PL153030B1 - Method for purification of 1,4-benzodiazepine derivatives - Google Patents

Description

RZECZPOSPOLITA PATENT DESCRIPTION 153 030 POLAND

OFFICE

PATENT

RP

Additional patent to patent no - Int. Cl. ^s C07D 243/26

Reported: 88 07 04 (P. 273565)

Priority - READERS

G Ć L H

Application announced: 90 01 08

Patent description published: 1991 11 29

Creators of the invention: Bogumiła Krawczyńska, Bogdan Morawski, Romualda Chojnacka, Jadwiga Kaliś

The holder of the patent: Tarchomińskie Zakłady Farmaceutyczne "Polfa,

Warsaw Poland)

Purification method of 1,4-benzodiazepine derivative

The present invention relates to a process for the purification of a 1,4-benzodiazepine derivative, such as 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2 with sedative and hypnotic properties. . This compound is used in medicine under the name temazepam.

The scientific literature describes the method of obtaining 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2 in an alkaline reaction with a pH value of 8.0 with simultaneous an indication that the phenomenon of isomerization to 7-chloro-1-methylol, 3-dihydro-5-phenyl-2H-1,4-benzodouazepine-2,3-dione occurs frequently in the preparation of this compound. It is a byproduct of the manufacturing process and an additional impurity of the grade product (J. Org. Chem. 27 1681/1962).

According to German patent description No. 2,333,382, impurities can be removed from some derivatives of 1,4-benzodiazepine by treating the contaminated compound with p-toluenesulfonic acid, forming such a combination with 1,4-benzodiazepine derivatives, which is then decomposed by aqueous sodium hydroxide solution. This method is disadvantageous for the purification of 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2 due to the use of an alkaline solution.

There are well known methods of purification of compounds from the 1,4-benzodiazepine group by crystallization from organic solvents, especially methanol, which are uneconomical carried out under industrial conditions, causing excessive loss of the finished product during its crystallization, especially multiple crystallization.

It turned out that it was possible to create a new, previously unknown complex compound 7-chlorol, 3-douhydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2 with ferric chloride, then released in the form of crystalline from inert organic solvents.

The decomposition of the complex under the action of acidified water results in complete purification of 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2.

153 030

In the process according to the invention, the precipitate of 7-c] chloro-l ₎ 3-dihydro-5-phenyl-3-y-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2, contaminated with other derivatives of 1,4-benzodiazepine, is treated with ferric chloride or its crystalline salt with six water molecules, in a water-immiscible organic solvent, then the complex compound formed is isolated and decomposed in an aqueous solution with the addition of a mineral acid or an organic acid at the pH value of the solution 5-6, whereupon the product is isolated in a known way.

Aliphatic chlorinated hydrocarbons, preferably methylene chloride or ethylene, are used as water-immiscible organic solvents. Of the mineral acids, hydrochloric acid is preferably used and of the organic acids, acetic acid.

The advantage of the process according to the invention is the possibility of isolating the pure compound 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2 from the crystalline sediments containing, apart from the active substance, also other organic substances from 1,4-benzodiazepine groups as by-products, for example 1,4-benzodiazepine-2,3-dione derivatives. During the formation of the crystalline complex of the basic product with ferric chloride, these derivatives remain dissolved in the organic solution and thus make it possible to obtain a purified compound.

The reaction for the formation of the complex 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H1,4-benzodiazepinone-2 according to the invention takes place in organic solvents immiscible with water, especially aliphatic hydrocarbons chlorinated, but aromatic hydrocarbons such as benzene or toluene can also be used.

The product purified by the method according to the invention is characterized by high purity. The quality of the substance obtained after purification meets the requirements for manufactured pharmaceutical forms.

The following examples illustrate the invention.

Example 1 0.5 kg containing 93% 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2 was dissolved in 1 dcm ³ of ethylene chloride at room temperature and 275 g of anhydrous ferric chloride were added to the solution. After stirring for 3 hours at room temperature, the solution was cooled to 10 ° C and the orange precipitate of 1,4-benzodiazepine derivative with ferric chloride, mp 187-189 ° C with decomposition, was filtered off. The separated precipitate of the complex was suspended in

2.5 dcm ^{3 of} pure ethylene chloride and 2.5 dcm ^{3 of} water with an addition of acetic acid at pH 5.5 was added dropwise to the suspension obtained. After total addition of water was added, the mixture was stirred for 3 hours at room temperature, the mixture was filtered through diatomaceous earth, and the organic layer was separated from the aqueous layer. The organic solution was washed with water until a colorless solution was obtained with a pH of 7.0. After washing the organic solution, the solvent was distilled off under reduced pressure to evaporate the solution to dryness. After distillation, the dry residue was crystallized from methanol with the addition of active carbon. 325 g of the product 7-chloro-1,3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2 was obtained. Analysis of the product by thin layer chromatography in the chloroform-methanol system in the ratio 10: 1 showed the presence of only one substance. The melting point of the product is 159-161 ° C.

Example 2: 0.5 kg of sludge containing 90% 7-chloro-1,3-dihydro-5-phthnyl-3-hydroctyl-methyl-2H-1,4-benzodiazepinone-2 was dissolved in 1.25 dcm ³ of methylene chloride in 0.5 kg of ferric chloride hexahydrate was added to the obtained solution, and the mixture was stirred for 3 hours at room temperature. The solution was then cooled to 10 ° C. An orange precipitate of the benzodiazepine derivative ferric chloride complex was separated from the cooled solution by filtration. A sample was taken of it. The melting point of a sample of the dried complex is 184-188 ° C with decomposition. The separated precipitate of the complex was suspended in 2.5 dcm ^{3 of} pure methylene chloride, and then 2.5 dcm ^{3 of} water acidified with hydrochloric acid was added dropwise to the suspension to pH 5.0. After adding the total amount of acidified water and stirring it for three hours at room temperature, the mixture was filtered through diatomaceous earth. The organic layer was then separated from the aqueous layer, and the organic solution was washed with water until a colorless solution was obtained, pH 7.0. The resulting solution was evaporated to dryness by distilling off the solvent under reduced pressure. The dry residue was crystallized from methanol with the addition of activated carbon. 300 g of a product was obtained containing more than 90% of 7-chlorol, 3-dihydro-5-phenyl-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2. Analysis of the product by thin layer chromatography in the 10: 1 chloroform-methanol system revealed only one substance. The melting point of the product is 159-161 ° C.

Claims (4)

Patent claims The method of purification of 1,4-benzodiazepine derivative, characterized in that the precipitate of 7-chloro1,3-dihydro-5-phenyl-o-3-hydroxy-1-methyl-2H-1,4-benzodiazepinone-2, contaminated with other 1,4-benzodiazepine derivatives are treated with ferric chloride or its crystalline salt with six water molecules in an organic solvent immiscible with water, then the formed complex compound is isolated and decomposed in an aqueous solution with the addition of mineral acid or organic acid at the pH value solution 5-6, and then the product is isolated in a known manner. 2. The method according to p. A process as claimed in claim 1, characterized in that aliphatic chlorinated hydrocarbons, preferably methylene chloride or ethylene, are used as water-immiscible organic solvents. 3. The method according to p. A process as claimed in claim 1, characterized in that hydrochloric acid is preferably used from the mineral acids. 4. The method according to p. A process as claimed in claim 1, characterized in that acetic acid is preferably used as the organic acid.