SU359819A1 - METHOD OF OBTAINING 1,3-DIHIDRO-7-NITRO-5-PHENYL-2H-1,4- - Google Patents

Description

The invention relates to an improvement in the process for the preparation of 1,3-dihydro-7-nitro-5phenyl-2H-1, 4-benzodiazepin-2-one, which is an integral part of many valuable medicines.

A method of producing 1,3-dihydro-7-nitro-5-phenyl-2H-1, 4-benzodiazepin-2-one is known by cyclizing 2-glycylamido-5-nitrobenzophenone at a pH of 7. Solution. excess inorganic acid, cyclization of 2-glycylamido-5-nitrobenzophenone does not occur.

The use of an organic acid or catalytic amounts of inorganic according to the invention leads to the formation of a stable acid addition compound, and cyclization of 2-glycylamido-5-nitrobenzophenone to 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2- it occurs spontaneously.

In order to improve the quality and yield of the target product, a method for producing 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one is proposed, which consists in that 2-glycylamido-5-nitrobenzophenone is subjected to cyclization in an aqueous or indifferent organic solvent at pH of the solution is less than 7.

or catalytic amounts of inorganic.

Formic acid, acetic acid, phosphoric acid, hydrochloric acid, sulfuric acid are used, which can be used in the presence of solvents such as dioxane, dimethylformamide, chloroform, acetonitrile, and also in the form of aqueous solutions. Additional heating of the reaction mixture above room temperature is not necessary. The yield of products obtained by the proposed method is 63-82%.

The preparation of 1,3-dngidro-7-nitro-5-phenyl-2H1, 4-benzodiazepin-2-it occurs without the formation of by-products, in particular, the formation of 3-amino-1,2-dihydro always observed in the known methods is difficult. -6-nitro-4-phenylquinolone-2.

In addition, it is possible to associate the process for the preparation of 2-glynamido-5-n-trobenzophenone, which is used as a starting product, with the proposed cyclization method. 2 -Glycylamido-5-nitrobenzophenone can be easily and with very good yield to obtain (and with a high degree of purity), for example, from 2- (O-arylsulfonylglycolylamino) -b-nitrobenzophenone and ammonia. The resulting 2-glycylamido-5-nitrobenzophenone is not isolated from the reaction mixture, but directly after the preparation is introduced into the acid cyclization process corresponding to the invention. For this purpose, after finishing the treatment with 2- (0-a rilsulfonyl glycoloyl but) -5-nitrobenzophenone gaseous ammonia, for example, in dioxane used as a solvent, a stream of air is blown through the reaction mixture in order to more fully remove excess ammonia. Immediately following this, the reaction mixture is acidified, whereby the cyclization according to the invention occurs. Example 1 12.8 g of 2-glycylamido-5-nitrobenzophenone are diluted with shaking or stirring at room temperature in 60 ml of 30% acetic acid. After 5-10 hp, the solution is filtered and left to stand to crystallize the product. The precipitation of crystals begins after about 30-60 pts and ends after 20-24 hours. The separated crystals of 1,3-dihydro-7-nitro-5-phenyl-2H-I, 4benzo-diazepin-2-one is aspirated and washed with 10 ml of alcohol "10 fAA of ethyl acetate. 9.7 g (respectively, 82% of the theoretically possible amount) of yellowish 1,3-dihydro-7-nitro-5-phenyl-2H1, 4-benzodiazepin-2-one crystals are obtained. After recrystallization from ethylacetate, the product becomes almost white and has a melting point of 226-228 ° C. Example 2. 5.4 g of 2-glyc | Ilamido-5-n-trobenzophenone are mixed or injected with 95 ml of dioxane and 4 ml of 1 and. hydrochloric acid solution at room temperature for 20 hours. The solution is filtered off from a slight turbidity and the filtrate is introduced in portions into 250 ml of water. 1,3-Dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one gradually crystallizes out of the milky-turbid liquid. The yield of brownish crystals is 3.2 g, respectively, 63% of the theoretically possible amount. After recrystallization from ETHYL. OTHER Acetic acid ester, the melting point of almost white crystals is 226-228.5 ° C. Example 3. 5.3 g of 2-glycylamido-5-nitrobenzophenone are shaken or mixed with PO ml of dimethylformamide and 2 ml of 2N. sulfuric acid. After 24 hours, clear pacTBqp is added in portions with 200 ml of water; 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one crystallizes during mashing. The crystals are filtered off with suction, washed with 25 ml of water, 10 ml of alcohol and 5 ml of ethyl acetate. The yield is 3.3 g, respectively 66% of the theoretically possible amount. After recrystallization from butyl alcohol, the melting point of the product is 225-227.5 ° C. Example 4. 50 g of 2- (0-chlorobenzenesulfonylglycoloylamido) -5-nitrobenzophenone are suspended: in 500 ml of dioxane and at room temperature and stirring, ammonia gas is slowly passed over 8 hours. The reaction mixture was incubated for 8 hours, then, by passing an air stream into the reaction mixture for 15 minutes, the excess amount of dissolved ammonia was removed. After that, the reaction mass is acidified with 50 ml of glacial acetic acid, the mixture is kept under periodic stirring for 24 hours, and the resulting 1,3-dihydro - 7 - nitro-5-phenyl-2H-1,4-benzodiazepin-2-one is separated, add 1500 ml of water. The target product is filtered off with suction, washed with 200 ml of water, 40 ml of methyl alcohol and 25 ml of ethyl acetate. The yield of the product is 18.4 g, respectively, 63% of the theoretically possible amount. After recrystallization, for example, from chlorobenzene, the melting point of the crystals is 225 ° C. The subject matter of the invention 1. The method for producing 1,3-dihadro-7-nitro-5phenyl-2H-1, 4-benzodiazepin-2-one by cyclization with 2-glycylamido-5-nitrobenzophenone followed by isolation of the target product by the known methods, characterized in that In order to improve the quality and yield of the target product, the cyclization is carried out in an aqueous or indifferent crystalline solvent at a pH of less than 7. 2. The method according to claim 1, characterized in that the pH of the solution is less than 7 is achieved by adding stoichiometric amounts or "excess organic acid or kata iticheskogo amount of an inorganic acid. 3. A method according to claim 1, characterized in that dioxane, dimethylformamide, chloroform or acetonitrile are used as an indifferent organic solvent.