The starting compounds (IV) and (VII) are obtained as follows: a) Methyl 4-acetylamino-2-hydroxybenzoate (I) is converted to the 2-ethoxy derivative (II) with ethyl iodide, and then chlorination of (II) with N-chlorosuccinimide followed by alkaline hydrolysis of (III) gives benzoic acid (IV). b) The reaction of 2-[(4-fluorobenzyl)amino]ethanol (V) with N-(2,3-epoxypropyl)phthalimide (VI), followed by treatment with concentrated sulfuric acid, affords intermediate (VII). The condensation of 4-Amino-5-chloro-2-ethoxybenzoic acid (IV) with 4-(4-fluorobenzyl)-2-(methylamino) morpholine (VII) by means of ethyl chloroformate and triethylamine in CHCl3 gives 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl] benzamide, which is converted to mosapride citrate, by treatment with citric acid.
The synthesis of the optical enantiomers of mosapride has been described: The reductocondensation of 4-fluorobenzaldehyde (I) with ethanolamine (II) by means of NaBH4 and NaHCO3 in refluxing methanol gives 2-(4-fluorobenzylamino)ethanol (III), which is condensed with epichlorohydrin (IV) to yield the diol (V). Compound (V), without isolation, is cyclized with conc. H2SO4 to afford 2-(chloromethyl)-4-(4-fluorobenzyl)morpholine (VI), which is treated with refluxing water-formamide to afford the corresponding methanol derivative (VII). Tosylation of (VII) with tosyl chloride and triethylamine/4-(dimethylamino)pyridine in dichloromethane gives the tosylate (VIII) as a racemic mixture. The optical resolution of (VIII) with N-(p-toluenesulfonyl)-L-glutamic acid in methanol affords the (S)-tosylate [(S)-IX] and the (R)-tosylate [(R)-IX]. The reaction of both [(S)-IX] and [(R)-IX] with sodium azide followed by reduction with bis(2-methoxyethoxy)aluminum hydride (vitride) gives the chiral amines [(S)-X] and [(R)-X], which are finally condensed with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) in dichloromethane, yielding the (S)- and (R)-enantiomers of mosapride.
The chiral sulfonate [(R)-IX] has been obtained in a different way: The cyclization of 2(S)-(benzyloxymethyl)oxirane (XII) with 2-aminoethyl hydrogen sulfate sodium salt (XIII) by means of NaOH in methanol gives 2(R)-(benzyloxymethyl)morpholine (XIV), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to the chiral alcohol (XV). The condensation of (XV) with 4-fluorobenzyl chloride (XVI) by means of K2CO3 and NaI in refluxing butanone affords 4-(4-fluorobenzyl)-2(R)-(hydroxymethyl)morpholine (XVII), which is finally tosylated with tosyl chloride as before to afford [(R)-IX], already obtained.
The synthesis of the metabolites of mosapride, 4-amino-5-chloro-2-ethoxy-N-(2-morpholinylmethyl)benzamide (M-1) and 4-amino-5-chloro-2-ethoxy-N-(5-oxo-2-morpholinylmethyl)benzamide (M-2), has been described: 1) The hydrogenolysis of mosapride (I) with H2 over 10% Pd/C in aqueous ethanol/acetic acid gives 4-amino-2-ethoxy-N-(2-morpholinylmethyl)benzamide (II), which is acetylated with acetic anhydride in methanol/CHCl3, yielding the corresponding diacetyl derivative (III). The chlorination of (III) with N-chlorosuccinimide (NCS) in DMF affords the 5-chloro derivative (IV), which is finally deacetylated with refluxing 10% HCl, yielding the metabolite M-1 as the hydrochloride salt.
2) The reaction of N-(2,3-epoxypropyl)phthalimide (I) with dibenzylamine (II) at 80 C gives 1-(dibenzylamino)-3-(phthalimido)-2-propanol (III), which is hydrolyzed with refluxing concentrated HCl to afford 1-amino-3-(dibenzylamino)-2-propanol (IV). The acylation of (IV) with chloroacetyl chloride (V) in CHCl3 yields the corresponding chloroacetamide (VI), which is cyclized by means of potassium tert-butoxide in refluxing ethanol to give 6-(dibenzylaminomethyl)morpholin-3-one (VII). The debenzylation of (VII) with H2 over Pd(OH)2/C in ethanol yields 6-(aminomethyl)morpholin-3-one (VIII), which is condensed with 4-(acetamido)-5-chloro-2-ethoxybenzoyl chloride (IX) by means of triethylamine in CHCl3 to afford the monoacetylated derivative of metabolite M-2 (X). Finally, this compound is hydrolyzed with HCl in refluxing ethanol/water to give metabolite M-2. The two final steps of this sequence can also be performed in a single step by condensation of morpholinone (VIII) with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of carbonyldiimidazole (CDI) in THF to afford directly the metabolite M-2 after neutralization with aqueous NH4OH.
The synthesis of deuterated mosapride citrate has been reported: The cyclization of N-(4-fluorobenzyl)ethanolamine (I) with 2-chloroacrylonitrile (II) in ethyl ether gives 4-(4-fluorobenzyl)morpholine-2-carbonitrile (III), which is submitted to alcoholysis with ethanol and H2SO4, yielding the corresponding ethyl ester (IV). The reduction of (IV) with deuterated sodium borohydride (NaBD4) in THF affords the deuterated hydroxymethyl derivative (V), which is condensed with phthalimide (VI) by means of triphenylphosphine and dimethyl azodicarboxylate (AZDC) in THF to give the N-substituted phthalimide (VII). The cleavage of (VII) with hydrazine hydrate in refluxing ethanol yields the deuterated methylamine derivative (VIII), which is finally condensed with 4-amino-5-chloro-2-ethoxybenzoic acid (IX) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCD) in dichloromethane, and treated with citric acid in the usual way.
Two minor metabolites of mosapride 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (A) and 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(2-morpholinylmethyl)benzamide (B) have been synthesized as follows: 1) The alkylation of 2,3-dihydroxybenzaldehyde (I) with NaH and ethyl iodide in DMSO gives 2-ethoxy-3-hydroxybenzaldehyde (II), which is nitrated with HNO3 in acetic acid yielding 2-ethoxy-3-hydroxy-4-nitrobenzaldehyde (III). The oxidation of (III) with AgNO3 in methanol/water affords the expected benzoic acid (IV), which is condensed with 2-(aminomethyl)morpholin-5-one (V) by means of carbonyldiimidazole (CDI) in THF giving the corresponding benzamide (VI). The hydrogenation of the nitro group of (VI) with H2 over Pd/C in aqueous ethanol yields 4-amino-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (VII), which is finally chlorinated to the metabolite (A) with N-chlorosuccinimide in hot DMF. 2) The reaction of the benzoic acid (IV) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VIII), which is condensed with 2-(aminomethyl)-4-(4-fluorobenzyl)morpholine (IX) by means of triethylamine in dichloromethane to yield the expected amide (X). The debenzylation of (X) with 1-chloroethyl chloroformate (ACE-Cl) and reprotection with di-tert-butyl carbonate affords N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxy-4-nitrobenzamide (XI), which is submitted to a reductive acetylation (H2 over Pd/C in acetic anhydride) giving 4-acetamido-N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxybenzamide (XII). The chlorination of (XII) with N-chlorosuccinimide (NCS) in chloroform/DMS yields the corresponding 5-chlorobenzamide (XIII), which is finally deprotected with refluxing aqueous HCl to afford metabolite (B).