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

Reaktionsgleichung

Reaktionsgleichung von HRID 1446767
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]

Komponenten

7

Edukt 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

Produkt 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]-acetamideAusbeute 20,7 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 74236Tetrabutylammonium BromideKatalysatorHCID 13387N-methyl-2-pyrrolidoneLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-8a89385d1aa44aedb3f951a6ae52103e
Quelldatensatz
uspto-grants-2010_02
Patentnummer
US07666879B2

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