New, azide-free transformation of epoxides into 1,2-diamino compounds: Synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)
New, azide-free transformation of epoxides into 1,2-diamino compounds: Synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)
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DOI：
10.1021/jo005702l
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发表时间：
2001-03-23
影响因子：
3.6
通讯作者：
Trussardi, R
中科院分区：
文献类型：
--
作者：
Karpf, M;Trussardi, R
描述了一种新的，无叠氮的关键前体环氧化物6向流感神经氨酸酶抑制剂前体药物磷酸奥司他韦(1，达菲)的转化。这一序列代表了一种新的高效的环氧化物到1，2-二氨基化合物的转化，没有潜在的有毒和危险的叠氮试剂和中间体，并避免了还原和加氢条件。使用催化的溴化镁。OEt2作为一种新的廉价的Lewis酸，第一氨基的引入是通过用烯丙胺开环，然后Pd/C催化脱烯丙基生成氨基醇16来完成的。然后第二氨基的引入是通过涉及多米诺骨牌序列的有效反应级联完成的，最好是利用瞬时亚氨基保护。得到的二胺17在酸性条件下进行选择性乙酰化，得到结晶的4-乙酰氨基-5N-烯丙基氨基衍生物18，它在Pd/C上脱烯丙基并形成磷酸盐形成药物物质1。该路线的总收率为6/35-38%，超过了叠氮化物法的产率(27-29%)，不需要任何层析纯化。
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.