Development of an Efficient Large-Scale Synthesis for a 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide Derivative for Depression and Anxiety
详细信息 查看全文
- 作者：Nicola Giubellina ; Paolo Stabile ; Gilles Laval ; Alcide D. Perboni ; Zadeo Cimarosti ; Pieter Westerduin ; Jason W. B. Cooke
- 刊名：Organic Process Research & Development
- 出版年：2010
- 出版时间：July 16, 2010
- 年：2010
- 卷：14
- 期：4
- 页码：859-867
- 全文大小：395K
- 年卷期：v.14,no.4(July 16, 2010)
- ISSN：1520-586X
文摘
The development and scale-up of an optimized synthesis for a novel drug candidate for depression and anxiety is presented. The updated synthesis represents a convergent and efficient four-stage approach to the API, overcoming high cost of goods (COG), general lack of convergence, and low yield of previous routes. A lower cost of goods resulted from using 3-nitrosalicylaldehyde as a starting material and introducing the expensive side chain (2-methyl-5-(piperazin-1-yl)quinoline) at a later stage. Green chemistry principles were applied when a direct amidation enabled a straightforward conversion of the 4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxylate to the corresponding amide in the last step. In addition, the total number of stages was reduced from seven to four, and solvent usage was greatly minimized. The modified synthesis was demonstrated on a kilogram pilot scale, allowing the isolation of the API in 17% overall yield with the required purity.