Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1997-11-14
2001-06-19
Bernhardt, Emily (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
06248888
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride dihydrate, hereinafter referred to as Terazosin.HCl dihydrate. More particularly, the present invention relates to a heretofore unknown one-step process for synthesizing Terazosin.HCl dihydrate and to the Terazosin.HCl dihydrate produced by the process.
BACKGROUND OF THE INVENTION
1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride (“terazosin hydrochloride”) is disclosed in U.S. Pat. No. 4,026,894. The compound is used for the treatment of hypertension and benign prostatic hyperplasia. Pharmaceutical compositions comprising terazosin and its salts are disclosed in U.S. Pat. No. 4,112,097.
Terazosin hydrochloride exists in several polymorphic forms including non-solvated crystalline forms: Form I-Form IV, a methanolate form, a monohydrate crystalline form and a dihydrate crystalline form. Form I is disclosed in U.S. Pat. No. 4,026,894. Form II is disclosed in U.S. Pat. No. 5,294,615. Form III and the methanolate form are disclosed in U.S. Pat. No. 5,412,095. Form IV is disclosed in U.S. Pat. No. 5,504,207 and was also disclosed in published Japanese Patent Application No. 5-078352 as type A-2. A monohydrate form was disclosed in U.S. Pat. No. 5,587,377. Terazosin.HCl dihydrate is disclosed in U.S. Pat. No. 4,251,532, and is marketed under the trade name Hytrin©.
U.S. Pat. No. 4,251,532 describes a process for the preparation of Terazosin.HCl dihydrate which involves as an initial step the preparation of terazosin anhydrous base using an acid scavenger. In a further step, the base form is converted to Terazosin.HCl dihydrate by the addition of hydrochloric acid.
U.S. Pat. No. 5,504,207 also relates to a process for the preparation of Terazosin.HCl dihydrate. The disclosed multi-step process involves an initial step in which terazosin Form IV is first prepared in the absence of an acid scavenger. The Form IV is then converted by a second reaction to Terazosin.HCl dihydrate.
Canadian Pat. No. 2,150,985 describes a process for preparing Terazosin.HCl dihydrate which initially involves the preparation of terazosin free base. The free base form is then reacted by suspension in water and the addition thereto of a molar equivalent of aqueous hydrochloric acid to produce Terazosin.HCl dihydrate.
The known methods discussed hereinabove are not as industrially efficient or as commercially optimized as possible. Generally speaking, the references require various forms of terazosin for their initial step and subsequent processes steps are required to separate these forms from the reaction by-products. Then, one must still perform more work to convert these terazosin forms to Terazosin.HCl dihydrate. It is well known in industrial economics that every processing step usually adds to the complexity and thereby the cost of a process. Additional cost factors include increasing preparation time and increasing the volumes and types of materials which must be kept on hand as starting materials and as waste products of the process. Moreover, any Terazosin.HCl dihydrate process which calls for the conversion of terazosin introduces a possibility of having other terazosin forms as impurities in the product which must then be separated out.
OBJECTS AND SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a novel one-step process for the preparation of Terazosin.HCl dihydrate and to provide the Terazosin.HCl dihydrate produced thereby.
It is a further object of the present invention to provide a novel process for the preparation of Terazosin.HCl dihydrate which is highly efficient.
It is another object of the present invention to provide a novel process for the preparation of Terazosin.HCl dihydrate which is less complex than known processes.
It is still another object of the present invention to provide a novel process for the preparation of Terazosin.HCl dihydrate which minimizes the level of non-dihydrate crystalline forms in the product.
It is yet another object of the present invention to provide a novel process for the preparation of Terazosin.HCl dihydrate which reduces the costs and labor associated with known processes.
It is yet a further object of the present invention to provide a novel process for the preparation of Terazosin.HCl dihydrate which reduces the use of highly corrosive, environmentally unfriendly materials and further reduces occupational hazards caused by using materials according to known processes.
These objectives and other objects not mentioned hereinabove are achieved by the process of the present invention in which Terazosin.HCl dihydrate is prepared directly in one simple and safe step. Terazosin.HCl dihydrate (Product) is as follows:
The process of the present invention comprises reacting by heating 2-chloro-4-amino-6,7-dimethoxyquinazoline (Reactant I):
with 1-(2-tetrahydrofuroyl)piperazine (Reactant II)
in a polar organic reaction solution comprising a polar organic solvent and water. The water is present in a minimum amount effective to obtain the desired product, Terazosin.HCl dihydrate. The reaction mixture is then heated and preferably maintained at reflux until completion as determined by such monitoring methods as intermittent HPLC. The reaction solution is thereafter allowed to cool, preferably to room temperature, and the crystalline product material is collected by filtration.
REFERENCES:
patent: 4026894 (1977-05-01), Winn et al.
patent: 4112097 (1978-09-01), Winn et al.
patent: 4243666 (1981-01-01), Campbell et al.
patent: 4251532 (1981-02-01), Roteman
patent: 4775673 (1988-10-01), Koenig et al.
patent: 5212176 (1993-05-01), Kyncl et al.
patent: 5294615 (1994-03-01), Meyer et al.
patent: 5362730 (1994-11-01), Bauer et al.
patent: 5412095 (1995-05-01), Morley et al.
patent: 5504207 (1996-04-01), Mannino et al.
patent: 5587377 (1996-12-01), Patel et al.
patent: 5675006 (1997-10-01), Karimian et al.
patent: 2150985 (1996-12-01), None
patent: 708104 (1996-04-01), None
patent: 2007656 (1979-05-01), None
patent: 5-78352 (1993-03-01), None
patent: WO-94/05628 (1994-03-01), None
Database Chemical Abstracts on STN, American Chemical Society, (Columbus, OH, USA) Vol. 127, No. 318981, Ponge et al. “Solvent System for producing terazosin,” abstract, HU 75100 A2, Apr. 28, 1987 (Hungarian).
Gershon Neomi
Mendelovici Marioura
Schwartz Eduard
Bernhardt Emily
Kenyon & Kenyon
Teva Pharmaceutical Industries Ltd.
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