# US 5,350,850 A · Process for the preparation of substituted tetrahydrofolico derivatives in the [6(R,S)(-)] forms and of their active [6(S)(-)] N.sup.5 diastereoisomers in form of alkali and alkaline earth metal salts > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,350,850 A - Document ID: US5350850A - Status: Granted - Kind: A - Application number: 07/957,176 - Filed: 1992-10-07 - Granted: 1994-09-27 - Earliest claimed: 1991-10-10 - Assignees: APR Applied Pharma Research S.A. - Inventors: Giuseppe Vecchi - Web page: https://patentgrep.com/patent/US5350850A ## CPC - C07D 475/04: with a nitrogen atom directly attached in position 2 - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract Process for the preparation of the optically active [6(S)(-)]N.sup.5 alkaline earth metal salts of methyltetrahydrofolic acid and formyltetrahydrofolic acid wherein an aqueous solution of folic acid is hydrogenated with a high stoichiometric excess of sodium borohydride followed by treating the reaction product with formic aldehyde and optionally further with sodium borohydride when the methyl derivative is desired. Reaction with a salt of the alkaline earth metal precipitates the desired optically active alkaline earth metal salt. ## Claims ### Claim 1 A process for the preparation of the optically active [6(S)(-)]N.sup.5 alkaline earth metal salts of formyltetrahydrofolic acid, said process comprising the steps of: a) mixing an aqueous solution of folic acid with a stoichiometric excess of NaBH.sub.4 in aqueous alkaline solution at a temperature of 5.degree. C. to 30.degree. C. and for a time period of 5 to 60 minutes; b) heating the mixture produced in step a) at a temperature of from 70.degree. C. to 100.degree. C. and for a time of 20 to 30 minutes to reduce the folic acid; c) acidifying the product of step b) to cause tetrahydrofolic acid to precipitate; d) dissolving the precipitate produced in step c) and reacting the resulting solution with formic aldehyde at a temperature less than 90.degree. C.; e) treating the product of step d) with a strong acid and adjustment of the pH of the resulting solution to about 7 to cause precipitation of inorganic salts from solution; f) adding to the solution obtained in step e) an aqueous solution of a salt of an alkaline earth metal salt while maintaining the solution obtained at pH 7 and at a temperature of -5.degree. C. to 10.degree. C.; and g) allowing the optically active [6(S)(-)]N.sup.5 alkaline earth metal salt of formyltetrahydrofolic acid to crystallize. ### Claim 2 (depends on 1) A process according to claim 1, wherein in step f) the solution obtained in step e) is maintained at a controlled temperature of between -2.degree. C. and +2.degree. C. and said salt of said alkaline earth metal is calcium, barium or magnesium chloride. ### Claim 3 (depends on 1) A process according to claim 1, wherein in step a) an aqueous solution of folic acid maintained at a temperature of 5.degree. C. is added to a 20% NaOH aqueous solution in which the stoichiometric excess of NaBH.sub.4 is dissolved under stirring and is maintained at 20.degree. C. ### Claim 4 (depends on 1) A process according to claim 1, wherein in the NaBH.sub.4 is present in least four times the stoichiometric amount. ### Claim 5 (depends on 3) A process according to claim 3, wherein a sodium salt of ethylendiaminotetraacetic acid (EDTA) is added to the mixture of folic acid and NaBH.sub.4 and the temperature of the solution is brought to 0.degree. to 5.degree. C. ### Claim 6 (depends on 1) A process according to claim 1, wherein in step a) the temperature is from 20.degree. C. to 25.degree. C. ### Claim 7 (depends on 1) A process according to claim 1, wherein the time period in step a) is 20-30 minutes. ### Claim 8 (depends on 1) A process according to claim 1, wherein step b) is carried out at 90.degree.-95.degree. C. for a period of 20 minutes. ### Claim 9 (depends on 1) A process according to claim 1, wherein in step f) said aqueous alkaline earth metal solution is a 4M aqueous solution of calcium chloride. ### Claim 10 A process for the preparation of the optically active [6(S)(-)]N.sup.5 alkaline earth metal salts of methyltetrahydrofolic acid, said process comprising the steps of: a) mixing an aqueous solution of folic acid with a stoichiometric excess of NaBH.sub.4 in aqueous alkaline solution at a temperature of 5.degree. C. to 30.degree. C. and for a time period of 5 to 60 minutes; b) heating the mixture produced in step a) at a temperature of from 70.degree. C. to 100.degree. C. and for a time of 20 to 30 minutes to reduce the folic acid; c) reacting the product of step c) with formic aldehyde at a temperature less than 90.degree. C.; d) heating the product of step c) with an aqueous alkaline solution of NaBH.sub.4 at a temperature of about 60.degree. C.; e) treating the product of step d) with a strong acid and adjustment of the pH of the resulting solution to about 7 to cause precipitation of inorganic salts from solution; f) adding to the solution obtained in step e) an aqueous solution of a salt of an alkaline earth metal salt while maintaining the solution obtained at pH 7 and at a temperature of -5.degree. C. to 10.degree. C.; and g) allowing the optically active [6(S)(-)]N.sup.5 alkaline earth metal salt of methyltetrahydrofolic acid to crystallize. ### Claim 11 (depends on 10) A process according to claim 10, wherein in step f) the solution obtained in step e) is maintained at a controlled temperature of between -2.degree. C. and +2.degree. C. and said salt of said alkaline earth metal is calcium, barium or magnesium chloride. ### Claim 12 (depends on 10) A process according to claim 10, wherein in step a) an aqueous solution of folic acid maintained at a temperature of 5.degree. C. is added to a 20% NaOH aqueous solution in which the stoichiometric excess of NaBH.sub.4 is dissolved under stirring and is maintained at 20.degree. C. ### Claim 13 (depends on 12) A process according to claim 12, wherein a sodium salt of ethylendiaminotetraacetic acid (EDTA) is added to the mixture of folic acid and NaBH.sub.4 and the temperature of the solution is brought to 0.degree. to 5.degree. C. ### Claim 14 (depends on 10) A process according to claim 10, wherein in the NaBH.sub.4 is present in least four times the stoichiometric amount. ### Claim 15 (depends on 10) A process according to claim 10, wherein in step a) the temperature is from 20.degree. C. to 25.degree. C. ### Claim 16 (depends on 10) A process according to claim 10, wherein the time period in step a) is 20-30 minutes. ### Claim 17 (depends on 10) A process according to claim 10, wherein step b) is carried out at 90.degree.-95.degree. C. for a period of 20 minutes. ### Claim 18 (depends on 10) A process according to claim 10, wherein in step f) said aqueous alkaline earth metal solution is a 4M aqueous solution of calcium chloride.