Emtricitabine preparation

For the treatment of AIDS, TDF is now available in three commercial preparations, as such (Viread ), in combmation with emtricitabine (Truvada ) and m combination with emtricitabme and efavirenz (Atripla ). The latter represents a three-drugs-in-once combination piU, which has become available for the treatment of AIDS since July 2006. The different milestones mat marked the development and ultimate commercialization of Atripla (m 2006) smce the original identification of adefovir as an antiretroviral agent (m 1986) have been previously reviewed (De Clercq 2006, 2007a-c). 

Osborne AP, Brick D, Ruecroft G, Taylor IN. Immobilization of cholesterol esterase for use in multiple batch biotransformations to prepare (-)-FTC (Emtricitabine). Org Process Res Dev 2006 10 670 672. 

Most of the methods describing the preparation of Emtricitabine (and Racivir) rely on the construction of 1,3-oxathiolane ring by reaction of glycoMdehyde or glyoxalic acid derivatives with mercaptoacetic add or mercaptoacetic aldehyde (which exists as 1,4-ditiane 154). For example, one of the first of syntheses of this type commenced from allyl alcohol which was silylated and then subjected to ozon-olysis to give glycoMdehyde derivative 155 (Schane 36) [142], Reaction of 155 with mercaptoacetic add afforded 1,3-oxathiolane 156, which was reduced with LiAlH(OtBu)3 or DIBAL and then acetylated to form 157. Finally, reaction of 157 with silylated fluorocytosine derivative 158 followed by deprotection led to the formation of racemic 8 (Racivir). 

More than 15 preparations described in patents are variations of the above synthetic schane. hi particular, to obtain optically pure Emtricitabine, lipase-catalyzed enzymatic resolution, as well as chiral stationary phase HPLC was used [143]. However, the most effective procedure included separation of menthyl derivatives. This method evolved significantly since the first publication (which in fact relied on separation of all the 4 possible diastereomers) [144] one of the recent multigram preparations is shown in the Scheme 37 [145]. The first step of the synthesis included formation of methyl ester 159 from glyoxalic acid and L-menthol. Reaction of 159 with 1,4-ditiane 154 gave 1,3-oxathiolane 160 as a mixture of cis diastereomers. 

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