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Treatment of 2,5-dimethyl-2-5-hexanediol (I) with dry hydrogen chloride in EtOH gives rise to the dichloro compound (II). Subsequent Friedel-Crafts condensation of dichloride (II) with toluene (III) in the presence of AlCl3 affords the tetrahydronaphthalene derivative (IV) (1). This is then condensed with mono-methyl terephthalic acid chloride (V) to produce ketone (VI). Wittig reaction of (VI) with methylene triphenylphosphorane leads to olefin (VII). Finally, alkaline hydrolysis of the methyl ester group of (VII) furnishes the target carboxylic acid

合成路线4

The intermediate tetrahydronaththalene (VI) has been prepared by an alternative procedure. Friedel-Crafts condensation of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone (I) with toluene (II) by means of AlCl3 produces tetrahydronaphthalenone (III). This is reduced to alcohol (IV) employing NaBH4 in MeOH. Subsequent dehydration of (IV) with POCl3 in pyridine leads to the dihydronaphthalene (V). Then, catalytic hydrogenation of (V) over Pd/C provides the key pentamethyltetrahydronaphthalene (VI)

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The Friedel Crafts condensation of 2,5-dichloro-2,2,5,5-tetramethylhexane (I) with toluene (II) by means of AlCl3 gives 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (III), which is submitted to a new condensation with the pyridine-2-carbonyl chloride (IV) by means of AlCl3 in dichloromethane to yield the diaryl ketone (V). The reaction of (V) with methyltriphenylphosphonium bromide (VI) and NaNH2 affords the 1,1-diarylethylene (VII), which is treated with Et2Zn and Cl-CH2-I in dichloromethane to provide the 1,1-diarylcyclopropane (VIII). Finally, the ester group of (VIII) is hydrolyzed with KOH in methanol/water to yield the target carboxylic acid.

合成路线7

Friedel-Crafts condensation of 2,5-dichloro-2,5-dimethylhexane (I) with toluene (II) in the presence of AlCl3 or FeCl3 afforded the tetrahydronaphthalene (III). Subsequent acylation of (III) with monomethyl terephthalic acid chloride (IV) provided keto ester (V), which was hydrolyzed to keto acid (VI) with methanolic KOH. Condensation of (VI) with hydroxylamine hydrochloride gave the corresponding oxime as a mixture of geometric isomers. The required Z isomer was then isolated by recrystallization from chloroform/hexane.