New, azide-free transformation of epoxides into 1,2-diamino compounds: Synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)

被引:140
作者
Karpf, M [1 ]
Trussardi, R [1 ]
机构
[1] F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev, Chem Proc Res, CH-4070 Basel, Switzerland
关键词
D O I
10.1021/jo005702l
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and,and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr2. OEt2 as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not require any chromatographic purification.
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页码:2044 / 2051
页数:8
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