RU2046796C1 - Method of isolation and purification of 10-dialkylaminoalkylphenothiazine hydrochloride - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 10-dialkylaminoalkylphenothiazine hydrochloride of the formula (I)

Description

HCl где R Н низший алкил;
R₁ нормальный или разветвленный низший алкил;
R₂ атом водорода или хлора, относится к области фармацевтических препаратов, в частности выделению и очистке таких нейролептических лекарственных препаратов, как аминазин, пропазин, дипразин и динезин.The method of isolation and purification of 10-dialkylaminoalkylphenothiazine hydrochlorides of the general formula (I):

HCl where R H is lower alkyl;
R _{1 is} straight or branched chain lower alkyl;
R _{2 is} a hydrogen or chlorine atom, relates to the field of pharmaceutical preparations, in particular the isolation and purification of antipsychotic drugs such as chlorpromazine, propazine, diprazine and dinesin.

 Medicines chlorpromazine, diprazine, propazine and dinesin, produced under the current Pharmacopoeia Articles in Russia, do not meet the requirements of foreign pharmacopoeias. The proposed method for the isolation and purification of 10-dialkylaminoalkylphenothiazine hydrochlorides can raise the quality of these drugs to international standards.

A known method for the preparation and purification of 2-chloro-10- (3-dimethylaminopropyl) 2-chlorophenothiazine (chlorpromazine) [1]
The method consists in the interaction of 2-chlorophenothiazine with 3-dimethylaminopropyl chloride in the presence of sodium hydroxide in an environment of solvents of toluene and chlorobenzene with continuous distillation of the resulting water. The organic layer was extracted with water, dried and dispersed in vacuo at 1 mm Hg. The resulting chlorpromazine base is dissolved in toluene, a 10% hydrochloric acid solution is added to a pH of 3.4. The chlorpromazine solution is separated from the toluene layer, sodium carbonate is added to a pH of 8.5-9.0, and the chlorpromazine base is extracted with ethyl acetate. After drying chlorpromazine isolated by addition of isopropyl alcohol saturated with hydrogen chloride and crystallized at 0-5 ^{° C,} filtered, washed with ethanol and dried. The yield of chlorpromazine 82% of the theoretical amount, counting on 2-chlorophenothiazine (prototype).

A known method of purification of hydrochloride of 2-chloro-10- (3-dimethylaminopropyl) phenothiazine by crystallization from a mixture of solvents toluene isopropyl alcohol in a ratio of 2.5: 1 [2]
The disadvantage of the above methods is the mismatch of the product with the requirements of the drug according to the British and International pharmacopoeias on the content of impurities, the pH of the solution and transparency on the pharmacopoeia of the GDR (table).

 The aim of the invention is to improve the quality of the target product.

 The method is as follows.

где R, R₁ и R₂ имеют вышеуказанные значения полученного после конденсации фенотиазина или его хлорпроизводного с диалкиламинохлоралкила гидрохлоридом, обрабатывают 1,2%-ным раствором уксусной кислоты, при этом водородный показатель реакционной массы имеет значение 5,6, слои разделяют, отгоняют остатки воды. После этого к толуольному раствору приливают изопропиловый спирт, насыщенный хлористым водородом, до рН 3,4 при 15-25^оС, а затем отгоняют смесь толуол изопропиловый спирт вода при температуре не выше 100^оС и остаточном давлении 0,3 кгс/см². Полученный технический 10-диалкиламиноалкилфенотиазина гидрохлорид кристаллизуют, фильтруют и промывают толуолом. Для получения фармакопейного продукта полученный технический продукт растворяют в смеси органических растворителей, таких как толуол и изопропиловый спирт, нагревают до температуры кипения реакционной массы, кристаллизуют при -5-0^оС, промывают изопропиловым спиртом и сушат. Выход фармакопейного продукта не ниже прототипа и его аналогов. Содержание примесей соответствует международной фармакопее.A solution of the base 10-dialkylaminoalkylphenothiazine of General formula (II):

where R, R ₁ and R ₂ have the above values obtained after condensation of phenothiazine or its chlorine derivative with dialkylaminochloroalkyl hydrochloride, treated with a 1.2% solution of acetic acid, while the pH of the reaction mass is 5.6, the layers are separated, the residues are distilled off water. Thereafter, the toluene solution poured isopropyl alcohol saturated with hydrogen chloride until pH 3.4 at 15-25 ^{° C,} and then toluene was distilled off the mixture isopropyl alcohol, water at a temperature not higher than 100 ^{° C} and residual pressure of 0.3 kgf / cm ² . The resulting technical 10-dialkylaminoalkylphenothiazine hydrochloride is crystallized, filtered and washed with toluene. For Pharmacopeial product obtained crude product was dissolved in a mixture of organic solvents such as toluene and isopropyl alcohol was heated to reflux temperature of the reaction mass is crystallized at -5-0 ^{° C,} washed with isopropyl alcohol and dried. The output of the pharmacopoeial product is not lower than the prototype and its analogues. The content of impurities corresponds to the international pharmacopeia.

 New in the proposed technical solution is the removal of impurities by treatment of a toluene solution of 10-dialkylaminoalkylphenothiazine or chlorine-substituted phenothiazine with a solution of acetic acid at pH 5.5-5.7 with the formation of 10- (monoalkylaminoalkyl) phenothiazine acetate, which is readily soluble in water and thus removed from the target the product, which is then treated with isopropyl alcohol saturated with hydrogen chloride at pH 3.4 to form 10-dialkylaminoalkylphenothiazine hydrochloride.

 Currently, the quality of pharmacopoeial medicines of chlorpromazine, propazine, diprazine and dinesin complies with the requirements of GF X, but does not meet the world level, the requirements of foreign pharmacopeias.

 The quality of chlorpromazine does not correspond to the world level due to the high content of impurities (more than 0.5%), the pH of the solution (pH 5.0 instead of 3.5-4.5) and its transparency.

 Pharmacopoeial chlorpromazine contains propazine impurities with Rf 0.4 and a more polar impurity relative to the main substance with Rf 0.26 when the product is studied by thin layer chromatography (TLC).

2-хлор-10-(3-метиламинопропил)-фенотиазин
Содержание этой примеси составляет около 1,8%
Исходя из основности органических аминов авторы предположили, что от данной примеси можно освободиться пpедваритель- ным подкислением толуольного раствора основания аминазина. Для подтверждения данного предположения авторы изучали свойства примесей 10-(моноалкиламинопропил)фенотиазина, объединенных родственной химической структурой и содержащихся как в аминазине, так и в его аналогах; пропазине, дипразине, динезине. На основании исследований была выбрана уксусная кислота, потому что использование других соединений приводило помимо удаления примесей к частичному осаждению основного продукта. Установлено, что оптимальное соотношение уксусной кислоты к основанию аминоназина составляет 1:7,5. При этом количество примеси с Rf 0,26 в аминазине снижается с 1,8 до 0,2-0,4%
Качество фармакопейного и технического аминазина, очищенного и выделенного предлагаемым способом, соответствует всем требованиям Британской и других зарубежных фармакопей по заключению отдела технического контроля комбината "Акрихин". Сертификат качества и хроматограммы прилагаются (хроматограммы фиг. 1,2).According to the literature (I), a substance with Rf 0.26 supposedly has the following structure:

2-chloro-10- (3-methylaminopropyl) phenothiazine
The content of this impurity is about 1.8%
Based on the basicity of organic amines, the authors suggested that one can get rid of this impurity by preliminary acidification of the toluene solution of the chlorpromazine base. To confirm this assumption, the authors studied the properties of impurities of 10- (monoalkylaminopropyl) phenothiazine, combined by a related chemical structure and contained both in chlorpromazine and its analogues; propazine, diprazine, dinesine. Based on the studies, acetic acid was chosen because the use of other compounds, in addition to removing impurities, led to a partial precipitation of the main product. It was found that the optimal ratio of acetic acid to aminonazine base is 1: 7.5. The amount of impurities with Rf 0.26 in chlorpromazine decreases from 1.8 to 0.2-0.4%
The quality of the pharmacopeia and technical chlorpromazine, purified and isolated by the proposed method, meets all the requirements of the British and other foreign pharmacopeias according to the conclusion of the technical control department of the Akrikhin plant. Certificate of quality and chromatograms are attached (chromatograms of Fig. 1,2).

 The quality of diprazine also does not meet the requirements of the international pharmacopoeia, however, it complies with the requirements of the state pharmacopoeia. The total content of impurities in the farm. up to 1.5% is allowed in the article. According to the proposed method, the total content of impurities in diprazine decreases to 0.8%. The amount of impurities with Rf 0.31 of 10- (2-monomethylaminopropyl) -phenothiazine is reduced from 1 to 0.2% (chromatograms of FIG. . 3.4).

 The proposed cleaning method can also improve the quality of propazine and dinesin. The content of 10- (3-monomethylaminopropyl) phenothiazine impurity with Rf 0.17 in propazine decreases from 0.5 to 0.1% (chromatograms in Fig. 5.6) and 10- (2-monoethylaminoethyl) phenothiazine impurity with Rf 0.26 in dinesin decreases from 0.7% to trace amounts (chromatograms of Fig. 7.8).

 The use of the present invention will improve the quality of medicines of chlorpromazine, propazine, diprazine, dinesin to the requirements of international standards and will make the products competitive.

 PRI me R 1. In a round-bottomed two-necked flask equipped with a mechanical stirrer, load 100 g of 2-chloro-10- (3-dimethylaminopropyl) -phenothiazine (base of chlorpromazine) and dissolved in 400 ml of toluene.

 60.5 ml of distilled water are loaded into the toluene base of the chlorpromazine and 0.7 ml of acetic acid (98%) is slowly added dropwise dropwise with stirring to a pH of 5.6. The solution was kept at room temperature with stirring for 15 minutes. Sludge and divide the layers, drive off the remaining water.

Then, 40 ml of isopropyl alcohol saturated with hydrogen chloride (content of hydrogen chloride 30-32%) are added at room temperature until the Congo reaction is weakly acidic (pH 3.4), the mixture is allowed to stand for 15 minutes, the isopropyl alcohol-water mixture is distilled off at temperature not higher than 100 ^about With and a residual pressure of 0.3 kgf / cm ³ .

The resulting suspension is cooled to 20-25 ^about C, filtered and washed with 150 ml of toluene. Obtain 103.6 g of paste of technical chlorpromazine.

 Obtaining pharmacopoeial chlorpromazine.

93.2 g of technical chlorpromazine, 67 ml of isopropyl alcohol, 167 ml of toluene are loaded into the flask, the reaction mixture is heated to boiling and the mixture is allowed to stand for 30 minutes. The mass is cooled to 5-0 ^about C, filtered and washed with isopropyl alcohol.

 Get 69 g of pharmacopoeial chlorpromazine, which corresponds to 74% counting on a technical product.

 PRI me R 2. Obtaining diprazine technical.

10 g of diprazine base are dissolved in 50 ml of toluene. Toluene solution of diprazine base is washed with 40 ml of distilled water, and then treated with 50 ml of a 1.2% solution of acetic acid. Separate the layers. 10 ml of toluene-water mixture are distilled off with a vacuum from the toluene layer of diprazine base. The distillation is conducted at a temperature not higher than 100 ^{° C} and residual pressure of 0.3 kgf / cm ^2. The toluene solution of the base diprazina cooled to 20-25 ^{° C} and isolating Promethazine technical isopropyl alcohol containing 30-32% of hydrogen chloride at room temperature to slightly acidic "Kongo" on paper, poured 25 ml of isopropyl alcohol. The mixture is allowed to stir for 15 minutes, the solvent mixture is distilled off, filtered and washed with toluene.

 13.77 g of technical diprazine are obtained, which is 61.03% based on diprazine base.

 Obtaining diprazine pharmacopeia.

 13.77 g of technical diprazine are dissolved in 60 ml of distilled water. With stirring, add 13 ml of a 20% solution of soda ash until pink color appears on phenolphthalein paper. The isolated base is extracted with 50 ml of toluene. The layers are separated, add 11 g of potash. After drying, the solution is filtered and pharmacopoeial diprazine isopropyl alcohol containing 30-32% hydrogen chloride is isolated at room temperature until a slightly acidic reaction is obtained on Congo paper. Aged for 1 hour, filtered and washed with chilled isopropyl alcohol.

 Get 10 g of pharmacopoeial diprazine, which is 72.35% based on technical diprazine.

PRI me R 3. 50 g of the base of dinesin is dissolved in 200 ml of toluene. Toluene solution of dinesin base is washed with 200 ml of distilled water, and then treated with 140 ml of a 1.2% solution of acetic acid. The layers are separated. From a toluene layer of a dinesin base, 35 ml of a mixture of toluene and water are distilled off under vacuum. The distillation is conducted at a temperature not higher than 100 ^{° C} and residual pressure of 0.3 kgf / cm ^3. Dinezina base toluene solution was cooled to 20-25 ^C and was isolated dinezin technical isopropyl alcohol containing 30-32% of hydrogen chloride at room temperature until the reaction at a weakly acid paper "Kongo". The mixture is allowed to stir for 15 minutes, the solvent mixture is distilled off, filtered and washed with toluene.

 44.5 g of technical dinesin are obtained with a yield of 79.32% based on dinesin base.

 Obtaining dinesin pharmacopeia.

44.5 g of technical dinesine, 90 ml of toluene, 45 ml of n-butyl alcohol are charged into the flask, the reaction mixture is heated to boiling and the mixture is allowed to stand for 30-40 minutes. The mass is cooled to 5-0 ^about C, filtered and washed with isopropyl alcohol.

 Get 42.5 g of pharmacopeia dinesin, which corresponds to 95.5% based on the technical product.

PRI me R 4. 10 g of propazine base is dissolved in 30 ml of toluene. Toluene solution of propazine base is washed with 40 ml of distilled water, and then extracted with 30 ml of a 1.2% solution of acetic acid. From the toluene layer of the propazine base, 7 ml of a mixture of toluene-water are distilled off with a vacuum. The distillation is conducted at a temperature not higher than 100 ^{° C} and residual pressure of 0.3 kgf / cm ^3. Propazina base toluene solution was cooled to 20-25 ^C and was isolated propazine technical isopropyl alcohol containing 30-32% of hydrogen chloride at room temperature until the reaction at a weakly acid paper "Kongo". The mixture is allowed to stir for 15 minutes, the solvent mixture is distilled off, filtered and washed with toluene.

 Get 10.3 g of technical propazine, which is a yield of 91.3% based on the basis of propazine.

 Obtaining propazine pharmacopeia.

10.3 g of technical propazine, 22 ml of toluene, 11 ml of n-butyl alcohol are loaded into the flask, the reaction mixture is heated to boiling and the extract is allowed to stand for 30 minutes. The mass was cooled ^to 5 ° C, filtered and washed with isopropyl alcohol.

 9.7 g of pharmacopoeial propazine are obtained, which corresponds to 94.2, based on the loaded product.

Claims (1)

METHOD FOR ISOLATION AND PURIFICATION OF 10-DIALKYLAMINOalkylphenothiazine HYDROCHLORIDE of general formula I:

where R n is lower alkyl;
R ^{1 is} straight or branched chain lower alkyl;
R ^{2 is} a hydrogen or chlorine atom,
by treating a base of 10-dialkylaminoalkylphenothiazine of general formula II,

where R, R ¹ and R ² have the indicated meanings,
saturated hydrogen chloride lower alkyl alcohol in an organic solvent medium followed by distillation of the solvents, isolation of 10-dialkylaminoalkylphenothiazine hydrochloride of the general formula I by crystallization and purification of the isolated product by crystallization from a mixture of toluene and lower alkyl alcohol, characterized in that the solution of the base is 10-dialkylaminoalkylphenothiazine previously in an organic solvent is treated with an aqueous solution of acetic acid at pH 5.5-5.7, the aqueous layer is separated, the aze is distilled off water-organic solvent, then the resulting product is treated with isopropyl alcohol saturated with hydrogen chloride at a pH of 3.3 to 3.5 with subsequent stages of isolation and purification of the target product.

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