Structure of 215918-21-1
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CAS No. : | 215918-21-1 |
Formula : | C10H17F2NO3 |
M.W : | 237.24 |
SMILES Code : | O=C(N1[C@H](CO)CC(F)(F)C1)OC(C)(C)C |
MDL No. : | MFCD12755205 |
InChI Key : | KQLZXWXCBWPDAD-ZETCQYMHSA-N |
Pubchem ID : | 20648576 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation 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). |
Tags: 215918-21-1 synthesis path| 215918-21-1 SDS| 215918-21-1 COA| 215918-21-1 purity| 215918-21-1 application| 215918-21-1 NMR| 215918-21-1 COA| 215918-21-1 structure
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