Processes for the preparation of 4-morpholin-3-one

A process for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one of the formula (II),

• comprising:
• a) reacting 4-(4-morpholin-3-onyl)aniline of the formula (VII) or a salt thereof
• with R-epichlorohydrin of the formula (VI),
• in an organic solvent selected from the group consisting of an alcohol selected from the group consisting of methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol, hexanol, and octanol, ethers selected from the group consisting of tetrahydrofuran and 1,4-dioxane and aprotic solvents selected from the group consisting of acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) or mixtures thereof, to give 4-[4-(3-chloro-2(R)-hydroxy-propyl amino)-phenyl]-morpholin-3-one of the formula (V),
• b) cyclization of the formula (V) compound or a salt thereof using a suitable reagent selected from the group consisting of carbonyl diimidazole, phosgene, triphosgene, methyl chloroformate, benzyl chloroformate and phenyl chloroformate in the presence of an organic solvent selected from the group consisting of halogenated solvents selected from the group consisting of dichloromethane, ethylene dichloride and chloroform, esters selected from the group consisting of ethyl acetate and isopropyl acetate, hydrocarbon solvents selected from toluene and xylene, ethers selected from tetrahydrofuran, 1,4-dioxane, aprotic polar solvents selected from the group consisting of acetonitrile, N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide and N-methylpyrrolidone (NMP) or mixtures thereof to give 4-[4-(5(R)-chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one of the formula (IV)
• c) reacting the formula (IV) compound with potassium phthalimide in the presence of an organic solvent selected from the group consisting of halogenated solvents selected from the group consisting of dichloromethane, ethylene dichloride and chloroform, esters selected from the group consisting of ethyl acetate and isopropyl acetate, aprotic polar solvents selected from the group consisting of acetonitrile, N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide and N-methylpyrrolidone (NMP) or mixtures thereof to give 2-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)phenyl]-oxazolidin-5(S)ylmethyl}-isoindole-1,3-dione of the formula (III), and
• d) reacting the formula (III) compound with a suitable reagent selected from the group consisting of hydrazine hydrate and aqueous methyl amine in the presence of an organic solvent selected from the group consisting of alcohols selected from the group consisting of methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol, hexanol and octanol, ethers selected from the group consisting of tetrahydrofuran and 1,4-dioxane, aprotic polar solvents selected from the group consisting of acetonitrile, N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide and N-methylpyrrolidone (NMP) or mixtures thereof or their aqueous mixtures to give the formula II compound.

A process for the preparation of 2-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5(S)-ylmethyl}-isoindole-1,3-dione of the formula (III)

• comprising:
• a) reacting 4-[4-(3(R)-Chloro-2-hydroxy-propyl amino)-phenyl]-morpholin-3-one of the formula (V) or a salt thereof,
• with a suitable phthalimide derivative selected from the group consisting of sodium phthalimide, potassium phthalimide or mixtures thereof in the presence of an organic solvent selected from the group consisting of halogenated solvents selected from the group consisting of dichloromethane, ethylene dichloride and chloroform, esters selected from the group consisting of ethyl acetate and isopropyl acetate and aprotic polar solvents selected from the group consisting of acetonitrile, N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide and N-methylpyrrolidone (NMP) or mixtures thereof,
• to give 2-{2(R)-hydroxy-3-[4-(3-oxo-morpholin-4-yl)-phenylamino]-propyl}-isoindole-1,3-dione of the formula (VIII), and
• b) cyclization of the formula (VIII) compound or a salt thereof using a suitable reagent selected from the group consisting of carbonyldiimidazole, phosgene, triphosgene, methyl chloroformate, benzyl chloroformate and phenylchloroformate or mixtures thereof in the presence of an organic solvent selected from halogenated solvents selected from dichloromethane, ethylene dichloride and chloroform, esters selected from the group consisting of ethyl acetate and isopropyl acetate, hydrocarbon solvents selected from the group consisting of toluene and xylene, ethers selected from the group consisting of tetrahydrofuran, 1,4-dioxane aprotic polar solvents selected from the group consisting of acetonitrile, N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide and N-methylpyrrolidone (NMP) or mixtures thereof to give a formula (III) compound.