Sunepitron hydrochloride, CP-93393-1, CP-93393(free base)

1-[[(7S,9aS)-2-嘧啶-2-基-1,3,4,6,7,8,9,9a-八氢吡啶并[1,6-a]吡嗪-7-基]甲基]吡咯烷-2,5-二酮盐酸盐 1-{[(7S,9aS)-2-(嘧啶-2-基)辛氢-2H-吡啶[1,2-a]吡嗪-7-基]甲基}吡咯里定-2,5-二酮 Chemical Name: (7S,9aS)-7-(2,5-Dioxopyrrolidin-1-ylmethyl)-2-(2-pyrimidinyl)octahydro-1H-pyrido[1,2-a]pyrazine hydrochloride; (7S,9aS)-1-[2-(2-Pyrimidinyl)perhydropyrido[1,2-a]pyrazin-7-ylmethyl]pyrrolidine-2,5-dione hydrochloride
CAS No. 148408-65-5, 131831-03-3 (free base), 131744-27-9 (racemic free base)
项目整合开发状态: Phase III
项目研究机构: Pfizer (Originator)
合成路线:The esterification of pyridine-2,5-dicarboxylic acid (I) with thionyl chloride/methanol gives the corresponding dimethyl ester (II),which is hydrogenated with H2 over PtO2 in acetic acid yielding piperidine-2,5-dicarboxylic acid dimethyl ester (III),as a mixture of the cis- and trans-isomers.The condensation of (III) with 2-chloroacetonitrile (IV) by means of Na2CO3 in refluxing isobutyl methyl ketone affords the expected 1-(cyanomethyl) derivative (V),which is cyclized by hydrogenation with H2 over RaNi in methanol/ethyl acetate giving racemic cis-1-oxo-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid methyl ester (VI).The reduction of (VI) with LiAlH4 in refluxing THF yields the corresponding hydroxymethyl derivative (VII),which is condensed with 2-chloropyrimidine by means of Na2CO3 in refluxing water affording racemic cis-7-(hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (IX).The reaction of (IX) with methanesulfonyl chloride and triethylamine gives the expected mesylate (X),which is treated with sodium azide in DMF to afford the corresponding azido derivative (XI).The reaction of (XI) with hydrazine in refluxing ethanol gives the racemic cis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XII),which is submitted to optical resolution by formation of the corresponding salt with (-)-mandelic acid,separation of the diastereomers by crystallization,and decomposition of the desired salt with NaOH to yield (7R,9aS)-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XIII).Finally,this compound is condensed with succinic anhydride (XIV) in refluxing xylene.