Process for the preparation of high purity Pemirolast

Details Process for the preparation of high purity Pemirolast Process for the preparation of high purity Pemirolast

2002-07-17

2004-03-09

Rotman, Alan L. (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06703505

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for the purification of Pemirolast, whose potassium salt is an anti-allergic pharmaceutical product.
BACKGROUND OF THE INVENTION
Pemirolast, or 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido-[1, 2-a]-pyrimidin-4-one, has the following formula:
Several patents disclose processes for the preparation of Pemirolast Potassium.
According to all known methods, the product is firstly obtained in the acid form and then converted into the corresponding potassium salt.
As the product recovered in the acid form is very poorly soluble in conventional solvents, it always contains several by-products which can hardly be removed and only with remarkable losses in yields. The purification is usually carried out either directly on the acid form or on the corresponding potassium salt.
SUMMARY OF THE INVENTION
A novel process for the purification of Pemirolast acid form which provides high purity (>99,8% HPLC) and high yields (>85%) has now been found, and this is the object of the present invention.
The process of the invention comprises the salification of Pemirolast acid form in the presence of an amount of a primary or secondary amine ranging from 1 equivalent to 1.5 equivalents relative to Pemirolast and an amount of protic solvents such as water, C
1
-C
3
-alcohols or mixtures thereof ranging from 1 volume to 10 volumes relative to Pemirolast. The use of a 2:1 methanol:water mixture is preferred.
The salification is carried out at a temperature which allows to completely solubilize the salt, generally at a temperature ranging from 20 to 100° C., preferably from 40 to 80° C. When the solubilization is complete, the solution is acidified with mineral or organic acids to pH ranging from 2 to 4 in order to promote the precipitation of Pemirolast in the acid form which is then filtered, washed and dried to give a product with >99.8% HPLC purity. Suitable acids comprise formic acid, acetic acid and hydrochloric acid.
Said product can then be transformed into the corresponding potassium salt without further purification.
Primary amines for use according to the invention are C
1
-C
6
-alkylamines, or arylamines wherein the aryl residue can be phenyl, naphthyl or an optionally substituted aromatic heterocyclic nucleus.
Secondary amines for use according to the invention are di(C-C
6
)alkylamines, alkylarylamines or diarylamines, wherein the alkyl or aryl residues are as defined above, or are an aliphatic and aromatic substituent and wherein the meanings for aliphatic and aromatic are those indicated above.


REFERENCES:
patent: 4122274 (1978-10-01), Juby
patent: 5254688 (1993-10-01), Sano et al.
patent: 243 821 (1987-03-01), None
patent: 0 462 834 (1991-10-01), None
patent: 93/25557 (1993-12-01), None

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