By condensation of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidyl)benzamide (I) with 1-(3-chloropropoxy)-4-fluorobenzene (II) by means of KI and triethylamine in hot DMF.
By condensation of 4-amino-5-chloro-2-methoxybenzoyl chloride (III) with 4-amino-1-[3-(fluorophenoxy)propyl]-3-methoxypiperidine (IV) by means of triethylamine in CHCl3.
The bromination of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with Br2 in chloroform gives 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (II), which is treated with NaOMe in methanol to yield 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (III). The methylation of (III) with NaH and MeI in DMF affords 3,4,4-trimethoxypiperidine-1-carboxylic acid ethyl ester (IV), which is hydrolyzed with refluxing 1% aq. H2SO4 to provide 3-methoxy-4-oxopiperidine-1-carboxylic acid ethyl ester (V). The reductocondensation of (V) with benzylamine and H2 over Pd/C in methanol in the presence of thiophene gives cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (VI), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (VII) by means of ethyl chloroformate and TEA in chloroform to yield the benzamide (VIII). The hydrolysis of the carbamate group of (VIII) with KOH in refluxing isopropanol affords the free piperidine derivative (IX), which is finally condensed with 3-(4-fluorophenoxy)propyl chloride (X) by means of TEA and KI in hot DMF to provide the target, cisapride.
The reaction of 4-amino-5-chloro-2-methoxybenzoic acid (I) with benzyl chloride (II) and NaHCO3 in refluxing water gives the N-benzyl protected compound (III), which is condensed with cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (IV) by means of methyl chloroformate and TEA in dichloromethane to yield the benzamide (V). The deprotection of (V) with KOH in refluxing isopropanol affords compound (VI) with a free piperidinic NH group that is acylated with 3-(4-fluorophenoxy)propyl chloride (VII) by means of Na2CO3 in refluxing methylisobutylketone to provide the protected adduct (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot methanol to give the target compound. Alternatively, the piperidine derivative (VI) is treated with p-toluenesulfonic acid in refluxing toluene and then debenzylated and simultaneously reductocondensed with 3-(4-fluorophenoxy)propionaldehyde (IX) by means of H2 over Pd/C in methanol to give the target compound.
The title compound has been obtained by condensation of methanesulfonate (I) with 4-fluorophenol (II) by means of NaNH2 in DMF.
The title compound has been obtained by hydrogenation of 4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-1,2,5,6-tetrahydropyridin-4-yl]-2-methoxybenzamide (I) with H2 over Pt/C or Rh/Al2O3 in methanol.
The title compound has been obtained by hydrogenation of 4-(4-amino-5-chloro-2-methoxybenzamido)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypyridinium iodide (I) with H2 over PtO2 in methanol, or with NaBH4 and RhCl3 or NiCl2 in methanol.
The title compound has been obtained by condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidine-4-amine (II) by means of DCC in dichloromethane or PCl3 in benzene.
The reductive amination of 4-cyano-4-(4-fluorophenyl)cyclohexanone (I) with (-)-benzyl 3-methyl-4-phenyl-4-piperidinecarboxylate (II) by means of H2 and Pt/C 5% in the presence of thiophene in isopropyl alcohol at normal pressure and at 50 C gives a 9:1 mixture of (-)-benzyl [3S-[1(cis)-3alpha,4beta]]-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate and (-)-benzyl [3S-[1(trans)-3alpha,4beta]]-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidine-carboxylate. Chromatographic separation [dry column, silica gel, eluted with organic phase of a mixture of chloroform and methanol (99.0:1.0 by volume) yields the pure (-)-benzyl [3S-[1(cis)-3alpha,methyl-4-phenyl-4-piperidinecarboxylate (III), which is hydrogenolized in tetrahydrofuran at normal pressure and room temperature. The resulting free carboxylic acid is transformed to the monohydrochloric acid in methanol.
The decarboxylation of 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (I) with KOH in refluxing isopropanol gives the piperidine (II), which is condensed with 3-(4-fluorophenoxy)propyl chloride (III) by means of K2CO3 in refluxing methyl isobutyl ketone to afford the alkylated piperidine (IV). The esterification of the OH group of (IV) with benzoyl chloride (V) and DMAP in dichloromethane provides the ester (VI), which is treated with sulfuric acid in dichloromethane to obtain the piperidinone (VII). The rearrangement of (VII) by means of ammonium acetate and acetic acid provides the amide (VIII), which is treated with TFA in dichloromethane to give the oxo amide (IX). The regioselective hydrogenation of the oxo group of (IX) with potassium selectride in THF affords the cis-hydroxyamide (X), which is hydrogenated with H2 over Pd/C in acetic acid to provide the 4-aminobenzamide (XI). Finally, the free OH group of (XI) is methylated with NaH and dimethyl sulfate in THF.
The reductive amination of 1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-one (I) with benzylamine by hydrogenation with H2 over Pd/C, followed by crystallization of the HCl or HNO3 salts, gives cis-1-[3-(4-fluorophenyl)propyl]-3-methoxypiperidine-4-amine (II). This compound is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (III) by means of ethyl chloroformate, TEA and HOBt to afford the target amide.
The 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (III), an intermediate in the synthesis of cisapride, has been obtained as follows: The bromination of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with Br2 in methanol followed by neutralization of the resulting HBr with NaOMe in the same solvent gives 3-bromo-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (II), which is finally hydrolyzed with aq. 2N HBr or HCl to afford the target intermediate 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (III).
Saponification of 4-acetylamino-2-methoxybenzoate methyl ester (I) with NaOH in MeOH provides carboxylic acid (II), which is then coupled to cis-4-amino-1-[3-(fluorophenoxy)propyl]-3-methoxypiperidine (III) by means of ethyl chloroformate and Et3N in chloroform, affording benzamide (IV). Removal of the acetyl group either by means of HCl at reflux or with NaOH in refluxing MeOH furnishes derivative (V), which is finally converted into the desired product by chlorination with N-chlorosuccinimide (NCS) in acetic acid. Alternatively, compound (IV) can be converted into the target compound by first chlorination with NCS in HOAc, providing chloro derivative (VI), followed by acetyl removal either with HCl at 90 C or with NaOH in refluxing MeOH.
The condensation of 3-(4-fluorophenoxy)propionic acid (I) with 4-piperidone (II) by means of pivaloyl chloride and TEA in refluxing toluene gives the amide (III), which is submitted to oxidation with diacetoxyiodobenzene and KOH in methanol, yielding the hydroxy-dimethoxyketal (IV). The methylation of the OH group of (IV) with Me-I and Ag2O in DMF affords the corresponding methoxy compound (V), which is hydrolyzed with HOAc to provide the methoxypiperidone (VI). The reaction of (VI) with O-benzylhydroxylamine (VII) and pyridine in refluxing toluene gives the oxime (VIII), which is diastereoselectively reduced with BH3 in THF, yielding the cis-isomer (IX). Finally, this amine is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (X) by means of ethyl chloroformate, TEA and HOBt in DMF to afford the target amide.
This compound has been obtained by two related ways: 1. The reaction of 1-benzyl-3-bromopiperidin-4-one (I) with sodium methoxide in methanol gives the intermediate epoxide, which in the reaction medium yields 1-benzyl-3-hydroxypiperidin-4-one dimethylacetal (III). The hydrogenation of (III) with H2 over Pd/C in methanol affords 3-hydroxypiperidin-4-one dimethylacetal (IV), which is condensed with ethyl chloroformate (V) by means of NaOH in THF to provide 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (VI), which is methylated with methyl iodide and NaH in DMF to give the 3,4,4-trimethoxy compound (VII). The hydrolysis of the acetal group of (VII) by means of H2SO4 in refluxing water yields the piperidinone (VIII), which by reductocondensation with benzylamine and H2 over Pd/C in methanol affords the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX). The decarboxylation of (IX) by means of KOH in refluxing isopropanol provides the cis-4-(benzyloxy)-3-methoxypiperidine (X), which is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF, giving the N-substituted piperidine (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C in methanol yields the 4-aminopiperidine (XIII), which is finally condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to obtain the target carboxamide. 2. The debenzylation of the cis- 4-(benzylamino)-3-methoxypiperidine-1-carboxylic acid ethyl ester (IX) with H2 over Pd/C in methanol gives the cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (XV), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (XIV) by means of ethyl chloroformate and TEA in chloroform to yield the corresponding amide (XVI). The decarboxylation of (XVI) with KOH in refluxing isopropanol affords (XVII), with a free NH group that is alkylated with 3-(4-fluorophenoxy)propyl chloride (XI) by means of TEA in DMF to obtain the target carboxamide.
The condensation of 4-amino-5-chloro-2-methoxybenzoic acid (I) with 3-methoxypyridine-4-amine (II) by means of ethyl chloroformate and DEA in chloroform gives the corresponding amide (III), which is condensed with 3-(4-fluorophenoxy)propyl chloride (IV) by means of phenol in hot toluene to yield the pyridinium chloride (V). Finally, this compound is hydrogenated with H2 over PtO2/C in ethanol containing NaHCO3 to afford the target cisapride.