GB2212801A - Preparation of an alkanolamine derivatives - Google Patents

Abstract

A compound of formula <IMAGE> is prepared by the hydrolysis of a nitrile of the formula: <IMAGE>

Description

PreParation of alkanolamine derivatives This invention is concerned with improvements in and relating to the preparation of alkanolamine derivatives. More particularly, the invention relates to the preparation of atenolol, that is 4(2-hydroxy-3isopropylamino-propanoxy)-phenyl-acetamide of the formula:

Various routes have been proposed for the preparation of atenolol, see for example GB-A-1285038, One commonly employed route for the preparation of atenolol comprises reacting an epoxide of the formula:

with isopropylamine. This route, however, suffers from the disadvantage that the reaction should be carried in an organic solvent system since the intermediate (II) would be subject to hydrolysis in an aqueous solvent system.

It has now been found, in accordance with the present invention. that atenolol may be obtained in good yield and using aqueous solvent systems by the hydrolysis of the corresponding nitrile of the formula:

which may, in turn, be prepared by the reaction of an epoxy nitrile of the formula:

with isopropylamine. The epoxynitrile of formula (IV) may simply be prepared by the reaction of g-hydroxybenzylcyanide with epichlorohydrin as described, for example, in GB-A-1227480.

The overall process in accordance with the invention, starting, E-hydroxybenzylcyanide. may be carried out using aqueous solvent systems and is thus convenient to carry out on an industrial scale.

Further, in general, the process leads to a better yield of pure end product with the amounts of by products/impurities being substantially reduced so that the final product often requires little or no further purification after isolation.

In the first stage of a preferred process of the invention starting from g-hydroxybenzylcyanide, this compound is treated, in aqueous solution and at room temperature, with aqueous potassium hydroxide solution and is then reacted with epichlorohydrin, with stirring, for 5 to 20 hours, preferably 6 to 10 hours, until the reaction is complete. The reaction mixture is subsequently acidified with glacial acetic acid to give a pH of from 5 to 6 to prevent formation of the diol of formula (V) below (where R is a hydroxyl group). The reaction mixture is then extracted into an organic solvent, preferably dichloromethane.

The organic solvent and excess epichlorohydrin are removed in vacuo to give the compound of formula (IV) [l-(4-cyanomethylphenoxy)-2,3-epoxypropane] in good yield. Any diol impurity (formula (V), R = OH) is kept to a minimum and any impurity of formula (V) in which R is chlorine will be subsequently converted to the product of formula (III), as will the epoxide, in the subsequent step of the process.

In the second stage of the preferred overall process, an aqueous water/isopropylamine mixture (preferably in a volume ratio of 1:1) is added to the product from the first stage. When the reaction is complete1 excess isopropylamine is removed by distillation under atmospheric pressure. Water is then added to the reaction mixture which is worked up by conventional methods to give the material of formula (III).

In the third stage of the preferred overall process the material of formula (III) is hydrolysed to give atenolol. In this stage, hydrogen chloride gas is bubbled through concentrated hydrochloric acid, maintaining the temperature below 100C, so as to saturate the solution to an amount of from 30 to 45%, preferably 38 -43%, of hydrogen chloride. The process is suitably carried out in a pressure vessel. The product of the second stage [the material of formula (III)) is then added to the saturated acid and the mixture heated in a sealed vessel, preferably for about 30 minutes at about 50 C. After cooling and releasing the pressure, the mixture is again basified with cooling to give the desired product (atenolol) in good yield and high purity.

In order that the invention may be well understood the following example is given by way of illustration.

Example (a) l-(4-Cyanomethvlhenoxy)-2, 3-epoxypropane 50% Aqueous potassium hydroxide solution (187.06g) was added to a mixture of p-hyroxybenzyl cyanide (200 g, 1.5 moles) and water (1300 ml). Epichlorohydrin (278.8 g, 3.0 moles) was then added and the mixture stirred at room temperature for 6 - 10 hours until reaction was complete, as shown by HPLC. Glacial acetic acid was then added to adjust the pH to 5 - 6 and the mixture extracted with dichloromethane (1 x 100 ml, 2 x 50 ml).

The organic solvent and excess epichlorohydrin were removed in vacuo and the product was obtained as an oil (300-320 g).

(b) 1-(4-CYanomethYlPhenoxv)-2-hYdroxv-3-isoProPYlamino- propane (III) The product of (a) above (100 g) was treated with isopropylamine (500 ml) and then water (500 ml) and heated at 65" for 20 minutes. The excess isopropylamine was removed at atmospheric pressure by distillation at a head temperature of 950C.

The rection mixture was worked up as follows: The mixture was cooled, water (400 ml) added and the solution stirred and heated for 15 minutes at 400C in the presence of Hyflo, charcoal and glacial acetic acid to dissolve the oil. After filtration the filtrate was cooled to OOC - 50C and 50% aqueous potassium hydroxide solution is added to pH 12-13. The gelatinous mass was extracted with dichloromethane, the organic solvent was then removed in-vacuo to leave an off-white solid (106 g), which could be used without further purification.

Alternatively the reaction mixture could be worked up as as follows.

The reaction mixture is cooled to 50 and water (400 ml) added. The oil which separates is then separated off and added directly to a saturated hydrochloric acid solution pre-heated to 500 [(see (c) below)3.

(c) 4-(2-hvdroxv-3-isoPropvlamino-propanoxy)-phen acetamide Concentrated hydrochloric acid (900 ml) was saturated with gaseous hydrogen chloride, with cooling (OOC - 100C), to give a 42-43% solution in a pressure vessel. The product of (b) above (100 g) was added and the vessel sealed and the mixture heated to 500C for 30 minutes. The reaction mixture was cooled, the pressure was released and 50% aqueous potassium hydroxide solution added with cooling, until the pH was 12-13.

The product was filtered off and washed with water and dried. The purity at this point was very high affording an almost quantitative yield. Further purification could be achieved, e.g. by recrystallisation from isopropanol.

Claims (3)

CLAIMS:

1. A process for the preparation of the compound of the formula: -

which comprises hyfrolysing the compound of the formula:

2. A process as claimed in claim 1 in which the compound of formula (III) is prepared by reaction of a compound of the formul:

with isopropylamine.

3. A process as claimed in claim 1 substantially as hereinbefore described with reference to the Example.