FI61474B - FAR OIL FRAMSTAELLNING AV SYRAADDITIONSSALTER AV 3,4-DIACYLOXI-ALPHA - ((METHYLAMINO) -METHYL) -BENYL ALCOHOL - Google Patents

Description

61474

Process for the preparation of acid addition salts of 3,4-diacyloxy-α - ((methylamino) methyl) -benzyl alcohol The present invention relates to a process for the preparation of O-acyl-substituted catecholamine derivatives, namely 3,4-diacyloxy-α - ((methylamino) methyl) benzyl alcohol of the formula RI-O (I)

«Y ~ \? H

R-C-O- (fx-ch-ch2-nh-ch3 wherein R is alkyl or aralkyl, preferably tert-butyl-10 / l) for its preparation and isolation as its acid addition salt, preferably the hydrochloride.

The compounds according to the invention are known for their sympathomimetic properties and have been used successfully e.g. for the treatment of glaucoma. The long-term effect of said compounds compared to the corresponding 3,4-dihydroxy compound, i.e. adrenaline, is based on the literature for O-acyl protection, which in the case of adrenaline prevents very rapid oxidation in the body to ineffective compounds.

Despite the protection of the reactive groups, the acyl compounds of the formula I are unstable under temporal conditions because the hydrolysis of the acyloxy groups is immediately followed by the formation of oxidation products. In acidic solutions, on the other hand, these compounds are relatively stable. For the reasons described above, the amines of formula I cannot be isolated by conventional methods used in the preparation of amines.

The processes for the preparation of the compounds of the formula I described in the literature treat the ortho-diacylated catecholamines as salts in alcohol-type solvents, such as methanol or ethanol, without the harmful phenomena described above. In U.S. Patent Nos. 3,809,714 and 4,035,405, a compound of this type is prepared from a compound 9 of formula II containing the keto function, R-C-0.

"(II> RCO - (/> -C-CH2-NH-CH3 where R is as defined above, from the hydrochloride salt by catalytic pressure hydrogenation in methanol or ethanol in the presence of a platinum oxide catalyst. The product is isolated in the usual manner by filtering off the catalyst from the reaction mixture, evaporating the solvent and evaporating the solvent. a salt of a compound of formula I from a suitable solvent mixture.

In FI patent publication 55,988 a compound of formula I is prepared by reducing a compound of formula III

R-K

R-c-o ^ h \ (III) + ° c * H2 \ / R-C-O y-C-CH2-N-CH3 \ = / wherein R is as defined above, by catalytic hydrogenation in an aqueous solvent with palladium on activated carbon acting as a catalyst.

However, these known methods are cumbersome because catalytic hydrogenation requires the use of pressure vessels. In addition, catalytic hydrogenation always involves a substantial risk of spontaneous combustion.

Process for the preparation of compounds of formula I according to the invention is characterized in that the acid addition salt of the above compound of formula II is reduced with sodium or potassium borohydride in an acidic solvent, preferably acetic acid, and the acid addition salt of the compound of formula I is isolated by adding water to the reaction mixture. said salt to a chlorinated hydrocarbon.

The reduction according to the invention can simply be carried out under normal conditions and using normal vessels, thus avoiding the above-mentioned disadvantages associated with catalytic hydrogenation.

The reducing effect of the reducing agent depends on the solvent, as a result of which the choice of a suitable solvent in the reduction is important, and glacial acetic acid has proved to be a particularly preferred solvent.

The isolation of the reaction product, on the other hand, is based on the surprising finding that the acid addition salts of the amine of formula I can be easily extracted from their aqueous solutions into chlorinated hydrocarbons such as chloroform or methylene chloride. The higher the group R, the better the solubility of the product in chlorinated carbon-20 hydrogens.

According to a preferred embodiment of the invention, a compound of formula I is prepared by reducing the hydrochloride salt of an amine of formula II with sodium borohydride in acetic acid at a temperature of 0-50 ° C and a reaction time of 1-2 hours. Particularly preferably, the reaction is carried out at or below room temperature (0-25 ° C), whereby the exotherm of the reaction requires cooling.

The reaction product is isolated by adding water to the reaction mixture, after which the hydrochloride salt of the product amine of formula I is extracted, for example into chloroform. The optional acetic acid is washed from chloroform with, for example, sodium bicarbonate solution, after which the chloroform phase is treated with dilute hydrochloric acid. Evaporation of the chloroform gives the hydrochloride of the compound of formula I, which can be crystallized from a suitable solvent mixture.

The starting compound of formula II can be prepared from 4,61474 adrenalone in a manner known in the literature, for example as described in U.S. Patents 3,809,714 and 4,035,405.

The following embodiment illustrates the invention.

5 Example:

Dissolve 7.7 g (0.02 mol) of dipivaloyl adrenalone hydrochloride in 50 ml of acetic acid at room temperature. The reaction mixture is added with cooling and stirring over a half hour 2.5 g of sodium borohydride.

The reaction mixture is stirred in an ice-water bath for a further hour, after which 150 ml of water are carefully added to the mixture. The progress of the reaction can be monitored by thin layer chromatography using a mixture of CH 2 NO 3, isopropanol, NH 3 (95%) - (12: 3: 1). The aqueous solution is extracted with 3 x 50 ml of chloro-15 form, then the chloroform solution is washed with 50 ml of concentrated NaHCO 3 solution, 50 ml of 2N hydrochloric acid and 50 ml of water. The chloroform solution is dried and evaporated to dryness and the residue, 7.0 g, is crystallized from acetone-hexane. Yield 5.5 g (71%) of dipivaloyl adrena-20 line hydrochloride, m.p. 158.5-160 ° C (letter 159-160 ° C), titrimetrically determined purity 99.9%.

Claims (7)

61474 Claims; A process for the preparation of 3,4-diacyloxy-α-Z-methylamino) -methyl-7-benzyl alcohol of the formula? RC-O (I) Ϊ f ~ \? H Rco— (fy-ch-ch2-nh-ch3 where R is alkyl or aralkyl) for its preparation and isolation as its acid addition salt, characterized in that the corresponding keto-functional amine which formula is RC-O-R (II) RC-O-VC-CH2-NH-CH3 wherein R is as defined above, the acid addition salt is reduced with sodium or potassium borohydride in an acidic solvent, preferably acetic acid, and the resulting formula I The acid addition salt of the compound of the invention is isolated by adding water to the reaction mixture and extracting said salt with a chlorinated hydrocarbon. Process according to Claim 1, characterized in that its hydrochloride is used as the acid addition salt of the amine of the formula II. Process according to Claim 1 or 2, characterized in that chloroform or methylene chloride is used as the chlorinated hydrocarbon. Process according to one of Claims 1 to 3, characterized in that glacial acetic acid and a reaction temperature of 0 to 50 ° C, preferably 0 to 25 ° C, are used as solvents in the reduction. Process according to Claim 2, characterized in that the chlorinated hydrocarbon solution obtained after extraction is first washed with a basic solution and then treated with dilute hydrochloric acid. A process for the preparation and isolation of 3,4-10 diacyloxy-α- (7-methylamino) -methyl-7-benzyl alcohol with the formula R-Lo (I) S //? H Rco— (f Λ-ch-ch2-nh-ch3) i is selected from the group consisting of alkyl or aralkyl, i form av sitt syra-additionssalt, kännetecknat därav, att ett syra-additionssalt av motsvarande, en keto-function inne-15 hällande Amin med formuleln 9 * ~ c ~ ° \ _v n (II) H // \? RC-0 — V \\ - C-CH2-NH-CH3