DD206671A3 - PROCESS FOR PREPARING THE CRYSTALLINE ALPHA FORM OF 1- (4-AMINO-6,7-DIMETHOXY-2-CHINAZOLINYL) -4- (2-FUROYL) -PIPERAZINE HYDROCHLORIDE - Google Patents

Abstract

THE CRYSTALLINE ALPHA FORM OF 1- (4-AMINO-6,7-DIMETHOXY-2-CHINAZOLINYL) -4- (2-FUROYL) -PIPERAZINE HYDROCHLORIDE CAN BE PREPARED BY PREPARING 2-CHLORO-4-AMINO-6, 7-DIMETHOXYCHINAZOLINE WITH 1- (2-FUROYL) -PIPERAZINE IN DEMETHYLSULFOXIDE, OR MIXTURES THEREOF, OR WITH AROMATIC HYDROCARBONS SUCH AS BENZENE OR TOLUENE OR ALCOHOLS WITH 2 TO 4 C ATOMICS OR THESE ALCOHOLS SOLVENT TO 75 TO 95 DEGREES C, AND THAT IMMEDIATELY OBTAINED CRYSTALLINE ALPHA FORM OF 1- (4-AMINO-6,7-DIMETHOXY-2-CHINAZOLINYL) -4- (2-FUROYL) -PIPERAZINE HYDROCHLORIDE, EVEN AFTER COOLING THE REACTION MIXTURE, SEPARATES.

Description

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Title of the invention

A process for the formation of the crystalline α-form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -pi perazine-hydrochloride

Application area of the invention

The invention relates to a process for the preparation of the crystalline oC-form of the 1- (4-amino-6 _f 7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride of the formula

-C-

, HCl

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This compound can be used for the treatment of hypertension The ^ -form represents a special crystal modification of this compound, which is characterized by a relatively low hygroscopicity, making it particularly suitable for the galenic shaping because of the resulting more precise dosage possibility · The compound itself is also known as prazosin hydrochloride ·

Characteristic of the known technical solutions

It is known from DD-PS 129 652 to prepare the crystalline (^ form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride thereby that a less suitable for therapeutic purposes crystal form thereof as the ß-form or the V ^ -form or a hydrate or solvate in an aliphatic or cycloaliphatic alcoholic solvent having about 5 to 7 carbon atoms to a temperature of about 125 to 160 ⁰ G heated to virtually complete formation of the crystalline ^ -form ·

This method is bound to both the solvent and the temperature range, because on page 7 of DD-PS 129 652 it says: "If in carrying out the above process, the prazosin hydrochloride, although heated in an alcoholic solvent such as isoamyl alcohol is, but to a temperature which is slightly below about 125 ⁰ C, or even to a higher temperature within the above preferred temperature range for producing the o <-form

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is heated by prazofsin hydrochloride, but for an insufficient duration, the product obtained consists either of the crystalline polymorphic form of prazosinhydrochloride, which is referred to herein as the ^ form, or of a mixture of the s <- form and of the / ^ - form "

Another disadvantage of this process is that the crude 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride prepared in some way is not directly in the crystalline form "Form receives and purification of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride in any crystal form because of its low solubility in almost all solvents is very expensive ,

The purification of crude 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride by recrystallization, which in itself is very complicated but necessary, still involves the additional disadvantage that That, depending on the selected conditions, the preferred form of therapy for therapeutic purposes is often not directly obtained. Thus, Example 3 of DD-PS 129,652 describes that the β- form of 1- (4-amino-6-yl ^ -dimethoxy ^ -quinazolinyl) -4- (2-furoyl) piperazine hydrochloride by recrystallization from isoamyl alcohol with heating the solution to 115 ⁰ C, the fl ~ form wins. On the other hand, as shown in Example 4 of the same patent, by heating a slurry, the ^ T form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride also becomes in isoamyl alcohol, but with heating to 130 to 132 ⁰ C, the o (form obtained

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It is more advantageous to prepare the free base prepared by this method for purifying the crude 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride prepared by any means whatsoever can be purified by recrystallization or other Y / eiae than their hydrochlorides from the purified base can then be obtained in ethanol with a solution of hydrogen chloride in ether according to DE-PS 22 22 231, the hydrochloride,

A disadvantage of this process is that very much solvent is required (about 1 part by weight of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine · base is about 150 Parts by weight of ethanol required) and that under these conditions does not form the crystalline oc-form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride additional operation, according to DD-FS 129 652 by heating in an alcohol with 5 to 7 C-streams, from which the crystalline itf-form can be produced.

 I 'I

Object of the invention, ''

The invention makes it possible to obtain the crystalline tf form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride under much simpler conditions, in particular at significantly lower temperatures and with less solvent and thus with better space-time yield, pure produce.

- 5 Presentation of the essence of the invention

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The object of the invention is to produce the crystalline oc-form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride in a substantially simpler manner ·

According to the present invention, one can see the crystalline reaction of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine-hydride directly in the reaction of 2-chloro 4-amino-6,7-dimethoxy-quinazoline with 1- (2-puroyl) -piperazine obtained by reacting these two reactants, optionally with stirring, in dimethylsulfoxide, dimethylformamide or mixtures thereof with each other or with aromatic hydrocarbons such as benzene or toluene or alcohols having 2 to 4 carbon atoms or these alcohols alone heated to 75 to 95 ⁰ C and the immediately obtained crystalline itf-form, optionally after cooling the reaction mixture, separated «

The duration of time until complete reaction of the reactants and formation of the oc-Porm can be between 5 and 20 hours, depending on the solvent used or the solvent mixture. When solvent mixtures are used, the mixing ratio of the solvent components can vary within wide limits.

The determination of the time when the crystalline reaction mixture (p-form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride is virtually complete in the reaction mixture is professional and can be done, for example, by spectroscopic examination of samples.

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Auaflihrungsbeiapiele

In the following examples, the crystalline 0 <-form of the 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride (T) was constantly obtained. The determination of the crystal structure was carried out in all cases by IR spectroscopic examination of the solvent-wet samples. The drying of I was carried out at 110 to 120 ^° C.

Example 1:

To a obtained at 90 ⁰ C solution of 4.8 g (0.02 mol) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 3.6 g (0.02 mole) of 1- (2-furoyl) -piperazine in 15 ml Dimethylaulfoxid is added 75 ml of toluene and the solution is heated with stirring for 15 hours at 90 ⁰ C After cooling, the product is filtered off, washed with toluene and acetone and dried. Yield: 6g I (71.4 % of Theory)·

Example 2:.

An obtained at 90 ⁰ C solution of 4.8 g (0.02 mol) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 3.6 g (0.02 mole) of 1- (2-furoyl) - piperazine in a mixture of 60 ml of dimethylformamide and 60 ml of toluene is heated to 90 ^° C. with stirring for 12 hours. The product is filtered off with suction in the heat, washed with toluene and acetone and dried

Yield: 6 g I (71.4 % of theory).

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Example 3:

9.6 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 7.2 g of 1- (2-furoyl) -piperazine are heated with stirring for 12 hours in 80 ml of n-butanol to 90 ⁰ C · After Cool the product is separated, washed with acetone and dried

 Yield: 15.7 g of I (93.4% of theory).

Example 4:

The same result as in Examples 1 to 3 is obtained by carrying out the reaction in dimethyl sulfoxide, dimethylformamide or mixtures of dimethyl sulfoxide or dimethylformamide with each other or with aromatic hydrocarbons such as, benzene or alcohols having 2 to 4 carbon atoms or these alcohols alone. ^

Claims (1)

- 8 claim 235638 A process for the preparation of the crystalline oC form of 1- (4-amino-6,7-direthoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride by the addition of 2-chloro-4-amino-6 , 7-dimethoxy-quinazoline with 1- (2-furoyl) -piperazine and heating a 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride 8 in one ottaiiischea solvent 'to higher' temperatures bia for virtually complete formation of the crystalline t / form, characterized in that 2-chloro-4 ~ amino-6,7-dimethoxy-quinazoline with 1- (2-furoyl) piperazine in dimethyl sulfoxide, dimethylformamide, or mixtures thereof heated with each other or with aromatic hydrocarbons such as benzene or toluene or alcohols with 2 bia 4 C atoms or these alcohols alone at 75 to 95 ⁰ C and the immediately obtained crystalline <3 <-Porm of 1- (4-amino-6,7 -dimethoxy-2-quinazolinyl) -4 - (, 2-fluoroethyl) piperazine hydrochloride, optionally after cooling the reaction mixture, separated ·