Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1993-08-16
1995-02-21
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C07D47504
Patent
active
053917383
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the separation of folinic acids and for the obtention of the (6S(-)) diastereoisomer, particularly as the calcium salt. The separation of the mixture of diastereoisomers consisting of the [6(R,S)-N.sup.5 -formyltetrahydrofolic] acid has a great interest since only the (6S) diastereoisomer (levofolinic acid) is endowed with biological and pharmacological activity. The form in which the folinic acid is mostly administered is that of the calcium salt thereof.
Thus a process for the isolation of the levofolinic acid directly as the calcium salt has a great industrial importance.
To this end a research work has been started in order to evaluate the possibility of sequestering part of the calcium ion released from an aqueous solution of racemic calcium folinate, in the presence of a suitable chelating agent such as the sodium salt of the ethylendiaminotetraacetic acid (tetrasodium EDTA), The purpose was that of achieving the relative precipitation of the calcium S-(-)-folinate, described as the less soluble of the two diastereoisomers (Lederle patent PCT/EP 88/00341), keeping the other diastereoisomer in form of sodium salt.
It has been surprisingly found and is the object of the present invention that, by treating a solution of racemic calcium folinate with tetrasodium EDTA in the ratio of half mole thereof per mole of folinate and salting out the solution with sodium chloride, in order to promote the precipitation of the less soluble species, the mother liquors, upon being separated from the thus obtained precipitate, are highly enriched with the less soluble species, namely calcium S-(-)-folinate, which can be obtained at the solid state by adding calcium chloride and filtering the precipitate.
A more extended investigation has been carried out about the causes of such a surprising behaviour. The optimization tests, aiming to increase yield and optical purity of the precipitate enriched with the levorotatory form, have casted some light on the probable mechanism involved.
It has been firstly found that the best yields are obtained by adding to the starting solution, besides the half mole of tertasodium EDTA, half mole of calcium chloride; however, in order to precipitate the enriched levorotatory form from the mother liquors it is necessary to add the filtrate with a further half mole of calcium chloride. The weight ratios between the first precipitate, obtained after the salting out, and the second one, enriched with the levorotatory form, together with the determination of the folinic acid in the two precipitates by means of HPLC, lead to the conclusion that the first precipitate essentially consists of a mixture of calcium edetate and calcium folinate, whereas the second precipitate does not contain great amounts of EDTA.
A hypothesis consistent with these data, although herein reported without limiting intention, is that a mixed salt is formed in solution, which can be represented by the structure (1), it being more insoluble either than calcium folinate and than EDTA salts. Moreover of the two forms which can be originated, it is to be supposed that the one formed by EDTA and calcium d-folinate is the most insoluble. ##STR1##
Another evidence confirming such a supposition is the fact that if an attempt is made of forcing the first precipitation by cooling the solution after the salting out, the result is poor, contrarily to what could have to be expected if it would be a mere precipitation of an insoluble species already present in the starting solution. This phenomenon can be on the contrary adequately interpreted by making the supposition that an insoluble species (mixed salt) is formed in the solution according to the times dictated by the reaction kinetics.
It has been found that, as a matter of fact, the maximum amount of precipitate after the salting out is obtained by heating the mixture or by increasing the stirring times.
The optimization of the operating conditions leads to a significant result from the point of view of the preparation of calcium S
REFERENCES:
patent: 4959472 (1990-09-01), Wood et al.
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patent: 5324836 (1994-06-01), Mueller et al.
Aitilio et al Chemical Abstr. vol 120, Entry 288693 (1993) abstracting EP 539987.
Vecchi Chemical Abstr. vol. 119 Entry 270915 (1993) abstracting EP 537,842.
APR Applied Pharma Research S.A.
Daus Donald G.
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