CS229927B2 - Production method of 3,4-diacyloxy-alfa ( ( methylamino(-methyl) )benzylalcohol - Google Patents

Description

The invention relates to a process for the preparation and isolation of O-acyl = substituted catecholamine derivatives, i.e. 3,4-diacyloxy-.alpha .- [(methylamino) methyl] benzyl alcohol of the formula I

wherein R is C 1 -C 4 alkyl or benzyl, preferably tert-butyl, and its acid addition salts, preferably its hydrochloride.

The compounds of the invention are known for their sympathomimetic properties and can be used, inter alia, for the treatment of glaucoma. The prolonged action of these compounds compared to the corresponding 3,4-dihydroxy compound, i.e., adrenaline, is reported to be due to O-acyl protection, which, in the case of adrenaline, prevents very rapid oxidation in the body to a compound that has no effect.

Regardless of the protection of the reactive groups, the acyl compounds of the formula I are not stable under alkaline conditions, since the hydrolysis of the acyloxy groups is immediately followed by the formation of oxidation products. However, these compounds are fairly stable in acidic solutions. For these reasons, the amines of the compound of formula (I) cannot be isolated by conventional methods used to produce amines.

According to the process for the preparation of the compounds of the formula I described in the literature, ortho-diacylated catecholamines are treated as salts in alcohol-type solvents such as methanol or ethanol, thus avoiding the aforementioned disadvantageous phenomenon. In U.S. Patent Nos. 3,809,714 and 4,035,405, such a compound is prepared from the hydrochloride salt of a ketofunctional compound of Formula II

(II) where

R is as defined above, by catalytic hydrogenation under pressure in methanol or ethanol in the presence of a platinum oxide catalyst. The product is isolated in a conventional manner by filtering off the catalyst from the reaction mixture, evaporating the solvent, and crystallizing the product of formula (I) from a mixture of suitable solvents.

According to Finnish Patent No. 55,988, a compound of formula I is disclosed. produced by reducing the compound of formula III (pco ₀ CHiQ)

R @ ^{1 =} CH3 -N-CH4 ^{= 7} (III) where

R is as defined above, by catalytic hydrogenation in an aqueous solvent using palladium on charcoal as a catalyst.

However, these known methods are difficult to perform because catalytic hydrogenation requires the use of pressure vessels. This is always associated with a substantial risk of autoignition associated with catalytic hydrogenation.

The process according to the invention for the preparation of the compounds of the formula (I) consists in reducing the acid addition salt of the compound of the formula (II) with sodium borohydride or potassium borohydride in an acidic solvent, preferably in an acidic solvent. . glacial acetic acid at. temperature. 0. to 50 ° C, preferably 0 to 25 ° C. The acid addition salt of the compound of formula (I) is. Isolate by adding water to the reaction mixture. Reaction-. the product is extracted with a chlorinated hydrocarbon and treated with the corresponding acid.

The reduction according to the invention can easily be carried out under ordinary conditions - and using ordinary vessels, since the disadvantages associated with the catalytic hydrogenation mentioned above are avoided.

The reducing effect of the reducing agent depends on the solvent. The choice of a suitable solvent for the reduction is therefore important. Glacial acetic acid has been found to be a very preferred solvent.

The reaction product can be easily extracted from its aqueous solution into chlorinated hydrocarbons such as chloroform or methylene chloride. The higher the R group, the better the solubility of the product in chlorinated hydrocarbons.

According to a preferred embodiment of the invention, the compound of formula I is prepared by dissolving the hydrochloride salt of the amine of formula II in acetic acid and reacting with sodium borohydride at a temperature of from 0 to 50 degrees Celsius and a reaction time of 1 to 2 hours. The reaction is particularly preferably carried out at room temperature or below (from 0 to 25 ° C). This exothermic reaction requires cooling.

The reaction product is separated by adding water to the reaction mixture and then extracted, for example with chloroform. Optionally the co-extracted acetic acid is washed from chloroform, for example by treatment with sodium hydrogen carbonate solution, and then the chloroform phase is treated with dilute hydrochloric acid. The chloroform solution is evaporated to give a hydrochloride residue of the compound of formula (I) which can be crystallized from a mixture of suitable solvents.

The starting compound of formula (II) may be prepared from adrenaline by a method known in the literature, for example as described in the US patents. no. 3 809 .715. a. .4.035. 405

The following example illustrates the invention.

Example

7.7 g (0.02 mol) of dipivaloyladrenaline hydrochloride are dissolved in 50 ml of acetic acid at room temperature. 2.5 g of sodium borohydride are added to the reaction mixture while cooling and stirring for half an hour. The reaction mixture was stirred on an ice bath for an additional hour and then 150 mL of water was carefully added. The reaction can be monitored by thin layer chromatography using a mixture of CH 3 NO 2, isopropanol and ammonia (95% w / v) in a ratio of 12: 3: 1. The free solution is extracted three times with 50 ml each. chloroform and then the chloroform solution is washed with 50 ml of concentrated sodium bicarbonate solution, 50 ml of 2 N hydrochloric acid and 50 ml of water. The chloroform solution is dried and then evaporated to dryness. The residue (7.0 g) was crystallized from acetone / hexane. Yield: 5.5 grams (71%) of dipivaloyladrenaline hydrochloride, m.p. 158.5-160 ° C (reference: 159-160 ° C). According to volumetric analysis the product has a purity of 99.9%.

Claims (2)

1. A process for the preparation of a. Isolation of 3,4-diacyloxy-.alpha .- [(methylamino) methyl] benzyl alcohol of the formula I: O ^ ^c \ ^o \ OH (I) where R is C 1 -C 4 alkyl or benzyl, in the form of its acid addition salt, characterized in that the acid addition salt derived from the corresponding ketofunctional amine of formula (II) is disclosed wherein: R is as defined above, reduced with sodium borohydride or potassium borohydride in an acidic solvent, preferably glacial acetic acid, at 0 to 50 ° C, preferably 0 to 25 ° C, then the acid addition salt of the compound of formula I is isolated by addition water to the reaction mixture, the product is extracted with a chlorinated hydrocarbon, and treated with the corresponding acid. 2. A process according to claim 1 wherein the addition salt is extracted with chloroform or methylene chloride.