Diisopropylethylamine → (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide

HRID 19015

반응식

HRID 19015 반응식
Cl.OC(C)(C)[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])=[CH:19][C:18]2=[O:31])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.CN1C=CC(N)=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])=[CH:19][C:18]2=[O:31])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1

참가 물질

7

반응물 4

HCID 81531DiisopropylethylamineHCID 1372541-Methyl-3-aminopyrazoleHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 66899077(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

생성물 1

HCID 57920055(S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide

시약·촉매·용매 2

HCID 6228Dimethylformamide용매HCID 8857Ethyl Acetate용매

반응 조건

온도
25 °C

실험 절차

A solution of (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methy-1-pentanoic acid (prepared as in Example 77, 120 mg, 0.34 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (50 mg, 0.51 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (303 mg, 0.68 mmol) and N,N-diisopropylethylamine (110 mg, 0.85 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, water, a 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, 0% to 70% ethyl acetate/hexanes) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide as a waxy material. This material was dissolved in diethyl ether (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The resulting mixture was filtered to give (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (58 mg, 36%) as an orange solid: HR-ES-MS m/z calculated for C20H22Cl2N4O3 [M+Na]+ 459.0961, observed 459.0961; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H) 0.92 (d, J=6.6 Hz, 3H) 1.31-1.64 (m, 2H) 1.64-1.82 (m, 1H) 3.71 (s, 3H) 4.21 (d, J=18.4 Hz, 1H) 4.59 (d, J=18.4 Hz, 1H) 4.82-4.89 (m, 1H) 4.90 (s, 1H) 6.38 (d, J=2.1 Hz, 1H) 7.40-7.57 (m, 3H) 7.62 (dd, J=7.8, 1.5 Hz, 1H) 10.73 (s, 1H).

후처리

  1. washwashed with saturated ammonium chloride, water
  2. dry with materiala saturated sodium chloride solution and dried over sodium sulfate
  3. concentrationThe organic layer was concentrated
  4. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 70% ethyl acetate/hexanes)

출처 및 근거

ORD 기록
ord-0b20bfcd0e37461aa3df531824354dda
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07741327B2

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