DD209356A3 - 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-quinazolinyl) -4- (2-furoyl) -pipirazine hydrochloride can be prepared by adding to a solution or slurry of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine in dimethyl sulfoxide, dimethylformamide or alcohols having 2 to 4 carbon atoms or in mixtures of dimethyl sulfoxide or dimethylformamide with each other or with aromatic hydrocarbons such as benzene or toluene, halogenated aliphatic hydrocarbons such as chloro- or carbon tetrachloride, ketones such as acetone, ethers such as dioxane or alcohols having 2 to 4 carbon atoms hydrogen chloride or a solution of hydrogen chloride in a suitable solvent such as methanol, ethanol, isopropanol or dioxane Temperatures of 40 to 95 degrees C is added and the forming crystalline alpha form optionally crystallize under cooling.

Description

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Title of the invention

Process for the preparation of crystalline <^ -

of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-fluoro)

royl) -piperazine hydrochloride Field of application of the invention

The invention relates to a process for preparing the crystalline <x-Porm of 1- {4-amino-6,7 ~ dijaetho3y-2-quinazolinyl) -4- (2-f-uroyl) piperazine hydrochloride of the formula

"Ό

, HCl

IH.

ic '^ ^: 7 ~! Ti 9 o

-P-

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This compound can be used to treat hypertension. The <x-Porm represents a special crystal modification of this compound, which is characterized by a relatively low hygroscopicity, making it particularly suitable for galeniache shaping because of the resulting more precise dosage option, 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 o ( -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- or the y "-form or a hydrate or solvate in an aliphatic or cycloaliphatic alcoholic solvent having 5 to 7 carbon atoms to a temperature of 125 to 160 ⁰ C to the practical complete formation of the crystalline <form heated

: This method is bound to both the solvents and the temperature range, because on page 7 of DD-PS 129 652 it says: "When. Performing the above process, the Prazosin hydrochloride, although in an alcoholic solvent, such as isoamyl but heated to a temperature slightly below about 125 ^° C. or even heated to a higher temperature within the above preferred temperature range for the preparation of the 0 <-form of prazosin hydrochloride

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for an insufficient duration, ao the product obtained either consists of. the crystalline polymorphic form of prazosin hydrochloride, referred to herein as / ^ Fora, or a mixture of the s <- form and the ^

Another drawback of this process is that one does not use the crude 1- (4-amino-6,7-diynetho3: 7-2-quinazolinyl) -4- (2-f-uro-7l) -piperazine hydrochloride prepared in any way obtained directly in the crystalline o <- form and a purification of i- (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-dimeth-3-yl-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride by recrystallization, which in itself is very complicated, but which is necessary, still excludes the additional disadvantage that, depending on the selected conditions, the <X-form, which is preferred for therapeutic purposes, is often not directly obtained. Thus, in Example 3 of DD-PS 129 652 described that one from the jS form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-f-uroyl) piperazine hydrochloride dixrch recrystallization from isoamyl alcohol with heating of the solution to 115 ⁰ C, the ^ -form wins. On the other hand, as shown in Example 4 of the same patent, by heating a slurry, the ^ 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 - 132 ⁰ G the oC- form obtained

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In order to purify the crude 1- (4-amino-6,7-dimethcsy-2-iminazolinyl) -4- (2-furoyl) -piperazine hydrochloride prepared in any way, it is more suitable to prepare the free Baae from it easier to clean by Umkriatalliaation or otherwise allows ala their hydrochloride. The hydrochloride can then be obtained from the purified base in ethanol using a solution of hydrogen chloride in ether in accordance with German Pat. No. 2,222,231.

A disadvantage of this process is that very much solvent is needed (to dissolve 1 part by weight of 1- (4-affinol-6,7-iminethos: y-2-quinazolinyl) -4- (2-furoyl) piperazine base about 150 parts by weight of ethanol are required) and that under these conditions, the crystalline c <-Porm of 1- (4-amino-6,7-dimethosy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride does not arise , Only in an additional operation, according to the DD-PS 129 652 by heating in an alcohol with 5 to 7 carbon atoms, it can be the crystalline <? <-? Orni produced.

Object of the invention

The invention makes it possible, the crystalline o <-Porm of 1- (4-amino-6,7-dimethosy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride under much simpler conditions, especially at significantly lower temperatures and with less solvent and thus with better space-time yield, pure produce.

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Explanation of the essence of the invention

The invention is based on the object, the crystalline s <-Forjn of 1- (4-amino-6,7-d: ünetho: xy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride in a much simpler Make pure Weiae.

In accordance with the present invention, a solution or slurry of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine in Birnethylsülfoxid, dimethylformamide or alcohols having 2 to 4 C is added -Atoms or in mixtures of dimethylsulfoxide or dimethylformamide with each other or with aromatic hydrocarbons such as benzene or toluene, halogenated aliphatic hydrocarbons such as chloroform or carbon tetrachloride, ketones such as acetone, Ithem such as diosan or alcohols having 2 to C atoms hydrogen chloride or a solution of hydrogen chloride in one suitable solvents such as methanol, ethanol, isopropanol or diosan at temperatures of 40 to 95 ⁰ G and leaves the forming crystalline o <form of 1- {4-amino-6,7-dimethoxy-2-quinazolinyl) -4- Optionally crystallize (2-furoyl) -piperazine hydrochlorides with stirring and optionally with cooling

It may be advantageous to accelerate the crystallization of the <> form by seeding. When using solvent mixtures, the mixing ratio of the solvent components can vary within wide limits. Mixtures in a ratio of 10: 1 to 1:10 have proved to be particularly favorable.

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Particularly advantageous solvents are dimethylauloxide and dimethylformamide and mixtures thereof with the other abovementioned solvents.

For the preparation of the crystalline cX-form of the 1- {4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) -piperazine hydrochloride is generally the equimolar amount of hydrogen chloride or a solution of hydrogen chloride in However, sufficient organic solvent can be an excess, ζ,, from 5 to 10% Chlorwas- J serstoff be applied ·

The duration of the reaction until complete formation of the desired u- form can be between 2 and 20 hours, depending on the temperature and the solvent used. In the temperature range of z. 3. 50 bia 70 ⁰ C and in the presence of dimethyl sulfoxide or dimethylformamide alone or in mixtures thereof with other solvents are generally sufficient 2 to 6 hours.

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

Ausführungabeiapiele

In the following examples, the crystalline cxT form of the 1- {4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride (I) was always obtained. The

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Determination of the crystal structure was carried out in all cases by IR spectroscopy of the solvent-wet samples. The drying of I was carried out at 110 to 120 ⁰ C.

Example 1:

To a filtered solution of 9.6 g (0.025 mol) of 1- (4-amino-6,7-dimethoxy-2-chinaylsolinyl) -4- (2-furoyl) -piperazine (II) in 48 ml of dimethylsulfoxide is added 4 Add 4 ml of a solution of hydrogen chloride in isopropanol (0.026 mol EC1) and 48 ml of isopropanol. The mixture is heated for 2 hours at 79 ⁰ C, after cooling, the product is filtered off with suction through a third and washed with isopropanol and acetone. After drying at 110 to 120 ^° C., 9.2 g of I (87.6 %) are obtained.

Example 2 _:

Analogously to Example 1, from 9.6 g of II, 48 ml of dimethyl sulfoxide, 48 ml of carbon tetrachloride and 4.4 ml of a solution of hydrogen chloride in isopropanol (0.02 6 mol, - ^ HCl) by heating to 82 ⁰ C 8 for ² hours, 8g I (.83.8 % of theory).

Example 3:

Analogously to Example 1, 9.2 g of II, 48 ml of dimethyl sulfoxide, 48 ml of acetone and 4.4 ml of a solution of hydrogen chloride in isopropanol (0.026 mol HCl) are heated to 73 ^° C. for 2 hours. 9.2 g of I (88, 6 % of theory).

Example 4:

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9.6 g of II are dissolved in 48 ml of dimethyl sulfoxide with heating and the solution is sucked through a frit. At room temperature, dry hydrogen chloride gas is introduced up to pH 6. The mixture is subsequently heated to 50 ^° C. for 4 hours. After cooling, the crystallized product is filtered off with suction through a frit and washed successively with toluene and acetone. Yield: 8.9 g I (84.8 % of theory) «

Example 5:

To a solution of 19 g of II (0.05 mol) in 95 ml of dimethyl sulfoside is added at 50 C 8 ml of a solution of hydrogen chloride in isopropanol (0.05 mol HCl) and inoculated with little 1 ~ (4-amino-6, 7-dimetho: xy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride. The mixture is stirred three times for four hours at 50 ^° C. and left to stand at room temperature over Hacht · Working up is carried out as described in Example 4. Yield; 17.2 g 1 (81.9 % of theory).

Example 6:

Analogously to Example 1 is obtained from 9.6 g of II (0.025 mol), 48 ml of dimethyl sulfoxide, 48 ml of toluene and 7.8 ml of a solution of hydrogen chloride in dioxane (0.026 mol HCl) by heating for six hours at 60 ⁰ C 9.7 g I (92.4% of theory),

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Example 7:

Analogously to Example 1 is obtained from 9.6 g of II (0.025 mol), 48 ml of dimethyl sulfoxide, 48 ml of toluene and 4.4 ml of a solution of hydrogen chloride in isopropanol (0.026 mol HCl) by heating for six hours at 60 ⁰ C 8.7 g I (82.9 % of theory).

Example 8:. .

To a solution prepared at 90 ⁰ C the filtered solution of 9.6 g of II (0.025 mol) in 70 ml of dimethylformamide is allowed at 50 ⁰ C with stirring over 45 minutes 4 ml of a solution of hydrogen chloride in isopropanol (0.025 mol HCl) added dropwise · The mixture is then stirred at 50 ^° C. for 4 hours. The workup is carried out according to Example 4 · Yield: 3.05 g of I (76.7 % of theory).

Example 9:

9.6 g of II (0.025 mol), 48 ml of Diine thylaulf oxide 48 ml of toluene and 5.4 ml of a solution of hydrogen chloride in methanol (0.026 mol HCl) by heating for six hours at 60 ⁰ C 9, 8 g I (93.3 % of theory).

Example 10:

To a slurry of 9.6 g of II (0.025 mol) in a mixture of 10 ml of dimethylauloxide and 90 ml of anhydrous ethanol was added 4.4 while stirring. ml of a solution of hydrogen chloride in isopropanol (0.026 mol HCl)

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and the mixture is heated for 2 hours at 60 to 65 ⁰ C. After cooling, the product is filtered off with suction, washed with acetone and dried

Yield: 9.7 g I (92.4 % of theory).

Example 11:

Analogously to Example 10 is obtained by heating five hours of 9.6 g of II in a mixture of 10 ml of dimethyl sulfoxide and 90 ml of isopropanol with 4.4 ml of a solution of hydrogen chloride in isopropanol (0.026 mol HCl) to 60 to 65 ⁰ C 9.9 g I (94.3% of theory).

Example 12;

Analogously to Example 10 is obtained by heating for six hours of 9.6 g II in a mixture of 10 ml of thylsulf oxide and 90 ml of carbon tetrachloride with 4.4 ml of a solution of hydrogen chloride in isopropanol (0.026 fflol HCl) to 60 to 65 ⁰ C 9 , 7 g I (92.4 % of theory).

Example 13:

Analogously to Example 10 is obtained by heating 4 hours of 9j6 g of II in a mixture of 10 ml of dimethyl sulfoside and 90 ml of acetone with 4.4. ml of a solution of hydrogen chloride in iaopropanol (0.026 mol HCl) to 60 to 65 ⁰ C 9.6 g of I (91.4 % of theory).

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Example H:

Analog Beiapiel 10 is obtained by heating for 5 hours of 9.6 g II in a mixture of 10 ml Dime thylaulfoxid and 90 ml of chloroform with 4.4 ml of a solution of hydrogen chloride in isopropanol (0.026 mol HCl) to 60 to 65 ⁰ C 10 g 1 (95.2 % of theory).

Beiapiel 15:

Analogously to Example 10 is obtained by heating five hours of 9.6 g II in a mixture of 10 ml of thylsulfoxid and 90 ml of benzene with 4.4 ml of a solution of hydrogen chloride in isopropanol (0.026 mol HCl) to 60 to 65 ⁰ C 9, 6 g I (91.4 % of theory).

Example 16:

Analogously to Example 10 is obtained by three hours of heating of 9.6 g II in a mixture of 10 ml whore thy Isiil fox id and 90 ml of toluene with 4.4 ml of a solution of Chlorwaaaeratoff in isopropanol (0.026 mol HCl) at 60 to 65 ⁰ C 9.7 g I (92.4 % of theory).

Example 17:

Analogously to Example 10 is obtained by heating two hours of 9.6 g II with 6 ml of a solution of hydrogen chloride in isopropanol (0.025 mol HCl) in 100 ml of anhydrous ethanol at 60 to 65 ⁰ C 10.1 g of I (96.2% of Theory).

Claims (1)

-12- 235637 4 claim A process for preparing the crystalline cX form of 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride by reacting 1- (4-amino-6, 7-dimethoxy-2-quinazolinyl) -4- (2-furoyl) piperazine with HCl and heating the 1- (4-amino-6,7-dimetho: y-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride in an - organic solvent at temperatures up to the höhere- substantially complete formation of the crystalline o <-form, characterized in that it is added to a solution or slurry of 1- (4-amino-6,7-dimetho2: y-2-quinazolinyl) -4- (2-furoyl) -piperazine in Dimethyisulfosid, dimethylformamide or alcohols having 2 to 4 carbon atoms or in mixtures of Dime thylaulfosid or dimethylformamide with each other or with aromatic Kohlenwasaersto.ffen such as benzene or toluene, halogenated aliphatic hydrocarbons such as chloroform or carbon tetrachloride, ketones such as acetone, ethers such as diosan or alcohols with 2 to 4 carbon atoms hydrogen chloride or a solution of hydrogen chloride in a suitable solvent such as methanol, ethanol, * isopropanol or Diossn at temperatures of 40 to 95 ⁰ C is added and the forming crystalline oC 'form. of 1- (4-amino-6,7-dime thosy-2-quinazolinyl) -4- (2-furoyl) piperazine hydrochloride, optionally under. Stirring and optionally crystallize with cooling,