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With hydrogenchloride In 1,4-dioxane; ethyl acetate at 20℃; for 0.583333 h; Cooling with ice
A solution of (2S,5f?)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide (which may be prepared as described herein for Description 6) (5.46 g, 17.37 mmol) in ethyl acetate (140 ml_) was stirred for 30 minutes and filtered. The filtrate was treated with 4M HCI in dioxan (6.51 ml_, 26.05 mmol) and the mixture was stirred at room temperature for 20 minutes and then cooled in an ice bath for 15 minutes. The resulting solid was collected by filtration and washed with cold ethyl acetate (2 x 20 ml) and then dried under vacuum at 35°C overnight, then at 50°C for 2 hours to give product as an off white solid (E1), (5.87 g, 96percent). LC-MS MH+ = 315 (C18H19FN2O2) NMR (d6-DMSO): 1.95-2.20 (2H, m), 2.30 (2H, m), 3.35 (1 H, s), 4.30 (1 H, m), 4.61 (1 H, m), 5.18 (2H, s), 7.10 (2H, d, J = 9 Hz), 7.18-7.30 (2H, m), 7.40 (1 H, m), 7.47 (2H, d, J = 9 Hz), 7.56 (1 H, ), 7.72 (1 H, s), 8.07 (1 H, s), 10.60 (1 H, br s).
93%
With hydrogenchloride In 1,4-dioxane; methanol; ethyl acetate at 0℃; for 1.5 h;
To a solution of E1 ( 72 mg, 0.23 mmol) in a mixture of ethyl acetate (1.0 ml) and methanol (1.0 ml) was added 4M HCI in 1 ,4-dioxane (57.5 uL, 0.23 mmol) at 0°C. The mixture was stirred for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (75 mg, 93percent yield).1H NMR (300 MHz, DMSO-d6) δ 10.89 (1 H, br. s), 8.12 (1 H, s), 8.1 1 (1 H, br. s), 7.73 (1 H, s), 7.60-7.39 (4H, m), 7.30-7.21 (2H, m), 7.13-7.06 (2H, m), 5.18 (2H, s), 4.66-4.56 (1 H, m), 4.36-4.28 (1 H, m), 2.42-1.94 (4H, m).
With acetyl chloride; In methanol; ethyl acetate; at 0℃; for 1.5h;
(5R)-5-(4-{r(2-fluorophenyl)methylloxy)phenyl)-L-prolinamide hydrochloride (E2):.HCIProcedure 1 : To a solution of 1 ,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-[(2- fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate (D10, 51mg, 0.123mmol) in a mixture of ethyl acetate (0.9ml) and methanol (1ml) was added acetylchloride (28 mul, 2.5eq) at 00C. The mixture was shaken for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with EPO <DP n="46"/>diethyl ether to afford the title compound as a white solid (42mg, quant.); Chiral HPLC: Column: chiralcel OD 10 urn, 250 x 4.6 mm; Mobile phase: A: n-Hexane; B: Ethanol; Gradient: isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200-400 nm; Analysis time: 22 min; ret. time: 12.0min. [alpha]D = -30.5. MS: (ES/+) m/z: 315 [MH+], C18H19FN2O2 requires 314; 1H NMR (400 MHz, DMSO-d6) delta ppm 10.19 (br. s., 1 H), 8.13 (br. s., 1 H), 7.94 (s, 1 H), 7.60 - 7.77 (m, 1 H), 7.51 (dt, 1 H), 7.43 (d, 2H), 7.34 - 7.41 (m, 1 H), 7.23 (d, 1 H), 7.18 (dd, 1 H), 7.05 (d, 2H), 5.13 (s, 2H), 4.49 - 4.60 (m, 1H), 4.19 - 4.28 (m, 1 H), 2.17 - 2.38 (m, 2H), 2.05 - 2.16 (m, 1 H), 1.92 - 2.03 (m, 1 H).
100%
With acetyl chloride; In methanol; ethyl acetate; at 0℃; for 1.5h;Product distribution / selectivity;
To a solution of 1 ,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-[(2- fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate (51 mg, 0.123mmol) in a mixture of ethyl acetate (0.9ml) and methanol (1 ml) was added acetylchloride (28 mul, 2.5eq) at 00C. The mixture was shaken for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (42mg, quant.); Chiral HPLC: Column: chiralcel OD 10 urn, 250 x 4.6 mm; Mobile phase: A: n-Hexane; B: Ethanol; Gradient: isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200-400 nm; Analysis time: 22 min; ret. time: 12.0min. [alpha]D = -30.5. MS: (ES/+) m/z: 315 [MH+], C18H19FN2O2 requires 314; 1H NMR (400 MHz, DMSO-d6) delta ppm 10.19 (br. s., 1 H), 8.13 (br. s., 1 H), 7.94 (s, 1 H), 7.60 - 7.77 (m, 1 H), 7.51 (dt, 1 H), 7.43 (d, 2H), 7.34 - 7.41 (m, 1 H), 7.23 (d, 1 H), 7.18 (dd, 1 H), 7.05 (d, 2H), 5.13 (s, 2H), 4.49 - 4.60 (m, 1 H), 4.19 - 4.28 (m, 1 H), 2.17 - 2.38 (m, 2H), 2.05 - 2.16 (m, 1 H), 1.92 - 2.03 (m, 1 H).
96%
With hydrogenchloride; In isopropyl alcohol; at 20 - 35℃; for 2h;Large scale;
A reactor was charged with terf-butyl (2S, 5S)-2-carbamoyl-5-(4-((2- fluorobenzyl)oxy)phenyl)pyrrolidine-1-carboxylate (160 kg) and isopropanol (1280 kg) at 20 - 30 C. A solution of 2.6M HCI in isopropanol (5.3 eq) was added over about 2 h at 20 - 35 C. The contents of the reactor were warmed to 30 - 35 C, and the progress of the reaction was monitored for completion (HPLC). The contents of the reactor were cooled to about 10 C over about 3 h, concentrated in vacuo for about 1 h and aged at 5 - 10 C for about 2 h under an inert atmosphere of nitrogen. Solids were filtered, washed with isopropanol (125 kg) and dried to constant weight in vacuo at 60 - 70 C to give 132.05 kg (96%) of the title compound.
With hydrogenchloride; In 1,4-dioxane; ethyl acetate; at 20℃; for 0.583333h;Cooling with ice;
A solution of (2S,5f?)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide (which may be prepared as described herein for Description 6) (5.46 g, 17.37 mmol) in ethyl acetate (140 ml_) was stirred for 30 minutes and filtered. The filtrate was treated with 4M HCI in dioxan (6.51 ml_, 26.05 mmol) and the mixture was stirred at room temperature for 20 minutes and then cooled in an ice bath for 15 minutes. The resulting solid was collected by filtration and washed with cold ethyl acetate (2 x 20 ml) and then dried under vacuum at 35C overnight, then at 50C for 2 hours to give product as an off white solid (E1), (5.87 g, 96%). LC-MS MH+ = 315 (C18H19FN2O2) NMR (d6-DMSO): 1.95-2.20 (2H, m), 2.30 (2H, m), 3.35 (1 H, s), 4.30 (1 H, m), 4.61 (1 H, m), 5.18 (2H, s), 7.10 (2H, d, J = 9 Hz), 7.18-7.30 (2H, m), 7.40 (1 H, m), 7.47 (2H, d, J = 9 Hz), 7.56 (1 H, ), 7.72 (1 H, s), 8.07 (1 H, s), 10.60 (1 H, br s).
93%
With hydrogenchloride; In 1,4-dioxane; methanol; ethyl acetate; at 0℃; for 1.5h;
To a solution of E1 ( 72 mg, 0.23 mmol) in a mixture of ethyl acetate (1.0 ml) and methanol (1.0 ml) was added 4M HCI in 1 ,4-dioxane (57.5 uL, 0.23 mmol) at 0C. The mixture was stirred for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (75 mg, 93% yield).1H NMR (300 MHz, DMSO-d6) delta 10.89 (1 H, br. s), 8.12 (1 H, s), 8.1 1 (1 H, br. s), 7.73 (1 H, s), 7.60-7.39 (4H, m), 7.30-7.21 (2H, m), 7.13-7.06 (2H, m), 5.18 (2H, s), 4.66-4.56 (1 H, m), 4.36-4.28 (1 H, m), 2.42-1.94 (4H, m).
With hydrogenchloride; In diethyl ether; dichloromethane; at 0 - 25℃; for 1 - 2.5h;Product distribution / selectivity;
Procedure 2: ((5R)-5-(4-[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E 1 , 109g) was dissolved in DCM (654mL) and Et2O (654mL) was added at room temperature. HCI 1 N in Et2O (380.4mL) was added dropwise at room temperature. The suspension was cooled to O0C and stirred at this temperature for 1 hr. The solid was filtered, washed with Et2O (2 x 327mL) and dried at 4O0C under vacuum overnight to afford Form 1 crystals of the title compound (121.24g). 1H NMR (600 MHz, DMSO-d6) delta(ppm): 10.72 (bs, 1 H); 8.10 (bs, 1 H); 8.08 (s, 1 H); 7.72 (s, 1 H); 7.56 (td, 1 H); 7.49 (d, 2H); 7.43 (qd, 1 H); 7.25 (m, 2H); 7.10 (d, 2H); 5.17 (s, 2H); 4.61 (dd, 1 H); 4.30 (dd, 1 H); 2.32 (m, 2H); 2.16 (m, 1 H); 2.02 (m, 1 H).; Procedure 3: ((5R)-5-(4-[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1 , 10g, 31.8mmol) was dissolved in DCM (50ml) and stirred with charcoal (1g), then filtered, washing with DCM (30ml). The residue was concentrated under vacuum, removing about 20ml of DCM. Ether (60ml) was added, followed by a solution of HCI in ether (0.84N, 40ml), and the mixture was then stirred at 20-250C for 30 min, then cooled to 0-50C and stirred for 2 hours. The solid was filtered, washed with ether, then dried at room temperature to give Form 1 crystals of title compound (10.25g). 1H NMR (300 MHz, DMSO-d6) delta (ppm): 2.04 (m, 1 H); 2.18 (m, 1 H); 2.32 (m, 2H); 4.34 (m, 1 H); 4.64 (m, 1H); 5.18 (s, 2H) ; 7.10 (d, 2H) ; 7.25 (m, 2H); 7.40-7.60 (m, 4H); 7.77 (s, 1 H) ; 8.24 (s, 1 H) ; 11.03 (b, 1 H).
With hydrogenchloride; In methanol; diethyl ether; ethyl acetate; at 0℃; for 1h;Product distribution / selectivity;
In a round bottom flask, a solution of ((5R)-5-(4-[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1 , 1.4g, 4.45mmol) in ethylacetate (14ml) and MeOH (2.5ml) at 0C was treated with HCI 1M in diethylether (1.1 eq, EPO <DP n="47"/>4.89ml).The precipitation occurred quite soon and the mixture was stirred at 00C for 1h. The mixture was then diluted with dry diethylether (10ml) and then filtered on a Gooch filter (porosity 4, diameter 5cm). The cake was washed on the filter with dry diethylether (2x20ml) and the white solid thus obtained was transferred into a round bottom flask, dried under high vacuum at 400C for 2h and then at room temperature for 18hours. A white solid was obtained (1.51g) of Form 1 crystals of the title compound
With hydrogenchloride; In diethyl ether; ethyl acetate; at 0 - 25℃; for 3h;Product distribution / selectivity;
((5R)-5-(4-[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1 , 25g, 79.5mmol) was dissolved in ethyl acetate (750ml) and stirred with charcoal(2.5g), then filtered, washing with ethyl acetate (125ml). To the filtrate and washings, a solution of HCI in ether (1N, 103ml), was added over 30 minutes at 20-250C and the mixture was then stirred at 20-250C for 30 min, then cooled to 0-50C and stirred for 2 hours. The solid was filtered, washed with ethyl acetate (2 x 70ml), then dried at room temperature to give Form 1 crystals of the title compound. (25.5g).Unique and discriminating peaks of Form 1 of the title compound of Example 2 have been identified and are illustrated in the table below:Melting point: 230 C.
With hydrogenchloride; In diethyl ether; dichloromethane; at 0 - 20℃; for 1h;Product distribution / selectivity;
((5/?)-5-(4-[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (109g) was dissolved in DCM (654ml_) and Et2O (654ml_) was added at room temperature. HCI 1 N in Et2O (380.4ml_) was added dropwise at room temperature. The suspension was cooled to O0C and stirred at this temperature for 1 hr. The solid was filtered, washed with Et2O (2 x 327ml_) and dried at 4O0C under vacuum overnight to afford Form 1 crystals of the title compound (121.24g). 1H NMR (600 MHz, DMSO-d6) delta(ppm): 10.72 (bs, 1 H); 8.10 (bs, 1 H); 8.08 (s, 1 H); 7.72 (s, 1 H); 7.56 (td, 1 H); 7.49 (d, 2H); 7.43 (qd, 1 H); 7.25 (m, 2H); 7.10 (d, 2H); 5.17 (s, 2H); 4.61 (dd, 1 H); 4.30 (dd, 1 H); 2.32 (m, 2H); 2.16 (m, 1 H); 2.02 (m, 1 H).
With hydrogenchloride; pyrographite; In diethyl ether; dichloromethane; at 0 - 25℃; for 2.5h;Product distribution / selectivity;
((5/?)-5-(4-[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (1 Og, 31.8mmol) was dissolved in DCM (50ml) and stirred with charcoal (1g), then filtered, washing with DCM (30ml). The residue was concentrated under vacuum, removing about 20ml of DCM. Ether (60ml) was added, followed by a solution of HCI in ether (0.84N, 40ml), and the mixture was then stirred at 20-250C for 30 min, then cooled to 0-50C and stirred for 2 hours. The solid was filtered, washed with ether, then dried at room temperature to give Form 1 crystals of title compound (10.25g). <n="33"/>1H NMR (300 MHz, DMSO-d6) delta (ppm): 2.04 (m, 1 H); 2.18 (m, 1 H); 2.32 (m, 2H); 4.34 (m, 1 H); 4.64 (m, 1 H); 5.18 (s, 2H) ; 7.10 (d, 2H) ; 7.25 (m, 2H); 7.40-7.60 (m, 4H); 7.77 (s, 1 H) ; 8.24 (s, 1 H) ; 11.03 (b, 1 H).
With hydrogenchloride; In methanol; diethyl ether; ethyl acetate; at 0℃; for 1h;Product distribution / selectivity;
In a round bottom flask, a solution of ((5R)-5-(4-[(2- fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (1.4g, 4.45mmol) in ethylacetate (14ml) and MeOH (2.5ml) at 00C was treated with HCI 1 M in diethylether (1.1eq, 4.89ml).The precipitation occurred quite soon and the mixture was stirred at 00C for 1 h. The mixture was then diluted with dry diethylether (10ml) and then filtered on a Gooch filter (porosity 4, diameter 5cm). The cake was washed on the filter with dry diethylether (2x20ml) and the white solid thus obtained was transferred into a round bottom flask, dried under high vacuum at 400C for 2h and then at room temperature for 18hours. A white solid was obtained (1.51 g) of Form 1 crystals of the title compound.
With pyrographite; In diethyl ether; ethyl acetate; at 0 - 25℃; for 3h;Product distribution / selectivity;
((5/?)-5-(4-[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (25g, 79.5mmol) was dissolved in ethyl acetate (750ml) and stirred with charcoal (2.5g), then filtered, washing with ethyl acetate (125ml). To the filtrate and washings, a solution of HCI in ether (1 N, 103ml), was added over 30 minutes at 20-250C and the mixture was then stirred at 20-250C for 30 min, then cooled to 0-50C and stirred for 2 hours. The solid was filtered, washed with ethyl acetate (2 x 70ml), then dried at room temperature to give Form 1 crystals of the title compound. (25.5g).