RU2530496C1 - Method of producing di(4-cyanophenyl)bromomethane - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method of producing di(4-cyanophenyl)bromomethane can be used as an intermediate product in synthesis of medicinal agents, particularly anticancer drug letrozole. The disclosed method of producing di(4-cyanophenyl)bromomethane includes bromation of di(4-cyanophenyl)methane with bromosuccinimide in an inert solvent in the presence of benzoyl peroxide while heating. The reaction is carried out with an excess of 0.2-0.3 mol bromosuccinimide at 105-115°C.

EFFECT: method increases output and purity of the product.

2 cl, 2 ex

Description

The present invention relates to organic chemistry and relates to a method for producing di (4-cyanophenyl) bromomethane.

Di (4-cyanophenyl) bromomethane is used as an intermediate in the synthesis of drugs, in particular the anti-cancer agent letrozole.

A known method of producing di (4-cyanophenyl) bromomethane by bromination of di (4-cyanophenyl) methane with bromosuccinimide (WO 2007/144896 A1), which is the prototype of the present invention. In accordance with it, a solution of di (4-cyanophenyl) methane and bromosuccinimide in a 1: 1 molar ratio in chloroform in the presence of benzoyl peroxide is boiled for 10 hours, poured onto water, extracted with chloroform, the extract is washed with water, dried over sodium sulfate and evaporated. Hexane was added to the residue, stirred for 1 hour, the precipitate formed was filtered off, and di (4-cyanophenyl) bromomethane was obtained in 60% yield, so pl. 120.8 ° C, 96% pure (HPLC). Under these conditions, as it turned out when reproducing the prototype methodology, the target reaction does not reach the end (the unreacted starting compound remains) and is accompanied by an adverse reaction, which leads to contamination of the product. Its purification by recrystallization is associated with large additional yield losses.

The disadvantages of the prototype are not high enough yield and purity of the product.

The objective of the invention is the improvement of the method with increasing yield and purity of the product.

The problem is solved in that the reaction is carried out with an excess of 0.2-0.3 mol of bromosuccinimide at 105-115 ° C.

A solvent suitable for boiling point is used, in particular chlorobenzene.

It should be noted that the side reaction, which proceeds in parallel with the main one, is unexpected and consists in the entry of the second bromine atom into the same α-position of di (4-cyanophenyl) methane. This is proved by establishing the structure of the impurity based on the data of elemental analysis and the PMR spectrum (complete symmetry of the molecule and absence of an aliphatic proton). Since the brominating agent is also consumed in it, an excess is necessary for complete conversion. However, the formation of di (4-cyanophenyl) dibromomethane increases with increasing amount of bromosuccinimide and the duration of the reaction. Therefore, the process should be carried out with a minimal excess of bromosuccinimide and as soon as possible. This can be achieved by using a higher boiling solvent. In benzene, with a temperature increase of 20 ° C compared with chloroform (prototype), the reaction accelerates 2-3 times, but a significant excess of bromosuccinimide and many hours of heating are required. And in chlorobenzene with an excess of 0.2-0.3 mol and a temperature of 105-115 ° C, complete conversion is achieved in 2-3 hours. A further increase in temperature (boiling point of chlorobenzene 132 ° C) is impractical because of the thermal lability of benzoyl peroxide, the initiator of the formation of radicals. Instead of chlorobenzene, other bromosuccinimide-inert solvents can be used, for example benzene or ethane polychlorides.

The reaction mixture (solution) is washed with hot water from the succinimide formed, ~ 90% chlorobenzene (and azeotropically water) is distilled off, the residue is diluted with hexane and the di (4-cyanophenyl) bromomethane precipitated is filtered off; yield 95%, purity higher than 99% (the bulk of the dibromide impurity goes to the filtrate).

The following examples illustrate the invention.

Example 1

To a solution of 4.36 g (0.020 mol) of di (4-cyanophenyl) methane in 40 ml of chlorobenzene, 4.63 g (0.026 mol) of bromosuccinimide and 0.3 g of benzoyl peroxide are added, heated to 105-110 ° C and stirred at this temperature 3 hours; washed with hot water, distilled off 35 ml of chlorobenzene, the residue was diluted with 50 ml of hexane, the precipitate was filtered off, washed with hexane, air-dried on the filter and 5.64 g (95% yield) of di (4-cyanophenyl) bromomethane were obtained, 99.42% purity (HPLC) mp. 121.5-122 ° C (from a mixture of benzene - hexane).

Example 2

The process is carried out as in example 1, using dichlorobenzene instead of chlorobenzene. Get the product with a yield of 95% and the same characteristics as in example 1.

Thus, the proposed method provides a significant increase in yield (95% versus 60% for the prototype) and purity (> 99% against 96% for the prototype) of the product.

Claims (2)

1. The method of producing di (4-cyanophenyl) bromomethane by bromination of di (4-cyanophenyl) methane with bromosuccinimide in an inert solvent in the presence of benzoyl peroxide by heating, characterized in that the reaction is carried out with an excess of 0.2-0.3 mol of bromosuccinimide temperature 105-115 ° C. 2. The method according to claim 1, characterized in that chlorobenzene is used as a solvent.