合成路线1

YM-796 can be obtained by two different ways: 1) The Wittig condensation of 1-methylpiperidin-4-one (I) with 2-(diethoxyphosphoryl)acetic acid ethyl ester (II) by means of NaH in dimethoxyethane gives 2-(1-methylpiperidin-4-ylidene) acetic acid ethyl ester (III), which is cyclized with ethyl lactate (IV) by means of NaH in DMSO yielding 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylic acid ethyl ester (V). The decarboxylation of (V) with refluxing aqueous 1N HCl affords 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one (VI), which is submitted to a new Wittig condensation with methyltriphenylphosphonium iodide (or bromide) (VII) by means of NaH in DMSO to give racemic 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (VIII). Finally, this compound is submitted to optical resolution with L-tartaric acid or with di-p-toluoyl-D-tartaric acid. 2) The Wittig condensation of 4-oxopiperidine-1-carboxylic acid ethyl ester (IX) with phosphorane (VII) as before gives the corresponding methylene derivative (X), which is submitted to alkoxybromination with N-bromosuccinimide (NBS) and (S)-3-butyn-2-ol (XI) yielding (S)-4-(bromomethyl)-4-(1-methyl-2-propynyloxy)piperidine-1-carboxylic acid ethyl ester (XII). The radical cyclization of (XII) with NaBH4 catalyzed by bis(dimethylglyoximato)(pyridine)cobalt(III) chloride [chlorocobaloxime(III)] affords (S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (XIII), which is finally reduced with sodium bis(2-methoxyethoxy)aluminum hydride (vitride) in toluene and treated with fumaric acid to obtain the sesquifumarate salt.