofuran (180 mL). The resulting suspension was heated to 60-70 °C. To the suspension was added a solution of potassium hydroxide (69.79 g, 1.05 mol) in water (180 mL), keeping the temperature between 60 and 70 0C. The mixture was heated to reflux and to this mixture was added dropwise a solution of 5-(2-bromoethyl)-2,3- dihydro-1-benzofuran (56.98 g, 0.25 mol) in 2-methyltetrahydrofuran (270 mL). The resulting mixture was heated at reflux for 16 h and cooled to room temperature. The phases were separated and the organic phase was washed twice with 180 mL of a 10percent aqueous solution of ammonium chloride. The remaining water was distilled azeotropically and hydrobromic acid 48percent (28.19 mL) was added dropwise at room temperature. The resulting suspension was cooled to 0-5 °C, stirred at this temperature for 2 h and filtered. An almost white solid was obtained (188.0 g, l.o.d. = 48.83percent, 90.67percent yield, HPLC purity (method B): 98.96percent). This solid can be optionally dried at 60 °C under vacuum. This solid can be optionally further purified as in Example 4.[0049] The results demonstrate a process for preparing (S)-2- { 1 -[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide of formula (IV) in high yield and purity.
84.92%
Stage #1: With potassium hydroxide In water; butanone at 75℃; for 6 h; Stage #2: With hydrogen bromide In water; butanone at 0 - 5℃; for 2 h;
This Example illustrates a process for preparing a compound of formula (IV). [0054] To a 500 mL, three-neck round bottom flask, equipped with a reflux condenser and a thermometer, was added 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide L-(+)-tartrate (54.15 g, 125.8 mmol), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (34.86 g, 153.5 mmol), potassium hydroxide (20.78 g, 370.4 mmol), methyltriethylammonium chloride (2.810 g, 18.53 mmol), methylethylketone (170 mL) and water (34.0 mL). The reaction mixture was heated to reflux (about 75 °C) and stirred at this temperature for 6 hours, after which time it was cooled to 20-25 0C and methylethylketone (96 mL) and water (106 mL) were added. The mixture was stirred and the layers were separated. To the organic layer 10percent aqueous solution of ammonium chloride (106 mL) was added. The mixture was stirred and the layers were separated. The organic layer was evaporated to dryness and methylethylketone (106 , mL) was added to the residue. The mixture was stirred until complete dissolution and hydrobromic acid (13 mL) was added resulting in the formation of a precipitate. The resulting suspension was cooled to 0-5 0C and stirred at this temperature for 2 h. The suspension was filtered and the solid was washed with methylethylketone (2 x 20 mL). A slightly brown solid was obtained (90.72 g, l.o.d. = 41.51percent, 84.92 percent yield, HPLC purity (method C): 95.68percent).
76.3%
Stage #1: With potassium hydroxide In toluene at 100℃; for 16.25 h; Stage #2: With hydrogen bromide In water; toluene
This Example illustrates a process for preparing a compound of formula (IV). [0042] 3-(5)-(l-carbamoyl-l,l-diphenyhnethyl)pyrrolidine L-(+)-tartrate (1.0 g, 2.33 mmol), potassium hydroxide (0.45 g, 7.04 mmol), methyltriethylammonium chloride (0.05 g, 0.32 mmol) and 10 mL of toluene were charged into the bottom flask; a yellowish solution is formed. A solution of 5-(2-bromoethyl)-2,3-dihydrobenzofuran (0.6 g, 2.64 mmol) in 5 mL <n="13"/>of toluene was added dropwise in 15 minutes. The reaction mixture was heated to 100 °C and stirred for 16 hours; then the reaction mixture was cooled down to 20 °C, and 15 mL of toluene and 20 mL of water were added. The mixture was stirred for 20 minutes at atmospheric pressure and the layers were separated. The aqueous layer was extracted and the organic layer was dried with Na2SO4. After that, 1 mL of concentrated hydrobromic acid solution was charged and the mixture was concentrated by distillation under vacuum. Then 10 mL of acetone and 10 mL of diisopropylether were charged and the solvent was evaporated by distillation under vacuum to give 0.9 g (76.3percent molar yield) of a yellowish solid. (HPLC purity (method A): 65.46percent).[0043] The results demonstrate that a compound of formula (IV) can be prepared by reacting the L-(+)-tartrate salt of 3-(5)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine of formula (V) with 5-(2-bromoethyl)-2,3-dihydrobenzofuran of formula (VI) in the presence of toluene, methyltriethylammonium chloride, and potassium hydroxide.
Reference：
[1] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 12-13
[2] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 13
[3] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 14
[4] Patent: WO2008/29257, 2008, A2, . Location in patent: Page/Page column 11-12
[5] Patent: WO2011/70419, 2011, A1, . Location in patent: Page/Page column 12-15
[6] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1591 - 1597
2
[ 133033-99-5 ]
[ 133099-07-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: at 45 - 50℃; for 6 - 7 h; Stage #2: With hydrogen bromide In water; butan-1-ol
Example 22; Synthesis of (SyZ-n-^-^.S-dihydrobenzofuran-S-vnethyli-S-pyrrolidinvU- 2,2-diphenylacetamide fPRF.HBf); [00174] Pd/C 10percent (0.8g) was added to a solution of S)-2-{l-[2-(benzofuran-5- yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetaraide (8g) in acetic acid (160 ml). The mixture was hydrogenated at 45-500C and at atmospheric pressure for about 6-7 hrs. Catalyst was filtered off and solution was concentrated under vacuum obtaining an oily residue, n- Butanol (40 ml) was added and stirred to obtain a solution. 48percent HBr (3,5 g) was added and a mixture n-Butanol/water was eliminated by distillation to reduce water content to less then 1percent. Darifenacin .HBr crystallizes and after 2 hrs at 15-200C was filtered and washed with n-Butanol ( 3x5ml). After drying at 55-600C under vacuum 8.1 g of Darifenacin hydrobromide were obtained. (Yield 85percent).
Stage #1: With potassium hydroxide; triethylmethylammonium chloride In water; butanone at 75℃; for 6 h; Heating / reflux Stage #2: With hydrogen bromide In water; butanone
EXAMPLE 3; This example illustrates a process for preparing (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide or a salt thereof wherein a substantially enantiomerically pure 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide or salt thereof, as determined by the inventive method, is used as an intermediate compound. In particular, this example illustrates that when using 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide having less than 0.2percent of the (R)-enantiomer as determined by the HPLC method of Example 1, the obtained (S)-darifenacin hydrobromide has less than 0.06percent of the (R)-enantiomer of darifenacin hydrobromide as determined by the HPLC method of Example 2.To a flask was added: 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (54.15 g, 125.8 mmol, 99.63percent ee as determined by chiral HPLC method of Example 1), 5-(2-bromoethyl)-2,3-dihydrobenzofuran (34.86 g, 153.5 mmol), potassium hydroxide (20.78 g, 370.4 mmol), methyltriethylammonium chloride (2.810 g, 18.53 mmol), methylethylketone (170 mL) and water (34.0 mL). The reaction mixture was heated to reflux (approximately 75° C.) and stirred for 6 hours, after which time the reaction mixture was cooled to 20-25° C. After cooling, methylethylketone (96 mL) and water (106 mL) were added with stirring and the layers were separated. Ammonium chloride (106 mL, 10percent aqueous solution) was added to the organic layer with stirring and the layers were separated. The organic layer was evaporated to dryness and methylethylketone (106 mL) was added to the residue. The mixture was stirred until dissolution and hydrobromic acid (13 mL) was added, after which a precipitate formed. The resulting suspension was cooled to 0-5° C. and stirred at this temperature for 2 hours. The suspension was filtered and the solid was washed with methylethylketone (2.x.20 mL). A solid was obtained (90.72 g, l.o.d.=41.51percent, 84.92percent yield, 95.68percent HPLC purity, 99.88percent ee as determined by chiral HPLC method of Example 2).
Reference：
[1] Patent: US2008/312455, 2008, A1, . Location in patent: Page/Page column 7
[2] Patent: US2010/204296, 2010, A1, . Location in patent: Page/Page column 7
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 6, p. 824 - 828
4
[ 133099-04-4 ]
[ 133099-07-7 ]
Yield
Reaction Conditions
Operation in experiment
65%
With hydrogen bromide In water; acetone
The residue (2.2 gm) was dissolved in acetone (9 ml) and added aqueous hydrobromide(0.87 gm). The reaction mixture was cooled to 00C, and the product was collected by filtration, washed with acetone and dried at 5O0C under reduced pressure to afford (3S)-(l-carbamoyl- l,l-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromfde . Dry Weight : 1.7 g Yield : 65 percent HPLC purity : 99.84 percent Other isomer : 0.23 percent
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 10, p. 1591 - 1597
[2] Patent: WO2009/125426, 2009, A2, . Location in patent: Page/Page column 11; 18
[3] Patent: WO2008/100651, 2008, A2, . Location in patent: Page/Page column 41
[4] Patent: WO2008/100651, 2008, A2, . Location in patent: Page/Page column 41-42
[5] Patent: WO2009/94957, 2009, A1, . Location in patent: Page/Page column 9-10
[6] Patent: WO2008/126106, 2008, A2, . Location in patent: Page/Page column 13; 17; 28-29; 32
[7] Patent: WO2009/125430, 2009, A2, . Location in patent: Page/Page column 7; 11
5
[ 943034-50-2 ]
[ 134002-25-8 ]
[ 133099-07-7 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With sodium hydroxide; water In ethyl acetate at 25 - 35℃; for 0.25 h; Stage #2: at 95℃; for 15 h; Stage #3: With hydrogen bromide In water; acetone for 1 h;
EXAMPLE 13: PREPARATION OF DARIFENACIN HYDROBROMIDE (FORMULA I); 3-(S)-(+)-(1-cyano-1 ,1-diphenylmethyl)-pyrrolidine (25 g), ethyl acetate (125 ml) and water (125 ml) were taken into a round bottom flask and stirred for about 10 minutes. Caustic lye (25 ml) was added to it slowly at 25 to 35 0C and stirred{00010077.1} <n="42"/>for about 15 minutes. The organic layer was separated and the aqueous layer was extracted into ethyl acetate (50 ml). The combined ethyl acetate layer was washed with 10percent sodium chloride solution (125 ml) and the ethyl acetate layer was distilled off completely to get a residue. To the residue obtained 5-chloroethyl-2,3- dihydrobenzofuran (14.4 g), and triethylamine (12 ml) were added and heated to about 95 0C. The reaction mass was maintained at the same temperature for about 15 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, ethyl acetate (125 ml) was added to the reaction mass at 40 to 45 0C, followed by addition of water (125 ml). The organic layer was separated and the aqueous layer was extracted into ethyl acetate (75 ml). The combined ethyl acetate layer was washed with 10percent sodium chloride solution (125 ml) and then distilled at about 45 0C to get a residue. To the residue obtained acetone (122 ml) was added and stirred at about 30 0C for 1 hour. To the above solution aquoues hydrobromic acid (12.8 g) was added and stirred for another 1 hour. The separated solid was filtered and washed with acetone (61 ml). The wet solid was dried at 60-65 °C for about 4 hours to yield 24.6 g of the title compound (percent yield: 70 percent). Purity By HPLC: 98.78percent.
Stage #1: With potassium carbonate In water at 101 - 103℃; for 2.5 - 5 h; Stage #2: With hydrogen bromide In water; butan-1-ol
Example 12; Preparation of (SVdaiifenacin hvdrobromide; [00159] A 50 ml reactor was loaded with -(SH+Ml -carbamoyl- 1,1- diphenylmethyl)pyrrolidine Tartrate (4 g, 9.29mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42mmoles), and water (12.5 ml), to obtain a heterogeneous mixture. The heterogeneous mixture was heated to reflux (103°C) for 2.5 hours. After cooling, dichloromethane, EtOAc or BuOAc (15 ml) were added, and, after stirring, the phases were separated. Acetic anhydride (0.5 ml) was added to the organic phase, and, after 1 hour at room temperature, the residual 3-(S)-(+)-(l- carbamoyl-l,l-diphenylmethyl)pyrrolidine was transformed into N- Acetyl derivative. The solvent was removed by distillation, and n-butanol (25 ml) was added to the residue. 48percent hydrobromic acid (1.72 g) was also added, and the residual DCM was removed under vacuum distillation. In the case of EtOAc or BuOAc, distillation under vacuum is useful to eliminate water. Darifenacin hydrobromide crystallized, and, after cooling to room temperature, the darifenacin hydrobromide was filtered and washed. (Wet solid 4.17 g).; Example 14; Preparation of (S)-darifenacin hvdrobromide; [00161] A 150 ml reactor was loaded with water (37.5 ml), potassium carbonate (12 g), and 2(2,3-Dihydrobenzofuran-5-yl-ethylchloride (DBF-EtCl) (5.48 g). The mixture was warmed to 60-650C and DBF-EtCl melted. Then, (S)-(+)-(l -carbamoyl- 1,1- diphenylmethyl)pyrrolidine tartrate (12 g) was loaded and the heterogeneous mixture was warmed to reflux (101-1020C) for 5 hrs.[00162] The reaction mixture was cooled to 80-850C and n-butanol (60 ml) was added.The internal temperature was maintained at 75-800C, and the mixture was stirred until complete dissolution was obtained. Then, the mixture was cooled to 25-300C and the phases were separated. The organic phase was washed twice with water (30 ml) and the phases were separated.[00163] Water was removed by vacuum distillation until a residual volume of 60 ml was obtained, and then n-butanol (30 ml) was added. Then, acetic anhydride (0.6 ml) was loaded and the mixture was stirred at 20-300C for 1 hr, followed by loading HBr 48percent (4.7g) at 25-27°C. The water and 20 ml of butanol were removed by vacuum distillation to obtain a suspension of darifenacin hydrobromide. The suspension was stirred at 25-300C for 2 hrs, and then cooled to 0-50C, and filtered after 1 hr. The cake was washed with cold n-Butanol (3x 3ml), and dried under vacuum at 50-550C for 6-7 hrs. (Dry weight 11.2- 11.5. Yield 79- 81percent). Example 23; Preparation of Darifenacin hydrobromide; [00175] Water (ml 203) Potassium carbonate (g 65) and DBF-EtCl (g 29.7) were heated to 60-650C To the mixture (S)-DIPAMP Tartrate (g 65) was added and the heterogeneous mixture was heated to reflux (101-1020C) for 5 hrs. After cooling to 85-900C n-Butanol(ml 325) was added and after stirring phases were separated.[00176] The organic phase was washed twice with water ml 160 (each) and then water was removed from organic phase by vacuum distillation, n- Butanol(ml 160) and Acetic anhydride (ml 3.25) were added and the solution was stirred at 20-300C for 1 hr. 48percent HBr (g25.5) was dropped, water was removed by vacuum distillation and DRF-HBr crystallized.Initial volume was restored by addition of n-BuOH. Suspension was stirred at 15-200C for 2 hrs, than product was recovered by filtration. The cake was washed with n-Butanoi (3x30ml) and wet solid (85-9Og) was crystallized without drying.[00177] Crude wet DRF-HBr (85g), n-Butanol( 455 ml) and charcoal (4.63 g) were warmed to reflux to obtain a solution. After half an hour charcoal was filtered off keeping mixture at near reflux. Clear solution at 1000C was seeded with DBR.HBr and after 30 min at 1000C the solution was cooled to 15-200C in 2 hrs. Suspension was stirred at 15-200C for 2 hrs and then product was recovered by filtration. Cake was washed with n-butanol (3 x25ml). Wet pure DRF-HBr was dried under vacuum at 50-550C for 10-12 hrs.Dry weight 59.2 g. Overall Yield 77.2 percent
(S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate[ No CAS ]
[ 133099-07-7 ]
Yield
Reaction Conditions
Operation in experiment
93.2%
This Example illustrates a process for preparing a compound of formula (IV). [0045] 3-(S)-(I -carbamoyl- l,l-diphenylmethyl)pvrrolidine L-(+)-tartrate (1.0 g, 2.33 mmol), potassium hydroxide (0.45 g, 7.04 mmol), methyltriethylammonium chloride (0.05 g, 0.32 mmol), 2 mL of water and 10 mL of toluene were charged into the bottom flask; a yellowish solution was formed. A solution of <strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong> (0.6 g, 2.64 mmol) in 7 mL of toluene was added dropwise in 15 minutes. The reaction mixture was heated to 100 0C and stirred for 15 hours. Then the reaction mixture was cooled down to 20 °C. After that, 15 mL of toluene and 10 mL of water were added, the mixture was stirred for 20 minutes at atmospheric pressure and the layers were separated. The aqueous layer was extracted and the organic layer was dried with Na2SO4. Then 1 mL of concentrated hydrobromic acid solution was charged and the mixture was concentrated by distillation under vacuum. Then 10 mL of acetone and 10 mL of diisopropylether were charged and then the solvent was evaporated by distillation under vacuum to give 1.1 g (93.2percent molar yield) of a yellowish solid. (HPLC purity (method A): 92.19percent). [0046] The results demonstrate the improved yield of a compound of formula (IV) prepared by reacting the L-(+)-tartrate salt of 3 -(S)-(I -carbamoyl- 1,1- diphenylmethyl)pyrrolidine of formula (V) with <strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong> of <n="14"/>formula (VI), methyltriethylammonium chloride, and potassium hydroxide, in the presence of toluene and water.
90.67%
This Example illustrates a process for preparing a compound of formula (IV). This Example also illustrates the conversion of a compound of formula (IV) to the hydrobromide salt.[0048] Into a reaction vessel were charged 2,2-diphenyl-2-[(35)-pyrrolidin-3- yl]acetamide L-(+)-tartrate (90.00 g, 0.21 mol), methyltriethylammonium chloride (4.82 g, 0.03 mol) and 2-methyltetrahydrofuran (180 mL). The resulting suspension was heated to 60-70 °C. To the suspension was added a solution of potassium hydroxide (69.79 g, 1.05 mol) in water (180 mL), keeping the temperature between 60 and 70 0C. The mixture was heated to reflux and to this mixture was added dropwise a solution of 5-(2-bromoethyl)-2,3- dihydro-1-benzofuran (56.98 g, 0.25 mol) in 2-methyltetrahydrofuran (270 mL). The resulting mixture was heated at reflux for 16 h and cooled to room temperature. The phases were separated and the organic phase was washed twice with 180 mL of a 10percent aqueous solution of ammonium chloride. The remaining water was distilled azeotropically and hydrobromic acid 48percent (28.19 mL) was added dropwise at room temperature. The resulting suspension was cooled to 0-5 °C, stirred at this temperature for 2 h and filtered. An almost white solid was obtained (188.0 g, l.o.d. = 48.83percent, 90.67percent yield, HPLC purity (method B): 98.96percent). This solid can be optionally dried at 60 °C under vacuum. This solid can be optionally further purified as in Example 4.[0049] The results demonstrate a process for preparing (S)-2- { 1 -[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide of formula (IV) in high yield and purity.
84.92%
This Example illustrates a process for preparing a compound of formula (IV). [0054] To a 500 mL, three-neck round bottom flask, equipped with a reflux condenser and a thermometer, was added 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide L-(+)-tartrate (54.15 g, 125.8 mmol), <strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong> (34.86 g, 153.5 mmol), potassium hydroxide (20.78 g, 370.4 mmol), methyltriethylammonium chloride (2.810 g, 18.53 mmol), methylethylketone (170 mL) and water (34.0 mL). The reaction mixture was heated to reflux (about 75 °C) and stirred at this temperature for 6 hours, after which time it was cooled to 20-25 0C and methylethylketone (96 mL) and water (106 mL) were added. The mixture was stirred and the layers were separated. To the organic layer 10percent aqueous solution of ammonium chloride (106 mL) was added. The mixture was stirred and the layers were separated. The organic layer was evaporated to dryness and methylethylketone (106 , mL) was added to the residue. The mixture was stirred until complete dissolution and hydrobromic acid (13 mL) was added resulting in the formation of a precipitate. The resulting suspension was cooled to 0-5 0C and stirred at this temperature for 2 h. The suspension was filtered and the solid was washed with methylethylketone (2 x 20 mL). A slightly brown solid was obtained (90.72 g, l.o.d. = 41.51percent, 84.92 percent yield, HPLC purity (method C): 95.68percent).
76.3%
This Example illustrates a process for preparing a compound of formula (IV). [0042] 3-(5)-(l-carbamoyl-l,l-diphenyhnethyl)pyrrolidine L-(+)-tartrate (1.0 g, 2.33 mmol), potassium hydroxide (0.45 g, 7.04 mmol), methyltriethylammonium chloride (0.05 g, 0.32 mmol) and 10 mL of toluene were charged into the bottom flask; a yellowish solution is formed. A solution of <strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong> (0.6 g, 2.64 mmol) in 5 mL <n="13"/>of toluene was added dropwise in 15 minutes. The reaction mixture was heated to 100 °C and stirred for 16 hours; then the reaction mixture was cooled down to 20 °C, and 15 mL of toluene and 20 mL of water were added. The mixture was stirred for 20 minutes at atmospheric pressure and the layers were separated. The aqueous layer was extracted and the organic layer was dried with Na2SO4. After that, 1 mL of concentrated hydrobromic acid solution was charged and the mixture was concentrated by distillation under vacuum. Then 10 mL of acetone and 10 mL of diisopropylether were charged and the solvent was evaporated by distillation under vacuum to give 0.9 g (76.3percent molar yield) of a yellowish solid. (HPLC purity (method A): 65.46percent).[0043] The results demonstrate that a compound of formula (IV) can be prepared by reacting the L-(+)-tartrate salt of 3-(5)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine of formula (V) with <strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong> of formula (VI) in the presence of toluene, methyltriethylammonium chloride, and potassium hydroxide.
Stage-2PREPARATION OF DARIFENACIN HYDROBROMIDE3- (S)-(-)-(l -Carbamoyl- l ,l-diphenylmethyl)pyrrolidine L-(+)-tartrate (5 g, 0.01 mol), anhydrous potassium carbonate (1 1.25 g, 0.08 mol) and 5-(2-bromoethyl)-2,3- dihydrobenzofuran (2.5 g, 0.01 mol) were suspended in anhydrous acetonitrile (50 ml) under nitrogen atmosphere at 25 +/- 2°C. The reaction suspension was heated to 70 +/- 2 °C and stirred for 4 h. Reaction progress was monitored by HPLC. The reaction mass was cooled to 30 +/- 2°C, salts were filtered and washed with acetonitrile (5 ml). The filtrate was concentrated under reduced pressure at 50 +/- 2 0 C. The residue was dissolved in dichloromethane (25 ml), water (25 ml) was added and the pH was adjusted to 2 +/- 0.1 with 24percent w/w aqueous hydrobromic acid at 25- 30°C. The layers were separated and the aqueous layer was extracted with dichloromethane (10 ml). Water (25 ml) was added to the combined dichloromethane layer and pH was adjusted to 9 +/- 0.1 with 25percent w/w aqueous potassium carbonate solution at 25 +/- 2°C. The layers were separated and the organic layer was concentrated under reduced pressure at 35-40°C. The residue was dissolved in acetone (25 ml), cooled to 5-10°C and the pH was adjusted to acidic with 48percent w/w aqueous hydrobromic acid at 5-10°C. The residue was stirred for 2 h at 20-25°C, cooled to Q-5°C and stirred for 1 h at 0-5°C. The product was filtered, washed with chilled acetone (5 ml) and dried at 50-55°C.Yield: 4.5 gChromatographic purity (By HPLC): 99.24percent5-(2-bromoethyl)-2,3-dihydiObenzofuran: NilDarifenacin dimer impurity: 0.39percent.; EXAMPLE - 3PURIFICATION OF DARIFENACIN HYDROBROMIDE Darifenacin hydrobromide (10 g) was suspended in acetic acid (15 g) at 25 +/- 2°C and heated to 65-70°C. Activated carbon (0.25 g) was added and stin-ed for 15 min at 65-70°C. Carbon was filtered off through hyflo and washed with hot acetic acid (5 g). Water (200 ml) was added to the filtrate slowly at 50-55°C, cooled to 45°C and Darifenacin hydrobromide seed (0.05 g) was added. The resulting solution was cooled to 20-25 °C and stin-ed for 1 h and further cooled to 0-5 °C and stirred for 1 h. The solid was filtered and washed with cold water (10 ml). The product was dried at 50-55°C.Yield: 7.6 gChromatographic purity (By HPLC): 99.52percent<strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong>: Nil 5-(2-Tosyloxyethyl)-253-dihydrobenzofuran: NilDarifenacin dimer impurity: 0.20percent.EXAMPLE - 4PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (15 g) was suspended in a mixture of acetic acid (25 g) and water (25 ml) at 25 +/- 2°C and heated to 65-70°C. Activated carbon (0.75 g) was added and stirred for 15 min at 65-70°C. Carbon was filtered off through hyflo and washed with a mixture of acetic acid and DM water (10 g). Water (120 ml) was added to the filtrate slowly at 50-55°C, cooled to 45°C and Darifenacin hydrobromide seed (0.05 g) was added. The resulting solution was cooled to 20- 25°C and stirred for 1 h and further cooled to 0-5°C and stirred for 1 h. The solid was filtered and washed with cold water (30 ml). The product was dried at 50-55°C. Yield: 1 1.9 gChromatographic purity (By HPLC): 99.71 percent<strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong>: Nil5-(2-Tosyloxyethyl)-2,3-dihydrobenzofuran: NilDarifenacin dimer impurity: 0.20percent. EXAMPLE - 5PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (9 g) was suspended in acetone (45 ml) at 25 +/- 2°C, heated to 55-60°C and stirred for 30 + 5 min at 55-60°C. The resulting solution was cooled to 20-25°C and stin-ed for 30 + 5 min, which is further cooled to 0-5°C and stirred for 1 h. The solid was filtered and washed with chilled acetone (9 ml). The product was dried at 50-55°C.Yield: 8.8 gChromatographic purity (By HPLC): 99.87percent<strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong>: Nil5-(2-Tosyloxyethyl)-2,3-dihydrobenzofuran: NilDarifenacin dimer impurity: 0.08percent. EXAMPLE - 6PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (9 g) was suspended in a mixture of acetone (45 ml) and DM water (1.77 ml) at 25 +/- 2°C, heated to 55-60°C and stirred for 30 + 5 min at 55- 60°C. The resulting solution was cooled to 20-25°C and stirred for 30 + 5 min, which was further cooled to 0-5°C and stirred for 1 h. The product was filtered and washed with chilled acetone (9 ml). The product was dried at 50-55°C.Yield: 8.4 gChromatographic purity (By HPLC): 99.88percentEXAMPLE - 7PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (10 g) was suspended in a mixture of acetone (50 ml) and DM water (3.95 ml) at 25 +/- 2°C, heated to 55-58°C and stirred for 30 +/- 5 min. The resulting solution was cooled to 20-25°C and stirred for 30 +/- 5 min, which was further cooled to 0-5 °C and stirred for 1 hour. The product was filtered and washed with chilled acetone (10ml, 0-5°C). The product was dried at 50-55°C.Yield: 8.30gChromatographic Purity (By HPLC): 99.83 percentDarifenacin dimmer: 0.10percentEXAMPLE - 8PURI...
Stage #1: In methanol at 45 - 50℃; for 0.5h;
Stage #2: In methanol at 45 - 50℃; for 0.166667h; Carbon;
Stage #3: In methanol; cyclohexane at 25 - 65℃;
17
EXAMPLE 17: PURIFICATION OF DARIFENACIN HYDROBROMIDE (FORMULA I); Darifenacin hydrobromide (3.75 kg), and methanol (30 liters) were taken into a reactor and heated to 45 to 50 0C. The reaction mass was maintained at 45 to 50 0C for about 30 minutes to get a clear solution and then carbon (0.19 kg) was added to it and stirred at the same temperature for another 10 minutes. The reaction mixture was then filtered over a celite bed and the bed was washed with methanol (7.5 liters). The filtrate was taken into another reactor and heated to 60 to 65 0C. About 50 to 60% of the total volume of methanol was distilled off from the filtrate and cyclohexane (37.5 liters) was added to it and then allowed to cool to 25 to 35 0C. Another 11.25 liters of cyclohexane was added to the above reaction mass and maintained at 25 to 35 0C for about 30 minutes. The separated solid was filtered and washed with cyclohexane (7.0 liters). The wet solid was dried at 70 0C under reduced pressure for about 12 hours to yield 3.12 kg of the title compound (% yield: 83.2%). Purity By HPLC: 99.8%. All other individual impurities: Less than 0.1 %. Residual Organic Solvents: Methanol: 288 ppm,Cyclohexane: 252 ppm, Particle Size Distribution: D10: 4.8 μm, D50: 17.1 μm, D90: 47.3 μm
68%
In butan-1-ol at 0 - 100℃; for 0.0833333 - 4.5h; Charcoal; Heating / reflux;
15; 17
Example 15; Crystallization of (S Vdarifenacin hvdrobrorm'de; [00164] A 100 ml reactor was loaded with crude darifenacin hydrobromide (10 g), n-butanol (70 ml), and charcoal (0.3g). The mixture was warmed to reflux to obtain a solution. The charcoal was filtered at reflux and washed with n-butanol (5ml). [00165] The solution was maintained at 1000C and seeded to induce crystallization.After 30 min at 1000C, the mixture was cooled to 00C over 3 hrs, and after 1 hr at 00C the mixture was filtered. The product was washed with cold butanol (3x3ml). (Dry weight 8.8- 8.9g. Yield 88-89%. HPLC purity 99.65-99.75% area).; Example 17; Purification of Darifenacin HBr; [00169] The product of Example 16 (3.6 g) was suspended in n-Butanol (25 ml), and heated to reflux to obtain a solution. Charcoal (0.1 g) was added, and, after 5 minutes at reflux, was filtered off. After cooling to room temperature, Darifenacin HBr was filtered, washed, and dried at 45-500C under vacuum for 10 hours. (Dry solid 3.20 g; overall yield 68%; HPLC purity 99.86% area).
7 (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (X)
EXAMPLE 7 (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (X) Method 1: A solution of (S)-2-{1-[-2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide toluene solvate (VIII) (30.4 g, 0.059 moles) in butan-2-one (213 mL) is warmed to 33° C. to attain solution and then cooled to 15° C. 48% aqueous hydrobromic acid(9.9 g, 0.059 moles) is then added and the mixture stirred at 15° C. for 1 hour and 0° C. for 2 hours. The (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (X) is collected by filtration, washed with butan-2-one (65 mL) and dried under vacuum at 50° C. for 18 hours. Yield (24.6 g, 83%). Method 2: To a solution of (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrate (IX) (3.60 g, 0.0081 moles) in butan-2-one (30 mL) is added 48% aqueous hydrobromic acid(1.36 g, 0.0081 moles). The mixture is stirred at 20° C. for 1 hour and 0° C. for 1 hours and the (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (X) is collected by filtration, washed with butan-2-one (10 mL) and dried under vacuum at 50° C. for 18 hours. Yield (3.90 g, 95%). m.p.=232° C. ν=3468, 3211, 3052, 2995, 2870, 2693, 2586, 1668, 1585, 1492, 1442, 1243, 983, 850 cm-1. 1H NMR (300 MHz, CDCl3): δ=2.10-2.23 (1H, m); 2.81-2.99 (2H, m); 3.00-3.15 (4H, m); 3.15 (2H, t); 3.18-3.29 (1H, m); 3.48 (1H, t); 3.69 (1H, s); 3.80-3.95 (1H, m); 4.52 (2H, t); 5.58 (1H, bs); 5.62 (1H, bs); 6.63 (1H, d); 6.84 (1H, d); 6.84 (1H, d); 7.01 (1H, s); 7.19-7.40 (10H, m); 11.48 (1H, bs).
Stage #1: In methanol at 26℃; for 0.166667h;
Stage #2: In methanol for 0.25h; Charcoal carbon;
19
EXAMPLE 19: PREPARATION OF DARIFENACIN HYDROBROMIDE AMORPHOUS FORM (FORMULA I); Darifenacin hydrobromide (0.5 g) and methanol (25 ml) were taken into a round bottom flask followed by stirring at about 26 °C for about 10 minutes. To the resultant homogenous solution charcoal carbon (0.05 g) was added followed by stirring for about 15 minutes. The resultant reaction suspension was filtered through a celite bed and the bed was washed with methanol (5 ml). The filtrate was distilled completely at about 55 0C under reduced pressure to afford 0.4 g of the title compound having an XRPD pattern substantially in accordance with Fig. 3.
In methanol for 0.5h; Heating / reflux;
25; 26
Example-25:Preparation of amorphous darifenacin hydrobromide: Darifenacin hydrobromide 5 gm was dissolved in 50 ml of methanol and heated to get a clear solution. The clear solution was then spray dried at below 500C until a white amorphous powder of darifenacin was obtained. Yield: 4 grams Example 26:Preparation of amorphous darifenacin hydrobromide:Darifenacin hydrobromide 10 gram was dissolved in 100 ml of methanol and heated to reflux to get a clear solution. Refluxed the reaction mixture for 30 min and distilled off the methanol completely to dryness under vacuum to get the solid. Added 50 ml of n-heptane and cooled to 3O0C. Filtered the solid and dried. Yield: 8.2 grams. Purity by HPLC: 99.89%; 0.07 %( RRT 0.30)
In ethyl acetate; N,N-dimethyl-formamide for 0.666667h; Heating / reflux;
27
Example 27:Purification of darifenacin hydrobromide:Darifenacin hydrobromide (50 grams) was suspended in a mixture of dimethyl formamide (75 ml) and ethyl acetate (175 ml). The reaction mixture was heated to reflux and stirred for 40 min. The reaction mixture was slowly cooled to 25-30° C and stirred for 2 hrs. The solid was filtered, washed with of dimethyl formamide and ethyl acetate and dried, to get pure darifenacin hydrobromide. . Yield: 45 grams
4
[ 608127-89-5 ]
[ 133099-07-7 ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: (-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide With potassium hydroxide; tert-Amyl alcohol at 60℃; for 22 - 23h; Heating / reflux;
Stage #2: With hydrogen bromide In water; butanone
6
Example 6; Preparation of 3-(SV(-V(l-carbamoyl-l.l-diphenylmethylVl-f2-(2,3- dihydrobenzofuran-5-vDethyl]pyrrolidine hydrobromide (Formula HI); [00148] KOH (1.95 g, 0.03134 moles) was added to 2-methyl-2-butanol (7 ml), to obtain a suspension. The suspension was warmed to 600C for 1 hour, followed by adding (S)-2-{l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2- acetonitrile hydrobromide (1 g, 0.00204 moles), and warming the reaction mixture (suspension) to reflux for 21-22 hours. After cooling, water (5 ml) was added to the reaction mixture to form a two- phase mixture, and the phases were separated. The solvent was distilled from the organic phase under vacuum, and a residue (0.900 g) was obtained and dissolved in methylethylketone (3 ml). The solution was filtered to eliminate undissolved solid, and 48% HBr (0.344 g, 0.00204 moles) was added. The solvent was distilled under vacuum, and a solid foam was obtained. The foam was slurried in diisopropylether, filtered, and washed to give the title compound. (Dry weight 0.750 g; yield 72%).
72%
Stage #1: (-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide With potassium hydroxide In tert-Amyl alcohol at 60 - 108℃;
Stage #2: With water
Stage #3: With hydrogen bromide In acetic acid; acetone at 20℃;
5
EXAMPLE 5 Obtaining Darifenacin Hydrobromide [Show Image] A suspension of 20.7 g (0.37 moles) of KOH in 90 ml of 2-methyl-2-butanol was heated at 60°C for 1 hour, then 9.06 g (0.0185 moles) of 3-(S)-(-)-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-pyrrolidine hydrobromide (S-Ia) were added; the resulting mixture was heated until reaching 108°C and was maintained at said temperature for 30 hours. Once the reaction was finished, the reaction mixture was cooled at room temperature and 90 ml of water were added. After the separation of the phases, the organic phase was concentrated to a residue at reduced pressure and was redissolved with 45 ml of acetone. Approximately 1.07 ml (0.0185 moles) of 33% HBr in acetic acid was added little by little to this solution stirred at room temperature, it was stirred at room temperature for 1 hour and the solvent was removed at reduced pressure. The resulting residue was redissolved with 100 ml of isopropanol and was maintained under stirring for 1 hour at room temperature and for half an hour at 0-5°C, giving a suspension. The resulting solid was isolated by filtration to give 6.77g (72% yield) of a white solid which coincides with commercial Darifenacin both in relation to its physical characteristics and by means of spectroscopic identification.
27.5%
Stage #1: (-)-3S-(1-carbonitrile-1,1-diphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromide With potassium hydroxide In iso-butanol at 105 - 110℃; for 50h;
Stage #2: With hydrogen bromide; acetic acid In acetone for 1h;
Stage #3: With sodium hydroxide; water; hydrogen bromide; acetic acid more than 3 stages;
14
EXAMPLE 14: PREPARATION OF DARIFENACIN HYDROBROMIDE (FORMULA I); 3-(S)-(-)-(1 -cyano-1 , 1 -diphenylmethyl)-1 -[2-(2,3-dihydrobenzofuran-5-yl)- ethyl]-pyrrolidine hydrobromide (20 g) was added to a solution of potassium hydroxide (57.2 g) in 2-butanol (300 ml). The mixture was allowed to reflux at 105 to 1 10 0C for about 50 hours. Reaction completion was checked using thin layer chromatography. After the reaction is completed, water (100 ml) was added to the reaction mass and the organic layer was separated. The organic layer was washed with water (200 ml) in two equal lots followed by washing with 20 % sodium chloride solution (100 ml). The organic layer was then distilled off completely at 60 to 65 0C, and the residue obtained was co-distilled with acetone (40 ml). To the residue obtained, acetone (72 ml) was added followed by addition of hydrogen bromide in acetic acid (14.8 g). The mixture was stirred for about 1 hour and the separated solid was filtered. The wet solid was taken into another round bottom flask and n-propanol (162 ml) was added to it. The mixture was{00010077.1} heated to 90 to 95 0C and maintained for about 10 minutes. Then it was cooled to 25 to 35 0C and maintained for about 1 hour. The separated solid was filtered and washed with n-propanol (27 ml). The process was repeated twice with the wet compound using n-propanol (135 ml) and the separated solid was filtered and washed with 27 ml of n-propanol. The final wet solid was dried at 65 0C for about 5 hours to yield 7.6 g of the title compound.The dry compound was again taken into another round bottom flask and ethyl acetate (56 ml), and water (56 ml) were added to it and stirred at 25 to 35 0C for about 10 minutes. A solution of caustic lye (7 ml) in water (7 ml) was then added to the above mixture and stirred for about 20 minutes. The organic layer was separated and the aqueous layer was extracted into ethyl acetate (27 ml). The combined organic layer was washed with 10 % sodium chloride solution (35 ml) and then distilled off completely to get a residue. To the residue obtained acetone (24 ml) and a solution of hydrogen bromide in acetic acid (5.9 g) was added and stirred for about 1 hour. The separated solid was filtered and washed with acetone (12 ml). The wet solid was dried at 65 °C for about 5 hours to yield 5.7 g of the title compound (% yield: 27.5%). Purity By HPLC: 99.59%.
Stage #1: 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With sodium hydroxide; water In ethyl acetate at 25 - 35℃; for 0.25h;
Stage #2: 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride With triethylamine at 95℃; for 15h;
Stage #3: With hydrogen bromide In water; acetone for 1h;
13
EXAMPLE 13: PREPARATION OF DARIFENACIN HYDROBROMIDE (FORMULA I); 3-(S)-(+)-(1-cyano-1 ,1-diphenylmethyl)-pyrrolidine (25 g), ethyl acetate (125 ml) and water (125 ml) were taken into a round bottom flask and stirred for about 10 minutes. Caustic lye (25 ml) was added to it slowly at 25 to 35 0C and stirred{00010077.1} for about 15 minutes. The organic layer was separated and the aqueous layer was extracted into ethyl acetate (50 ml). The combined ethyl acetate layer was washed with 10% sodium chloride solution (125 ml) and the ethyl acetate layer was distilled off completely to get a residue. To the residue obtained 5-chloroethyl-2,3- dihydrobenzofuran (14.4 g), and triethylamine (12 ml) were added and heated to about 95 0C. The reaction mass was maintained at the same temperature for about 15 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, ethyl acetate (125 ml) was added to the reaction mass at 40 to 45 0C, followed by addition of water (125 ml). The organic layer was separated and the aqueous layer was extracted into ethyl acetate (75 ml). The combined ethyl acetate layer was washed with 10% sodium chloride solution (125 ml) and then distilled at about 45 0C to get a residue. To the residue obtained acetone (122 ml) was added and stirred at about 30 0C for 1 hour. To the above solution aquoues hydrobromic acid (12.8 g) was added and stirred for another 1 hour. The separated solid was filtered and washed with acetone (61 ml). The wet solid was dried at 60-65 °C for about 4 hours to yield 24.6 g of the title compound (% yield: 70 %). Purity By HPLC: 98.78%.
Stage #1: 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride; 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide With potassium carbonate In water at 101 - 103℃; for 2 - 5h;
Stage #2: With hydrogen bromide In water; butan-1-ol
13
Example 13; Preparation of (S)-darifenacin hvdrobromide; [00160] A 50 ml reactor was loaded with (S)-(+)-(l-carbamoyl-l,l- diphenylmethyl)pyrrolidine free base (2.6 g, 9.29mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42mmoles), and water (12.5 ml) to obtain a heterogeneous mixture. The heterogeneous mixture was heated to reflux (1030C) for 2 to 5 hours. After cooling, dichloromethane, Ethyl acetate, or Butylacetate (15 ml) was added, and, after stirring, the phases were separated. Acetic anhydride (0.5 ml) was added to the organic phase, and, after 1 hour at room temperature, the residual 3-(S)-(+)-(l- carbamoyl-l,l-diphenylmethyl)pyrrolidine was transformed into N- Acetyl derivative (as described in example 11). Half of the solvent was removed by distillation, and n-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72 g) was also added, and the residual DCM was removed under vacuum distillation. In the case of EtOAC or BuOAc, distillation under vacuum is useful to eliminate water. Darifenacin hydrobromide crystallized, and, after cooling to room temperature, the darifenacin hydrobromide was filtered and washed. (Dry solid 2.5 g).
Stage #1: 2-(2,3-dihydrobenzofuran-5-yl)ethylchloride; (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate With potassium carbonate In water at 101 - 103℃; for 2.5 - 5h;
Stage #2: With hydrogen bromide In water; butan-1-ol
12; 14; 23
Example 12; Preparation of (SVdaiifenacin hvdrobromide; [00159] A 50 ml reactor was loaded with -(SH+Ml -carbamoyl- 1,1- diphenylmethyl)pyrrolidine Tartrate (4 g, 9.29mmoles), 2(2,3-Dihydrobenzofuran-5-y) ethylchloride (1.95 g, 10.68mmoles), potassium carbonate (6.14 g, 44.42mmoles), and water (12.5 ml), to obtain a heterogeneous mixture. The heterogeneous mixture was heated to reflux (103°C) for 2.5 hours. After cooling, dichloromethane, EtOAc or BuOAc (15 ml) were added, and, after stirring, the phases were separated. Acetic anhydride (0.5 ml) was added to the organic phase, and, after 1 hour at room temperature, the residual 3-(S)-(+)-(l- carbamoyl-l,l-diphenylmethyl)pyrrolidine was transformed into N- Acetyl derivative. The solvent was removed by distillation, and n-butanol (25 ml) was added to the residue. 48% hydrobromic acid (1.72 g) was also added, and the residual DCM was removed under vacuum distillation. In the case of EtOAc or BuOAc, distillation under vacuum is useful to eliminate water. Darifenacin hydrobromide crystallized, and, after cooling to room temperature, the darifenacin hydrobromide was filtered and washed. (Wet solid 4.17 g).; Example 14; Preparation of (S)-darifenacin hvdrobromide; [00161] A 150 ml reactor was loaded with water (37.5 ml), potassium carbonate (12 g), and 2(2,3-Dihydrobenzofuran-5-yl-ethylchloride (DBF-EtCl) (5.48 g). The mixture was warmed to 60-650C and DBF-EtCl melted. Then, (S)-(+)-(l -carbamoyl- 1,1- diphenylmethyl)pyrrolidine tartrate (12 g) was loaded and the heterogeneous mixture was warmed to reflux (101-1020C) for 5 hrs.[00162] The reaction mixture was cooled to 80-850C and n-butanol (60 ml) was added.The internal temperature was maintained at 75-800C, and the mixture was stirred until complete dissolution was obtained. Then, the mixture was cooled to 25-300C and the phases were separated. The organic phase was washed twice with water (30 ml) and the phases were separated.[00163] Water was removed by vacuum distillation until a residual volume of 60 ml was obtained, and then n-butanol (30 ml) was added. Then, acetic anhydride (0.6 ml) was loaded and the mixture was stirred at 20-300C for 1 hr, followed by loading HBr 48% (4.7g) at 25-27°C. The water and 20 ml of butanol were removed by vacuum distillation to obtain a suspension of darifenacin hydrobromide. The suspension was stirred at 25-300C for 2 hrs, and then cooled to 0-50C, and filtered after 1 hr. The cake was washed with cold n-Butanol (3x 3ml), and dried under vacuum at 50-550C for 6-7 hrs. (Dry weight 11.2- 11.5. Yield 79- 81%). Example 23; Preparation of Darifenacin hydrobromide; [00175] Water (ml 203) Potassium carbonate (g 65) and DBF-EtCl (g 29.7) were heated to 60-650C To the mixture (S)-DIPAMP Tartrate (g 65) was added and the heterogeneous mixture was heated to reflux (101-1020C) for 5 hrs. After cooling to 85-900C n-Butanol(ml 325) was added and after stirring phases were separated.[00176] The organic phase was washed twice with water ml 160 (each) and then water was removed from organic phase by vacuum distillation, n- Butanol(ml 160) and Acetic anhydride (ml 3.25) were added and the solution was stirred at 20-300C for 1 hr. 48% HBr (g25.5) was dropped, water was removed by vacuum distillation and DRF-HBr crystallized.Initial volume was restored by addition of n-BuOH. Suspension was stirred at 15-200C for 2 hrs, than product was recovered by filtration. The cake was washed with n-Butanoi (3x30ml) and wet solid (85-9Og) was crystallized without drying.[00177] Crude wet DRF-HBr (85g), n-Butanol( 455 ml) and charcoal (4.63 g) were warmed to reflux to obtain a solution. After half an hour charcoal was filtered off keeping mixture at near reflux. Clear solution at 1000C was seeded with DBR.HBr and after 30 min at 1000C the solution was cooled to 15-200C in 2 hrs. Suspension was stirred at 15-200C for 2 hrs and then product was recovered by filtration. Cake was washed with n-butanol (3 x25ml). Wet pure DRF-HBr was dried under vacuum at 50-550C for 10-12 hrs.Dry weight 59.2 g. Overall Yield 77.2 %
Stage #1: (S)-darifenamine With sodium tetrahydroborate In ethanol at 20℃; for 3h;
Stage #2: With water In ethanol
Stage #3: With hydrogen bromide In water; butan-1-ol
16
Example 16; Preparation, of (SVdarifenacin hydrobromide via (S)-darifenamine; [00166] 3-(S)-(+)-(l-Carbamoyl-l,l-diphenylmethyl)pyrrolidine (2.1 g, 7.5 mmoles) and 2,3-dihydrobenzofuran-5-yl,acetaldehyde (1 A g, 8.6 mmoles) were combined with toluene (20 ml) at room temperature, and reacted for 15 hours to give (S)-darifenamine. [00167] At this point, a solution OfNaBH4 (0.57 g, 15 mmoles) in ethanol (10 ml) was added slowly, and after 3 hours at room temperature, HPLC analysis revealed formation of (S)-D arifenacin. After washing with water, the solvent was eliminated by distillation, and the obtained residue was dissolved in n-BuOH followed by the addition of HBr 48% (1.5 g, 9 mmoles). Water was eliminated under vacuum, and a slow crystallization was observed. After cooling, the product was filtered and washed with n-BuOH to give the title compound. (Dry weight 0.7 g).[00168] The same reaction has been performed in presence of molecular sieves and titanium isopropylate with similar results.
Stage #1: (S)-2-{1-[2-(benzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide With hydrogen; acetic acid at 45 - 50℃; for 6 - 7h;
Stage #2: With hydrogen bromide In water; butan-1-ol
22
Example 22; Synthesis of (SyZ-n-^-^.S-dihydrobenzofuran-S-vnethyli-S-pyrrolidinvU- 2,2-diphenylacetamide fPRF.HBf); [00174] Pd/C 10% (0.8g) was added to a solution of S)-2-{l-[2-(benzofuran-5- yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetaraide (8g) in acetic acid (160 ml). The mixture was hydrogenated at 45-500C and at atmospheric pressure for about 6-7 hrs. Catalyst was filtered off and solution was concentrated under vacuum obtaining an oily residue, n- Butanol (40 ml) was added and stirred to obtain a solution. 48% HBr (3,5 g) was added and a mixture n-Butanol/water was eliminated by distillation to reduce water content to less then 1%. Darifenacin .HBr crystallizes and after 2 hrs at 15-200C was filtered and washed with n-Butanol ( 3x5ml). After drying at 55-600C under vacuum 8.1 g of Darifenacin hydrobromide were obtained. (Yield 85%).
With hydrogen bromide In water; acetone at 0 - 20℃; for 7h;
65%
With hydrogen bromide In water; acetone
7
The residue (2.2 gm) was dissolved in acetone (9 ml) and added aqueous hydrobromide(0.87 gm). The reaction mixture was cooled to 00C, and the product was collected by filtration, washed with acetone and dried at 5O0C under reduced pressure to afford (3S)-(l-carbamoyl- l,l-diphenylmethyl)-l-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]pyrrolidine hydrobromfde . Dry Weight : 1.7 g Yield : 65 % HPLC purity : 99.84 % Other isomer : 0.23 %
With hydrogen bromide In water; acetone for 1.25 - 2.33333h;
15
EXAMPLE 15: PREPARATION OF DARIFENACIN HYDROBROM I DE (FORMULA I); Darifenacin (1 g) and acetone (5 ml) were taken into a round bottom flask followed by stirring for about 5-10 minutes. 48% aqueous hydrogen bromide (0.4 g) was added over about 15 to 20 minutes followed by stirring for about 1 to 2 hours. Separated solid was filtered and washed with acetone (5 ml). The solid obtained was dried at about 60-70 0C to afford 0.4 g of the title compound. Purity by HPLC: 98.01 %.
With ammonium bromide In methanol at 15℃; for 1.5h;
16
EXAMPLE 16: PREPARATION OF DARIFENACIN HYDROBROMIDE USING AMMONIUM BROMIDE (FORMULA I); 3-(S)-(-)-(1-carbamoyl-1 ,1-diphenylmethyl)-1-[2-(2,3- dihydrobenzofuran-5- yl)-ethyl]-pyrrolidine (1 g) and methanol (20 ml) were taken into a clean and dry round 4 neck bottom flask followed by stirring for about 10 minutes. The resultant reaction solution was cooled to about 15 0C followed by addition of ammonium bromide (0.5 g). The reaction mixture was stirred for about 1.5 hours followed by{0Q010077.1 } addition of charcoal carbon (0.2 g). The resultant suspension was stirred for about 5 minutes then filtered through a celite bed and the bed was washed with 4 ml of methanol. The filtrate was distilled completely at about 65 0C under reduced pressure to afford 2.1 g of a crude form of the title compound. To the crude solid obtained, dichloromethane (50 ml) was added followed by stirring for about 20 minutes. The mixture was filtered and the solid was washed with dichloromethane (50 ml). The filtrate was distilled completely at about 42 0C under reduced pressure to afford 1.8g of residue. To the residue acetone (10 ml) was added followed by stirring at about 26 0C for about 20 minutes. The mixture was filtered and the solid was washed with acetone (4 ml) followed by drying the solid at about 75 0C for about 12 hours to afford 0.7 g of the title compound in pure form. Purity by HPLC: 99.2%.SOR: [α]D25 = + 43.93° (C= 1 in methylene chloride)
With hydrogen bromide In water; butanone
1; 2; 3
Advanced intermediate VII (4.3 g; 0.01 mol) is stirred up in an aqueous solution of potassium phosphate (9.43 g; 0.041 mol in 20 ml of water) at the laboratory temperature. A toluene solution (20 ml) of intermediate VIII (2.41 g; 0.011 mol) is added to the mixture and the mixture is heated up in an oil bath T=90 0C while being stirred for 3.5 h. After cooling the toluene layer is separated and the aqueous layer is extracted with toluene. The combined toluene extracts are shaken with water and the solvent is distilled off at a reduced pressure. The evaporation residue is dissolved in ethylmethylketone, and an equimolar amount of 48% hydrobromic acid is added. The separated darifenacin hydrobromide is filtered off and dried.Yield: 85% of theory.Example 2Advanced intermediate VII (4.3 g; 0.01 mol) is stirred up in an aqueous solution of potassium carbonate (6.1 g; 0.044 mol in 20 ml of water) at the laboratory temperature. A toluene solution (20 ml) of intermediate VIII (2.41 g; 0.011 mol) is added to the mixture and the mixture is heated in an oil bath T=90 °C while being stirred for 3.5 h. After cooling the toluene layer is separated and the aqueous layer is extracted with toluene. The combined toluene extracts are shaken with water and the solvent is distilled off at a reduced pressure. The evaporation residue is dissolved in ethylmethylketone, and an equimolar amount of 48% hydrobromic acid is added. The separated darifenacine hydrobromide is filtered off and dried.Yield: 86% of theory.Example 3Advanced intermediate VII (4.3 g; 0.01 mol) is stirred up in an aqueous solution of potassium phosphate (9.43 g; 0.041 mol in 20 ml of water) at the laboratory temperature. A solution of intermediate VIII (2.41 g; 0.011 mol) in cyclohexane (20 ml) is added to the mixture and the mixture is heated in an oil bath T=90 0C while being stirred for 3.5 h. The layers are separated while hot. The cyclohexane solution is cooled to the laboratory temperature under intensive stirring. This way the darifenacin base is separated. The product is filtered off and dried. The base is dissolved in ethylmethylketone, and an equimolar amount of 48% hydrobromic acid is added. The separated darifenacin hydrobromide is filtered off and dried.Yield: 85% of theory.
With hydrogen bromide In water; acetone at 0 - 30℃; for 2.25 - 12h;
11; 19
Example 11:Preparation of darifenacin hydrobromide:To 3 -(S)-(+)-(l -carbamoyl -1,1 diphenyl methyl) pyrrolidine tartrate (100 grams) taken in water (500 ml), a solution of aqueous sodium hydroxide was added till the pH reached 14. The reaction mixture was stirred for 20 min at 25-30°C and sodium chloride(150 grams) was added to it and stirred for 20min. The reaction mixture was heated to55-6O0C and extracted with toluene. The toluene layer was washed with 5% sodium chloride solution and the solvent distilled off under reduced pressure. The residue was dissolved in acetonitrile, 5-(2-bromoethyl)-2,3-dihydrobenzofuran (66 grams dissolved in 800 ml acetonitrile) and potassium hydroxide (13 grams) was added to it. The reaction mixture was heated to 40-50°C and stirred for 18 hrs. The reaction mixture was cooled to 25-30°C and filtered. The acetonitrile solvent was distilled off under reduced pressure. The residue was dissolved in acetone, cooled to 0-5°C and hydrobromic acid (36 ml) was added to it. The temperature was raised to 25-30°C and stirred for 12 hrs. The reaction mixture was cooled to 0-5° C, the solid obtained was filtered, washed with acetone and dried. It was purified using methanol and acetone to provide the title compound as a white solid.Yield: 75 gramsSOR: +45 (C=I, dichloromethane) Example 19:Preparation of darifenacin hydrobromide:A mixture of 28 grams of darifenacin and 125 ml of acetone was cooled to 0-5°C and hydrobromic acid (9 ml) was added to the above reaction mixture at 0-5 °C. Raised the temperature to 25-30°C and stirred the reaction mixture for 15 minutes at 25-30°C. Cooled the reaction mixture to 0-50C and stirred for 2 hours. The precipitated solid was filtered and washed with chilled acetone. The solid was purified using acetone and methanol to get the pure darifinacin hydrobromide.Yield: 19 gramsPurity by HPLC : 98.73%; 0.02% (RRT : 0.30); 0.42% (RRT : 0.47); 0.04% (RRT : 0.87); 0.10% (RRT : 0.89); 0.05% (RRT : 1.11); 0.10% (RRT : 1.13); 0.17% (RRT :1.16); 0.06% (RRT : 1.26); 0.15%(RRT : 1.30); 0.04% (RRT : 1.34); 0.14% (RRT :1.38).
With hydrogen bromide In acetone at 10 - 25℃;
6
5-(2-Bromoethyl)benzo[2,3-b]furan (17.2 g) was added to the mixture of 3-(S)- (+)-( 1 -carbamoyl- 1 , 1 -diphenylmethyl)pyrrolidine.L-(+)-tartrate (25 g), potassium hydroxide (11.4 g) in acetonitrile solvent at 25-35° C. Reaction mass was heated to 40- 45° C and maintained up to completion of the reaction . The reaction mass was then cooled to R.T and extracted with dichloromethane, the solvent distilled off under vacuum to give residue. Acetone was added to the residue and cooled to 10-15° C. Hydrobromic acid was added to the above solution and heated to 20-25° C and maintained for 10-12 hours. The reaction mass is filtered to give darifenacin hydrobromide.
2
Solutions of crystalline darifenacin hydrobromide were prepared according to Table 1. Crystalline darifenacin hydrobromide was dissolved in the solvent identified in Table 1 at the concentration indicated therein.The solvent from each sample was removed from the solution by heating (40° C.) under vacuum. The obtained solid from each sample was analyzed by means of X-ray powder diffraction (XRPD). The diffractogram is shown in FIG. 3.
In dichloromethane at 40℃;
2
Solutions of crystalline darifenacin hydrobromide were prepared according to Table 1. Crystalline darifenacin hydrobromide was dissolved in the solvent identified in Table 1 at the concentration indicated therein.The solvent from each sample was removed from the solution by heating (40° C.) under vacuum. The obtained solid from each sample was analyzed by means of X-ray powder diffraction (XRPD). The diffractogram is shown in FIG. 3.
In methanol at -20 - 60℃;
2; 4
Solutions of crystalline darifenacin hydrobromide were prepared according to Table 1. Crystalline darifenacin hydrobromide was dissolved in the solvent identified in Table 1 at the concentration indicated therein.The solvent from each sample was removed from the solution by heating (40° C.) under vacuum. The obtained solid from each sample was analyzed by means of X-ray powder diffraction (XRPD). The diffractogram is shown in FIG. 3. EXAMPLE 4 This example illustrates a process for preparing amorphous darifenacin hydrobromide in accordance with an embodiment of the invention.A solution of darifenacin hydrobromide (4.8 g) in methanol (150 mL) was spray dried using a Buchi B290 spray dryer equipped with Buchi inert loop B295 operating in closed loop mode with nitrogen gas.The following parameters were used: inlet temperature (actual) of 60° C.; outlet temperature (actual) of 42° C.; aspirator of 100% (equivalent to approximately 35 m3/hour); nozzle cleaning of 5; nitrogen flow of 30 mm (equivalent to approximately 440 L/hour); and inert loop condenser temperature (set point) of -20° C. The peristaltic pump to feed the product solution was set to 15% (equivalent to approximately 5 mL/min).The obtained solid was analyzed by means of X-ray powder diffraction (XRPD). The diffractogram was in accordance with the diffractogram shown in FIG. 3.These results demonstrate that amorphous darifenacin hydrobromide can be prepared from a solution of darifenacin hydrobromide.
12; 20; 21
Example 12: Purification of darifenacin hydrobromide:Dissolved 38 grams of darifenacin hydrobromide in 400 ml of methanol and heated the solution to reflux. Stirred the reaction mixture for 10 minutes at reflux temperature. Activated carbon 2 grams was added to the reaction mixture and stirred for 30 minutes at reflux temperature. Filtered the solution through hyflow and washed with hot methanol. Distilled off the filtrate under reduced pressure at below 60°C. 20 ml of acetone was added to the reaction mixture and distilled off under reduced pressure at below 6O0C. Added 200 ml of acetone to the above reaction mixture. Heated the reaction mixture to reflux and stirred for 30 min. Cooled the reaction mixture to 25-3O0C and stirred for 30 minutes at 25-300C. Further cooled the reaction mixture to 0-50C and stirred for 1 hour. Filtered the precipitated solid and washed with chilled acetone. Dried the solid to get pure darifenacin hydrobromide. Yield: 27 grams; (Purity by HPLC 99.8 %). Example 20: Purification of darifenacin hydrobromide:Dissolved 38 grams of darifenacin hydrobromide in 400 ml of methanol and heated the solution to reflux. Stirred the reaction mixture for 10 minutes at reflux temperature. Activated carbon 2 grams was added to the reaction mixture and stirred for 30 minutes at reflux temperature. Filtered the solution through hyflow and washed with hot methanol. Distilled off the filtrate under reduced pressure at below 6O0C. 20 ml of acetone was added to the reaction mixture and distilled off under reduced pressure at below 600C. Added 200 ml of acetone to the above reaction mixture. Heated the reaction mixture to reflux and stirred for 30 min. Cooled the reaction mixture to 25-3O0C and stirred for 30 minutes at 25-300C. Further cooled the reaction mixture to 0-50C and stirred for 1 hour. Filtered the precipitated solid and washed with chilled acetone. Dried the solid to get pure darifenacin hydrobromide. Thus obtained pure darifenacin hydrobromide in a crystalline form matched with PXRD, IR and DSC disclosed in figure- 3, figure-4 and figure-5 respectively. Yield: 27 grams.Purity by HPLC 99.88%; 0.03% (RRT: 0.29); 0.07% (RRT: 0.30); 0.02% (RRT: 1.11). Particle size: D(0.1) is 3.377 μm, D(0.5) is 9.823 μm, D(0.9) is 28.069 μm, D(l.O) is 128.1 μm and mean D[4,3] is 13.894 μm. SOR: + 46.5 (1.0 % in methylene chloride) Example 21: Purification of darifenacin hydrobromide:Darifenacin hydrobromide (10 grams) was dissolved in 40 ml of methanol. It was treated with charcoal at reflux temperature. The solution was cooled to 50°C and filtered through celite. Isopropyl alcohol 40 ml was added to the filtrate at 45°C. The reaction mixture was cooled to 25-3O0C and stirred for 60 min. The reaction mixture was further cooled to 0-5°C and stirred for 2 hours. Filtered the precipitated solid and washed with a mixture of methanol and isopropyl alcohol. Thus obtained pure darifenacin hydrobromide in a crystalline form matched with PXRD, IR and DSC disclosed in figure-3, figure-4 and figure-5 respectively. Yield: 6 grams.
11
[ 127264-14-6 ]
[ 134002-25-8 ]
[ 133099-07-7 ]
Yield
Reaction Conditions
Operation in experiment
84.92%
EXAMPLE 3; This example illustrates a process for preparing (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide or a salt thereof wherein a substantially enantiomerically pure 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide or salt thereof, as determined by the inventive method, is used as an intermediate compound. In particular, this example illustrates that when using 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide having less than 0.2percent of the (R)-enantiomer as determined by the HPLC method of Example 1, the obtained (S)-darifenacin hydrobromide has less than 0.06percent of the (R)-enantiomer of darifenacin hydrobromide as determined by the HPLC method of Example 2.To a flask was added: 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetamide (54.15 g, 125.8 mmol, 99.63percent ee as determined by chiral HPLC method of Example 1), <strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong> (34.86 g, 153.5 mmol), potassium hydroxide (20.78 g, 370.4 mmol), methyltriethylammonium chloride (2.810 g, 18.53 mmol), methylethylketone (170 mL) and water (34.0 mL). The reaction mixture was heated to reflux (approximately 75° C.) and stirred for 6 hours, after which time the reaction mixture was cooled to 20-25° C. After cooling, methylethylketone (96 mL) and water (106 mL) were added with stirring and the layers were separated. Ammonium chloride (106 mL, 10percent aqueous solution) was added to the organic layer with stirring and the layers were separated. The organic layer was evaporated to dryness and methylethylketone (106 mL) was added to the residue. The mixture was stirred until dissolution and hydrobromic acid (13 mL) was added, after which a precipitate formed. The resulting suspension was cooled to 0-5° C. and stirred at this temperature for 2 hours. The suspension was filtered and the solid was washed with methylethylketone (2.x.20 mL). A solid was obtained (90.72 g, l.o.d.=41.51percent, 84.92percent yield, 95.68percent HPLC purity, 99.88percent ee as determined by chiral HPLC method of Example 2).
The reaction mixture of 3(S)-(-)-(1-cabamoyl-1,1-diphenylmethyl)-1-pyrrolidine (32.5 gm), potassium carbonate (45.26 gm) and <strong>[127264-14-6]5-(2-bromoethyl)-2,3-dihydrobenzofuran</strong> (31.65 gm) in acetonitrile (450 ml) was heated at 70-75° C. and maintained for 2 hours. The insoluble material was filtered and washed with acetonitrile (50 ml). Acetonitrile was distilled out completely followed by the addition of acetone (500 ml) and aqueous HBr (17.5 gm) at 10-15° C. The reaction mixture was stirred for 6 hours at 20-25° C. followed by cooling at 0° C. and stirred for 1 hour at 0-5° C. The solid mass was filtered and washed with acetone (50 ml). The material was dried at 50-55° C. to produce 42 gm of darifenacin hydrobromide.
2; 4
EXAMPLE 2This example illustrates a method for differentiating and quantifying the enantiomers, thereby determining the enantiomeric purity of a compound of formula (I). In particular, this example illustrates a method for differentiating and quantifying the enantiomers of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide using normal phase conditions.A mobile phase is prepared by mixing 600 mL of hexane and 400 mL of isopropanol with 1 mL of diethylamine. The mobile phase is mixed and filtered through 0.22 μm nylon membrane under vacuum.Samples comprising darifenacin hydrobromide, the (R)-enantiomer of darifenacin hydrobromide, and a racemic mixture of darifenacin hydrobromide are prepared at a concentration of 1.0 mg per mL using a mixture of hexane/isopropanol/diethylamine (60:40:1) as the solvent. Forty microliters of the sample is loaded onto a chiral HPLC column (Daicel CHIRALPAK IA, 5 μm, 4.6×250 mm) and eluted for at least 30 minutes at a flow rate of 1.0 mL per minute at room temperature (20-25° C.). The chromatograph is equipped with a detector monitoring at 230 nm.FIG. 4 is a HPLC chromatogram of a sample comprising a racemic mixture of darifenacin hydrobromide analyzed using these conditions. The peaks for each enantiomer are listed below in Table 4. TABLE 4 Peak Retention Time (minutes) % Area 1 9.3 48.0 2 16.8 51.8 The data from FIG. 4 can be used to differentiate and identify the retention times of both enantiomers of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide from a racemic mixture. The peak at 9.3 minutes corresponds to the (R)-enantiomer and the peak at 16.8 minutes corresponds to the (S)-enantiomer.FIG. 5 is a HPLC chromatogram of a sample comprising (S)-darifenacin hydrobromide analyzed using these conditions. The peak for (S)-darifenacin is listed below in Table 5. TABLE 5 Peak Retention Time (minutes) % Area 1 16.7 99.6 The data from FIG. 5 can be used to determine the enantiomeric purity of the (S)-enantiomer of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (i.e., darifenacin hydrobromide). The peak at 16.7 minutes corresponds to darifenacin hydrobromide. The enantiomeric purity of darifenacin hydrobromide was quantified to be 99.70% ee.FIG. 6 is a HPLC chromatogram of a sample comprising (R)-darifenacin hydrobromide analyzed using these conditions. The peak for (R)-darifenacin is listed below in Table 6. TABLE 6 Peak Retention Time (minutes) % Area 1 9.2 99.6 The data from FIG. 6 demonstrates a method for identifying the retention time of the (R)-enantiomer of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (i.e., (R)-enantiomer of darifenacin hydrobromide). The peak at 9.2 minutes corresponds to the (R)-enantiomer of darifenacin hydrobromide. The enantiomeric purity of the (R)-enantiomer of darifenacin hydrobromide was quantified to be 99.67% ee. EXAMPLE 4This example illustrates a method for differentiating and quantifying the enantiomers, thereby determining the enantiomeric purity of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide using normal phase conditions.A mobile phase is prepared by mixing 100 mL of hexane and 900 mL of a solution of 0.1% of diethylamine in isopropanol. The mobile phase is mixed and filtered through 0.22 μm nylon membrane under vacuum.Samples comprising darifenacin hydrobromide, the (R)-enantiomer of darifenacin hydrobromide, and a racemic mixture of darifenacin hydrobromide are prepared at a concentration of 2.0 mg per mL using a mixture of hexane/isopropanol/diethylamine (10:89.1:0.9) as the solvent. Ten microliters of the sample are loaded onto a chiral HPLC column (Daicel CHIRALPAK IA, 5 μm, 4.6×250 mm) and eluted for at least 30 minutes at a flow rate of 0.7 mL per minute at room temperature (20-25° C.). The chromatograph is equipped with a detector monitoring at 230 nm.FIG. 7 is a HPLC chromatogram of a sample comprising a racemic mixture of darifenacin hydrobromide analyzed using these conditions. The peaks for each enantiomer are listed below in Table 7. TABLE 7 Peak Retention Time (minutes) % Area 1 11.1 49.0 2 18.2 50.8 The data from FIG. 7 can be used to differentiate and identify the retention times of both enantiomers of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide from a racemic mixture. The peak at 11.1 minutes corresponds to the (R)-enantiomer and the peak at 18.2 minutes corresponds to the (S)-enantiomer.FIG. 8 is a HPLC chromatogram of a sample (S)-darifenacin hydrobromide analyzed using these conditions. The peak for (S)-darifenacin hydrobromide is listed below in Table 8. TABLE 8 Peak Retention Time (minutes) % Area 1 18.5 99.8 The data from FIG. 8 can be used to determine the enantiomeric purity of the (S)-enantiomer of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (i.e., darifenacin hydrobromide). The peak at 18.5 minutes corresponds to darifenacin hydrobromide (>99.90% ee).FIG. 9 is a HPLC chromatogram of a sample comprising (R)-darifenacin hydrobromide analyzed using these conditions. The peak for (R)-darifenacin hydrobromide is listed below in Table 9. TABLE 9 Peak Retention Time (minutes) % Area 7 11.1 99.4 The data from FIG. 9 can be used to determine the enantiomeric purity of the (R)-enantiomer of 2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide (i.e., (R)-enantiomer of darifenacin hydrobromide). The peak at 11.1 minutes corresponds to the (R)-enantiomer of darifenacin hydrobromide (99.17% ee).
(S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate[ No CAS ]
(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenylacetamide hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 6Preparation of Crude Darif enacin Hydromide (II)100 gms (0.23 moles) 3-(S)-(+)-(l-carbamoyl-l,l-diphenylmethyl)pyrrolidine tartrate was suspended in 300 ml water under stirring at 20C - 30C. Powdered potassium carbonate 160.46 gms (1.16 moles) was then added to the reaction mixture. 5- (2- bromoethyl) dihydrobenzofuran, 60.71 gms (0.267 moles) was added to the reaction mixture and heated to about 80C -100C. The reaction mixture was stirred maintaining the temperature at 80C - 100C for about 1 to 2 hours. The reaction mixture cooled rapidly to attain a temperature of about 40C - 50C. Toluene 300 ml was added to the reaction mixture, cooled to 20C -30C and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted twice with 300 ml toluene. All the toluene extracts were combined together, and the product was extracted in 400 ml of 20percent aqueous acetic acid solution thrice. The combined acetic acid extracts were washed twice with 200 ml toluene. The pH of the acetic acid was adjusted to about 1-2 using 20percent hydrochloric acid solution. The reaction mass was extracted with 400 ml MDC thrice. All the MDC extracts were combined together and washed with 300 ml 20percent hydrochloric acid solution and then with 300 ml water. The reaction mixture was further washed with 300 ml of saturated aqueous solution sodium bicarbonate twice and then with 300 ml of water. The reaction mass was dried over anhydrous sodium sulfate and concentrated under vacuum maintaining temperature below 40C to obtain oily residue. Acetone 500 ml was added to the oily residue and maintained at 20C - 30C for 15 minutes. 38 gms of 48percent aqueous HBr solution was added to the reaction mixture at 20C - 30C. The reaction mixture was further stirred at 20C - 30C for 2 hrs. The precipitated product was filtered and washed with 300 ml chilled acetone. The wet product was dried at 40C- 45°C under vacuum to obtain 95 gms of crude darifenacin hydrobromide as white crystals with an HPLC Purity >98.5percent.
1
Darifenacin Hydrobromide (10 gm) was taken in water (500 ml) at 20-25° C. and the pH was adjusted to 12+/-0.5 with 20% NaOH solution. The product was extracted with dichloromethane (500 ml) and the organic layer was washed with water (100 ml). The resulting methylene chroride layer was distilled under vacuum to produce amorphous darifenacin base (Yield: 7.5 gm).
Stage #1: (S)-2,2-diphenyl-2-(pyrrolidin-3-yl)-acetamide L-tartrate; 2-(2,3-dihidrobenzofuran-5-yl)ethyl tosylate With potassium carbonate In acetonitrile at 25 - 70℃; Inert atmosphere;
Stage #2: With hydrogen bromide In dichloromethane; water at 5 - 30℃;
1.2; 3; 4; 5; 6; 7; 8
Stage-2:PREPARATION OF DARIFENACIN HYDROBROMIDE3-(S)-(-)-(l -Carbamoyl- l , l -diphenylmethyl)pyrrolidine L-(+)-tartrate (10 g, 0.02 mol), anhydrous potassium carbonate (22.50 g, 0.16 mol) and 5-(2-tosyloxyethyl)- 2,3-dihydrobenzofuran (7 g, 0.02 mol) were suspended in anhydrous acetonitrile ( 100 ml) under nitrogen atmosphere at 25 +/- 2°C. The reaction suspension was heated to 70 +/- 2 °C and stirred for 4 h. Reaction progress was monitored by HPLC. The reaction mass was cooled to 30 + 2°C, the salts were filtered and washed with acetonitrile (10 ml). The filtrate was concentrated under reduced pressure at 50 +/- 2 °C. The residue was dissolved in dichloromethane (50 ml), water (50 ml) was added and the pH was adjusted to 2 +/- 0.1 with 24% w/w aqueous hydrobromic acid at 25- 30°C. The layers were separated and the aqueous layer was extracted with aqueous dichloromethane (20 ml). Water (50 ml) was added to the combined dichloromethane layer and pH was adjusted to 9 +/- 0.1 with 25% w/w aqueous potassium carbonate solution at 25 +/- 2°C. The layers were separated and concentrated under reduced pressure at 35-40°C. The residue was dissolved in acetone (50 ml), cooled to 5-10°C and the pH was adjusted to acidic with 48% w/w aqueous hydrobromic acid at 5-10°C. The residue was stirred for 2 h at 20-25°C, cooled to 0-5°C and stirred for 1 h at 0-5°C. The product was filtered, washed with chilled acetone (10 ml) and dried at 50-55°C.Yield: 9.4 gChromatographic purity (By HPLC): 98.2%.5 -(2-Tosy loxyethy l)-2, 3 -dihydrobenzofuran : NilDarifenacin dimer impurity: 0.96%.; EXAMPLE - 3PURIFICATION OF DARIFENACIN HYDROBROMIDE Darifenacin hydrobromide (10 g) was suspended in acetic acid (15 g) at 25 +/- 2°C and heated to 65-70°C. Activated carbon (0.25 g) was added and stin-ed for 15 min at 65-70°C. Carbon was filtered off through hyflo and washed with hot acetic acid (5 g). Water (200 ml) was added to the filtrate slowly at 50-55°C, cooled to 45°C and Darifenacin hydrobromide seed (0.05 g) was added. The resulting solution was cooled to 20-25 °C and stin-ed for 1 h and further cooled to 0-5 °C and stirred for 1 h. The solid was filtered and washed with cold water (10 ml). The product was dried at 50-55°C.Yield: 7.6 gChromatographic purity (By HPLC): 99.52%5-(2-bromoethyl)-2,3-dihydrobenzofuran: Nil 5-(2-Tosyloxyethyl)-253-dihydrobenzofuran: NilDarifenacin dimer impurity: 0.20%.EXAMPLE - 4PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (15 g) was suspended in a mixture of acetic acid (25 g) and water (25 ml) at 25 +/- 2°C and heated to 65-70°C. Activated carbon (0.75 g) was added and stirred for 15 min at 65-70°C. Carbon was filtered off through hyflo and washed with a mixture of acetic acid and DM water (10 g). Water (120 ml) was added to the filtrate slowly at 50-55°C, cooled to 45°C and Darifenacin hydrobromide seed (0.05 g) was added. The resulting solution was cooled to 20- 25°C and stirred for 1 h and further cooled to 0-5°C and stirred for 1 h. The solid was filtered and washed with cold water (30 ml). The product was dried at 50-55°C. Yield: 1 1.9 gChromatographic purity (By HPLC): 99.71 %5-(2-bromoethyl)-2,3-dihydrobenzofuran: Nil5-(2-Tosyloxyethyl)-2,3-dihydrobenzofuran: NilDarifenacin dimer impurity: 0.20%. EXAMPLE - 5PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (9 g) was suspended in acetone (45 ml) at 25 +/- 2°C, heated to 55-60°C and stirred for 30 + 5 min at 55-60°C. The resulting solution was cooled to 20-25°C and stin-ed for 30 + 5 min, which is further cooled to 0-5°C and stirred for 1 h. The solid was filtered and washed with chilled acetone (9 ml). The product was dried at 50-55°C.Yield: 8.8 gChromatographic purity (By HPLC): 99.87%5-(2-bromoethyl)-2,3-dihydrobenzofuran: Nil5-(2-Tosyloxyethyl)-2,3-dihydrobenzofuran: NilDarifenacin dimer impurity: 0.08%. EXAMPLE - 6PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (9 g) was suspended in a mixture of acetone (45 ml) and DM water (1.77 ml) at 25 +/- 2°C, heated to 55-60°C and stirred for 30 + 5 min at 55- 60°C. The resulting solution was cooled to 20-25°C and stirred for 30 + 5 min, which was further cooled to 0-5°C and stirred for 1 h. The product was filtered and washed with chilled acetone (9 ml). The product was dried at 50-55°C.Yield: 8.4 gChromatographic purity (By HPLC): 99.88%EXAMPLE - 7PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (10 g) was suspended in a mixture of acetone (50 ml) and DM water (3.95 ml) at 25 +/- 2°C, heated to 55-58°C and stirred for 30 +/- 5 min. The resulting solution was cooled to 20-25°C and stirred for 30 +/- 5 min, which was further cooled to 0-5 °C and stirred for 1 hour. The product was filtered and washed with chilled acetone (10ml, 0-5°C). The product was dried at 50-55°C.Yield: 8.30gChromatographic Purity (By HPLC): 99.83 %Darifenacin dimmer: 0.10%EXAMPLE - 8PURIFICATION OF DARIFENACIN HYDROBROMIDEDarifenacin hydrobromide (10 g) was suspended in a mixture of acetone (50 ml) and DM water (7.9 ml) at 25 +/- 2°C, heated to 55-60°C and stirred for 30 + 5 min. The resulting solution was cooled to 20-25°C and stirred for 30 +/- 5 min, which was further cooled to 0-5°C and stirred for 1 hour. The product was filtered and washed with chilled acetone (10 ml, 0-5°C). The product was dried at 50-55°C.Yield: 6.70gChromatographic Purity (By HPLC): 99.94 %Darifenacin dimmer: Nil.
Multi-step reaction with 3 steps
1.1: ethanol / 1 h
2.1: potassium carbonate / water / 0.5 h / 25 - 30 °C
2.2: 12 h / 25 - 75 °C
3.1: hydrogen bromide / water; acetone / 7 h / 0 - 20 °C
Multi-step reaction with 2 steps
1: potassium hydroxide / acetonitrile / 18 h / 40 - 50 °C
2: hydrogen bromide / water; acetone / 2.25 - 12 h / 0 - 30 °C
Multi-step reaction with 3 steps
1: water / 50 - 60 °C
2: potassium hydroxide / acetonitrile / 25 - 45 °C
3: hydrogen bromide / acetone / 10 - 25 °C
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