Potassium Phosphate, Tribasic → (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate

HRID 718417노트

반응식

HRID 718417 반응식
[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Br)=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]1[CH:61]=[CH:60][C:39]([CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46](B3OC(=O)CN(C)CC(=O)O3)=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C(O[Pd]OC(=O)C)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:46]3[CH:45]=[CH:44][C:43]([O:42][CH2:41][CH2:40][C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:61][CH:60]=4)=[CH:48][CH:47]=3)=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

참가 물질

9

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 118307778(S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateHCID 1317341662-(4-(4-Fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

생성물 1

HCID 118307842(S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate수율 39.1%

시약·촉매·용매 4

HCID 167845palladium(II) acetate촉매HCID 962Water용매HCID 8857Ethyl Acetate용매HCID 312751,4-Dioxane용매

반응 조건

온도
90 °C

실험 절차

The diacetoxypalladium (11.3 mg, 0.05 mmol) was added to a argon purged and degassed solution of (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (267 mg, 0.502 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (205 mg, 0.553 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (41 mg, 0.10 mmol), and potassium phosphate tribasic (800 mg, 3.77 mmol) in dioxane (4 mL) and water (0.8 mL) and stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-35% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 131 mg (39%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.43-7.37 (m, 2H), 7.24-7.22 (m, 2H), 7.18-7.12 (m, 4H), 7.10 (t, J=7.3 Hz, 2H), 6.99-6.92 (m, 3H), 5.92 (s, 1H), 4.97-4.92 (m, 1H), 4.21 (t, J=6.2 Hz, 2H), 3.37-3.37 (m, 4H), 3.06 (t, J=6.2 Hz, 2H), 2.46 (br. s, 2H), 2.42 (s, 3H), 2.02 (s, 3H), 1.70 (t, J=8.8 Hz, 1H), 1.45-1.43 (m, 1H), 1.37-1.34 (m, 1H), 1.29-1.22 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.14 (d, J=3.2 Hz, 3H), 1.09 (m, 9H). UPLC (M+H)=667.5.

후처리

  1. custompurged
  2. temperatureto cool
  3. washthe organic layer was washed with brine
  4. dry with materialdried (MgSO4)
  5. additionThe crude product was charged (DCM)
  6. washto a 40 g ISCO silica gel cartridge and gradient elution (0-35% EtOAc/hexanes)

출처 및 근거

ORD 기록
ord-91b8b48c2dd64881b85757f7fe0fa483
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09193720B2

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