A practical and highly efficient protocol for the production of Autotaxin (ATX) inhibitor Ziritaxestat (1) was described. The procedure began with a catalyst-free bicomponent cyclization for the construction of the imidazo[1,2-a]pyridine skeleton 16. Subsequently, a typical Curtius rearrangement of carboxylic acid 17 followed by nucleophilic attacking of 3,5-dichlorobenzyl alcohol 18f led to the carbamate analogue 19f. N-methylated 20 was readily deprotected through HBr/HOAc treatment, which further conveniently took part in an alternative K₂CO₃-induced N-alkylation reaction with 9 to give 10. 10 coupled directly with piperazine to furnish 13, which ideally circumvent the removal of the Boc group. As a result, the hypertoxic KCN and the hypertoxic and costly isonitrile 3 involved in the tricomponent cyclization were carefully avoided. Ultimately, a novel, scalable, and cost-effective route was favorably developed to afford Ziritaxestat in a 20.4% overall yield.

中文翻译：

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无催化剂的环化和Curtius重排诱导的官能团转化：一流的ATX抑制剂Ziritaxestat（GLPG-1690）的改进合成策略

描述了一种生产Autotaxin（ATX）抑制剂Ziritaxestat（1）的实用且高效的方法。该程序从无催化剂双组分环化开始，用于构建咪唑并[1,2- a ]吡啶骨架16。随后，典型的羧酸17的库尔修斯重排，随后对3，5-二氯苄基醇18f的亲核攻击导致氨基甲酸酯类似物19f。N-甲基化的20很容易通过HBr / HOAc处理脱保护，它进一步方便地参与了另一种K ₂ CO ₃诱导的N-9的烷基化反应，得到10。10与哌嗪直接偶联，得到13，理想地避免了Boc基团的除去。结果，小心地避免了涉及三组分环化的高毒性KCN和高毒性且昂贵的异腈3。最终，开发出新颖，可扩展且具有成本效益的途径，从而以20.4％的总收率获得了Ziritaxestat。