SUN-C5174
5-[3-[4-(4-氟苯)吡喃嗪-1-基]丙基]-8(S)-羟基-1-甲基-1,4,5,6,7,8-六氢吡咯酸[3,2-c]阿泽平-4-1Chemical Name: 5-[3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl]-8(S)-hydroxy-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one
CAS No. 191592-36-6, 191592-35-5 ((S)-isomer), 191592-09-3 (undefined isomer)
项目整合开发状态: Phase II
项目研究机构: Daiichi Suntory Pharma (Originator)
合成路线:The condensation of 1-methylpyrole-3-carboxylic acid (I) with beta-alanine benzyl ester (II) by means of diethyl phosphorocyanidate (PCA) in DMF gives the corresponding amide (III),which is debenzylated with H2 over Pd/C in THF yielding the substituted beta-alanine (IV).The cyclization of (IV) by means of polyphosphoric acid (PPA) at 100 C affords the pyrroloazepine (V),which is alkylated with 1-bromo-3-chloropropane (VI) and potassium tert-butoxide in THF giving the 3-chloropropyl derivative (VII).The condensation of (VII) with 1-(4-fluorophenyl)piperazine (VIII) by means of K2CO3 and NaI in refluxing acetonitrile yields the expected addition product (IX),which is selectively reduced at the 8-position with NaBH4 in ethanol affording the 8-hydroxy derivative (X) as a racemic mixture.Finally,this compound is submitted to optical resolution by chiral chromatography providing the target chiral compound.
📌 参考资料/链接：
参考文献标题:Pyrroloazepine derivs.
文献作者:Mizuno,A.; Shibata,M.; Iwamori,T.; Shimamoto,T.; Nakanishi,K.; Inomata,N.(Suntory Ltd.)
参考来源:EP 0807632; US 5962448; WO 9720845
📄 详细内容
合成路线:The condensation of 1-methylpyrole-3-carboxylic acid (I) with beta-alanine benzyl ester (II) by means of diethyl phosphorocyanidate (PCA) in DMF gives the corresponding amide (III),which is debenzylated with H2 over Pd/C in THF yielding the substituted beta-alanine (IV).The cyclization of (IV) by means of polyphosphoric acid (PPA) at 100 C affords the pyrroloazepine (V),which is alkylated with 1-bromo-3-chloropropane (VI) and potassium tert-butoxide in THF giving the 3-chloropropyl derivative (VII).The condensation of (VII) with 1-(4-fluorophenyl)piperazine (VIII) by means of K2CO3 and NaI in refluxing acetonitrile yields the expected addition product (IX),which is selectively reduced at the 8-position with NaBH4 in ethanol affording the 8-hydroxy derivative (X) as a racemic mixture.Finally,this compound is submitted to optical resolution by chiral chromatography providing the target chiral compound.
合成路线:The condensation of 1-methylpyrrole-3-carboxylic acid (I) with 3-(3-chloropropylamino)propionic acid ethyl ester (II) by means of WSC and TEA gives the corresponding amide (III),which is hydrolyzed with NaOH to yield the amino acid (IV).The cyclization of (IV) by means of Ms-OH and P2O5 affords the pyrroloazepinedione (V),which is condensed with 1-(4-fluorophenyl)piperazine (VI) by means of K2CO3 or NaHCO3 and NaI to provide the adduct (VII).Finally,this compound is regioselectively monoreduced with NaBH4 to give the racemic alcohol (VIII),which is submitted to optical resolution by crystallization of its L-(+)-tartrate salt to afford the target (S)-enantiomer.
参考文献标题:Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds
文献作者:Mizuno,A.; Ogata,A.; Kamei,T.; Shibata,M.; Shimamoto,T.; Hayashi,Y.; Nakanishi,K.; Takiguchi,C.; Oka,N.; Inomata,N.
参考来源:Chem Pharm Bull 2000,48(5),623
产品链接: CAS No. 191592-36-6›› 产品链接: CAS No.191592-09-3››