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[ CAS No. 101385-93-7 ]

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Chemical Structure| 101385-93-7
Chemical Structure| 101385-93-7
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Product Details of [ 101385-93-7 ]

CAS No. :101385-93-7MDL No. :MFCD01631194
Formula : C9H15NO3 Boiling Point : 270.9°C at 760 mmHg
Linear Structure Formula :-InChI Key :N/A
M.W :185.22Pubchem ID :471360
Synonyms :

Computed Properties of [ 101385-93-7 ]

TPSA : 46.6 H-Bond Acceptor Count : 3
XLogP3 : 0.7 H-Bond Donor Count : 0
SP3 : 0.78 Rotatable Bond Count : 2

Safety of [ 101385-93-7 ]

Signal Word:WarningClass:N/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H302-H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 101385-93-7 ]

  • Upstream synthesis route of [ 101385-93-7 ]
  • Downstream synthetic route of [ 101385-93-7 ]

[ 101385-93-7 ] Synthesis Path-Upstream   1~27

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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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).
Reference: [1] Patent: WO2007/11284, 2007, A1, . Location in patent: Page/Page column 28-29
[2] Patent: EP3269715, 2018, A1, . Location in patent: Paragraph 0061; 0174; 0175
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Reference: [1] Patent: WO2005/77924, 2005, A1, . Location in patent: Page/Page column 71-72
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YieldReaction ConditionsOperation in experiment
10.8 g 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
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Reference: [1] Patent: EP202048, 1991, B1,
[2] Patent: US4771046, 1988, A,
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Reference: [1] Patent: US6235731, 2001, B1,
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Reference: [1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 6, p. 807 - 812
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Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 2, p. 1022 - 1033
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 7, p. 1645 - 1649
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
[4] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 20, p. 2691 - 2696
[5] Patent: US2016/96837, 2016, A1,
[6] Patent: WO2017/17630, 2017, A1,
[7] Patent: EP3239143, 2017, A2,
[8] Patent: EP3269715, 2018, A1,
[9] Patent: EP1550660, 2005, A1,
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Reference: [1] Patent: US2006/189643, 2006, A1, . Location in patent: Page/Page column 9
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Reference: [1] Patent: US2004/29887, 2004, A1,
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Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 48, p. 15274 - 15278[2] Angew. Chem., 2017, vol. 129, p. 15476 - 15480,5
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Reference: [1] Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 10, p. 3902 - 3911
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4399 - 4403
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YieldReaction ConditionsOperation in experiment
51%
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.

Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 21, p. 9738 - 9755
[2] Patent: WO2015/35278, 2015, A1, . Location in patent: Page/Page column 81
[3] Patent: WO2010/141809, 2010, A1, . Location in patent: Page/Page column 64
[4] Patent: US2014/45813, 2014, A1, . Location in patent: Paragraph 0110; 0111
[5] Patent: US2014/275014, 2014, A1, . Location in patent: Paragraph 0128; 0129; 0130
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[8] Patent: US2017/233339, 2017, A1,
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YieldReaction ConditionsOperation in experiment
61%
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] Patent: EP2719696, 2014, A1, . Location in patent: Paragraph 0210; 0211
[2] Patent: WO2005/21515, 2005, A2, . Location in patent: Page/Page column 75-76
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  • [ 101385-93-7 ]
  • [ 114214-71-0 ]
Reference: [1] Patent: US2007/208001, 2007, A1, . Location in patent: Page/Page column 34
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YieldReaction ConditionsOperation in experiment
52%
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).
Reference: [1] Organic Letters, 2015, vol. 17, # 8, p. 1934 - 1937
[2] Patent: WO2015/130905, 2015, A1, . Location in patent: Paragraph 00206
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  • [ 1194376-31-2 ]
  • [ 942190-60-5 ]
YieldReaction ConditionsOperation in experiment
32.6% 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).
Reference: [1] Patent: US2017/107202, 2017, A1, . Location in patent: Paragraph 0452; 0453; 0454; 0455
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YieldReaction ConditionsOperation in experiment
4.21 g 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).
Reference: [1] Patent: WO2017/149313, 2017, A1, . Location in patent: Page/Page column 48
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  • [ 143-33-9 ]
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  • [ 871115-54-7 ]
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Reference: [1] Patent: US2005/277633, 2005, A1, . Location in patent: Page/Page column 20
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  • [ 67-56-1 ]
  • [ 101385-93-7 ]
  • [ 149-73-5 ]
  • [ 1263283-20-0 ]
Reference: [1] Patent: WO2006/70284, 2006, A1, . Location in patent: Page/Page column 39
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  • [ 7677-24-9 ]
  • [ 24424-99-5 ]
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  • [ 1067239-08-0 ]
Reference: [1] Patent: WO2011/44498, 2011, A1, . Location in patent: Page/Page column 64-65, 72
[2] Patent: WO2010/132777, 2010, A2, . Location in patent: Page/Page column 46-47; 152-153
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  • [ 1226781-82-3 ]
Reference: [1] Patent: WO2011/103256, 2011, A1,
[2] Patent: WO2011/37793, 2011, A1,
[3] Organic Process Research and Development, 2015, vol. 19, # 11, p. 1760 - 1768
[4] Patent: US9181262, 2015, B2,
[5] Patent: CN105348286, 2016, A,
[6] Patent: EP3159344, 2017, A1,
[7] Patent: WO2017/81590, 2017, A1,
[8] Patent: TW2017/8222, 2017, A,
[9] Patent: TW2017/8223, 2017, A,
[10] Patent: WO2011/146358, 2011, A1,
  • 26
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  • [ 1226781-81-2 ]
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Reference: [1] Organic Process Research and Development, 2015, vol. 19, # 11, p. 1760 - 1768
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  • [ 1280210-79-8 ]
Reference: [1] Patent: WO2011/103256, 2011, A1,
[2] Patent: WO2011/37793, 2011, A1,
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 19, p. 5361 - 5366
[4] Patent: EP3144310, 2017, A1,
[5] Patent: EP3159344, 2017, A1,
[6] Patent: WO2017/81590, 2017, A1,
[7] Patent: TW2017/8221, 2017, A,
[8] Patent: TW2017/8222, 2017, A,
[9] Patent: CN106905325, 2017, A,
[10] Patent: TW2017/8223, 2017, A,
[11] Patent: WO2011/146358, 2011, A1,
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