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首页> 外文期刊>Organic process research & development >First, Second, and Third Generation Scalable Syntheses of Two Potent H3 Antagonists
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First, Second, and Third Generation Scalable Syntheses of Two Potent H3 Antagonists

机译：两种强效H3拮抗剂的第一代，第二代和第三代可扩展合成

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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 · HC1 (1 · HC1). 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 · HCl (2 · HCI). 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.
机译：我们的团队最近完成了针对两种结构相似的H3受体拮抗剂的扩大推广活动。开发了第一代和第二代工艺，用于合成107和125 g批次的（4-环丁基-1,4-二氮杂-1-基）（6-（4-氟苯氧基）吡啶-3-基）甲酮·HCl （1·HC1）。第三代工艺用于生产104克3-（（5-（4-环丁基-1,4-二氮杂戊-1-羰基）吡啶-2-基）氧基）苄腈·HCl（2·HCl）。通过使用对称的高哌嗪而不是更昂贵的单保护变体，希望将商品成本降至最低，从而推动了从第一代工艺到第二代工艺的发展，对后期中间体的项目需求（可以提供1或2种）导致了额外的路线搜寻和这些分子类型的第三种可扩展合成的最终确定。将醇锂用于路易斯碱催化的酯到酰胺的转化代表了第三代合成的关键改进。

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