Azetidine → 2-Fluoro-4-(3-(1-(7-fluoroquinolin-2-YL)azetidin-3-YL)pyrazin-2-YL)-N-methylbenzamide

HRID 624524노트

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HRID 624524 반응식
FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([NH:38][CH3:39])=[O:37])=[C:34]([F:42])[CH:33]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=2)[N:56]=1)(=O)=O.N1CCC1>O.CS(C)=O>[F:42][C:34]1[CH:33]=[C:32]([C:27]2[C:26]([CH:24]3[CH2:23][N:22]([C:55]4[CH:64]=[CH:63][C:62]5[C:57](=[CH:58][C:59]([F:65])=[CH:60][CH:61]=5)[N:56]=4)[CH2:25]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:41]=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37]

참가 물질

7

반응물 4

HCID 10422AzetidineHCID 11430Potassium CarbonateHCID 866941337-Fluoroquinolin-2-yl trifluoromethanesulfonateHCID 867054064-(3-(Azetidin-3-YL)pyrazin-2-YL)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate)

생성물 1

HCID 726942252-Fluoro-4-(3-(1-(7-fluoroquinolin-2-YL)azetidin-3-YL)pyrazin-2-YL)-N-methylbenzamide수율 78%

시약·촉매·용매 2

HCID 679Dimethyl Sulfoxide용매HCID 962Water용매

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온도
50 °C

실험 절차

A mixture of 4-(3-(azetidin-3-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide tris(2,2,2-trifluoroacetate) (0.953 g, 1.517 mmol), potassium carbonate (0.839 g, 6.070 mmol), 7-fluoroquinolin-2-yl trifluoromethanesulfonate (0.537 g, 1.821 mmol, prepared according to Step 3 of Example 2), and DMSO (10 mL) was stirred at 50° C. for 1 h. LCMS showed the product and no more azetidine starting material. The mixture was diluted with water and extracted with CH2Cl2 three times. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude was purified by silica gel chromatography: 40 g, 5-100% EtOAc-hexane. The impurity 2-hydroxyquinoline was further removed by trituration with CH2Cl2 and hexane twice. The product was obtained as a white solid (510 mg, 78%). 1H NMR (400 MHz, chloroFORM-d) δ ppm 3.09 (d, J=4.50 Hz, 3 H) 4.33-4.50 (m, 5 H) 6.56 (d, J=9.00 Hz, 1 H) 6.81 (d, J=7.04 Hz, 1 H) 6.98 (td, J=8.61, 2.54 Hz, 1 H) 7.31-7.45 (m, 3 H) 7.56 (dd, J=8.71, 6.36 Hz, 1 H) 7.84 (d, J=9.00 Hz, 1 H) 8.28 (t, J=8.02 Hz, 1 H) 8.57 (d, J=2.15 Hz, 1 H) 8.64 (d, J=2.35 Hz, 1 H). m/z=432 (M+1 ).

후처리

  1. extractionextracted with CH2Cl2 three times
  2. dry with materialThe organic layer was dried over Na2SO4
  3. concentrationconcentrated in vacuo
  4. customThe crude was purified by silica gel chromatography
  5. customThe impurity 2-hydroxyquinoline was further removed by trituration with CH2Cl2 and hexane twice

출처 및 근거

ORD 기록
ord-43bc2685674a42e2835200e360db6156
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09303028B2

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