Cesium carbonate → 5-(3,3-Difluoro-azetidin-1-yl)-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

HRID 1480142노트

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HRID 1480142 반응식
[CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18](Br)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[F:81][C:82]1([F:86])[CH2:85][NH:84][CH2:83]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]([N:84]3[CH2:85][C:82]([F:86])([F:81])[CH2:83]3)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 902039835-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

생성물 1

HCID 762837015-(3,3-Difluoro-azetidin-1-yl)-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide수율 28%

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 1140Toluene용매

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온도
120 °C

실험 절차

To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 78g, 0.05 g, 111 μmol) in dry Toluene (1 ml) under argon atmosphere were added palladium(II) acetate (3.75 mg, 16.7 μmol), BINAP (10.4 mg, 16.7 μmol), cesium carbonate (90.7 mg, 278 μmol) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 15.9 mg, 122 μmol). The reaction mixture was stirred at 120° C. for 45 minutes under microwave radiation. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethylacetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (14.2 mg, 28%) as a white solid. MS (ESI, m/z): 462.4 (M+H+).

후처리

  1. filtrationThe reaction mixture was filtered through a pad of Celite
  2. concentrationthe filtrate was concentrated in vacuo
  3. dissolutionThe residue was dissolved in ethylacetate
  4. extractionextracted with an 1.0M aqueous solution of sodium bicarbonate
  5. dry with materialThe organic phase was dried over sodium sulfate
  6. customevaporated down to dryness
  7. customThe crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient

출처 및 근거

ORD 기록
ord-5672effe9e904464a10af4aae96a8909
출처 데이터셋
uspto-grants-2016_08
특허 번호
US09409866B2

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