合成路线1

Benzocycloheptapyridinone (I) was reduced to alcohol (II) with NaBH4 in MeOH. Subsequent treatment of (II) with SOCl2 in toluene gave the tricyclic chloride (III). Finally, alkylation of N-acetyl piperazine (IV) with chloride (III) in the presence of Et3N in boiling THF provided the title compound.

合成路线2

Coupling of 4-chloro-3-nitrocinnamic acid (I) with 1-acetylpiperazine (II) using EDC gave rise to the corresponding amide (III). Displacement of the chlorine atom of (III) with 2-isopropylthiophenol (IV) in the presence of K2CO3 furnished the title thioether.

合成路线3

Reaction of 3,4-dichlorobenzalzehyde (I) with methyl 3-mercaptopropionate in the presence of K2CO3 in hot DMF afforded the thioether (II). Subsequent condensation of (II) with malonic acid under Knoevenagel conditions produced the substituted cinnamic acid (III), which was further converted to the corresponding acid chloride (IV) upon treatment with oxalyl chloride and a catalytic amount of DMF. Coupling of acid chloride (IV) with N-acetylpiperazine (V) furnished amide (VI). Treatment of (VI) with potassium tert-butoxide caused the elimination of methyl acrylate, producing the potassium thiolate (VII). Thiolate (VII) was then condensed with 1-methyl-7-bromoindole (VIII) to give the title compound.

合成路线4

Aromatic nucleophilic substitution of 3-chloro-4-fluorobenzaldehyde (I) with methyl 3-mercaptopropionate (II) yielded the mercapto aldehyde (III). This was subjected to Knoevenagel condensation with malonic acid to furnish the cinnamic acid derivative (IV), which was further converted to the corresponding acid chloride (V) by using oxalyl chloride. Condensation of acid chloride (V) with N-acetylpiperazine (VI) yielded the diacyl piperazine (VII). The protected benzenethiol of (VII) was released by treatment of the beta-mercaptopropionate (VII) with potassium tert-butoxide to give the potassium thiolate (VIII). Finally, Ullmann coupling of (VIII) with 6-iodobenzodioxan (IX) furnished the title compound.

合成路线5

The reductocondensation of 3-amino-5-(chloromethyl)benzoic acid methyl ester (I) with 2-aminothiazol-5-ylisothiocyanate (II) by means of NaBH4 gives the thioether (III), which is condensed with 4-(dimethylamino)benzoyl chloride (IV) by means of pyridine in dichloromethane to yield the amide (V). The hydrolysis of the ester group of (V) with NaOH in methanol affords the corresponding carboxylic acid (VI), which is finally condensed with 1-acetylpiperazine (VII) by means of WSC, HATU and DIEA in THF to provide the target piperazide.

合成路线6

Casopitant can be prepared by two related methods starting from either racemic 2-(4-fluoro-2-methylphenyl)-4-piperidinone (I) or from the corresponding (R)-enantiomer (II). Optically pure piperidinone (II), obtained either by asymmetric synthesis or by resolution of (I) with L-mandelic acid, is treated with triphosgene and NaHCO3 to give the carbamoyl chloride (III), which is then coupled with N-methyl-1(R)-[3,5-(bis-trifluoromethyl)phenyl]ethylamine (IV) to afford the urea adduct (V). Alternatively, reaction of racemic piperidinone (I) with triphosgene and DIEA followed by coupling of the resulting carbamoyl chloride (VI) with the 1-aryl-ethylamine (IV) leads to a diastereomeric mixture of urea adducts, from which the target (R,R)-diastereoisomer (V) can be isolated using flash column chromatography. The N-carbamoyl piperidone (V) is then subjected to reductive amination with N-acetylpiperazine (VII) in the presence of NaBH(OAc)3 to generate a mixture of epimeric 4-piperazinylpiperidines, from which the 4(S)-isomer casopitant is finally obtained through recrystallization as the corresponding methanesulfonate salt (1, 2). Scheme 1.

合成路线7