* 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.
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 13, p. 2321 - 2327
4
[ 95656-88-5 ]
[ 100858-32-0 ]
[ 100858-33-1 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 3, p. 509 - 512
5
[ 95656-88-5 ]
[ 100858-33-1 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 1, p. 207 - 215
6
[ 108-22-5 ]
[ 95656-88-5 ]
[ 100858-32-0 ]
[ 100858-33-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 13, p. 2321 - 2327
7
[ 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
8
[ 79-37-8 ]
[ 95656-88-5 ]
[ 130312-02-6 ]
Yield
Reaction Conditions
Operation in experiment
86%
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).
Reference：
[1] Patent: US6469023, 2002, B1,
9
[ 114615-82-6 ]
[ 7529-22-8 ]
[ 95656-88-5 ]
[ 130312-02-6 ]
Reference：
[1] Patent: US6331545, 2001, B1,
10
[ 501-53-1 ]
[ 95656-88-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate In tetrahydrofuran at 20℃; for 16 h;
Procedure 35 Procedure 35 provides a preparation of 3-cyclopropylmethoxypyrrolidine from hydroxypyrrolidine. A solution of 3-hydroxy-pyrrolidine-hydrochloride (162 mmol) in tetrahydrofuran (100 mL) was treated with potassium carbonate (210 mmol) and a solution of benzyl chloroformate (210 mmol) in tetrahydrofuran (50 mL). The resulting solution was maintained for 16 h at rt. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with brine (3*100 mL), dried (magnesium sulfate), and concentrated to provide the protected amine in 90percent yield as a yellow liquid.
87%
With sodium carbonate In tetrahydrofuran; water at 20℃; for 1 h;
To a stirred solution of intermediate A (10.00 g, 81 mmol) in H2O/THF=1/1(200 mL) was added Na2C03 (24.30 g 0.23 mol) and Cbz-CI (23.50 g, 0.14 mol). The resulting mixture was stirred at r.t for 1h. The reaction was quenched by addition of 1M HCI and the aqueous layer extracted twice with DCM. 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=1:4) to give B (15.50 g 87percent) as white solid. The structure was confirmed by LC-MS spectra. TLC:Rf=0.3(silica gel,EA:PE=1 :2, v/v) LC-MS : [M+H]+= 222 ; [M+23]= 244.
With triethylamine In dichloromethane at 20℃; for 12 h;
To a solution of pyrrolidin-3-ol (10.45 g, 120.1 mmol) in dichloromethane (300 mL) was added benzyl chloroformate (24.6 g, 144 mmol) and triethylamine (24.3 g, 240.2 mmol). The resulting solution was stirred at room temperature for 12 hours. After concentrating the reaction, the remaining material was partitioned between ethyl acetate (100 mL) and water (60 mL). The layers were separated. The organic layer was washed with water (60 mL), aqueous saturated sodium chloride solution (60 mL), dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to give benzyl 3-hydroxypyrrolidinyl-1-carboxylate (15.2 g, 57percent) as a colorless gum. LCMS m/z = 222.1 [M+H]+.
49%
for 20 h;
Prβparatlon 16; S-Hydroxy-pyrrolldlne-i-carboxyllc acid benzyl ester; 3-Pyrrolidiπol (6.99g, 68.9 mmol), benzyl chloroformata (10.66 mL, 75.8 mmol) and CH2CI2 (200 mL) were stirred for 2Oh then washed with water and brine, dried (MgSO4) and concentrated to give a thick yellow oil. Chromatography, flushing first with 20percent EtOAc/ hexaπes then eluting with 30percent MeOH/EtOAc, afforded 7.4Og (49percent) of the title compound: NMR (CDCI3) δ 7.35-7.26 (m, 5H), 5.11 (s, 2H), 4.46 (br s, 1H), 3.60-3.38 (m, 4H)1 2.00-2.82 (m, 2H).
Reference：
[1] Chemical Communications, 2007, # 21, p. 2136 - 2138
[2] Patent: WO2017/216726, 2017, A1, . Location in patent: Page/Page column 581
[3] Patent: WO2007/60526, 2007, A1, . Location in patent: Page/Page column 44; 71
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 12, p. 2818 - 2841
[5] Bulletin of the Chemical Society of Japan, 1996, vol. 69, # 1, p. 207 - 215
[6] Journal of Medicinal Chemistry, 1998, vol. 41, # 21, p. 4080 - 4100
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S207-S209
[8] Patent: US5786358, 1998, A,
[9] Patent: EP761668, 1997, A2,
[10] Advanced Synthesis and Catalysis, 2007, vol. 349, # 8-9, p. 1475 - 1480
[11] Synthesis, 2011, # 22, p. 3669 - 3674
12
[ 31970-04-4 ]
[ 95656-88-5 ]
Yield
Reaction Conditions
Operation in experiment
51%
Stage #1: With borane In tetrahydrofuran at 0 - 20℃; Inert atmosphere Stage #2: With water; dihydrogen peroxide; sodium hydroxide In tetrahydrofuran at 0 - 20℃; Inert atmosphere
A 1M solution of borane in THF (9 mL) was added to a solution of intermediate 6.ii (1.81 g) in THF (25 mL) at 0° C. under nitrogen. The reaction mixture was stirred at rt for 16 k and was cooled to 0° C. 20percent NaOH (1.8 mL) was carefully added dropwise followed by 35percent aq. hydrogen peroxide (1.2 mL). The mixture was stirred at 0° C. for 30 min and at rt for 2 h. Et2O and an aq. 40percent sodium bisulfite solution were added and the reaction mixture stirred vigorously for 15 min. The residue obtained after work up (Et2O) was purified by chromatography (Hex/EA 5:5 to 3:7) to give 1.01 g (51percent yield) of a colorless oil. 1H NMR (DMSOd6; δ ppm): 1.67-1.82 (1H, m); 1.82-1.96 (1H, m); 3.16-3.25 (1H, m); 3.28-3.44 (3H, m); 4.20-4.29 (1H, broad); 4.92 (1H, d, J=3); 5.06 (2H, s); 7.27-7.41 (5H, m).
51%
Stage #1: With borane In tetrahydrofuran at 0 - 20℃; for 16 h; Stage #2: With sodium hydroxide; water; dihydrogen peroxide In tetrahydrofuran at 0 - 20℃; for 2.5 h; Stage #3: With water; sodium hydrogensulfite In tetrahydrofuran for 0.25 h;
6. Ui. (RS) -3 -hydroxy-pyrrolidine- 1-carboxylic acid benzyl ester:A \\M solution of borane in THF (9 ml) was added to a solution of intermediate 6.ii (1.81 g) in THF (25 ml) at 0 0C under nitrogen. The reaction mixture was stirred at rt for 16 h and was cooled to 0 0C. 20percent NaOH (1.8 ml) was carefully added dropwise followed by 35percent aq. hydrogen peroxide (1.2 ml). The mixture was stirred at 0 0C for 30 min and at rt for 2 h. Et2O and an aq. 40percent sodium bisulfite solution were added and the reaction mixture stirred vigorously for 15 min. The residue obtained after work up (Et2O) was purified by chromatography (Hex/EA 5:5 to 3:7) to give 1.01 g (51percent yield) of a colourless oil. 1H NMR (DMSOd6; δ ppm): 1.67-1.82 (IH, m); 1.82-1.96 (IH, m); 3.16-3.25 (IH, m); 3.28-3.44 (3H, m); 4.20-4.29 (IH, broad); 4.92 (IH, d, J = 3); 5.06 (2H, s); 7.27-7.41 (5H, m).
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] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1582 - 1589
13
[ 40499-83-0 ]
[ 31139-36-3 ]
[ 95656-88-5 ]
Yield
Reaction Conditions
Operation in experiment
47%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 3 h;
To the solution of pyrrolidin-3-ol (1.0 g, 11 mmol) in THF (5 mL) and 1M NaOH (5 mL) was added dibenzyldicarbonate (3.3, 11 mmol) at room temperature. The reaction mixture was stirred for 3 h then the THF removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed successively with saturated NaHCO3 (2.x.20mL) and saturated NaCl (2.x.20 mL). The solution was dried over Na2SO4, decanted and concentrated. Benzyl 3-hydroxypyrrolidine-1-carboxylate (1.1 g, 47percent) was isolated 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 4.93 min. LCMS: 1.21 min [M+1] 222.06 (2 min gradient, MeOH/H2O 0.1percent TFA).
6. Ui. (RS) -3 -hydroxy-pyrrolidine- 1-carboxylic acid benzyl ester:A M solution of borane in THF (9 ml) was added to a solution of intermediate 6.ii (1.81 g) in THF (25 ml) at 0 0C under nitrogen. The reaction mixture was stirred at rt for 16 h and was cooled to 0 0C. 20% NaOH (1.8 ml) was carefully added dropwise followed by 35% aq. hydrogen peroxide (1.2 ml). The mixture was stirred at 0 0C for 30 min and at rt for 2 h. Et2O and an aq. 40% sodium bisulfite solution were added and the reaction mixture stirred vigorously for 15 min. The residue obtained after work up (Et2O) was purified by chromatography (Hex/EA 5:5 to 3:7) to give 1.01 g (51% yield) of a colourless oil. 1H NMR (DMSOd6; delta ppm): 1.67-1.82 (IH, m); 1.82-1.96 (IH, m); 3.16-3.25 (IH, m); 3.28-3.44 (3H, m); 4.20-4.29 (IH, broad); 4.92 (IH, d, J = 3); 5.06 (2H, s); 7.27-7.41 (5H, m).
51%
A 1M solution of borane in THF (9 mL) was added to a solution of intermediate 6.ii (1.81 g) in THF (25 mL) at 0 C. under nitrogen. The reaction mixture was stirred at rt for 16 k and was cooled to 0 C. 20% NaOH (1.8 mL) was carefully added dropwise followed by 35% aq. hydrogen peroxide (1.2 mL). The mixture was stirred at 0 C. for 30 min and at rt for 2 h. Et2O and an aq. 40% sodium bisulfite solution were added and the reaction mixture stirred vigorously for 15 min. The residue obtained after work up (Et2O) was purified by chromatography (Hex/EA 5:5 to 3:7) to give 1.01 g (51% yield) of a colorless oil. 1H NMR (DMSOd6; delta ppm): 1.67-1.82 (1H, m); 1.82-1.96 (1H, m); 3.16-3.25 (1H, m); 3.28-3.44 (3H, m); 4.20-4.29 (1H, broad); 4.92 (1H, d, J=3); 5.06 (2H, s); 7.27-7.41 (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 triethylamine; In dichloromethane; at 20℃; for 12h;
To a solution of pyrrolidin-3-ol (10.45 g, 120.1 mmol) in dichloromethane (300 mL) was added benzyl chloroformate (24.6 g, 144 mmol) and triethylamine (24.3 g, 240.2 mmol). The resulting solution was stirred at room temperature for 12 hours. After concentrating the reaction, the remaining material was partitioned between ethyl acetate (100 mL) and water (60 mL). The layers were separated. The organic layer was washed with water (60 mL), aqueous saturated sodium chloride solution (60 mL), dried and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to give benzyl 3-hydroxypyrrolidinyl-1-carboxylate (15.2 g, 57%) as a colorless gum. LCMS m/z = 222.1 [M+H]+.
49%
In dichloromethane; for 20h;
Prbetaparatlon 16; S-Hydroxy-pyrrolldlne-i-carboxyllc acid benzyl ester; 3-Pyrrolidi?ol (6.99g, 68.9 mmol), benzyl chloroformata (10.66 mL, 75.8 mmol) and CH2CI2 (200 mL) were stirred for 2Oh then washed with water and brine, dried (MgSO4) and concentrated to give a thick yellow oil. Chromatography, flushing first with 20% EtOAc/ hexa?es then eluting with 30% MeOH/EtOAc, afforded 7.4Og (49%) of the title compound: NMR (CDCI3) delta 7.35-7.26 (m, 5H), 5.11 (s, 2H), 4.46 (br s, 1H), 3.60-3.38 (m, 4H)1 2.00-2.82 (m, 2H).
8.87 g (81%)
In potassium hydroxide;
A. A solution of 4.29 g (48.9 mmol) of 3-hydroxypyrrolidine in 30 mL of 2N potassium hydroxide was cooled to 0 C. and 10.2 mL of benzyl chloroformate were added with stirring. The reaction was stirred for four hours at 0 C. and then extracted with ethyl acetate (3*100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacua. The residue was chromatographed on silica gel with 70/30 hexanes/ethyl acetate. The correct fractions were combined and concentrated in vacuo to give 8.87 g (81%) of benzyl 3-hydroxypyrrolidine-1-carboxylate as a viscous clear oil. Rf=0.11 in 50/50 hexanes/ethyl acetate Mass Spectrum (FD+): M+221; IR (CHCl3, cm-1): 913, 977, 993, 1100, 1117, 1175, 1236, 1360, 1427, 1454, 1498, 1694, 2884, 2954, 3013, 3020, 3436 (broad), 3610; UV (C2 H5 OH) lambdamax =205 (epsilon=9112), 264 (epsilon=142); 1 H NMR (300 MHz, CDC13) delta: 1.91-2.05 (m-, 2H); 3.00 (broad s, 1H); 3.39-3.61 (m, 4H); 4.41 (s, 1H); 5.12 (s, 2H); 7.30-7.43 (m, 5H).
8.87 g (81%)
In potassium hydroxide;
A. A solution of 4.29 g (48.9 mmol) of 3-hydroxypyrrolidine in 30 mL of 2N potassium hydroxide was cooled to 0C and 10.2 mL of benzyl chloroformate were added with stirring. The reaction was stirred for four hours at 0C and then extracted with ethyl acetate (3 x 100 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel with 70/30 hexanes/ethyl acetate. The correct fractions were combined and concentrated in vacinoto give 8.87 g (81%) of benzyl 3-hydroxypyrrolidine-1-carboxylate as a viscous clear oil.
Reference Example 79 To a mixture of benzyl 3-hydroxy-1-pyrrolidine carboxylate (5.00 g) and pyridine (50 mL) was added p-toluenesulfonyl chloride (4.74 g) at 0C. After the mixture was stirred at room temperature for 20 hours, the reactant was poured into water and extracted with ethyl acetate. The extracts were washed with 1 N hydrochloric acid, a sodium hydrogen carbonate solution and brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain benzyl 3-[[(4-methylphenyl)sulfonyl]oxy]-1-pyrrolidine carboxylate (4.98 g). 1H-NMR (300 MHz, CDCl3) delta: 1.95-2.24 (2H, m), 2.45 (3H, d, J=2.7 Hz), 3.45-3.64 (4H, m), 5.05-5.12 (3H, m), 7.33-7.36 (7H, m), 7.77-7.80 (2H, m).
(a) 3-Hydroxy-pyrrolidine-1-carboxylic acid benzyl ester. 3-Hydroxy-pyrrolidine (10 g, 115 mmol, 1.0 equiv) was dissolved in 2 N NaOH (100 mL) and the mixture was cooled to 0 C. Benzylchloroformate (21 g, 126 mmol, 1.1 equiv) was added dropwise over a 45 min period. After addition, the reaction was stirred at room temperature for 4 h at which time the pH was adjusted to 7-8 using concentrated HCl. The product was extracted with 3*100 mL of CH2Cl2. The organic extracts were combined and dried over Na2SO4, decanted and concentrated in vacuo to yield the desired product as a light yellow oil (24.1 g, 95%) that was used without further purification.
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).
Preparatory Example 35 N-(Benzyloxycarbonyl)-3-pyrrolidinol STR245 30 g of 3-pyrrolidinol was dissolved in 500 ml of chloroform, to which 53 ml of triethylamine was added, followed by gradually dropping 52 ml of benztloxycarbonyl chloride at room temperature. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The solvent was distilled off under reduced pressure and the resultant residue was purified by column chromatography (eluding solvent: hexane-ethyl acetate) to obtain 70.67 g of the intended compound. 1 H-NMR(90 MHz, CDCl3) delta:1.7-2.1(m,2H), 2.8-3.2(m,1H), 3.2-3.7(m,4H), 4.2-4.5(m,1H), 5.1(s,2H), 7.3(s,5H)
(S)-3-Hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester When the above procedure was repeated using 12.4 g (0.1 mol) of (S)-3-hydroxypyrrolidine hydrochloride, the yield of the title compound was 20.1 g.
(S)-3-Hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester When the above procedure was repeated using 12.4 g (0.1 mol) of (S)-3-hydroxypyrrolidine hydrochloride, the yield of the title compound was 20.1 g.
Part A. Preparation of N-(benzyloxycarbonyl)-3-pyrrolidinol. To a stirring solution of 3-pyrrolidinol (1780 mg, 20.4 mmol, Aldrich) and dry triethylamine (4130 mg, 40.9 mmol, Aldrich) in dry CH2Cl2 (120 mL) at 0 C. was benylchloroformate (3.83 mg, 22.5 mmol, Aldrich). The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was quenched by the addition of 1M aqueous HCl (100 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine, dried over Na2SO4, and conc. in vacuo to a colorless oil. The oil was purified by flash chromatography (SiO2, hex:EtOAc, 2:1) to yield of pure N-(benzyloxycarbonyl)-3-pyrrolidinol. MS (ESI) 222 (M+H).
26
[ 124-63-0 ]
[ 95656-88-5 ]
[ 138232-44-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
With triethylamine; In dichloromethane;
Compound 26 (2.6 g, 11.8 mmol) and triethylamine (3.3 mL,17.6 mmol) were added in dichloromethane (30 ml). Methanesulfonylchloride (1.4 mL, 17.6 mmol) was added dropwise andthe mixture was kept below 5 C and then heated to 25 C for 3.5 h.The reaction was monitored by TLC. After the end of the reaction,the mixture was filtered and the filtrate was washed with 1M HCl(20 mL), saturated aqueous solution of sodium bicarbonate (20 mL)and brine (20 mL). Then the mixture was dried by anhydrous sodiumsulfate and filtered. The filtrate was evaporated underreduced pressure to give an oily compound (3.1 g, 80% yield). 1HNMR (300 MHz, DMSO-d6): delta= 7.35 (m, 5H, Ar-H), 5.22 (s, 2H,OCH2-Ar), 5.09 (m, 1H, OCH(CH2)2), 3.78 (m, 2H, CHCH2N), 3.56 (m,2H, CHCH2CH2N), 3.09 (s, 3H, SO2CH3), 2.05 (m, 2H, CHCH2CH2N)ppm.
In pyridine;
(R)-3-(Methylsulfonyl)oxy]-1-pyrrolidinecarboxylic acid, phenylmethyl ester A solution of 17.5 g (84 mmol) of (R)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 150 ml of dry pyridine was cooled to 5 and treated dropwise with 11.5 g (0.1 mol) of methanesulfonyl chloride keeping the temperature at 5. The reaction mixture was stirred at 5 for two hours and stored at 5 for 18 hours. The reaction mixture was allowed to warm to room temperature over three hours and the solvent was then removed in vacuo. The residue was partitioned between ethyl acetate/water (500 ml each) and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with water, dried (MgSO4), and evaporated in vacuo to give 21.2 g of the title compound.
In pyridine;
(R)-3-[(Methylsulfonyl)oxy]-1-pyrrolidinecarboxylic acid, phenylmethyl ester A solution of 17.5 g (84 mmol) of (R)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 150 ml of dry pyridine was cooled to 5 and treated dropwise with 11.5 g (0.1 mol) of methanesulfonyl chloride keeping the temperature at 5. The reaction mixture was stirred at 5 for two hours and stored at 5 for 18 hours. The reaction mixture was allowed to warm to room temperature over three hours and the solvent was then removed in vacuo. The residue was partitioned between ethyl acetate/water (500 ml each) and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were washed with water, dried (MgSO4) and evaporated in vacuo to give 21.2 g of the title compound.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
Step 1 Benzyl 3-((methylsulfonyl)oxy)pyrrolidine-1 -carboxylateTo a stirred solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (500 mg, 2.26 mmol) in DCM (10 mL) was added triethylamine (686 mg, 0,94 mL, 6.78 mmol) at room temperature. The resulting mixture was cooled to 0 C. Then methanesulfonyl chloride (388 mg, 3.39 mmol) was added dropwise into the mixture and the mixture was slowly warmed to room temperature over 2his under N2 atomsphere. The mixture was diluted with DCM (20 mL) and washed with H20 (10 mE x 2), hydrochloric acid (10 ml x 2, iN), saturated NaHCO3 (10 mE). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give the crude desired product (600 mg) as a brown oil which was used in the next step without further purification.
With triethylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice;
TDI01272-2 (5.20 g, 23.6 mmol) was dissolved in dichloromethane (150 mL), triethylamine (7.15 g, 70.8 mmol)was added, and methylsulfonyl chloride (4.04 g, 35.5 mmol) was added under ice bath cooling. The reaction wasperformed at room temperature for 3 h. Thin layer chromatography indicated the reaction was complete. The reactionsolution was quenched by water (100 mL), and extracted with dichloromethane (300 mL). The combined organic phasewas washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to afford TDI01272-3 (7.50 g, yellow oil, crude product).1H NMR (400 MHz, CDCl3) delta 7.33 - 7.29 (m, 4H), 7.28 - 7.24 (m, 1H), 5.21 - 5.15 (m, 1H), 3.68 (d, J = 12.8 Hz, 1H),3.62 (d, J = 12.8 Hz, 1H), 2.98 (s, 3H), 2.86 - 2.78 (m, 3H), 2.53 - 2.47 (m, 1H), 2.35 - 2.28 (m, 1H), 2.11 - 2.04 (m, 1H).
(R)-3-Hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester A solution of 10.2 g (82.6 mmol) of R-3-hydroxypyrrolidine hydrochloride (Chem. Letts., 1966, pp 893-6) in 50 m of water was cooled to 0 and treated with 22.5 ml (90 mmol) of 4.0 N sodium hydroxide. The neutral solution was treated dropwise with 15.6 g (87 mmol) of carbobenzyloxy chloride maintaining the pH at 11.0+-0.5 by the dropwise addition of 87 ml of 1.0 N sodium hydroxide and the temperature below 5 with a salt-ice bath. When the addition was complete, the mixture was stirred at 5 for two hours and stored at 5 for 18 hours. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (2 *500 ml). The combined organic layers were washed with 1.0 N sodium hydroxide (4*50 ml), water, dried (MgSO4) and evaporated in vacuo to give 17.5 g of the title compound.
With sodium hydroxide; sodium chloride; In water;
(R)-3-Hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester A solution of 10.2 g (82.6 mmol) of R-3-hydroxypyrrolidine hydrochloride (Chem. Letts., 1966, pp 893-6) in 50 ml of water was cooled to 0 and treated with 22.5 ml (90 mmol) of 4.0N sodium hydroxide. The neutral solution was treated dropwise with 15.6 g (86 mmol) of carbobenzyloxy chloride maintaining the pH at 11.0+-0.5 by the dropwise addition of 87 ml of 1.0N sodium hydroxide and the temperature below 5 with a salt-ice bath. When the addition was complete, the mixture was stirred at 5 for two hours and stored at 5 for 18 hours. The reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (2*500 ml). The combined organic layers were washed with 1.0N sodium hydroxide (4*50 ml), water, dried (MgSO4) and evaporated in vacuo to give 17.5 of the title compound.
(S)-1-[4-[3-(Acetyloxy)-1-pyrrolidinyl]-2-butynyl]-2-pyrrolidinone[ No CAS ]
[ 95656-88-5 ]
Yield
Reaction Conditions
Operation in experiment
With sodium chloride; triethylamine; In dichloromethane; toluene;
EXAMPLE 43 (S)-1-[4-[3-(Acetyloxy)-1-pyrrolidinyl]-2-butynyl]-2-pyrrolidinone A 0.5 g portion of (S)-3-hydroxypyrrolidine, as described in Example 42, was reconcentrated twice from toluene, dissolved in 80 ml of dichloromethane and cooled to 0 C. A 3.8 ml portion of triethylamine and 2.8 ml of benzylchloroformate were added with stirring. The reaction was stirred overnight, diluted with 300 ml of dichloromethane and extracted with 80 ml of 5% hydrochloric acid and 5% sodium bicarbonate solution. The aqueous phases were combined, saturated with sodium chloride and extracted with 3*150 ml of ethyl acetate. The organic phases were combined, dried, filtered and concentrated in vacuo. The residue was purified by chromatography (alumina) giving 940 g of (S)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester as a yellow oil [alpha]D26 =+21 (c, 1.054 methanol).
With pyridine; dmap; acetic anhydride; In methanol; dichloromethane;
A mixture of 2.87 g of (S)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester, 2.0 ml of acetic anhydride, 2.0 ml of pyridine and 20 mg of 4-dimethylaminopyridine in 25 ml of dichloromethane was stirred for 72 hours. Methanol (2 ml) and dichloromethane (50 ml) were added. The dichloromethane solution was washed with 40 ml each of 1N hydrochloric acid and 5% sodium bicarbonate solution, dried, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 3.1 g of (S)-3-(acetyloxy)-1-pyrrolidinecarboxylic acid, phenylmethyl ester as a colorless oil, [alpha]D26 =+17 (dichloromethane).
B. Twelve grams (54.2 mmol) of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> were dissolved in 150 mL of pyridine. This solution was cooled to 0C in an ice/water bath and 23.66 g (124.5 mmol) of p-toluenesulfonyl acid chloride were added at once. The reaction was allowed to stand at refrigerator temperatures for 18 hours and then acidified with 5N hydrochloric acid to pH<2. This residue was extracted with ethyl acetate (4x200 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel with 50% ethyl acetate/hexane and the product eluted to give 13.4 g (66%) of benzyl 3-(p-methylbenzenesulfonyloxy)pyrrolidine-1-carboxylate as an orange oil. Rf = 0.49 (1/1 hexanes/ethyl acetate); Mass Spectrum (FD+): M+= 375; IR (CHCl3, cm-1): 815, 837, 899, 953, 1020, 1050, 1086, 1115, 1175, 1307, 1359, 1425, 1452, 1497, 1600, 1699, 2897, 3692; UV (C2H5OH) lambdamax=226 (epsilon = 11821), 263 (epsilon = 725), 274 (epsilon = 439); Anal. Calcd. for C19H21N1O5S: C,60.78; H,5.64; N,3.73; S, 8.54. Found: C, 60.57; H, 5.69; N, 3.52; S, 8.56; 1H NMR (300 MHz,CDCl3) delta 1.96-2.13 (m, 2H); 2.42 (s, 3H); 3.43-3.62 (m, 4H); 5.05 (s, 1H); 5.10 (s, 2H); 7.33 (s, 7H); 7.77 (d, j=7.9Hz, 2H).
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).
With potassium carbonate; In tetrahydrofuran; at 20℃; for 16h;
Procedure 35 Procedure 35 provides a preparation of 3-cyclopropylmethoxypyrrolidine from hydroxypyrrolidine. A solution of 3-hydroxy-pyrrolidine-hydrochloride (162 mmol) in tetrahydrofuran (100 mL) was treated with potassium carbonate (210 mmol) and a solution of benzyl chloroformate (210 mmol) in tetrahydrofuran (50 mL). The resulting solution was maintained for 16 h at rt. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with brine (3*100 mL), dried (magnesium sulfate), and concentrated to provide the protected amine in 90% yield as a yellow liquid.
87%
With sodium carbonate; In tetrahydrofuran; water; at 20℃; for 1h;
To a stirred solution of intermediate A (10.00 g, 81 mmol) in H2O/THF=1/1(200 mL) was added Na2C03 (24.30 g 0.23 mol) and Cbz-CI (23.50 g, 0.14 mol). The resulting mixture was stirred at r.t for 1h. The reaction was quenched by addition of 1M HCI and the aqueous layer extracted twice with DCM. 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=1:4) to give B (15.50 g 87%) as white solid. The structure was confirmed by LC-MS spectra. TLC:Rf=0.3(silica gel,EA:PE=1 :2, v/v) LC-MS : [M+H]+= 222 ; [M+23]= 244.
With sodium hydroxide; In water; at 5 - 20℃; for 3h;pH 7.0;
Into a 500 mL 3-necked round-bottom flask, was placed a solution of pyrrolidin-3-ol hydrochloride (20.2 g, 163.43 mmol) in H2O (60 mL) while cooling to 5 C. Adjustment of the pH to 7 was accomplished by the NaOH(10%). This was followed by the addition of a solution of Cbz-Cl (36.8 g, 216.47 mmol), which was added dropwise with stirring, while cooling to a temperature of 5 C. The resulting solution was allowed to react, with stirring, for 2 h at 5 C. Then the resulting solution was allowed to react, with stirring, for 1 h while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:2). The resulting solution was extracted three times with 100 mL of EtOAc and the organic layers combined and dried over MgSO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 30 g (crude) of benzyl 3-hydroxypyrrolidine-1-carboxylate as brown oil.
With sodium hydroxide; In water; at 5 - 20℃; for 3h;pH 7.0;
Pyrrolidin-3-ol hydrochloride (163 mmol) was dissolved in water (60 mL), cooled to 5 C, and the pH of the reaction mixture was adjusted to 7 with 10% sodium hydroxide. Benzyl chloro formate (216 mmol) was added dropwise and the reaction mixture was maintained for 2 h at 5 C and for an additional 60 min at rt. The reaction mixture was extracted with ethyl acetate (3 x 100 mL) and the combined <n="102"/>organic layers were dried (magnesium sulfate) and concentrated to provide crude benzyl 3- hydroxypyrrolidine-1-carboxylate as brown oil.
With sodium hydroxide; In water; at 5 - 20℃; for 3h;
Into a 500 mL 3-necked round-bottom flask was placed a solution of pyrrolidin-3-ol hydrochloride (20.2 g, 163.43 mmol) in H2O (60 mL) while cooling to 5 C. Adjustment of the pH to 7 was accomplished by the NaOH(10%). This was followed by the addition of a solution of benzyl chloroformate (36.8 g, 216.47 mmol), which was added dropwise with stirring, while cooling to a temperature of 5 C. The resulting solution was allowed to react, with stirring, for 2 hours at 5 C. Then the resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting solution was extracted three times with 100 mL of ethyl acetate and the organic layers combined and dried over MgSO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 30 g (crude) of benzyl 3-hydroxypyrrolidine-1-carboxylate as brown oil.
2. Synthesis of benzyl 3-hydroxypyrrolidine-1-carboxylate; Pyrrolidin-3-ol hydrochloride (163 mmol) was dissolved in water (60 mL), cooled to 5 C., and the pH of the reaction mixture was adjusted to 7 with 10% sodium hydroxide. Benzyl chloroformate (216 mmol) was added dropwise and the reaction mixture was maintained for 2 h at 5 C. and for an additional 60 min at rt. The reaction mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide crude benzyl 3-hydroxypyrrolidine-1-carboxylate as brown oil.
2. Synthesis of benzyl 3-hydroxypyrrolidine-l-carboxylate.Pyrrolidin-3-ol hydrochloride (163 mmol) was dissolved in water (60 mL), cooled to 5 0C, and the pH of the reaction mixture was adjusted to 7 with 10% sodium hydroxide. Benzyl chloro formate (216 mmol) was added dropwise and the reaction mixture was maintained for 2 h at 5 0C and for an additional 60 min at rt. The reaction mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide crude benzyl 3-hydroxypyrrolidine-l-carboxylate as brown oil.
Pyrrolidin-3-ol hydrochloride (163 mmol) was dissolved in water (60 mL), cooled to 5 C., and the pH of the reaction mixture was adjusted to 7 with 10% sodium hydroxide. Benzyl chloroformate (216 mmol) was added dropwise and the reaction mixture was maintained for 2 h at 5 C. and for an additional 60 min at rt. The reaction mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide crude benzyl 3-hydroxypyrrolidine-1-carboxylate as brown oil.
With sodium hydroxide; In water; at 5 - 20℃; for 3h;pH 7.0;
2. Synthesis of benzyl 3-hvdroxypyrrolidine-l-carboxylate.Pyrrolidin-3-ol hydrochloride (163 mmol) was dissolved in water (60 mL), cooled to 5 0C, and the pH of the reaction mixture was adjusted to 7 with 10% sodium hydroxide. Benzyl chloro formate (216 mmol) was added dropwise and the reaction mixture was maintained for 2 h at 5 0C and for an additional 60 min at rt. The reaction mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide crude benzyl 3-hydroxypyrrolidine-l-carboxylate as brown oil.
Pyrrolidin-3-ol hydrochloride (163 mmol) was dissolved in water (60 mL), cooled to 5 C., and the pH of the reaction mixture was adjusted to 7 with 10% sodium hydroxide. Benzyl chloroformate (216 mmol) was added dropwise and the reaction mixture was maintained for 2 h at 5 C. and for an additional 60 min at rt. The reaction mixture was extracted with ethyl acetate (3*100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide crude benzyl 3-hydroxypyrrolidine-1-carboxylate as brown oil.
With sodium hydroxide; In water; at 5 - 20℃; for 3h;pH 7.0;
Into a 500 mL 3-necked round bottom flask was placed a solution of rhoyrrolidin-3-ol hydrochloride (20.2 g, 163.43 mmol) in H2O (60 mL) while cooling to 5 0C. Adjustment of the pH to 7 was accomplished by the NaOH(10%). This was followed by the addition of a solution of benzyl chloroformate (36.8 g, 216.47 mmol), which was added dropwise with stirring, while cooling to a temperature of 5 0C. The resulting solution was allowed to react, with stirring, for 2 hours at 5 0C. Then the resulting solution was allowed to react, with stirring, for lhour while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1:2). The resulting solution was extracted three times with 100 mL of ethyl acetate and the organic layers combined and dried over MgSO4 and concentrated by evaporation <n="138"/>under vacuum using a rotary evaporator. This resulted in 30 g (crude) of benzyl 3-hydroxypyrrolidine- 1-carboxylate as brown oil.
2.6 g
With potassium carbonate; In dichloromethane; water; at 25℃; for 5h;
3-Hydroxypyrrolidine hydrochloride (25) (3 g, 14.8 mmol) andK2CO3 (10.2 g, 73.9 mmol) were added in dichloromethane (30 mL)and water (30 mL). Benzyl chloroformate (2.5 g, 14.8 mmol) wasadded dropwise and the mixture was kept below 5 C and thenheated to 25 C for 5 h. The reaction was monitored by TLC. Afterthe end of the reaction, the mixture was separated and the aqueouslayer was extracted with dichloromethane (30 mL). The organiclayer was washed with saturated aqueous solution of sodium bicarbonate(20 mL) and brine (20 mL).Then the mixturewas dried byanhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure to give an oily compound (2.6 g).
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 3h;
To the solution of pyrrolidin-3-ol (1.0 g, 11 mmol) in THF (5 mL) and 1M NaOH (5 mL) was added dibenzyldicarbonate (3.3, 11 mmol) at room temperature. The reaction mixture was stirred for 3 h then the THF removed under reduced pressure. The residue was dissolved in DCM (50 mL) and washed successively with saturated NaHCO3 (2×20mL) and saturated NaCl (2×20 mL). The solution was dried over Na2SO4, decanted and concentrated. Benzyl 3-hydroxypyrrolidine-1-carboxylate (1.1 g, 47%) was isolated 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 4.93 min. LCMS: 1.21 min [M+1] 222.06 (2 min gradient, MeOH/H2O 0.1% TFA).
With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 1.16667h;
Synthesis of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate Into a 250 mL 3-necked round-bottom flask, was placed a solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (10 g, 45.23 mmol) in CH2Cl2 (100 mL). To this was added 3,4-dihydro-2H-pyran (19 g, 226.19 mmol). To the mixture was added P-TSA (389 mg, 2.26 mmol) and the resulting solution was allowed to react, with stirring, for 10 min while the temperature was maintained at 0 C. The resulting solution was allowed to react, with stirring, for an additional 1 h at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:2). The reaction mixture was then quenched by the adding 100 mL of NaHCO3. The resulting mixture was washed 1 time with 100 mL of NaHCO3 and 1 time with 100 mL of brine. The mixture was dried over MgSO4 and concentrated under vacuum using a rotary evaporator. This resulted in 15 g (98%) of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate as a yellow oil.
98%
With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 1h;
3,4-Dihydro-2H-pyran (226 mmol) and p-toluenesulfonic acid (2.26 mmol) were added to a solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (45.2 mmol) in dichloromethane (100 mL) at 0 C. The reaction mixture was allowed to warm to rt and was maintained for 60 min. The reaction mixture was washed with sodium bicarbonate (100 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated to provide benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate in 98% yield as yellow oil.
98%
3. Synthesis of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate Into a 250 mL 3-necked round-bottom flask was placed a solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (10 g, 45.23 mmol) in CH2Cl2 (100 mL). To this was added 3,4-dihydro-2H-pyran (19 g, 226.19 mmol). To the mixture was added P-TSA (389 mg, 2.26 mmol) and the resulting solution was allowed to react, with stirring, for 10 minutes while the temperature was maintained at 0 C. The resulting solution was allowed to react, with stirring, for an additional 1 hour at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The reaction mixture was then quenched by the adding 100 mL of NaHCO3. The resulting mixture was washed 1 time with 100 mL of NaHCO3 and I time with 100 mL of brine. The mixture was dried over MgSO4 and concentrated under vacuum using a rotary evaporator. This resulted in 15 g (98%) of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate as yellow oil.
98%
toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃;
3. Synthesis of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate; 3,4-Dihydro-2H-pyran (226 mmol) and p-toluenesulfonic acid (2.26 mmol) were added to a solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (45.2 mmol) in dichloromethane (100 mL) at 0 C. The reaction mixture was allowed to warm to rt and was maintained for 60 min. The reaction mixture was washed with sodium bicarbonate (100 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated to provide benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate in 98% yield as yellow oil.
98%
toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃;
3. Synthesis of benzyl 3-(tetrahydro-2//-pyran-2-yloxy)pyrrolidine-l-carboxylate.3,4-Dihydro-2H-pyran (226 mmol) and />-toluenesulfonic acid (2.26 mmol) were added to a solution of benzyl 3-hydroxypyrrolidine-l-carboxylate (45.2 mmol) in dichloromethane (100 mL) at 0 0C. The reaction mixture was allowed to warm to rt and was maintained for 60 min. The reaction mixture was washed with sodium bicarbonate (100 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated to provide benzyl 3-(tetrahydro-2H-pyran-2- yloxy)pyrrolidine-l-carboxylate in 98% yield as yellow oil.
98%
With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃;
3,4-Dihydro-2H-pyran (226 mmol) and p-toluenesulfonic acid (2.26 mmol) were added to a solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (45.2 mmol) in dichloromethane (100 mL) at 0 C. The reaction mixture was allowed to warm to rt and was maintained for 60 min. The reaction mixture was washed with sodium bicarbonate (100 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated to provide benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate in 98% yield as yellow oil.
98%
toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 1.16h;
Into a 250 mL 3-?ecked round bottom flask was placed a solution of benzyl 3- hydroxypyrrolidine-1 -carboxylate (10 g, 45.23 mmol) in CH2Cl2 (100 mL). To this was added 3,4- dihydro-2H-pyran (19 g, 226.19 mmol). To the mixture was added p-toluenesulfonic acid (389 mg, 2.26 mmol) and the resulting solution was allowed to react, with stirring, for 10 minutes while the temperature was maintained at 0 0C. The resulting solution was allowed to react, with stirring, for an additional 1 hour at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether = 1:2). The reaction mixture was then quenched by the adding 100 mL of NaHCO3. The resulting mixture was washed with 100 mL of NaHCtheta3 and 100 mL of brine. The mixture was dried over MgSO4 and concentrated under vacuum using a rotary evaporator. This resulted in 15 g (98%) of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-l-carboxylate as yellow oil.
With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃;
3,4-Dihydro-2H-pyran (226 mmol) and p-toluenesulfonic acid (2.26 mmol) were added to a solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (45.2 mmol) in dichloromethane (100 mL) at 0 C. The reaction mixture was allowed to warm to rt and was maintained for 60 min. The reaction mixture was washed with sodium bicarbonate (100 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated to provide benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-1-carboxylate in 98% yield as yellow oil
With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃;
3. Synthesis of benzyl 3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidine-l-carboxylate.3,4-Dihydro-2H-pyran (226 mmol) and /7-toluenesulfonic acid (2.26 mmol) were added to a solution of benzyl 3-hydroxypyrrolidine-l-carboxylate (45.2 mmol) in dichloromethane (100 mL) at 0 0C. The reaction mixture was allowed to warm to rt and was maintained for 60 min. The reaction mixture was washed with sodium bicarbonate (100 mL) and brine (100 mL), dried (magnesium sulfate), and concentrated to provide benzyl 3-(tetrahydro-2H-pyran-2- yloxy)pyrrolidine-l-carboxylate in 98% yield as yellow oil.
Sodium hydride (280 mmol) was added in portions to a cold (0 C.) solution of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> (76.9 mmol) in N,N-dimethylformamide (100 mL). The mixture was maintained for 60 min and was then treated with a solution of (bromomethyl)cyclopropane (231 mmol) in N,N-dimethylformamide (100 mL) and potassium iodide (0.66 mmol). The reaction mixture was allowed to warm to rt where it was maintained for 30 min. The reaction mixture was subjected to microwave irradiation for 2 h at 90 C. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (200 mL) and water (200 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3*200 mL) and the combined organic layers were washed with brine (2*200 mL) and dried (magnesium sulfate). The residue was purified by chromatography (20/1 petroleum ether/ethyl acetate) to provide the product in 81% yield.
With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 80℃;
A solution of 1.29 g of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidine-1-carboxylate</strong> in 80 ml of THF is cooled to 0 C., 0.245 g of 60% NaH in oil is added and then 1.26 g of [(2-bromoethoxy)methyl]benzene and 0.108 g of tetrabutylammonium iodide and it is heated at 80 C. for 3 hours. 0.28 g of NaH and 0.40 g of [(2-bromoethoxy)methyl]benzene are added and it is heated at 80 C. for 2 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with 0.1M HCl solution, with a saturated solution of NaHCO3, it is dried and the solvent is evaporated under vacuum. The product thus obtained is purified by preparative HPLC and 0.46 g of the expected compound is obtained.
With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; oil; at 80℃; for 5h;
Preparation 7.92-(Pyrrolidin-3-yloxy)ethanol.Step 1 : Benzyl 3-(2-benzyloxyethoxy)pyrrolidine-1 -carboxylate.A solution of 1 .29 g of benzyl 3-hydroxypyrrolidine-1 -carboxylate in 80 ml of THF is cooled to 0C, 0.245 g of 60% NaH in oil is added and then 1 .26 g of [(2- bromoethoxy)methyl]benzene and 0.108 g of tetrabutylammonium iodide and it is heated at 80C for 3 hours. 0.28 g of NaH and 0.40 g of [(2- bromoethoxy)methyl]benzene are added and it is heated at 80C for 2 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with 0.1 M HCI solution, with a saturated solution of NaHC03, it is dried and the solvent is evaporated under vacuum. The product thus obtained is purified by preparative HPLC and 0.46 g of the expected compound is obtained.
Intermediates 90-93: benzyl 3-([4-(2-methoxy-2 oxoethyl) cyclohexyl] oxyl pyrrolidine- 1- carboxylateRacemic benzyl 3 -hydroxypyrrolidine-1 -carboxylate (5 g, 22.6 mmol) was dissolved in anhydrous THF (150 ml) at 0C, TEA (3.46 ml, 24.86 mmol) added, followed by drop wise addition of TMS-Cl (3.03 ml, 23.73 mmol). The reaction mixture aged for 30 min then diluted with hexane (150 ml) and filtered through a small pad of celite eluting with hexane and concentrated. The crude product and cis/trans methyl 2-(4-oxocyclohexyl)acetate (3.69 g, 21.69 mmol) were dissolved in dichloromethane (150 ml) at -60C, triethylsilane (3.97 ml, 24.86 mmol) was added, followed by drop wise addition of TMS-OTf (2.04 ml, 11.3 mmol). The mixture was allowed to warm to 0C and age for 30 min. 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.
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 25℃; for 16h;Inert atmosphere;
To a solution of compound 2.3 (800 mg, 7.27 mmol, 1 eq) in DCM (30 mL) was added compound 50 (1.61 g, 7.27 mmol, 1 eq), PPh3 (2.86 g, 10.91 mmol, 1.50 eq) andDIAD (2.21 g, 10.91 mmol, 2.12 mL, 1.50 eq) in turn at 0C underN2. The resulting mixture was stirred at 25C for 16 hours. The reaction mixture was added water 20 mL, extracted with EtOAc (2OmL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 1:1). Compound 2.2 (750 mg, 2.39 mmol, 32.92% yield) was obtained as a white solid. ?H NIVIR(400 MHz, chloroform-d) ppm 2.09 - 2.20 (m, 2 H) 3.51 - 3.74 (m, 4 H) 4.45 (s, 2 H) 4.90 (s,1 H) 5.93 (s, 1 H) 6.21 (d, 1=6.0 Hz, 1 H) 7.33 - 7.37 (m, 5 H) 7.91 (d, J=6.4 Hz, 1 H).
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