M-274773, ZM-274773

N-[2(S)-(3,4-二氯苯基)-4-[4-(2-氧基氢嘧啶-1-酰)哌啶-1-基]丁基]-N-甲基苯甲酰胺二盐酸盐Chemical Name: N-[2(S)-(3,4-Dichlorophenyl)-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidin-1-yl]butyl]-N-methylbenzamide dihydrochloride
CAS No. 164518-66-5
项目整合开发状态: Preclinical
项目研究机构: AstraZeneca (Originator)
合成路线:The reaction of 2-bromoethanol (I) with dihydropyran by means of a strong acid ion exchange resin gives the tetrahydropyranyl ether (II),which is condensed with 2-(3,4-dichlorophenyl)acetonitrile (III) by means of NaH in THF yielding thebutyronitrile (IV).The reduction of (IV) with H2 over RaNi in ethanol/NH4OH affords the butylamine (V),which is deprotected with HCl in methanol providing racemic 2-(3,4-dichlorophenyl)-4-hydroxybutylamine (VI).The optical resolution of (VI) with D-tartaric acid affords the corresponding (S) isomer (VII),which is treated with ethyl chloroformate and triethylamine in dichloromethane to give the carbamate (VIII).The reduction of (VIII) with LiAlH4 in THF yields N-[2(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methylamine (IX),which is acylated with benzoyl chloride (X) and triethylamine in dichloromethane to affords the amide (XI).Oxidation of the hydroxyl group of (XI) with Dess-Martin periodinane yields the corresponding aldehyde (XII),which is reductocondensed with 4-[N-(trifluoroacetyl)-N-[3-(trifluoroacetamido)propyl]amino]piperidine (XIII) by means of NaBH3CN in methanol/acetic acid providing the bis(trifluoroacetylated) intermediate (XIV).The deprotection of (XIV) with KOH in methanol/water gives the diamine intermediate (XV),which is finally cyclized with carbonyldiimidazole (CDI) in chloroform.

合成路线:The trifluoroacetylated intermediate (XIII) has been obtained as follows: The reductocondensation of 1-(benzyloxycarbonyl)-4-piperidone (XVI) with propylene-1,3-diamine (XVII) by means of NaBH3CN in methanol/acetic acid gives 4-(3-aminopropylamino)-1-(benzyloxycarbonyl)piperidine (XVIII),which is acylated with trifluoroacetyl anhydride and triethylamine in chloroform yielding the protected diacylated piperidine (XIX).Finally,this compound is deprotected by hydrogenation with H2 over Pd/C in ethanol to afford the target intermediate (XIII).