合成路线1

The addition of methyl magnesium iodide to 2-acetylthiophene (I) and subsequent reduction of the propenyl derivative (II) with H2 over Pd/C in methanol yields the 2-isopropylthiophene (III), which is acetylated with acetyl chloride. Reduction of 2-isopropyl-5-acetylthiophene (IV) with lithium aluminum hydride gives the corresponding alcohol, which is converted to the triphenylphosphonium salt (V). By Wittig reaction with 4-ethoxycarbonyl benzaldehyde (VI) the ethyl ester obtained is then hydrolyzed with potassium hydroxide to yield the free acid.

合成路线2

Reaction of 2-acetylthiophene (I) with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-1-propanone (II), which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene to yield (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (IV). The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI), which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene and treated with oxalic acid.

合成路线3

The ketone intermediate (II) can also be reduced with NaBH4 in ethanol to the racemic alcohol (VII), which is submitted to optical resolution with (S)-(+)-mandelic acid to provide the (S)-enantiomer (IV) already described.

合成路线4

The reaction of 2-acetylthiophene (I) with [14C]-paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-[3-14C]propan-1-one (II), which is enantioselectively reduced in toluene with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene to yield (S)-3-(dimethylamino)-1-(2-thienyl)-[3-14C]propan-1-ol (IV). The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI), which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene.

合成路线5

The reaction of [carbonyl-14C]-2-acetylthiophene (I) with paraformaldehyde and dimethylamine in ethanol gives 3-(dimethylamino)-1-(2-thienyl)-[1-14C]propan-1-one (II), which is enantioselectively reduced with a 2:1 complex of (2R,3S)-4-(dimethylamino)-3-methyl-1,2-diphenyl-2-butanol (III) and LiAlH4 in toluene, yielding (S)-3-(dimethylamino)-1-(2-thienyl)[1-14C] propan-1-ol (IV). The condensation of (IV) with 1-fluoronaphthalene (V) by means of NaH in DMSO affords the corresponding naphthyl ether (VI), which is finally monodemethylated with 2,2,2-trichloroethyl chloroformate and Zn in toluene.

合成路线6

Condensation of 2-acetylthiophene (I) with dimethylformamide dimethylacetal produced enaminone (II), which was subsequently cyclized to the isoxazole (III) upon treatment with hydroxylamine. Further condensation of (III) with dimethylformamide dimethylacetal, with concomitant isoxazole ring opening, gave rise to the enamino nitrile (IV). This was then cyclized with aminoguanidine nitrate (V) under basic conditions to furnish the intermediate aminopyrazole (VI).

合成路线7