Process for the preparation of sodium divalproate

Details Process for the preparation of sodium divalproate Process for the preparation of sodium divalproate

2002-06-26

2003-12-23

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

Reexamination Certificate

active

06667420

ABSTRACT:

The present invention relates to a process for the preparation of sodium divalproate.
Valproic acid and its sodium salt have been used for some time as anticonvulsant drugs, particularly in the treatment of epilepsy attacks and convulsive seizures.
Both drugs can, however, involve formulation problems, because the acid is in the liquid form, while the sodium salt is a hygroscopic solid and has therefore poor stability; furthermore, its formulation causes problems, well known to those skilled in the art whenever dealing with hygroscopic materials. Therefore, attempts have been made to prepare a valproic acid derivative having such better characteristics as to allow an easy formulation in suitable pharmaceutical forms.
As a result of such attempts, sodium divalproate, of formula (I)
which is a complex, non hygroscopic salt, having remarkable stability, has been developed.
However, the processes at present known (see, for example, PCT/US80/00954) for the preparation of this salt start from sodium valproate, whose above mentioned hygroscopicity involves production problems, in that it can adversely affect the chemical and microbiological stability, thus leading to problems in terms of preservation. The presence of high relative humidity can, in fact, even make mould growth possible. It is therefore evident that a process using such highly hygroscopic starting material as sodium valproate is not ideal from the industrial point of view.
It has now been found, and it is the object of the present invention, a process for the preparation of sodium divalproate, which does not use the valproic acid sodium salt as starting material.
According to the present invention, sodium divalproate is in fact prepared starting from valproic acid and sodium methoxide, according to the following reaction scheme:
The reaction is carried out in hydrocarbon solvents, such as heptane, hexane, ligroin and the like. The valproic acid to sodium methoxide molar ratio can range from 2.5 to 0.8, and is more preferably 2:1.
The methanol formed during the reaction is removed by azeotropical distillation, after that any insoluble impurities are filtered off and the salt is recovered by concentration to dryness and melting to about 110-120° C. The molten mass is then cooled to about 60° C. and crystallized from acetone or diisopropyl ether to obtain extremely pure sodium divalproate.
The process of the present invention is illustrated in greater detail in the following example.


REFERENCES:
patent: 1144558 (1983-04-01), None

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