NO165918B - PROCEDURE FOR THE PREPARATION OF A BENZAMIDE DERIVATIVE AND BENZAMID INTERMEDIATE PRODUCT. - Google Patents

Description

The present invention relates to a method for producing a benzamide derivative. More specifically, the invention relates to a new and improved process for the production of 2-hydroxy-5-£1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide and pharmaceutically acceptable acid addition salts thereof.

It is known that 2-hydroxy-5-{.1-hydroxy-2-[ (1-methyl-S-phenylpropyl)-amino]-ethyl)-benzamide is a useful and widely used α- and β-blocking hypotensive agent .

Within the state of the art, a number of procedures for the production of 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide have been described. According to DOS 2 032 642, 2-hydroxy-5-acetylbenzamide is brominated, the iu-bromoacetyl derivative thus obtained is reacted with N-benzyl-N-(1-methyl-3-phenylpropyl)-amine, and the keto group in 2-hydroxy-5-[ 2-[N-benzyl-N-(1-methyl-3-phenylpropyl)-amino]-acetyl}-benzamide is reduced by catalytic hydrogenation while the protecting N-benzyl group is split to form 2-hydroxy-5-{l -hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide.

The disadvantage of this method is that the final product is obtained by means of a synthesis which comprises many steps and in low yields. Furthermore, the N-benzyl-N-(1-methyl-S-phenyl-propyl)-amine component can only be prepared by a multi-step synthesis in a complicated manner.

According to another method described in DOS 2 032 64 2, 2-hydroxy-5-(bromoacetyl)-benzamide is reacted with N,N-dibenzyl-amine, and the obtained 2-hydroxy-5-(N,N-dibenzylglycyl)- benzamide of formula is reacted with 1-phenyl-3-butanone under reducing conditions. The yields obtained are medium. A further disadvantage of this method consists in the fact that 1-phenyl-3-butanone is not available on an industrial scale, and within the state of the art no industrial production process for the specified compound has been described.

According to a further method described in specified

DOS, 5-(2-amino-1-hydroxyethyl)-salicylamide is reacted with 1-phenyl-3-butanone in ethanolic solution under reducing conditions to form the desired compound 2-hydroxy-5-$1-hydroxy-2-[ (1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide.

In the corresponding example, however, no dividend is specified. A disadvantage of this method is, as previously indicated, that the 1-phenyl-3-butanone starting material is not available on an industrial scale.

In Belgian patent document 840 779 and DOS 2 616 403, a method for the preparation and separation of diastereoisomers of 2-hydroxy-5-L1-hydroxy-2-f(1-methyl-3-phenylpropyl)-amino]-ethyl} is described -benzamide. In the methods described there, as a result of the formation of the chiral center, the number of reaction steps increases, and the total yield of the synthesis is relatively low.

According to the general formulas stated in Hungarian patent document 165 291, 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl]-benzamide can be prepared by condensing 2 -hydroxy-5-glyoxylylbenzoic acid ester with l-phenyl-3-butylamine, after which the Schiff base thus obtained is subjected to catalytic hydrogenation. In the patent, however, no example is given for the preparation of 2-hydroxy-5-(1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide.

An aim of the invention is to develop a method for the production of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide which eliminates the above-mentioned disadvantages of the known methods which give higher yields, are easily feasible on an industrial scale and which use readily available starting materials.

The invention thus relates to a process for the production of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino}-ethyl^-benzamide of the formula

and pharmaceutically acceptable acid addition salts thereof, which method is characterized in that 2-hydroxy-5--£1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide of formula

is hydrogenated in the presence of a catalyst in an inert organic solvent, and, if desired, that the compound of formula I is converted to a pharmaceutically acceptable acid addition salt.

The reduction of the Schiff base of formula V can be carried out by catalytic hydrogenation. The catalyst used is preferably palladium, platinum, nickel or an Adams catalyst. The catalyst can also be supplied on a carrier (e.g. bone charcoal, barium sulphate). The hydrogenation can be carried out at a temperature between 10 and 40°C, preferably at a temperature of 20-30°C, and under a pressure of 1-10 atm., preferably 2-4 atm. It is particularly advantageous to work at 25°C and under a pressure of 3 atm. The reduction is carried out in an inert organic solvent. An ether (e.g. diethyl ether, dioxane or tetrahydrofuran) or an alcohol (e.g. methanol or ethanol), in particular tetrahydrofuran, is preferably used as the reaction medium. During the course of the reaction, two equivalents of hydrogen are consumed, and both the azomethine bond and the carbon-carbon double bond are saturated. The reaction can be carried out in the presence of a small amount of an organic acid (e.g. glacial acetic acid). The yields obtained are practically theoretical e.

The reaction mixture can be worked up in a known manner. The catalyst is preferably filtered off, and the filtrate is evaporated. The hydrochloride can be isolated by adding anhydrous ethanolic hydrogen chloride or a mixture of concentrated hydrochloric acid and ethanol to the hydrogenated filtrate.

The starting material of formula V is a new compound and can be prepared by reacting 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamide of formula

with 1-phenyl-but-1-en-3-one of formula

The reaction can be carried out in an inert, organic solvent. An ether (e.g. diethylether, dioxane or tetrahydrofuran), alcohol (e.g. methanol or ethanol) or an aromatic hydrocarbon (e.g. benzene, toluene or xylene), in particular tetrahydrofuran, is preferably used as the reaction medium. The reaction can be carried out at a temperature between 25 and 100°C, preferably at a temperature of around 40°C. The reaction can optionally be carried out in the presence of a base (eg triethylamine or morpholine).

The thus obtained compound of formula V can either be isolated or subjected to catalytic hydrogenation in situ without isolation.

According to one embodiment of the method according to the invention, the compound of formula II can be prepared by catalytic hydrogenation of the compound of formula

are used. Preferably, a compound of formula VI is subjected to catalytic hydrogenation, the compound of formula II thus formed is reacted in situ with the compound of formula III, and the compound of formula V thus formed is hydrogenated without isolation.

According to a further embodiment of the method according to the invention, the compound of formula II prepared by catalytic hydrogenation of the compound of formula IV is used. The compound of formula IV is subjected to catalytic hydrogenation, the compound of formula II thus formed is reacted in situ with a compound of formula III, and the compound of formula V formed is hydrogenated without isolation.

The two latter embodiments of the method according to the invention can preferably be carried out at an elevated temperature, preferably at 50-70°C and a pressure of between 1 and 100 atm, preferably under a pressure of around 50 atm. The reaction can be carried out in an inert organic solvent. An alcohol (e.g. methanol or ethanol) can preferably be used as the reaction medium. The reaction mixture may also contain an acid (e.g. acetic acid). Palladium, platinum, nickel or Adams catalyst can be used as a catalyst. The catalyst can be supplied on a carrier, e.g. bone charcoal, barium sulphate etc, if desired.

The main advantage of the method according to the invention is that the starting materials used for the preparation of the compound of formula V can be produced from materials (e.g. benzalacetone) which are readily available on an industrial scale, the process is easily feasible and economical on an industrial scale, and high yields are achieved .

Without limiting the scope of the invention by theoretical considerations, it is assumed that this is due to the fact that, due to conjugation, the keto group of 1-phenyl-but-1-en-3-one (benzalacetone) used in the method according to the invention is more reactive than the keto group of 1-phenyl-butan-3-one used in the method described in DOS 2 032 64 2. For this reason, the compound of formula III reacts with 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamide of formula II while forming the corresponding 2-hydroxy-5-^1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl]-benzamide much more easily than the corresponding intermediate which is formed by the method described in DOS 2 032 642, namely 2-hydroxy-5-{_1-hydroxy-2-[(1-phenyl-but-3-ylidene)-imino]-ethyl}-benzamide or 2-hydroxy- 5-{1-keto-2-[(1-phenyl-but-3-ylidene)-imino]-ethyl}-benzamide.

The invention is further illustrated in the following examples.

Example 1

Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene n-3-ylidene)-amino]-ethyl)-benzamide

2.30 g (10 millimoles) of 2-hydroxy-5-(1-hydroxy-2-amino-ethyl)-benzamide hydrochloride and 1.46 g (10 millimoles) of 1-phenyl-but-l-ene-3- was mixed with 10 ml of tetrahydrofuran, whereupon

with further stirring and ice cooling, 1.20 ml of triethylamine was added dropwise at a temperature of 10-15°C.

When the addition was complete, the reaction mixture was stirred at room temperature for an additional 5 hours, and the precipitated triethylamine hydrochloride was filtered off. From the filtrate, 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide was isolated by column chromatography on silica gel. 1.56 g of the desired compound were thus obtained, yield 48%, m.p. 142-146°C.

Example 2

Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide

2.30 g (10 millimoles) of 2-hydroxy-5-(1-hydroxy-2-amino-ethyl)-benzamide hydrochloride and 1.46 g (10 millimoles) of 1-phenyl-but-l-ene-3- was mixed with 10 ml of tetrahydrofuran, after which 4 ml of morpholine was added dropwise at a temperature of 10-15°C while stirring and cooling with ice. The reaction mixture was stirred at room temperature for an additional 5 hours, the precipitated morpholine hydrochloride was filtered off, and the filtrate was heated to boiling for 3 hours. From the filtrate, the desired compound was isolated by column chromatography on silica gel. 2.05 g of the desired compound were thus obtained, yield 63%, mp: 142-145°C.

Example 3

Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino]-ethyl}-benzamide hydrochloride

3.24 g (10 millimoles) of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide prepared according to Example 1 or 2, was dissolved in 25 ml of tetrahydrofuran, whereupon 0.5 g of 10% palladium-on-carbon catalyst was added, and the mixture was hydrogenated at a temperature of 25°C under a pressure of 3 atm. When the reduction was finished, the catalyst was filtered off, and 5 ml of ethanol containing 20% hydrochloric acid was added to the filtrate. The precipitated white crystals were filtered off and washed with ethanol. 3.46 g of the desired compound were thus obtained, yield 95%,

m.p. 188-189°C.

Example 4

Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino]-ethyl)-benzamide hydrochloride

To a solution of 3.74 g (10 millimoles) of 2-hydroxy-5-(N,N-dibenzylglycyl)-benzamide, 1.46 g (10 millimoles) of 1-phenyl-but-l-en-3-one and 50 ml of methanol was added to 1.0 ml of glacial acetic acid, 1.0 g of 10% palladium-on-carbon catalyst and 0.1 g of platinum oxide (Adams catalyst). The reaction mixture was hydrogenated at a temperature of 60°C and under a pressure of 50 atm. The catalyst was filtered off and the filtrate was evaporated to a small volume. 3 ml of propanol saturated with hydrogen chloride and 5 ml of ethyl acetate were added to the residue. On standing, crystals were separated which were filtered off and washed. 2.62 g of the desired compound were thus obtained with a yield of 72%, m.p. 187-190°C.

Example 5

Preparation of 2-hydroxy-5-£1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino]-ethyl)-benzamide hydrochloride

To a solution of 3.76 g (10 millimoles) of 2-hydroxy-5-[1-hydroxy-2-(dlbenzylamino)-ethyl]-benzamide and 1.46 g

(10 millimoles) of 1-phenyl-but-1-en-3-one in 50 ml of methanol was added 1.0 ml of glacial acetic acid, 1.0 g of a 10% palladium-o-carbon catalyst and 0.1 g of platinum oxide (Adams catalyst), and the reaction mixture was hydrogenated at a temperature of 60°C

and under a pressure of 50 atm. The react ion mixture..jle up the work, and the product was isolated as described in example 4. 2.77 g of the desired product were thus obtained, yield 76%, m.p. 188-189°C.

Claims (8)

1. Process for the preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide of formula and pharmaceutically acceptable acid addition salts thereof, characterized in that 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide of formula is hydrogenated in the presence of a catalyst in an inert organic solvent, and, if desired, that the compound of formula I is converted into a pharmaceutically acceptable acid addition salt. 2. Method according to claim 1, characterized in that a palladium, platinum or nickel catalyst or a mixture thereof is used as catalyst. 3. Method according to any one of claims 1 to 2, characterized in that the reaction is carried out at a temperature between 10 and 40°C, preferably at a temperature of 20 to 30°C, and under a pressure of 1 to 10 atm , preferably 2 to 4 atm. 4. Method according to claim 1, characterized in that a compound of formula V prepared by reacting 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamide of formula is used as starting material with 1-phenyl-but-1-en-3-one of formula 5. Method according to claim 4, characterized in that an ether, alcohol or aromatic hydrocarbon is used as solvent. 6. Process according to claim 1 or 4, characterized in that 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamide of formula II prepared in situ by catalytic hydrogenation of 2-hydroxy-5-[l- hydroxy-2-(N,N-dibenzylamino)-ethyl]-benzamide of "ormel wherein the compound of formula II is reacted without isolation in situ with the compound of formula III, and that the thus obtained compound of formula V is hydrogenated in situ without isolation. 7. Process according to claim 1 or 4, characterized in that 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamide of formula II produced in situ by catalytic hydrogenation of 2-hydroxy-5-(N, N-dibenzylglycyl)-benzamide of formula (IV), wherein the compound of formula II is reacted without isolation in situ with the compound of formula III, and that the thus formed compound of formula V is subjected to hydrogenation in situ without isolation. 8 . 2-hydroxy-5-(1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl)-benzamide, characterized in that it has a structural formula