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Azide-free Synthesis of Tamiflu Starting from (-)-shikimic Acid

Author: WangFeiFeng
Tutor: ShiXiaoXin
School: East China University of Science and Technology
Course: Pharmaceutical Engineering
Keywords: (-)-Shikimi acid Tamiflu synthesis
CLC: TQ463
Type: Master's thesis
Year: 2013
Downloads: 3
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Abstract


Tamiflu is the most effective medicine to treat the influenza at present, and it is widely used in the treatment and prevention of influenza. This paper has reviewedthe tamiflu’s syntheses from the chiral material both at home and abroad. It has also introduced the achievements and defects of our group’s (The Shi’s group) previous syntheses of tamiflu. In order to make the synthesis of tamiflu more suitable for industrialization, we have developed two new synthetic routes of tamiflu without using NaN3. The two routes take advantge of the highly reactivity of the allylic position of the rawmaterial(-)-Shikimic acid to introduce various groups withhigh chemo-and regioselectivities to get chiral drug Tamiflu.(1) In the first synthetic route, we used the Roche’s key epoxide intermediate III-6as the starting material. The two key characteristic steps are the BF3.OEt2-catalyzedhighly regioselectiveMeCN-attacked epoxide-opening andthe diallylamine-attacked aziridine-opening.Theroute successfullyavoided the use of NaN3, and alsocompletely solved the difficulty in workup due to reduction of azideintermediateswith Ph3P. Except for the Roche’s5steps from (-)-shikimic acid to the key epoxide intermediate, weused another5steps to get the product Tamifluin65%overall yield.(2)In the second synthetic route,the characteristicsteps are highly regioselective chlorination toget compoundⅢ-27and formation of epoxide III-28,which takes advantge of the highly reactivity of theallylic position of the (-)-Shikimic acid.The nitrogen-containing functional group was introducedby the regioselective epoxy ring opening with allylamine. Without use of NaN3,We synthesized the Tamiflu through11steps in48%overall yield.

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CLC: > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug
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