Process Research and Development for an Efficient Synthesis of the HIV Protease Inhibitor BMS-232632

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• 作者：Zhongmin Xu ; Janak Singh ; Mark D. Schwinden ; Bin Zheng ; Thomas P. Kissick ; Bharat Patel ; Michael J. Humora ; Fernando Quiroz ; Lin Dong ; Dau-Ming Hsieh ; James E. Heikes ; Madhusudhan Pudipeddi ; Mark D. L
• 刊名：Organic Process Research & Development
• 出版年：2002
• 出版时间：May 2002
• 年：2002
• 卷：6
• 期：3
• 页码：323 - 328
• 全文大小：85K
• 年卷期：v.6,no.3(May 2002)
• ISSN：1520-586X

文摘

Development of an efficient and scalable process for the humanimmunodeficiency virus (HIV) protease inhibitor BMS-2326321-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)-L-tert-leucinyl]-amino}-4(S)-hydroxy-6-phenyl-2-azahexane, isdescribed. The key step in the synthesis of the intermediate N-1-(tert-butyloxycarbonyl)-N-2-[4-(pyridin-2-yl)benzylidene]hydrazone (11) was the Pd-mediated coupling of boronic acid 9 with2-bromopyridine. An efficient procedure was developed for thechemoselective reduction of hydrazone 11 to hydrazine carbamate 4. The key intermediate N-(tert-butyloxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxy-butane (6) was prepared stereoselectively from chiral diol 10. The subsequent union of 4 and6 followed by coupling with N-methoxycarbonyl-L-tert-leucineprovided the free base BMS-232632 in high yield. Evaluationof a variety of salts and identification of bisulfate salt 19 withenhanced bioavailability are also described.