The intermediate amine (IV) was prepared by alkylation of 4-cyano-4-phenylpiperidine (I) with N-(3-bromopropyl)phthalimide (II), followed by hydrazinolysis of the substituted phthalimide (III).
The Knoevenagel condensation between benzyl propionylacetate (V) and 2,4-difluorobenzaldehyde (VI) afforded the benzylidene derivative (VII), which was cyclized with O-methylisourea hemisulfate (VIII), yielding the dihydropyrimidine (IX). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (X). Resolution of the enantiomers of (X) was achieved by condensation with the chiral auxiliary (S)-(-)-alpha-methylbenzylamine (XI) to obtain a mixture of diastereomeric amides, which were separated by flash chromatography. The alpha-methylbenzylaminocarbonyl moiety was then removed from the desired diastereomer (+)-(XII) by treatment with DBU, and the resulting chiral dihydropyridine was again condensed with 4-nitrophenyl chloroformate to give (+)-(X). Coupling of the chiral carbamate (+)-(X) with amine (IV) provided adduct (XIII), which on treatment with aqueous HCl gave the dihydropyrimidinone (XIV). After catalytic hydrogenolysis of the benzyl ester of (XIV), the resulting acid was converted to the title amide by reaction with ammonia in the presence of EDC and DMAP.
The Knoevenagel condensation between methyl acetoacetate (I) and 3,4-difluorobenzaldehyde (II) afforded the benzylidene derivative (III), which was cyclized with O-methylisourea hemisulfate (IV), yielding the dihydropyrimidine (V). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (VI) (1,2). Treatment of (VI) with aqueous HCl gave the dihydropyrimidinone (VII), which was subsequently coupled with 3-bromopropylamine稨Br (VIII) to give the bromopropyl amide (IX) (1). The intermediate N-(2-carboxamidophenyl)piperazine (XIII) was obtained by condensation of 2-bromobenzonitrile (X) with piperazine (XI), followed by partial hydrolysis of the nitrile group with H2SO4. The title compound was finally obtained by condensation between piperazine (XIII) and bromide (IX) in the presence of KI and K2CO3 in refluxing acetone.
Condensation of 2-pyridylacetonitrile (I) with N,N-bis-(2-chloroethyl)benzylamine (II) under phase-transfer conditions produced the pyridylpiperidine (III). The cyano group of (III) was hydrolyzed to carboxamide (IV) with concentrated sulfuric acid and then decarboxylated to (V) by treatment with methanolic HCl. Subsequent hydrogenolysis of the N-benzyl group of (V) afforded piperidine (VI). N-Boc-3-bromopropylamine (VIII) was prepared by treatment of 3-bromopropylamine (VII) with di-tert-butyl dicarbonate. Alkylation of piperidine (VI) with bromide (VIII) gave adduct (IX). The N-Boc protecting group of (IX) was then removed by treatment with trifluoroacetic acid to yield intermediate aine (X).
Methyl 4-methoxyacetoacetate (XIV) was transesterified with 3-hydroxypropionitrile (XV) at 180 C to yield the 2-cyanoethyl ester (XVI). Subsequent condensation between 3,4-difluorobenzaldehyde (XVII) and ketoester (XVI) in the presence of piperidine acetate furnished the benzylidene derivative (XVIII), which was cyclized with O-methylisourea hemisulfate (XIX) to produce the racemic pyrimidine (XX). Resolution of (XX) was achieved via conversion to the 4-nitrophenyl carbamate (XXI), which was then condensed with (R)-1-phenylethylamine (XXII) to afford a separable mixture of diastereoisomeric amides. The desired isomer (XXIII) was treated with DBU in hot toluene to give the (+)-pyrimidine (XXIV). This was again converted to the corresponding 4-nitrophenyl carbamate (XXV) by reaction with 4-nitrophenyl chloroformate and DMAP.
Coupling of (XXV) with the intermediate amine (X) gave urea (XXVI). The methoxydihydropyrimidine ring (XXVI) was hydrolyzed to the tetrahydropyrimidinone (XXVII) by treatment with HCl, and the cyanoethyl ester group was further removed using NaOH in aqueous acetone. The resultant carboxylic acid (XXVIII) was finally esterified with methanol by using EDC and DMAP as the coupling reagents.
In a related synthetic method, condensation between 4-methoxyacetoacetate (XIV), 3,4-difluorobenzaldehyde (XVII) and urea (XXIX) in the presence of copper acetate and boron trifluoride etherate furnished the racemic pyrimidinone (XXX). Enzymatic resolution of (XXX) by incubation with subtilisin yielded a separable mixture of the (R)-acid (XXXII) and the unreacted (S)-ester (XXXI). Alternatively, the (S)-enantiomer (XXXI) was isolated by chiral preparative HPLC. Pyrimidinone (XXXI) was activated by conversion to either aryl carbamate (XXXIII) using 4-nitrophenyl chloroformate or to imidazolide (XXXIV) with carbonyl diimidazole. Finally, coupling of the intermediate amine (X) with either the carbamate (XXXIII) or the imidazolide (XXXIV) furnished the title compound.
The addition of ethylmagnesium bromide to 3,4-difluorobenzaldehyde (I) gave alcohol (II), which was oxidized to ketone (III) by using pyridinium chlorochromate. Treatment of (III) with iodobenzene diacetate in methanolic KOH produced the hydroxy ketone (IV). This was converted to oxime (V) and subsequently reduced with LiAlH4, yielding amino alcohol (VI) as a mixture of diastereoisomers. The mixture of amino alcohols (VI) was treated with Boc2O to afford carbamate (VII), which was then cyclized in the presence of NaH in THF. The resulting diastereomeric mixture of oxazolidinones (VIII) was first separated by column chromatography, and the racemic trans-isomer was then resolved by means of chiral HPLC to provide the required (+)-trans-oxazolidine (IX).
Addition of 4-fluorophenylmagnesium bromide (XIII) to 1-benzyl-4-piperidinone (XII) afforded carbinol (XIV), which was dehydrated to the tetrahydropyridine (XV) by treatment with p-toluenesulfonic acid in refluxing toluene. Hydrogenation of the olefin (XV) with concomitant benzyl group hydrogenolysis gave 4-(4-fluorophenyl)piperidine (XVI) (1). This compound was also obtained by catalytic hydrogenation of the commercially available 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (XVII). Alkylation of piperidine (XVI) with N-(3-bromopropyl)phthalimide (XVIII) provided adduct (XIX), which was subjected to hydrazinolysis in refluxing MeOH to furnish the primary amine (XX). Deprotonation of oxazolidine (IX) with n-butyllithium in THF at -78 C, followed by condensation with p-nitrophenyl chloroformate, gave the p-nitrophenoxycarbonyl derivative (XXI). This was finally coupled with amine (XX) to furnish the title carboxamide.
In an alternative method, 2,4'-dipyridyl (XI) was alkylated with 3-bromopropylamine hydrobromide (VII) in hot DMF to provide the pyridinium salt (XII). Reduction of (XII) with NaBH4 gave the tetrahydropyridine (XIII), which was further hydrogenated in the presence of Pearlman's catalyst to yield the intermediate pyridylpiperidine (X).