* 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 recombinant Rhodococcus erythropolis DSM 43297 ketoredutase; nicotinamide adenine dinucleotide In aq. phosphate buffer; isopropyl alcohol at 50℃; for 21 h; Enzymatic reaction
General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5percent (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 °C. For ChKRED20, 40percent (v/v) 2-propanol and a reaction temperature of 40 °C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
Reference：
[1] Process Biochemistry, 2017, vol. 56, p. 90 - 97
2
[ 130312-02-6 ]
[ 100858-33-1 ]
Yield
Reaction Conditions
Operation in experiment
84%
With recombinant Chryseobacterium sp. CA 49 ketoreductase; nicotinamide adenine dinucleotide In aq. phosphate buffer; isopropyl alcohol at 40℃; for 24 h; Enzymatic reaction
General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5percent (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 °C. For ChKRED20, 40percent (v/v) 2-propanol and a reaction temperature of 40 °C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
Reference：
[1] Process Biochemistry, 2017, vol. 56, p. 90 - 97
3
[ 95656-88-5 ]
[ 130312-02-6 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine In dichloromethane; dimethyl sulfoxide at 0℃;
A solution of intermediate 6.iii (1.10 g) in DCM (8 mL) was cooled to 0° C. and DIPEA (2.5 mL) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 mL). The reaction mixture was stirred at 0° C. for 1 h and was quenched by the addition of water (6 mL). The aq. layer was extracted with Et2O/Hex (1:1, 3*5 mL) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1:1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96percent yield) of a yellowish oil. 1H NMR (DMSOd6; δ ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m).
96%
Stage #1: With pyridine-SO3 complex; N-ethyl-N,N-diisopropylamine In dichloromethane; dimethyl sulfoxide at 0℃; for 1 h; Stage #2: With water In dichloromethane; dimethyl sulfoxide
6.iv. 3 -oxo-pyrrolidine- 1-carboxylic acid benzyl ester:A solution of intermediate .iii (1.10 g) in DCM (8 ml) was cooled to 0 0C and DIPEA (2.5 ml) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 ml). The reaction mixture was stirred at 0 0C for 1 h and was quenched by the addition of water (6 ml). The aq. layer was extracted with Et2O/Hex (1 :1, 3 x 5 ml) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1 :1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96percent yield) of a yellowish oil. 1H NMR (DMSOd6; δ ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m).
90%
With sulfur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1 h;
To a stirred solution of intermediate B (15.50 g, 0.07 mol) in DCM (100 mL) was added DIPEA (35.2 mL 0.21 mol) at 0°C . A solution of pyridine sulfur trioxide (25.2g, 0.16 mol) in DMSO (70 mL) was added dropwise and the resulting mixture stirred at 0°C for 1 h. The reaction was quenched by addition of H20 and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The crude product obtained was purified by flash chromatography (EtOAc/Pet ether=1 :2) to give compound C (13.80 g, 90percent) as yellow solid. It's structure was confirmed by LC-MS spectra. TLC:Rf=0.7(silica gel,EA:PE=1 : 1 , v/v) LC-MS :[M+23]= 242.
79%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 70℃; for 2 h;
A mixture of benzyl 3-hydroxypyrrolidinyl-1-carboxylate (14 g, 63.3 mmol) and IBX (21.3 g, 76 mmol) in acetonitrile (200 mL) was stirred at 70 °C for 2 hours. The mixture was filtered and the filtrate concentrated. The remaining residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:1) to give benzyl 3-oxopyrrolidinyl-1- carboxylate (11 g, 79percent) as a colorless oil.1H NMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.25 (m, 5H), 5.13 (s, 2H), 3.83 - 3.64 (m, 4H), 2.57 (s, 2H).
27%
With pyridinium chlorochromate In dichloromethane at 20℃; for 72 h;
Benzyl 3-hydroxypyrrolidine-1-carboxylate (0.30 g, 1.34 mmol) was dissolved in DCM (20 mL) and pyridinium chlorochromate was added (0.44 g, 2.0 mmol). The resulting slurry was stirred at room temperature for 72 h. Benzyl 3-oxopyrrolidine-1-carboxylate (0.080 g, 27percent) was isolated as a colorless oil by prep. HPLC YMC ODSA 30.x.100 mm, 20-100percent MeOH/H2O (0.1percent TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.25 min. LCMS: 1.20 min [M+1] not observed (2 min gradient, MeOH/H2O 0.1percent TFA).
5.6%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60 - -50℃; for 0.5 h; Stage #2: at 20℃;
(ii) N-Benzyloxycarbonyl-3-pyrrolidinone: To a chilled (-60°C) solution of oxalyl chloride (23 mL, 98percent, 258.6 mmol) in dichloromethane (400 mL) was added dropwise a solution of anhydrous dimethyl sulfoxide (36.7 mL, 517.3 mmol) in dichloromethane (20 mL) at such a rate to keep the temperature below -40°C. The reaction mixture was then stirred at -60°C for 15 min. Then a solution of N-benzyloxycarbonyl-3-pyrrolidinol (58.22 g, step i, no more than 224.9 mmol) in dichloromethane (80 mL) was added dropwise, keeping the reaction mixture temperature below -50°C. The reaction mixture was then stirred at -60°C for 30 min before adding triethylamine (158.3 mL, 99percent, 1.125 mol). The resulting mixture was allowed to warm up to room temperature and then washed with water (600 mL), 1M HCl aqueous solution (580 mL) and water (400 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to leave 54.5 g of amber oil, which was further pumped under high vacuum with stirring at room temperature for 25 min. to give 52.08 g (5.6percent over theoretical yield) of the crude title compound suitable for the next step without any further purification.
Reference：
[1] Patent: US2009/247578, 2009, A1, . Location in patent: Page/Page column 14
[2] Patent: WO2008/56335, 2008, A1, . Location in patent: Page/Page column 34
[3] Patent: WO2014/32, 2014, A1, . Location in patent: Page/Page column 51; 52
[4] Chemical Communications, 2007, # 21, p. 2136 - 2138
[5] Patent: WO2017/216726, 2017, A1, . Location in patent: Page/Page column 581
[6] Patent: US2007/161685, 2007, A1, . Location in patent: Page/Page column 126
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 12, p. 2818 - 2841
[8] Patent: EP1087934, 2004, B1, . Location in patent: Page 26
[9] Journal of Medicinal Chemistry, 1992, vol. 35, # 8, p. 1393 - 1398
[10] Patent: US2002/58809, 2002, A1,
[11] Patent: EP1553074, 2005, A1, . Location in patent: Page/Page column 51
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane for 2 h; Molecular sieve; Inert atmosphere
Step 2: preparation of benzyl 3-oxopyrrolidine-1-carboxylate. To a solution ofbenzyl (3S)-3-hydroxypyrrolidine-1-carboxylate (7.5 g, 33.9 mmol) in dichloromethane(1.2 L) was added 4-methylmorpholine N-oxide (5.96 g, 50.0 mmol), tetrapropylammonium perruthenate (0.60 g, 1 .7 mmol), and 4 A molecular sieves (7.0 g). The reaction mixture was allowed to stir under nitrogen for 2 h, after which it was filtered through a silica gel plug and eluted with diethyl ether. The filtrate canconcentrated to afford the title compound as clear oil (6.5 g, 88percent).
With dimethyl sulfoxide; triethylamine In dichloromethane; water
Example A 1-Benzyloxycarbonyl-3-pyrrolidone A dichloromethane (40 ml) solution of 16.58 ml (233.6 mmol) of dimethyl sulfoxide was added dropwise to a dichloromethane (200 ml) solution of 10.19 ml (116.8 mmol) of oxalyl chloride at -78° C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction solution was added dropwise a solution of 23.50 g of literary known 1-benzyloxycarbonyl-3-hydroxypyrrolidine in 200 ml of dichloromethane at -78° C., followed by 60 minutes of stirring at the same temperature. This solution was mixed with 74.02 ml (531.1 mmol) of triethylamine at -78° C., and stirred for 60 minutes at the same temperature and then at room temperature for 60 minutes. After completion of the reaction, 500 ml of water was added dropwise to the reaction solution, and the organic layer was separated. The aqueous layer was washed with dichloromethane (100 ml*2), and combined organic layer was washed with saturated brine (300 ml*1). After drying the organic layer over sodium sulfate, the solvent was evaporated. The resulting residue was subjected to a silica gel column chromatography to yield 20.1 g (86percent) of the title compound as an oily product from the elude of n-hexane:ethyl acetate=1:1. 1H-NMR (400 MHz, CDCl3) δ: 2.58-2.62 (2H, m), 3.82-3.87 (4H, m), 5.18 (2H, s), 7.30-7.37 (5H, m).
6.iv. 3 -oxo-pyrrolidine- 1-carboxylic acid benzyl ester:A solution of intermediate .iii (1.10 g) in DCM (8 ml) was cooled to 0 0C and DIPEA (2.5 ml) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 ml). The reaction mixture was stirred at 0 0C for 1 h and was quenched by the addition of water (6 ml). The aq. layer was extracted with Et2O/Hex (1 :1, 3 x 5 ml) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1 :1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96% yield) of a yellowish oil. 1H NMR (DMSOd6; delta ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m).
96%
With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine; In dichloromethane; dimethyl sulfoxide; at 0℃;
A solution of intermediate 6.iii (1.10 g) in DCM (8 mL) was cooled to 0 C. and DIPEA (2.5 mL) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 mL). The reaction mixture was stirred at 0 C. for 1 h and was quenched by the addition of water (6 mL). The aq. layer was extracted with Et2O/Hex (1:1, 3*5 mL) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1:1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96% yield) of a yellowish oil. 1H NMR (DMSOd6; delta ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m).
90%
With sulfur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;
To a stirred solution of intermediate B (15.50 g, 0.07 mol) in DCM (100 mL) was added DIPEA (35.2 mL 0.21 mol) at 0C . A solution of pyridine sulfur trioxide (25.2g, 0.16 mol) in DMSO (70 mL) was added dropwise and the resulting mixture stirred at 0C for 1 h. The reaction was quenched by addition of H20 and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The crude product obtained was purified by flash chromatography (EtOAc/Pet ether=1 :2) to give compound C (13.80 g, 90%) as yellow solid. It's structure was confirmed by LC-MS spectra. TLC:Rf=0.7(silica gel,EA:PE=1 : 1 , v/v) LC-MS :[M+23]= 242.
79%
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In acetonitrile; at 70℃; for 2h;
A mixture of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidinyl-1-carboxylate</strong> (14 g, 63.3 mmol) and IBX (21.3 g, 76 mmol) in acetonitrile (200 mL) was stirred at 70 C for 2 hours. The mixture was filtered and the filtrate concentrated. The remaining residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:1) to give benzyl 3-oxopyrrolidinyl-1- carboxylate (11 g, 79%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) delta ppm 7.46 - 7.25 (m, 5H), 5.13 (s, 2H), 3.83 - 3.64 (m, 4H), 2.57 (s, 2H).
27%
With pyridinium chlorochromate; In dichloromethane; at 20℃; for 72h;
Benzyl 3-hydroxypyrrolidine-1-carboxylate (0.30 g, 1.34 mmol) was dissolved in DCM (20 mL) and pyridinium chlorochromate was added (0.44 g, 2.0 mmol). The resulting slurry was stirred at room temperature for 72 h. Benzyl 3-oxopyrrolidine-1-carboxylate (0.080 g, 27%) was isolated as a colorless oil by prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0.1% TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.25 min. LCMS: 1.20 min [M+1] not observed (2 min gradient, MeOH/H2O 0.1% TFA).
5.6%
(ii) N-Benzyloxycarbonyl-3-pyrrolidinone: To a chilled (-60C) solution of oxalyl chloride (23 mL, 98%, 258.6 mmol) in dichloromethane (400 mL) was added dropwise a solution of anhydrous dimethyl sulfoxide (36.7 mL, 517.3 mmol) in dichloromethane (20 mL) at such a rate to keep the temperature below -40C. The reaction mixture was then stirred at -60C for 15 min. Then a solution of <strong>[95656-88-5]N-benzyloxycarbonyl-3-pyrrolidinol</strong> (58.22 g, step i, no more than 224.9 mmol) in dichloromethane (80 mL) was added dropwise, keeping the reaction mixture temperature below -50C. The reaction mixture was then stirred at -60C for 30 min before adding triethylamine (158.3 mL, 99%, 1.125 mol). The resulting mixture was allowed to warm up to room temperature and then washed with water (600 mL), 1M HCl aqueous solution (580 mL) and water (400 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to leave 54.5 g of amber oil, which was further pumped under high vacuum with stirring at room temperature for 25 min. to give 52.08 g (5.6% over theoretical yield) of the crude title compound suitable for the next step without any further purification.
With triethylamine; In dichloromethane; water;
After addition, the mixture was stirred for an additional 25 min and then a solution of <strong>[95656-88-5]3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester</strong> (11 g, 50 mmol, 1.0 equiv) in 20 mL of CH2Cl2 was added dropwise over a 10 min period. After complete addition the reaction was stirred an additional a hour at -78 C. Et3N (55 mL, 398 mmol, 8.0 equiv) was added over a period of 10 min. The cold-bath was removed and the mixture was stirred while warming for 2 h. The mixture was diluted with 500 mL of water. After thorough mixing, the layers were separated and the aqueous layer was extracted 2xl50 mL of CH2Cl2. The combined organic layers were washed with 200 mL of sodium bicarbonate solution and 200 mL of brine, dried over Na2SO4, decanted, and concentrated to a yellow oil. The product was purified by flash chromatography on silica gel using CH2Cl2 as eluent to yield the desired product as a colorless oil (8.5 g).
With dipyridinium dichromate; In dichloromethane; at 20℃; for 72h;
Reference Example 82 A mixture of benzyl 3-hydroxy-1-pyrrolidine carboxylate (10.0 g), pyridinium nichromate (14.6 g), and dichloromethane (150 mL) was stirred at room temperature for 3 days. Insolubles were filtered off using celite and washed with dichloromethane. Mother liquor was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain benzyl 3-oxo-1-pyrrolidine carboxylate (4.39 g). 1H-NMR (300 MHz, CDCl3) delta: 2.61 (2H, t, J=7.5 Hz), 3.83-3.89 (4H, m), 5.18 (2H, s), 7.33-7.39 (5H, m).
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; at 20 - 30℃; for 2h;Molecular sieves;
A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, condenser, and nitrogen bubbler was charged with 351 g (1.61 mol) of benzyl (3R)-3-hydroxypyrrolidine-1-carboxylate (Intermediate 1, Step A), 6 L of dichloromethane, 500 g of powdered molecular sieves, and 400 g (3. 41 mol) of N-methylmorpholine-N-oxide. The resultant suspension was stirred at ambient temperature and to this was added 12.9 g (0.0367 mol) of tetrapropylammonium perruthenate. The reaction temperature was kept at < 30 C with a cold water bath. The mixture was stirred at ambient temperature for 2 h. The mixture was poured onto a plug of 5 kg of silica gel and eluted with 10% ethyl ACETATE/DICHLOROMETHANE to give the title compound as an orange oil.
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; at 20 - 30℃; for 2h;
INTERMEDIATE 3; 3,3-Difluoropyrrolidine hydrochloride Step A: Benzyl 3-oxopyrrolidine-1-carboxylate A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, condenser, and nitrogen bubbler was charged with 351 g (1.61 mol) of benzyl (3R)-3- hydroxypyrrolidine-1-carboxylate (Intermediate 1, Step A), 6 L of dichloromethane, 500 g of powdered molecular sieves, and 400 g (3.41 mol) of N-methylmorpholine-N-oxide. The resultant suspension was stirred at ambient temperature and to this was added 12.9 g (0.0367 mol) of tetrapropylammonium perruthenate. The reaction temperature was kept at < 30 C with a cold water bath. The mixture was stirred at ambient temperature for 2 h. The mixture was poured onto a plug of 5 kg of silica gel and eluted with 10% ethyl acetate/dichloromethane to give the title compound as an orange oil.
With 4-methylmorpholine N-oxide;tetrapropylammonium perruthennate; In dichloromethane; at 20 - 30℃; for 2h;Molecular sieve;
A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, condenser, and nitrogen bubbler was charged with 351 g (1.61 mol) of benzyl (3R)-3-hydroxypyrrolidine- 1-carboxylate (Intermediate 1, Step A), 6 L of dichloromethane, 500 g of powdered molecular sieves, and 400 g (3.41 mol) of N-methylmorpholine-N-oxide. The resultant suspension was stirred at ambient temperature and to this was added 12.9 g (0.0367 mol) of tetrapropylammonium perruthenate. The reaction temperature was kept at < 30 C with a cold water bath. The mixture was stirred at ambient temperature for 2 h. The mixture was poured onto a plug of 5 kg of silica gel and eluted with 10% ethyl acetate/dichloromethane to give the title compound as an orange oil.
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; at 20 - 30℃; for 2h;
A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, condenser, and nitrogen bubbler was charged with 351 g (1.61 mol) of benzyl (3R)-3-hydroxypyrrolidine-1-carboxylate (Intermediate 1, Step A), 6 L of dichloromethane, 500 g of powdered molecular sieves, and 400 g (3.41 mol) of N-methylmorpholine-N-oxide. The resultant suspension was stirred at ambient temperature and to this was added 12.9 g (0.0367 mol) of tetrapropylammonium perruthenate. The reaction temperature was kept at or below 30 C with a cold water bath. The mixture was stirred at ambient temperature for 2 h. The mixture was poured onto a plug of 5 kg of silica gel and eluted with 10% ethyl acetate/dichloromethane to give the title compound as an orange oil.
With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 14h;
Benzyl 3-oxopyrrolidine-1-carboxylate (0.080 g, 0.37 mmol) was dissolved at room temperature in DCM. Diethylaminosulfurtrifluoride (0. 16 mL, 1.1 mmol) was added and the reaction mixture was stirred for 14 h. The solution was diluted with DCM (ca 20 mL), washed with saturated NaCl (2×20 mL), dried over Na2SO4, decanted and concentrated. Benzyl 3,3-difluoropyrrolidine-1-carboxylate (0.050 g, 50% yield) was isolated as a yellow oil by prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0.1% TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 6.38 min. LCMS: 1.58 min [M+Na] 264.50 (2 min gradient, MeOH/H2O 0.1% TFA). 1H NMR (CDCl3, 400 MHz): 7.29ppm, 5H, m; 5.09 ppm, 2H, s; 3.69 ppm, 2H, m; 3.62 ppm, 2H, m; 2.28 ppm, 2H, m.
With diethylamino-sulfur trifluoride; In toluene; at 20℃; for 96h;
Reference Example 83 A mixture of <strong>[130312-02-6]benzyl 3-oxo-1-pyrrolidine carboxylate</strong> (4.00 g), diethylaminosulfur trifluoride (90%, 10.0g), and toluene (50 mL) was stirred at room temperature for 4 days. The reactant was poured into water and extracted with ethyl acetate. The extracts were washed with water, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain benzyl 3,3-difluoro-1-pyrrolidine carboxylate (3.23 g). 1H-NMR (300 MHz, CDCl3) delta: 2.27-2.41 (2H, m), 3.62-3.80 (4H, m), 5.15 (2H, s), 7.32-7.38 (5H, m).
With diethylamino-sulfur trifluoride; In dichloromethane; at 20 - 25℃; for 3h;
A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 292 g (1.33 mol) of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> and 3 L of dichloromethane. To the stirring solution at ambient temperature was added dropwise 530 mL (4.0 mol) of (diethylamino) sulfur trifluoride over a period of about 3 h, keeping the internal temperature less than 25 C using a cold water bath. The mixture was stirred at ambient temperature overnight. The mixture was poured into a large extractor containing ice and solid sodium bicarbonate. Eight liters of ethyl acetate were then added and the mixture was made basic with sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to 309 g of a brown oil. Purification by flash chromatography (silica gel, 10 to 20% ethyl acetate/hexane gradient) gave the title compound.
With diethylamino-sulfur trifluoride; In dichloromethane; at 20 - 25℃;
Step B: Benzyl 3,3-difluoropyrrolidine-1-carboxylate; A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 292 g (1.33 mol) of benzyl 3-oxopyrrolidine-1- carboxylate and 3 L of dichloromethane. To the stirring solution at ambient temperature was added dropwise 530 mL (4.0 mol) of (diethylamino) sulfur trifluoride over a period of about 3 h, keeping the internal temperature less than 25 C using a cold water bath. The mixture was stirred at ambient temperature overnight. The mixture was poured into a large extractor containing ice and solid sodium bicarbonate. Eight liters of ethyl acetate were then added and the mixture was made basic with sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to 309 g of a brown oil. Purification by flash chromatography (silica gel, 10 to 20% ethyl acetate/hexane gradient) gave the title compound.
With diethylamino-sulfur trifluoride; In dichloromethane; at 20 - 25℃;
A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 292 g (1.33 mol) of benzyl 3-oxopyrrolidine-l- carboxylate and 3 L of dichloromethane. To the stirring solution at ambient temperature was added dropwise 530 mL (4.0 mol) of (diethylamino) sulfur trifluoride over a period of about 3 h, keeping the internal temperature less than 25 C using a cold water bath. The mixture was stirred at ambient temperature overnight. The mixture was poured into a large extractor containing ice and solid sodium bicarbonate. Eight liters of ethyl acetate were then added and the mixture was made basic with sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to 309 g of a brown oil. Purification by flash chromatography (silica gel, 10 to 20% ethyl acetate/hexane gradient) gave the title compound.
With diethylamino-sulfur trifluoride; In dichloromethane; at 20 - 25℃;
A 12-L, 3 neck round bottom flask equipped with a mechanical stirrer, thermocouple, addition funnel and nitrogen bubbler was charged with 292 g (1.33 mol) of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> and 3 L of dichloromethane. To the stirred solution at ambient temperature was added dropwise 530 mL (4.0 mol) of (diethylamino) sulfur trifluoride over a period of about 3 h, keeping the internal temperature less than 25 C using a cold water bath. The mixture was stirred at ambient temperature overnight. The mixture was poured into a large extractor containing ice and solid sodium bicarbonate. Eight liters of ethyl acetate were then added and the mixture was made basic with sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to 309 g of a brown oil. Purification by flash chromatography (silica gel, 10 to 20% ethyl acetate/hexane gradient) gave the title compound.
benzyl 4-(trifluoromethylsulfonyloxy)-2,3-dihydro-1H-pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
212A. Preparation of benzyl 4-(trifluoromethylsulfonyloxy)-2,3-dihydro-1H-pyrrole-1-carboxylate A solution of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> (300 mg, 1.4 mmol) in THF (10 mL) was treated with lithium bis(trimethylsilyl)amide (1.5 mL, 1M in THF, 1.5 mmol) at -78 C. After stirring 15 minutes at -78 C., N-phenyltrifluoromethanesulfonimide (600 mg, 1.7 mmol) was added. The reaction mixture was then warmed to room temperature. The reaction was quenched with the addition of saturated aqueous NaHCO3 (10 mL), and then extracted with ethyl ether (10 mL). The organic layer was washed with saturated aqueous NaCl solution (10 mL), and then dried over Na2SO4. The crude mixture was filtered, concentrated and purified by flash chromatography (SiO2, 30% ethyl acetate/hexane) to afford the title compound (400 mg, 82%). 1H-NMR (500 MHz, CDCl3) delta 7.26 (m, 5H), 5.50 (s, 1H), 4.76 (s, 2H), 3.20 (m, 2H).
With toluene-4-sulfonic acid; In benzene; for 20h;Heating / reflux;
Benzyl 1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate. A solution of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> (11.2 g, 51.09 mmol), ethylene glycol (2.4 g, 38.67 mmol) and TsOH.H2O (10 mg) in benzene (100 mL) was heated at reflux using Dean-Stork condenser. After 20 h, the reaction mixture was cooled, diluted with EtOAc (100 mL), washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give yellow oil. Flash column chromatography purification on silica gel column with 1:4 followed by 3:7 EtOAc:hexanes provided desired product (10.32 g, 100%) as colorless liquid. 1H NMR (500 MHz, CDCl3) delta: 7.38-7.28 (5H, m), 5.13 (2H, s), 3.99-3.92 (4H, m), 3.58-3.54 (2H, m), 3.45 (2H, d, J=10.7 Hz), 2.07-2.02 (2H, m).
6.8%
toluene-4-sulfonic acid; In toluene; for 16h;Heating / reflux;
(iii) 7-Benzyloxycarbonyl-1,4-dioxa-7-azaspiro[4,4]nonane: A mixture of N-benzyloxycarbonyl-3-pyrrolidinone (51.98 g, step ii, no more than 224.9 mmol) and ethylene glycol (18.8 mL, 99+%, 337.4 mmol) in toluene (180 mL) with a catalytic amount of p-toluenesulfonic acid monohydrate (1.04 g, 5.4 mmol) was refluxed in a Dean & Stark apparatus for 16 hours. The reaction mixture was then diluted with more toluene (250 mL) and washed with saturated sodium bicarbonate aqueous solution (150 mL) and saturated sodium chloride aqueous solution (2 x 150 mL). The combined aqueous layers were back-extracted with toluene (100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to leave 79.6 g of dark oil. The crude product was dissolved in ethanol (500 mL), and running it through a bed of activated carbon (80 g), decolorized the resulting solution.The charcoal was washed with more ethanol (1000 mL) and toluene (500 mL). The filtrate was concentrated in vacuo and further pumped under high vacuum for 1 hour to yield 63.25 g (6.8% over theoretical yield) of the crude title compound suitable for the next step without any further purification.
toluene-4-sulfonic acid; In toluene; at 120℃; for 6h;
A) Production of benzyl 1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate A mixture of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> (2.00 g), ethane-1,2-diol (2.85 mL), p-toluenesulfonic acid monohydrate (10 mg) and toluene (20 mL) was stirred with heating in a Dean-Stark apparatus at 120C for 6 hr. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (10 mL), washed successively with water (5 mLx2) and brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.1 g) as a pale-yellow liquid. 1H-NMR(CDCl3) delta 2.00-2.13(2H,m), 3.42-3.49(2H,m), 3.51-3.62(2H,m), 3.93-4.02(4H,m), 5.13(2H,s), 7.28-7.41(5H,m).
To a solution of methyl-2-iodobenzoate(8.8 niL, 0.060 mol) in THF (300 niL) at -60 C was slowly added a solution of isopropylmagnesium bromide in THF (1.0 M, 66.0 mL), and the mixture was stirred below -50 C for 1 h. A solution of benzyl-3-oxopyrrolidine-l-carboxylate (11.0 g, 0.05 mol) in THF (20.0 mL) was added to the above mixture and the reaction mixture was stirred below - 20 C for 2 h. The reaction was quenched by the addition of saturated NH4CI aqueous solution and the resulting mixture was extracted with ethyl acetate several times. The combined extract was washed with water followed by brine, dried (NaSO4), and concentrated in-vacuo. The product was purified by CombiFlash eluting with hexane/ethyl acetate.
With water; sodium hydrogensulfite; In tetrahydrofuran; at 0℃; for 3h;
Example 41; Preparation of (+/-)-6-({r(1-{2-r3-fluoro-6-(methyloxy)-1 ,5-naphthyridin-4-yllethyl>-3-hydroxy- 3-pyrrolidinyl)methyllamino)methyl)-2H-pyridof3,2-i? ,41thiazin-3(4H)-one; a) (+/-)-phenylmethyl S-cyano-S-hydroxy-i-pyrrolidinecarboxylate; To a stirred solution of phenylmethyl 3-oxo-i-pyrrolidinecarboxylate (1.0 g, 4.56 mmole) and KCN (0.81 g, 12.54 mmole) in THF (5 ml_) and H2O (15 mL) at 00C was added NaHSO3 (1.14 g, 10.9 mmole) in H2O (5.0 mL). After 3h, the reaction contents were concentrated in vacuo, extracted with CHCI3 (2 x 100 mL), and the organics dried over Na2SO^ Purification on silica (hexanes/EtOAc, 1 :1) afforded the title compound(0.92 g, 82%) as a light yellow oil: LC-MS (ES) m/e 247 (M+H)+.
With dimethyl sulfoxide; triethylamine; In dichloromethane; water;
Example A 1-Benzyloxycarbonyl-3-pyrrolidone A dichloromethane (40 ml) solution of 16.58 ml (233.6 mmol) of dimethyl sulfoxide was added dropwise to a dichloromethane (200 ml) solution of 10.19 ml (116.8 mmol) of oxalyl chloride at -78 C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction solution was added dropwise a solution of 23.50 g of literary known <strong>[95656-88-5]1-benzyloxycarbonyl-3-hydroxypyrrolidine</strong> in 200 ml of dichloromethane at -78 C., followed by 60 minutes of stirring at the same temperature. This solution was mixed with 74.02 ml (531.1 mmol) of triethylamine at -78 C., and stirred for 60 minutes at the same temperature and then at room temperature for 60 minutes. After completion of the reaction, 500 ml of water was added dropwise to the reaction solution, and the organic layer was separated. The aqueous layer was washed with dichloromethane (100 ml*2), and combined organic layer was washed with saturated brine (300 ml*1). After drying the organic layer over sodium sulfate, the solvent was evaporated. The resulting residue was subjected to a silica gel column chromatography to yield 20.1 g (86%) of the title compound as an oily product from the elude of n-hexane:ethyl acetate=1:1. 1H-NMR (400 MHz, CDCl3) delta: 2.58-2.62 (2H, m), 3.82-3.87 (4H, m), 5.18 (2H, s), 7.30-7.37 (5H, m).
With hydrogenchloride;titanium tetrachloride; In tetrahydrofuran;
Example B 1-Benzyloxycarbonyl-3-methylenepyrrolidine A 8.44 ml (77 mmol) portion of titanium tetrachloride was added dropwise to 350 ml of tetrahydrofuran solution containing 36.6 g (600 mmol) of zinc at 0 C., and the mixture was stirred for 60 minutes at the same temperature. To the reaction solution cooled at 0 C. was added dropwise 24.32 ml (350 mmol) of dibromomethane dissolved in 100 ml of tetrahydrofuran, followed by stirring at room temperature overnight. To the reaction solution was added dropwise tetrahydrofuran (100 ml) solution of 15.35 g (70 mmol) 1-benzyloxycarbonyl-3-pyrrolidone at room temperature, followed by 50 minutes of stirring at the same temperature. After completion of the reaction, the reaction solution was mixed with 500 ml of 1 N hydrochloric acid and extracted with ethyl acetate (500 ml*2), and the organic layer was washed with saturated brine (300 ml*1). After drying the organic layer over anhydrous sodium sulfate, the solvent was evaporated. The resulting residue was subjected to a silica gel column chromatography to yield 12.4 g (82%) of the title compound as an oily product from the elude of n-hexane:ethyl acetate=2:1. 1H-NMR (400 MHz, CDCl3) delta: 2.57 (2H, br s), 3.55 (2H, dd, J=7.82, 16.12 Hz), 4.01 (2H, d, J=5.86 Hz), 4.97 (2H, 2 s), 5.14 (2H, s), 7.29-7.38 (5H, m).
Preparatory Example 36 N-(Benzyloxycarbonyl)-3-pyrrolidone STR246 150 ml of oxalic acid chloride was added to 2 liters of dichloromethylene. 245 ml of dimethylsulfoxide was gradually added at -70 to -50 C. in a stream of argon. 70.67 g of N-(N-(benzyloxycarbonyl)-3-pyrrolidinol dissolved in dichloromethylene was dropped. After gradual dropping of 720 ml of triethylamine, the mixture was raised to room temperature. After completion of the reaction, the reaction solution was poured into water and extracted with dichloromethylene, followed by removal of the solvent by distillation under reduced pressure. The residue was purified by column chromatography (eluding solvent: hexane-ethyl acetate), thereby obtaining 66.55 g of the intended compound. 1 H-NMR(90 MHz, CDCl3) delta:2.6(t,J=7.5 Hz,2H), 3.7-4.0(m,4H), 5.12(s,2H), 7.3(s,5H)
17
[ 114615-82-6 ]
[ 7529-22-8 ]
[ 95656-88-5 ]
[ 130312-02-6 ]
Yield
Reaction Conditions
Operation in experiment
silica gel; In dichloromethane;
Part B. Preparation of N-(benzyloxycarbonyl)-3-pyrrolidinone. To a stirring solution of N-(benzyloxycarbonyl)-3-pyrrolidinol (1600 mg, 7.2 mmol) and 4-methylmorpholine oxide (1269 mg, 10.8 mmol, Aldrich) in dry CH2Cl2 (100 mL) with activated molecular sieves (1000 mg) was added tetrapropylammonium perruthenate (127 mg, 0.36 mmol, Aldrich). The reaction was stirred for 1 h and then filtered through a pad of silica gel. The silica gel was washed with EtOAc (500 mL). The organic filtrates were combined and conc. in vacuo to a colorless oil of pure N-(benzyloxycarbonyl)-3-pyrrolidinone. MS (ESI) 220 (M+H).
benzyl 3-(4,4-difluoro-piperidin-1-yl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example A6: 4-(5-[3-(4,4-difluoropiperidin-1-yi)pyrrolidin-1-yl]sulfonyl}pyridin-2-yl)benzonitrile A6(iii) Intermediate A6(i) and A6(ii): benzyl (3R)-3-(4,4-difluoropiperidin-1-yl)pyrrolidine-1-carboxylate and benzyl (3S)-3-(4,4-difluoropiperidin-1-yl)pyrrolidine-1-carboxylate To a solution 4,4-difluoropiperidine (11.68 g, 53.5 mmol) in tetrahydrofuran (250 ml) was added benzyl 3- oxopyrrolidine-1-carboxylate (1 mol eq), acetic acid (2 mol eq.). After stirring for 10 min at room EPO <DP n="27"/>temperature sodium triacetoxyborohydride (2 mol eq) was added and the mixture stirred at ambient temperature for 20 hours. After such time the mixture was concentrated in vacuo and treated with aqueous K2CO3 (200 ml), extracted with dichloromethane (3 x 400 ml), dried over Na2SO4., filtered and concentrated in vacuo. The residue was purified via flash column chromatography (SiO2, petroleum etherethyl acetate 100:0 to 70:30) to return desired product as a 1 :1 mixture of enantiomers. The enantiomers were resolved via super critical fluid chromatography (Chiralpak IA, 20% 1 :1 methanol:acetonitrile (at) 140 bar, 2.5 mL/min. prep: 20% methanol:acetonitrile (at) 140 bar, 55 mL/min) to afford first peak at 2.833 min. designated as S enantiomer. Low resolution mass spectrometry APCI+ 325 [M+H+]+ 100% and second peak at 3.806 min designated as R enantiomer Low resolution mass spectrometry APCI+ 325 [M+H+]+ 100%.
benzyl (3R,3'R)-3-[([3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrrolidine-1'-carboxylate[ No CAS ]
benzyl (3R,3'S)-3-[([3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrrolidine-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Benzyl (3/?)-3-[([3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-l,3'-bipyrroIidine-l'- carboxylate (1)[00124] To a solution of N-{2-oxo-2-[(3/?)-py?Olidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (500 mg, 1.59 mmol; prepared according to WO2004/050024A2) in methanol (5 mL) at room temperature was added benzyl 3-oxopyrrolidine-l-carboxylate (434 mg, 1.98 mmol) followed by sodium triacetoxyborohydride (470 mg, 2.22 mmol); the reaction mixture was stirred for 16 hours. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The <n="47"/>organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford, as a mixture of diastereomers, benzyl (3i?)-3-[([3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-l,3'-bipyrrolidine-l - carboxylate (906 mg, 88%) as a white solid. 1H-NMR (CDCl3) delta: 1.30-1.44 (m, 2H), 1.50-1.68 (m, 2H),1.80-2.00 (m, 2H), 2.10-3.29 (m, IH), 2.30-2.43 (m, IH), 2.55-23.05 (m, 3H), 3.15-3.28 (m, IH), 3.58-4.20 (m, 3H), 4.30-4.50 (m, IH), 5.09 (s, 2H), 6.70-6.87 (m, IH), 7.20-7.50 (m, 6H), 7.52 (t, J = 8.7 Hz,IH), 7.72 (d, J = 7.2 Hz, IH), 7.99 (d, 7= 7.2 Hz, IH), 8.09 (s, IH). MS m/z: 519 (M + 1)
Preparation 18; S-Hydroxy-S-beta-isopropyl-phenyl-py?olidine-i-carboxylic acid benzyl ester; Magnesium turnings (1.63g, 67.1 mmol) and a few flakes of iodine were heated until the iodine sublimed. After cooling to rt, a solution of 3-bromoisopropylbenzene (6.09g, 30.5mmol) and 2 drops of 1 ,2-dibromoethane in ether (50 mL) was added. The mixture was refluxed for 1hr and cooled to rt. Oxo-pyrrolidine-1-carboxylic acid benzyl ester (Preparation 7, 3.34g, 15.3 mmol) in ether (150 mL) was added dropwise over 15 min. After addition, the reaction was stirred for 10 min during which time a white precipitate formed. Saturated aq. NH4CI was added, the organics were separated and the aq. phase was re-extracted with <n="73"/>thetather. The combined organics were washed with brine, dried (Na2SO4) and concentrated to yield a yellow oil. Chromatography with 30% EtOAc/hexa?es afforded 4.14g (80%) of the title compound as a yellow oil: NMR (CDCI3) delta 7.37-7.15 (m, 9H), 5.16-5.04 (m, 2 H), 3.83-3.63 (m, 4H), 2.90 (hept, J = 6.8 Hz, 1H), 2.31-2.13 (m, 2H), 1.23 (d, J = 7.1 Hz, 6H).
6.v. 3 -methylene-pyrrolidine- 1-carboxylic acid benzyl ester: t-BuOK (617 mg) was added in one portion to a white suspension of methyl triphenylphosphonium bromide (1.98 g) in THF (10 ml) at rt under nitrogen. The yellow suspension was stirred at rt for 1 h and then cooled to -10 0C. A solution of intermediate 6. iv (1.05 g) in THF (2 ml) was added dropwise over 10 min and the EPO <DP n="36"/>reaction mixture was allowed to warm to rt over 2 h. The reaction was quenched by the addition of sat. aq. NH4Cl (1 ml) and diluted with EA. The residue obtained after work up (EA) was purified by chromatography (Hex/EA 90:10) to give 633 mg (64% yield) of a yellowish liquid. 1H NMR (DMSOd6; delta ppm): 2.48-2.61 (2H, m); 3.36-3.53 (2H, m); 3.84-4.01 (2H, m); 4.97-5.03 (2H, m); 5.08 (2H, s); 7.27-7.41 (5H, m).
64%
t-BuOK (617 mg) was added in one portion to a white suspension of methyl triphenylphosphonium bromide (1.98 g) in THF (10 mL) at rt under nitrogen. The yellow suspension was stirred at rt for 1 h and then cooled to -10 C. A solution of intermediate 6.iv (1.05 g) in THF (2 mL) was added dropwise over 10 min and the reaction mixture was allowed to warm to rt over 2 h. The reaction was quenched by the addition of sat. aq. NH4Cl (1 mL) and diluted with EA. The residue obtained after work up (EA) was purified by chromatography (Hex/EA 90:10) to give 633 mg (64% yield) of a yellowish liquid. 1H NMR (DMSOd6; delta ppm)-2.48-2.61 (2H, m); 3.36-3.53 (2H, m); 3.84-4.01 (2H, m); 4.97-5.03 (2H, m); 5.08 (2H, s); 7.27-7.41 (5H, m).
With ammonium acetate; In ethanol; for 4h;Heating / reflux;
A solution of benzyl 3-oxopyrrolidine-l-carboxylate (2.03 g, 10 mmol) and ammonium acetate (977 mg, 12.7 mmol) in EtOH (10 mL) was treated with ethyl malonate (1.07 mL, 9.09 mmol). The resulting solution was heated to reflux for 4 h and cooled to room temperature. Ethyl acetate (200 mL) was added and the solution was washed with saturated NaHCO3 (25 mL), brine (25 mL), dried over MgSO4 and concentrated to dryness. The mixture was filtered through a silica gel plug with ethyl acetate followed by methanol to elute the title compound as a yellow oil (600 mg, 19%). 1H NMR (400 MHz, CD3OD) delta 7.40-7.32 (m, 5H), 4.23 (q, 2H, J = 7.4 Hz), 3.81-3.76 (m, IH), 3.66-3.56 (m, 3H), 2.94 (s, 2H), 2.29- 2.24 (m, 2H), 1.29 (t, 3H, J = 7.4 Hz). MS ESI 307.1 [M + H]+, calcd for [Ci6H22N2O4 + H]+ 307.16.
With ammonium chloride; zinc; In tetrahydrofuran; water; at 20 - 30℃; for 0.5 - 0.75h;
To a suspension of benzyl 3 -oxopyrrolidine- 1 -carboxylate (4.50 g, 0.0205 mol), 4-bromo-2- methyl-2-butene (4.75 mL, 0.0412 mol) in 25.0 mL saturated ammonium chloride and tetrahydrofuran (4.75 mL, 0.0586 mol), at room temperature, was added zinc (2.70 g, 0.0412 mol). As soon as stirring was started, gas and heat were evolved. After 30 to 45 min, the resulting light grey mixture was filtered through celite. The filtrate was extracted with EtOAc. The organic layers were combined, washed with brine, dried and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexanes, to provide the desired product (5.22 g, 87.89%). LCMS (M+H) 290.2.
With 18-crown-6 ether; In dichloromethane; at 20℃;Cooling with ice;
Alternatively compound 11 BH can be prepared as follows: To an ice cold solution of 3-Oxo-pyrrolidine-1-carboxylic acid benzyl ester 1a (25Og, 1.14 mol) in 3.5L anhydrous dichloromethane was added KCN (7.5g, 0.12 mol), followed by 18-crown-6 (3Og, 0.11 mol), though not completely dissolved, was added TMSCN (183 ml_, 1.37 mol) slowly over a period of 20 min. The reaction was stirred at ambient temperature for 1 overnight. A semi-saturated NaHCO3 solution (2L) was added at 150C, stirred for 10 min and then the organic layer was separated, dried over magnesium sulfate, filtered and evaporated to give 3-Cyano-3- trimethylsilanyloxy-pyrrolidine-1 -carboxylic acid benzyl ester 2a, 422 g (>100%).
To a solution of methyl-2-iodobenzoate (8.8 mL, 0.060 mol) in THF (300 mL) at -60 C. was slowly added a solution of isopropylmagnesium bromide in THF (1.0 M, 66.0 mL) and the mixture was stirred below -50 C. for 1 h. A solution of benzyl-3-oxopyrrolidine-1-carboxylate (11.0 g, 0.05 mol) in THF (20.0 mL) Was added to the above mixture and the reaction mixture was stirred below -20 C. for 2 h. The reaction was quenched by the addition of saturated NH4Cl aqueous solution, and the resulting mixture was extracted with ethyl acetate several times. The combined extract was washed with water followed by brine, then dried and then concentrated. The product was purified by CombiFlash using hexane/ethyl acetate.
To a solution of methyl-2-iodobenzoate (8.8 mL, 0.060 mol) in THF (300 mL) at -60 C. was slowly added a solution of isopropylmagnesium bromide in THF (1.0 M, 66.0 mL) and the mixture was stirred below -50 C. for 1 h. A solution of benzyl-3-oxopyrrolidine-1-carboxylate (11.0 g, 0.05 mol) in THF (20.0 mL) was added to the above mixture and the reaction mixture was stirred below -20 C. for 2 h. The reaction was quenched by the addition of saturated NH4Cl aqueous solution and the resulting mixture was extracted with ethyl acetate several times. The combined extracts were washed with water and brine, dried, and concentrated in-vacuo. The product was purified by CombiFlash eluding with hexane/ethyl acetate.
benzyl 3-[trans-4-(2-methoxy-2-oxoethyl)cyclohexyl]oxy}pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Alternatively benzyl (3R)-3-[trans-4-(2-methoxy-2- oxoethyl)cyclohexyl] oxy} pyrrolidine- 1 -carboxylate and its enantiomers were obtained as following:Methyl 2-(trans-4-hydroxycyclohexyl)acetate (3.84 g, 22.3 mmol) was dissolved in anhydrous THF (120 ml) at 0C, DIEA (4.28 ml, 24.53 mmol) added, followed by drop wise addition of TMS-Cl (2.99 ml, 23.41 mmol). The reaction mixture was aged for 2 hours then diluted with hexane (50 ml) and filtered through a small pad of celite eluted with hexane and concentrated. The crude product and benzyl 3-oxopyrrolidine-l-carboxylate (4.64 g, 21.18 mmol) were dissolved in dichloromethane (80 ml) at -60-65C. Triethylsilane (7.12 ml, 44.6 mmol) was added, followed by drop wise addition of TMS-OTf (2.02 ml, 11.15 mmol). The reaction mixture was allowed to warm to 0C and aged for 2 days. The reaction mixture was diluted with EtOAc (100 ml), 1 M H3PO4 (30 ml) was added, the organic layer was washed with brine (2x 20 ml) and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column eluted with ethyl acetate/hexane 0-80%. This resulted in racemic mixture, which was resolved by SFC (Chiral AD column, 250x30mm, 30% 2: 1 MeOH:MeCN/C02) to afford benzyl (3R)-3-[trans-4-(2-methoxy-2- oxoethyl)cyclohexyl]oxy}pyrrolidine-l-carboxylate as colorless oil , LC-MS (ES, m/z)
To a stirred solution of trimethylsulfoxonium iodide (32.70 g, 0.15 mol) in (100 mL) was added t-BuOK (14.30 g 0.13) and the reaction stirred at 50 C for 1 h. Intermediate C (13.00 g 60 mmol) was then added and the resulting mixture was stirred at 50C for a further 48 h. The reaction mixture was quenched by addition of saturated NH4CI solution and partitioned against EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic layers were then washed with brine, dried (Na2S04), filtered and concentrated. The crude product was purified by flash chromatography (EtOAc /Pet ether=1 :2) to give D (2.70 g 18%) as yellow oil. The structure was confirmed by LC-MS and H-NMR spectra. TLC:Rf=0.36(silica gel,EA:PE=1 :2, v/v) LC-MS : [M+H]+=248 ; [M+Na]=270.
12%
To a solution of trimethylsulfoxonium iodide in tert-butanol (78 mL) was added potassium tert-butanolate (11.6 g, 103.4 mmol). The mixture was stirred at 50 C for 1 hour and then <strong>[130312-02-6]benzyl 3-oxopyrrolidinyl-1-carboxylate</strong> (10.3 g, 47 mmol) was added. The mixture was stirred at 50 C for an additional 48 hours. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (100 mL), dried, and concentrated. The remaining residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 3:1) to give benzyl 1-oxa-6- azaspiro[3.4]octane-6-carboxylate (1.5 g, 12%) as a light yellow oil. LCMS m/z = 248.0 [M+H]+.
benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
Step 3: preparation of benzyl 3-[2-(tert-butoxycarbonyl)hydrazino]pyrrolid me-i -carboxylate. To a solution of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> (3.0 g, 13.7 mmol)in tetrahydrofuran (30 mL) was added tert-butyl hydrazinecarboxylate (1.81 g, 13.7mmol). The mixture was heated to reflux for 24h, then cooled to 15C, after whichsodium cyanoborohydride (0.86 g, 13.7 mmol) was added, followed by drop wiseaddition of para-toluene sulfonic acid (2.6 g, 15.1 mmol) in tetrahydrofuran (15 mL). The reaction mixture was allowed to stir at ambient temperature for an additional 16 h, then concentrated in vacuo. The resulting residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, thenadded to 30 mL of 1 N aqueous sodium hydroxide and allowed to stir for 30 mm. The aqueous layer was removed and the organic washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a clear oil (4.4 g, 97%).
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; for 2h;Molecular sieve; Inert atmosphere;
Step 2: preparation of benzyl 3-oxopyrrolidine-1-carboxylate. To a solution of<strong>[100858-32-0]benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate</strong> (7.5 g, 33.9 mmol) in dichloromethane(1.2 L) was added 4-methylmorpholine N-oxide (5.96 g, 50.0 mmol), tetrapropylammonium perruthenate (0.60 g, 1 .7 mmol), and 4 A molecular sieves (7.0 g). The reaction mixture was allowed to stir under nitrogen for 2 h, after which it was filtered through a silica gel plug and eluted with diethyl ether. The filtrate canconcentrated to afford the title compound as clear oil (6.5 g, 88%).
The compound 1(500mg, 2.7mmol) was diluted with anhydrous MeOH (15 ml) and catalytic amount of PPTS (10mg g) was added. The reaction mixture was stirred for 1 h and then diluted with Dichloromethane and work up with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with Dichloromethane (2 x 15ml). The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo to afford title product (500mg, 79%).
Example 4 3-cyclohexyl-3-pyrrolidinol To a frame-dried three-neck flask, lanthanum chloride bis(lithium chloride) (LaCl3·2LiCl) (0.6 M, 100 mL) was added. Bromo(cyclohexyl)magnesium (1 M, 33 mL) was added thereto and under an argon atmosphere, the mixture was stirred at room temperature for 1 hour. At 0C, a solution of <strong>[130312-02-6]benzyl 3-oxo-1-pyrrolidine carboxylate</strong> (5.00 g) in tetrahydrofuran (THF) (10 mL) was added dropwise to the reaction solution which was then heated gradually and stirred overnight at room temperature. To the reaction solution, 10% acetic acid (100 mL) was added and stirred for 15 minutes. The organic layer was then separated and the solvent was distilled off. The resulting residue was partially purified by silica gel chromatography (hexane : ethyl acetate = 9:1 ? 0:100) and after distillation of the solvent, diluted with methanol (50 mL) and ethyl acetate (50 mL). To the diluted solution, 5% palladium-carbon (100 mg) was added and under a hydrogen atmosphere, stirred at room temperature for 2 hours. The solution was filtered with celite and the solvent was distilled off to give the titled compound having the following physical properties as 1.40 g of the primary crystal and 2.0 g of the residue. 1H-NMR (CD3OD): delta 3.40 - 3.20, 2.00 - 1.20.
Step 1: A solution of compound 229-1 (2.0 g, 10 mmol) and cis-2,6-dimethyl morpholine (1.25 g, 11 mmol) in DCM (40 mL) was stirred at 0C for 1h, then sodium triacetoxyborohydride (6.0 g, 30 mmol) was added at 20C and the mixture was stirred at 20C for 5h. Then the reaction mixture was quenched with saturated sodium carbonate aqueous solution, extracted with DCM (30×2 mL). The organic phases were combined and dried over sodium sulfate and concentrated under reduced pressure. 0 The residue was purified by silica gel column chromatography (PE/EtOAc= 5:1-1:1) to deliver compound 229-2 (1.5 g, 60%) as white solid. MS ESI calcd for C18H26N2O3 [M+H]+ 319, found 319.
With recombinant Rhodococcus erythropolis DSM 43297 ketoredutase; nicotinamide adenine dinucleotide; In aq. phosphate buffer; isopropyl alcohol; at 50℃; for 21h;pH 7.0;Enzymatic reaction;
General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5% (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 C. For ChKRED20, 40% (v/v) 2-propanol and a reaction temperature of 40 C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
With recombinant Chryseobacterium sp. CA 49 ketoreductase; nicotinamide adenine dinucleotide; In aq. phosphate buffer; isopropyl alcohol; at 40℃; for 24h;pH 7.0;Enzymatic reaction;
General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5% (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 C. For ChKRED20, 40% (v/v) 2-propanol and a reaction temperature of 40 C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
benzyl 3-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 0 - 40℃; for 18h;
Step IV: To a solution of tert-butyl4-aminobenzylcarbamate (compound 18D, 200 mg,0.9 mmol) and benzyl3-oxopyrrolidine-l-carboxylate (197 mg, 0.9 mmol) in DCM (10 mL) was5 added AcOH (65 mg, 1.08 mmol) and NaBH(OAc)3 (267 mg, 1.26 mmol) at 0C. After thereaction was heated at 40 C for 18 hrs, it was quenched with NaOH (2 N, 20 mL), diluted withH20 (100 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washedwith brine (20 mL x 2), dried over N a2S04 and concentrated. The crude product was purified bysilica gel chromatography (PE/EA= 2:1) to give benzyl3-((4-(((tert-1 0 butoxycarbonyl)amino )methyl)phenyl)amino )pyrrolidine-1-carboxylate (compound 18F, 300 mg,78%) as a yellow solid. MS: calc'd 426 (M+Ht, measured 426 (M+H)+
benzyl 3-ethyl-3-hydroxypyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
In tetrahydrofuran; diethyl ether; at 0℃; for 2h;
1 -Carbobenzyloxy-3-pyrrolidinone (5.0 g, 22.81 mmol) in THF (10 mL) was added to a solution of EtMgBr (15.2 mL, 45.6 mmol, 3.0 M in Et20) in THF (40 mL) at 0C and the reaction was stirred for 2 hrs. Saturated aqueous NH4CI solution (100 mL) was added and the mixture was extracted with EtOAc (200 mLx3). The combined organic extracts were washed with H20 (200 mL), dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with pet. Ether: EtOAc (100:0 to 50:50) to afford the title compound as a colourless oil, 2.6g , 46%. 1H NMR (400 MHz, CDCI3): delta 0.96-1 .04 (m, 3H), 1 .63-1 .71 (m, 2H), 1 .76- 1 .98 (m, 2H), 3.29 (dd, 1 H), 3.45 (dd, 1 H), 3.55-3.64 (m, 2H), 5.08-5.18 (m, 2H), 7.29- 7.39 (m, 5H). LCMS m/z = 250 [M+H]+
Compound 1 (200 g, 0.91 mol)And 3-buten-1-ol is dissolved in dichloromethane (2000 mL),Then, methanesulfonic acid (526 g, 5.48 mol) was added dropwise to the reaction system at room temperature.After reacting for 12 hours at room temperature, TLC (dichloromethane/methanol volume ratio = 20/1) showed that the reaction was completed.The reaction solution was poured into water, then extracted with methylene chloride, and the organic phase was separated.The organic phase is washed several times with saturated sodium bicarbonate and saturated brine.Then, it is dried and concentrated to give the crude compound 2, which is purified by silica gel column chromatography.Yield: 35.7%.
With cesium chloride; In tetrahydrofuran; at -78 - 20℃; for 2h;Inert atmosphere;
Step 1: To a solution of 1-N-Cbz-3-pyrrolidone (1.2 g, 5.47 mmol) in tetrahydrofuran (80 mL) cesium chloride (5 g, 29.7 mmol) was added to the solution.The system was purged with nitrogen to a temperature of -78 C, then cyclopropylmagnesium bromide (18.6 mL,18.6 mmol) was slowly added dropwise to the above system. The reaction was slowly warmed to room temperature and stirred for 2 hr. EtOAc was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfateThe residue was flash chromatographed (petroleum ether / ethyl acetate = 1/1)Purification afforded 1-indole-Cbz-3-cyclopropyl-3-hydroxypyrrolidine (500 mg, yield: 35 %) as a colorless liquid.
With lanthanium (III) chloride bis(lithium chloride) complex; In tetrahydrofuran; at 0 - 20℃; for 21h;Inert atmosphere;
General procedure: To a dried round two neck bottomed flask equipped with a magneticstir bar were added 0.6M LaCl3-2LiCl in THF (1.5 eq) under nitrogen,Grignard reagents in THF (1.5 eq) was added slowly through syringe at0 C. After stirring at room temperature for 3 h, a solution of ketones (5or 23a-b) (1.0 eq) in THF (1.0 M) was added into the mixture. Thereaction was stirred for another18 h until the reaction was completed asdetermined by TLC and then quenched with 25% acetic acid. Themixture was extracted with ethyl acetate, the ethyl acetate layer waswashed with saturated brine and dried over anhydrous MgSO4. Afterfiltration and concentration, the crude product was used directly for thenext step without purification.
7-methoxy-3,4-dihydro-1H-pyrrolo[3,4-b]indole-2-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N,N'-Dimethylurea; tartaric acid; at 85℃; for 3h;
Mixing 1,3-dimethylurea (9.58 g, 109 mmol) with tartaric acid (4.10 g, 27.3 mmol), Heat to 85 C until the solids melt clear, (4-methoxyphenyl)hydrazine hydrochloride (1.80 g, 10.3 mmol) and 1-benzyloxycarbonyl-3-pyrrolidone (2.00 g, 9.12 mmol), Continue the reaction for 3 hours. The reaction was quenched with water (30 mL). Extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with a saturated sodium chloride solution (30 mL). Dry over anhydrous sodium sulfate and concentrate by suction filtration. The residue was subjected to silica gel column chromatography [Petroleum ether / ethyl acetate (v / v) = 2 / 1] purification, The title compound was obtained (1.99 g, yield 68%). It is a yellow solid.
benzyl 3-hydroxy-3-(prop-2-yn-1-yl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With Zn-Cu couple; In tetrahydrofuran; at 0 - 40℃; for 2h;Sonication;
Zn-Cu couple (2.6 g, 20 mmol) was added to a mixture of <strong>[130312-02-6]benzyl 3-oxopyrrolidine-1-carboxylate</strong> (4 g, 18.1 mmol) and 3-bromoprop-1-yne (4.1 g, 27 mmol, 80% in toluene) in THF (50mL) at 0 C in portions. The mixture was sonicated (20 C 4O C) for 2 h. After the reaction was finished, the reaction mixture was quenched with saturated aqueous NH4C1 and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel columnchromatography (EtOAc in hexanes) to give benzyl 3-hydroxy-3-(prop-2-yn-1-yl)pyrrolidine-1- carboxylate. LCMS (Ci5Hi8NO3) (ES, m/z): 260 [M+H]t
benzyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihyro-1H-pyrrol-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -5 - 20℃; for 4h;Inert atmosphere;
Tf 2O (6.0 mL, 36 mmol) was added dropwise into a solution of benzyl 3-oxopyrrolidin-1-carboxylate (5.03 g, 22.90 mmol) and DIPEA (8.00 mL, 48.41 mmol) in DCM (50 mL) at -5 under an cold bath condition and nitrogen protection. 30 min later, the reaction mixture was warmed to room temperature and stirred for 3.5 h. Then to the reaction mixture was added saturated aqueous NaHCO 3 (40 mL) to quench the reaction, and the aqueous layer was extracted with DCM (40 mL×3) . The combined organic layers were washed with saturated aqueous NaCl (30 mL) , dried over anhydrous Na 2SO 4, and concentrated in vacuo to give a crude product, which was purified by silica-gel column chromatography (eluent: PET/DCM/EtOAc (v/v/v) = 10/1/1) to give yellow oily liquid (1.33 g, 17%) . [0656] 1H NMR (400 MHz, CDCl 3) delta (ppm) : 7.37 (s, 5H) , 5.75 (d, J = 21.9 Hz, 1H) , 5.17 (s, 2H) , 4.30 (m, 3H) , 3.93 (t, J = 9.6 Hz, 1H) .
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