Treatment of trans-2,5-dimethylpiperazine (I) with ethyl chloroformate gave racemic ethyl carbamate (II), which was subsequently alkylated with allyl bromide, and then deprotected with ethanolic KOH to yield racemic piperazine (IV). Separation of the desired enantiomer (V) was achieved through recrystallization of the salt with di-p-toluoyl-D-tartaric acid, followed by liberation of the base with NaOH.

Alternatively, a chiral synthesis of intermediate (V) was developed from enantiopure amino acids. N-Boc-D-alanine (VI) was N-alkylated with allyl bromide in the presence of two equivalents of NaH, and the resulting N-allyl amino acid (VII) was coupled with L-alanine methyl ester (VIII) using 1-dimethylaminopropyl-3-ethylcarbodiimide (DEC) to provide dipeptide (IX). Subsequent acid treatment of (IX) produced both Boc deprotection and cyclization to the diketopiperazine (X), which was finally reduced to piperazine (V) with LiAlH4.

The title compound was synthesized by two related procedures. 3-Fluoro-N-methylaniline (XIV) was obtained from 3-fluoroaniline (XI) by condensation with 1-(hydroxymethyl)benzotriazole (XII), followed by reduction of the anilinomethylbenzotriazole (XIII) with NaBH4. Subsequent condensation with 3-formylbenzoyl chloride (XV) (prepared from the corresponding acid and SOCl2) provided amide (XVI). Then, condensation of (XVI) with piperazine (V) and benzotriazole in the presence of a catalytic amount of Et3N in refluxing toluene furnished (XVII) as a mixture of epimers. 3-Bromophenol (XVIII) was protected as the silyl ether (XIX) with tert-butyldimethylsilyl chloride and imidazole. This compound was converted to the organolithium derivative with n-butyllithium in THF at -78 C, and further transformed to the arylmagnesium reagent (XX) by treatment with magnesium bromide etherate in THF. Condensation of (XVII) with organometallic compound (XX) afforded the benzhydrylpiperazine (XXI) as a 10:1 mixture of epimers. Desilylation of (XXI) by treatment with HCl in aqueous THF, followed by recrystallization of the major isomer from EtOAc/hexane yielded the title compound.

In an alternative procedure, the silylether of 3-bromophenol (XIX) was converted to the organolithium compound (XXII) and then coupled to 3-bromobenzaldehyde (XXIII) in THF at -78 C. The resulting benzhydrol (XXIV) was treated with SOCl2 to give chloride (XXV), which was subsequently condensed with piperazine (V) in refluxing acetonitrile. The diastereomeric mixture of benzhydryl piperazines (XXVI) was desilylated with tetraethylammonium fluoride, and the major isomer (XXVII) was isolated by recrystallization from acetonitrile. The bromo substituent of (XXVII) was then substituted for a cyano group upon treatment with CuCN in N-methylpyrrolidinone at 170 C. Basic hydrolysis of nitrile (XXVIII) gave acid (XXIX), which was protected as the tert-butyldimethylsilyl ether and further converted to acid chloride (XXX) by reaction with oxalyl chloride and a catalytic amount of DMF. Finally, acid chloride (XXX) was condensed with N-methyl-3-fluoroaniline (XIV), and the silyl protecting group was removed by treatment with tetraethylammonium fluoride in acetonitrile.

Treatment of trans-2,5-dimethylpiperazine (I) with ethyl chloroformate gave racemic ethyl carbamate (II), which was subsequently alkylated with allyl bromide, and then deprotected with ethanolic KOH to yield racemic piperazine (IV). Separation of the desired enantiomer (V) was achieved through recrystallization of the salt with di-p-toluoyl-D-tartaric acid, followed by liberation of the base with NaOH.

Alternatively, a chiral synthesis of intermediate (V) was developed from enantiopure amino acids. N-Boc-D-alanine (VI) was N-alkylated with allyl bromide in the presence of two equivalents of NaH, and the resulting N-allyl amino acid (VII) was coupled with L-alanine methyl ester (VIII) using 1-dimethylaminopropyl-3-ethylcarbodiimide (DEC) to provide dipeptide (IX). Subsequent acid treatment of (IX) produced both Boc deprotection and cyclization to the diketopiperazine (X), which was finally reduced to piperazine (V) with LiAlH4.

The title compound was synthesized by two related procedures. 3-Fluoro-N-methylaniline (XIV) was obtained from 3-fluoroaniline (XI) by condensation with 1-(hydroxymethyl)benzotriazole (XII), followed by reduction of the anilinomethylbenzotriazole (XIII) with NaBH4. Subsequent condensation with 3-formylbenzoyl chloride (XV) (prepared from the corresponding acid and SOCl2) provided amide (XVI). Then, condensation of (XVI) with piperazine (V) and benzotriazole in the presence of a catalytic amount of Et3N in refluxing toluene furnished (XVII) as a mixture of epimers. 3-Bromophenol (XVIII) was protected as the silyl ether (XIX) with tert-butyldimethylsilyl chloride and imidazole. This compound was converted to the organolithium derivative with n-butyllithium in THF at -78 C, and further transformed to the arylmagnesium reagent (XX) by treatment with magnesium bromide etherate in THF. Condensation of (XVII) with organometallic compound (XX) afforded the benzhydrylpiperazine (XXI) as a 10:1 mixture of epimers. Desilylation of (XXI) by treatment with HCl in aqueous THF, followed by recrystallization of the major isomer from EtOAc/hexane yielded the title compound.

In an alternative procedure, the silylether of 3-bromophenol (XIX) was converted to the organolithium compound (XXII) and then coupled to 3-bromobenzaldehyde (XXIII) in THF at -78 C. The resulting benzhydrol (XXIV) was treated with SOCl2 to give chloride (XXV), which was subsequently condensed with piperazine (V) in refluxing acetonitrile. The diastereomeric mixture of benzhydryl piperazines (XXVI) was desilylated with tetraethylammonium fluoride, and the major isomer (XXVII) was isolated by recrystallization from acetonitrile. The bromo substituent of (XXVII) was then substituted for a cyano group upon treatment with CuCN in N-methylpyrrolidinone at 170 C. Basic hydrolysis of nitrile (XXVIII) gave acid (XXIX), which was protected as the tert-butyldimethylsilyl ether and further converted to acid chloride (XXX) by reaction with oxalyl chloride and a catalytic amount of DMF. Finally, acid chloride (XXX) was condensed with N-methyl-3-fluoroaniline (XIV), and the silyl protecting group was removed by treatment with tetraethylammonium fluoride in acetonitrile.