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Structure of 101385-93-7 * Storage: {[proInfo.prStorage]}
* 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] Patent: US2009/29963, 2009, A1, . Location in patent: Page/Page column 14
[2] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14836 - 14843
3
[ 101385-93-7 ]
[ 83220-73-9 ]
[ 101469-92-5 ]
Yield
Reaction Conditions
Operation in experiment
85.3 % ee
at 30℃; for 48 h; Microbiological reaction
General procedure: The strains selected in the secondary screening were used as biocatalysts in liquid medium for the reduction of cyclic ketones using cyclohexanone as a model substrate by adapting a methodology previously reported [28]. The microorganisms were cultured as mentioned above (see standard growth conditions), and then cyclohexanone (10mM) was added. The reaction was carried out at 30°C in an orbital shaker at 180rpm for 2days. After removing the cells by centrifugation, the supernatants were extracted using ethyl acetate or diethyl ether, and the organic layers were analyzed by Gas Chromatography (GC).
Reference：
[1] ChemBioChem, 2018, vol. 19, # 3, p. 239 - 246
[2] Process Biochemistry, 2017, vol. 58, p. 137 - 144
4
[ 541-41-3 ]
[ 101385-93-7 ]
[ 146256-98-6 ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium hydride In N,N-dimethyl-formamide at 0 - 5℃; for 2.66667 h;
1000ml four-necked flask by adding Boc-pyrrolidone 120g, DMF 600ml, Stirring down to 0-5 , Sodium hydride was added to 26 g, 70.5 g of ethyl chloroformate was slowly added dropwise with stirring, 40min drop finished. 0-5 reaction 2h, TLC detection reaction is completed, Slowly add 3L ice water, With dilute hydrochloric acid to adjust the pH = 7 after ethyl acetate extraction, dry, Concentrated to give intermediate 1. Yield 85percent.
Reference：
[1] Patent: CN106905325, 2017, A, . Location in patent: Paragraph 0030-0032
5
[ 83220-73-9 ]
[ 101385-93-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 2.08333 h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 3 h;
To a cold (-78° C.) solution of oxalyl chloride (2.8 mL, 32.4 mmol) in CH2Cl2 (20 mL) was added DMSO (4.6 mL, 64.8 mmol) in CH2Cl2 (40 mL) and stirred for 5 min at -78° C., followed by the addition of N-Boc-3-pyrrolidinol (4.04 g, 21.6 mmol) in CH2Cl2 (60 mL) and the reaction mixture was stirred for 2 h at -78° C. Triethylamine (15 mL, 108 mmol) was added to the reaction mixture and stirred for 1 h at -78° C. The reaction mixture was warmed to room temperature and stirred for 2 h at room temperature. It was cooled to 0° C. and quenched with saturated NaHCO3 and diluted with ethyl acetate. The organic layer was washed with saturated NaHCO3 and saturated brine. The combined organic layer was dried over MgSO4, filtered and evaporated to give the desired product (4 g, 100percent) that was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.79-3.75 (m, 4H), 2.58 (t, J=8.0 Hz, 2H), 1.47 (s, 9H).
97%
With oxalyl dichloride; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine In dichloromethane at -60 - 20℃; for 1.5 h;
[0356] Part A: To a solution of oxalyl chloride (1.3 mL, 15 mmol) in 20 mL of dichloromethane at -60° C. was added methyl sulfoxide dropwise over period of 10 min. After stirring at -60° C., a solution of 1,1-dimethylethyl 3-hydroxypyrrolidine-1-carboxylate (1.87 g, 10 mmol) in 20 mL of dichloromethane was added over 20 min. Then, diisopropylethylamine (8.8 mL, 50 mmol) was added over 5 min. The resulting mixture was stirred at -60° C. for 25 min, and at room temperature for 30 min. The reaction was diluted with dichloromethane (100 mL). The organic layer was washed sequentially with saturated sodium bisulfate solution (2.x.), saturated sodium bicarbonate solution, water, and brine; dried over sodium sulfate; and concentrated to afford 1.8 g (97percent) of 1,1-dimethylethyl 3-oxo-pyrrolidine-1-carboxylate: 1H-NMR (CDCl3) δ 3.75 (4H, m), 2.58 (2H, t, J=7.8 Hz), 1.49 (9H, s).
97%
With Dess-Martin periodane In dichloromethane
To a solution of 3-hydroxy-pyrrolidine-1-carboxylic acid tert-b\\xty\\ ester (10 g, 54 mmol) in dichloromethane (300 mL) is added Dess-Martin Reagent (45.9 g, 108 mmol) in three portions. The resulting mixture is stirred for 16 hours. The mixture is filtered through CeIi te and the solvent removed in vacuo. The crude material is purified via silica gel chromatography using a gradient elution of 0-8percent ethyl acetate/hexanes to afford the desired product as a glassy solid (9.8 g, 97percent).
96%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -69 - -40℃; for 0.5 h; Inert atmosphere
A 3 L, four-necked round-bottomed flask was equipped with a mechanical stirrer, 500 mL addition funnel, cooling bath, K-type thermocouple and a nitrogen inlet. The flask was charged with oxalyl chloride (149.8 g, 1.18 mol) and dichloromethane (700 mL) and cooled to -69° C. The stirred solution was treated drop-wise with a solution of dimethyl sulfoxide (99.2 g, 1.27 mol) in dichloromethane (150 mL), maintaining an internal temperature below -60° C. (copious gas generation). This mixture was briefly warmed to -40° C. before cooling to -69° C. A solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (100.0 g, 0.534 mol) in dichloromethane (350 mL) was charged drop-wise to the batch, maintaining an internal temperature below -60° C. The stirred reaction mixture was allowed to age at -50° C. for 30 minutes and cooled to -69° C. Neat triethylamine (270 g, 2.67 mol) was added drop-wise, while maintaining an internal temperature below -60° C. Upon completion of the addition, the batch was allowed to age for 30 minutes at -60° C., before warming to ambient temperature over about 1 hour. The reaction mixture was washed with 5percent mass to volume aqueous citric acid solution (2*180 mL). The separated aqueous layer was extracted with dichloromethane (2*200 mL), and the combined the organic phases were dried over anhydrous sodium sulfate (30 g), filtered and concentrated under reduced pressure. The title compound was obtained as a dark brown oily product (95.0 g, 96percent yield) and was used in the next step without further purification.
89%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.333333 h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 2 h;
Oxalyl chloride (6.0 mL, 70.5 mmol) was added to 300 mL of DCM and cooled to - 78°C. DMSO (9.9 mL, 139mmol) was added thereto, and the mixture was stirred for 15 minutes. tert-butyl 3-hydroxypyrrolidin-1-carboxylate (8.98g, 48 mmol) obtained in Step A was added thereto, and the mixture was stirred for 20 minutes. TEA (32 mL, 0.23 mol)was added thereto, and the mixture was stirred at -78°C for 1 hour and addtionally stirred at room temperature for 1hour. After addition of water, the reaction solution was extracted with DCM. The organic layer was dried with MgSO4and purified by column chromatography to obtain the title compound (7.92 g, 89 percent).1H-NMR (CDCl3) δ 3.77 (4H, m), 2.59 (2H, t), 1.48 (9H, s)
71%
With pyridinium chlorochromate In dichloromethane at 20℃;
N-Boc-3-pyrrolidinol (17.192 g, 0.092 mole) in 50 mL anhydrous methylene chloride was added to a solution of (60 g, 0.276 mole) of pyridinechlorochromate in 300 mL anhydrous methylene chloride which was surrounded by a water bath at room temperature. After stirring at room temperature for 4 hours an additional (60 g, 0.276 mole) of pyridinechlorochromate was added and the reaction was stirred over night. The reaction had gone to completion by the next morning and was diluted with 400 mL diethyl ether and filtered through a pad of celite 521 filter aid using excess diethyl ether to wash through. Evaporation gave a black oil which was flash chromatographed over silica gel eluting with 40percent ethyl acetate in hexane to provide the title compound (12.5 g, 71percent) as an oil. Mass Spec FD+MI=184.9, (MW=185) 1H NMR (300 MHz CDCl3) δ 1.49 (9H, s); 2.56-2.61 (2H, t); 3.75-3.80 (4H, t).
58%
With pyridine-SO3 complex; triethylamine In dimethyl sulfoxide at 20℃;
a) 3-Oxo-pyrrolidine-l-carboxylic acid tert-butyl ester In a 1 1 three-necked flask, 10 g of N-Boc-3- hydroxypyrrolidine are dissolved in 350 ml of dimethyl sulphoxide in the presence of 52.3 ml of triethylamine . 28 g of pyridine-sulphur trioxide complex dissolved in 350 ml of dimethyl sulphoxide are added dropwise to the above solution. The reaction mixture is stirred for 4 hours at ambient temperature. The reaction medium is acidified to pH 4.5-5 with a IM solution of hydrochloric acid and the reaction mixture is then extracted with ethyl acetate. The organic phases are combined and then dried over anhydrous sodium sulphate. The residue is filtered through silica gel (1/1 heptane/ethyl acetate) . 5.7 g of 3-oxo-pyrrolidine-l- carboxylic acid tert-butyl ester are obtained. Yield: 58percent.
51%
With pyridinium chlorochromate In dichloromethane at 20℃; for 16 h;
Pyridinium chlorochromate (481 mmol) was added to a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (160 mmol) in dichloromethane (800 mL) and the reaction mixture was maintained at rt for 16 h. The insoluble solids were removed by filtration and the filtrate was concentrated. The residue was purified by Flash chromatography (20/1 to 10/1 petroleum ether/ethyl acetate) to provide tert-butyl 3-oxopyrrolidine-1-carboxylate in 51percent yield as light yellow oil.
Reference：
[1] Patent: US2005/277633, 2005, A1, . Location in patent: Page/Page column 20
[2] Patent: US2004/186134, 2004, A1, . Location in patent: Page 241
[3] Patent: WO2010/5783, 2010, A1, . Location in patent: Page/Page column 151
[4] Patent: US2016/96837, 2016, A1, . Location in patent: Paragraph 0139; 0140
[5] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0266
[6] Patent: US2014/66635, 2014, A1, . Location in patent: Paragraph 0033
[7] Patent: US6353008, 2002, B1, . Location in patent: Page column 36
[8] Synthetic Communications, 1985, vol. 15, # 7, p. 587 - 598
[9] Patent: WO2010/63774, 2010, A1, . Location in patent: Page/Page column 23-24
[10] Patent: US2010/29629, 2010, A1, . Location in patent: Page/Page column 66
[11] Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 10, p. 3902 - 3911
[12] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 20, p. 2691 - 2696
[13] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 7, p. 1645 - 1649
[14] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 9, p. 2115 - 2137
[15] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 2, p. 1022 - 1033
[16] Patent: WO2005/21515, 2005, A2, . Location in patent: Page/Page column 75
[17] Patent: US2005/209249, 2005, A1, . Location in patent: Page/Page column 38
[18] Patent: US2005/215603, 2005, A1, . Location in patent: Page/Page column 39
6
[ 83220-73-9 ]
[ 101385-93-7 ]
Yield
Reaction Conditions
Operation in experiment
77.3%
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 0.2 h; Inert atmosphere
To a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (Intermediate 8-step 1, 4.5 g, 24.1 mmol) in DCM (60 ml) under N2atmosphere, was added DMP (20.45 g, 48.12 mmol) at 0 °C. The reaction mixture was allowed to room temperature and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1 : 1 mixture of saturated NaHC03and saturated Na2S203solution. The reaction mixture was extracted with DCM (2x100 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Purification by column chromatography with EtOAc and hexane (15:85) to afford the desired compound (3.44 g, yield: 77.3percent) as an oil. 1H NMR (300 MHz, CDC13): δ 3.80-3.75 (m, 4H), 2.61-2.56 (m, 2H), 1.48 (s, 9H)
77.3%
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 2 h; Inert atmosphere
To a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (4.5 g, 24.1 mmol) in DCM (60 ml) under N2 atmosphere, was added DMP (20.45 g, 48.12 mmol) at 0° C. The reaction mixture was allowed to room temperature and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1:1 mixture of saturated NaHCO3 and saturated Na2S2O3 solution. The reaction mixture was extracted with DCM (2*100 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Purification by column chromatography with EtOAc and hexane (15:85) to afford the desired compound (3.44 g, yield: 77.3percent) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.80-3.75 (m, 4H), 2.61-2.56 (m, 2H), 1.48 (s, 9H).
34%
With pyridine-SO3 complex; triethylamine In dimethyl sulfoxide at 20℃;
1) N-tert-Butoxycarbonyl-3-pyrrolidinone Pyridine-sulfur trioxide (4.12 g) was added to a solution of (3R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (2.47 g) and triethylamine (9.19 mL) in dimethylsulfoxide (30 mL) at room temperature, and the resultant mixture was stirred overnight. The reaction solution was poured onto water and extracted with diethyl ether. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain N-tert-butoxycarbonyl-3-pyrrolidinone (855 mg, 34percent) as an oily product. 1H-NMR (400MHz, CDCl3)δ: 1.47(9H, d, J=9.3Hz), 2.59(2H, t, J=7.8Hz), 3.75-3.80(4H, t, J=7.9Hz).
Reference：
[1] Patent: WO2017/17630, 2017, A1, . Location in patent: Page/Page column 56
[2] Patent: US2018/237472, 2018, A1, . Location in patent: Paragraph 0166; 0167
[3] Patent: EP1785418, 2007, A1, . Location in patent: Page/Page column 61-62
[4] Organic Process Research and Development, 2017, vol. 21, # 9, p. 1419 - 1422
[5] Patent: EP1550660, 2005, A1, . Location in patent: Page/Page column 9
7
[ 101469-92-5 ]
[ 101385-93-7 ]
Yield
Reaction Conditions
Operation in experiment
81%
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 48 h;
b) tert-Butyl 3-oxopyrroIidine-l-carboxylate; To a solution of step a) product (10 g, 0.053 mol) in dry CH2Cl2 (200 mL) was added Dess-Martin periodinane (45.3 g, 0.106 mol) at 0 °C under nitrogen arm and stirred at RT for 2 days. To the reaction mixture was added sodium thiosulphate solution and filtered The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 10OmL). The combined organic layers were washed with 10 percent NaHCO3 solution and brine, dried over Na2SO4 and concentrated. The crude product was purified by column EPO <DP n="30"/>chromatography using 30 percent EtOAc in pet. ether. Yield = 8.0 g (81 percent). The product was used directly in step c).
With 2,6-di-tert-butyl-4-methyl-phenol In water; dimethyl sulfoxide; toluene for 6 h;
Ethyl N-Boc pyrrolidonecarboxylate (20.0 g) (compound of formula (II) wherein R is Et) was dissolved in toluene (30 ml) and dimethylsulfoxide Mixture and 20 mg of 3,5-di-tert-butyl-4-hydroxytoluene (BHT) was added.The resulting mixture was heated to 115 ° C (internal temperature) and water (4.2 ml, 3.0 eq) was added dropwise over 5 h maintaining the internal temperature at 110-115 ° C.The desired conversion was achieved 1 hour after the water addition was completed.The reaction mixture was cooled to 20 ° C and diluted with water (10 ml).The layers were separated and the aqueous layer re-extracted with toluene (20 ml).The combined organic layers were washed with 20 ml of 5percent w / w aqueous NaCl and then with 10percent w / w NaCl (40 ml) and finally with 20 ml of water.The resulting toluene solution was treated with activated carbon.After filtration, the filtrate was concentrated to dryness to give an orange oil (14 g).Cyclohexane (12 ml) was added at -5 / -10 ° C and the resulting suspension was filtered and washed twice with 3.5 ml of cyclohexane.The solid was dried under vacuum in a 25 ° C oven to give 10.8 g of a white solidbody.The molar yield after separation was 75percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
[2] Patent: CN103992258, 2017, B, . Location in patent: Paragraph 0015; 0043; 0052-0061; 0064
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 48, p. 15274 - 15278[2] Angew. Chem., 2017, vol. 129, p. 15476 - 15480,5
17
[ 58632-95-4 ]
[ 101385-93-7 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 10, p. 3902 - 3911
18
[ 146256-97-5 ]
[ 101385-93-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
19
[ 124-63-0 ]
[ 101385-93-7 ]
[ 141699-57-2 ]
Yield
Reaction Conditions
Operation in experiment
63.5%
With triethylamine In dichloromethane at 0℃; for 3.5 h;
ter^-Butyl 3-[(methyIsulfonyl)oxy]pyrrolidine-l-carboxylate; 5 tert-Butyl 3-hydroxypyrrolidine-l-carboxylate (3.0Og, 16.02mmol) was dissolved in dry DCM (5OmL) and cooled in an ice-water bath. Methanesulfonyl chloride (2.38g, 20.83mmol) was added followed by TEA (2.43g, 24.03mmol) and the reaction mixture was stirred at 0°C for 3.5h. The reaction mixture was washed with water (25OmL) and dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system 10 (40+M column, isocratic run heptane/EtOAc (50:50)) affording the title compund (2.7Og, 63.5percent). 1H NMR (500MHz, CDCl3): 6 1.38 (s, 9H), 2.07 (bs, IH), 2.18 (bs, IH), 2.97 (s, 3H), 3.35-3.61 (m, 4H), 5.16-5.18 (m, IH); 13C NMR (125MHz, CDCl3): δ 28.59, 31.84, 32.76, 38.80, 43.61, 52.16, 80.12, 154.30.
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: at 0 - 20℃; for 3 h;
1.0 M THF solution of potassium tert-butoxide (2.97 mL, 2.97 mmol) was added to the suspension of methyltriphenylphosphonium bromide (1.11 g, 2.97 mmol) in THF (20 mL) at 0 °C and warmed up to rt for 1 hr. The reaction mixture was cooled back to 0°C and a solution of tert-butyl 3 -oxopyrrolidine- 1 -carboxylate (220 mg, 1.19 mmol) in THF (2 ml) was added. The resulting reaction mixture was warmed to rt over a period of 3 hrs., quenched with saturated NH4C1 (10 ml) and concentrated under reduced pressure. The reaction mixture is extracted with ethyl acetate (100 ml), washed with water, brine, dried (MgSO4), concentrated and the residue was purified by flash silica gel chromatography using a mixture of 15percent ethyl acetate in hexane to provide tert-butyl 3- methylenepyrrolidine-1-carboxylate (110 mg, 0.600 mmol, 51percent yield). ‘H-NMR (400 MHz, CD3OD) ö ppm 5.00 (m, 2H), 3.91 (br. s., 2H), 3.44 (t, J=7.4 Hz, 2H), 2.58 (t, J=6.7 Hz, 2H), 1.46 (s, 9H).
50%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at 0℃; for 0.0833333 h; Stage #2: at 0 - 20℃; for 2.5 h;
Step A: 3-Methylene pyrrolidine-1 -carboxylic acid te/f-butyl ester. To a suspension consisting of methyl triphenylphosphonium bromide (18 g, 51 mmol) and THF (200 ml_) at 0 0C was added n-butyl lithium (1.6 M solution in hexanes, 32 ml_). The resulting orange solution was stirred at 0 °C for 5 min, then a solution of 3-oxo-pyrrolidine-1 -carboxylic acid te/t-butyl ester (9.0 g, 48 mmol) in THF (40 ml_) was added via cannula. The reaction mixture was stirred at 0 °C for 90 min, then warmed to rt and stirring was continued for 1 h. The reaction mixture was then cooled to 0 °C, quenched with sat. NH4CI, and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated. The crude residue was suspended in hot hexanes and filtered. The filtrate was concentrated and purified (FCC) to give the title compound (4.4 g, 50percent).
36%
With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 2 h; Inert atmosphere
To a solution of PPh3CH3Br (578 g, 1.62 mol) in THF (3.5 L) is added a solution of n-BuLi (600 mL, 1.5 mol) at −78° C. under N2. The mixture is stirred at 0° C. for 1 h then R-2 (200 g, 1.08 mol) in THF (2.0 L) is added to the reaction mixture at 0° C. The mixture is allowed to warm to ambient temperature, stirred for 1 h, then poured into H2O and extracted with EtOAc. The organic layers are washed with brine, dried with Na2SO4, concentrated and purified by flash chromatography (SiO2, Hep to 25percent EtOAc in Hep) to give compound R-3 (70 g, 36percent).
36%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 1 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere
[0130] To a solution of PPh3CH3Br (578 g, 1.62 mol) inTHF (3.5 L) is added a solution ofn-Buli (600 mL, 1.5 mol)at -78° C. under N2 . The mixture is stirred at oo C. for 1 h then the solution ofR-2 (200 g, 1.08 mol) in THF (2.0 L) is addedto the reaction mixture at oo C. The mixture is allowed towarm to ambient temperature, stirred for 1 h, then poured intoH20 and extracted with EtOAc. The organic layers arewashed with brine, dried with Na2S04 , concentrated andpurified by flash chromatography (Si02 , Hep to 25percent EtOAcin Hep) to give compound 1-4 (70 g, 36percent ).
36%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 0℃; for 1 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere
To a solution of PPh3CH3Br (578 g, 1.62 mol) in THF (3.5 L) is added a solution of n- BuLi (600 mL, 1.5 mol) at -78°C under N2. The mixture is stirred at 0°C for 1 h then R-2 (200 g, 1.08 mol) in THF (2.0 L) is added to the reaction mixture at 0°C. The mixture is allowed to warm to ambient temperature, stirred for 1 h, then poured into H20 and extracted with EtOAc. The organic layers are washed with brine, dried with Na2S04, concentrated and purified by flash chromatography (Si02, Hep to 25 EtOAc in Hep) to give compound R-3 (70 g, 36percent).
33%
With potassium <i>tert</i>-butylate In tetrahydrofuran; diethyl ether at 20℃; Inert atmosphere
General procedure: To a stirred suspension of methyltriphenylphosphonium bromide (1.5 equiv.) in diethylether(25-45 mL) under argon was added dropwisea solution of potassium-tert-butoxide 1M in THF (1.5 equiv.). The reaction mixture was immediately turned to yellow. After refluxing for 1 hour, the corresponding ketone (1.0 equiv.) was added in portions. The mixture was stirred at room temperature overnight. After completion, the reaction mixture was then hydrolyzed by water (5-8mL). The organic phase was separated and aqueous phase was extracted by diethyl ether (2 x 10mL). The combined organic phases were washed with water (20mLx2), brine (20mLx1), dried over anhydrous MgSO4 and concentrated under reduced pressure to yield crude product. Purification of this crude product by a suitable method afforded the corresponding alkene.
Stage #1: With sodium hydride In tetrahydrofuran at 5 - 10℃; for 1 h; Inert atmosphere Stage #2: at 5 - 20℃; for 12 h; Inert atmosphere
General procedure: Synthesis of substituted alkenes (2) (Scheme I, Step a) [0211] To a suspension of methyl triphenyl phosphonium iodide (50 mmol) in anhydrous THF (100 ml) sodium hydride (75 mmol) was added gradually in the inert atmosphere at 5°C. The reaction mixture was stirred for 1 h at 10°C. After that a solution of corresponding carbonyl compound 1 (45 mmol) in anhydrous THF (20 ml) was added to the reaction mixture at 5°C. The resulting reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, resulting mixture was poured into the water (150 ml) and extracted with dichloromethane (2x70 ml). Organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel. The yields are specified in Table 2
Reference：
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 6, p. 807 - 812
27
[ 4637-24-5 ]
[ 101385-93-7 ]
[ 157327-42-9 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 105℃; for 1 h;
[00377] Step 1: Synthesis of tert-butyl 3-((dimethylamino)methylene)-4- oxopyrrolidine– 1-carboxylate. A suspension of tert-butyl 3-oxopyrrolidine-1-carboxylate (10 g, 54.05 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (120 mL) was stirred at 105°C for 1 h., cooled down to room temperature, the solvent was removed in vacuo and the residue was purified by chromatographic column on silicagel (DCM/MeOH = 60/1 to 20/1) to give tert-butyl 3-((di-methyl- amino)methylene)-4-oxopyrrolidine-1-carboxylate (10.78 g, 83percent yield). ESI-LCMS (m/z): 241.2[M+1]+;1HNMR (400 MHz, CDCl3) δ ppm: 7.26 (s, 1H), 4.57 (s, 2H), 3.86 (s, 2H), 3.09 (s, 6H), 1.48 (s, 9H).
46%
at 100℃; for 17 h;
Preparation 31 3-Dimethylaminomethylene-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours. The dioxane was removed in vacuo. The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered. The solid was rinsed with hexanes (2*80 mL) and air dried. Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46percent).
46%
at 100℃; for 17 h;
Preparation 31 3-Dimethylaminomethylene-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours. The dioxane was removed in vacuo. The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered. The solid was rinsed with hexanes (2*80 mL) and air dried. Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46percent).
41 g
at 105℃; for 0.666667 h;
The 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (40g, 216mmol) was dissolved in 300ml DMF-DMA was heated at 105 deg. C 40 minutes. The solution was cooled and evaporated under reduced pressure, hexane was added, and filtered to give an orange solid 41g, and dried, it was used for the next reaction without purification.
41 g
at 105℃; for 0.666667 h;
(0086) 3-oxopyrrolidine-1-tert-butyl carboxylate (40g, 216mmol) was dissolved in 300mL DMF-DMA, heated for 40 minutes at 105°C. Cooled and concentrated to dry under vacuum, treated with hexane, filtered to obtain orange solid 41g, dried, the product can be used in the reaction of the next step without purification.
4.7 g
at 100℃; for 1.5 h;
A solution of N-Boc-3-pyrrolidinone (CAS Number 101385-93-7; 5.0 g, 27.0 mmol) in DMF- DMA (32.17 g, 270 mmol) was heated at 100°C for 1.5 h. The resulting mixture was cooled to rt and concentrated under reduced pressure. The obtained residue was triturated with n-pentane (100 ml). The resulting solid was dried under high vacuum yielding tert-butyl 3-((dimethylamino)methylene)-4- oxopyrrolidine-l-carboxylate (4.700 g, 19.58 mmol). LCMS: Method 1, 1.556 min, MS: ES+ 241.43.
Reference：
[1] Patent: WO2016/44641, 2016, A2, . Location in patent: Paragraph 00377
[2] Heterocycles, 2002, vol. 56, # 1-2, p. 257 - 264
[3] Patent: US2013/237538, 2013, A1, . Location in patent: Paragraph 0308
[4] Patent: US2013/237537, 2013, A1, . Location in patent: Paragraph 0292-0293
[5] Patent: WO2007/97931, 2007, A2, . Location in patent: Page/Page column 32
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 19, p. 5361 - 5366
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 24, p. 5767 - 5771
[8] Patent: CN105622612, 2016, A, . Location in patent: Paragraph 0126; 0127
[9] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10498 - 10519
[10] Patent: EP3144310, 2017, A1, . Location in patent: Paragraph 0085-0086
[11] Patent: WO2017/158381, 2017, A1, . Location in patent: Page/Page column 73
[12] Patent: US9951069, 2018, B1, . Location in patent: Page/Page column 14-15
28
[ 68-12-2 ]
[ 101385-93-7 ]
[ 157327-42-9 ]
Yield
Reaction Conditions
Operation in experiment
81.5%
With N,N-dimethyl acetamide In tetrahydrofuran for 3 h; Reflux; Heating; Large scale
Step (1) 70kg of tetrahydrofuran was added to the 200L reaction vessel, was added 1-tert-butoxycarbonyl-3-pyrrolidinone 6.9kg, then added with DMF-DMA 13.5kg, stirred and heated to reflux for 3 hours, TLC sheet monitoring point, after the reaction, was cooled to room temperature. Concentrated under reduced pressure, and dried to give a reddish brown solid 7.3kg, a yield of 81.5percent; was used directly in the next step.
Reference：
[1] Patent: CN105348286, 2016, A, . Location in patent: Paragraph 0049
[2] Patent: CN106543187, 2017, A, . Location in patent: Paragraph 0167-0169
29
[ 101385-93-7 ]
[ 74-89-5 ]
[ 454712-26-6 ]
Yield
Reaction Conditions
Operation in experiment
92.5%
Stage #1: at 0 - 20℃; for 2 h; Stage #2: at 20℃; for 1 h;
To a solution of 1-(ferf-butyloxycarbonyl)pyrrolidin-3-one (74 g, 0.4 mol) in MeOH (450 mL) was added an alcohol solution of MeNH2 (137.8 g, 1.2 mol) at O0C, and the resulting mixture was stirred at room temperature for 2 h. Then, NaBH4 (15.2 g, 0.4 mol) was added, and this mixture was stirred at room temperature for another 1 h, then concentrated under reduced pressure to give the residue. This residue was partitioned between CH2CI2 (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SO4), and evaporated to afforded 1-(ferf- butyloxycarbonyl)-3-methylaminopyrrolidine (74 g, 92.5percent), which was used in the next step without purification: 1H NMR (400 MHz, CDCI3) δ ppm 3.54 (m, 4 H), 3.29 (m, 2 H), 2.45 (s, 3 H), 2.20 (m, 1 H), 1.38 (s, 9 H).
52%
With 5%-palladium/activated carbon; hydrogen In methanol at 60℃;
The mixture of 1 7a (5 g, 27.0 mmol), 30percent of methyl amine in methanol (50 mE) and 5percent Pd/C (500 mg) in methanol (50 mE) was heated at 60° C. under H2 (50 psi) overnight, then cooled and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel colunm chromatography (methanol:dichloromethane=1 :40) to provide 17b (2.8 g, 52percent yield). ‘H-NMR (CDC13, 400 MHz):ö=9.99 (s, 1H), 3.79-3.83 (m, 1H), 3.61-3.72 (m, 3H), 3.40 (d, 1H), 2.71 (s, 3H), 2.33-2.36 (m, 2H), 1.75 (s, 9H), EC-MS:201 [M+1]
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 3.5 h;
Part A: Tert-butyl 3-(trifluoromethylsulfonyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (370 mg, 2.0 mmol) in THF (15 ml) at -78° C. was added lithium bis(trimethylsilyl)amide (1M in THF, 2.2 ml, 2.2 mmol) and the reaction solution was stirred for 1 h. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (864 mg, 2.2 mmol) in THF (20 ml) was added drop wise. The reaction mixture was stirred for another 0.5 h and allowed to warm to room temperature over 3 h and quenched with saturated sodium bicarbonate. The reaction mixture was diluted with ethyl acetate and washed with 15percent potassium hydrogen sulfate, saturated sodium bicarbonate solution, 1 N sodium hydroxide, water and brine. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Flash chromatography (silica gel, 10percent ethyl acetate/hexane) gave the product as a colorless oil (214 mg, 34percent yield)
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -75℃; for 0.5 h; Stage #2: at -75 - 0℃;
To a solution of the product from Step A (5.0 g, 27 mmol) in tetrahydrofuran (50 mL) at -75 °C is added a IM solution of sodium hexamethyldisilazane in tetrahydrofuran (50 mL) and the resulting mixture is stirred for 30 minutes. A solution of N-phenyl-bis- trifluoromethansulfonimide (10.7 g, 30.0 mmol) in tetrahydrofuran (100 mL) is then added slowly to the reaction. The mixture is warmed to 0 °C and stirred for 2 hours. Ice-water (100 mL) is added to the reaction mixture and the mixture is diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic phase is dried over Νa2SO4, filtered, and the solvent is removed in vacuo. The crude material is purified via neutral alumina chromatography using 10percent ethyl acetate/petroleum ether as the eluent to afford the desired product as an oil (4.0 g, 62percent). MS: 318.38 (M+Η+).
60%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.25 h; Inert atmosphere Stage #2: at -78 - 30℃; for 4 h; Inert atmosphere
Under nitrogen at -78 , tert-butyl 3-keto-1-carboxylate pyrrolidinone (5.0g, 27mmol) in tetrahydrofuran (50mL) was slowly added dropwise LiHMDS (30mL, 30mmol, 1M in THF) of in tetrahydrofuran (100mL) solution.After addition, the mixture was stirred at this temperature for fifteen minutes, the 1,1,1-trifluoro-phenyl -N- -N - ((trifluoromethyl) sulfonyl) methanesulfonamide (11.35g, 30mmol) in tetrahydrofuran (100mL) was added to the reaction mixture, maintaining the reaction mixture was stirred at -78 3 hours, then raised to 30 for 1 hour. The reaction was washed with sodium bicarbonate solution (10percent, 500mL) was quenched with ethyl acetate ( . 100mL × 2) was extracted and the combined organic phases were washed with brine (100mL × 2) washing the organic phase was dried over anhydrous sodium sulfate, and concentrated to give the crude product by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100/1 to 10/1) to give tert-butyl 3 - (((trifluoromethyl) sulfonyl) oxy) -2,5-dihydro-1H - pyrrol-1-carbonate (5.1g, 60percent yield ) as a yellow liquid.
59.8%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere; Cooling with acetone-dry ice Stage #2: at 0℃; for 2 h;
To an oven dried flask under N2 was added tert-butyl 3-oxopyrrolidine-1-carboxylate (20.0 g, 0.11 mol, 1.0 eq) and THF (200 mL). The solution was cooled in acetone ice bath (-78 ° C.). To that was added LiHMDs (125 mL, 0.12 mol, 1.15 eq) (1 M solution in THF). The reaction mixture was stirred at - 78 °C for 30 mm then added dropwise a solution of 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (46.3 g, 0.13 mol, 1.2 eq) in THF (200 mL). The reaction mixture was stirred for 30 mm then warmed to 0 °C and stirred for 1.5 h. The reaction mixture was quenched with satd. sodium bicarbonate solution and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (PE/EA=30/1, v/v) to provide tert-butyl 3- (((trifluoromethyl)sulfonyl)oxy)-2,5 -dihydro- 1H-pyrrole- 1 -carboxylate (20.5 g, 59.8percent).
55.5%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.25 h; Inert atmosphere Stage #2: at -78 - 0℃; for 2 h;
Step 1. tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate To an oven dried flask under N2 was added tert-butyl 3-oxopyrrolidine-1-carboxylate (2 g, 10.8 mmol) and THF (16 mL). The solution was cooled in acetone ice bath (-78° C.). To that was added lithium bis(trimethylsilyl)amide (12.96 mL, 12.96 mmol) (1 M solution in THF). The reaction mixture was stirred at -78° C. for 15 min then added dropwise a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methanesulfonamide (4.05 g, 11.34 mmol) in THF (16 mL). The reaction mixture was stirred for 30 min then warmed to 0° C. and stirred for 1.5 h. The reaction mixture was quenched with satd. sodium bicarbonate solution and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by ISCO column (0-30percent EtOAc/heptane) providing tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.9 g, 55.5percent).
53%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.25 h; Stage #2: at -78 - 20℃;
Step 1 In a 100 mL three-necked flask, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.24 mmol, Eq: 1.00) in THF (30.0 ml) was treated with lithium bis(trimethylsilyl)amide 1M in THF (5.6 ml, 5.6 mmol, Eq: 1.07) at -78° C. After stirring for 15 min at -78° C., a solution of N-phenylbis(trifluoromethanesulfonimide) (2.27 g, 6.28 mmol, Eq: 1.20) in THF (10 ml) was added by drop. The reaction mixture was then warmed to room temperature. The reaction was quenched with the addition of saturated aqueous NaHCO3, and then extracted with ethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0percent to 30percent EtOAc/Hex gradient) to give 3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (880 mg, 53percent).
49%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h; Stage #2: at -78 - 20℃;
To a solution of tert-butyl 3-oxopyrrolidine-l-carboxylate 1 (5.0 g, 27.0 mmol) in tetrahydrofuran (130 mL) in a three-necked flask was added lithium diisopropylamide (2.0M, 16.2 mL, 32.4 mmol) at -78 °C. After stirring for 2 h at -78 °C, a solution of trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (10.1 g, 28.4 mmol) in tetrahydrofuran (20 mL) was added, and the solution was stirred for another 30 min at this temperature, then warmed to room temperature and stirred for 3 h. Water (30 mL) was added to quench the reaction, and the solution was extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether to afford the title compound as a brown oil (4.2 g, 49percent).MS (ESI): m/z = 318.1 [M + H]+.
48%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78℃; for 4 h;
1-N-Boc-3-pyrrolidinone (1000 mg, 5.40 mmol) was dissolved in THF (10 mL) and chilled to-78°C. 1M LHMDS in THF (9.99 mmol, 9.99 mL) was added slowly (within approx. 10-15 mm). The reaction mixture was stirred for 30 mm. Next 1,1,1-Trifluoro-N-phenyl-N- (trifluoromethyl)sulfonylmethanesulfonamide (2141 mg, 5.99 mmol in THF (20 mL) was added slowly (30 mm). The reaction mixture was stirred for an additional 30 mm at -78 O The acetone bath was replaced with an ice-water bath and the reaction was stirred for anadditional 3h. After quenching the reaction by addition of ice cold water (20 mL), the reaction mixture was transfered to a separatory funnel. EtOAc (100 mL) was added and the organic layer was separated. The water layer was extracted with EtOAc (2 x 30 mL). The organic layer was dried (anh. MgSO4) and evaporated under reduced pressure. The oily residue was dissolved in cyclohexane and injected onto an equilibrated neutral A1203column (5percent EtOAc in cyclohexane). The product was eluted with EtOAc-cyclohexane gradient (5-15percent EtOAc in cyclohexane) and the product containing fraction were concentrated in vacuo to yield the target compound as a yellowish oil (830 mg, 48 percent). LCMS (Method A): RT = 1.81 mi mlz = 262 [M+H-56].1H NMR (500 MHz, CDCI3) O 5.81-5.64 (m, 1H), 4.38-4.14 (m, 4H), 1.48 (5, 9H).
35%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.833333 h; Stage #2: for 3 h;
To a solution of lithium diisopropylamide (2M in heptane/THF/ethylbenzene, 6.5 mL, 12.96 mmol) in THF (30 mL) at -78° C. was added a solution of N-Boc-3-pyrrolidinone (2 g, 10.8 mmol) in THF (30 mL) over 10 min. After 40 min, a solution of N-phenylbis(trifluoromethanesulfinimide) (4.24 g, 11.88 mmol) in THF (30 mL) was added. After 3 hours, the mixture was quenched with saturated aqueous solution of NaHCO3 and diluted with ethyl ether (250 mL). The aqueous phase was discarded and the organic phase was washed with 5percent citric acid (2.x.50 mL), 10percent aq NaOH (2.x.50 mL), water (50 mL), and brine (50 mL). The organic phase was dried (Na2SO4), filtered and concentrated. The crude product was absorbed on silica gel followed by column chromatography [n-hex/EtOAc (15:1 v/v) followed by n-hex/EtOAc (9:1 v/v)]gave 3-trifluoromethanesulfonyloxy-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (1.2 g, 35percent) as an oil. 1H NMR (d6-DMSO, 300 MHz) δ1.42 (s, 9H), 4.06-4.26 (m, 4H), 6.02-6.18 (m, 1H); MS (ESI) m/z=262 (MH+-tBu).
34.8%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -60℃; for 0.25 h; Stage #2: at 20℃; for 0.25 h;
1M LHMDS in toluene (30.9 mL, 30.9 mmol) was added to a stirred solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5.2 g, 28.1 mmol) in THF (75 mL) at -60 °C, stirred for 15 mm, then added a solution of N,N-bis(trifluoromethylsulfonyl)aniline (11.03 g, 30.9 mmol) in THF (25 mL). The mixture was allowed to come to roomtemperature and stirred for 15 minutes. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase was dried (MgSO4) and concentrated to afford crude product. The crude product was subjected to ISCO flash chromatography (silica gel/hexane-DCM 100:0 to 0:100 gradient) to afford tert-butyl 3 -(((trifluoromethyl)sulfonyl)oxy)-2,5 -dihydro- 1 H-pyrrole1-carboxylate (3.1 g, 34.8percent yield). ‘H NMR (400MHz, chloroform-d) ö 5.96-5.60 (m,1H), 4.44-4.05 (m, 4H), 1.48 (s, 9H).
Stage #1: With sodium hydrogen sulfate In diethyl ether; water at 0℃; for 0.25 h; Stage #2: at 20℃;
To a solution of 3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (6 g, 32.4 mmol) in H2O/ether (85 mL/60 mL) was added sodium bisulphate (5.06 g, 48.6 mmol) at 0°C, stirred for 15 min and potassium cyanide (3.16 g, 48.6 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water 4 times. The orgnic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by flash column chromatography (DCM/MeOH::0-3percent) to provide the titled compound (52percent, 3.6 g). LCMS: 13.0(M+H), Rt. 3.2 min, 99.2percent (max).
With potassium cyanide; 18-crown-6 ether In dichloromethane at 0 - 20℃; for 16 h;
Intermediate: tert-butyl 3-cyano-3-hydroxypyrrolidine-1-carboxylate To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.40 mmol) in DCM (10 mL) was added trimethylsilyl cyanide (0.724 mL, 5.40 mmol), KCN (0.035 g, 0.540 mmol) and 18-CROWN-6 (0.143 g, 0.540 mmol) at 0° C. The reaction mixture was warmed to rt and stirred at rt for 16 h. The reaction mixture was cooled to 0° C., and quenched with sat. NaHCO3, then diluted with EtOAc. The organic phase was separated, washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel chromatography (0-100percent EtOAc/hex) to yield tert-butyl 3-cyano-3-((trimethylsilyl)oxy)pyrrolidine-1-carboxylate (0.5 g, 1.758 mmol, 32.6percent yield) and tert-butyl 3-cyano-3-hydroxypyrrolidine-1-carboxylate (0.306 g, 1.442 mmol, 26.7percent yield). tert-butyl 3-cyano-3-((trimethylsilyl)oxy)pyrrolidine-1-carboxylate: LC/MS (Cond. N-1): [M+H]+ 213.2, RT=4.359 min. 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 3.83-3.72 (m, 1H), 3.72-3.43 (m, 3H), 2.33 (q, J=6.8 Hz, 2H), 1.52-1.42 (m, 9H), 0.19-0.10 (m, 9H).
With sodium hydrogencarbonate In diethyl ether; water at 0 - 20℃; for 24 h;
To a stirred solution of N-Boc-3-pyrrolidinone (CAS Number 101385-93-7; 4.0 g, 21.6 mmol) in diethyl ether (50 ml) and water (8 ml) was added NaHC03(3.6 g, 43 mmol) in water (5 ml) at 0°C. NaCN (3.17 g, 64.8 mmol) was added to the reaction mixture at 0°C. The reaction mixture was stirred at rt for 24 h. The resulting reaction mixture was poured into water (500 ml) and extracted with diethyl ether (2 x 300 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure yielding tert-butyl 3-cyano-3-hydroxypyrrolidine-l-carboxylate (4.21 g, 19.9 mmol). This material was used directly for the next step without further purification.1HNMR (400 MHz, DMSO-d6) δ ppm: 6.90 (s, 1 H), 3.48 - 3.63 (m, 2 H), 3.36 - 3.44 (m, 1 H), 3.20 - 3.32 (m, 1 H), 2.27 - 2.33 (m, 1 H), 2.13 - 2.20 (m, 1 H), 1.42 (s, 9 H).
To an ice-cold solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.0 g, 5.40 mmol) in Et2O (20 mL) was added methylmagnesium bromide (3.50 mL, 10.80 mmol.) drop wise under an inert atmosphere. The mixture was stirred at RT for 1 h, then quenched with NH4Cl solution followed by extraction with EtOAc (3*100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration with n-pentane gave i (1.0 g, 92percent). 3-Methylpyrrolidin-3-ol hydrochloride (Precursor 52): To a solution of 4M HCl in 1,4-dioxane (10 mL) at 0° C. was added i (0.850 g, 4.22 mmol) and the mixture stirred for 2 h at RT.
83.8%
Stage #1: With lithium chloride; zinc(II) chloride In tetrahydrofuran; diethyl ether at -10℃; for 1 h; Stage #2: for 0.5 h;
(2) Preparation of tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate To a 30 L reaction kettle was added 4 L dry THF at -10° C. After stirring, to the mixture were added ZnCl2 (118 g, 0.86 mol) and LiCl (402 g, 9.5 mol). After half an hour, to the resulting mixture was slowly added a solution of MeMgBr (3 mol/L) in diethyl ether (6.4 L, 19.2 mol) dropwisely. The stirring was continued for half an hour. To the resulting mixture was slowly added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1600 g, 8.6 mol) in THF dropwisely. After the completion of reaction by HPLC detection, to the system was dropwisely added a saturated NH4Cl solution to quench off the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate as a pale yellow solid (1450 g) in a yield of 83.8percent.
83.8%
With lithium chloride; zinc(II) chloride In tetrahydrofuran; diethyl ether
(2) Preparation of tert-butyl 3-hydroxy-3-methylpyrrolidine -1-carboxylate To a 30 L reaction kettle was added 4 L dry THF at -10°C. After stirring, to the mixture were added ZnCl2 (118g, 0.86mol) and LiCl (402g, 9.5mol). After half an hour, to the resulting mixture was slowly added a solution of MeMgBr (3mol/L) in diethyl ether (6.4 L, 19.2mol) dropwisely. The stirring was continued for half an hour. To the resulting mixture was slowly added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1600g, 8.6mol) in THF dropwisely. After the completion of reaction by HPLC detection, to the system was dropwisely added a saturated NH4Cl solution to quench off the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate as a pale yellow solid (1450 g) in a yield of 83.8 percent.
83.8%
With lithium chloride; zinc(II) chloride In tetrahydrofuran; diethyl ether at -10℃; for 0.5 h;
(2) Preparation of tert-butyl 3-hydroxy-3-methylpyrrolidine -1-carboxylate To a 30 L reaction kettle was added 4 L dry THF at -10°C. After stirring, to the mixture were added ZnCl2 (118g, 0.86mol) and LiCl (402g, 9.5mol). After half an hour, to the resulting mixture was slowly added dropwisely a solution of MeMgBr (3mol/L) in diethyl ether (6.4 L, 19.2mol). The stirring was continued for half an hour. To the resulting mixture was slowly added a solution of tert-butyl 3-oxopyrrolidine -1-carboxylate (1600g, 8.6mol) in THF dropwisely. After the completion of reaction by HPLC detection, to the system was dropwisely added a saturated NH4Cl solution to quench off the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate as a pale-yellow solid (1450g) in a yield of 83.8 percent.
70%
at -78℃; for 4 h;
The solution of (0.070 g, 0.38 mmol) tert-butyl 3-oxopyrrolidine-l- carboxylate in anhydrous THF (2 mL) was cooled to -78°C. Then the solution of 1 M methylmagnesium bromide in butyl ether was added dropwise. The reaction was stirred at - 78°C for 4 h and quenched by water (2 mL). After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted once more with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica flash chromatography (gradient elution, using 1 : 1 hexane-ethyl acetate and ethyl acetate) to provide the title compound (0.054 g, 70percent).
69%
at 0 - 20℃; for 1 h;
EXAMPLE 310 Synthesis of rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-/\/-(thiazol-4-yl)benzenesulfonamide Step 1. Preparation of rac-te/f-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate To a cooled (0 °C) solution of te/f-butyl 3-oxopyrrolidine-1-carboxylate (0.975 g, 5.26 mmol) in anhydrous diethyl ether (20 mL)) was added a 3 M solution of methylmagnesium bromide in diethyl ether (3.50 mL, 10.53 mmol). The reaction was allowed to warm to ambient temperature, stirred for 1 hour, and then cooled to 0 °C and quenched by addition of saturated aqueous ammonium chloride (15 mL). The aqueous layer was separated and extracted with ethyl acetate (3 χ 100 mL). The combined organic phases were washed with brine (50 mL), dried with magnesium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0-40percent of ethyl acetate in hexanes, provided the title compound as a yellowish oil (0.735 g, 69percent yield) H NMR (300 MHz, CDCIs) 3.54-3.44 (m, 2H), 3.42-3.33 (m, 1 H), 3.28-3.20 (m, 1 H), 1.93-1.79 (m, 2H), 1.60-1.56 (m, 1 H), 1.46 (s, 9H), 1.42 (s, 3H); MS (ES+) m/z 202.3 (M + 1).
105 mg
at 0 - 20℃; for 1 h;
3.0 M ether solution of methylmagnesium bromide (540 .il, 1.62 mmol) wasadded to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (100 mg, 0.540 mmol) in THF (2 ml) at 0 °C and warmed up to rt for 1 hr., quenched with saturated NH4C1 (2 ml), extracted with ethyl acetate (60 ml), washed with water, brine, dried (MgSO4) andconcentrated under reduced pressure to provide tert-butyl 3 -hydroxy-3 -methylpyrrolidine1-carboxylate (105 mg) which was used as such for the next step without purification. ‘H NMR (400MHz, CDC13) ö ppm 3.60 - 3.18 (m, 4H), 1.97 - 1.80 (m, 2H), 1.56 - 1.38 (m, 12H).
Reference：
[1] Patent: US2013/252938, 2013, A1, . Location in patent: Paragraph 0514
[2] Patent: US2014/45896, 2014, A1, . Location in patent: Paragraph 0134; 0135; 0199; 0200
[3] Patent: EP2703398, 2014, A1, . Location in patent: Paragraph 0119; 0120
[4] Patent: EP2703398, 2014, A1, . Location in patent: Paragraph 0173; 0174
[5] Journal of the American Chemical Society, 2015, vol. 137, # 35, p. 11270 - 11273
[6] Patent: WO2008/24725, 2008, A1, . Location in patent: Page/Page column 123
[7] Patent: WO2017/201468, 2017, A1, . Location in patent: Page/Page column 420-421
[8] Patent: WO2015/35278, 2015, A1, . Location in patent: Page/Page column 87
44
[ 101385-93-7 ]
[ 74-88-4 ]
[ 412278-02-5 ]
Yield
Reaction Conditions
Operation in experiment
64%
With iodine; magnesium In diethyl ether at 0 - 20℃; for 1.5 h; Inert atmosphere
To a stirred suspension of magnesium (2.59 g, 106 mmol, 1.97 equiv) in 50 mL of dry ether were added iodine (catalytic) and methyl iodide (6.7 mL, 108 mmol, 2 equiv) slowly drop wise at 0°C under argon atmosphere. This was added to a solution of tert-butyl 3- oxopyrrolidine-1-carboxylate (10 g, 54 mmol, 1 equiv) in 50 mL of ether at 0°C. The reaction mixture was warmed to room temperature and stirred for 1.5 h. After completion, the reactionwas quenched with saturated ammonium chloride solution at 0 °C and extracted with EtOAc. The combined organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel column chromatography (20percent EtOAc hexanes) afforded 7.0 g of tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate (Yield = 64percent).
48%
Stage #1: With magnesium In diethyl ether Stage #2: at 0 - 20℃; for 1.5 h; Stage #3: With water; ammonium chloride In diethyl ether at 0℃;
c) tert-Bntyl S-hydroxy-S-methylpyrrolidine-l-carboxylate; Methyl magnesium iodide [prepared from magnesium metal (1.73 g, 0.071 mol) and methyl iodide (4.7 mL, 0.074 mol) in dry ether (50 mL)] was slowly added to the solution of step b) product (6.6 g, 0.036 mol) in dry ether (150 mL) at 0 0C under nitrogen atm. The reaction mixture was slowly warmed to RT and stirred for 1.5 h and after cooling to 0 0C, it was quenched with saturated NH4Cl solution. The two layers were separated and the aqueous layer was extracted with ethyl acetate (3xl00mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 40 percent EtOAc in pet. ether. Yield =3.4 g (48 percent). The product was used directly in step d).
Stage #1: at -20℃; for 3 h; Stage #2: With hydrogenchloride In 1,4-dioxane
(1) Preparation of 3-methylpyrrolidin-3-ol hydrochloride A solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (11.17g, 0.06mol) in THF (45mL) was slowly added to a solution of MeMgI (21.41g, 0.129mol) in diethyl ether. The reaction was conducted at -20°C under stirring for 3 hours. A small amount of water was added to the reaction solution. The resulting reaction solution was filtered by suction. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to produce a crude product of tert-butyl 3-hydroxy-3-methyl-pyrrolidine-1-carboxylate. The above crude product was dissolved in 20mL 1,4-dioxane. To the resulting solution was introduced an HCl gas. The resulting mixute was stirred overnight and filtered by suction to produce the title product as a red solid (1.67g) in a yield of 20percent (two steps).
With 18-crown-6 ether In dichloromethane at 0 - 20℃;
To a solution of 3-oxo-pyrrolidine-1 -carboxylic acid tert-butyl ester 1W (10 g, 52.3 mmol) in CH2CI2 (150 ml) at 0 0C was added trimethylsilyl cyanide (8.5ml, 63.6 mmol), potassium cyanide (0.34 g, 5.23 mmol) and 18-crown-6 (1.38 g, 5.23 mmol). The reaction mixture was brought to room temperature and stirred overnight. The <n="442"/>reacton mixture was cooled to 0 °C and quenched with saturated NaHCO3 (200 ml).The organic layer was separated, dried over Na2SO4, filtered and concentrated. The . -residue wa^DJjriSed on silica, αel elutinα with 1/8 EtOAc/hexane to αive the desired product 2W (2 g, 81percent).
With potassium cyanide; 18-crown-6 ether In dichloromethane at 0 - 20℃; for 16 h;
Intermediate: tert-butyl 3-cyano-3-hydroxypyrrolidine-1-carboxylate To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.40 mmol) in DCM (10 mL) was added trimethylsilyl cyanide (0.724 mL, 5.40 mmol), KCN (0.035 g, 0.540 mmol) and 18-CROWN-6 (0.143 g, 0.540 mmol) at 0° C. The reaction mixture was warmed to rt and stirred at rt for 16 h. The reaction mixture was cooled to 0° C., and quenched with sat. NaHCO3, then diluted with EtOAc. The organic phase was separated, washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel chromatography (0-100percent EtOAc/hex) to yield tert-butyl 3-cyano-3-((trimethylsilyl)oxy)pyrrolidine-1-carboxylate (0.5 g, 1.758 mmol, 32.6percent yield) and tert-butyl 3-cyano-3-hydroxypyrrolidine-1-carboxylate (0.306 g, 1.442 mmol, 26.7percent yield). tert-butyl 3-cyano-3-((trimethylsilyl)oxy)pyrrolidine-1-carboxylate: LC/MS (Cond. N-1): [M+H]+ 213.2, RT=4.359 min. 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 3.83-3.72 (m, 1H), 3.72-3.43 (m, 3H), 2.33 (q, J=6.8 Hz, 2H), 1.52-1.42 (m, 9H), 0.19-0.10 (m, 9H).
With 2,6-di-tert-butyl-4-methyl-phenol; In water; dimethyl sulfoxide; toluene; for 6h;
Ethyl N-Boc pyrrolidonecarboxylate (20.0 g) (compound of formula (II) wherein R is Et) was dissolved in toluene (30 ml) and dimethylsulfoxide Mixture and 20 mg of 3,5-di-tert-butyl-4-hydroxytoluene (BHT) was added.The resulting mixture was heated to 115 ° C (internal temperature) and water (4.2 ml, 3.0 eq) was added dropwise over 5 h maintaining the internal temperature at 110-115 ° C.The desired conversion was achieved 1 hour after the water addition was completed.The reaction mixture was cooled to 20 ° C and diluted with water (10 ml).The layers were separated and the aqueous layer re-extracted with toluene (20 ml).The combined organic layers were washed with 20 ml of 5percent w / w aqueous NaCl and then with 10percent w / w NaCl (40 ml) and finally with 20 ml of water.The resulting toluene solution was treated with activated carbon.After filtration, the filtrate was concentrated to dryness to give an orange oil (14 g).Cyclohexane (12 ml) was added at -5 / -10 ° C and the resulting suspension was filtered and washed twice with 3.5 ml of cyclohexane.The solid was dried under vacuum in a 25 ° C oven to give 10.8 g of a white solidbody.The molar yield after separation was 75percent.
With recombinant Chryseobacterium sp. CA 49 ketoreductase; nicotinamide adenine dinucleotide; In aq. phosphate buffer; isopropyl alcohol; at 40℃; for 10h;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.
Stage #1: isoquinolin-5-ylamine; 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid In tetrahydrofuran at 32℃; for 0.166667 - 0.5h;
Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20 - 32℃; for 6h;
1
Preparation of tert-butyl 3-(isoquinolin-5-ylamino)pyrrolidine-l- carboxylate (Scheme 5, Step 1)A 5L flask (Flask A) equipped with a mechanical stirrer, internal temperature probe and addition funnel was charged with 5-aminoisoquinoline (300 g, 2.08 mol) and 2.7 L of tetrahydrofuran. Trifluoroacetic acid (543 mL, 7.29 mol) was added slowly while maintaining an internal temperature of <320C. l-Boc-3-pyrrolidinone (462.5 g, 2.50 mol) was added and the mixture was stirred for 10-30 minutes. A separate 12L flask (Flask B) equipped with an internal temperature probe, mechanical stirrer and nitrogen inlet was flushed with nitrogen and charged with sodium triacetoxyborohydride (662.5 g, 3.13 mol) and 1.5 L of tetrahydrofuran. The contents of Flask A were slowly transferred to Flask B while maintaining an internal temperature in Flask B of < 320C. The reaction was stirred at 20-320C for 6 hours and all 5-aminoisoquinoline was consumed. The reaction was quenched with 3L of 5N NaOH maintaining a temperature of < 450C. After 20 minutes, the aqueous layer was separated. The organic phase was washed with 3L of 2N NaOH at 4O0C (with external heating). The organic phase was diluted with isopropyl acetate (2.25 L), washed with 1.5 L of water at 4O0C (with external heating), and concentrated to ~2 L by distillation. The resulting solution was cooled to ~20°C. The resulting slurry was filtered, washed (3 x 200 mL of MTBE), and dried in a vacuum oven at ~ 6O0C. Approximately 536 g of tert- Butyl 3-(isoquinolin-5-ylamino)pyrrolidine-l-carboxylate was isolated as a solid (82% yield).1H NMR (DMSO-d6, 300 MHz, 6O0C) δ 9.12 (d, IH. J = 0.9 Hz), 8.40 (d, IH, J = 6.0 Hz), 8.10 (dt, IH, J = 0.9 Hz), 7.45 (t, IH, J = 7.9 Hz), 7.30 (dt, IH, J - 0.9 Hz), 6.79 (m, IH), 6.15 (d, IH, J - 6.0 Hz), 4.19 (m, IH), 3.69 (dd, IH, J = 10.9, 6.4 Hz), 3.30 (m, IH, J - 10.9, 4.7 Hz), 3.49 (m, IH), 3.38 (m, IH), 2.25 (m, IH), 2.00 (m, IH), 1.41 (s, 9H);13C NMR (DMSO-d6, 75 MHz, 6O0C) δ 151.78, 141.05, 114.79, 125.56, 142.10, 107.15, 127.86, 114.59, 128.91, 51.77, 50.57, 43.88, 30.10, 153.38, 77.96, 27.94.
65%
With sodium tris(acetoxy)borohydride; acetic acid; sodium sulfate at 20℃;
With sodium tris(acetoxy)borohydride; acetic acid at 0 - 20℃;
To a homogenous solution of isoquinolin-5-amine (15g, 104 mmol) and tert-butyl 3-oxopyrrolidine- 1 -carboxylate (23.12g, 125 mmol, 1 .2 eq) in AcOH (300 mL) at 0°C was added dropwise a solution of NaBH(OAc)3 (44.1 g, 208 mmol, 2eq) in AcOH (200 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Then, the residue was adjusted to pH 10 by addition of saturated aqueous solution of Na2C03 and extracted with DCM (x3). The combined organic layers were dried over Na2S04, filtered and then concentrated in vacuo to afford the expected compound, which was used directly in the next step without further purification.
With sodium tris(acetoxy)borohydride; acetic acid at 0 - 20℃;
B.B.1 Intermediate 6: 3-[3-(Isoquinolin-5-ylamino)-pyrrolidin-1-ylmethyl]-benzoic acid
To a homogenous solution of isoquinolin-5-amine (15 g, 104 mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (23.12 g, 125 mmol, 1.2 eq) in AcOH (300 mL) at 0° C. was added dropwise a solution of NaBH(OAc)3 (44.1 g, 208 mmol, 2 eq) in AcOH (200 mL). The mixture was stirred at room temperature overnight and concentrated to dryness. Then, the residue was adjusted to pH 10 by addition of saturated aqueous solution of Na2CO3 and extracted with DCM (*3). The combined organic layers were dried over Na2SO4, filtered and then concentrated in vacuo to afford the expected compound, which was used directly in the next step without further purification.
Stage #1: isoquinolin-5-ylamine; 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium sulfate In acetic acid at 20℃; for 0.5h;
Stage #2: With sodium tris(acetoxy)borohydride In acetic acid at 0 - 20℃; for 18h;
Stage #3: With sodium hydrogencarbonate In water
1
(R)-pyrrolidinol (Tokyo Chemical Industry Co., Ltd., 12.4 g, 100 mmol) was dissolved in 100 ml of a 3 N aqueous solution of sodium hydroxide. A solution (50 ml) of di-tert-butyl dicarbonate (Tokyo Chemical Industry Co., Ltd., 25.0 g, 120 mmol) in tetrahydrofuran was added dropwise thereto at 0°C. The pH value of the mixture was determined with a pH test paper and was found to be 11. The mixture was then stirred at room temperature for 2 hr and was then concentrated to remove a major part of tetrahydrofuran. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product and triethylamine (20 ml) were dissolved in anhydrous dimethylsulfoxide (100 ml), and a trituated sulfur trioxide/trimethylamine complex (Aldrich, 28.0 g, 200 mmol) was added little by little thereto at room temperature. The mixture was stirred at room temperature for 18 hr. Water (200 ml) was then added to the reaction solution to stop the reaction. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product was loaded on a silica gel column and developed with chloroform, followed by development with chloroform only to give an intermediate (11.25 g). The intermediate (3.70 g, 20 mmol) and 5-aminoisoquinoline (Aldrich, 2.48 g, 17 mmol) were dissolved in 100 ml of acetic acid. Sodium sulfate (14.2 g, 100 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0°C, sodium hydride triacetate (Aldrich, 4.44 g, 20 mmol) was added thereto little by little, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under the reduced pressure to remove a major part of acetic acid. The reaction mixture was then adjusted to pH = 8 by the addition of a saturated sodium hydrogencarbonate solution and was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product in methylene chloride was loaded on a silica gel column and developed with hexane. The development was first carried out with hexane only, subsequently with hexane/chloroform (1 : 1), and finally with chloroform only to collect a fraction having UV absorption with Rf = 0.6 to give the title compound (3.70 g, 12 mmol). 1H-NMR (CDCl3, 400 MHz): 1.46 (s, 9H), 1.75 - 1.94 (m, 1H), 2.02 - 2.10 (m, 1 H), 3.35 - 3.55 (m, 31 H), 3.75 - 3.86 (m, 1 H), 4.17 - 4.24 (m, 1 H), 4.705 - 4.90 (m, 1 H), 6.91 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 8.42 (d, J = 6.4 Hz, 1 H), 9.20 (s, 1 H). Mass spectrometric value (ESI-MS, m/z): 314 (M++1)
To a solution of 1-(ferf-butyloxycarbonyl)pyrrolidin-3-one (74 g, 0.4 mol) in MeOH (450 mL) was added an alcohol solution of MeNH2 (137.8 g, 1.2 mol) at O0C, and the resulting mixture was stirred at room temperature for 2 h. Then, NaBH4 (15.2 g, 0.4 mol) was added, and this mixture was stirred at room temperature for another 1 h, then concentrated under reduced pressure to give the residue. This residue was partitioned between CH2CI2 (3 X 500 mL) and water (300 mL). The combined organic layers were dried (Na2SO4), and evaporated to afforded 1-(ferf- butyloxycarbonyl)-3-methylaminopyrrolidine (74 g, 92.5%), which was used in the next step without purification: 1H NMR (400 MHz, CDCI3) delta ppm 3.54 (m, 4 H), 3.29 (m, 2 H), 2.45 (s, 3 H), 2.20 (m, 1 H), 1.38 (s, 9 H).
52%
With 5%-palladium/activated carbon; hydrogen; In methanol; at 60℃; under 2585.81 Torr;
The mixture of 1 7a (5 g, 27.0 mmol), 30% of methyl amine in methanol (50 mE) and 5% Pd/C (500 mg) in methanol (50 mE) was heated at 60 C. under H2 (50 psi) overnight, then cooled and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel colunm chromatography (methanol:dichloromethane=1 :40) to provide 17b (2.8 g, 52% yield). ?H-NMR (CDC13, 400 MHz):oe=9.99 (s, 1H), 3.79-3.83 (m, 1H), 3.61-3.72 (m, 3H), 3.40 (d, 1H), 2.71 (s, 3H), 2.33-2.36 (m, 2H), 1.75 (s, 9H), EC-MS:201 [M+1]
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20℃; for 16h;
Step 1: tert-butyl 3-(methylamino)pyrrolidine-l-carboxyIate (107)A mixture compound 37 (1 gm, 5.4 mmol) and methyl amine (4 mL, 2.0 M in tetrahydrofuran) in 1 ,2-dichloroethane was stirred for 5 min followed by addition of glacial /acetic acid (0.28 mL) followed by sodium triacetoxyborohydride (3.18 gm, 15 mmol). The reaction mixture was stirred 16 h at room temperature and quenched with 1 N sodium hydroxide and stirred for 10 min. The reaction mixture was extracted with ethyl acetate, concentrated, purified on silica gel column to afford the pure product (0.9 gm).
Example 24: [2-(lH-IndoI-4-ylV4-morpholin-4-yl-thienof3,2-dlpyrimidin-6-- yImethyll-(l-methanesulfonvI-pyrroIidin-3-yl)-methyl-amine; To a solution of l-N-BOC-3-pyrrolidinone (3.0 g) in methanol (30 ml) was added a solution of freshly prepared methylamine (0.75 g) in methanol (3.1 ml). The reaction mixture was stirred for 1 hour and then sodium borohydride (0.61 g) was added. After stirring for 4 hours the reaction mixture was then diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo to give S-methylamino-pyrrolidine-l-carboxylic acid tert- butyl ester (3.18 g).
In diethyl ether; at 20℃; for 1h;Inert atmosphere;
To an ice-cold solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.0 g, 5.40 mmol) in Et2O (20 mL) was added methylmagnesium bromide (3.50 mL, 10.80 mmol.) drop wise under an inert atmosphere. The mixture was stirred at RT for 1 h, then quenched with NH4Cl solution followed by extraction with EtOAc (3*100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Trituration with n-pentane gave i (1.0 g, 92%). 3-Methylpyrrolidin-3-ol hydrochloride (Precursor 52): To a solution of 4M HCl in 1,4-dioxane (10 mL) at 0 C. was added i (0.850 g, 4.22 mmol) and the mixture stirred for 2 h at RT.
83.8%
(2) Preparation of tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate To a 30 L reaction kettle was added 4 L dry THF at -10 C. After stirring, to the mixture were added ZnCl2 (118 g, 0.86 mol) and LiCl (402 g, 9.5 mol). After half an hour, to the resulting mixture was slowly added a solution of MeMgBr (3 mol/L) in diethyl ether (6.4 L, 19.2 mol) dropwisely. The stirring was continued for half an hour. To the resulting mixture was slowly added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1600 g, 8.6 mol) in THF dropwisely. After the completion of reaction by HPLC detection, to the system was dropwisely added a saturated NH4Cl solution to quench off the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate as a pale yellow solid (1450 g) in a yield of 83.8%.
83.8%
With lithium chloride; zinc(II) chloride; In tetrahydrofuran; diethyl ether;
(2) Preparation of tert-butyl 3-hydroxy-3-methylpyrrolidine -1-carboxylate To a 30 L reaction kettle was added 4 L dry THF at -10C. After stirring, to the mixture were added ZnCl2 (118g, 0.86mol) and LiCl (402g, 9.5mol). After half an hour, to the resulting mixture was slowly added a solution of MeMgBr (3mol/L) in diethyl ether (6.4 L, 19.2mol) dropwisely. The stirring was continued for half an hour. To the resulting mixture was slowly added a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1600g, 8.6mol) in THF dropwisely. After the completion of reaction by HPLC detection, to the system was dropwisely added a saturated NH4Cl solution to quench off the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate as a pale yellow solid (1450 g) in a yield of 83.8 %.
83.8%
With lithium chloride; zinc(II) chloride; In tetrahydrofuran; diethyl ether; at -10℃; for 0.5h;
(2) Preparation of tert-butyl 3-hydroxy-3-methylpyrrolidine -1-carboxylate To a 30 L reaction kettle was added 4 L dry THF at -10C. After stirring, to the mixture were added ZnCl2 (118g, 0.86mol) and LiCl (402g, 9.5mol). After half an hour, to the resulting mixture was slowly added dropwisely a solution of MeMgBr (3mol/L) in diethyl ether (6.4 L, 19.2mol). The stirring was continued for half an hour. To the resulting mixture was slowly added a solution of tert-butyl 3-oxopyrrolidine -1-carboxylate (1600g, 8.6mol) in THF dropwisely. After the completion of reaction by HPLC detection, to the system was dropwisely added a saturated NH4Cl solution to quench off the reaction. The reaction was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate as a pale-yellow solid (1450g) in a yield of 83.8 %.
70%
In tetrahydrofuran; dibutyl ether; at -78℃; for 4h;
The solution of (0.070 g, 0.38 mmol) tert-butyl 3-oxopyrrolidine-l- carboxylate in anhydrous THF (2 mL) was cooled to -78C. Then the solution of 1 M methylmagnesium bromide in butyl ether was added dropwise. The reaction was stirred at - 78C for 4 h and quenched by water (2 mL). After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted once more with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica flash chromatography (gradient elution, using 1 : 1 hexane-ethyl acetate and ethyl acetate) to provide the title compound (0.054 g, 70%).
69%
In diethyl ether; at 0 - 20℃; for 1h;
EXAMPLE 310 Synthesis of rac-4-((1-benzyl-3-methylpyrrolidin-3-yl)oxy)-5-chloro-2-fluoro-//-(thiazol-4-yl)benzenesulfonamide Step 1. Preparation of rac-te/f-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate To a cooled (0 C) solution of te/f-butyl 3-oxopyrrolidine-1-carboxylate (0.975 g, 5.26 mmol) in anhydrous diethyl ether (20 mL)) was added a 3 M solution of methylmagnesium bromide in diethyl ether (3.50 mL, 10.53 mmol). The reaction was allowed to warm to ambient temperature, stirred for 1 hour, and then cooled to 0 C and quenched by addition of saturated aqueous ammonium chloride (15 mL). The aqueous layer was separated and extracted with ethyl acetate (3 chi 100 mL). The combined organic phases were washed with brine (50 mL), dried with magnesium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0-40% of ethyl acetate in hexanes, provided the title compound as a yellowish oil (0.735 g, 69% yield) H NMR (300 MHz, CDCIs) 3.54-3.44 (m, 2H), 3.42-3.33 (m, 1 H), 3.28-3.20 (m, 1 H), 1.93-1.79 (m, 2H), 1.60-1.56 (m, 1 H), 1.46 (s, 9H), 1.42 (s, 3H); MS (ES+) m/z 202.3 (M + 1).
105 mg
In tetrahydrofuran; at 0 - 20℃; for 1h;
3.0 M ether solution of methylmagnesium bromide (540 .il, 1.62 mmol) wasadded to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (100 mg, 0.540 mmol) in THF (2 ml) at 0 C and warmed up to rt for 1 hr., quenched with saturated NH4C1 (2 ml), extracted with ethyl acetate (60 ml), washed with water, brine, dried (MgSO4) andconcentrated under reduced pressure to provide tert-butyl 3 -hydroxy-3 -methylpyrrolidine1-carboxylate (105 mg) which was used as such for the next step without purification. ?H NMR (400MHz, CDC13) oe ppm 3.60 - 3.18 (m, 4H), 1.97 - 1.80 (m, 2H), 1.56 - 1.38 (m, 12H).
At room temperature, N,N-dimethylformamide dimethylacetal (30 ml) was added to 1-(tert-butoxycarbonyl)-3-pyrrolidone (4.57 g) The resulting mixture was heated at 140C for 1 hour. After the reaction mixture was allowed to cool down to room temperature, it was concentrated under reduced pressure. Hexane was added to the residue and a yellow powder thus precipitated was collected by filtration. The powder was dissolved in ethanol (100 ml). Methylisothiourea sulfate (9.24 g) and sodium ethoxide (4.52 g) were added to the resulting solution at room temperature. The resulting mixture was heated under reflux for 24 hours. Saturated saline and diethyl ether were added to the reaction mixture to separate the layers. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (methanol:methylene chloride = 1:99) on a silica gel column, whereby the title compound (1.10 g) was obtained.1H-NMR (CDCl3) delta: 1.51(9H,s), 2.57(3H,m), 4.15-4.45(4H,m), 8.39(1/2H,s), 8.43(1/2H,s). MS (FAB) m/z: 268 (M+H)+.
With diethylamino-sulfur trifluoride; In benzene; at 0 - 20℃; for 72.0h;
2) 3, 3-Difluoropyrrolidine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, (diethylamino)sulfur trifluoride (1.45 mL) was added to a solution of N-tert-butoxycarbonyl-3-pyrrolidinone (846 mg) in benzene (30 mL) under ice cooling, and the resultant mixture was stirred for 3 days at room temperature. Diethyl ether was added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel thin layer chromatography (ethyl acetate-hexane), to obtain 3, 3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (669 mg, 71%) as an oily product. 1H-NMR(400MHz, CDCl3)δ: 1.45(9H, s), 2.26-2.36(2H, m), 3.57-3.65(4H, m).
54.7%
With diethylamino-sulfur trifluoride; In toluene; at 0 - 20℃; for 23.0h;
[0357] Part B: To a solution of part A compound (1.8 g, 9.7 mmol) in 2 mL of toluene was added a solution of (diethylamino)sulfur trifluoride (1.3 mL, 9.7 mmol) at 0 C. The mixture was stirred at 0 C. for 1 h and at room temperature for 22 h. The resulting mixture was then poured onto ice and extracted with ethyl acetate (3×). The organic layer was washed with saturated sodium bicarbonate aqueous solution, brine and dried over magnesium sulfate. The crude product was purified over silica gel to afford 1.1 g (54.7%) of 1,1-dimethylethyl 3,3-difluoropyrrolidine-1-carboxylate: 1H-NMR (CDCl3, δ) 3.62 (4H, m), 2.34 (2H, m), 1.48 (9H, s).
41.92%
With diethylamino-sulfur trifluoride; In dichloromethane; at 0℃; for 0.6h;Inert atmosphere;
To a stirred solution of tert-butyl 3-oxopyrrolidine-l-carboxylate (step 1, 3.44 g, 18.59 mmol) in DCM (40 ml) under N2atmosphere at 0 C, was added DAST (2.7 ml, 20.45 mmol) and stirred for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of ice cold water. The solution was extracted with DCM (2x100 mL) and the combined organic phases were washed with brine, dried over Na2S04and concentrated under reduced pressure to give the crude product. Purification by column chromatography with EtOAc and hexane (1 :9) to afford the desired compound (1.61 g, yield: 41.92%) as an oil. 1H MR (300 MHz, CDC13): δ 3.65-3.55 (m, 4H), 2.38-2.24 (m, 2H), 1.46 (s, 9H).
41.92%
With diethylamino-sulfur trifluoride; In dichloromethane; at 0℃; for 6.0h;Inert atmosphere;
To a stirred solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (step 1, 3.44 g, 18.59 mmol) in DCM (40 ml) under N2 atmosphere at 0 C., was added DAST (2.7 ml, 20.45 mmol) and stirred for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of ice cold water. The solution was extracted with DCM (2*100 mL) and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product. Purification by column chromatography with EtOAc and hexane (1:9) to afford the desired compound (1.61 g, yield: 41.92%) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.65-3.55 (m, 4H), 2.38-2.24 (m, 2H), 1.46 (s, 9H).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 0 - 20℃; for 11.0h;
To a solution of 3-OXO-PYRROLIDINE-1-CARBOXYLIC acid ter-butyl ester (1G) in CH2CI2 (10ML) is added [bis (2-methoxyethyl) amino] sulfer trifluoride (2mL) at 0C, and stirred for 11 HR at room temperature. The reaction mixture is poured in aqueous NaHC03 and extracted with Et20. The organic layer is successively washed with H20 and aqueous NACI, dried over MgS04, and concentrated in vacuo. The residue is purified by column chromatography to give a colorless oil. To a solution of the oil in ET20 (1 OmL) was added HCI in EtOAc (4N, 5mL) and stirred for 3hr at room temperature. The reaction mixture is concentrated in vacuo, and the residue is suspended in Et20. White precipitate in the Et20 is collected by filtration to to provide the title compound.
With diethylamino-sulfur trifluoride; In dichloromethane; at -50 - 20℃; for 16.0h;
A mixture of Example 70B (6.35 g, 34.29 mmol) in 100 mL of dichloromethane was cooled to -50 C. followed by the addition of (diethylamino)sulfur trifluoride (1.6 eq., 9.94 mL). The mixture was slowly allowed to come to room temperature and stirred for 16 hours. Saturated aqueous NaHCO3 solution was added slowly, and the mixture extracted with methylene chloride (3*25 mL). The combined organic extracts were dried (Na2SO4), filtered, concentrated and purified by flash chromatography (10% ethyl acetate/hexane) to provide the titled product. MS (CI) m/z+208 [M+H]+.
With diethylamino-sulfur trifluoride; In dichloromethane; at -50 - 20℃; for 16.0h;Product distribution / selectivity;
As shown in Scheme 13, compounds of formula 25 when treated under oxidative conditions of oxalyl chloride in DMSO followed by the addition of triethylamine will provide the ketone of formula 26. The ketone of formula 26 when treated with DAST ((diethylamino)sulfur trifluoride) in dichloromethane will provide difluoro compounds of formula 27. The Boc group of compounds of formula 27 may be removed using trifluoroacetic acid in dichloromethane to provide compounds of formula 28. ; Example 70C 3,3-Difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of Example 70B (6.35 g, 34.29 mmol) in 100 mL of dichloromethane was cooled to -50 C. followed by the addition of (diethylamino)sulfur trifluoride (1.6 eq., 9.94 mL). The mixture was slowly allowed to come to room temperature and stirred for 16 hours. Saturated aqueous NaHCO3 solution was added slowly, and the mixture extracted with methylene chloride (3*25 mL). The combined organic extracts were dried (Na2SO4), filtered, concentrated and purified by flash chromatography (10% ethyl acetate/hexane) to provide the titled product. MS (CI) m/z+208 [M+H]+.
With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 5.0h;
DAST (4.03 g, 67.6 mmol, 2.5 eq.) was added to a solution of tert-butyl 3- oxopyrrolidine-l-carboxylate (5 g, 27.0 mmol, 1.0 eq.) in dichloromethane (30 mL). The reaction was stirred for 5 hours at room temperature. The reaction mixture was poured into ice cold sat. NaHCCL solution (100 mL) and extracted with dichloromethane for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude Boc-3,3-difluoropyrrolidine (5.9 g, quantitative yield), which was then treated with 6 N HC1 in dioxane to give 3,3-difluoropyrrolidine hydrochloride (4.1 g, quantitative yield). LC-MS m/z [M+H]+ calc’d for C4H8CIF2N, 110; found, 110.
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere;
Step 1: To a solution of N-Boc-3-pyrrolidone (2.8 g, 15 mmol) in tetrahydrofuran (30 mL), (trifluoromethyl)trimethylsilane (2.6 mL)Tetrabutylammonium fluoride (528 mg, 1.7 mmol). The system was stirred to room temperature under nitrogen for 12 hours. Aqueous saturated ammonium chloride (24 mL) was added and stirred for 15 min. The organic phases were combined and washed with brine.Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.The residue was flash chromatographed (petroleum ether / ethyl acetate = 4/1)Purification afforded Nu-Boc-3-hydroxy-3-(trifluoromethyl)pyrrolidine (3.1 g, yield: 82%) as a white solid.
tert-Butyl 3-oxopyrrolidine-1-carboxylate (926 mg, 5.0 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0C, trimethyl (trifluoromethyl) silane (0.872 mL) and tetrabutylammonium fluoride (TBAF) (176 mg, 0.557 mmol) were added. The ice-bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated aqueous NH4CI solution (8 mL) was added and stirring was continued. After 15 min TBAF (2.36 g TBAF in 7.5 mL THF) was added and the reaction mixture was stirred at room temperature for 1h. The reaction mixture was extracted with ethyl acetate, washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum spirit) to give the subtitled compound (800 mg). 1H-NMR (CDCl3, 400 MHz): delta 3.78-3.38 (m, 4H); 2.25 (m, 1H) ; 2.00 (m, 1H) ; 1.40 (s, 9H).
With tetrabutyl ammonium fluoride; ammonium chloride; In tetrahydrofuran; at 20℃; for 1.5h;
A) Production of 3-(trifluoromethyl)pyrrolidin-3-ol A mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (600 mg), trimethyl(trifluoromethyl)silane (0.57 mL), 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (0.50 mL) and tetrahydrofuran (6 mL) was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution (2 mL) and 1M N,N,N-tributylbutane-1-aminium fluoride/tetrahydrofuran solution (1 mL) were added, and the reaction mixture was stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate, washed successively with water and brine, 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 a pale-brown solid. The obtained solid was dissolved in methanol (1 mL), and 4M hydrochloric acid/ethyl acetate solution (2 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hr, and the reaction system was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (1 mL) was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (260 mg) as a brown solid. 1H-NMR(CDCl3) delta 1.80-1.91(1H,m), 2.14-2.25(1H,m), 2.93-3.10(2H,m), 3.12-3.29(2H,m).
With Methylenetriphenylphosphorane; In tetrahydrofuran; toluene; at 0 - 20℃;
To methyl(triphenyl)phosphorane hydrobromide (1.43 g, 0.00400 mol) in toluene (12.0 mL) was added sodium hexamethyldisilazane in tetrahydrofuran (1.00 M, 4.00 mL). The mixture was stirred at rt for 2 h. The solution was added to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (0.74 g, 0.0040 mol) in toluene (10 mL) at 0 C. over a period of 5 min. The ice bath was removed and the mixture was allowed to warm up to room temperature (RT). The mixture was then stirred at RT for overnight. The reaction mixture was diluted with hexane (30 mL), and filtered through a pad of silica gel and washed with hexane to give tert-butyl 3-methylenepyrrolidine-1-carboxylate (650 mg, 88.6%).
With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 0.2h;Inert atmosphere;
To a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (Intermediate 8-step 1, 4.5 g, 24.1 mmol) in DCM (60 ml) under N2atmosphere, was added DMP (20.45 g, 48.12 mmol) at 0 C. The reaction mixture was allowed to room temperature and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1 : 1 mixture of saturated NaHC03and saturated Na2S203solution. The reaction mixture was extracted with DCM (2x100 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Purification by column chromatography with EtOAc and hexane (15:85) to afford the desired compound (3.44 g, yield: 77.3%) as an oil. 1H NMR (300 MHz, CDC13): δ 3.80-3.75 (m, 4H), 2.61-2.56 (m, 2H), 1.48 (s, 9H)
77.3%
With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
To a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (4.5 g, 24.1 mmol) in DCM (60 ml) under N2 atmosphere, was added DMP (20.45 g, 48.12 mmol) at 0 C. The reaction mixture was allowed to room temperature and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1:1 mixture of saturated NaHCO3 and saturated Na2S2O3 solution. The reaction mixture was extracted with DCM (2*100 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Purification by column chromatography with EtOAc and hexane (15:85) to afford the desired compound (3.44 g, yield: 77.3%) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.80-3.75 (m, 4H), 2.61-2.56 (m, 2H), 1.48 (s, 9H).
34%
With pyridine-SO3 complex; triethylamine; In dimethyl sulfoxide; at 20℃;
1) N-tert-Butoxycarbonyl-3-pyrrolidinone Pyridine-sulfur trioxide (4.12 g) was added to a solution of (3R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (2.47 g) and triethylamine (9.19 mL) in dimethylsulfoxide (30 mL) at room temperature, and the resultant mixture was stirred overnight. The reaction solution was poured onto water and extracted with diethyl ether. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain N-tert-butoxycarbonyl-3-pyrrolidinone (855 mg, 34%) as an oily product. 1H-NMR (400MHz, CDCl3)δ: 1.47(9H, d, J=9.3Hz), 2.59(2H, t, J=7.8Hz), 3.75-3.80(4H, t, J=7.9Hz).
With sulfur trioxide trimethylamine complex; triethylamine; In dimethyl sulfoxide; at 20℃; for 18h;
(R)-pyrrolidinol (Tokyo Chemical Industry Co., Ltd., 12.4 g, 100 mmol) was dissolved in 100 ml of a 3 N aqueous solution of sodium hydroxide. A solution (50 ml) of di-tert-butyl dicarbonate (Tokyo Chemical Industry Co., Ltd., 25.0 g, 120 mmol) in tetrahydrofuran was added dropwise thereto at 0C. The pH value of the mixture was determined with a pH test paper and was found to be 11. The mixture was then stirred at room temperature for 2 hr and was then concentrated to remove a major part of tetrahydrofuran. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product and triethylamine (20 ml) were dissolved in anhydrous dimethylsulfoxide (100 ml), and a trituated sulfur trioxide/trimethylamine complex (Aldrich, 28.0 g, 200 mmol) was added little by little thereto at room temperature. The mixture was stirred at room temperature for 18 hr. Water (200 ml) was then added to the reaction solution to stop the reaction. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product was loaded on a silica gel column and developed with chloroform, followed by development with chloroform only to give an intermediate (11.25 g). The intermediate (3.70 g, 20 mmol) and 5-aminoisoquinoline (Aldrich, 2.48 g, 17 mmol) were dissolved in 100 ml of acetic acid. Sodium sulfate (14.2 g, 100 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0C, sodium hydride triacetate (Aldrich, 4.44 g, 20 mmol) was added thereto little by little, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under the reduced pressure to remove a major part of acetic acid. The reaction mixture was then adjusted to pH = 8 by the addition of a saturated sodium hydrogencarbonate solution and was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product in methylene chloride was loaded on a silica gel column and developed with hexane. The development was first carried out with hexane only, subsequently with hexane/chloroform (1 : 1), and finally with chloroform only to collect a fraction having UV absorption with Rf = 0.6 to give the title compound (3.70 g, 12 mmol). 1H-NMR (CDCl3, 400 MHz): 1.46 (s, 9H), 1.75 - 1.94 (m, 1H), 2.02 - 2.10 (m, 1 H), 3.35 - 3.55 (m, 31 H), 3.75 - 3.86 (m, 1 H), 4.17 - 4.24 (m, 1 H), 4.705 - 4.90 (m, 1 H), 6.91 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 8.42 (d, J = 6.4 Hz, 1 H), 9.20 (s, 1 H). Mass spectrometric value (ESI-MS, m/z): 314 (M++1)
With ammonia; ammonium chloride; In methanol; at 20℃; for 6h;Heating / reflux;
To a mixture of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5.34 mmol), ammonium chloride (316 mg, 5.9 mmol) and sodium cyanide (289 mg, 5.9 mmol) was added 2 M NH3 in MOH (20 mL) and refluxed for 3 h and cooled to room temperature. Another 2M NH3 in MeOH (20 mL) was added and refluxed for 3 h again. The reaction mixture was cooled to room temperature and methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated to give 1.1 g in 1:1 mixture of the desired product and cyanohydrin. The crude mixture was used without further purification.
With triethylamine; In dichloromethane; at 0℃; for 3.5h;
ter^-Butyl 3-[(methyIsulfonyl)oxy]pyrrolidine-l-carboxylate; 5 tert-Butyl 3-hydroxypyrrolidine-l-carboxylate (3.0Og, 16.02mmol) was dissolved in dry DCM (5OmL) and cooled in an ice-water bath. Methanesulfonyl chloride (2.38g, 20.83mmol) was added followed by TEA (2.43g, 24.03mmol) and the reaction mixture was stirred at 0C for 3.5h. The reaction mixture was washed with water (25OmL) and dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system 10 (40+M column, isocratic run heptane/EtOAc (50:50)) affording the title compund (2.7Og, 63.5%). 1H NMR (500MHz, CDCl3): 6 1.38 (s, 9H), 2.07 (bs, IH), 2.18 (bs, IH), 2.97 (s, 3H), 3.35-3.61 (m, 4H), 5.16-5.18 (m, IH); 13C NMR (125MHz, CDCl3): delta 28.59, 31.84, 32.76, 38.80, 43.61, 52.16, 80.12, 154.30.
With hydrogenchloride; In ethyl acetate; for 8.5h;
To 3-oxo-pyrrolidine-1 -carboxylic acid tert- butyl ester (4.05 g) in 20 ml. of trimethylorthoformate was added 40 ml_ of a 4 N solution of HCI in methanol. The solution was stirred for 4.5 h, and the volume was reduced to ca 15 ml_ under vacuum. The solution was diluted with 60 ml_ of ethyl acetate and the mixture was stirred for 4 h. The resultant solids were collected via filtration to provide 2.97 g of the title compound as an off-white solid.
Step 1: (+-)-N-BOC-trans-3-fluoro-4(methylamnino)pyrrolidine 2-3 A cooled solution (-78 C.) of N-BOC-3-pyrrolidinone (1.0 g, 5.41 mmol) in THF (50 mL) was treated with a solution of NaHMDS (7.03 mL of a 1M soln in THF). After stirring for 30 min, the solution was treated with chlorotriethylsilane (1.18 mL, 7.03 mmol). The reaction was stirred for 1 hr at -78 C., warmed to 0 C., diluted with 1:1 brine/water and hexanes. The mixture was extracted with EtOAc. The organic solution was dried over Na2SO4, filtered, and concentrated. The residue was not further purified. A solution of the 3-fluoro-N-BOC-pyrrolidinone (0.31 g, 1.53 mmol) in dichloroethane (10 mL) was treated with methylarnine (1.53 mL of a 2M soln in THF) and Na(OAc)3BH (0.49 g, 2.3 mmol). After stirring for 12 h at room temperature, the reaction was diluted with EtOAc and washed with satd NaHCO3. The organic solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2; 80% CHCl3/10% MeOH/10% EtOAc) to provide racemic 2-3. Data for 2-3: 1H-NMR (500 MHz, CDCl3) delta 5.11 (br d, J=55 Hz, 1H), 3.85-3.62 (m, 2H), 3.51 (m, 1H), 3.20 (m, 1H), 3.03 (m, 1H), 2.50 (s, 3H), 1.46 (s, 9H) ppm.
With 18-crown-6 ether In dichloromethane at 0 - 20℃;
37.1
To a solution of 3-oxo-pyrrolidine-1 -carboxylic acid tert-butyl ester 1W (10 g, 52.3 mmol) in CH2CI2 (150 ml) at 0 0C was added trimethylsilyl cyanide (8.5ml, 63.6 mmol), potassium cyanide (0.34 g, 5.23 mmol) and 18-crown-6 (1.38 g, 5.23 mmol). The reaction mixture was brought to room temperature and stirred overnight. The reacton mixture was cooled to 0 °C and quenched with saturated NaHCO3 (200 ml).The organic layer was separated, dried over Na2SO4, filtered and concentrated. The . -residue wa^DJjriSed on silica, αel elutinα with 1/8 EtOAc/hexane to αive the desired product 2W (2 g, 81%).
EXAMPLE 329A tert-butyl 3-oxopyrrolidine-1-carboxylate The procedure described in Example 328A was followed, substituting 1-benzylpyrrolidin-3-one (Acros) for 1-benzylpiperidin-3-one to provide the title compound. MS (DCI/NH3) m/e 186 (M+H)+; 203 (M+NH4)+.
1-(t-butoxycarbonyl)-3-(7-benzo(b)furan)-3-hydroxypyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Scheme I, step C: A 500 mL round bottom flask is charged with anhydrous THF (150 mL), and <strong>[133720-60-2]7-bromobenzo(b)furan</strong> (13.0 g, 0.066 mol, prepared above in Scheme I, step B), and the solution is cooled to -78 C. n-Butyllithium (41.2 mL of a 1.6 M solution in THF, 0.066 mol) is added over 3 minutes followed by addition of 1-(t-butoxycarbonyl)-3-pyrrolidone (0.063 mol). The reaction mixture is then allowed to warm to room temperature over 18 hours with stirring. The reaction is then quenched with water (4 mL) and extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide a tan oil. The tan oil is then purified by flash chromatography (silica gel, 2 times) to provide the title compound
1-(t-butoxycarbonyl)-3-(4-fluoro-7-benzo(b)furan)-3-hydroxypyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Scheme I, step C: 4-Fluoro-7-bromo-benzo(b)furan (5.58 g, 26 mmol) is combined with magnesium (1.26 g, 52 mmol) in diethyl ether (100 mL) and the mixture is stirred for 30 minutes. Then 1,2-dibromoethane (0.5 mL) is added. After 15 minutes an additional amount of 1,2-dibromoethane (1.7 mL) is added over 2 hours. It is then heated to gentle reflux for one hour and then cooled to room temperature. 1-(t-Butoxycarbonyl)-3-pyrrolidone (23.6 mmol) dissolved in diethyl ether is then added to the reaction mixture and the reaction is stirred overnight. Then ethyl acetate (100 mL) and water (200 mL) are added followed by addition of 1N HCl until the layers separate. The layers are separated and the aqueous is extracted with ethyl acetate (2 times). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound.
The title compound was prepared in analogy to intermediate 9 by reaction of intermediate 8 with pyrolidinone hydrochloride (prepared by HCl in dioxane deprotection of Boc-pyrrolidinone) affording the product as a colourless oil. MS: 368.1 (MH+).
[Referential Example 47] tert-Butyl 2-(methylsulfanyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate: 1-tert-Butoxycarbonyl-3-pyrrolidone (4.57 g) was added to N,N-dimethylformamide dimethyl acetal (30 ml) at room temperature, and the mixture was heated for 1 hour at 140C. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure.. hexane was added to the residue, and yellow powder deposited was collected by filtration.. This powder was dissolved in ethanol (100 ml), and methylisothiourea sulfate (9.24 g) and sodium ethoxide (4.52 g) were added to the resultant solution at room temperature, and the mixture was heated under reflux for 24 hours.. Saturated aqueous solution of sodium chloride and diethyl ether were added to the reaction mixture to separate an organic layer.. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol: methylene chloride = 1:99) to obtain the title compound (1.10 g).1H-NMR (CDCl3) delta: 1.51(9H,s), 2.57(3H,m), 4.15-4.45(4H,m), 8.39(1/2H,s), 8.43(1/2H,s). MS (FAB) m/z: 268(M+H)+.
Intermediate (i); 2-Methyl-[l,3']bipyrrolidinyl-l'-carboxylic acid tert-butyl ester; <n="28"/>To a solution of N-BOC-3-pyrrolidinone (4.22 g, 22.9 mmol) and 2-methylpyrrolidine(1.95 g, 22.9 mmol) (HCl salt was made by addition of 22.9 mL of 1 M HCl in ether into theDCM solution of 2-methylpyrroline, then evaporated) in DCE (60 mL) was added powdered sodium triacetoxyborohydride slowly under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS - m/z 255 and 199 ([M+H]+ and [[M+H]-tBu]+).The reaction was quenched with aq. NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (20 mLx2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (5 mLx2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM and 7.5% MeOH in DCM to get the title compound as a liquid 5.50 g (yield: 94%). MS: 255 (M+H)+; TLC: 0.5 (10% MeOH in DCM).
94%
Intermediate (i); 2-Methyl-[l,3']bipyrrolidinyl-l'-carboxylic acid tert-butyl ester; To a solution of N-BOC-3-pyrrolidinone (4.22g, 22.9 mmol) and 2-methylpyrroline(1.95 g, 22.9 mmol) (HCl salt was made by addition of 22.9 mL of 1 M HCl in ether into the DCM solution of 2-methylpyrroline, then evaporated) in DCE (60 mL) was added powdered sodium triacetoxyborohydride slowly under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS - m/z 255 and 199 (base and M-tBu).The reaction was quenched with aq. NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (20 mLx2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (5 mLx2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM and 7.5% MeOH in DCM to get the title compound as a liquid 5.50 g (yield: 94%). MS: 255 (M+H+); TLC: 0.5 (10% MeOH in DCM).
94%
Intermediate (i); 2-Methyl-[l,3']bipyrrolidinyl-l'-carboxylic acid tert-butyl ester; To a solution of N-BOC-3-pyrrolidinone (4.22 g, 22.9 mmol) and 2-methylpyrrolidine(1.95 g, 22.9 mmol) (HCl salt was made by addition of 22.9 mL of 1 M HCl in ether into theDCM solution of 2-methylpyrroline, then evaporated) in DCE (60 mL) was added powdered sodium triacetoxyborohydride slowly under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS - m/z 255 and 199 ([M+H]+ and [[M+H]-tBu]+).The reaction was quenched with aq. NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (20 mLx2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (5 mLx2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM and 7.5% MeOH in DCM to get the title compound as a liquid 5.50 g (yield: 94%). MS: 255 (M+H)+; TLC: 0.5 (10% MeOH in DCM).
94%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃;Inert atmosphere;
Intermediate (i) 2-methyl-[1,3']bipyrrolidinyl-1'-carboxylic acid tert-butyl ester To a solution of N-BOC-3-pyrrolidinone (4.22g, 22.9 mmol) and 2-methylpyrroline (1.95 g, 22.9 mmol) (HCI salt was made by addition of 22.9 ml_ of 1 M HCI in ether into the DCM solution of 2-methylpyrroline, then evaporated) in DCE (60 ml_) was added powdered sodium triacetoxyborohydride slowly under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS - m/z 255 and 199 (base and M-tBu).The reaction was quenched with aq. NaHCO3 solution (100 ml_). The two layers were separated, and the aqueous layer was extracted with DCM (20 ml_ x 2). The combined DCM extracts were washed with sodium bicarbonate (10 ml_), and brine (5 ml_x2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM and 7.5% MeOH in DCM to get 5.50 g (yield: 94%) of the title compound as a liquid. MS: 255 (M+H+); TLC: 0.5 (10% MeOH in DCM).
With zinc(II) iodide In tetrahydrofuran at 20℃; for 24h;
N-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 9 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid.N-Boc-l-amino-but-3-ene3-Buten-l -amine (4.93 g, 0.069 mol) was submitted to Procedure 7 for Boc protection to yield a crude, which was purified by flash chromatography (silica gel/hexanes: ethyl acetate 0-30%) to yield N-Boc-l-amino-but-3-ene (6.47 g, 0.038 mol, 55.1 % yield).; Procedure 9: General Procedure for Synthesis of α-hydroxy carboxylic acidsStep No. 1. O-(Trimethylsilyl) cyanohydrines: A 50-mL flask equipped with a magnetic stirring bar and drying tube was charged with the ketone or aldehyde (0.010 mmol), followed by THF (50 mL), trimethylsilyl cyanide (1.39 g, 14 mmol), and zinc iodide (0.090 g, 0.28 mmol), and the reaction mixture was stirred at room temperature for 24 hr. Solvent evaporation gave a residue, which was dissolved in EtOAc (60 mL), washed with 5% aq. NaHCO3 (2 x 30 mL), H2O (30 mL), and brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness to yield a crude, which was carried through to the next step without further purification.
In tetrahydrofuran at 20℃; for 24h;
N-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 9 to yield the desired N-Boc-3 -hydroxy-pyrrolidine-3 -carboxylic acid.
With zinc(II) iodide In tetrahydrofuran at 20℃; for 24h;
34
Example 34 6'-(2-Hydroxy-ethyl)-l-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomicinN-Boc-S-hydroxypyrrolidine-S-carboxylic acidN-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 15 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid. Procedure 15: General Procedure for Synthesis of α-hydroxy carboxylic acidsStep No. 1. O-fTrimethylsilyl) cyanohydrines: A 50-mL flask equipped with a magnetic stirring bar and drying tube was charged with the ketone or aldehyde (0.010 mmol), followed by THF (50 mL), trimethylsilyl cyanide (1.39 g, 14 mmol), and zinc iodide (0.090 g, 0.28 mmol), and the reaction mixture was stirred at room temperature for 24 hr. Solvent evaporation gave a residue, which was dissolved in EtOAc (60 mL), washed with 5% aq. NaHCO3 (2 x 30 mL), H2O (30 mL), and brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness to yield a crude, which was carried through to the next step without further purification.
With zinc(II) iodide In tetrahydrofuran at 20℃; for 24h;
9.1
N-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 9 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid.; Procedure 9: General Procedure for Synthesis of α-hydroxy carboxylic acidsStep No. 1. O-(Trimethylsilyl) cyanohydrines: A 50-mL flask equipped with a magnetic stirring bar and drying tube was charged with the ketone or aldehyde (0.010 mmol), followed by THF (50 mL), trimethylsilyl cyanide (1.39 g, 14 mmol), and zinc iodide (0.090 g, 0.28 mmol), and the reaction mixture was stirred at room temperature for 24 hr. Solvent evaporation gave a residue, which was dissolved in EtOAc (60 mL), washed with 5% aq. NaHCO3 (2 x 30 mL), H2O (30 mL), and brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness to yield a crude, which was carried through to the next step without further purification.
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78 - 20℃; for 14.25h;
Example 16; (2,3-Dihydrobenzo[1,4]oxazin-4-yl)[3-(4-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl]methanone (Compound No. 159); 16.1: tert-Butyl 3-trifluoromethanesulfonyloxy-2,5-dihydropyrrole-1-carbamate; 27 ml of a 2.5N solution of n-butyllithium in hexane are added dropwise, in a 500 ml three-necked flask under nitrogen, to a solution of 9.86 ml of diisopropylamine in 40 ml of tetrahydrofuran cooled to -78 C. After stirring for ¼ of an hour, a solution of 10 g of tert-butyl 3-oxopyrrolidine-1-carbamate in 40 ml of tetrahydrofuran is added dropwise at -78 C. Finally, still at -78 C., 21.22 g of N-phenyltrifluoromethanesulfonimide are added. After stirring at ambient temperature for 14 hours, the tetrahydrofuran is evaporated and the product is purified on silica gel using a cyclohexane/ether 9/1 mixture as eluent. 10.2 g of tert-butyl 3-trifluoromethanesulfonyloxy-2,5-dihydropyrrole-1-carbamate are obtained as a 1/1 mixture with C,C,C-trifluoro-N-phenylmethanesulfonamide.(M-tbu)+H+=262
Stage #1: N-(t-butoxycarbonyl)-4-chloroaniline With tert.-butyl lithium In diethyl ether; pentane at -15℃; for 2h; Inert atmosphere;
Stage #2: With lanthanium (III) chloride bis(lithium chloride) complex In tetrahydrofuran; diethyl ether; pentane at -70℃; for 0.0833333h; Inert atmosphere;
Stage #3: 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester In tetrahydrofuran; diethyl ether; pentane at -70 - 25℃; for 1h; Inert atmosphere;
General procedure: Synthesis of substituted alkenes (2) (Scheme I, Step a) [0211] To a suspension of methyl triphenyl phosphonium iodide (50 mmol) in anhydrous THF (100 ml) sodium hydride (75 mmol) was added gradually in the inert atmosphere at 5C. The reaction mixture was stirred for 1 h at 10C. After that a solution of corresponding carbonyl compound 1 (45 mmol) in anhydrous THF (20 ml) was added to the reaction mixture at 5C. The resulting reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, resulting mixture was poured into the water (150 ml) and extracted with dichloromethane (2x70 ml). Organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel. The yields are specified in Table 2
The solution of a compound triphenylmethylphosphonium iodide (2.24 g, 0.0055 mole), potassium TERT-BUTOXIDE (517 mg, 0.0046 mole) in tetrahydrofuran (10 mL) was stirred AT-78C for 20 minutes and then at room temperature for 1 hour. To the resulting reaction mixture was added a solution OF 3-METHYLENE-PYRROLIDINE-1-CARBOXYLIC ACID TERT-BUTYL ester (340 mg, 0.0018 mol) in tetrahydrofuran (10 mL) at 0 C. The resulting reaction mixture was stirred at room temperature for 10 min. followed by diluting it with water. Tetrahydrofuran was evaporated under reduced pressure, extracted with ethyl acetate, washed with anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using ethylacetate in hexane (10: 90) solvent mixture as eluent. Yield: 170 MG.
tert-Butyl 3-(2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate: A mixture of <strong>[3080-99-7]3,4-dihydro-2H-benzo[b][1,4]thiazine</strong> (1.00 g, 6.61 mmol), N-boc-3-pyrrolidinone (1.34 g, 7.27 mmol), and acetic acid (0.94 mL, 16.52 mmol) in 1,2-dichloroethane (20 mL) was cooled to 0 C. and then treated with solid sodium triacetoxyborohydride (2.10 g, 9.92 mmol). The reaction was brought to room temperature and was stirred for 11 hours. Additional equivalents of each of sodium triacetoxyborohydride (1.40 g, 6.61 mmol) and N-boc-3-pyrrolidinone (1.22 g, 6.61 mmol) were added to the reaction mixture. The reaction was stirred for 2 more days and was then quenched with 3 N NaOH (50 mL). The mixture was transferred to a separatory funnel and extracted with EtOAc (2×50 mL). The organic phase was washed with brine (50 mL) and dried (Na2SO4). The crude material was subject to flash chromatography on silica gel (10% EtOAc/hexanes then 20% EtOAc/hexanes). The sample was subject to additional flash chromatography on silica gel (7.5-15% EtOAc/hexanes) to give viscous oil (0.41 g, 19%). 1H NMR (CDCl3) delta 7.08 (dd, J=0.9, 7.5 Hz, 1H), 7.04-6.99 (m, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.67-6.72 (m, 1H), 4.39-4.36 (m, 1H), 3.73-3.72 (m, 6H), 3.10-3.06 (m, 2H), 2.20-2.00 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 345, 343 (M+Na, 4), 322, 320 (MH+, 3), 267, 265 (100).
Intermediate (i) 2-Methyl-[1 ,3']bipyrrolidinyl-1 '-carboxylic acid tert-butyl esterTo a solution of N-BOC-3-pyrrolidinone (4.22g, 22.9 mmol) and 2- methylpyrroline (1.95 g, 22.9 mmol) (HCI salt was made by addition of 22.9 mL of 1 M HCI in ether into the DCM solution of 2-methylpyrroline, then evaporated) in DCE (60 ml_) was added powdered sodium triacetoxyborohydride slowly under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS - m/z 255 and 199 (base and M-tBu).The reaction was quenched with aq. NaHCO3 solution (100 ml_). The two layers were separated, and the aqueous layer was extracted with DCM (20 ml_ x 2). The combined DCM extracts were washed with sodium bicarbonate (10 ml_), and brine (5 ml_x2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM and 7.5percent MeOH in DCM to get 5.50 g (yield: 94percent) of the title compound as a liquid. MS: 255 (M+H+); TLC: 0.5 (10percent MeOH in DCM).
With n-hexyllithium; In diethyl ether; hexane; at -78 - 20℃;Inert atmosphere;
Preparation 10; TERT-BUTYL 3-(2,3-DIFLUOROPHENYL)-S-HYDROXYPYRROLIDINE-I - CARBOXYLATETo a solution of <strong>[38573-88-5]1-<strong>[38573-88-5]bromo-2,3-difluorobenzene</strong></strong> (8 g, 41.4 mmol) in dry diethyl ether (100 mL), under nitrogen, was added dropwise at -780C, n-hexyllithium (2.3 M in hexane, 18 ml, 41.4 mmol). The mixture was stirred for 1 min after which a solution of 1 -N-boc-3-pyrrolidone (7.66 g, 41.4 mmol) in dry diethyl ether (50 mL) was added dropwise. The resulting mixture was brought to ambient temperature and stirred for 2h, aqueous saturated ammonium chloride solution (50 ml) was added and the mixture was extracted with ethylacetate (2x50 ml). The combined organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography (ethylacetate/isooctane, 1 :9 to 1 :1 ) to give the title compound (8.12 g, 66percent). MS m/z (rel. intensity, 70 eV) 243 (26), 198 (48), 141 (33), 127 (38), 57 (bp).
66%
Preparation 10 TERT-BUTYL 3-(2,3-DIFLUOROPHENYL)-3-HYDROXYPYRROLIDINE-1 -CARBOXYLATETo a solution of <strong>[38573-88-5]1-<strong>[38573-88-5]bromo-2,3-difluorobenzene</strong></strong> (8 g, 41.4 mmol) in dry diethyl ether (100 mL), under nitrogen, was added dropwise at -78° C., n-hexyllithium (2.3 M in hexane, 18 ml, 41.4 mmol). The mixture was stirred for 1 min after which a solution of 1-N-boc-3-pyrrolidone (7.66 g, 41.4 mmol) in dry diethyl ether (50 mL) was added dropwise. The resulting mixture was brought to ambient temperature and stirred for 2h, aqueous saturated ammonium chloride solution (50 ml) was added and the mixture was extracted with ethylacetate (2x50 ml). The combined organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (8.12 g, 66percent). MS m/z (rel. intensity, 70 eV) 243 (26), 198 (48), 141 (33), 127 (38), 57 (bp).
MTBE (60 mL) was charged to a 3-neck round bottom flask followed by bromo-2,3- difluoro-benzene (12 mL, 107 mmol). The solution was cooled in ice/salt bath. When the internal temperature reached 40C addition of i-PrMgClLiCl solution in THF (1.3M, 90.7 mL, 118 mmol) was started. The higher internal temperature during addition was 2 °C(bath temperature was -8°C to -5°C); addition time 17 mm. After addition was complete the reaction mixture was stirred at -5°C to 0°C for one hour. Tert-Butyl 3-oxopyrrolidine-1 - carboxylate (21 .8 g, 118 mmol) solution in MTBE (200 mL) was added to the reaction mixture at -4°C to -2°C during 15 mm. under vigorous stirring. The reaction mixture was stirred at -2°C to 0°C for 3 hours and then quenched by addition of 20percent aqueousammonium chloride solution (260 mL). The internal temperature rose from 0 °C to 15 °C during addition. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. Layers were separated and the aqueous phase was re-extracted with MTBE (120 mL). Combined organic extracts were washed with brine (160 mL) and water (2 x 120 mL). Organic layer was concentrated to approx. 120 mL volume. MTBE(120 mL) was added and solvent evaporated to 120 mL volume left. 120 mL of MTBE was added again and evaporated till 120 mL volume left. Cyclohexane (120 mL) was added and mixture concentrated until remaining volume was 120 mL. Co-evaporation with cyclohexane was repeated two times using 120 mL of cyclohexane each time. Final solution (160 mL) was stirred at room temperature. After 30 minutes, solution becamecloudy and crystallization started. The slurry was stirred for 2 hours at room temperature and then for 2 hours at 5 to 10 °C. Precipitate was filtered off, washed on the filter with cyclohexane (2 x 30 mL). Since the freezing of cyclohexane causes suction to dry on the filter, wet material was dried under vacuum at 40 00. There was obtained 22 g (69percent) of the Compound of Formula (VIa) as a solid and the purity thereof was 98 areapercent as determined by HPLC (UV detection at 220 nm). Content of the impurity Compound of Formula (VIII) as described herein was 1 .2percent as determined by HPLC (UV detection at220 nm).
Preparation 5 TERT-BUTYL 3-(3-CHLORO-5-FLUOROPHENYL)-3-HYDROXYPYRROLIDIN-1-CARBOXYLATE To a solution of <strong>[33863-76-2]1-bromo-3-chloro-5-fluorobenzene</strong> (4.0 g, 19.1 mmol) in dry tetrahydrofuran (40 mL), under nitrogen, was added magnesium turnings (0.47 g, 21.0 mmol) and a small piece of iodine. The mixture was heated with a heat-gun until the colour disappeared and then stirred at ambient temperature for 0.5 h after which a solution of 1-N-boc-3-pyrrolidinone (2.8 g, 15.3 mmol) in dry tetrahydrofuran (10 mL) was added drop wise. The reaction mixture was stirred for 0.5 h at ambient temperature and then quenched with water (70 mL). Aqueous saturated ammonium chloride (20 mL) was added and the mixture was extracted with ethyl acetate (2*100 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:1) gave the title compound (2.43 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 1), 259 (14), 214 (22), 184 (13), 143 (11), 57 (bp).
Preparation 26 TERT-BUTYL 3-(3-CHLORO-2-FLUOROPHENYL)-3-HYDROXYPYRROLIDIN-1-CARBOXYLATE To a solution of <strong>[144584-65-6]1-bromo-3-chloro-2-fluorobenzene</strong> (5.0 g, 23.8 mmol) in dry tetrahydrofuran (50 mL) under nitrogen at -78 C., was added dropwise n-butyllithium (2.5 M in tetrahydrofuran, 9.5 mL, 23.8 mmol). The mixture was stirred for 0.5 h at -78 C. after which a solution of 1-N-boc-3-pyrrolidinone (4.37 g, 23.8 mmol) in dry tetrahydrofuran (20 mL) was added drop wise. The resulting mixture was brought to ambient temperature, aqueous saturated ammonium chloride (50 mL) was added and the mixture was extracted with ethyl acetate (3*50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 4:1 to 1:1) gave the title compound (4.42 g). MS m/z (rel. intensity, 70 eV) 315 (M+, 1), 259 (16), 214 (31), 157 (17), 57 (bp).
With iodine; magnesium; In diethyl ether; at 0 - 20℃; for 1.5h;Inert atmosphere;
To a stirred suspension of magnesium (2.59 g, 106 mmol, 1.97 equiv) in 50 mL of dry ether were added iodine (catalytic) and methyl iodide (6.7 mL, 108 mmol, 2 equiv) slowly drop wise at 0C under argon atmosphere. This was added to a solution of tert-butyl 3- oxopyrrolidine-1-carboxylate (10 g, 54 mmol, 1 equiv) in 50 mL of ether at 0C. The reaction mixture was warmed to room temperature and stirred for 1.5 h. After completion, the reactionwas quenched with saturated ammonium chloride solution at 0 C and extracted with EtOAc. The combined organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel column chromatography (20% EtOAc hexanes) afforded 7.0 g of tert-butyl 3-hydroxy-3-methylpyrrolidine-1-carboxylate (Yield = 64%).
48%
c) tert-Bntyl S-hydroxy-S-methylpyrrolidine-l-carboxylate; Methyl magnesium iodide [prepared from magnesium metal (1.73 g, 0.071 mol) and methyl iodide (4.7 mL, 0.074 mol) in dry ether (50 mL)] was slowly added to the solution of step b) product (6.6 g, 0.036 mol) in dry ether (150 mL) at 0 0C under nitrogen atm. The reaction mixture was slowly warmed to RT and stirred for 1.5 h and after cooling to 0 0C, it was quenched with saturated NH4Cl solution. The two layers were separated and the aqueous layer was extracted with ethyl acetate (3xl00mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography using 40 % EtOAc in pet. ether. Yield =3.4 g (48 %). The product was used directly in step d).
A 2L, 3-neck RB flask was fitted with a mechanical stirrer, a nitrogen inlet, thermocouple and thermocontroller, and a water cooling bath. In the flask, 7-bromopyrrolo[2,1- f][1,2,4]triazin-4-amine (18.4 g, 86.3 mmol) was suspended in tetrahydrofuran (250 mL) and treated with chlorotrimethylsilane (18.8 g, 172 mmol). The mixture was allowed to <n="85"/>stir 16 h at rt. A solution of isopropylmagnesium bromide in THF (2M, 173 mL, 345 mmol) was added slowly over 20 mi? taking care that the internal temperature never rose above 40 C. After 1.5 h, a sample quenched in MeOH and analyzed by RP-HPLC indicated that the metallation was 95% complete. The water bath was replaced with an ice-acetone bath and stirring was continued until the internal temperature fell to -10 0C. teri-Butyl 3- oxopyrrolidine-1-carboxylate (20 g, 108 mmol) was added as a solid, and the reaction allowed to warm to rt over 30 min. The reaction was again cooled to -10 0C and cautiously treated with trifluoroacetic anhydride (45.4 g, 216 mmol), diisopropylethylamine (33.5 g, 259 mmol) and dimethylaminopyridine (527 mg, 4.3 mmol). The reaction was warmed to rt and allowed to stir for 30 min, then treated with a 25% solution of NaOMe in MeOH (46 g, 215 mmol) and stirred for an additional 15 min. The reaction was partitioned between EtOAc and 1 N aq citric acid. After 15 min stirring the organic layer was separated, washed with brine and dried with sodium sulfate. After filtering the solution through a plug of silica, the organic were removed in vacuo and the residue triturated with ethyl ether to provide the desired product as a bright yellow solid (16.8 g, 65 %). 1H-NMR (DMSO): delta 7.72 (dd, 1 H), 7.61 (dd, 1 H), 7.23 to 7.36 (m, 3H)1 7.15. to 7.20 (m, 2H), 6.96 (dd, 1H), 5.60 (s, 2H), 2.58 (s, 1H); MS: LC/MS (+esi): m/z=275.1 [MH]+ ; LC/MS rt = 3.51 min.
65%
A 2L, 3 -neck RB flask was fitted with a mechanical stirrer, a nitrogen inlet, thermocouple and thermocontroller, and a water cooling bath. In the flask, 7-bromopyrrolo[2,l- f][l,2,4]triazin-4-amine (18.4 g, 86.3 mmol) was suspended in tetrahydrofuran (250 mL) <n="197"/>and treated with chlorotrimethylsilane (18.8 g, 172 mmol). The mixture was allowed to stir 16 h at rt. A solution of isopropylmagnesium chloride in THF (2M, 173 mL, 345 mmol) was added slowly over 20 min taking care that the internal temperature never rose above 40 0C. After 1.5 h, a sample was quenched in MeOH and analyzed by RP-HPLC indicated that the metallation was 95% complete. The water bath was replaced with an ice-acetone bath and stirring was continued until the internal temperature fell to -10 0C. tert-Butyl 3- oxopyrrolidine-1-carboxylate (20 g, 108 mmol) was added as a solid, and the reaction was allowed to warm to rt over 30 min. The reaction was again cooled to -10 0C and cautiously treated with trifluoroacetic anhydride (45.4 g, 216 mmol), diisopropylethylamine (33.5 g, 259 mmol) and dimethylaminopyridine (527 mg, 4.3 mmol). The reaction was warmed to rt and allowed to stir for 30 min, then treated with a 25% solution of NaOMe in MeOH (46 g, 215 mmol) and stirred for an additional 15 min. The reaction was partitioned between EtOAc and IN aq citric acid. After 15 min stirring the organic layer was separated, washed with brine and dried with sodium sulfate. After filtering the solution through a plug of silica, the filtrate was concentrated in vacuo and the residue triturated with ethyl ether to provide the desired product as a bright yellow solid (16.8 g, 65 %). 1H-NMR (DMSO): delta 7.72 (dd, IH), 7.61 (dd, IH), 7.23 to 7.36 (m, 3H), 7.15 to 7.20 (m, 2H), 6.96 (dd, IH), 5.60 (s, 2H), 2.58 (s, IH); MS: LC/MS (+esi): m/z=275.1 [MH]+ ; LC/MS it = 3.51 min.
[00732] Methyltriphenylphosphonium bromide (4.24g, ii .89minol) was suspended in dry THF (20 mL) and n-BuLi (12 mL, 32.4 minol) was added dropwise at -78C under a nitrogen atmosphere. The reaction mixture was stirred for 30 min. at -78C. tert-Butyl 3-oxopyrrolidine-1- carboxylate (2.0 g, 10.81 minol) was added slowly and the reaction was allowed to warm to RT and stirred overnight. The reaction mixture was filtered. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (1 x 2OmL) and brine (1 x 20 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The crude material was purified by FCC to afford tertbutyl 3-methylenepyrrolidine-1-carboxylate (1.2 g, 61%). 1H NMR (400 MHz, CDCI3): O 5.01 (m, 2H), 3.94-3.97 (t, 2H), 3.47-3.51 (t, 2H), 2.60 (d, J= 7.3 Hz, 2H), 1.50 (5, 9H).
51%
1.0 M THF solution of potassium tert-butoxide (2.97 mL, 2.97 mmol) was added to the suspension of methyltriphenylphosphonium bromide (1.11 g, 2.97 mmol) in THF (20 mL) at 0 C and warmed up to rt for 1 hr. The reaction mixture was cooled back to 0C and a solution of tert-butyl 3 -oxopyrrolidine- 1 -carboxylate (220 mg, 1.19 mmol) in THF (2 ml) was added. The resulting reaction mixture was warmed to rt over a period of 3 hrs., quenched with saturated NH4C1 (10 ml) and concentrated under reduced pressure. The reaction mixture is extracted with ethyl acetate (100 ml), washed with water, brine, dried (MgSO4), concentrated and the residue was purified by flash silica gel chromatography using a mixture of 15% ethyl acetate in hexane to provide tert-butyl 3- methylenepyrrolidine-1-carboxylate (110 mg, 0.600 mmol, 51% yield). ?H-NMR (400 MHz, CD3OD) oe ppm 5.00 (m, 2H), 3.91 (br. s., 2H), 3.44 (t, J=7.4 Hz, 2H), 2.58 (t, J=6.7 Hz, 2H), 1.46 (s, 9H).
50%
Step A: 3-Methylene pyrrolidine-1 -carboxylic acid te/f-butyl ester. To a suspension consisting of methyl triphenylphosphonium bromide (18 g, 51 mmol) and THF (200 ml_) at 0 0C was added n-butyl lithium (1.6 M solution in hexanes, 32 ml_). The resulting orange solution was stirred at 0 C for 5 min, then a solution of 3-oxo-pyrrolidine-1 -carboxylic acid te/t-butyl ester (9.0 g, 48 mmol) in THF (40 ml_) was added via cannula. The reaction mixture was stirred at 0 C for 90 min, then warmed to rt and stirring was continued for 1 h. The reaction mixture was then cooled to 0 C, quenched with sat. NH4CI, and extracted with Et2O. The organic layer was dried (MgSO4) and concentrated. The crude residue was suspended in hot hexanes and filtered. The filtrate was concentrated and purified (FCC) to give the title compound (4.4 g, 50%).
36%
With n-butyllithium; In tetrahydrofuran; at -78 - 20℃; for 2h;Inert atmosphere;
To a solution of PPh3CH3Br (578 g, 1.62 mol) in THF (3.5 L) is added a solution of n-BuLi (600 mL, 1.5 mol) at -78 C. under N2. The mixture is stirred at 0 C. for 1 h then R-2 (200 g, 1.08 mol) in THF (2.0 L) is added to the reaction mixture at 0 C. The mixture is allowed to warm to ambient temperature, stirred for 1 h, then poured into H2O and extracted with EtOAc. The organic layers are washed with brine, dried with Na2SO4, concentrated and purified by flash chromatography (SiO2, Hep to 25% EtOAc in Hep) to give compound R-3 (70 g, 36%).
36%
[0130] To a solution of PPh3CH3Br (578 g, 1.62 mol) inTHF (3.5 L) is added a solution ofn-Buli (600 mL, 1.5 mol)at -78 C. under N2 . The mixture is stirred at oo C. for 1 h then the solution ofR-2 (200 g, 1.08 mol) in THF (2.0 L) is addedto the reaction mixture at oo C. The mixture is allowed towarm to ambient temperature, stirred for 1 h, then poured intoH20 and extracted with EtOAc. The organic layers arewashed with brine, dried with Na2S04 , concentrated andpurified by flash chromatography (Si02 , Hep to 25% EtOAcin Hep) to give compound 1-4 (70 g, 36% ).
36%
To a solution of PPh3CH3Br (578 g, 1.62 mol) in THF (3.5 L) is added a solution of n- BuLi (600 mL, 1.5 mol) at -78C under N2. The mixture is stirred at 0C for 1 h then R-2 (200 g, 1.08 mol) in THF (2.0 L) is added to the reaction mixture at 0C. The mixture is allowed to warm to ambient temperature, stirred for 1 h, then poured into H20 and extracted with EtOAc. The organic layers are washed with brine, dried with Na2S04, concentrated and purified by flash chromatography (Si02, Hep to 25 EtOAc in Hep) to give compound R-3 (70 g, 36%).
33%
With potassium tert-butylate; In tetrahydrofuran; diethyl ether; at 20℃;Inert atmosphere;
General procedure: To a stirred suspension of methyltriphenylphosphonium bromide (1.5 equiv.) in diethylether(25-45 mL) under argon was added dropwisea solution of potassium-tert-butoxide 1M in THF (1.5 equiv.). The reaction mixture was immediately turned to yellow. After refluxing for 1 hour, the corresponding ketone (1.0 equiv.) was added in portions. The mixture was stirred at room temperature overnight. After completion, the reaction mixture was then hydrolyzed by water (5-8mL). The organic phase was separated and aqueous phase was extracted by diethyl ether (2 x 10mL). The combined organic phases were washed with water (20mLx2), brine (20mLx1), dried over anhydrous MgSO4 and concentrated under reduced pressure to yield crude product. Purification of this crude product by a suitable method afforded the corresponding alkene.
With potassium tert-butylate;
A) tert-butyl 3-methylenepyrrolidine-1-carboxylate To a mixture of methyltriphenylphosphonium bromide (23.1 g) and THF (80 mL) was added potassium tert-butoxide (9.0 g) at 0 C., and the mixture was stirred at 0 C. for 30 min. tert-Butyl 3-oxopyrrolidine-1-carboxylate (10 g) was added at 0 C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into cold water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.73 g). 1H NMR (300 MHz, CDCl3) delta 1.46 (9H, s), 2.55 (2H, t, J=6.9 Hz), 3.42-3.47 (2H, m), 3.92 (2H, brs), 4.96-4.98 (2H, m).
General Procedure for Synthesis of q-hydroxy carboxylic acids. Step No. 1. O-(Trimethylsilyl) cyanohydrines: A 50-mL flask equipped with a magnetic stirring bar and drying tube was charged with the ketone or aldehyde (0.010 mmol), followed by THF (50 mL), trimethylsilyl cyanide (1.39 g, 14 mmol), and zinc iodide (0.090 g, 0.28 mmol), and the reaction mixture was stirred at room temperature for 24 hr. Solvent evaporation gave a residue, which was dissolved in EtOAc (60 mL), washed with 5% aq. NaHC03 (2 x 30 mL), H20 (30 mL), and brine (30 mL), dried over Na2S04, filtered and concentrated to dryness to yield a crude, which was carried through to the next step without further purification. Step No. 2. Acid hydrolysis to g-hydroxy carboxylic acid: AcOH (25 ml) and cone. HC1 (25 ml) were added to the unpurified material from step No.1 and the reaction mixture was refluxed for 2-3 hr. The reaction mixture was then concentrated to dryness to give a white solid, which was carried through to the next step without further purification.Step No. 3. Boc protection: To a stirring solution of solid from step No.2 in 2 M NaOH (20 mL) and i-PrOH (20 mL) at 0C was added Boc20 (6.6 g, 3 mmol) in small portions, and the reaction mixture was allowed to warm to room temperature over 4 h. i-PrOH was then evaporated, and H20 (50 mL) was added, and the aqueous phase was separated and extracted with Et20 (2 x 30 ml). The aqueous layer was acidified to pH 3 by addition of dilute H3P04 and was extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H20 (2 x 30 mL) and brine (30 mL), dried over Na2S04, filtered and concentrated to yield the desired N-Boc-a-hydroxy carboxylic acids in 56-72% yield.
N-Boc-3-hydroxypyrrolidine-3-carboxylic acidN-Boc-3-pyrrolidone (0.010 mmol) was submitted to Procedure 15 to yield the desired N-Boc-S-hydroxy-pyrrolidine-S-carboxylic acid; Procedure 15: General Procedure for Synthesis of alpha-hydroxy carboxylic acidsStep No. 1. O-(Trimethylsilyl) cvanohydrines: A 50-mL flask equipped with a magnetic stirring bar and drying tube was charged with the ketone or aldehyde (0.010 mmol), followed by THF (50 mL), trimethylsilyl cyanide (1.39 g, 14 mmol), and zinc iodide (0.090 g, 0.28 mmol), and the reaction mixture was stirred at room temperature for 24 hr. Solvent evaporation gave a residue, which was dissolved in EtOAc (60 niL), washed with 5% aq. NaHCO3 (2 x 30 mL), H2O (30 mL), and brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness to yield a crude, which was carried through to the next step without further purification.Step No. 2. Acid hydrolysis to alpha-hydroxy carboxylic acid: AcOH (25 ml) and cone. HCl (25 ml) were added to the unpurified material from step No.1 and the reaction mixture was refluxed for 2-3 hr. The reaction mixture was then concentrated to dryness to give a white solid, which was carried through to the next step without further purification.Step No. 3. Boc protection: To a stirring solution of solid from step No.2 in 2 M NaOH (20 mL) and i-PrOH (20 mL) at 00C was added BoC2O (6.6 g, 3 mmol) in small portions, and the reaction mixture was allowed to warm to room temperature over 4 h. i-PrOH was then evaporated, and H2O (50 mL) was added, and the aqueous phase was separated and extracted with Et2O (2 x 30 ml). The aqueous layer was acidified to pH 3 by addition of dilute H3PO4 and was extracted with EtOAc (2 x 60 ml). The combined organic layers were washed with H2O (2 x 30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated to yield the desired N-Boc-alpha-hydroxy carboxylic acids in 56-72% yield. Aldehydes and ketones used: N-Boc-3-Pyrrolidonone, N-Boc-3- azetidinone, N-Boc-4-piperidone and N-Boc-3-azetidincarboxaldehyde.
To a solution of <strong>[15861-23-1]indoline-5-carbonitrile</strong> (1 10 mg, 0.75 mmol) in 2.5 mL of MeOH was added tert-butyl 3-oxopyrrolidine-l-carboxylate (166 mg, 0.90 mmol) and HO Ac (0.1 1 mL, 1.88 mmol) subsequently. After stirring at room temperature for 10 minutes, NaCNBH3 (57 mg, 0.90 mmol) was added and the mixture was then stirred at ambient temperature for 2 days. The volatiles were removed under vacuum. The residue was diluted with EtOAc, then washed with 1 N NaOH solution and brine, dried over Na2S04, and evaporated in vacuo to afford the crude title compound for the next step use without further purification.
Intermediate 10tert-butyl 3-(5-cyanoindolin-l-yl)pyrrolidine-l-carboxylate[0109] To a solution of <strong>[15861-23-1]indoline-5-carbonitrile</strong> (110 mg, 0.75 mmol) in 2.5 mL of MeOH was added tert-butyl 3-oxopyrrolidine-l-carboxylate (166 mg, 0.90 mmol) and HO Ac (0.11 mL, 1.88 mmol) subsequently. After stirring at room temperature for 10 minutes, NaC BH3 (57 mg, 0.90 mmol) was added and the mixture was then stirred at ambient temperature for 2 days. The volatiles were removed under vacuum. The residue was diluted with EtOAc, then washed with 1 N NaOH solution and brine, dried over Na2S04, and evaporated in vacuo to afford the crude title compound for the next step use without further purification.
tert-butyl 3-(5-cyanoindolin-1-yl)pyrrolidine-1-carboxylate To a solution of <strong>[15861-23-1]indoline-5-carbonitrile</strong> (110 mg, 0.75 mmol) in 2.5 mL of MeOH was added tert-butyl 3-oxopyrrolidine-1-carboxylate (166 mg, 0.90 mmol) and HOAc (0.11 mL, 1.88 mmol) subsequently. After stirring at room temperature for 10 minutes, NaCNBH3 (57 mg, 0.90 mmol) was added and the mixture was then stirred at ambient temperature for 2 days. The volatiles were removed under vacuum. The residue was diluted with EtOAc, then washed with 1 N NaOH solution and brine, dried over Na2SO4, and evaporated in vacuo to afford the crude title compound for the next step use without further purification.
Example 265A tert-butyl 3-(1-cyanocyclobutyl)-3-hydroxypyrrolidine-1-carboxylate To a solution of <strong>[4426-11-3]cyclobutanecarbonitrile</strong> (1.75 g, 21.5 mmol) in THF (15 mL) was added 2.0M lithium diisopropylamide (11 mL, 22.5 mmol) dropwise and the solution was stirred at -78 C. for 45 minutes. Then a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (4.0 g, 21.5 mmol) in THF (2 mL) was added to the solution and the mixture was stirred at -78 C. for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (25 mL*3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluted with petroleum ether: EtOAc=2:1 to obtain the title compound (0.9 g, 38.2% yield) as a white solid. 1H NMR: (400 MHz, CDCl3): delta 3.64-3.40 (m, 4H), 2.44 (t, J=7.8 Hz, 2H), 2.33-2.23 (m, 2H), 2.13-1.88 (m, 4H), 1.47 (s, 9H)
38.2%
General procedure: tert-butyl 3 -( 1 -cyanocyclobutyl)-3 -hydroxypyrrolidine- 1 -carboxylate[619] To a solution of <strong>[4426-11-3]cyclobutanecarbonitrile</strong> (1.75 g, 21.5 mmol) in THF (15mL) was added 2.0M lithium diisopropylamide (11 mL, 22.5 mmol) dropwise and the solution was stirred at -78 C for 45 minutes. Then a solution of tert-butyl 3-oxopyrrolidine-l- carboxylate (4.0 g, 21.5 mmol) in THF (2 mL) was added to the solution and the mixture was stirred at -78 C for 2 hours. The reaction mixture was quenched with saturated NH4C1 solution and extracted with EtOAc (25 mL x 3). The organic phase was washed with brine (20 mL), dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography eluted with petroleum ether: EtOAc = 2: 1 to obtain the title compound (0.9 g, 38.2 % yield) as a white solid. XH NMR: (400 MHz, CDC13): ? 3.64-3.40 (m, 4H), 2.44 (t, J= 7.8 Hz, 2H), 2.33-2.23 (m, 2H), 2.13-1.88 (m, 4H), 1.47(s, 9H)
[00524] To a mixture of t-BuOK (727.1 mg, 6.5 mmol, 1.20 eq) in DMSO (10 mL), was added trimethylsulfoxonium iodine (1.4 g, 6.5 mmol, 1.20 eq) by portions. The mixture was stirred at 15 C for 0.5 h. DME (5 mL) was added, and the mixture was cooled to 0 C. A solution of 144-1 (1.0 g, 5.4 mmol, 1.00 eq) in DMSO (2 mL) and DME (4 mL) was added dropwise at 0 C. The resulting mixture was stirred at 0 C for 2 h. TLC showed the reaction was complete. The mixture was diluted with water (20 mL), and extracted with DCM (20 mL*3). The combined organic layers were dried over anhydrous Na2S04, and concentrated under vacuum. The residue was purified by silica gel chromatography to provide 144-2 (200.0 mg, 1.0 mmol, 18.6% yield). 1HNMR (400MHz, CHLOROF ORM-<f) 3.72- 3.49 (m, 3H), 3.26 (t, J = 1 1.4 Hz, 1H), 2.93 (s, 2H), 2.26 - 2.24 (m, 1H), 1.88 -1.78 (m, 1H), 1.46 (s, 9H).
Step 1) 5-(tert-butoxycarboxyl)-l-oxa-5-azaspiro|"2.4"|heptane [0209] To themixture of trimethylsulfoxonium iodide (2.57 g, 11.7 mmol) in DMSO (8.8 mL) was added NaH (351 mg, 80% dispersion in mineral oil) at 10C. The mixture was stirred at rt for 2 h, then a solution of l-(tert-butoxymethyl)pyrrolidin-3-one (2.00 g, 10.8 mmol) in DMSO (3.0 mL) was added. The reaction was continued to stir for 3 h, then quenched with ice water (50 mL)followed by brine (50 mL), and then extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2S04, and concentrated in vacuo to yield viscous brown oil, which was used for the next step without further purification.
In tetrahydrofuran; diethyl ether; at -20℃; for 3h;
A solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (11.17 g, 0.06 mol) in THF ( 45 mL) was slowlyadded to a solutionofMeMgl (21.41 g, 0.129 mol) indiethylether. The reaction was conducted at -20 C. under stirringfor 3 hours. A small amount of water was added to the reaction solution. The resulting reaction solution was filtered by suction.The filtrate was extracted with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated to produce a crudeproduct of tert-butyl 3-hydroxy-3-methyl-pyrrolidine-1-carboxylate.The above crude product was dissolved in 20 mL1 ,4-dioxane. To the resulting solution was introduced an HCIgas. The resulting mixute was stirred overnight and filtered bysuction to produce the title product as a red solid (1.67 g) in ayield of 20% (two steps).
(1) Preparation of 3-methylpyrrolidin-3-ol hydrochloride A solution of tert-butyl 3-carbonylpyrrolidine-1-carboxylate (11.17g, 0.06mol) in THF (45mL) was slowly added to a solution of MeMgI (21.41g, 0.129mol) in diethyl ether. The reaction was conducted at -20C under stirring for 3 hours. A small amount of water was added to the reaction solution. The resulting reaction solution was filtered by suction. The filtrate was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to produce a crude product of tert-butyl 3-hydroxy-3-methyl-pyrrolidine-1-carboxylate. The above crude product was dissolved in 20mL 1,4-dioxane. To the resulting solution was introduced an HCl gas. The resulting mixute was stirred overnight and filtered by suction to produce the title product as a red solid (1.67g) in a yield of 20% (two steps).
To a solution of 3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (6 g, 32.4 mmol) in H2O/ether (85 mL/60 mL) was added sodium bisulphate (5.06 g, 48.6 mmol) at 0C, stirred for 15 min and potassium cyanide (3.16 g, 48.6 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water 4 times. The orgnic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by flash column chromatography (DCM/MeOH::0-3%) to provide the titled compound (52%, 3.6 g). LCMS: 13.0(M+H), Rt. 3.2 min, 99.2% (max).
tert-butyl 3-(4-cyano-3-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
> 94%
. Step D. tert-butyl 3-(4-cvano-3-(trifluoromethyl)phenyl)pyrrolidine-l-carboxylate A suspension of tert-butyl 4-(4-cyano-3-(trifluoromethyl)phenyl)-2,3-dihydro-lH-pyrrole- 1-carboxylate and tert-butyl 3-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dihydro-lH- pyrrole-l-carboxylate (370 mg, 1.10 mmol) and Pd/C (100 mg) in THF (8 mL) was stirred under hydrogen at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to afford tert-butyl 3-(4-cyano-3- (trifluoromethyl)phenyl)pyrrolidine-l-carboxylate as a white powder (350 mg, 94%), which was used for the next step without further purification. LCMS (ESI) m/z: 285.1 [M- 56+H]+.
tert-butyl 3-(4-cyano-3-(trifluoromethyl)phenyl)-3-hydroxypyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
Step A. tert-butyl 3-(4-cvano-3-(trifluoromethyl)phenyl)-3-hvdroxypyrrolidine-l- carboxylate To a mixture of <strong>[101066-87-9]4-iodo-2-(trifluoromethyl)benzonitrile</strong> (946 mg, 2.702 mmol) in THF (5 mL) at 0 C was added a solution of BuLi in hexane (1.29 mL, 3.25 mmol) and stirred under nitrogen for 1 hour. To the mixture at 0 C was added a solution of tert-butyl 3- oxopyrrolidine-l-carboxylate (500 mg, 2.702 mmol) in THF (5 mL) and stirred at room temperature for 4 hours. The reaction mixture was quenched with H20 (20 mL) and extracted with ethyl acetate (20 mL x 2). The extracts were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 3 -(4-cyano-3 -(trifluoromethyl)phenyl)-3 -hydroxypyrrolidine- 1 - carboxylate as a white solid (368 mg, 38%). LCMS (ESI) m/z: 301.0 [M-56+H]+.
tert-butyl 4-(4-cyano-3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrole-1-carboxylate[ No CAS ]
tert-butyl 3-(4-cyano-3-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step C. tert-butyl 4-(4-cvano-3-(trifluoromethyl)phenyl)-2,3-dihvdro-lH-pyrrole-l- carboxylate and tert-butyl 3-(4-cvano-3-(trifluoromethyl)phenyl)-2,5-dihydro-lH-pyrrole- 1 -carboxylate A mixture of of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro-lH- pyrrole-1 -carboxylate and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5- dihydro-lH-pyrrole-l-carboxylate (770 mg, 2.61 mmol), 4-iodo-2- (trifluoromethyl)benzonitrile (775 mg, 2.61 mmol), potassium carbonate (1.08 g, 7.83 mmol), and Pd(PPh3)4 (100 mg, 0.09 mmol) in 1,4-dioxane (5 mL) was stirred at 90 C overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc:petroleum ether (1 : 10) as eluting solvents to afford a mixture of tert-butyl 4-(4-cyano-3-(trifluoromethyl)phenyl)-2,3- dihydro-lH-pyrrole-l-carboxylate and tert-butyl 3-(4-cyano-3-(trifluoromethyl)phenyl)- 2,5-dihydro-lH-pyrrole-l-carboxylate as a white solid (400 mg, 45%), which was used in the next step without further purification. LCMS (ESI) m/z: 283.1 [M-56+H]+.
7-bromo-2-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 18h;
7-Brorno- I ,2,3,4-tetraliydro-isoquinoline (211 Ing, I mmol) and tert-hutyl 3-oxopyrrolidine-carboxylate (185 mg. 1 mmoi) were dissolved in 1 ,2-dichioroeihane at room temperature. NaBH(OAc)3 (254mg, 1 2 mmoi) and 1 drop of acetic acid was added to the mixture. The reaction was stirred at room temperature for 18 hours. Then, saturated sodium bicarbonate solution was added to quench the reaction. Ethyl acetate was added to reaction mixture and layers were separated. Theorganic layer was combined and concentrated to give crude material. The crude material was stirred with 4N HCI in dioxane (2 rnL) for 18 hours. The reaction was basified with 2N sodium hydroxide solution until pH=IO. Then the reaction was extracted with 3X10 ml methylene chloride. The combined methylene chloride was dried with sodium sulfate and removed under vacuum. The crude product was used in next step without further purification.
With potassium cyanide; 18-crown-6 ether; In dichloromethane; at 0 - 20℃; for 16h;
Intermediate: tert-butyl 3-cyano-3-hydroxypyrrolidine-1-carboxylate To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.40 mmol) in DCM (10 mL) was added trimethylsilyl cyanide (0.724 mL, 5.40 mmol), KCN (0.035 g, 0.540 mmol) and 18-CROWN-6 (0.143 g, 0.540 mmol) at 0 C. The reaction mixture was warmed to rt and stirred at rt for 16 h. The reaction mixture was cooled to 0 C., and quenched with sat. NaHCO3, then diluted with EtOAc. The organic phase was separated, washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel chromatography (0-100% EtOAc/hex) to yield tert-butyl 3-cyano-3-((trimethylsilyl)oxy)pyrrolidine-1-carboxylate (0.5 g, 1.758 mmol, 32.6% yield) and tert-butyl 3-cyano-3-hydroxypyrrolidine-1-carboxylate (0.306 g, 1.442 mmol, 26.7% yield). tert-butyl 3-cyano-3-((trimethylsilyl)oxy)pyrrolidine-1-carboxylate: LC/MS (Cond. N-1): [M+H]+ 213.2, RT=4.359 min. 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 3.83-3.72 (m, 1H), 3.72-3.43 (m, 3H), 2.33 (q, J=6.8 Hz, 2H), 1.52-1.42 (m, 9H), 0.19-0.10 (m, 9H).
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 5℃; for 2.66667h;
1000ml four-necked flask by adding Boc-pyrrolidone 120g, DMF 600ml, Stirring down to 0-5 , Sodium hydride was added to 26 g, 70.5 g of ethyl chloroformate was slowly added dropwise with stirring, 40min drop finished. 0-5 reaction 2h, TLC detection reaction is completed, Slowly add 3L ice water, With dilute hydrochloric acid to adjust the pH = 7 after ethyl acetate extraction, dry, Concentrated to give intermediate 1. Yield 85percent.
With sodium hydrogencarbonate; In diethyl ether; water; at 0 - 20℃; for 24h;
To a stirred solution of N-Boc-3-pyrrolidinone (CAS Number 101385-93-7; 4.0 g, 21.6 mmol) in diethyl ether (50 ml) and water (8 ml) was added NaHC03(3.6 g, 43 mmol) in water (5 ml) at 0C. NaCN (3.17 g, 64.8 mmol) was added to the reaction mixture at 0C. The reaction mixture was stirred at rt for 24 h. The resulting reaction mixture was poured into water (500 ml) and extracted with diethyl ether (2 x 300 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure yielding tert-butyl 3-cyano-3-hydroxypyrrolidine-l-carboxylate (4.21 g, 19.9 mmol). This material was used directly for the next step without further purification.1HNMR (400 MHz, DMSO-d6) delta ppm: 6.90 (s, 1 H), 3.48 - 3.63 (m, 2 H), 3.36 - 3.44 (m, 1 H), 3.20 - 3.32 (m, 1 H), 2.27 - 2.33 (m, 1 H), 2.13 - 2.20 (m, 1 H), 1.42 (s, 9 H).
tert-butyl 3-(5-bromo-2-fluorophenyl)-3-hydroxypyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
A solution of isopropyl magnesium chloride-lithium chloride in tetrahydrofuran (30 mL of 1.3 M, 39.00 mmol) was cooled to -78 C a. At -40 C, 4-bromo-1-fluoro-2-iodo-benzene (approximately 11.18 g, 37.14 mmol) was added. The temperature was maintained between -40 C and -35 C. After approximately 2 hours, tetrahydrofuran (20 mL) was added the mixture was maintained at -35C. tert-butyl 3-oxopyrrolidine-1-carboxylate (approximately 7.016 g, 37.88 mmol) was added over 10 minutes. The reaction mixture was removed from the cold bath after a further 5 minutes. Aqueous saturated ammonium chloride was carefully added with cooling (ice bath) and then the reaction mixture was extracted twice with ethyl acetate. The combined organics were washed with aqueous saturated ammonium chloride, brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to give a liquid that solidified over time. The solid was sonicated in the presence of 7% ethyl acetate/heptane and then filtered The resulting white solid was air dried by suction on a frit for 20 minutes to yield tert-butyl 3-(5-bromo-2-fluoro- phenyl)-3 -hydroxy-pyrrolidine-1-carboxylate (8.3 g, 62%). MR (400 MHz, OMSO-de) delta 7.69 (d, J = 7.0 Hz, 1H), 7.55 (ddd, J = 8.6, 4.2, 2.6 Hz, 1H), 7.19 (dd, J = 11.3, 9.1 Hz, 1H), 5.73 (d, J = 4.5 Hz, 1H), 3.61 - 3.38 (m, 4H), 2.29 (s, 1H), 2.12 - 2.02 (m, 1H), 1.41 (s, 9H) ppm.
tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
To a mixture of ((4-bromobutoxy)methyl)benzene (9.45 g, 38.87 mmol) and Mg (1.89 g, 77.74 mmol) in Et2O (20 mL) was added 12 (202 mg, 1.09 mmol). The reaction mixture was stirred at 40 C. for 1 h. After cooled to room temperature, the mixture was added to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.4 g, 12.96 mmol) in 30 mL of Et2O at 5 C. The reaction was stirred at room temperature overnight, then quenched with aq. NH4Cl (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether:EtOAc 5:12:1) to give the desired product tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate as a yellow oil (1.7 g). Yield 38% (ESI 294 (M+H-56)+).
38%
[0132] To a mixture of ((4-bromobutoxy)methyl)benzene (9.45 g, 38.87 mmol) and Mg (1.89 g, 77.74 mmol) in Et2O (20 mL) was added l2 (202 mg, 1.09 mmol). The reaction mixture was stirred at 40 C for 1 h. After cooled to room temperature, the mixture was added to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.4 g, 12.96 mmol) in 30 mL of Et2O at 5 C. The reaction was stirred at room temperature overnight, then quenched with aq. NH4Cl (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether:EtOAc 5:1~2:1) to give the desired product tert-butyl 3-(4-(benzyloxy)butyl)-3-hydroxypyrrolidine-1-carboxylate as a yellow oil (1.7 g). Yield 38% (ESI 294 (M+H-56)+).
tert-butyl 3-hydroxy-3-(4-octylphenyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
General procedure: A 3-neck round-bottomed flask equipped with a thermometer and a condenser was flame-dried and flushed with Ar. The flask was then charged with Mg0 (1.1 eq.), a single I2 crystal and another vacuum/Ar cycle was performed. Et2O (C=0.65M) was added resulting in a bright orange suspension of Mg0 pellets. Phenyl octyl bromide (1.0 eq.) was then added in one portion and the suspension was heated via a heatgun until the internal temperature reached 32C and stabilized for 5-10s, indicating that the Grignard formation had started. The reaction was stirred at rt until disappearance of the starting material by 1H NMR analysis (e.g.?1h). (0031) The Grignard solution (3.0 eq., C=0.65M) was then syringed to another flask containing substrate (1.0. eq.) in dry Et2O (C=0.05M). The solution was stirred at rt until disappearance of the starting material by TLC analysis. Saturated aqueous NH4Cl solution was added and the aqueous layer was extracted x2 with EtOAc. The organic layers were collected, washed x1 brine, dried over Na2SO4, filtered, concentrated in vacuo.
tert-butyl 3-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With sodium tris(acetoxy)borohydride; In methanol; at 20℃;Molecular sieve;
To the mixture of tert-butyl 3-oxopyrrolidine-1-carboxylate (0.388 g, 2 mmol) and benzyl (2-aminoethyl)carbamate (0.185 g, 1 mmol) in MeOH (10 mL) was added 4A molecular sieves and NaBH(OAc)3 (0.64 g, 3.0 mmol). It was stirred at room temperature and checked by TLC. After the reaction was complete, it was concentrated under reduced pressure and extracted with EtOAc and the organic layer concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide the product as a colorless oil (0.15 g, 41% yield).
Compound TDI01209-1 (1.0 g, 4.3 mmol), tert-butyl 3-oxopyrrolidine-1-carboxylate (800 mg, 4.3 mmol), 1,2-dichloroethane (30 mL) and glacial acetic acid (8 drops) were added to a 50 mL single neck flask, and the reaction wasperformed at room temperature (15?25°C) for 1.5 h. Sodium triacetoxyborohyride (2.73 g, 12.9 mmol) was then added,and the reaction was performed at 50°C for 2 h. The reaction solution was added with 40 mL water, and extracted withdichloromethane (15 mL * 2). The organic phase was combined, washed with saturated brine, dried over anhydroussodium sulfate, and purified by column chromatography (petroleum ether : ethyl acetate=10:1-7:1) to afford TDI01209-2(1.44 g, light yellow solid, yield: 83.7percent).1H NMR (400 MHz, CDCl3) delta 8.04 - 7.94 (m, 2H), 6.88 (dd, J = 8.9, 2.1 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 3.47 (s, 4H),2.22 (s, 1H), 1.95 (d, J = 9.0 Hz, 1H), 1.71 (s, 9H), 1.46 (s, 10H), 1.26 (t, J = 7.1 Hz, 1H). MS m/z (ESI): 403.2 [M+H].
83.7%
Compound TDI01209-1 (1.0 g, 4.3 mmol), tert-butyl 3-oxopyrrolidine-1-carboxylate (800 mg, 4.3 mmol), 1,2-dichloroethane (30 mL) and glacial acetic acid (8 drops) were added to a 50 mL single neck flask, and the reaction was performed at room temperature (15?25°C) for 1.5 h. Sodium triacetoxyborohyride (2.73 g, 12.9 mmol) was then added, and the reaction was performed at 50°C for 2 h. The reaction solution was added with 40 mL water, and extracted with dichloromethane (15 mL * 2). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether : ethyl acetate=10:1-7:1) to afford TDI01209-2 (1.44 g, light yellow solid, yield: 83.7percent). 1H NMR (400 MHz, CDCl3) delta 8.04 - 7.94 (m, 2H), 6.88 (dd, J = 8.9, 2.1 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 3.47 (s, 4H), 2.22 (s, 1H), 1.95 (d, J = 9.0 Hz, 1H), 1.71 (s, 9H), 1.46 (s, 10H), 1.26 (t, J = 7.1 Hz, 1H). MS m/z (ESI): 403.2 [M+H].
tert-butyl 2-(3-bromo-2-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.71 g
To a mixture of tert-butyl 3-oxopyrrolidine-l-carboxylate (3.30 g) and toluene (28 ml) was added pyrrolidine (1.52 g) at room temperature. The mixture was stirred at room temperature for 30 min, heated under reflux using Dean-Stark apparatus for 30 min, and concentrated under reduced pressure. The residue was mixed with CH3CN (28 ml), and l-bromo-3- (bromomethyl) -2- fluorobenzene (4.77 g) and TBAI (1.32 g) were added to the mixture at room temperature. The mixture was heated under reflux for 4.5 hr, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g) . NMR (300 MHz, CDCI3) delta 1.45 (9H, s) , 2.12-2.30 (1H, m) , 2.44-2.59 (1H, m) , 2.97-3.40 (3H, m) , 3.74-4.02 (1H, m) , 4.21 (1H, t, J = 5.1 Hz), 6.89-6.96 (1H, m) , 7.05 (1H, t, J = 6.7 Hz), 7.43 (1H, ddd, J = 8.0, 6.4, 1.9 Hz).
tert-butyl 2-(3-bromo-5-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.83 g
To a mixture of tert-butyl 3-oxopyrrolidine-l-carboxylate (3.44 g) and toluene (30 ml) was added pyrrolidine (1.59 g) at room temperature. The mixture was stirred at room temperature for 20 min, heated under reflux for 20 min using Dean-Stark apparatus, and concentrated under reduced pressure. The residue was mixed with CH3CN (30 ml) , and l-bromo-3- (bromomethyl ) -5-fluorobenzene (4.98 g) and TBAI (1.37 g) were added to the mixture at room temperature. The mixture was heated under reflux for 4.5 hr, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.83 g) . MS: [M+H-Boc]+ 271.9.
tert-butyl 2-(3-bromo-4-fluorobenzyl)-3-oxopyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.59 mumol
To a mixture of tert-butyl 3-oxopyrrolidine-l-carboxylate (3.46 g) and toluene (30 ml) was added pyrrolidine (1.59 g) at room temperature. The mixture was stirred at room temperature for 30 min, heated under reflux for 30 min using Dean-Stark apparatus, and concentrated under reduced pressure. The residue was mixed with CH3CN (30 ml),, and 2-bromo-4- (bromomethyl) -1-fluorobenzene (5.00 g) and TBAI (1.38 g) were added to the mixture at room temperature. The mixture was heated under reflux for 4 hr, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.59 g) . MS: [M+H-Boc]+ 271.9.
tert-butyl 2-(biphenyl-3-ylmethyl)-3-oxopyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.92 g
To a mixture of tert-butyl 3-oxopyrrolidine-l-carboxylate (3.5 g) and toluene (30 mL) was added pyrrolidine (1.61 g) at room temperature. The mixture was stirred at 100C for 3 hr, and concentrated. CH3CN (30 mL) and 3- (bromomethyl ) biphenyl (4.67 g) were added thereto at room temperature. The mixture was stirred overnight under nitrogen atmosphere at 80C, and concentrated. The obtained residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.92 g) . MS: [M+H-Boc]+ 252.2.
A solution of <strong>[41731-23-1]2-bromo-5-methylthiazole</strong> (1.0 g, 5.59 mmol) in THF (20 mL) under a N2 atmosphere was treated with nBuLi (2.7 mL, 6.70 mmol) dropwise at -78C, and the resulting reaction mixture was stirred at -78C for 1 h. A solution of tert-butyl 3-oxopyrrolidine-l-carboxylate (1.2 g, 6.70 mmol) in THF (10 mL) was then added to the reaction mixture dropwise at -78 C. The reaction mixture was then allowed to warm to room temperature, and was stirred at room temperature for 3 h. The mixture was diluted with saturated aqueous NH4Cl (40 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10 : 1 to EtOAc) to give 1984-A (760 mg, 48%) as a light yellow solid. MS 285.2 [M+H]+.
To a solution of 2303-A (5.0 g, 28.4 mmol) in DCM (70 mL) was added n-BuLi (13.6 mL, 34.1 mmol) dropwise at -78 C and the reaction mixture was stirred for 1 h under N2 atmosphere. Then a solution of SM-A (6.3 g, 34.1 mmol) in DCM (20 mL) was added into the mixture dropwise. The resulting mixture was warmed to room temperature and stirred for 3 h. The mixture was then diluted with saturated NH4Cl (100 mL), extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10 : 1 to EtOAc) to give 2303-B (550 mg) as a crude product. The crude product was purified by Prep-HPLC to give 2303-B (177 mg, 2.2%) as a brown solid. MS 284.2 [M+H]+.
tert-butyl 3-(2-chloro-N-((S)-1-(4-chlorophenyl)ethyl)acetamido)-3-(isopropylcarbamoyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
In methanol; for 0.5h;
To a solution of (S)-l-(4-chlorophenyl)ethan-l -amine (2.4 mL, 16.7 mmol, 1.0 equiv) and tert- butyl 3-oxopyrrolidine-l-carboxylate (3.1 g, 16.7 mmol, 1.0 equiv) in MeOH (16 mL) were added 2-isocyanopropane (1.6 mL, 16.7 mmol, 1.0 equiv) and chloroacetic acid (1.6 g, 16.7 mmol, 1.0 equiv). The mixture was stirred for 30 min, concentrated, and purified by silica gel chromatography to provide 3.2 g (39%) of //77-butyl 3-(2-chloro-N-((S)- l-(4-chlorophenyl)ethyl)acetamido)-3-(isopropylcarbamoyl)pyrrolidine- l-carboxylate as a mixture of diastereomers. LRMS (ES) m/z 486.2 (M+H).
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 20℃;Cooling with ice;
Dissolve 1-tert-butoxycarbonyl-3-pyrrolidone (926mg, 5mmol) in 10mL tetrahydrofuran,Stir in an ice bath,Add 0.872mL trifluoromethylchlorosilane and tetrabutylammonium fluoride (176mg, 0.67mmol),React overnight at room temperature,Add 8mL saturated ammonium chloride solution to the reaction solution,Stir for 15min and add tetrabutylammonium fluoride (1.49g, 5.7mmol) in tetrahydrofuran solution (7.5mL),After stirring at room temperature for 1 hour,Extract with ethyl acetate (50mL×3), wash with water (100mL),After drying, it is concentrated and directly put into the next step.
tert-butyl 3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With sodium cyanoborohydride; acetic acid In methanol at 20℃; for 48h;
1 tert-butyl 3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)amino)pyrrolidine-1-carboxylate (82)
To a solution of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)-9H-purin-6-amine (500 mg, 1.63 mmol) and tert-butyl 3-oxopyrrolidine-1- carboxylate (453 mg, 2.45 mmol) in MeOH (10 mL) and AcOH (0.1 mL) was added NaBH3CN (154 mg, 2.45 mmol). The reaction mixture was stirred at room temperature for two days. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H2O = 5% - 95%, 254 nm, 30 min) to give compound 82 (200 mg, 26% yield) as yellow oil. MS Calcd.: 475; MS Found: 476 [M+H]+
tert-butyl 3-((3,3-difluorocyclobutyl)amino)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 16h;
Intermediate 6: N-(3,3-difluorocyclobutyl)pyrrolidin-3-amine·2HCl
tert-butyl 3-oxopyrrolidine-1-carboxylate (1310 mg, 7.07 mmol, 1 equiv) was dissolved in DCM (80 mL) and 3,3-difluorocyclobutan-1-amine (1120 mg, 7.78 mmol, 1.10 equiv) and sodium triacetoxyborohydride (4650 mg, 21.9 mmol, 3.10 equiv) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO3 (aq) and extracted with DCM three times. The combined organics were dried (MgSO4) and concentrated in vacuo to give crude tert-butyl 3- ((3,3-difluorocyclobutyl)amino)pyrrolidine-1-carboxylate, which was used without further purification.
General procedure: A mixture of 2a-2n (0.38 mmol), aldehyde 3a-3p and 44 (or ketone 39-43) (0.42 mmol) and piperidine (37.5 µL, 0.38 mmol) in ethanol (3.0 mL) was refluxed for the given time as described individually. The reaction was monitored by TLC. The purification was performed in either of the following two methods.
13%
With piperidine; In ethanol;Reflux;
General procedure: A mixture of 2a-2n (0.38 mmol), aldehyde 3a-3p and 44 (or ketone 39-43) (0.42 mmol) and piperidine (37.5 µL, 0.38 mmol) in ethanol (3.0 mL) was refluxed for the given time as described individually. The reaction was monitored by TLC. The purification was performed in either of the following two methods.
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