CS217944B1 - Process for the preparation of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one-4-oxide - Google Patents

Abstract

The invention relates to a process for the production of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2/1H/-one-4-oxide by reacting 6-chloro-2-chloro-methyl-4-phenylquinazoline-3-oxide or its hydrochloride, dissolved in an alkanol with 1 to 5 carbon atoms, with a gradually dosed aqueous solution of an alkali metal hydroxide, at a temperature of 15 to 20 °C and isolating the resulting salt.

Description

The present invention relates to a process for the preparation of 7-chloro-5-phenyl-3H-1,4-benzodiazepine-2 (1 'H) -one 4-oxide of the formula

Cl

a key intermediate of important, clinically used psychopharmaceuticals from the family of 1,4-benzodiazepine derivatives such as oxazepam, diazepam and others.

There are a number of procedures known in the literature which allow access to the 1,4-benzodiazepine derivatives, but are considerably less technologically feasible on an industrial scale.

In the practice of the art, the process of treating aqueous-alcoholic alkali metal hydroxide solutions on 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide or its hydrochloride / L is often used. H. Aternbach, E. Reeder, J. Org. Chem. 26, 4936 (1961); O. C. Bell et al., J. Org. Chem. 27, 562, 962]. The starting quinazoline derivative can be prepared from the alpha or beta-oximes of 2-amino-5-chlorobenzophenone either directly by treatment with chloroacetyl chloride in acetic acid / L. H. Sternbach et al., J. Am. Chem. Soc. 82, 475 (1960); US Pat. No. 2,893,992) or in two stages via 5-chloro-2- (chloroacetamido) -benzophenone oxime (U.S. Pat. No. 3,136,815j of German Pat. No. 1,190,946) or by the action of chloroacetaldehyde on the 2-amino-5-chlorobenzophenone beta-oxime and oxidation of the resulting 1,2-dihydro-derivative with dichromate in acetic acid / Dutch Pat. No. 6,515,499).

The base catalyzed transformation of the quinazoline skeleton to the 1,4-benzodiazepine skeleton is a sensitive reaction requiring strict adherence to the prescribed reaction conditions. A decisive factor in achieving optimum yields and quality is that the product formed does not remain for a longer period of time. in contact with an alkaline reaction medium. Otherwise, 2-amino-5-chloro-benzhydrylidene glycine-N-oxide is formed as a result of hydrolysis of the seven-ringed ring at the lactam moiety, and other intensely colored by-products are formed which adversely affect product quality. In order to meet this requirement, the pH of the reaction mixture should be brought very rapidly to the acid range to a value of 3 to 4 upon completion of the reaction.

According to the present process, the reaction is carried out in a homogeneous medium of an aqueous-alcoholic alkali metal hydroxide solution which is used in a five to six-fold molar excess based on the phenylquinazoline hydrochloride starting material. However, the low solubility of the reacting components requires the use of large volumes of solvents. Also, on a technical scale, the time lag between the end of the reaction and the change in pH of the solution to the desired value cannot be excluded. The 1,4-benzodiazepinone oxide thus obtained must be purified by crystallization from suitable solvents for the next synthesis step. However, the mother liquors after product isolation have a very unfavorable composition and do not allow economic recovery of the solvent.

In order to eliminate these disadvantages, the reaction conditions and the sequence of individual operations were studied in detail. This study led to surprising findings, which helped to eliminate the shortcomings of the existing production process and which, in addition, brought further effects leading to its optimization and economization.

On the basis of new knowledge, a process for the preparation of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one-4-oxide according to the invention has been developed. 2-Chloromethyl-4-phenylquinazoline-3-oxide, dissolved in a C 1 -C 5 alkanol, is treated successively with a dosed alkali metal hydroxide solution and the resulting salt is isolated. The alkali metal hydroxide is conveniently metered in the form of an aqueous solution at a temperature of 15 to 25 ° C.

The process according to the invention is based on the finding that the reaction of the starting phenylquinazoline derivative with an alkali metal hydroxide proceeds very rapidly to give the corresponding 1,4-benzodiazepine oxide salt. By suitably arranging the concentration ratios in the reaction mixture and gradually adding the alkali metal hydroxide solution to the phenylquinazoline solution, the corresponding 1,4-benzodiazepinone oxide salt formed can be continuously excreted as a crystalline suspension from the reaction mixture. This means that at any point in the reaction, a strong alkaline environment cannot be formed and hence the possibility of undesired side hydrolytic reactions. The precipitated 1,4-benzodiazepinone oxide salt forms a heterogeneous reaction system in which the possible subsequent reaction with an alkali metal hydroxide is severely restricted, respectively. not at all. The 1,4-benzodiazepinone oxide mine can be very easily isolated and used as such directly to the next step, or converted by acidification in aqueous solution to the free 1,4-benzodiazepinone oxide. In the described arrangement, the reaction proceeds with very good yields of a high-quality product, since the isolation of the salt is itself a highly efficient purification operation.

Other advantages of the process according to the invention include a substantial reduction in reaction time and energy savings, a reduction in the amount of organic solvents, a reduction in the amount of waste water and an improved process hygiene, and finally the possibility of processing a lower quality feedstock.

Further details of the method according to the invention are given in the exemplary embodiment, which illustrates but does not limit the method in any way:

Dissolve 6 g of 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide hydrochloride at not more than 45 ° C in 70 ml of methanol and filter. The filtrate is placed in a 250 ml three-necked flask equipped with a stirrer, thermometer and divider, cooled to 12-15 ° C and at this temperature a solution of 17.3 g of sodium hydroxide in 30 ml of water is added dropwise. The reaction temperature is maintained at 18-20 ° C. Depending on the cooling intensity, it takes 15 to 20 minutes to add dropwise. The sodium salt is gradually precipitated in crystalline form. After completion of the dosing, the sodium hydroxide solution is stirred for a further 0.5 h. The crystalline suspension is suction filtered at about 10 ° C and washed with 15 ml of methanol. The still wet product is dissolved in 200 ml of water and the pH is adjusted to 3-4 with dilute hydrochloric acid, the temperature not exceeding 20 ° C. The solution was cooled to about 10 ° C and maintained at this temperature for 2h. The crystallized precipitate was filtered off with suction, washed with water and dried at 70 ° C. 17 g (81.0% of theory) of 7-chloro-s-phenyl-3H-1,4-benzodiazepin-2 (1H) -one-4-oxide are obtained.

Claims (2)

A process for the preparation of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one-4-oxide comprising the steps of: 6-chloro-2-chloromethyl-4-phenylquinazoline The -3-oxide or its hydrochloride, dissolved in a C 1 -C 5 alkanol, is treated sequentially with a dosed alkali metal hydroxide solution and the resulting salt is isolated. 2. The process according to claim 1, wherein the alkali metal hydroxide is metered in the form of an aqueous solution at a temperature of 15 to 20 [deg.] C.