CS223449B1 - Method of preparation of the 5-aryl-7-chlor-1,3dihydro-1,4-benzodiazepine - Google Patents

Description

The invention relates to a process for the preparation of 5-aryl-7-chloro-1,3-dihydro-1,4-benzodiazepine-2-thiones of the general formula I, described and prepared by the reaction of 5-aryl-7-chloro-1,3-dihydro - 1,4-benzodiazepin-2-ones of formula II,

wherein R represents a hydrogen atom or a chlorine atom.

The compounds of the formula I have, on the one hand, psychotropic activity (centrally depressing, anxiolytic, myorelaxant and anticonvulsant), and, on the other hand, they are useful as intermediates for the production of other psychotropically active drugs, in particular substances of the series

6-aryl-8-chloro-4H-s-triazolo (4,3-a) -1,4-benzodiazepines (Moffett R. B., Lectures Heterocycl. Chem., 3, S-123, 1976).

The compounds of formula I were in the literature in which R is the same as in formula I, with phosphorus pentasulfide in boiling pyridine (Archer GA and Sternbach LH, J. Org. Chem. 29, 231, 1964; Hester JB Jr., Rudzik AD, Kamdar, V., J. Med. Chem., 14, 1078, 1971; U.S. Patents 3,144,439 and 3,243,427). All literature sources are characterized by having relatively low yields on the desired products ranging from 35 to 41%. Furthermore, it is typical that the disclosed methods employ an equimolecular ratio of the reacting components, i.e., compounds of formula II and phosphorus sulphide: thus, 1 molecule of phosphorus sulphide is used per molecule of formula 223449.

Upon closer study of the preparation of the compounds of formula (I) by the above reaction, it has now been found that the use of excess phosphorus sulphide results in a reduction in yields. Furthermore, it was surprising to find that using less than an equimolecular amount of phosphorus pentasulfide, on the contrary, increases the yield. This is probably due to the fact that more than 1 sulfur atom out of the 5 atoms of this element is present in the phosphorus sulphide molecule. The amount of phosphorus pentasulfide can be reduced up to half the equimolar amount while maintaining a high yield.

Accordingly, the present invention provides a process for the preparation of compounds of formula (I) by reacting compounds of formula (II) with phosphorus pentasulfide in boiling pyridine, wherein the problem is 50 to 90% of an equimolar amount of phosphorus pentasulfide. The advantages of this process are to increase the yield practically double that of the cited literature, to save a relatively valuable starting material, and finally to reduce the problems associated with waste disposal after the reaction (advantageous in terms of lower wastewater pollution and lower odor and toxic emissions).

He did

5-Phenyl-7-chloro-1,3-dihydro-1,4-benzodiazepine-2-thione

A mixture of 55.3 g (0.2 mol) of 5-phenyl-7-chloro-1,3-long-1,4-benzodlazepin-2-one (DD patent 57,126), 22.2 g of phosphorus sulphide (0, 1 mol) and 400 ml of pyridine are stirred and boiled for 30 min. under reflux in a nitrogen atmosphere. After stirring for 1 hour without heating, the cooled solution was poured into a stirred solution of 630 g of sodium chloride in 2.1 l of water. The mixture is cooled to 5 ° C, whereby the oily product precipitates in 10 minutes of stirring.

Claims (1)

Subject A process for the preparation of 5-aryl-7-chloro-1,3-dlhydro-1,4-benzodiazepine-2-thiones of formula I wherein R is hydrogen or chlorine by reaction of 5-aryl-7-chloro-1, The 3-dihydro-1,4-benzodiazepin-2-ones of formula II is. After standing for 1 hour, it is filtered, washed with water and dried in vacuo. This product was dissolved in 3 L of dichloromethane and filtered through a column of 200 g of neutral alumina (activity II). The solution obtained is washed with dichloromethane and evaporated under atmospheric pressure, the residue (43.8 g) is suspended in 200 ml of ethanol, the suspension is heated to boiling and left to stand at room temperature overnight. The precipitated product is then filtered off with suction, washed with a little ethanol and dried in air or under vacuum. 38.1 g (67%) of the desired product melting at 233-238 ° C are obtained, which product is pure enough for further use. Example 2 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione A mixture of 152.2 g (0.5 mol) of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-one (Vejdelek Z. et al., Collect. Czech. Chem. Commun., 45, 3593, 1980), 88.8 g (0.4 mol) of phosphorus pentasulfide and 880 ml of pyridine are stirred and refluxed for 1 hour under a nitrogen atmosphere. After cooling to 16 ^DEG C., it is poured into a stirred solution of 1.62 kg of sodium chloride in 5.4 l of water, cooled to 5 ^DEG C. The mixture is stirred for 2 hours, the precipitated crude product is filtered off with suction and washed thoroughly with water. Air drying gave 145.7 g (91%) of the crude product, mp 227-233 ° C. For purification, this product is dissolved in 150 ml of dimethylformamide at 140 ° C, the hot solution is suctioned off through a 0.5 cm layer of alumina and the still hot filtrate (100 ° C) is slowly poured into 550 ml of boiling ethanol. The mixture is allowed to stand overnight at 5 ° C, then the precipitated product is filtered off with suction, washed with ethanol and a little hexane and dried in air or in vacuum. 104.0 g (65%) of a pure product melting at 233-237 ° C are obtained. wherein R is the same as in Formula I, with phosphorus pentasulfide in boiling pyridine, characterized in that phosphorus pentasulfide is used in 50 to 90% equimolar amounts.