Hydrochloric Acid → (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride

HRID 19009

반응식

HRID 19009 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]([OH:13])=O)[C:7](=[O:21])[CH:6]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[NH2:33].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.Cl>ClCCl.C(OCC)(=O)C.C(OCC)C>[ClH:1].[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]([NH:33][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][N:27]=2)=[O:13])[C:7](=[O:21])[CH:6]=1

참가 물질

9

반응물 5

HCID 313Hydrochloric AcidHCID 78747AminopyrazineHCID 81531DiisopropylethylamineHCID 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 44251873(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride수율 33%

시약·촉매·용매 3

HCID 3283Diethyl Ether용매HCID 6344Dichloromethane용매2회HCID 8857Ethyl Acetate용매

반응 조건

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, 200 mg, 0.52 mmol) in dichloromethane (5 mL) was treated with pyrazin-2-ylamine (65 mg, 0.68 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (503 mg, 1.1 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 100% ethyl acetate/hexanes) to give a waxy material. This material was dissolved in dichloromethane (2 mL). The clear solution was treated with hydrogen chloride in diethyl ether (1M, 4 mL) and solvents were evaporated. The residue was triturated with diethyl ether and filtered to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride (28 mg, 33%) as a orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.37 (m, 6H) 1.43-1.95 (m, 7H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 5.00 (s, 1H) 5.02-5.12 (m, 1H) 7.36-7.57 (m, 3H) 8.38 (d, J=2.4 Hz, 1H) 8.40-8.47 (m, 1H) 9.27 (d, J=1.2 Hz, 1H) 11.20 (s, 1H). HR-ES-MS m/z calculated for C23H24ClFN4O3 459.1594, observed 459.1593 [M+H]+.

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)
  5. customto give a waxy material
  6. customwere evaporated
  7. customThe residue was triturated with diethyl ether
  8. filtrationfiltered

출처 및 근거

ORD 기록
ord-740c58233cc64e52b71a49e6f4a7df9b
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07741327B2

연결된 노트

불러오는 중…