A practical synthesis of capromorelin (1), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one [(±)-2] by (L)-tartaric acid salt formation, yielding (R)-2.L-tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of ∼98%. Treatment of (R)-2.L-tartaric acid with ammonium hydroxide provided (R)-2 without loss of chiral purity. In situ generated (R)-2 was coupled with (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonyl)-2-methylpropanamido)propanoic acid [(R)-3] to give predominantly a single diastereomer of N-Boc-protected capromorelin [(1R,3aR)-4]. This process was used to prepare bulk quantities of capromorelin from (±)-2 to support preclinical toxicology studies.

中文翻译：

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通过结晶诱导的动态拆分，实际合成生长激素促生长素capromorelin

描述了一种实际的合成Capromorelin（1）（生长激素促分泌剂）的方法，该方法利用（±）-3a-苄基-2-甲基-4,5,6的结晶诱导动态拆分（CIDR）作为关键步骤，通过（L）-酒石酸盐形成7-四氢-2H-吡唑并[4,3-c]吡啶-3（3aH）-一[（±）-2]，得到（R）-2.L-酒石酸化学产率高（＞ 85％），非对映异构体过量（de）约98％。用氢氧化铵处理（R）-2.L-酒石酸可提供（R）-2，而不会损失手性纯度。原位生成的（R）-2与（R）-3-（苄氧基）-2-（2-（叔丁氧基羰基）-2-甲基丙酰胺基）丙酸[（R-3）]偶合N-Boc保护的己内莫林[（1R，3aR）-4]的非对映异构体。此过程用于从（±）-2制备大量的己内莫林，以支持临床前毒理学研究。