# US 5,344,974 A · Process for the preparation of N-acyl derivatives of 5-aminolevulinic acid, as well as the hydrochloride of the free acid > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,344,974 A - Document ID: US5344974A - Status: Granted - Kind: A - Application number: 08/111,067 - Filed: 1993-08-24 - Granted: 1994-09-06 - Earliest claimed: 1992-08-24 - Assignees: Sudzucker Aktiengesellschaft Mannheim/Ochensfurt - Inventors: Gerand Descotes; Louis Cottier; Laurent Eymard; Knut M. Rapp - Web page: https://patentgrep.com/patent/US5344974A ## CPC - C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical - C07C 231/14: by formation of carboxamide groups together with reactions not involving the carboxamide groups - C07C 233/47: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton - C07D 307/60: Two oxygen atoms, e.g. succinic anhydride - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS ## Abstract The invention relates to a process for the preparation of N-acyl derivatives of 5-aminolevulinic acid of general formula R-CO-NH-CH.sub.2 -CO-CH.sub.2 -CH.sub.2 -COOH, in which R stands for methyl, ethyl, propyl, isopropyl, butyl, phenyl, benzyl, furyl or furfuryl, as well as the hydrochloride of the free acid by acid hydrolysis, characterized in that the 5-hydroxymethyl furfural is condensed with a nitrile in acid solution and the N-acyl-aminomethyl furfural compound obtained is converted by photooxidation into a N-acyl-5-aminomethyl-5-hydroxydihydro-2,5-furan-2-one and the latter is reduced with zinc in acetic acid under ultrasonic treatment to N-acyl-5-aminolevulinic acid and by acid hydrolysis the 5-aminolevulinic hydrochloride is obtained. ## Claims ### Claim 1 Process for the preparation of an N-acyl derivative of 5-aminolevulinic acid (ALA) of formula I R--CO--NH--CH.sub.2 --CO--CH.sub.2 --CH.sub.2 --COOH (I) in which R is methyl, ethyl, propyl, isopropyl, butyl, phenyl, benzyl, furyl or furfuryl, comprising reacting 5-hydroxymethyl furfural (HMF) of formula II ##STR4## with a nitrile of formula III R--C.tbd.N (III) in which R has the above meaning, in the presence of an acid catalyst to an N-acyl-5-amino-methyl furfural of formula IV ##STR5## in which R has the above meaning, and converting said N-acyl-5-aminomethyl-furfural by photooxidation into an N-acyl-5-aminomethyl-5-hydroxydihydro-2,5-furan-2-one of formula V ##STR6## in which R has the above meaning, and reducing said furanone into the N-acyl levulinic acid of formula I. ### Claim 2 (depends on 1) A process according to claim 1 wherein in the condensation reaction of HMF with said nitrile a mineral acid, a sulphonic acid or a mixture of methane sulphonic acid and phosphoric anhydride is used as the acid catalyst. ### Claim 3 (depends on 2) Process according to claim 2, wherein the molar ratio of HMF to the acid catalyst is in the range of 1:0.5 to 1:2. ### Claim 4 (depends on 2) Process according to claim 2, wherein the molar ratio of HMF to nitrile is in the range of 1:100 to 1:300. ### Claim 5 (depends on 2) Process according to claim 2, wherein the condensation reaction is performed at a temperature between 0.degree. and 50.degree. C. ### Claim 6 (depends on 1) Process according to claim 1 wherein the photooxidation of the N-acyl-5-aminofurfural is performed by oxygen in the presence of a photosensitizer and at a temperature between 0.degree. and 50.degree. C. ### Claim 7 (depends on 6) Process according to claim 6, wherein the photooxidation is performed in a polar solvent. ### Claim 8 (depends on 6) Process according to claim 6, wherein during the photooxidation, rose Bengal in solution or deposited on a resinous carrier is used as the photosensitizer. ### Claim 9 (depends on 1) Process according to claim 1 wherein the reduction of N-acyl-5-aminomethyl-5-hydroxydihydro-2,5-furan-2-one is performed by zinc in acetic acid under ultrasonic treatment at a temperature between 0.degree. and 60.degree. C. ### Claim 10 Process for preparing the hydrochloride of 5-aminolevulinic acid comprising reacting 5-hydroxymethyl furfural (HMF) of formula II ##STR7## with a nitrile of formula III R--C.tbd.N (III) where R is methyl, ethyl, propyl, isopropyl, butyl, phenyl, benzyl, furyl or furfuryl, in the presence of an acid catalyst to an N-acyl-5-amino-methyl furfural of formula IV ##STR8## in which R has the above meaning and converting said N-acyl-5-aminomethyl-furfural by photooxidation into an N-acyl-5-aminomethyl-5-hydroxydihydro-2,5-furan-2-one of formula V ##STR9## in which R has the above meaning, and reducing said furanone into an N-acyl derivative of 5-aminolevulinic acid (ALA) of formula I R--CO--NH--CH.sub.2 --CO--CH.sub.2 --CH.sub.2 --COOH (I) in which R has the above meaning, and acid hydrolyzing said acyl derivative of formula I with HCl. ### Claim 11 (depends on 7) Process according to claim 7, wherein said polar solvent is methanol, ethanol, acetone or dichloromethane.