* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 20℃;
To a solution of starting 1-[(phenylmethyl)oxy]carbonyl}-L-proline (8.0 g, 32.09 mmol), pyridine (1.5 mL), (BoC)2O (9.1 g, 41.72 mmol) in 1 ,4-dioxane (40 ml_) at rt was added ammonium hydrogen carbonate (3.2 g, 40.43 mmol). After stirring at room temperature overnight, the reaction mixture was treated with EtOAc (100 mL), and then the mixture was washed with water (50 mL), followed by 5percent H2SO4- The organic layer was collected, dried(Na2SO4), filtered. The volatiles were removed by evaporation in vacuo. The resulting clear oil was triturated with ether. The precipitates were filtered and further dried under vacuum to yield the title compound as a white solid (3.9 g, 49percent). MH+ 249.
13.5 g
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -5℃; for 0.333333 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at -5 - 20℃; for 18 h;
Step A - Syntheses of Intermediate Compound Int-13b (0313) (0314) Ethyl chloroformate (12 mL, 125 mmol) in 180 mL of THF was added drop-wise to a cooled solution (-5°C) of compound Z-Pro-OH (13.8 g, 55.5 mmol), TEA (7.71 mL, 55.5 mmol). The resulting slurry was allowed to stir for 20 minutes at -5°C before saturated NH4OH (15 mL) was added. The solution was allowed to stir at room temperature for 18 hours, volatiles were removed, and the resulting residue was taken up in EtOAc (180 mL). The undissolved white precipitate was filtered off and rinsed with EtOAc (100 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to provide the desired product (13.5 g) as off-white amorphous solid (Int-13b). MS (ESI) m/e (M+H+): 249
Reference：
[1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 1, p. 84 - 96
[2] Synlett, 2004, # 3, p. 558 - 560
[3] Patent: WO2005/121135, 2005, A1, . Location in patent: Page/Page column 240-241
[4] Canadian Journal of Chemistry, 2007, vol. 85, # 2, p. 85 - 95
[5] Journal of the American Chemical Society, 2018, vol. 140, # 5, p. 1627 - 1631
[6] Tetrahedron Asymmetry, 2004, vol. 15, # 12, p. 1831 - 1834
[7] European Journal of Organic Chemistry, 2005, # 20, p. 4287 - 4295
[8] Synlett, 2006, # 6, p. 889 - 892
[9] Chemische Berichte, 1983, vol. 116, # 5, p. 2037 - 2040
[10] Organic Syntheses, 2008, vol. 85, p. 72 - 87
[11] Carbohydrate Research, 2013, vol. 381, p. 12 - 18
[12] Pharmazie, 1992, vol. 47, # 9, p. 710 - 711
[13] Organic and Biomolecular Chemistry, 2011, vol. 9, # 1, p. 265 - 272
[14] Organic and Biomolecular Chemistry, 2017, vol. 15, # 34, p. 7196 - 7203
[15] Patent: WO2007/67904, 2007, A2, . Location in patent: Page/Page column 14; 24
[16] Journal of Pharmaceutical Sciences, 1991, vol. 80, # 9, p. 837 - 842
[17] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 3, p. 591 - 600
[18] Tetrahedron, 1996, vol. 52, # 10, p. 3521 - 3546
[19] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6568 - 6572
[20] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5260 - 5266
[21] Patent: WO2010/111483, 2010, A1, . Location in patent: Page/Page column 115-116
[22] Patent: WO2010/138791, 2010, A1, . Location in patent: Page/Page column 94-95
[23] Tetrahedron Letters, 2012, vol. 53, # 29, p. 3777 - 3779
[24] Tetrahedron Letters, 2012, vol. 53, # 28, p. 3672 - 3675
[25] Tetrahedron Letters, 2013, vol. 54, # 36, p. 4975 - 4977
[26] Tetrahedron Letters, 2014, vol. 55, # 50, p. 6831 - 6835
[27] Patent: EP2545060, 2015, B1, . Location in patent: Paragraph 0313; 0314
[28] Patent: WO2007/77186, 2007, A1,
2
[ 61350-60-5 ]
[ 34079-31-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
With ammonia In dichloromethane at 0 - 20℃; Large scale
The obtained N-benzyloxycarbonyl-L-prolyl chloride was stirred under cooling to 0 ~ 10 ° C, the temperature was controlled to 10 ~ 20 ° C, and ammonia gas was passed for 12 hours. After completion of the reaction, the resulting mixture was concentrated to dryness under reduced pressure. 100 kg dichloromethane was added, stirred to dissolve, cooled to 0 ~ 5 ° C, the temperature was controlled to 10 ~ 15 ° C, 30percent sodium hydroxide was added to adjust pH to 12 ~ 13, stirred at 10 ~ 15 ° C for 1 hour. pH was retested, the mixture was allowed to stand, liquid separation was carried out, aqueous layer was separated, 10 kg activated carbon was added to dichloromethane layer, stirred at 20-25° C for 40 minutes, filtered, and the resulting dichloromethane solution was washed twice with 200 kg of purified water, 30 kg anhydrous magnesium sulfate was added to dichloromethane layer, dehydrated, filtered, dichloromethane was distilled off, cooled to 5 ~ 10 ° C, 500 kg petroleum ether was added, solids were precipitated, stirred at 5 ~ 10 ° C for 8 hours, filtered, washed with 50 kg petroleum ether and dried to get 177 kg white solid. Yield 82.0percent, purity 99.8percent, optical purity of 99.9percent (HPLC area normalization method)
Stage #1: With borane In tetrahydrofuran at 0℃; for 7 h; Heating / reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃; for 6 h; Heating / reflux Stage #3: With sodium hydroxide In tetrahydrofuran; water
A typical procedure for the reduction is as follows: starting with a solution of (S)-2-carbamoyl-l-7V-CBz-pyrrolidine (0.5g, 2mmol) in THF (10ml), borane BH3 (12ml, 12mmol, 1 .OM THF solution) was added slowly at 0°C under N2. The resulting solution was heated to reflux for 7 hours, then cooled to 0°C, followed by slow addition of 4.5mL of 12N HC1 to destroy the B-N complex. The mixture was heated to reflux for 6 hours, cooled to roomed temperature (RT), then was neutralized to ph8 by a WNaOH aqueous solution. After THF and water were removed under reduced pressure, the crude product was purified by use offlash silica gel column chromatography (1/10 = MeOH/CHzC^) to afford a clear, slightlyyellow oil in 74percent yield (348mg).
Reference：
[1] Chemistry - A European Journal, 2006, vol. 12, # 16, p. 4321 - 4332
[2] Patent: WO2006/7586, 2006, A1, . Location in patent: Page/Page column 31-32
2-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1 H-benzoimidazol-2-yl}-pyrrolidine-1- carboxylic acid benzyl ester F-1 (12.0 g) is dissolved in pyridine (30 ml) and cooled under ice. POCI3 (3.6 ml) is added slowly and the mixture is stirred at O0C for 1 hour. The pyridine is removed under reduced pressure, the crude mixture is dissolved in ethyl acetate (150 ml) and washed with 1 N HCI solution (3 x 30ml), concentrated under reduced pressure, dissolved in ethyl acetate (50 ml) again, washed with 1 N HCI (50 ml) solution to completely remove the pyridine. The ethyl acetate solution is dried over MgSO4, filtered, concentrated under reduced pressure to yield 2-Cyano-pyrrolidine-1-carboxylic acid benzyl ester F-2 as a slightly yellow oil (6.1g, 26.5 mmol, 66%).
58%
With pyridine; trichlorophosphate; In dichloromethane; at -5℃; for 1h;
Phosphorus(lll) oxychloride (2.1 mL) in dichloromethane (4.2 mL) was added dropwise (15 min.) to a solution of phenylmethyl (2S)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate (3.9 g, 15.71 mmol) in pyridine (15 mL). The reaction mixture was stirred at -5 0C for 1 hr. After the reaction was complete, the mixture was poured over ice. The resulting mixture was stirred for 1 hr. Then it was extracted with ether, washed with CuSO4 solution, and then washed with 1 N HCI solution. The organics were dried (Na2SO4), filtered, and evaporated in vacuo to yield the title compound as a yellow oil (2.09 g, 58%). MH+ 231.
With pyridine; trifluoroacetic anhydride; In tetrahydrofuran; at 0℃; for 3h;
General procedure: To a solution of Nalpha-protected amino acid (10 mmol) in THF (10 mL), NMM(11 mmol) and ethyl chloroformate (11 mmol) were added at -15 C followed by stirring for 20 min NH3 solution (0.4 mL) was added and stirring was continued for another 4 h. After completion of the reaction (TLC), the solvent was removed in vacuo andthe residue was dissolved in EtOAc (30 mL), washed twice with 10% HCl (10 mL)(in case of Fmoc, Z-amino acids), or 10% citric acid (10 mL) (in case of Boc-amino acids), brine solution (10 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the crude product was purified by recryastallization from EtOAc:hexane (3:8). The solution of amino acid amide (10mmol) in dry THF (10 mL) was treated with pyridine (20 mmol) and TFAA (12 mmol)and the reaction mixture was stirred at 0 C for 3 h. After completion of the reaction (TLC), the solvent was evaporated and residue wasdissolved in EtOAc (30 mL), washed twice with 10% HCl (10 mL) (in case of Fmoc,Z-amino acids), or 10% citric acid (10 mL) (in case of Boc-amino acids), saturatedNaHCO3 (10 mL), brine solution (10 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (hexane:EtOAc 9:1).
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; at 20℃;
To a solution of starting 1-[(phenylmethyl)oxy]carbonyl}-L-proline (8.0 g, 32.09 mmol), pyridine (1.5 mL), (BoC)2O (9.1 g, 41.72 mmol) in 1 ,4-dioxane (40 ml_) at rt was added ammonium hydrogen carbonate (3.2 g, 40.43 mmol). After stirring at room temperature overnight, the reaction mixture was treated with EtOAc (100 mL), and then the mixture was washed with water (50 mL), followed by 5% H2SO4- The organic layer was collected, dried(Na2SO4), filtered. The volatiles were removed by evaporation in vacuo. The resulting clear oil was triturated with ether. The precipitates were filtered and further dried under vacuum to yield the title compound as a white solid (3.9 g, 49%). MH+ 249.
Ethyl chloroformate (12 mL, 125 mmol) in 180 mL of THF was added drop-wise to a cooled solution (-5C) of compound Z-Pro-OH (13.8 g, 55.5 mmol), TEA (7.71 mL, 55.5 mmol). The resulting slurry was stirred for 20 minutes at -5C before saturated NH4OH (15 mL) was added. The solution was stirred at RT for 18 hours, volatiles were removed, and the residue was taken up in EtOAc (180 mL). The undissoloved white precipitate was filtered off and rinsed with EtOAc (100 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give the desired product (13.5 g) as off-white amorphous solid. MS (ESI) m/e (M+H*): 249.
Ethyl chloroformate (12 niL, 125 mmol) in 180 niL of THF was added drop- wise to a cooled solution (-50C) of compound Z-Pro-OH (Int-12a, 13.8 g, 55.5 mmol), TEA (7.71 mL, 55.5 mmol). The resulting slurry was stirred for 20 minutes at -5C before saturated NH4OH (15 mL) was added. The solution was allowed to stir at room temperature for 18 hours, volatiles were removed, and the resulting residue was taken up in EtOAc (180 mL). The undissolved white precipitate was filtered off and rinsed with EtOAc (100 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide Compound Int-12b (13.5 g) as off-white amorphous solid. MS (ESI) m/e (M+H+): 249.
With candida antarctica lipase-B; ammonium benzoate; In toluene; at 50℃; for 16h;Molecular sieve; Enzymatic reaction;
General procedure: Cal-B (100 mg) was added to a mixture of Cbz-Xaa-OH (50 mg), ammonium benzoate (10 equiv) and 3 A MS (200 mg) in toluene (6 mL). The mixture was shaken at 50 C, 150 rpm for 16 h.
13.5 g
Step A - Syntheses of Intermediate Compound Int-13b (0313) (0314) Ethyl chloroformate (12 mL, 125 mmol) in 180 mL of THF was added drop-wise to a cooled solution (-5C) of compound Z-Pro-OH (13.8 g, 55.5 mmol), TEA (7.71 mL, 55.5 mmol). The resulting slurry was allowed to stir for 20 minutes at -5C before saturated NH4OH (15 mL) was added. The solution was allowed to stir at room temperature for 18 hours, volatiles were removed, and the resulting residue was taken up in EtOAc (180 mL). The undissolved white precipitate was filtered off and rinsed with EtOAc (100 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to provide the desired product (13.5 g) as off-white amorphous solid (Int-13b). MS (ESI) m/e (M+H+): 249
13.5 g
Ethyl chloroformate (12 mL, 125 mmol) in 180 mL of THF was added drop-wise to a cooled solution (-5 C.) of compound Z-Pro-OH (13.8 g, 55.5 mmol), TEA (7.71 mL, 55.5 mmol). The resulting slurry was stirred for 20 minutes at -5 C. before saturated NH4OH (15 mL) was added. The solution was stirred at RT for 18 hours, volatiles were removed, and the residue was taken up in EtOAc (180 mL). The undissoloved white precipitate was filtered off and rinsed with EtOAc (100 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give the desired product (13.5 g) as off-white amorphous solid. MS (ESI) m/e (M+H+): 249.
(S)-2-Ethoxycarbonyloxycarbonyl-pyrrolidine-1-carboxylic acid benzyl ester[ No CAS ]
[ 34079-31-7 ]
Yield
Reaction Conditions
Operation in experiment
With ammonia; In water; for 4h;
General procedure: To a solution of Nalpha-protected amino acid (10 mmol) in THF (10 mL), NMM(11 mmol) and ethyl chloroformate (11 mmol) were added at -15 C followed by stirring for 20 min NH3 solution (0.4 mL) was added and stirring was continued for another 4 h. After completion of the reaction (TLC), the solvent was removed in vacuo andthe residue was dissolved in EtOAc (30 mL), washed twice with 10% HCl (10 mL)(in case of Fmoc, Z-amino acids), or 10% citric acid (10 mL) (in case of Boc-amino acids), brine solution (10 mL) and dried over anhydrous Na2SO4. After evaporation of the solvent, the crude product was purified by recryastallization from EtOAc:hexane (3:8). The solution of amino acid amide (10mmol) in dry THF (10 mL) was treated with pyridine (20 mmol) and TFAA (12 mmol)and the reaction mixture was stirred at 0 C for 3 h. After completion of the reaction (TLC), the solvent was evaporated and residue wasdissolved in EtOAc (30 mL), washed twice with 10% HCl (10 mL) (in case of Fmoc,Z-amino acids), or 10% citric acid (10 mL) (in case of Boc-amino acids), saturatedNaHCO3 (10 mL), brine solution (10 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (hexane:EtOAc 9:1).
benzyl (2S)-2-(dimethylaminomethylenecarbamoyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
at 20 - 120℃; for 2h;
[0302] Part A: N,N-Dimethylformamide dimethyl acetal (5 mL) was added to benzyl (2S)-2-carbamoyl-pyrrolidine-1-carboxylate (1.05 g, 4.23 mmol) at ambient temperature. The resulting slurry was heated to 120 C. for 2 h then allowed to cool and poured into hexane (50 mL). The solvents were removed under reduced pressure yielding benzyl (2S)-2-(dimethylaminomethylenecarbamoyl)pyrrolidine-1-carboxylate as a colorless oil (1.35 g, crude quantative yield). HPLC (method 1) tR=1.70 min, Purity 100%; LCMS (method 4) tR=0.94 min, m/z 304 (M+1)
With Lawessons reagent; In toluene; at 20 - 100℃; for 3h;
[0294] Part A. Lawesson's reagent (90 mg, 0.22 mmol) was added to a stirred slurry of benzyl (S)-2-carbamoyl-pyrrolidine-1-carboxylate (100 mg, 0.40 mmol) in toluene (3 mL) at ambient temperature. The reaction mixture was heated to 100 C. for 3 h then the solvents were removed. The residue was purified by flash silica gel chromatography yielding benzyl (S)-2-thiocarbamoylpyrrolidine-1-carboxylate as white solid (108 mg, crude quantative yield): HPLC (method 1) tR=2.55 min, Purity 100%; LCMS (method 4) tR=1.34 min, m/z 287 (M+H).
74%
With Lawessons reagent; In toluene; for 2h;Heating / reflux;
Following the general procedure of Williams (Williams, D. R. et al, M. J. Org. Chem. 2001, 66, 8463), a mixture of N-Cbz-proline amide a (500 mg, 2.0 mmol) Lawesson's reagent (420 mg, 1.05 mmol) and toluene (5 mL) was heated at reflux for 2 h. The solution was concentrated, adsorbed onto Celite, and purified by flash chromatography (SiO2, 40% ethyl acetate- hexanes) to afford 393 mg (74%) of compound b as a colorless solid.
With Lawessons reagent; In benzene; for 2h;Heating / reflux;
A heterogeneous mixture of the N-CBz-L-prolinamide (1.12 g, 4.51 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent; 911.3 mg, 2.25 mmol) in benzene (20 mL) was stirred at reflux for about 1 h. Then an additional 933.0 mg of Lawesson's reagent was added and the reaction continued to reflux for about an additional hour. The reaction mixture was concentrated to yield the crude thioamide. The residue was dissolved with EtOH (10 mL), treated with ethyl bromopyruvate (300 uL, 1.00 mmol) and stirred at reflux overnight. Upon cooling to RT, the reaction mixture was treated with solid K2CO3, stirred for about 10 min and concentrated. The residue was dissolved with CHCl3 (50 mL), washed with H2O (2×), dried over Na2SO4, filtered and concentrated. The crude product was chromatographed on silica gel with 2% CH3OH in CHCl3 to provide the thiazole (0.63 g, 39% yield) as a light yellow oil. MS (loop pos) MH+=361 (50%), M+Na=383 (100%). 1H NMR (300 MHz, DMSO-d6), a mixture of rotamers, delta1.23 (t, J=7.32, 7.66, 3H), 1.93-2.37 (m, 3H), 3.50-3.59 (m, 2H), 4.30 (q, J=7.04, 7.05, 7.08 Hz, 2H), 4.94-5.22 (m, 3H), 7.08-7.38 (m, 5H), 8.32 (s, 0.33 H), 8.41 (s, 0.67 H).
With Lawessons reagent; In toluene; at 20 - 100℃;
Lawesson's reagent (16.1 g, 39.9 mmol) was added to a stirred slurry of the amide (18 g, 72.6 mmol) in PhMe (200 mL) at RT. The reaction mixture was heated to 100C for 3 hours before the solvent was removed. The residue was purified by flash SiO2 chromatography (DCM/MeOH=l:0-20:l) to afford the product (18 g). MS (ESI) m/e (M+H4): 265.
With Lawessons reagent; In toluene; at 100℃; for 3h;
Lawesson's reagent (16.1 g, 39.9 mmol) was added to a stirred slurry ofCompound Int-12b (18 g, 72.6 mmol) in toluene (200 mL) at room temperature. The reaction mixture was heated to 1000C for 3 hours before the solvent was removed. The residue was purified using flash column chromatography on silica gel (dichloromethane/MeOH=l:0-20: 1) to provide Compound Int-12c (18 g). MS (ESI) m/e (M+H+): 265.
18 g
With Lawessons reagent; In toluene; at 100℃; for 3h;
Step B - Synthesis of Intermediate Compound Int-13c (0315) (0316) Lawesson's reagent (16.1 g, 39.9 mmol) was added to a stirred slurry of the amide Int-13b (18 g, 72.6 mmol) in PhMe (200 mL) at room temperature. The reaction mixture was heated to 100C for 3 hours before the solvent was removed. The resulting residue was purified using flash chromatography on silica gel (DCM/MeOH=1:0-20:1) to provide Compound Int-13c (18 g). MS (ESI) m/e (M+H+): 265.
18 g
With Lawessons reagent; In toluene; at 100℃; for 3h;
Lawesson's reagent (16.1 g, 39.9 mmol) was added to a stirred slurry of the amide (18 g, 72.6 mmol) in PhMe (200 mL) at RT. The reaction mixture was heated to 100 C. for 3 hours before the solvent was removed. The residue was purified by flash SiO2 chromatography (DCM/MeOH=1:0-20:1) to afford the product (18 g). MS (ESI) m/e (M+H+): 265.
benzyl (2S)-2-(dimethylaminomethylenecarbamoyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Part A: N,N-Dimethylformamide dimethyl acetal (5 mL) was added to benzyl (2S)-2-carbamoyl-pyrrolidine-1-carboxylate (1.05 g, 4.23 mmol) at ambient temperature. The resulting slurry was heated to 120 C. for 2 h then allowed to cool and poured into hexane (50 mL). The solvents were removed under reduced pressure yielding benzyl (2S)-2-(dimethylaminomethylenecarbamoyl)pyrrolidine-1-carboxylate as a colorless oil (1.35 g, crude quantative yield). HPLC (method 1) tR=1.70 min, Purity 100%; LCMS (method 4) tR=0.94 min, m/z 304 (M+1).
Part A. Lawesson's reagent (90 mg, 0.22 mmol) was added to a stirred slurry of benzyl (S)-2-carbamoyl-pyrrolidine-1-carboxylate (100 mg, 0.40 mmol) in toluene (3 mL) at ambient temperature. The reaction mixture was heated to 100 C. for 3 h then the solvents were removed. The residue was purified by flash silica gel chromatography yielding benzyl (S)-2-thiocarbamoylpyrrolidine-1-carboxylate as white solid (108 mg, crude quantative yield): HPLC (method 1) tR=2.55 min, Purity 100%; LCMS (method 4) tR=1.34 min, m/z 287 (M+H).
To a solution of the resulting (S)-1-carbobenzoxypyrrolidine-2-carboxylic acid (52.2 g:0.21 mole) and triethylamine (21.2 g:0.21 mole) in 525 ml of chloroform was added isobutyl chloroformate (28.7 g:0.21 mole) with stirring under cooling on ice, followed by continuing the stirring for 15 minutes. Dried ammonia gas was bubbled into the mixture for 1 hour and then the mixture was allowed to warm to room temperature and stand overnight. The resulting white precipitate was removed by the filtration, and the filtrate was evaporated under reduced pressure. The residue was dissolved in 200 ml of chloroform and was washed with diluted aqueous hydrochloric acid and water, and dried over magnesium sulfate. Chloroform was distilled off to give 45.8 g of (S)-1-carbobenzoxypyrrolidine-2-carboxamide. Yield: 88%.
56
[ 61350-60-5 ]
[ 34079-31-7 ]
Yield
Reaction Conditions
Operation in experiment
82%
With ammonia; In dichloromethane; at 0 - 20℃;Large scale;
The obtained N-benzyloxycarbonyl-L-prolyl chloride was stirred under cooling to 0 ~ 10 C, the temperature was controlled to 10 ~ 20 C, and ammonia gas was passed for 12 hours. After completion of the reaction, the resulting mixture was concentrated to dryness under reduced pressure. 100 kg dichloromethane was added, stirred to dissolve, cooled to 0 ~ 5 C, the temperature was controlled to 10 ~ 15 C, 30% sodium hydroxide was added to adjust pH to 12 ~ 13, stirred at 10 ~ 15 C for 1 hour. pH was retested, the mixture was allowed to stand, liquid separation was carried out, aqueous layer was separated, 10 kg activated carbon was added to dichloromethane layer, stirred at 20-25 C for 40 minutes, filtered, and the resulting dichloromethane solution was washed twice with 200 kg of purified water, 30 kg anhydrous magnesium sulfate was added to dichloromethane layer, dehydrated, filtered, dichloromethane was distilled off, cooled to 5 ~ 10 C, 500 kg petroleum ether was added, solids were precipitated, stirred at 5 ~ 10 C for 8 hours, filtered, washed with 50 kg petroleum ether and dried to get 177 kg white solid. Yield 82.0%, purity 99.8%, optical purity of 99.9% (HPLC area normalization method)
With ammonia; In tetrahydrofuran; at 0 - 20℃; for 1h;
Pyrrolidine-1 ,2-dicarboxylic acid 1 -benzyl ester E-1 (10.0 g, 40 mmol) is dissolved in CH2CI2 (40 ml) and cooled under ice. SOCI2 (29.3 ml, 400 mmol, 10 equiv.) is added slowly and the mixture is heated at 50 0C for 2 h . After cooling to rt the solvent is removed under reduced pressure to give a slightly yellow oil. The oily intermediate is dissolved in THF (25 ml), cooled to 0C, and ammonia solution (38 ml, 96 mmol, 2.3 equiv.) is added. The mixture is stirred at rt for 1 hour and the solvent is removed under reduced pressure. The residue is partitioned between CH2CI2 (150 ml) and water (30 ml). The layers are separated, and the organic phase is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to yield 2-Carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester F-1 as a yellowish oil (12.0 g).
In an oven dried 10 mL side armed flask equipped with a reflux condenser, N-Cbz prolinamide (496 mg, 2 mmol) was suspended in anhydrous toluene (4 mL). Phenyl isocyanate (0.22 mL, 2 mmol) was then added under an argon atmosphere and the solution was refluxed. After completion of the reaction (40 h) as indicated by TLC, the solvent was evaporated to give a white residue, which was purified by column chromatography using ethyl acetate: petroleum ether (1:4) as eluent to give the desired product (600 mg, 82%) as a white solid. Mp 173-174 C; Rf (25% EtOAc/PE): 0.2; [alpha]25D=-105.3 [alpha]D25=-105.3 (c 1.11, CHCl3); IR (KBr) v(cm-1): 3242, 3188, 1728, 1702, 1667, 1603, 1553, 1218, 1183; 1H NMR (CDCl3) delta: 1.86-2.42 (m, 4H), 3.40-3.71 (m, 2H), 4.30-4.58 (m, 1H), 5.17 (ABq, J = 12.26, 10.73 Hz, 2H), 7.05-7.55 (m, 10H), 8.71 and 9.21 (br s, 1H, rotamers), 10.36 (br s, 1H); 13C NMR (CDCl3) delta: 23.7, 24.4, 29.3, 31.2, 47.0, 47.4, 61.1, 67.5, 120.3, 124.3, 128.0, 128.1, 128.4, 128.9, 136.0, 137.0, 151.1, 154.4, 155.8, 174.1, 174.8; Analysis for: C20H21N3O4; Calculated: C, 65.38; H, 5.76; N, 11.44. Found: C, 65.67; H, 5.48; N, 11.60.
General procedure: In an oven dried 10 mL side armed flask equipped with a reflux condenser, N-Cbz prolinamide (496 mg, 2 mmol) was suspended in anhydrous toluene (4 mL). Phenyl isocyanate (0.22 mL, 2 mmol) was then added under an argon atmosphere and the solution was refluxed. After completion of the reaction (40 h) as indicated by TLC, the solvent was evaporated to give a white residue, which was purified by column chromatography using ethyl acetate: petroleum ether (1:4) as eluent to give the desired product (600 mg, 82%) as a white solid.
3-[5-[1-[[4-[(3-benzo[b]thiophenylcarbonyl)amino]-5-chloro-2-fluorophenyl]acetyl]-(2S)-pyrrolidinyl]-2H-tetrazol-2-yl]propionic acid ethyl ester[ No CAS ]
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