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A new synthesis of dazoxiben has been described: The condensation of methyl 4-hydroxybenzoate (I) with 1,2-dibromoethane (II) by means of NaOH gives methyl 4-(2-bromoethoxy)benzoate (III), which is hydrolyzed with H2SO4 to the corresponding free acid (IV). Finally, this compound is condensed with imidazole (V) in refluxing butanol.

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The reaction of 4-tert-butylbenzyl chloride (I) with Mg in ether gives the corresponding Grignard reagent (II), which is condensed with epichlorohydrin (III) yielding 4-(4-tert-butylphenyl)-1,2-epoxybutane (IV). The condensation of (IV) with methyl 4-hydroxybenzoate (V) by means of KOH in refluxing methanol affords 4-[4-(4-tert-butylphenyl)-2-hydroxybutoxy]benzoic acid methyl ester (VI), which is finally saponified with KOH in refluxing ethanol/water.

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The condensation of aziridine (I) with methyl 4-hydroxybenzoate (II) in refluxing chloroform gives methyl 4-(2-aminoethoxy)benzoate (III), which is acylated with 4-isopropylbenzoyl chloride by means of K2CO3 in chloroform yielding methyl 4-[2-(4-isopropylbenzamido)ethoxy]benzoate (IV). Finally, this compound is hydrolyzed with NaOH in refluxing water.

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Reaction of methyl 4-hydroxybenzoate (XI) with difluorochloromethane and potassium tert-butoxide provided difluoromethyl ether (XII). After basic hydrolysis of the methyl ester of (XII), the resulting carboxylic acid (XIII) was converted to acid chloride (XIV) by means of refluxing SOCl2. Subsequent coupling of (XIV) with benzyl bromide in the presence of Zn and palladium catalyst produced the diaryl ethanone (XV). Reductive amination of (XV) with ammonium formate at 160 C gave formamide (XVI), which was hydrolyzed to racemic amine (XVII) with boiling HCl. Alkylation of this amine with the intermediate iodide (X) in THF at 110 C in a sealed flask yielded a diastereomeric mixture of secondary amines (XVIII), which were separated by column chromatography. The required (R,R)-isomer was desilylated employing tetrabutylammonium fluoride and AcOH to produce aminoalcohol (XIX). Finally, hydrogenolytic cleavage of the benzyl ether of (XIX) furnished the title compound.

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The reaction of adipic acid monomethyl ester (XIII) with SOCl2 gives the acyl chloride (XIV), which is brominated with NBS in carbon tetrachloride to yield 5-bromo-5-(chloroformyl)pentanoic acid methyl ester (XV). The reaction of (XV) with phenol (XVI) by means of DIEA in ethyl ether affords the mixed diester (XVII), which is reduced with tri-tert-butoxylithiumaluminum hydride in THF to provide 5-bromo-5-formylpentanoic acid methyl ester (XVIII). The cyclization of (XVIII) with chiral ethanone (XIX) by means of DIEA in hot dioxane gives the methyl ester (XX) of the target compound, which is finally hydrolyzed with NaOH in ethanol/water to obtain the target acid . The intermediate chiral ethanone (XIX) has been obtained as follows: The reaction of the chiral alcohol (VIII) with 4-hydroxybenzoic acid methyl ester (XXI) under Mitsunobu conditions (DEAD, PPh3) gives the chiral ether (XXII), which is then condensed with 2-methylpyridine (XXIII) by means of LiHMDS in THF to yield the target ethanone.

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Michael addition of itaconic acid (II) to 4-tert-butylaniline (I), and further lactamization afforded pyrrolidone carboxylic acid (III). This was esterified with H2SO4 in MeOH, and the resulting methyl ester (IV) was reduced to alcohol (V) with NaBH4 in boiling tetrahydrofuran. Optical resolution of (V) was achieved by condensation with phthalic anhydride (VI) to give amide (VII), followed by coupling of the remaining carboxylic acid group of (VII) with chiral alpha-methylbenzyl amine (VIII) yielding (IX). After separation of the diastereomeric mixture (IX), hydrolysis of the phthalate ester furnished the required (S)-alcohol (X) (2). Mesylate (XI), prepared from alcohol (X) and MsCl in the presence of Et3N, was condensed with methyl 4-hydroxybenzoate (XII) to afford ether (XIII). Then, basic hydrolysis of the methyl ester of (XIII) provided the title compound.

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The Michael addition of 4-tert-butylaniline (I) with 2-methylenesuccinic acid (II) followed by cyclization gives racemic 1-(4-tert-butylphenyl)-5-oxopyrrolidine-3-carboxylic acid (III) (1), which is treated with SOCl2 and condensed with (S)(-)-1-(4-methylphenyl)ethylamine (IV) to yield a diastereomeric mixture of amides (V). The resolution of (V) by silicagel chromatography affords the (S,S)-diastereomer (VI), which is treated with N2O4 and NaOAc in CCl4 to provide 1-(4-tert-butylphenyl)-5-oxopyrrolidine-3(S)-carboxylic acid (VII). The reduction of (VII) with BH3/THF in dichloromethane gives the corresponding carbinol (VIII), which is treated with MsCl and TEA in dichloromethane to yield the mesylate (IX). The condensation of (IX) with 4-hydroxybenzoic acid methyl ester (X) by means of K2CO3 in DMF affords the corresponding phenyl ether (XI), which is finally hydrolyzed with HCl/AcOH to furnish the target compound.

合成路线8

Methyl 4-hydroxybenzoate (I) is iodinated by means of iodine monochloride in hot AcOH, producing (II). Displacement of the aryl iodide (II) with CuCN gives nitrile (III). Then, ester group saponification in (III) leads to 3-cyano-4-hydroxybenzoic acid (IV). Coupling of (IV) with tert-butyl carbazate produces the N-Boc hydrazide (V), which is further deprotected to (VI) by treatment with trifluoroacetic acid

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