Catecholborane → Isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate

HRID 718394

반응식

HRID 718394 반응식
O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([F:36])([F:35])[F:34])[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]([F:36])([F:34])[F:35])[CH2:29][CH2:28]2)=[C:13]([CH:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]

참가 물질

5

반응물 3

HCID 67506CatecholboraneHCID 9838490(R)-2-Methyl-CBS-oxazaborolidineHCID 118307679Isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate

생성물 1

HCID 118307823Isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate수율 101.6%

시약·촉매·용매 1

HCID 1140Toluene용매

반응 조건

온도
-15 °C

실험 절차

The 1.4 mL of benzo[d][1,3,2]dioxaborole (797 mg, 6.65 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-oxoacetate (2 g, 4.43 mmol) and 0.89 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (246 mg, 0.89 mmol) in toluene (40 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3, diluted with EtOAc, and stirred for 30 min. The organic layer was washed with sat'd Na2CO3 solution, brine, and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate 2.04 g (100%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.97/5.82 (d, J=4.4 Hz, 1H), 4.97-4.92 (m, 1H), 3.65 (t, J=11.4 Hz, 1H), 3.20-3.17 (m, 1H), 2.99 (d, J=9.5 Hz, 1H), 2.85 (t, J=12.1 Hz, 1H), 2.53 (s, 3H), 2.40 (s, 3H), 2.31 (br. s, 1H), 1.83-1.77 (m, 2H), 1.69-1.55 (m, 2H), 1.15 (d, J=6.2 Hz, 3H), 1.07 (d, J=6.2 Hz, 3H). UPLC (M+H)=453.4.

후처리

  1. custombefore being placed in the freezer overnight
  2. customThe reaction was quenched with 1M Na2CO3
  3. additiondiluted with EtOAc
  4. washThe organic layer was washed with sat'd Na2CO3 solution, brine
  5. dry with materialdried (MgSO4)
  6. additionThe crude product was charged (DCM)
  7. washto a 40 g ISCO silica gel cartridge and gradient elution (0-30% EtOAc/hexanes)

출처 및 근거

ORD 기록
ord-5bbc94e7516441d6835aa19ef3c03948
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09193720B2

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