DA-5018.: Topical analgesic.

The 2-chloroethylation of ethyl homovanillate (I) with 1-bromo-2-chloroethane and K2CO3 in acetone gives ethyl 2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetate (II), which is treated with sodium azide in toluene followed by hydrolysis with aqueous NaOH in MeOH, yielding 2-[4-(2-azidoethoxy)-3-methoxyphenyl]acetic acid (IV). The reaction of (IV) with SOCl2 and Et3N affords the acyl chloride (V). The reaction of 3-iodo-o-xylene (VI) and acrylonitrile under the Heck reaction conditions - (Pd(OAc)(2), tri-o-tolylphosphine and Et3N in MeCN - gives an isomeric mixture of 3-(3,4-dimethylphenyl)-2-propenenitrile (VII), which is hydrogenated with Pd/C followed by Raney Nickel to provide 3-(3,4-dimethylphenyl)propylamine (IX). The coupling reaction between the acyl chloride (V) and amine (IX) with Et3N in CH2Cl2 gives the amide (X). Finally, Pd/C catalyzed hydrogenation of this compound affords 2-[4-(2-aminoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide (1-3). Scheme 1.