Tris(2,4-di-tert-butylphenyl) phosphite → N-[4-Dimethylaminomethyl-5-(1-methyl-cyclopropyl)-thiazol-2-yl]-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide

HRID 1446767

반응식

HRID 1446767 반응식
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]([C:21]3([CH3:24])[CH2:23][CH2:22]3)=[C:15]([CH2:17][N:18]([CH3:20])[CH3:19])[N:16]=2)=[O:10])=[C:4]([F:25])[CH:3]=1.[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]3[CH:38]=[CH:39][N:40]=[C:34]3[CH:33]=2)=[CH:28][CH:27]=1.C([O-])(=O)C.[K+].C(C1C=C(C(C)(C)C)C=CC=1OP(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(C)(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1C(=O)CCC1>[CH3:19][N:18]([CH2:17][C:15]1[N:16]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:38]3[N:35]4[CH:36]=[CH:37][C:32]([C:29]5[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=5)=[CH:33][C:34]4=[N:40][CH:39]=3)=[CH:3][C:4]=2[F:25])[S:13][C:14]=1[C:21]1([CH3:24])[CH2:23][CH2:22]1)[CH3:20]

참가 물질

7

반응물 4

HCID 91601Tris(2,4-di-tert-butylphenyl) phosphiteHCID 517044Potassium AcetateHCID 685456367-Pyridin-4-yl-imidazo[1,2-a]pyridineHCID 866343112-(4-bromo-2-fluoro-phenyl)-N-[4-dimethylaminomethyl-5-(1-methyl-cyclopropyl)-thiazol-2-yl]-acetamide

생성물 1

HCID 11853469N-[4-Dimethylaminomethyl-5-(1-methyl-cyclopropyl)-thiazol-2-yl]-2-[2-fluoro-4-(7-pyridin-4-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetamide수율 20.7%

시약·촉매·용매 2

HCID 74236Tetrabutylammonium Bromide촉매HCID 13387N-methyl-2-pyrrolidone용매

반응 조건

온도
120 °C

실험 절차

Combine 2-(4-bromo-2-fluoro-phenyl)-N-[4-dimethylaminomethyl-5-(1-methyl-cyclopropyl)-thiazol-2-yl]-acetamide (0.45 g, 1.06 mmol), 7-pyridin-4-yl-imidazo[1,2-a]pyridine (0.206 g, 1 equiv.), potassium acetate (0.52 g, 5 equiv.), tetrabutylammonium bromide (0.34 g, 1 equiv.), tris(2,4-di-t-butylphenyl)phosphite (0.034 g, 5 mol %) and NMP (10 mL). De-gas with nitrogen then add palladium (II) acetate (0.012 g, 5 mol %) and place under nitrogen. Heat at 120° C. for 24 hours then let stir at room temperature for an additional day. Dilute with ethyl acetate then wash with water, 1 N NaOH (aq), and aqueous saturated sodium chloride. Dry organics over MgSO4, then filter and concentrate. Purify by reverse phase C18 column HPLC employing a gradient of 5 to 65% to 100% acetonitrile versus 0.03% aqueous HCl then freebase by extraction with ethyl acetate versus 1 N NaOH (aq). Dry the organics over MgSO4, then filter, and concentrate to give product (118 mg tan solid, 21%). MS (ES), m/z 541 (M+1).

후처리

  1. customDe-gas with nitrogen
  2. additionDilute with ethyl acetate
  3. washthen wash with water, 1 N NaOH (aq), and aqueous saturated sodium chloride
  4. filtrationDry organics over MgSO4, then filter
  5. concentrationconcentrate
  6. customPurify by reverse phase C18 column HPLC
  7. extractionfreebase by extraction with ethyl acetate versus 1 N NaOH (aq)
  8. dry with materialDry the organics over MgSO4
  9. filtrationfilter
  10. concentrationconcentrate

출처 및 근거

ORD 기록
ord-8a89385d1aa44aedb3f951a6ae52103e
출처 데이터셋
uspto-grants-2010_02
특허 번호
US07666879B2

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