Diisopropylethylamine → 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

HRID 1990050노트

반응식

HRID 1990050 반응식
ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.Cl.[F:38][CH:39]([F:46])[N:40]1[CH:44]=[CH:43][C:42]([NH2:45])=[N:41]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:45][C:42]3[CH:43]=[CH:44][N:40]([CH:39]([F:46])[F:38])[N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1

참가 물질

6

반응물 4

HCID 81531DiisopropylethylamineHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 536296783-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acidHCID 536296981-(difluoromethyl)-1H-pyrazol-3-amine hydrochloride

생성물 1

HCID 536295863-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide수율 60.1%

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.088 mL, 0.66 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (171 mg, 0.44 mmol) in DCM (10 mL) and the reaction was stirred at RT for 30 minutes. After this time 1-(difluoromethyl)pyrazol-3-amine hydrochloride (75 mg, 0.44 mmol) and DIPEA (0.154 mL, 0.89 mmol) were added sequentially. The resulting solution was stirred at RT for 16 hours after which time the solvent was removed in vacuo and ethyl acetate (20 mL) and water (20 mL) were added. The aqueous phase was extracted with ethyl acetate (2×20 mL), washed with a saturated solution of sodium hydrogen carbonate (20 mL), and brine (20 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography on silica, eluting with 50-100% ethyl acetate in isohexane, to give the desired product as a white solid (132 mg). 1H NMR δ (CDCl3): 2.40-2.12 (m, 4H), 4.03-3.89 (m, 4H), 4.25 (t, 2H), 4.71 (t, 2H), 5.01-4.96 (m, 1H), 6.76 (t, 1H), 7.03 (t, 1H), 7.08 (d, 1H), 7.11 (s, 1H), 7.22 (s, 1H), 7.38 (dd, 1H), 7.75 (d, 1H), 8.13 (d, 1H), 8.33 (d, 1H), 8.50 (s, 1H); 19F NMR δ (CDCl3): −93.84; m/z 500 (M+H)+.

후처리

  1. stirringThe resulting solution was stirred at RT for 16 hours after which time the solvent
  2. customwas removed in vacuo and ethyl acetate (20 mL) and water (20 mL)
  3. additionwere added
  4. extractionThe aqueous phase was extracted with ethyl acetate (2×20 mL)
  5. washwashed with a saturated solution of sodium hydrogen carbonate (20 mL), and brine (20 mL)
  6. dry with materialThe combined organic extracts were dried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by flash column chromatography on silica
  10. washeluting with 50-100% ethyl acetate in isohexane

출처 및 근거

ORD 기록
ord-3a4093865f6e4043a4abe6704ad206dd
출처 데이터셋
uspto-grants-2010_01
특허 번호
US07642263B2

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