新产品编号:370697
Chemical Name: 5-Chloro-N-(1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-yl]-2-methoxy-4-(methylamino)benzamide dimaleate
CAS No. 206434-63-1, 206434-53-9 (free base), 206434-54-0 (free base, (S)-isomer), 206434-49-3 (free base, non-specified stereoch.)
项目整合开发状态: Preclinical
项目研究机构: Dainippon Pharmaceutical (Originator)
合成路线:The reductocondensation of ethanolamine (I) with 3-methylbenzaldehyde (II) by means of NaBH4 gives N-(3-methylbenzyl)ethanolamine (III),which is treated with SOCl2 to yield the 2-chloroethyl derivative (IV).The reaction of (IV) with methylamine (V) affords N-methyl-N'-(3-methylbenzyl)ethane-1,2-diamine (VI),which is condensed with the pyrazole-carboxamide derivative (VII) to provide the unstable compound (VIII)?? (IX).The reduction of (IX) with NaBH4 gives the racemic amide (X),which is submitted to optical resolution by preferential crystallization to yield the (R)-isomer (XI) (1,2).The hydrogenation of (XI) with H2 over Pd/C in ethanol affords the debenzylated compound (XII),which is alkylated by reductocondensation with acetaldehyde (XIII) and NaBH4 in methanol to provide the chiral N-(1-ethyl-4'-methylperhydro-1,4-diazepin-6-(R)-yl)-1H-pyrazole-3-carboxamide (XIV).Finally,this compound is treated with refluxing aqueous HCl to give the corresponding 6(R)-amino derivative (XV).
合成路线:The methylation of 2-hydroxy-4-(4-methylphenylsulfonamido)benzoic acid (XVI) with dimethyl sulfate and KOH in refluxing acetone gives the N,O-dimethylated benzoic acid (XVII),which is chlorinated by means of NCS in hot DMF to yield the chlorobenzoic acid derivative (XVIII).The hydrolysis of (XVIII) with H2SO4 affords 5-chloro-3-methoxy-4-(methylamino)benzoic acid (XIX),which is finally condensed with the aminodiazepine (XV) by means of EDC in dichloromethane to obtain the target chiral benzamide derivative.
📌 参考资料/链接：
参考文献标题:Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives,novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist
文献作者:Hirokawa,Y.; Harada,H.; Yoshikawa,T.; Yoshida,N.; Kato,S.
参考来源:Chem Pharm Bull 2002,50(7),941
📄 详细内容
合成路线:The reductocondensation of ethanolamine (I) with 3-methylbenzaldehyde (II) by means of NaBH4 gives N-(3-methylbenzyl)ethanolamine (III),which is treated with SOCl2 to yield the 2-chloroethyl derivative (IV).The reaction of (IV) with methylamine (V) affords N-methyl-N'-(3-methylbenzyl)ethane-1,2-diamine (VI),which is condensed with the pyrazole-carboxamide derivative (VII) to provide the unstable compound (VIII)?? (IX).The reduction of (IX) with NaBH4 gives the racemic amide (X),which is submitted to optical resolution by preferential crystallization to yield the (R)-isomer (XI) (1,2).The hydrogenation of (XI) with H2 over Pd/C in ethanol affords the debenzylated compound (XII),which is alkylated by reductocondensation with acetaldehyde (XIII) and NaBH4 in methanol to provide the chiral N-(1-ethyl-4'-methylperhydro-1,4-diazepin-6-(R)-yl)-1H-pyrazole-3-carboxamide (XIV).Finally,this compound is treated with refluxing aqueous HCl to give the corresponding 6(R)-amino derivative (XV).
参考文献标题:Synthesis and resolution of (?-N-[1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide by preferential crystallization
文献作者:Harada,H.; et al.
参考来源:Tetrahedron Asymmetry 1997,8(14),2367