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Romazarit (sodium salt) is prepared by a 7-step process from 4-chlorobenzoic acid, ethyl 2-chloroacetoacetate (VIII) and ethyl 2-methyl 2-hydroxypropionate (X). Reaction of the sodium salt of 4-chlorobenzoic acid (I) with ethyl 2-chloroacetoacetate (VIII) affords ethyl 3-oxo-2-(4-chlorophenylcarboxy)butyrate (II). Cyclization of (II) to ethyl 2-(4-chlorophenyl)-4-methyloxazole-5-carboxylate (III) is accomplished by treatment with formamide (IX)/sulfuric acid. Reduction of the ester (III) with lithium aluminum hydroxide in tetrahydrofuran yields 2-(4-chlorophenyl)-4-methyl-5-oxazolemethanol (IV). Chlorination of alcohol (IV) with thionyl chloride followed by reaction of crude chloromethyloxazole (V) with the sodium alkoxide derivative of ethyl 2-methyl-2-hydroxypropionate (X) yields ethyl [2-[(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionate (VI). Hydrolysis of the ester (VI), acidification and recrystallization affords Ro 31-3948 (VII) as a white solid, which is converted to the sodium salt by treatment with sodium isopropoxide in isopropanol.

合成路线2

Reaction of 4-hydroxy-3-nitrobenzaldehyde (I) with hydroxylamine and sodium formate in refluxing formic acid gives 4-hydroxy-3-nitrobenzonitrile (II), which is treated with thioacetamide in hot DMF to yield the corresponding thiobenzamide (III). The cyclization of (III) with 2-chloroacetoacetic acid ethyl ester (IV) in refluxing ethanol affords 2-(4-hydroxy-3-nitrophenyl)-5-methylthiazole-4-carboxylic acid ethyl ester (V), which is alkylated at the phenolic group by means of isobutyl bromide (VI) and K2CO3 in hot DMF, providing the isobutyl ether (VII). The reduction of the NO2 group of (VII) with H2 over Pd/C in ethanol/ethyl acetate gives the expected amino derivative (VIII), which is converted into 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (IX) by diazotation with NaNO2/HCl and treatment with CuCN and KCN. Finally, this compound is hydrolyzed with NaOH in hot THF.

合成路线3

The reaction of 4-nitrobenzonitrile (X) with KCN in hot DMSO, followed by treatment with isobutyl bromide (VI) and K2CO3, gives 4-isobutoxybenzene-1,3-dicarbonitrile (XI), which is treated with thioacetamide in hot DMF to yield 3-cyano-4-isobutoxythiobenzamide (XII). Cyclization of (XII) with 2-chloroacetoacetic acid ethyl ester (IV) in refluxing ethanol affords 2-(3-cyano-4-isoutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (IX), which is hydrolyzed with NaOH in hot THF/water.

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Diazotization of substituted aniline (I) followed by reaction with ethyl 2-chloro-3-oxobutanoate (II) in MeOH yields hydrazono chloroacetate derivative (III), which is converted into oxamidrazonate (IV) by means of NH3 (gas). Treatment of derivative (IV) with ethyloxalyl chloride (V) affords ethoxalyl derivative (VI), which is then heated until cyclization occurs, providing derivative (VII). Reduction of triazole dicarboxylate (VII) with iron in HOAc gives tricyclic compound (VIII), which is nitrated by means of HNO3 to afford nitro derivative (IX). Reduction of the nitro group of (IX) by means of iron in HOAc provides the corresponding 8-amino derivative (X), which is treated with diformylhydrazine and trimethylsilyl chloride (TMSCl) in pyridine to furnish ethyl carboxylate (XI). Finally, saponification of (XI) with NaOH in EtOH gives the desired compound.

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4-Trifluoromethylbenzamide (X) was converted to the corresponding thioamide (XI) by treatment with P4S10. Condensation of (XI) with ethyl 2-chloroacetoacetate (XII) provided thiazole (XIII). Subsequent reduction of the ester group of (XIII) with LiAlH4 gave alcohol (XIV). Conversion of (XIV) to the corresponding chloride (XV) was carried out by reaction with methanesulfonyl chloride and triethylamine. Chloride (XV) was then condensed with thiophenol (VII) in the presence of Cs2CO3 to yield thioether (XVI). The methyl ester group was finally hydrolyzed to the title acid employing LiOH.

合成路线6

The intermediate chloro hydrazone (I) is prepared by he following method. Diazotization of p-anisidine (XII) employing sodium nitrite in cold aqueous HCl yields the ntermediate diazonium salt (XIII), which undergoes Japp-Klingemann reaction with ethyl 2-chloroacetoacetate (XIV) in the presence of NaOAc to produce the target hydrazone (I) (1, 2). Scheme 2.

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