KR910006989B1 - A process for the preparation of cyanoethylated benzondiazepine - Google Patents

Abstract

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Description

Method for preparing cyanoethylated benzodiazepines derivatives

The present invention relates to a novel process for the preparation of cyanoethylated 3-hydroxy-1,4-benzodiazepin-2-one derivatives of the following structural formula (I), which are known as sleeping pills and have a therapeutic effect over similar preparations.

Wherein R ₁ is hydrogen, halogen, trifluoromethyl or nitro and R ₂ is hydrogen or halogen.

The above compound is optionally substituted with 3-hydroxy-1,4-benzodiazepin-2-one of formula (II) according to the method of Austrian Patent 361,429 (and corresponding British Patent No. 2,043,630). I am getting angry.

In the above formula, R ₁ and R ₂ are as defined above.

The selectivity of the substitution reaction for the NH group proceeds well by adding a phase transfer catalyst such as triethylbenzyl ammonium chloride. It is possible to carry out cyanoethylation reaction in the OH group without such a relatively inexpensive additive, which has the disadvantage that the monosubstituent and the disubstituent must be separated and the yield is reduced.

It is common that starting compounds of the general formula (II) are prepared by saponification of the corresponding O-acyl precursors of the following general formula (III).

In the above formula, R ₁ and R ₂ are as defined above and Acyl represents an acyl group. In this method, however, the 3-position is protected with an acyl so as not to be affected by the cyanoethylation reaction.

In preparing the sleeping agent of the general formula (I) in the present invention, the alkali is immediately reacted after reacting the O-acyl derivative (III) with the compound of the following general formula (IV) in a basic reaction medium without using a phase transfer catalyst. It is used to prepare a new intermediate of the following general structural formula so that the saponification reaction is made in a single step process from the structural formula III O-acyl precursor.

In the above formulas (IV) and (I), X is a reactive radical such as a halogen atom or a sulfonyloxy group, Y is hydrogen, X is together Y represents a second atomic bond, and R ₁ , R ₂ and Acyl are As defined. Thus, the Hi of general formula (I) can be obtained with good yield in a one step process. In other words, instead of using the known two-step method:

Equivalent amount of reactants by carrying out a one-step reaction from III → II (see Journ. Org. Chem. 27, 1691 (1962)) and II → (see Austrian Patent No. 361,492) III → (V) → I IV) has the advantage that it can be manufactured easily without any harm to the surrounding environment technically. The process of the present invention is surprising given the inability to predict the relative kinetics of the two reactions (cyanoethylation and saponification) in basic media. It is also difficult to predict that cyano groups in the intermediate (V) have resistance to further saponification reactions.

The present invention is explained according to the examples.

Example 1

5 g of 7-chloro-3-acetoxy-5- (2'-fluoro-phenyl) -1,3-dihydro-2-one was added to 20 ml of acetone and 10 ml of distilled water. 1 ml of nitrile was added, and then 3 ml of 1N NaOH was added dropwise, and the reaction mixture was stirred overnight (silica gel 60F 254, developer: toluene / ethanol / NH ₄ OH 25% = 70: 30: 1,5) As a result, it was confirmed that the conversion was almost complete.

Some of this product is saponified to give 1- (2-cyanoethyl) -7-chloro-3-hydroxy-5- (2'-fluoro-phenyl) -1,3-dihydro-2H-1,4 -Benzodiazepin-2-one was obtained.

While stirring the reaction mixture at room temperature, 14 ml of 1N NaOH was added dropwise, and the saponification reaction was completed within 5 hours. Then 16 ml of 1NHCl was slowly added and stirred again for 1 hour, then left at 4 ° C. overnight, washed with water by suction filtration and then with isopropanol.

1- (2-cyanoethyl) -7-chloro-3-hydroxy-5- (2'-fluoro-phenyl) -1,3-dihydro-2H-1,4-benzodiazepine-2 thus obtained The dry was obtained to give 4.7 g (l93% of theory) and acetone or recrystallized from methanol. (Melting point 190-193 ° C)

Example 2

The cyanoethylated intermediate is obtained pure in the following manner.

Stir by adding 5 g of 7-chloro-3-acetoxy-5- (2'-fluoro-phenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 20 ml of acryrylonitrile. Two drops of a 405 methanolic solution of benzyltrimethyl-ammonium hydroxide ("Triton B" solution) were added to the suspension, and the mixture was stirred overnight (silica gel 60F 254; 1) As a result, it was confirmed that the conversion was almost complete.

The suspension was diluted with petroleum ether, left at 4 ° C. for several hours, filtered off with suction, and washed slightly with isopropane. The melting point of the product, recrystallized from 5.4 g (93.7%) and methanol, was 200-202 degreeC.

Claims (1)

Saponification of a novel intermediate of general formula (V) with alkali immediately after 3-acyl-1,4-benzodiazepin-2-one of general formula (III) is reacted with a compound of general formula (IV) in a basic reaction medium. To prepare cyanoethylated 3-hydroxy-1,4-benzodiazepin-2-one derivative of general formula (I)

In the above formula, R ₁ is hydrogen, halogen, trifluoromethyl or nitro, R ₂ is hydrogen or halogen, Acyl is acyl, X is halogen atom or sulfonyloxy group, Y is hydrogen or X and Y Together represent a second atomic bond.