Patent EA-003454-B1 (EA)
Title: A process for the preparation of zofenopril calcium salt
Inventor: GIACHETTI ANTONIO
IPC: A61K31/401
Filed: 1999-07-30
Abstract: 1. A process for the preparation of polymorph A of zofenopril calcium salt in substantially pure form, which comprises: a) reaction of S(-)-3-benzoylthio-2-methylpropanoic acid chloride with cis-4-phenylthio-L-proline in water at pH ranging from 9.0 to 9.5 and recovery of zofenopril in the acidic form; b) salification of acid zofenopril with a potassium salt in alcoholic solution, and recovery of the resulting potassium salt; c) conversion of the potassium salt to calcium salt by addition of a zofenopril potassium salt aqueous solution to a CaCl2 aqueous solution at a temperature of 70-90 degree C with simultaneous seeding to promote the precipitation of polymorph A. 2. A process as claimed in claim 1, characterized in that, in step a), S(-)-3-benzoylthio-2-methylpropanoic acid chloride is prepared by reaction of the corresponding acid with a chlorinating agent in an aprotic organic solvent at temperatures from -10 to +50 degree C, and in that the reaction with cis-4-phenylthio-L-proline is carried out adding a solution of the acid chloride in an aprotic organic solvent to a cis-4-phenylthio-L-proline aqueous solution at pH 9.0-9.5, at temperatures ranging from -10 to + 50 degree C. 3. A process as claimed in claim 2 in which pH is kept within values ranging from 9.0 to 9.5 by addition of sodium hydroxide. 4. A process as claimed in claim 2 or 3 in which pH is kept at the value of 9.5. 5. A process according to any one of claims 2 to 4 in which the aprotic organic solvent is ethyl acetate, isobutyl acetate or methylene chloride. 6. A process as claimed in claim 1 wherein step b) is carried out in an alcoholic solvent by reaction with an organic acid potassium salt. 7. A process as claimed in claim 6 in which the organic acid potassium salt is potassium 2-ethyl hexanoate and the solvent is isopropanol. 8. A process as claimed in claim 1 wherein step c) is effected at a temperature of 80-85 degree C. 9. A process according to any one of the above claims characterized in that a polymorph A of zofenopril calcium salt having a content in polymorph B lower than 7% is obtained. 10. Pharmaceutical compositions containing as active ingredient substantially pure zofenopril calcium salt Polymorph A. 11. Pharmaceutical compositions containing as active 16 ingredient polymorph A of zofenopril calcium salt having a content in polymorph B lower than 15%. 12. Pharmaceutical compositions containing as active ingredient polymorph A of zofenopril calcium salt having a content in polymorph B lower than 7%. 13. The use of substantially pure zofenopril calcium salt Polymorph A for the preparation of medicaments for the treatment of essential hypertension, cardiac decompensation and acute myocardial infarction. 14. The use of substantially pure zofenopril calcium salt Polymorph A having a content in polymorph B lower than 15%, for the preparation of medicaments for the treatment of essential hypertension, cardiac decompensation and acute myocardial infarction. 15. The use of substantially pure zofenopril calcium salt Polymorph A having a content in polymorph B lower than 7%, for the preparation of medicaments for the treatment of essential hypertension, cardiac decompensation and acute myocardial infarction.