合成路线1

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2

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.

合成路线3

Cyclization of 4-hydroxythiobenzamide (XIII) with 2-bromoacetoacetic acid ethyl ester (XIV) in refluxing ethanol provides 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XV), which is formylated by reaction with hexamethylenetetramine (HMTA) and polyphosphoric acid (PPA) in hot HOAc/water to afford 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI). Alkylation af (XVI) with isobutyl bromide (VI), K2CO3 and KI in DMF gives 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVII), which is treated with formic acid, sodium formate and hydroxylamine hydrochloride to give the already reported 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-catboxylic acid ethyl ester (IX). Finally, this compound is hydrolyzed with NaOH in THF/EtOH. Alternatively, 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI) can also be treated first with formic acid, sodium formate and hydroxylamine hydrochloride to provide 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII), which is then alkylated with isobutyl bromide (VI), K2CO3 and KI in DMF to give the already reported 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (IX).

合成路线4

Alkylation of ethyl piperazine-2-carboxylate (I) with two equivalents of isobutyl bromide (II) under catalysis of KI afforded disubstituted piperazine (III). The title imidazoline was then obtained by reaction of the ester function of (III) with ethylenediamine (IV) in the presence of trimethylaluminum.

合成路线5

The alkylation of 3(R)-hydroxyhexanoic acid methyl ester (I) with isobutyl bromide (II) and LDA in THF gives 3(R)-hydroxy-2(R)-isobutylhexanoic acid methyl ester (III), which is hydrolyzed with LiOH in THF/MeOH/water to yield the corresponding lithium salt (IV). The condensation of (IV) with O-tetrahydropyranyl-hydroxylamine (V) by means of DCC in ethyl acetate affords the protected hydroxamic acid (VI), which is treated with Ms-Cl and pyridine to provide the mesylate (VII). The cyclization of (VII) by means of K2CO3 in refluxing acetone gives the chiral azetidinone (VIII), which is opened by means of NaOH in dioxane/water, yielding the carboxylic acid (IX). The formylation of the NH group of (IX) with acetic formic anhydride and pyridine in dichloromethane affords the intermediate (X). The condensation of the N-protected nitro arginine (XI) with 2-aminothiazole (XII) by means of EDC in DMF gives the argininamide (XIII), which is deprotected by means of HCl in dioxane to yield the intermediate (XIV). Condensation of (XIV) with (X) by means of diethyl phosphorylcyanide (DEPC) and NMM in DMF gives the protected dipeptide (XV), which is treated with AcOH in warm water to yield the target dipeptide.

合成路线6