First, Second, and Third Generation Scalable Syntheses of Two Potent H3 Antagonists
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- 作者：Daniel J. Pippel ; John E. Mills ; Chennagiri R. Pandit ; Lana K. Young ; Hua M. Zhong ; Frank J. Villani ; Neelakandha S. Mani
- 刊名：Organic Process Research & Development
- 出版年：2011
- 出版时间：May 20, 2011
- 年：2011
- 卷：15
- 期：3
- 页码：638-648
- 全文大小：1045K
- 年卷期：v.15,no.3(May 20, 2011)
- ISSN：1520-586X
文摘
Our teams have recently completed scale-up campaigns for two structurally similar H3 receptor antagonists. The first and second generation processes were developed for the synthesis of 107 and 125 g batches of (4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone路HCl (1路HCl). A third generation process was utilized for production of 104 g of 3-((5-(4-cyclobutyl-1,4-diazepane-1-carbonyl)pyridin-2-yl)oxy)benzonitrile路HCl (2路HCl). The evolution from first to second generation process was driven by a desire to minimize cost of goods through employment of symmetrical homopiperazine rather than a more expensive monoprotected variant. Project demands for a late stage intermediate that could provide 1 or 2 led to additional route scouting and the ultimate determination of a third scalable synthesis for these types of molecules. The use of a lithium alkoxide for Lewis base catalysis of an ester to amide transformation represents a key improvement for the third generation synthesis.