CS222765B1 - Method of purification of 2-methyl-3/2-tolyl / quinazolone-4 - Google Patents

Abstract

The invention relates to a method for purifying 2-methyl-3/2-tolyl/-quinazolone-4, a known clinically used hypnotic, prepared from acetylanthranilic acid and o-toluidine under the cyclizing action of phosphorus oxychloride. The essence of this method lies in the fact that after the reaction is complete, the reaction mixture is decomposed first with methanol and then with acetone, after which the separated very pure product is isolated from this medium.

Description

The invention relates to a process for purifying 2-methyl-3 (2-tolyl) -quinazoline-4 of the formula

of a clinically used byte.

As is known, the classical means of sleep chemotherapy, i.e. hypnotics, barbiturates, whose synthesis and pharmacological testing have already been essentially closed, have been known to be their chau. Due to their side effects, other substances have been sought. In 1946, a new route for the preparation of 4-quinazolones, starting from anthranilic acid and substituted primary amines under the cyclizing action of phosphorus trichloride / H.W. Grimmel et al., J. Am.Chem.Soc. 68, 542 (1946)]. He tried these substances as potential hypnotics M.L.Gujral se sp. (Indian J. Med. Hesearoh 43, 637, 1955), 2-methyl-3 (2-tolyl) quinazolone-4, which was introduced into clinical practice, proved to be the most advantageous.

The original preparation process was later significantly extended only in the field of cyclizing agents, namely to thionyl chloride and phosphorus oxychloride (f.Kolchakova et al., Parmaoija (Sofia, 20, 5, 1-4, 1970). More recently, a report based on literary references has emerged, utilizing the reactivity of acetylanthranil with primary amines to form cyclic products of the type

2 222 7 8 5 Benzodiazines / L. A. Brrede ae sp., J. Org. 41, 1976,

1763 /.

Both the purity of the intermediates and, in particular, the end product are decisive in the quality control of the substances used in the manufacture of the medicaments. Indeed, the closure of the diaphragm skeleton in the course of the reaction is accompanied by a series of side reactions that take place simultaneously with the cyclization. It is surprising that even if the reaction proceeds in a homogeneous or heterogeneous phase in the environment of org _and low solvents, its quality is almost identical according to chromatographic control. In addition to the starting materials, ie acetylanthranilic acid and o-toluidine, there is always transacylalo-formed acetyltoluidine, anthranilic acid (resulting in deaoylaloic acid) and probably a product of beer cyclization, ie acetylanthranilic acid o-toluide. that is, the removal of undesirable substances formed in the reaction or accompanying the reaction, which reaches the final product and which is difficult to remove with considerable losses. Also, the decomposition of a solid reakoe product, a mixture of many components, is difficult.

According to the invention, the above mentioned disadvantages and drawbacks are eliminated by the method of purification of 2-methyl-3 (2-tolyl) -quinazolone-4 ' prepared from acetylanthranilic acid and o-toluidine under the cyclizing action of phosphorus oxychloride completion of the cyclization reaction decomposes the reaction mixture first with methanol in an amount equal to 2/3 of the amount of toluene and then with acetone in an amount equal to the amount of toluene used as the reaction medium, whereupon the pure product is recovered from this mixture ·

In carrying out the process according to the invention, said solvents are added to the reaction mixture as soon as possible after the cyclization is complete, as soon as the temperature falls below the boiling point of methanol and acetone. Under these conditions, a homogeneous environment is formed from which the product is slowly released, not

- 3 222 765 immediately, while the balaetics remain in solution. The chromatographically pure 2-methyl-3 (2-tolyl) quinazolone hydrochloride is isolated, which is no longer required for purification, but only converted to the use form, i.e. base. The process according to the invention is advantageous over processes using a toluene medium in that the product obtained has no analytically detectable accompanying impurities and that its yield is identical to the high yields reported in the literature.

Further details of the process according to the invention can be seen from the following exemplary embodiment.

Acetylanthranilic acid (179.0 g, 1 mol) was mixed in a mixture of toluene (300 ml) and chloroform (50 ml). After addition of 107.0 g (1 mol) of o-tolulidine and at a temperature of up to 30 ° C, it adds 205 g of phosphorus oxychloride. The heterogeneous mixture is then heated at an internal temperature of 90 ° C for 3 hours, whereby the desired product is slowly precipitated from the oily emulsion of the reaction medium. Without further heating, the reaction mixture was quenched with 200 mL of methanol and 300 mL of acetone. After a short time, the impurity solvent is quantitatively dissolved and, after cooling, the pure white crystalline 2-methyl-3 (2-tolyl) quinazolone-4 hydrochloride is filtered off with suction and washed with acetone. Yield: 220.0 g (76.7%). The product is chromatographically pure.

Claims (1)

A process for the purification of 2-methyl-3/2-tolyl-quinazolone-4, prepared from acetyl anthranilic acid and o-toluidine under the cyclizing action of phosphorus oxychloride, in toluene, characterized in that after the cyclization reaction is complete an amount equal to 2/3 of the amount of toluene and then of acetone in an amount equal to the amount of toluene used as the reaction medium, whereupon the pure product is recovered from this mixture ·