Triethylamine → (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide

HRID 19024노트

반응식

HRID 19024 반응식
[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[CH:14][C:13]2=[O:28])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:35][N:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C(N(CC)CC)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])=[CH:14][C:13]2=[O:28])[C:9]([NH:41][C:38]2[CH:39]=[CH:40][N:36]([CH3:35])[N:37]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

참가 물질

8

반응물 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 1372541-Methyl-3-aminopyrazoleHCID 66893512(S)-3-cyclohexyl-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid

생성물 1

HCID 57920072(S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide

시약·촉매·용매 3

HCID 6228Dimethylformamide촉매HCID 6344Dichloromethane용매2회HCID 8857Ethyl Acetate용매

실험 절차

A solution of (S)-3-cyclohexyl-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (prepared as in Example 32, 100 mg, 0.25 mmol) in dichloromethane (4 mL) was treated with a dichloromethane solution of oxalyl chloride (2 M, 0.25 mL) and one drop of N,N-dimethylformamide. The mixture was stirred for 45 min and solvents were evaporated. The residue was dissolved in dichloromethane (4 mL) and treated with 1-methyl-1H-pyrazol-3-ylamine (30 mg, 0.30 mmol), and triethylamine (50 mg, 0.5 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride solution, water, saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100% ethyl acetate/hexanes) to afford (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide. This material was dissolved in dichloromethane (4 mL) and treated with 1M hydrogen chloride in diethyl ether (2 mL). Solvents were evaporated and the residue was triturated with diethyl ether and filtered to give (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[2-oxo-4-(2-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide hydrochloride (20 mg, 16%) as a tan solid: LR-ES-MS m/z calculated for C24H27F3N4O3 [M]+ 476, observed [M+H]+ 477; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.32 (m, 6H) 1.51-1.87 (m, 7H) 3.73 (s, 3H) 4.19 (d, J=18.7 Hz, 1H) 4.58 (d, J=18.7 Hz, 1H) 4.86-4.94 (m, 1H) 4.96 (s, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.47-7.58 (m, 2H) 7.65 (d, J=7.8 Hz, 1H) 7.74-7.90 (m, 2H) 10.72 (s, 1H).

후처리

  1. customsolvents were evaporated
  2. dissolutionThe residue was dissolved in dichloromethane (4 mL)
  3. stirringThe reaction mixture was stirred for 4 h at 25° C., under nitrogen
  4. washwashed with saturated ammonium chloride solution, water, saturated sodium chloride solution
  5. dry with materialdried over sodium sulfate
  6. concentrationThe organic layer was concentrated
  7. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100% ethyl acetate/hexanes)

출처 및 근거

ORD 기록
ord-aed2909ecc644ab59375450e02bd0f3c
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07741327B2

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