Process for the preparation of zofenopril calcium salt

Details Process for the preparation of zofenopril calcium salt Process for the preparation of zofenopril calcium salt

2002-05-28

2003-02-04

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06515012

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of zofenopril calcium salt. This compound can reportedly exist in the solid state in at least two polymorph forms, named A and B; the novel synthetic process according to the invention yields zofenopril calcium salt only in the form of polymorph A, substantially pure from the form B.
BACKGROUND OF THE INVENTION
Zofenopril, [(4S)-(2S)-3-(benzoylthio)-2-methylpropionyl-4 (phenylthio)-L-proline] calcium salt, has the following formula I
Zofenopril and other analogues thereof, have been described in U.S. Pat. No. 4,316,906. The synthesis used to obtain the calcium salt is schematized in Scheme I and it substantially comprises three steps:
a) condensation between cis-4-phenylthio-L-proline and D-3-(benzoylthio)2-methylpropionyl chloride in aqueous solution keeping pH at values of 8~8.5 by addition of 5N sodium hydroxide; subsequent acidification with HCl, extraction with isobutyl acetate and concentration of the extracts, washing with saline solution, to give (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L proline;
b) treatment of the resinous material from the previous step in isopropanol solution with potassium 2-hethylhexanoate to obtain the corresponding potassium salt;
c) dissolution of the potassium salt in water to a 57% concentration and very slow addition, with simultaneous seeding, of a slight excess of a 2N calcium chloride aqueous solution to precipitate the desired calcium salt. The resulting product is washed thoroughly with water, dried under vacuum at a comparatively high temperature to give the desired calcium salt as dry powder; melting point about 2500°. Alternatively:
d) (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropionyll-4-(phenylthio)-L-proline is dissolved in ethanol and treated with the same volume of an aqueous suspension containing one equivalent of CaO; after removing ethanol and subsequently washing with ether, the aqueous suspension is freeze-dried to obtain the calcium salt with melting point 235-237° (dec.).
The existence of polymorphs in the case of zofenopril calcium salt had been clearly defined in J. Pharmaceutical & Biomedical Analysis, 1994, Vol 12, pp. 173-177 which stated that tablets of zofenopril calcium salt prepared with polymorph A or with polymorph B could not be differentiated on the basis of the their dissolution rate, but reported no chemical-physical characterizations of the two polymorphs. The phenomenon of polymorphism, however, makes it difficult to prepare different batches of zofenopril calcium always having the same chemical-physical characteristics, which is a requisite indispensable to assure the maximum reproducibility for scientific, regulatory and therapeutical purposes.
It has now been found that polymorph A is more resistant to compression and/or micronisation than polymorph B, and therefore polymorph A is much more industrially preferable than polymorph B for the preparation of pharmaceutical formulations in the solid form, such as tablets; it is also evident, in view of what stated above, that polymorph A substantially pure from polymorph B is industrially preferred.
On the other hand, the previously known processes for the preparation of zofenopril calcium salt could not provide polymorph A sufficiently pure from polymorph B. In fact, the synthesis described in U.S. Pat. No. 4,316,906 (cited above at points a, b and c) mainly yields polymorph A, but also polymorph B in percentages very variable and never below 20%; moreover, the alternative synthesis described in U.S. Pat. No. 4,316,906 (cited at point d) gives a partially amorphous product, with very variable characteristics in which polymorph A, when present, is in concentrations much lower than those obtained in the preceding process.
These problems have been solved by the process of the invention which makes it possible to prepare a product in which only and always polymorph A substantially pure from polymorph B is present.


REFERENCES:
patent: 4105776 (1978-08-01), Ondetti et al.
patent: 4154935 (1979-05-01), Ondetti et al.
patent: 4316906 (1982-02-01), Ondetti et al.
XP-002125355, John Krapcho et al. “Angiotensin-Converting Enzyme Inhibitors. Mercaptan, Carboxyalkyl Dipeptide, and Phosphinic Acid Inhibitors Incorporating 4-Substituted Prolines”, Journal of Medicinal Chemistry, 1998, pp. 1148-1160.

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