Diisopropylethylamine → rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester

HRID 587310Notes

Reaction equation

HRID 587310 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)=[O:41]>ClCCl.CCOC(C)=O>[F:49][C:46]1[CH:47]=[CH:48][C:43]([O:42][C:40](=[O:41])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[CH:44][CH:45]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 27332564-Fluorophenyl chloroformateHCID 58009329rac-{4-[(3S,4R)-3-(3,4-Dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone

Product 1

HCID 58303061rac-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl esterYield 71%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (50 mg, 0.11 mmol) in dichloromethane (1 mL) were added N,N-diisopropyl ethyl amine (29 μl, 0.17 mmol), 4-fluorophenyl chloroformate (19 μl, 0.15 mmol) and the resulting mixture was stirred for 18 h at ambient temperature. It was diluted with EtOAc (15 mL) and washed with an aqueous solution of sodium carbonate (1M, 10 mL). The aqueous layers were extracted with dichloromethane (30 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 90:10) afforded the title compound (45 mg, 68%) as a light brown oil. MS m/e: 576.3 [M+H]+.

Workup

  1. washwashed with an aqueous solution of sodium carbonate (1M, 10 mL)
  2. extractionThe aqueous layers were extracted with dichloromethane (30 mL)
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customPurification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 90:10)

Sources & evidence

ORD record
ord-1f87a9c740934afabfd7e90302286e9e
Source dataset
uspto-grants-2016_01
Patent number
US09226916B2

Reaction notes

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