CS243571B1 - Crystallization Method of 5-Hydroxy-5- (3-dimethylaminopropyl) -10,11-dihydiodibenzone, dcykloheptene - Google Patents

Abstract

The solution concerns a new method of crystallization of the crude tricyclic basic carbinol amitriptyline of formula I, which is an important intermediate in the synthesis of the psychotropic drug amitriptyline. A very advantageous medium is the use of simple aliphatic ketones with a water content of 1 to 20%. From this medium, the carbinol AMT crystallizes very readily in high yield and in very good purity. The advantage of using aliphatic ketones as a crystallization medium is also evidenced by the fact that it was possible to obtain satisfactory carbinol AMT even from mother liquors after ethyl alcohol crystallization, while the reuse of ethanol for processing mother liquors did not lead to the goal.

Description

The present invention relates to a novel process for the crystallization of 5-hydroxy-5- (3-dimethylaminopropyl) -10,11-dihydrodibenz [a, d] cycloheptene.

In the synthesis of one of the most important sedative psychopharmaceuticals - Amitriptyline - an important intermediate is the tricyclic basic carbinol 5-hydroxy-5- (3-dimethylaminopropyl) -10,11-dihydrodibenz [a, d] cycloheptene of formula I:

In order to obtain this important drug (amitriptyline in high purity, it is essential that the final stage of the synthesis works with intermediates that no longer contain ballasts or traces of previous synthesis intermediates. All purification operations of the final product are then uneconomical and complicate the synthesis process.

The penultimate step of amitriptyline synthesis is the aforementioned tricyclic basic carbinol (hereinafter AMT carbinol), which allows some refining operations to be carried out so that the final product then meets the highest purity requirements. The carbinol AMT is predominantly prepared by Grignard reaction of dimethylaminopropylmagnesium halide with the corresponding cyclic ketone 10,11-dihydrodibenzo [a, d] cyclohepten-5-one, i. dibenzosuberone.

The course of the Grignard reaction is always dependent on many factors such as the purity of the magnesium used, the purity of the reaction components, and ultimately the reaction medium in which the Grignard reaction is carried out, as well as the reaction conditions chosen. In addition, the chosen method of isolating the resulting AMT carbinol from the reaction medium must also be taken into account, where by-conditions may increase the AMT carbinol by-products.

The current industrial production mainly prepares carbinol AMT by Grignard reaction of dimethylaminopropylmagnesium chloride with dibenzosuberone in either ether or toluene medium. After this reaction, carbinol AMT is isolated from this medium in an aqueous solution as an addition salt with a mineral acid. Here, in addition to partial dehydration of carbinol AMT, a number of other accompanying substances may occur due to low pH values and higher temperatures. Alkalization of the aqueous solutions of the carbinol AMT addition salt isolates the crude product, which should be crystallized from ethanol to give the satisfactory carbinol AMT.

It has recently been found that AMT carbinol crystallized from ethanol provides a satisfactory product only from high-quality crude AMT carbinol, but from less pure crude products, this crystallization is completely unsatisfactory and yields lower yields.

For these reasons, new crystallization media have been sought which do not reduce the yield and, moreover, improve the quality of this important intermediate step. Simple aliphatic ketones with a water content in the range of 1% to 20% appeared to be a very preferred medium. AMT carbinol is very readily crystallized from this medium and, in addition to its high yield, it is obtained in very good purity. The advantage of using aliphatic ketones as a crystallization medium is evidenced by the fact that it has been possible to obtain a satisfactory AMT carbinol from the mother liquors after ethanol crystallization, while the re-use of ethanol for the mother liquor treatment did not result in a target.

The examples illustrate but do not limit the scope of the invention.

Example 1 g of crude unsuitable carbinol AMT was dissolved in 3 parts (75 ml of 95% aqueous acetone) with gentle warming.

The obtained aqueous acetone solution of carbinol AMT is purified with 0.25 g of carboraffin. On cooling, 22.2 g (88.8%) of the crystalline AMT crystalline carbinol of m.p. 114 DEG-115 DEG C. are obtained which is chromatographically satisfactory.

Example 2 g of crude unsuitable carbinol AMT was dissolved in 4 parts of 95% aqueous diisopropyl ketone with gentle warming. The AMT carbinol solution is purified by 0.25 g carboraffin and cooled to give 90% of the satisfactory AMT carbinol. Mp 115 ° C and chromatographically satisfactory.

EXAMPLE 3 g of non-crystallized concentrated mother liquors after ethyl alcohol crystallization of AMT carbinol are dissolved under gentle warming in 3 parts of 95% aqueous acetone and after purification of 0.5 g carboraffin, cooling yields a high yield of satisfactory crystalline AMT carbinol. Mp 115 ° C, chromatographically suitable product.

Claims (1)

SUBJECT VYNALEZU 5-Hydroxy-5- (3-dimethylaminopropyl) -10,11-dihydrodibenz (a, d) cycloheptene crystallization process of formula I, CH * an aqueous aliphatic ketone of formula II, R1-CO-R2 II, wherein R1 and R2: -CH3, -C2H5, -C3H7, CH3 / —CH \ CH 3 characterized in that the crystallization is carried out from 2 to 5 parts by weight, preferably 3 parts, based on the crude carbinol AMT, wherein the concentration of the aliphatic ketone is 80 to 99% by weight, preferably 80% by weight.