Diisopropylethylamine → 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester

HRID 19007노트

반응식

HRID 19007 반응식
[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32][CH:31]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[CH:6][C:7]2=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:32][CH:31]=1

참가 물질

7

반응물 4

HCID 81531DiisopropylethylamineHCID 737487Methyl 6-aminonicotinateHCID 2733179PyBroPHCID 66893500(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid

생성물 1

HCID 442517366-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester수율 33%

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 8857Ethyl Acetate용매

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온도
25 °C

실험 절차

A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 206 mg, 0.54 mmol) in dichloromethane (5 mL) was treated with 6-amino-nicotinic acid methyl ester (110 mg, 0.72 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (503 mg, 1.1 mmol) and N,N-diisopropylethylamine (150 mg, 1.1 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 100% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (90 mg, 33%): 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.36 (m, 6H) 1.40-1.92 (m, 7H) 3.86 (s, 3H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 5.00 (s, 1H) 5.01-5.10 (m, 1H) 7.30-7.61 (m, 3H) 8.16 (d, J=8.8 Hz, 1H) 8.29 (dd, J=8.8, 2.1 Hz, 1H) 8.87 (d, J=2.1 Hz, 1H) 11.32 (s, 1H). HR-ES-MS m/z calculated for C26H27ClFN3O5 [M+H]+ 516.1696, observed 516.1696.

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 100% ethyl acetate/hexanes)

출처 및 근거

ORD 기록
ord-797f94d384f346ca8094e0e606522cac
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07741327B2

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