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
AssigneeAPR Applied Pharma Research S.A.
InventorGiuseppe Vecchi
Life of this patent
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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.
Claims18
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.;
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- g) allowing the optically active [6(S)(-)]N.sup.5 alkaline earth metal salt of formyltetrahydrofolic acid to crystallize.
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.;
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- g) allowing the optically active [6(S)(-)]N.sup.5 alkaline earth metal salt of methyltetrahydrofolic acid to crystallize.
Dependencies are inferred from the claim text.