Synthesis Of The Key Intermediates Of RO0098557 And Tamiflu

This dissertation comprises two parts:1. Synthesis of the key intermediates of RO00985571-{[(2S,3R)-2-(2,5-difluorobenzene-3-methyloxoethyl]]methyl}-1-hydro-1,2,4-trizole (structure unit 1) and 2-methylamino-3-hydroxymethyl pyridine (structure unit 2) are two key intermediates of RO0098557, an antifungal drug.Structure unit 1 was successfully synthesized via eight steps, including amidation of ester, protection of hydroxy, and arylation of carbonyl etc., using ethyl (s)-lactate as the starting material. In the arylation reaction, the temperature was meliorated from -40℃ to -15℃, which could be easy controlled with ice-salt bath. Furthermore, the reaction could be carried out reposefully by adding the initiator. In the sulfonylation reaction, the yield and purity of the product were improved notably by selecting the solvent and organic base.Structure unit 2 was conveniently synthesized from 3-cyanopyridine by methylation, rearrangement reaction, and reduction of formyl. Using CH₃Br as the methylation reagent improved the yield and reduced the cost. In the reduction reaction, KBH4 was used as the reagent which made the process easy operated.2. Synthesis of the key intermediates of TamifluEthyl (3R,4S,5S)-4,5-oxo-3-(1-ethyloxypropyl)-1-cyclohexenelformic is a key intermediate of Tamiflu, an important drug for preventing bird flu. The title compound was synthesized from shikimic acid via eight steps, including esterification of acid, proctection of hydroxy etc., and partial procedure was modified for easy industrialization.