3αR-苄基-1-(叔丁基)氧羰基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-c]吡啶-3-(3H)-酮的合成

Synthesis of 3αR-Benzyl-1-(tert-butyl)oxycarbonyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo-[4,3-c]pyridine-3(3αH)-one

在O-烯丙基-N-9-蒽甲基溴化辛可宁的催化下,1-苄基-3-乙氧羰基-4-哌啶酮与溴化苄经不对称苄基化反应制得( R )-1,3-二苄基-4-氧代哌啶-3-甲酸乙酯( 3 );3 脱除Bn保护基并经Boc保护转化为( R )-3-苄基-1-(叔丁基)氧羰基-4-氧代哌啶-3-甲酸乙酯( 5 );5 与甲基肼在乙醇中经环化反应合成了Capromorelin的关键中间体3 αR -苄基-1-(叔丁基)氧羰基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3- c]吡啶-3-(3H)-酮,收率70%,ee值 69.1%,其结构经^1H NMR,^13C NMR和HR-MS(ESI)确证。

Under the catalysis of O -allyl- N -9-anthracenemethylcindexnine bromide,( R )-1,3-dibenzyl-4- oxopiperidine-3-carboxylic acid ethyl ester( 3 ) was obtained by the asymmetric benzylation of 1-benzyl-3-ethoxycarbonyl-4-piperidone with benzyl bromide. Then 3 was converted into ethyl ( R )-3-benzyl-1-( tert - butyl)oxycarbonyl-4-oxopiperidine-3-carboxylate( 5 ) through two steps of protecting group change. 3 αR -Benzyl-1-( tert -butyl)oxycarbonyl-2-methyl-4,5,6,7-tetrahydro-2 H -pyrazolo[4,3- c ]pyridine-3-(3 H )-one( 6 ), a key intermediate for Capromorelin, was obtained with 70% yield and ee 69.1% by cyclization of 5 with methyl hydrazine in EtOH. The structure was confirmed by ^1H NMR ,^13C NMR and HR-MS(ESI).