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CAS No. :203866-17-5 MDL No. :MFCD03094918
Formula : C11H17F2NO4 Boiling Point : No data available
Linear Structure Formula :- InChI Key :RQDZKOOUQIDZOG-ZETCQYMHSA-N
M.W : 265.25 Pubchem ID :11129200
Synonyms :

Safety of [ 203866-17-5 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 203866-17-5 ]

* 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.

  • Downstream synthetic route of [ 203866-17-5 ]

[ 203866-17-5 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 102195-80-2 ]
  • [ 203866-17-5 ]
YieldReaction ConditionsOperation in experiment
92% With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; To intermediate 5a (300 rag, 1.23 mmol, 1.00 equiv) in diehloromethane (30 mL) at 0 C was added dropwise a solution of DAST (1.80 g, 11.2 mmol, 9.00 equiv) in diehloromethane (10 mL) and the resulting solution was stirred overnight at room temperature. The mixture was then washed with 1x30 mL of saturated aqueous sodium bicarbonate and 3x30 mL of brine, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to afford 300 mg (92%) of intermediate 5b as yellow oil.
91% With diethylamino-sulfur trifluoride; In dichloromethane; at -50 - 20℃; Example 3B 4, 4-DIFLUORO-PYRROLIDINE-1, 25-DICARBOXYLIC acid 1-TERT-BUTYL ester 2-methyl ester The compound from Example 3A (2.20 g) in 15 ML OF CH2C12 WAS cooled to- 50 C, then Et2NSF3 (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was stirred overnight. NAHC03 solution was added slowly to the mixture and the mixture was extracted with dichloromethane (3X). The combined organics were dried with NA2SO4 and purified with flash chromatography (10% ethyl ACETATE/HEXANE) to provide the difluoroester (1.81 g, 91%). MS (CI) m/z 266 (M+H) +.
91% With diethylamino-sulfur trifluoride; In dichloromethane; at -50℃; EXAMPLE 3B 4,4-Difluoro-pyrrolidine-1,2S-dicarboxylic acid 1-tert-butyl ester 2-methyl ester The compound from Example 3A (2.20 g) in 15 mL of CH2Cl2was cooled to -50 C., then Et2NSF3 (2.47 mL, 18.7 mmol) was added. After 10 minutes, the cooling bath was removed, and the mixture was stirred overnight. NaHCO3 solution was added slowly to the mixture and the mixture was extracted with dichloromethane (3*). The combined organics were dried with Na2SO4 and purified with flash chromatography (10% ethyl acetate/hexane) to provide the difluoroester (1.81 g, 91%). MS (CI) m/z 266 (M+H)+.
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h; To a solution of compound 14-2 (5.8 g, 23.9 mmol) in DCM (70 mL) at -78 C was added Et2NF3 (4.85 mL, 35.9 mmol) dropwise. At the end of addition, the mixture was stirred at -78 C for 2 hrs and then at rt for another 19 hrs. The reaction was quenched with NH4C1 aqueous solution (50 mL), and the resulting mixture was extracted with DCM (60 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 20/1 ) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) ml . 266.25 [M+H] +; NMR (400 MHz, CDC13) delta (ppm): 4.68-4.63 (m, 1 H). 4.01 -3.87 (m. 1 H), 3.78 (s. 3H), 3.75-3.63 (m, 1H). 2.84-2.66 (m. 1 H), 2.51 -2.31 (m. 1H). 1.43 (d. 9H, J =16 Hz).
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h;Inert atmosphere; Sealed tube; To a solution of compound 12-1 (5.81 g, 23.9 mmol) in DCM (70 mL) was added Et2NSF3 (4.85 mL, 35.9 mmol) dropwise at -78 C. At the end of the addition, the mixture was stirred at -78 C for 2.0 hrs and at rt for another 19 hrs. After the reaction was completed, the mixture was quenched with NH4C1 aqueous solution (50 mL). The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 266.2 [M+H]+; and NMR (400 MHz, CDC13) delta (ppm): 9.60 (brs, 1H), 4.60-4.57, 4.94-4.72 (m, m, 1H), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz).
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h; To a solution of compound 12-6 (5.81 g, 23.9 mmol) in DCM (70.0 mL) was added Et2NF3(4.85 mL, 35.9 mmol) dropwise at -78 C. At the end of the addition, the mixture was stirred at -78 C for 2.0 hrs and then at rt for another 19 hrs. After the reaction was completed, the mixture was quenched with NH4C1 aqueous solution (50 mL), and the resulting mixture was extracted with DCM (60 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S0 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data:MS (ESI. pos.ion) mlz: 266.25 [M+H]': and NMR (400 MHz, CDCh) 6 (ppm): 4.68-4.63 (m. 1H), 4.01-3.87 (m, 1H).3.78 (s.3H), 3.75-3.63 (in. 1H), 2.84-2.66 (m, 1 H).2.51-2.31 (m.1H).1.43 (d, 9H..7 = 16 Hz).
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 14h; To a solution of compound 15-2 (0.5 g, 2 mmol) in DCM (10 mL) at -78 C was added dropwise Et2NSF3 (0.82 mL, 6 mmol). The mixture was stirred at -78 C for 2 hours and at rt for another 12 hours. A small amount of water was added to the mixture, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 9/1) to give the title compound 15-3 (0.42 g, 79%). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 266.25 [M+H]+; and1H NMR (400 MHz, CDCl3): delta 4.43-4.47 and 4.55-4.53 (m, 1H), 3.80-3.83 (m, 2H), 3.77 (s, 3H), 2.66-2.74 (m, 1H), 2.40-2.52 (m, 1H), 1.42-1.47 (d, J = 20 Hz, 9H).
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h; To a solution of compound 5-9 (5.81 g, 23.9 mmol) in DCM (70 mL) at -78 C was added Et2NSF3 (4.85 mL, 35.9 mmol) dropwise slowly. At the end of the addition, the mixture was stirred for 2 hours at -78 C and then stirred at rt for 19 hours. After the reaction was completed, the reaction was quenched with an aqueous solution of NH4CI (50 mL) and the aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 266.3 [M+H]+; and H NMR (400 MHz, CDC13): delta 9.60 (brs, IH), 4.60-4.57, 4.94-4.72 (m, m, IH), 3.93-3.84 (m, 2H), 3.77 (s, 3H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h; 11121] To a solution of compound 14-2 (5.8 g, 23.9 mmol) in DCM (70 mE) at -78C. was added Et2NF3 (4.85 mE, 35.9 mmol) dropwise. At the end of addition, the mixture was stirred at -78C. for 2 irs and then at it for another 19 hrs. The reaction was quenched with NH4C1 aqueous solution (50 mE), and the resulting mixture was extracted with DCM (60 mEx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the title compound as pale yellow liquid (5.0 g, 79%). The compound was characterized by the following spectroscopic data:11122] MS (ESI, pos.ion) mlz: 266.25 [M+H]11123] ?H NMR (400 MHz, CDC13) oe (ppm): 4.68-4.63 (m, 1H), 4.01-3.87 (m, 1H), 3.78 (s, 3H), 3.75-3.63 (m, 1H),2.84-2.66 (m, 1H), 2.51-2.31 (m, 1H), 1.43 (d, 9H, J=16 Hz).
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 14h; To a solution of compound 15-2 (0.5 g, 2 mmol) in DCM (10 mL) at -78 C was added dropwise Et2NSF3 (0.82mL, 6 mmol). The mixture was stirred at -78 C for 2 hours and at rt for another 12 hours. A small amount of water wasadded to the mixture, and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic phaseswere dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v) = 9/1) to give the title compound 15-3 (0.42 g, 79%). The compound was characterized bythe following spectroscopic data:MS-ESI: m/z 266.25 [M+H]+; and1H NMR (400 MHz, CDCl3): delta 4.43-4.47 and 4.55-4.53 (m, 1H), 3.80-3.83 (m, 2H), 3.77 (s, 3H), 2.66-2.74 (m, 1H),2.40-2.52 (m, 1H), 1.42-1.47 (d, J = 20 Hz, 9H).
79% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 21h; Compound 26-3 (5.81 g, 23.9 mmol) was dissolved in DCM (70 mL) and Et 2NSF 3(4.85mL, 35.9 mmol) was slowly added dropwise to the system. After the addition wascompleted, the reaction was carried out at a constant temperature for 2.0 hours and atroom temperature for 19 hours. After the reaction was completed, the reaction wasquenched with aqueous ammonium chloride (50 mL) and the aqueous layer was extracted withDCM (100 mL x 3). The combined organic phases were dried over anhydrous Na 2SO 4Dried andconcentrated. The residue was purified by column chromatography (eluent: PE / EtOAc (v /v) = 20/1) to give 5.0 g of a pale yellow liquid. Yield: 79%.
73% With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; Step 2 Preparation of (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate To a stirred solution of (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (2.9 g, 11.9 mmol) in DCM (20 mL) was added DAST (5.76 g, 35.8 mmol) dropwisely at 0 C. After being stirred at r.t. overnight, the mixture was quenched with water (10 mL) at 0 C., pH was adjusted to 7?8, extracted with DCM (50 mL*3). The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=10:1) to afford (S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (2.3 g, 73%) as colorless oil.
61% With ethanol; diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 18h;Inert atmosphere; A solution of the (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (0.23 g, 0.946 mmol), obtained from step 1, in CH2Cl2 (3.0 mL), in a 25-mL flask equipped with a N2 inlet tube and stirring bar, was treated with a solution of diethylaminosulfur trifluoride (0.197 ml, 1.607 mmol) in CH2Cl2 (2.0 mL) at room temperature. Ethanol (0.011 ml, 0.189 mmol) was added (for in situ generation of catalytic quantities of HF) and the mixture was stirred for 18 h at room temperature. The solution was poured into saturated sodium bicarbonate and after CO2 evolution ceased it was extracted into CH2Cl2 (3*15 mL), dried (Na2SO4), filtered, and evaporated in vacuo. Chromatography on silica gel in DCM afforded a yellowish oil. Yield: 0.150 g, 61%. 1H NMR (400 MHz, CDCl3): delta 1.44 (br s, 9H), 2.45 (dq, J=13.6, 5.2 Hz, 1H), 2.61-2.81 (m, 1H), 3.75 (s, 3H), 3.60-3.90 (m, 2H), 4.45-4.55 (m, 1H). MS (ESI) m/z 266.1 [M+H]+
61% With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; Example 1 Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide Compound 1a: To a stirred solution of 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (1.9 g, 7.36 mmol, 1.0 equiv.), in DCM (15 mL), was added DAST (2.6 ml, 19.85 mmol, 2.6 equiv) drop wise at 0 C. over a period of 30 min, the reaction mixture was stirred at RT for overnight. Progress of the reaction was monitored by NMR. Water (50 mL) was added to the reaction mixture, stirred for 5 min and extracted with DCM (50 mL*3). Combined organic layer was washed with saturated sodium bicarbonate solution (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (1.25 g, 61% Yield) as a red oil. 1H NMR (400 MHz, DMSO-d6) delta 4.41-4.53 (m, 1H), 3.65-3.84 (m, 5H), 2.82-3.01 (m, 2H), 1.41 (s, 4H), 1.35 (s, 5H).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In chloroform; at 0 - 20℃; for 19h; 36.0 g of [bis(2-methoxyethyl)amino]sulfur trifluoride was added dropwise over a period of 5 minutes under ice cooling to a 150 mL chloroform solution of 18.0 g of the compound obtained in step 3-1, after which the reaction mixture was stirred for 19 hours at room temperature. The reaction solution was added dropwise over a period of 10 minutes under ice cooling to 300 mL of a saturated potassium carbonate aqueous solution. After liquid separation, the aqueous layer was extracted with chloroform (30 mL × 2), and the combined organic layer was washed with 30 mL of saturated brine and dried with magnesium sulfate, and the drying agent was filtered off, after which the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/n-hexane = 1/4; v/v) to obtain 15.4 g of the titled compound (yellow oily substance). MS (ESI pos.) m/z : 288([M+Na]+) 1 H-NMR (300 MHz, CDCl3) delta (ppm) ; 1.43 & 1.46 (each-s, 9 H), 2.36 - 2.56 (m, 1 H), 2.58 - 2.82 (m, 1 H), 3.69 - 3.92 (m, 2 H), 3.77 (s, 3 H) 4.40 - 4.61 (m, 1 H)
With diethylamino-sulfur trifluoride; In dichloromethane; at -78℃; Step B: Diethylaminosulfur trifluoride (1.88 mL, 14.2 mmol) was added to a -780C solution of l-tert-buty 2-methyl (25)-4-oxopyrrolidine-l,2-dicarboxylate (1.73 g, 7.1 mmol) in dichloromethane (20 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-tert-butyl 2-methyl (21S)-4,4-difluoropyrrolidine-l,2-dicarboxylate.
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In chloroform; at 0 - 20℃; for 19.0833h; Step 15-2: Synthesis of 1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate To a solution of 18.0 g of the compound obtained in Step 15-1 in CHCl3 (150 ml) was added dropwise 36.0 g of [bis(2-methoxy ethyl)amino]sulfur trifluoride under ice cooling over 5 minutes, then, the reaction mixture was stirred at room temperature for 19 hours. The reaction solution was added dropwise to a saturated aqueous solution of K2CO3 over 10 minutes under ice cooling. After liquid separation, the aqueous layer was extracted, the combined organic layer was washed with saturated brine, dried over MgSO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/4; v/v) to obtain 15.4 g of the title compound (yellow oil). MS (ESI pos.) m/z: 288 ([M+Na]+) 1H-NMR (300 MHz, CDCl3) delta (ppm); 1.43 & 1.46 (each-s, 9H), 2.36-2.56 (m, 1H), 2.58-2.82 (m, 1H), 3.69-3.92 (m, 2H), 3.77 (s, 3H) 4.40-4.61 (m, 1H)
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 11h; To a solution of 1-tert-butyl 2-methyl (2S)-4-oxo-1, 2-pyrrolidinedicarboxylate obtained in Example 8-1 (3.6g) in dichloromethane, was added diethylaminosulfur trifluoride (4mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for llhrs. To the resulting mixture was added NAHCO3, and the reaction mixture was quenched by adding saturated aqueous NAHCO3, and then water (1000mL) and CaCl2 (11.5g) in water (50mL) were added. The resulting suspension was extracted with ethyl acetate, the combined organic layer was washed with saturated aqueous NaCl, dried OVER MGS04, and concentrated in vacuo. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate = 5/1) to give the target compound as a yellow oil (3.6g). H-NMR (INCDCL3) : D 1. 53-1.36 (9H, m), 2.55-2. 35 (1H, M), 2.83-2. 58 (1H, m), 3.94-3. 71 (5H, m), 4.62-4. 37 (1H, m). MS (ESI+) : m/z 266.18 (M+H).
0.15 g With ethanol; diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 18h;Inert atmosphere; Step 2: (S)-1-fert-butyl 2-methyl 4,4-difluoropyrrolidine-1 ,2-dicarboxylate A solution of the (S)-1 -ieri-butyl 2-methyl 4-oxopyrrolidine-1 ,2-dicarboxylate (0.23 g, 0.946 mmol), obtained from step 1 , in CH2CI2 (3.0 m l_), in a 25-mL flask equipped with a N2 inlet tube and stirring bar, was treated with a solution of diethylaminosulfur trifluoride (0.197 ml, 1 .607 mmol) in CH2CI2 (2.0 m l_) at room temperature. Ethanol (0.01 1 ml, 0.1 89 mmol) was added (for in situ generation of catalytic quantities of HF) and the mixture was stirred for 18h at room temperature. The solution was poured into saturated sodium bicarbonate and after C02 evolution ceased it was extracted into CH2CI2 (3 x 15 ml_), dried (Na2S04), filtered, and evaporated in vacuo. Chromatography on silica gel in DCM afforded a yellowish oil. Yield: 0.150g, 61 %. 1 H NMR (400 MHz, CDCI3): delta 1 .44 (br s, 9H), 2.45 (dq, J= 13.6, 5.2 Hz, 1 H), 2.61 -2.81 (m, 1 H), 3.75 (s, 3H), 3.60-3.90 (m , 2H), 4.45-4.55 (m, 1 H). MS (ESI) m/z 266.1 [M + H]+
With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 16.5h;Inert atmosphere; To a stirred solution of (S) -1-tert-butyl 2-methyl4-oxopyrrolidine-1, 2-dicarboxylate (5 g, 20.55 mmol) in dry DCM (100 mL) at-78 was added diethylaminosulfur trifluoride (DAST, 8.5 mL, 61.66 mol) dropwise over a period of 30 minutes under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 1 h then at room temperature for 16 h. The reaction mixture was poured into the mixture of crushed ice and saturated NaHCO3aqueous solution till pH 8. The two layers were separated and the aqueous layer was extracted with DCM (20 mL×3) . The combined organic layer was washed with brine, dried over anhydrous Na2SO4then concentrated to get crude product (4.7 g, yellow oil) which was used in next step directly. MS: M/e 210 (M-55)+.
With diethylamino-sulfur trifluoride; In ethanol; dichloromethane; at 0 - 20℃; for 18h; Step B: To a solution of N-Boc-4-oxo-L-methyl prolinate (106.00 g, 435.75 mmol) in dichloromethane (500 mL) was added DAST (119.40 g, 740.78 mmol) in dichloromethane (500 mL) dropwise at 0 C. After the addition, the mixture was added with EtOH (4.02 g, 87.15 mmol) and the mixture was stirred for 18 h at 0-20 C. The mixture was poured into icy sat.aq NaHCO3 slowly. After CO2 overflowed totally, the mixture was extracted with dichloromethane (2000 mL) twice, and the dichloromethane was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give crude product. The crude product was purified by flash column chromatography eluted with Pet. Ether/EtOAc (50:1 to 10:1) to give N-Boc-4,4-fluor-L-methyl prolinate (70.00 g, 263.90 mmol, 60.56%). 1H NMR (CDCl3, 400 MHz): delta 4.57-4.40 (m, 1H), 3.89-3.72 (m, 5H), 2.78-2.60 (m, 1H), 2.45 (m, 1H), 1.44 (d, J = 20.0 Hz, 9H).
With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; To a solution of 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (10 g, 41.1 mmol, 1.0 eq) in CH2Cl2 (80 mL) at 0 C. was added dropwise a solution of DAST (12.2 g, 75.7 mmol, 10.0 mL, 1.84 eq) in CH2Cl2 (20 mL). The resulting mixture was allowed to warm slowly to RT, stirred for a further 16 hr and quenched by dropwise addition of saturated aq. NaHCO3 (50 mL) and H2O (50 mL). The layers were separated, the aqueous phase was extracted with CH2Cl2 (50 mL×3) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a viscous oil (11 g). 1H NMR (400 MHz, CDCl3): delta 4.55-4.43 (m, 1H), 3.89-3.81 (m, 2H), 3.77 (s, 3H), 2.71-2.65 (m, 1H), 2.52-2.44 (m, 1H), 1.47 (s, 9H).

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[31]Patent: US2019/270739,2019,A1 .Location in patent: Paragraph 0736-0737
  • 2
  • [ 203866-17-5 ]
  • [ 203866-15-3 ]
YieldReaction ConditionsOperation in experiment
99% PREPARATION 63CS^-l -iiert-ButoxycarbonylJ^^-difluoropyrrolidine^-carboxylic acid1.08 g (4.08 mmol) of (S)^ -ferf-butyl 2-methyl 4,4-difluoropyrrolidine-1 ,2-dicarboxylate (purchased from Aldrich; cat. no. 702463) were dissolved in a mixture of 10 mL of methanol and 10 mL of tetrahydrofurane and 6.12 mL of a 2M aqueous solution of sodium hydroxide were added. The solution was stirred at room temperature for 1 hour and then the organic solvents were removed. The remaining solution was diluted with water and 6.12 mL of 2M hydrochloric acid were added. The product that precipitated was extracted with dichloromethane (x3), the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. 1 .01 g (99% yield) of the title compound were obtained as a white solid.LRMS (m/z): 250 (M-1 )+.
94% To a solution of compound 14-3 (5.0 g. 18.86 mmol) in THF (40 mL) at 0 C was added LiOH aqueous solution (1.5 g, 20 mL). and the mixture was stirred at rt for 2 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M), and the solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a white solid (4.54 g, 94%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 252.23 [M+H] +; NMR (400 MHz, CDC13) S (ppm): 9.60 (brs, 1 H). 4.94-4.72, 4.60-4.57 (m. m, 1 H), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1 .44 (d, 9H, J = 16 Hz).
94% With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; Sealed tube; To a solution of compound 12-2 (5.0 g, 18.86 mmol) in THF (40 mL) was added LiOH aqueous solution (1.5 g, 20 mL) at 0 C, and the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M), and then the THF solvent was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a white solid (4.44 g, 94%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 252.2 [M+H]+; and H NMR (400 MHz, CDC13) delta (ppm): 9.60 (brs, 1H), 4.94-4.72, 4.60-4.57 (m, m, 1H), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz).
94% With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2h; To a solution of compound 12-7 (5.0 g.18.86 mmol) in THF (40.0 mL) was added LiOH aqueous solution (1.5 g, 20 mL) at 0 "C, and the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M). and the solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous Na2S04and concentrated in vacuo to give the title compound as a white solid (4.45 g, 94%). The compound was characterized by the following spectroscopic data:MS (ESI. pos.ion) mlz: 252.23 [M+H]"; and NMR (400 MHz. CDCh) S (ppm): 9.60 (brs.1H).4.94-4.72.4.60-4.57 (m. m. 1H).3.89-3.74 (m.2H). 2.78-2.48 (m.2H).1.44 (d.9H../= 16 Hz).
94% With lithium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2h; To a solution of compound 5-10 (5.0 g, 18.86 mmol) in THF (40 mL) at 0 C was added an aqueous solution of lithium hydroxide (1.5 g, 20 mL) dropwise. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was acidified with aqueous HC1 (1 M) till pH = 5 and then the THF was removed in vacuo. The aqueous layers were acidified with aqueous HC1 (1 M) till pH = 2 and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2SC>4 and concentrated in vacuo to give the title compound as a white solid (4.54 g, 94%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 252.3 [M+H]+; and NMR (400 MHz, CDC13): delta 9.60 (brs, IH), 4.60-4.57, 4.94-4.72 (m, m, IH), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J= 16 Hz) ppm.
94% With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2h; 11125] To a solution of compound 14-3 (5.0 g, 18.86 mmol) in THF (40 mE) at 0 C. was added EiOH aqueous solution (1.5 g, 20 mE), and the mixture was stirred at it for 2 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M), and the solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (80 mEx3). The combined organic layers were dried over anhydrous Na2504 and concentrated in vacuo to give the title compound as a white solid (4.54 g, 94%). The compound was characterized by the following spectroscopic data:11126] MS (ESI, pos.ion) mlz: 252.23 [M+H]11127] ?H NMR (400 MHz, CDC13) oe (ppm): 9.60 (brs, 1H), 4.94-4.72, 4.60-4.57 (m, m, 1H), 3.89-3.74 (m, 2H),2.78-2.48 (m, 2H), 1.44 (d, 9H, J=16 Hz).
94% With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2h; Compound 26-4 (5.0 g, 18.86 mmol) was dissolved in THF (40 mL) and an aqueouslithium hydroxide solution (1.5 g, 20 mL) was added to the system at 0 C. The mixturewas reacted at room temperature for 2.0 hours. After the reaction was completed, thereaction mixture was adjusted to pH 5 with dilute hydrochloric acid (1 M) to remove theTHF. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) andextracted with EtOAc (80 mL x 3). The organic phases were combined, Wash with saturatedbrine, anhydrous Na 2SO 4Drying and concentration gave 4.54 g of white solid, yield: 94%.
86% With water; potassium hydroxide; <strong>[203866-17-5](S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate</strong> (1.51 g, 5.69 mmol), obtained from step 2, was dissolved in 6 mL of 1M potassium hydroxide solution. The solution was stirred overnight. The mixture was washed with ether, acidified, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated to yield slightly brownish crystals. The crude mixture was used without further purification. Yield: 1.23 g, 86% 1H NMR (400 MHz, DMSO-d6): delta 1.38 (s, 9H), 2.32-2.48 (m, 1H), 2.78-2.98 (m, 1H), 3.65-3.77 (m, 2H), 4.31-4.37 (m, 1H), 13.0 (br s, 1H). MS (ESI) m/z 250.8 [M-H]- LC-MS (I) Rt 1.51 min, m/z 252.5 [M+H]+ (90%).
With lithium hydroxide; In tetrahydrofuran; methanol; water; for 2h; Example 3C 4, 4-Difluoro-pyrrolidine-1, 2S-DICARBOXYLIC acid 1-tert-butyl ester The compound from Example 3B (1.80 g, 6. 78 mmol) was dissolved in 3 mL each OF MEOH and THF, then 6.8 mL of 1.7 N LIOH was added. After stirring for 2 hours, the mixture was concentrated in vacuo, and ethyl acetate and IN HCl were added. The organic extracts were dried with NA2SO4 and concentrated to provide the crude acid (1.82 g).
40 mL of a 2 mol/L sodium hydroxide aqueous solution was added dropwise over a period of 4 minutes under ice cooling to a 152 mL methanol solution of 15.2 g of the compound obtained in step 3-2, after which the reaction mixture was stirred for 2.5 hours at the same temperature. Upon completion of the reaction, the methanol was distilled off under reduced pressure, 100 mL of chloroform was added to the aqueous layer thus obtained, and then 90 mL of 1 mol/L hydrochloric acid was added dropwise over a period of 6 minutes under ice cooling. Once it was confirmed that the aqueous layer was acidic, liquid separation was performed, and the aqueous layer was extracted with chloroform (30 mL × 2). The combined organic layer was washed with 50 mL of saturated brine and dried with magnesium sulfate, then the drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 14.1 g of residue (white solid). The residue thus obtained was crystallized from diisopropyl ether/n-hexane to obtain 12.6 g of the titled compound (colorless crystals). MS (ESI neg.) m/z : 250([M-H]-) 1H-NMR (300 MHz, DMSO-d6) delta (ppm) ; 1.36 & 1.41 (each-s, 9 H), 2.31 - 2.53 (m, 1 H), 2.69 - 3.02 (m, 1 H), 3.59 - 3.86 (m, 2 H) 4.30 - 4.43 (m, 1 H), 12.98 (brs, I H)
With sodium hydroxide; water; In methanol; at 20℃; for 1.5h; The crude product of 1-tert-butyl 2-methyl (2S) -4, 4-difluoro-1, 2-pyrrolidinedicarboxylate obtained in Example 8-2 (3.9g) was dissolved in methanol (LLML) and then 1N NaOH (22mL) was added at room temperature. After stirring for 1.5hrs, the resulting mixture was washed with diethyl ether, acidified with 1N HC1 (30ML), and then was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NACL, dried over MGS04, and concentrated in vacuo. The residue was triturated with hexane to give the target compound as a white powder (3. 1G). 1H-NMR (IN CDC13) : D 1. 62-1.30 (9H, m), 2.92-2. 39 (2H, M), 4.02-3. 60 (2H, m), 4.69-4. 41 (1H, m), 7.50 (1H, br-s). MS (ESI-) : m/z 250.19 (M-H).
EXAMPLE 3C 4,4-Difluoro-pyrrolidine-1,2S-dicarboxylic acid 1-tert-butyl ester The compound from Example 3B (1.80 g, 6.78 mmol) was dissolved in 3 mL each of MeOH and THF, then 6.8 mL of 1.7 N LiOH was added. After stirring for 2 hours, the mixture was concentrated in vacuo, and ethyl acetate and 1N HCl were added. The organic extracts were dried with Na2SO4 and concentrated to provide the crude acid (1.82 g).
With potassium hydroxide; Step 3: (S)-1-(iert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (S)-1 -ieri-butyl 2-methyl 4,4-difluoropyrrolidine-1 ,2-dicarboxylate (1 .51 g, 5.69 mmol), obtained from step 2, was dissolved in 6 m l_ of 1 M potassium hydroxide solution. The solution was stirred overnight. The mixture was washed with ether, acidified, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated to yield slightly brownish crystals. The crude mixture was used without further purification. Yield: 1 ,23g, 86% 1 H NMR (400 MHz, DMSO-c) : delta 1 .38 (s, 9H), 2.32 - 2,48 (m , 1 H), 2.78-2.98 (m, 1 H), 3.65 - 3.77 (m, 2H), 4.31 -4.37 (m , 1 H), 13.0 (br s, 1 H). MS (ESI) m/z 250.8 [M-H]~ LC-MS(I) Rt 1 .51 min, m/z 252.5 [M+H]+ (90%).
With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; at 20℃; for 1h; N-Boc-4,4-Difluoro-L-proline methyl ester (1.0 g, 3.77 mmol, 1.0 eq.) was dissolved in THF/MeOH (2 mL / 2 mL) and treated with a solution of lithium hydroxide monohydrate (316 mg, 7.53 mmol, 2.0 eq.) in water (4 mL). The resulting mixture was stirred at room temperature for lh, cooled to 0C, acidified with IN HCl solution, and then extracted three times with EtOAc. The combined organic phases were dried over Na2S04, filtered and concentrated under vacuum to give the desired product, which was used in the next step without further purification.
N-Boc-4,4-Difluoro-L-proline methyl ester (1.0 g, 3.77 mmol, 1.0 eq.) was dissolved in THF/MeOH (2 mL/2 mL) and treated with a solution of lithium hydroxide monohydrate (316 mg, 7.53 mmol, 2.0 eq.) in water (4 mL). The resulting mixture was stirred at room temperature for 1 h, cooled to 0 C., acidified with 1N HCl solution, and then extracted three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuum to give the desired product, which was used in the next step without further purification.
9 g With water; sodium hydroxide; In methanol; at 25℃; for 2h; To a solution of the product from the previous step (11 g, 41.47 mmol, 1.0 eq) in a mixture of THF (80 mL) and MeOH (80 mL) was added dropwise aqueous NaOH (2 M, 41.47 mL, 2.0 eq). The resulting mixture was stirred at 25 C. for 2 hr then concentrated under reduced pressure and partitioned between H2O (40 mL) and EtOAc (30 mL). The layers were separated; the aqueous phase was adjusted to pH 6 by addition of 2M aq. HCl, then extracted with EtOAc (50 mL×5). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (9 g) as a viscous oil. 1H NMR (400 MHz, CDCl3): delta 6.15 (br, 1H), 4.55-4.53 (m, 1H), 3.86-3.73 (m, 2H), 2.72-2.65 (m, 2H), 1.48 (s, 9H).

  • 3
  • [ 203866-17-5 ]
  • [ 126111-14-6 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride; In ethyl acetate; at 20℃; for 4h; A mixture of compound 15-3 (3 g, 11.3 mmol) and a solution of HCl in EtOAc (15 mL, 4 M) was stirred at rt for 4 hours and concentrated in vacuo to give the title compound 15-4 as a white solid (2.27 g, 100%). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 166.14 [M+H]+; and1H NMR (400 MHz, CDCl3): delta 4.70-4.69 (m, 1H), 3.75-3.87 (m, 2H), 3.71 (s, 3H), 2.91-3.00 (m, 1H), 2.70-2.81 (m, 1H).
With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h; To intermediate 5b (300 mg, 1.13 mmol, 1.00 equiv) in diehloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the resulting solution was stirred for 1 h at room temperature. The mixture was then concentrated under reduced pressure to afford 200 mg (crude) of intermediate 5c as a brown oil.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 4h; (0518) <strong>[203866-17-5](S)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate</strong> (0.472 g) in CH2Cl2 (1 ml) was treated with trifluoroacetic acid (1.4 ml), stirred at ambient temperature for 4 hours, and concentrated. The product was free-based using a MEGA BE-SCX column with 1:1 CH2Cl2/methanol as eluent for the trifluoroacetic acid. The product was released from the column with 5% (7 M ammonia in methanol) in CH2Cl2 as eluent.
  • 4
  • [ 203866-17-5 ]
  • [ 215918-21-1 ]
YieldReaction ConditionsOperation in experiment
99% With sodium tetrahydroborate; lithium chloride; In tetrahydrofuran; ethanol; at 0 - 20℃; for 25.25h; A stirred solution of methyl (S)-N-tert-butyloxycarbonyl-4,4-difluoropyrrolidine-2-carboxylate (15) (790 mg, 2.98 mmol, 1.00 equiv.) in THF (10 mL) was treated with LiCl anhydrous (278 mg, 6.55 mmol, 2.20 equiv.) and followed by NaBH4 (282 mg, 7.45 mmol, 2.50 equiv.) at ambient temperature. The resulting mixture was cooled to 0 C, before EtOH (20 mL) was added dropwise over 15 min. Subsequently the mixture was stirred at this temperature for 1 h and at r.t. for 24 h. After this time, the milky mixture was cooled to 0 C and acidified to pH 4 by addition of 10% aq. citric acid. The solvent was completely removed under reduced pressure and it was taken up in water (30 mL). The mixture was extracted with DCM (3 × 30 mL) and the combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 40% EtOAc in cyclohexane) to obtain a colorless oil (700 mg, 2.95 mmol, 99%). 1H NMR (300 MHz, CDCl3): delta = 4.26-4.02 (m, 1H, 2-CH), 3.95-3.54 (m, 4H, 5-CH2, 10-CH2), 2.60-2.38 (m, 1H, 3-CHa), 2.30-2.04 (m, 1H, 3-CHb), 1.48 (s, 9H, 9-CH3) ppm. 13C NMR (75 MHz, CDCl3): delta = 155.7 (6-CO), 126.4 (t, 1JC,F = 246.3 Hz, 4-CF2), 81.4 (8-CO), 65.1 (10-CH2), 58.3 (2-CH), 54.0 (t, 2JC,F = 31.2 Hz, 5-CH2), 36.5 (t, 2JC,F = 23.7 Hz, 3-CH2), 28.3 (3C, 9-CH3) ppm. 19F NMR (282 MHz, CDCl3): delta = -99.8 (br s, 4-CF2, rotamer B), -100.1 (d, 2JF,F = 232.2 Hz, 4-CF2, rotamer A), -101.4 (d, 2JF,F = 233.2 Hz, 4-CF2, rotamer A) ppm. HRMS (ESI+, MeOH): m/z = 260.1063 [M + Na]+; calcd. 260.1069 for C10H17F2NO3 + Na.
95% With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 0.5h;Inert atmosphere; To a stirred solution of 1-(tert-butyl) 2-methyl (S)-4, 4-difluoropyrrolidine-1, 2- dicarboxylate (2 g, 7.54 mmol) in dry THF (20 mL) under an argon atmosphere was added lithium aluminum hydride (286 mg, 7.54 mmol) at 0 oC. The reaction mixture was stirred for 30 min. After consumption of starting material (monitored by TLC), the reaction mixture was filtered, washed with EtOAc (100 mL) and the filtrate was concentrated in vacuo to obtain tert-butyl (S)-4, 4-difluoro-2-(hydroxymethyl) pyrrolidine-1-carboxylate (1.7 g, 95%) as a colorless oil used in the next step without further purification. 1H-NMR (CDCl3 500 MHz): delta 4.20-4.13 (m, 1H), 3.82-3.65 (m, 2H), 2.53-2.49 (m, 1H), 2.16-2.12 (m, 1H), 1.63-1.61 (m, 2H), 1.45 (s, 9H), 1.29-1.26 (m, 1H); TLC: 20% EtOAc:hexanes (Rf: 0.3).
95% With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 0.5h;Inert atmosphere; Synthesis of tert-butyl (S)-4,4-difluoro-2-(hydroxymethyl) pyrrolidine-1-carboxylate To a stirred solution of 1-(tert-butyl) 2-methyl (S)-4,4-difluoropyrrolidine-1, 2-dicarboxylate (2 g, 7.54 mmol) in dry THF (20 mL) under an argon atmosphere was added lithium aluminum hydride (286 mg, 7.54 mmol) at 0 C. The reaction mixture was stirred for 30 min. After consumption of starting material (monitored by TLC), the reaction mixture was filtered, washed with EtOAc (100 mL) and the filtrate was concentrated in vacuo to obtain tert-butyl (S)-4,4-difluoro-2-(hydroxymethyl) pyrrolidine-1-carboxylate (1.7 g, 95%) as a colorless oil used in the next step without further purification. 1H-NMR (CDCl3 500 MHz): delta 4.20-4.13 (m, 1H), 3.82-3.65 (m, 2H), 2.53-2.49 (m, 1H), 2.16-2.12 (m, 1H), 1.63-1.61 (m, 2H), 1.45 (s, 9H), 1.29-1.26 (m, 1H); TLC: 20% EtOAc:hexanes (Rf: 0.3).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; Step A] (S)-4,4-Difluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic Acid Tert-butyl Ester; Lithium aluminium hydride (0.42 g, 0.011 mol) was added in portions to a solution of commercially available (S)-4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 g, 0.0037 mol) in dry THF (25 mL) att 0 C. and allowed to stir for 3 h. The reaction was monitored by TLC and after completion, it was quenched with sat. solution of Na2SO4 in cold condition. The reaction mixture was filtered through a Celite plug. The filtrate was concentrated under reduced pressure using a rotary evaporator to give a crude material, which was purified via column chromatography (2-7% methanol:DCM, mesh Size-100-200 silica, diameter of column-2.5 cm, height of silica-approx. 6 inch) to give the desired (S)-4,4-difluoro-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g) as a beige solid.
With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; Ste linto a solution of 1-tert-butyl 2-methyl (2S)-4, 4-difluoropyrrolidine-l, 2- dicarboxylate (900 mg, 3.39 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added L1BH4 (200 mg, 9.1 mmol, 2.7 equiv) in batches at 0 C. The resulting solution was stirred overnight at room temperature, then was diluted with EtOAc and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 0,8 g of tert-buty. (2S)-4, 4-difluoro- 2~(hydroxymethyl) pyrrolidine- 1 -carboxylate as reddish oil.
With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; Into a solution of 1 -tert-butyl 2~methyl (2S)-4, 4-difluoropyrrolidine-l , 2~dicarboxylate (900 mg, 3,39 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added LiBILs (200 mg, 9.1 mmol, 2.7 equiv) in batches at 0 C. The resulting solution was stirred overnight at room temperature, then was diluted with EA and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of tert-butyl (2S)-4, 4-difluoro-2- (hydroxymethyl) pyrrolidine- 1 -carboxylase as reddish oil.
0.8 g With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; frito a solution of <strong>[203866-17-5]1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate</strong> (900 mg, 339 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added LiBH4 (200 mg, 9.1 mmol, 23 equiv) in batches at 0C. The resulting solution was stirred overnight at room temperature, then was diluted with EA and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate as reddish oil.
0.8 g With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; Step 1. Into a solution of <strong>[203866-17-5]1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate</strong> (900 mg, 3.39 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added LiBH4 (200 mg, 9.1 mmol, 2.7 equiv) in batches at 0 C. The resulting solution was stirred overnight at room temperature, then was diluted with EA and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate as reddish oil.
0.8 g With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; Step 1 Into a solution of <strong>[203866-17-5]1-tert-butyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate</strong> (900 mg, 3.39 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) was added LiBH4 (200 mg, 9.1 mmol, 2.7 equiv) in batches at 0 C. The resulting solution was stirred overnight at room temperature, then was diluted with EA and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate as reddish oil.
With sodium tetrahydroborate; lithium chloride; In tetrahydrofuran; ethanol; at 0 - 20℃; for 15h; To the solution of the product of Step A (4.7 g, 17.72 mmol) in THF (20 mL) was added NaBH4(1.88 g, 44.30 mmol) followed by LiCl (1.48 g, 38.98 mmol) . The mixture solution was cooled to 0 , EtOH (30 mL) was added dropwise. The final solution was stirred at rt for 15 hrs. And then the solution was cooled to 0 , neutralized by 4N HCl till pH4, then concentrated. The residue was washed by water, extracted with DCM (50 mL×3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated to get crude product (3.7 g, 88) as yellow oil, which was used in next step directly. MS: M/e 182 (M-55)+.
With sodium tetrahydroborate; lithium chloride; In tetrahydrofuran; ethanol; at 0 - 20℃; for 18h; To a stirring solution of N-Boc-4,4-fluor-L-methyl prolinate (50.00 g, 188.50 mmol) in THF (500 mL) wereadded LiCl (17.58 g, 414.70 mmol) and NaBH4 (17.83 g, 471.25 mmol) at 10-20 C. The mixture was cooled to 0C and EtOH (1 L) was added. The mixture was stirred for 1 h at 0C, and then was stirred for 17 h at 10-20C. Then the mixture was cooled to 0C and 10% aq. NaHSO4 was added to adjust pH to 3. The mixture was concentrated to remove the solvent, added with water (500 mL) and extracted with dichloromethane (1500 mL) for 3 times. The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give N-Boc-4,4-fluor-L-methyl prolinol (44.00 g, crude product). 1H NMR (CDCl3, 400 MHz): delta 4.19-3.95 (m, 2H), 3.84-3.40 (m, 4H), 2.42 (dq, J = 9.0, 13.1 Hz, 9H), 2.11 (br.s., 1H), 1.46-1.37 (m, 9H).

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