Organic compounds -- part of the class 532-570 series – Organic compounds – Pteroyl per se or having -c- – wherein x is chalcogen – bonded...
Reexamination Certificate
1998-06-03
2001-03-20
Bernhardt, Emily (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Pteroyl per se or having -c-, wherein x is chalcogen, bonded...
C548S371700
Reexamination Certificate
active
06204383
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the pharmaceutical chemical 5-[2-ethoxy-5-(4-methylpiperazin-1-yl sulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, known generically as sildenafil, and more specifically to novel processes for preparing sildenafil.
BACKGROUND OF THE INVENTION AND PRIOR ART
Sildenafil, of structural chemical formula:
is known, from e.g. European Patents EP-A-0463756 and EP-A-0812845. It has pharmaceutical utility in the treatment of male sexual dysfunction.
As a relatively complicated synthetic organic chemical molecule, sildenafil requires a multi-step chemical synthesis.
Any organic synthesis step, which is part of a complex multi-step synthesis, results in contamination of the intermediate with solvents, catalysts, starting materials and by-products and so introduces the requirement for purification. If a pharmaceutical grade of final product is to result, this cleaning must be done either as the contamination is caused, that is in the work-up of the particular step, or at some subsequent point in the process. A rugged process is desirable which is not demanding with regard to the purity of the intermediates and which allows for a very efficient cleaning during the isolation of the final drug product.
It is an object of the present invention to provide novel processes for preparing sildenafil which simplify the purification procedures and which produce sildenafil in substantially pure form without involving complex purification procedures.
It is a further object of the present invention to provide intermediates useful for the preparation of sildenafil by such novel processes.
SUMMARY OF THE INVENTION
The process of the present invention utilizes, as its last synthetic step, a reaction involving an intermediate of significantly less basicity than sildenafil itself, followed by phase shifting, according to which the sildenafil moves exclusively from the reaction mixture phase to an added, immiscible phase.
The phase shifting can be done in either of two ways, both of which are envisioned to fall within the scope of this invention. In the first way, the more basic tertiary amine functionality which is introduced into sildenafil in the last step is used to extract sildenafil into a predominantly aqueous phase by adjusting the pH of the aqueous phase to less than about 2.7. The less basic by-products and contaminants commingling with sildenafil can be extracted therefrom with common organic solvents essentially immiscible with the predominantly aqueous acid phase. It is essential to the invention that in this extractive purification the more basic functionality is introduced or unmasked in the last synthetic step, the step in which sildenafil is itself created. It is only thus that the benefit of highly pure sildenafil is obtained. An extensive description of methodology for determining preferred conditions for separating a more basic amine from less basic amines is more fully described by Arne Brandstrom in Acta Chem. Scand. B 33(1979) 731-734 which is incorporated herein by reference. In the second way to use phase shifts to purify sildenafil the crude substance along with all the residual starting materials, reagents and by-products are partitioned between a mixture of 1:1 v/v 85% phosphoric acid-water and an immiscible unreactive organic solvent. The phosphoric acid causes the sildenafil to dissolve completely in the predominantly aqueous phase. Non-basic impurities are extracted into the organic layer which is separated. A halogenated organic solvent such as chloroform, methylene chloride or the like is then added to the aqueous phosphoric acid containing phase followed by a molar equivalent compared to sildenafil of a salt of a monoanion, such as sodium bromide, sodium iodide, sodium nitrate, sodium thiocyanate, tetrafluoroborate, perchlorate or the like. The sildenafil ammonium cation with this-monoanion will be selectively extracted into the organic halogenated solvent. Low molecular weight basic compounds will not be so extracted nor will weakly basic compounds nor will salts of primary and secondary amines even if these compounds are strong bases. Thus the sildenafil is separated by simple ion pair extraction from several classes of impurities. The sildenafil itself can easily be recovered by basification and reextraction into an organic solvent from which it can be isolated either by crystallization or evaporation as desired. Further details useful for understanding the many ways the invention can be practiced can be found in an article entitled, “A Convenient Method for the Preparation of Salts of Amines,” Acta. Chem. Scand. 23(1969) 1215-18 incorporated herein by reference.
Accordingly, in such process, in one embodiment of the invention, the sildenafil can be extracted from the organic medium in which it is prepared, with an aqueous solvent, with appropriately chosen pH, so that a phase shift takes place whereby the desired end product is caused to move from one phase of the reaction medium to another, whilst unchanged reactants and other by-products are left in the original, organic phase of the reaction medium.
According to a second embodiment of the invention, the sildenafil can be extracted from a predominantly aqueous acid solution containing a large lipophilic monoanion with a halogenated organic solvent so that a phase shift takes place whereby the desired end product as an ammonium salt ion pair is caused to move from one phase of the reaction medium to another, whilst unchanged reactants and other by-products are left in the original aqueous acidic phase of the reaction medium. The ion pair is then neutralized and recovered. As a result, in all embodiments the process leads to the production of sildenafil in a very high degree of purity, whilst minimizing the number and complexity of the purification steps required.
Thus, according to one embodiment of the present invention, there is provided a process for preparing sildenafil in solution in an organic solvent and subsequently recovering the sildenafil from an organic solvent, characterized by converting a chemical intermediate of substantially lower basicity than sildenafil, by appropriate chemical reaction in an organic reaction medium, to sildenafil, treating the resultant sildenafil-containing reaction medium with an aqueous liquid medium containing a strong acid and a large lipophilic monoanion, separating the original reaction solvent, adding a halogenated organic solvent so as to cause a phase shift whereby the sildenafil ammonium anion pair with the monoanion is transferred from the aqueous phase to the halogenated organic phase to the exclusion of other, significantly less basic components of the reaction mixture, neutralizing the salt with organic base, washing out the inorganic salts with water and recovering the sildenafil from the organic halogenated phase.
REFERENCES:
patent: 5719283 (1998-02-01), Bell et al.
patent: 5955611 (1999-09-01), Dunn et al.
patent: 0463756 (1992-02-01), None
patent: 0812845 (1997-12-01), None
Antczak Casimir
Lu Yee-Fung
Oudenes Jan
Tao Yong
Bernhardt Emily
Nixon & Peabody LLP
Torcan Chemical Ltd.
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