Process Development of an Efficient Kilogram-Scale Preparation of a Preferential Dopamine D3 versus D2 Receptor Antagonist SIPI 6398 as a New Antipsychotic Candidate

Herein we describe the development of a kilogram-scale preparation of a preferential dopamine D3 versus D2 receptor antagonist SIPI 6398 (1) as a new alternative treatment for schizophrenia. Modification and optimization of the route includes one-pot synthesis of a trans/cis mixture of cyclohexyl et...

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Published inOrganic process research & development Vol. 23; no. 7; pp. 1442 - 1449
Main Authors Zhou, Ai-Nan, Chen, Xiao-Wen, Qi, Yang-Li, Duan, Geng-Li, Li, Jian-Qi
Format Journal Article
LanguageEnglish
Published American Chemical Society 19.07.2019
Subjects
crystallization
D3/D2 receptor preferential antagonist
schizophrenia
practical preparation
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Summary:Herein we describe the development of a kilogram-scale preparation of a preferential dopamine D3 versus D2 receptor antagonist SIPI 6398 (1) as a new alternative treatment for schizophrenia. Modification and optimization of the route includes one-pot synthesis of a trans/cis mixture of cyclohexyl ethyl acetate 19, direct crystallization of cyclohexyl acetic acid 21 in trans configuration, avoidance of hazardous reagents to obtain mesylate 24, and a salinization and recrystallization protocol to efficiently remove the olefinic impurity 31 from 12 (free base of 1). Ultimately these improvements led to the successful and facile preparation of 2.7 kg of SIPI 6398 in nine steps with an HPLC purity of >99.9%.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.9b00182