The reaction of N-(butoxycarbonyl)-3-[2-[3-(4-cyanophenyl)-4,5-dihydroisoxazol-5(R)-yl]acetamido]-L-alanine methyl ester (I) (intermediate (VII) in scheme no. 22467601a) with hydroxylamine and TEA in hot methanol gives the N-hydroxyamidine compound (II), which is treated with Ac2O in acetic acid to yield the N-acetoxyamidino compound (III). The cyclization of (III) by means of Ac2O in refluxing acetic aid affords the 1,2,4-oxadiazole derivative (IV), which is reduced with H2 over Pd/C in methanol/HOAc to provide the amidino derivative (V). Alternatively, the direct reduction of N-acetoxyamidino derivative (III) with H2 over Pd/C in acetic acid also gives the amidino derivative (V). Finally, the methyl ester group of compound (V) is hydrolyzed with LiOH in THF to yield the target roxifiban acetate.
Reaction of 4-cyanobenzaldehyde (I) with hydroxylamine sulfate in methanol gives 4-cyanobenzaldoxime (II). A 1,3-dipolar cycloaddition of (II) with isobutyl vinylacetate using N-chlorosuccinimide provides the racemic isoxazoline derivative (III). Treatment of (III) with lipase PS30 selectively converts the (R)-isomer to an optically pure acid (IV). Coupling of (IV) with methyl N2-(n-butyloxycarbonyl)-L-2,3-diaminopropionate (VI), which is derived from its corresponding commerically available acid (V), gives the intermediate (VII). Treatment of (VII) with HCl in methanol and ethyl acetate followed by ammonium acetate affords DMP 754 as a crystalline product. Saponification of DMP 754 using LiOH provides the corresponding acid (VIII).