Title compound has been prepared by several routes: Condensation of 4'-methoxyacetophenone (I) with diethyl oxalate in the presence of lithium hexamethyldisilazide provided lithium ethyl 4-methoxybenzoylpyruvate (II). Subsequent condensation of (II) with 4-methoxyphenylhydrazine hydrochloride (III) yielded diarylpyrazole (IV). This was coupled with bromide (V) in the presence of n-BuLi to afford ketone (VI). The oxazoline ring of (VI) was then hydrolyzed to carboxylic acid (VII) by successive treatments with HCl and with NaOH. Activation of the carboxylic acid of (VII) as the mixed anhydride with ethyl chloroformate, followed by treatment with gaseous ammonia provided amide (VIII). The required dimethyl ketal was finally introduced in (VIII) by means of trimethyl orthoformate in MeOH in the presence of p-TsOH.
Alternatively, pyrazole ester (IV) was hydrolyzed to carboxylic acid (IX) with NaOH in ethanol. Then, conversion of (IX) to acid chloride with SOCl2, followed by treatment with N,O-dimethylhydroxylamine provided N-methoxy amide (X). Subsequent coupling of (X) with bromide (V) in the presence of n-BuLi afforded ketone (VI). Oxazoline hydrolysis as before yielded acid (VII), which was protected as the methyl ester (XI) upon treatment with MeI and NaH. Ketalization of (XI) was carried out with trimethyl orthoformate in MeOH in the presence of p-TsOH yielding (XII), and the methyl ester function of (XII) was then hydrolyzed with NaOH to furnish acid (XIII). Finally, conversion to the target amide was effected by reaction with ammonia in the presence of EDC and HOBt.
An further synthetic route to the intermediate ketoester (XI) is depicted in Scheme 23794901c. Pyrazole aldehyde (XIV) was condensed with 5-bromo-2-chlorobenzoic acid (XV) in the presence of two equivalents of n--BuLi to afford carbinol (XVI). Subsequent reaction of (XVI) with (trimethylsilyl) diazomethane provided methyl ester (XVII). Then, oxidation of (XVII) with activated MnO2 in boiling 1,2-dichloroethane led to the required ketone (XI).