WAY-141608

Chemical Name: 1-[6,11-Dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl]-1-[4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)phenyl]methanone
CAS No. 220602-65-3
项目整合开发状态: Preclinical
项目研究机构: Wyeth Pharmaceuticals (Originator)
合成路线:Condensation between 1,2-phenylenediamine (I) and 2-chloronicotinic acid (II) in refluxing cyclohexanol generated the tricyclic system (III).Reduction of keto group of (III) with borane-dimethyl sulfide complex afforded 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (IV).Acid chloride (VI),prepared from 4-fluoro-2-(trifluoromethyl)benzoic acid (V),was then condensed with tricyclic amine (IV) to produce amide (VII).Finally,displamecement of the 4-fluoro group of (VII) by the sodium salt of 3-methylpyrazole (VIII) in hot DMF yielded a 5:1 mixture of the title 3-methylpyrazole derivative and its 5-methyl regioisomer (IX),which were separated by column chromatography.

合成路线:In a modified procedure,4-fluoro-2-(trifluoromethyl)benzoic acid (V) was converted to acid chloride (VI) and then esterified with methanol to give methyl ester (X).Condensation of (X) with 3-methylpyrazole (VIII) produced a mixture of regioisomeric pyrazoles (XI) and (XII) from which the major 3-methyl isomer (XI) could be isolated by either flash chromatography or by recrystallization from EtOAc-hexane.Basic hydrolysis of the methyl ester of (XI) gave acid (XIII),which was finally coupled with tricyclic amine (IV) via activation as the mixed anhydride with 2,4,6-trichlorobenzoic acid.

合成路线:An additional improvement in the ratio of regioisomeric pyrazoles was achieved by displacement of 4-fluoro-2-(trifluoromethyl)benzonitrile (XIV) with 3-methylpyrazole (VIII) in the presence of potassium tert-butoxide to afford a 9:1 mixture of the desired 3-methylpyrazole derivative (XV) and its 5-methyl isomer.Direct recrystallization from EtOH provided pure (XV) that was then hydrolyzed to the carboxylic acid (XIII) by means of NaOH in H2O-EtOH.