FI83635B - FOERFARANDE FOER FRAMSTAELLNING AV 2 -HYDROXI-5 1-HYDROXI-2 - / (1-METHYL-3-PHENYLPROPYL) -AMINO / EECL BENZENIDE OCH DESS PHARMACEUTICAL LAMP WITH SYRAADDITIONSSALT. - Google Patents

Description

83635

This invention relates to the preparation of benzamide derivatives, and more particularly to the preparation of benzamide derivatives, and in particular to the preparation of 2-hydroxy-5- {1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl) benzamide and its pharmaceutically acceptable acid addition salts. a new and improved process for the preparation of 2-hydroxy-5- {1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl) benzamide and its pharmaceutically acceptable acid addition salts.

It is known that 2-hydroxy-5- (1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl) benzamide is a useful and widely used alpha- and beta-blocking hypotensive agent.

Several methods for preparing 2-hydroxy-5- {1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl} benzamide have been described in the prior art. According to DOS No. 2,032,642, 2-hydroxy-5-acetylbenzamide is brominated, the ω-bromoacetyl derivative thus obtained is reacted with N-benzyl-N- (1-methyl-3-phenylpropyl) amine and 2-hydroxy-5 - The keto group of {2- [N-benzyl-N- (1-methyl-3-phenylpropyl) amino] acetyl) benzamide is reduced by catalytic hydrogenation while the N-benzyl protecting group is cleaved to give 2- hydroxy-5- {l-hydroxy-2- [l-methyl-3-phenylpropyl) amino] ethyl) benzamide.

The disadvantage of this method is that the final product is obtained by multi-step synthesis and in low yields. In addition, the N-benzyl-N- (1-methyl-3-phenylpropyl) amine component can also be prepared only in a multi-step synthesis in a complex manner.

According to another method disclosed in DOS No. 2,032,642, 2-hydroxy-5- (bromoacetyl) benzamide is reacted with Ν, Ν-dibenzylamine to give the formula 2,83635

R 1 -O 1 M

HO - (/ \ y- CO - CH0 - N, -V

2-Hydroxy-5- (Ν, Ν-dibenzylglycyl) -benzamide according to N = α-O is reacted with 1-phenyl-butan-3-one under reducing conditions. Average yields are obtained. Another disadvantage of this process is that phenyl-3-butanone is not available on an industrial scale and no economic industrial process for the preparation of said compound has been disclosed in the prior art.

According to another method of said DOS publication, 5- (2-amino-1-hydroxyethyl) salicylamide is reacted with 1-phenyl-3-butanone in ethanolic solution under reducing conditions to give the desired compound 2-hydroxy-5- {1-hydroxy- 2 - [(1-Methyl-3-phenylpropyl) -aminoethyl] -benzamide.

However, no yield is shown in the corresponding example. The disadvantage of this process is, as already mentioned above, that the 1-phenyl-3-butanone starting material is not available on an industrial scale.

BE Patent 840,779 and DOS No. 2,616,403 disclose a process for the preparation and separation of diastereomers of 2-hydroxy-5- [1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] benzamide. In the presented methods, due to the formation of the chirality center, the number of reaction steps increases and the overall yield of the synthesis is rather low.

According to the general formulas of HU Patent 165,291, 2-hydroxy-5- {1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] -benzamide can be prepared by condensing 2-hydroxy-5-3,83635 glyoxyllyl benzoic acid ester 1- with phenyl-3-butylaraine and subjecting the Schiff's base thus obtained to catalytic hydrogenation. However, the patent does not disclose an example for the preparation of 2-hydroxy-5- {{1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl} benzamide.

It is an object of the present invention to provide a process for the preparation of 2-hydroxy-5- [1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] benzamide, which eliminates the above-mentioned disadvantages of the known processes, provides higher yields, is easily feasible in industrial-scale production and using readily available starting materials.

It is found that the formula \ 2 (I) HO - / f \ -CH - CH0 \ = / I | 2-Hydroxy-5- 5-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl} benzamide of / CH3 OH NH-CHra can be prepared in a simpler and more economical manner by the formula COHHg HO- $ '' v -OH - CH, (ι (V).

\ = / I I / 3 _

° H N = C

CH = CH - (f-2-hydroxy-5- [1-hydroxy-2 - [(1-phenyl-but-1-en-3-ylidene) imino] ethyl) -benzamide.

4,83635

According to the present invention there is provided a process for the preparation of 2-hydroxy-5- {1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl} benzamide of formula I and pharmaceutically acceptable acid addition salts thereof, which comprises hydrogenating 2-Hydroxy-5- {1-hydroxy-2 - [(1-phenyl-but-1-en-3-ylidene) imino] ethyl} benzamide and, if desired, converting the compound of formula I thus obtained into a pharmaceutically acceptable acid addition salt .

More specifically, the invention is characterized by what is set forth in the characterizing part of claim 1.

The reduction of the Schiff's base of formula V can be performed by catalytic hydrogenation. As the catalyst, palladium, platinum, nickel or Adams catalyst (a mixture of palladium and platinum) can be preferably used. The catalyst may also be applied to a support (e.g. carbon, barium sulfate). The hydrogenation can be carried out at a temperature of 10 to 40 ° C, preferably at a temperature of about 20 to 30 ° C and a pressure of 1 to 10 atmospheres, preferably a pressure of 2 to 4 atmospheres. It is very advantageous to work at 25eC and 3 atmospheres. The reduction can be performed in an inert organic solvent. As the reaction medium, ether (e.g. diethyl ether, dioxane or tetrahydrofuran) or an alcohol (e.g. methanol or ethanol), especially tetrahydrofuran, can be preferably used. During the reaction, two equivalents of hydrogen are consumed and both the azomethane bond and the carbon-carbon double bond are saturated. The reaction may be carried out in the presence of a small amount of an organic acid (e.g. glacial acetic acid). The yields obtained are almost theoretical.

The reaction mixture can be finished by methods known per se. Preferably, the catalyst is 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.

5,83635

The starting material of formula v is a novel compound and can be prepared by reacting a 2-hydroxy-5- (1-hydroxy-2-aminoethyl) benzamide of the formula CONHo (UI) HO-f 7 'CH - CH 5 WI 12 OH NH 2 with the formula r with 1-phenyl-but-1-en-3-one according to N-phenyl-CH = CH-COCH.

The reaction can be carried out in an inert organic solvent. The reaction medium used is preferably an ether (e.g. diethyl ether, dioxane or tetrahydrofuran), an alcohol (e.g. methanol or ethanol) or an aromatic dehydrogen (e.g. benzene, toluene or xylene), especially tetrahydrofuran. The reaction can be carried out at a temperature of 25 to 100 ° C, preferably at a temperature of about 40 ° C. The reaction may optionally be carried out in the presence of a base (e.g. triethylamine or morpholine).

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

According to one embodiment of the process of the present invention, a compound of formula II prepared by catalytic hydrogenation of the formula 6,83635 (™ 2 / - \ HO ~ f \ - CH - CH 2 - N 2) = / (VI) ~ OH Nch 2 - 2 is used. compound. Preferably, work is carried out by subjecting the compound of formula VI to catalytic hydrogenation, reacting the compound of formula II thus formed in situ with the compound of formula III and hydrogenating the compound of formula V thus formed without isolation.

According to one embodiment of the process of the present invention, a compound of formula II prepared by catalytic hydrogenation of a compound of formula IV is used. Preferably, the compound of formula IV 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.

The latter two embodiments of the process of the present invention may be carried out preferably at elevated temperature, preferably at 50 to 70 ° C and at a pressure of 1 to 100 atmospheres, preferably about 50 atmospheres. The reaction can be carried out in an inert organic solvent. Alcohol (e.g. methanol or ethanol) can be preferably used as the reaction medium. The reaction mixture may also contain an acid (e.g. glacial acetic acid). Palladium, platinum, nickel or an Adams catalyst can be used as the catalyst. The catalyst may be applied, if desired, to a support, e.g. carbon, barium sulfate, etc.

The main advantage of the process according to the present invention is that the starting materials used for the preparation of the compound of formula V can be prepared from substances (e.g. benzalacetone) which are also readily available on an industrial scale and the yields are high.

Without limiting the scope of the invention to theoretical ideas, we assume 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 process of the present invention is more reactive than in DOS No. 2,032,642 the keto group of 1-phenyl-butan-3-one used in the method shown. Therefore, the compound of formula III reacts with 2-hydroxy-5- (1-hydroxy-2-aminoethyl) benzamide of formula II to give the corresponding 2-hydroxy-5- {1-hydroxy-2 - [(1 -phenyl-but-1-en-3-ylidene) imino] ethyl} benzamide is much more readily formed than the corresponding intermediate in the process described in DOS No. 2,032,642, namely 2-hydroxy-5 - {1-hydroxy-2- [(1-Phenyl-but-3-yl-diene) -imino] -ethyl} -benzamide or 2-hydroxy-5- (1-phenyl-but-3-ylidene) -imino] -ethyl} -benzamide.

The details of the method according to the invention will become apparent from the following examples without limiting the scope of protection to said examples.

Example 1 Preparation of 2-hydroxy-5- {1-hydroxy-2 - [(1-phenyl-but-1-en-3-ylidene) amino] ethyl} benzamide 2.30 g (10 mmol) of 2-hydroxy-5 - (1-hydroxy-2-arino-ethyl) benzamide hydrochloride and 1.46 g (10 mmol) of 1-phenyl-but-1-en-3-one are mixed with 10 ml of tetrahydrofuran, followed by further stirring and under ice-cooling, 1.20 ml of triethylamine are added dropwise at a temperature of 10 to 15 ° C. When the addition is complete, the reaction mixture is stirred at room temperature for a further 5 hours and the precipitated triethylamine hydrochloride is filtered off. 2-Hydroxy-5- [1-hydroxy-2 - [(1-phenyl-but-1-en-3-ylidene) imino] ethyl} benzamide is separated from the filtrate by column chromatography on 8,83635 silica gel. 1.56 g of the desired compound are 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 mmol) of 2-hydroxy-5- ( 1-hydroxy-2-aminoethyl) benzamide hydrochloride and 1.46 g (10 mmol) of 1-phenyl-but-1-en-3-one are mixed with 10 ml of tetrahydrofuran, followed by further stirring and ice-cooling. 4 ml of morpholine are added dropwise at a temperature of 10 to 15 ° C. The reaction mixture is stirred at room temperature for a further 5 hours, the precipitated morpholine hydrochloride is filtered off and the filtrate is heated to boiling for 3 hours. The desired compound is isolated from the filtrate by column chromatography on silica gel. 2.05 g of the desired compound are thus obtained, yield 63 *. M.p .: 142-145 ° C.

Example 3 Preparation of 2-hydroxy-5- {1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] benzamide hydrochloride 3.24 g (10 mmol) of 2-hydroxy-5- {1-hydroxy 2 - [(1-Phenyl-but-1-en-3-ylidene) imino] ethyl] benzamide prepared according to Example 1 or 2 is dissolved in 25 ml of tetrahydrofuran, followed by the addition of 0.5 g of 10i palladium. -carbon catalyst and the mixture is hydrogenated at 25 ° C at 3 atmospheres. When the reduction is complete, the catalyst is filtered off and into the filtrate. . 5 ml of ethanol containing 20 * of hydrochloric acid are added.

The precipitated white crystals are filtered off and washed with ethanol. 3.46 g of the desired compound are thus obtained, yield 95 *. mp: 188-189 ° C.

9 83635

Example 4 Preparation of 2-hydroxy-5- [1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] benzamide hydrochloride

To a solution of 3> 74 g (10 mmol) of 2-hydroxy-5- (N, N-dibenzylglycyl) benzamide, 1.46 g (10 mmol of α-1-phenyl-but-1-en-3-one) and 50 ml of methanol are added 1.0. ml of glacial acetic acid, 1.0 g of 10% palladium-on-carbon catalyst and 0.1 g of platinum oxide (Adaras catalyst). The reaction mixture is hydrogenated at 60 ° C and 50 atmospheres. The catalyst is filtered off and the filtrate is evaporated to a small volume. To the residue are added 3 ml of propanol saturated with hydrogen chloride and 5 ml of ethyl acetate. When left to stand, crystals precipitate and are filtered off and washed. 2.62 g of the desired compound are thus obtained, yield: 72 °, m.p .: 187-190 ° C.

Example 5 Preparation of 2-hydroxy-5- {N-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl] benzamide hydrochloride

To a solution of 3 to 76 g (10 mmol) of 2-hydroxy-5- [1-hydroxy-2- (dibenzylamino) ethyl] benzamide and 1.46 g (10 mmol) of 1-phenyl-but-1-ene- 3-one in 50 ml of methanol, 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) are added and the reaction mixture is hydrogenated at 60 ° C and At 50 atmospheres. The reaction mixture is finished and the product is isolated according to Example 4. 2.77 g of the desired product are thus obtained, yield 76 h, m.p .: 188-189 ° C.

Claims (6)

A process for the preparation of 2-hydroxy-5- {1-hydroxy-2 - [(1-methyl-3-phenylpropyl) amino] ethyl} benzamide of Formula I CONHO (I> HO - # 'V-CH - CH , C „Λ = / I OH / / OH OH HH - CH₂ - CH₂— / and pharmaceutically acceptable acid addition salts thereof, characterized in that 2-hydroxy-5- (1-hydroxy-2-aminoethyl) benzamide of formula II Y is reacted in an inert organic solvent with 1-phenyl-but-1-en-3-one of formula IIIa (III) CH * CH - COCH the obtained compound 2-hydroxy-5- {1-hydroxy-2 - [(1-phenyl-but-1-en-3-ylidene) imino] ethyl} benzamide of the formula V14436 CONH.) ~ Λ (v) "Ό ~ γγ · x"> ", -c is hydrogenated in the presence of a catalyst and at a temperature ρά between 10 - 40 ° C, preferably at a temperature of 20 - 30 ° C under a pressure of about 1 - 10 atmospheres, preferably 2 -4 atmospheres and, if desired, the recovered compound of formula I is transferred into a pharmaceutically acceptable oxygen addition salt. Process according to Claim 1, characterized in that palladium or mixture of palladium and platinum is used as catalyst. Process according to claim 1, characterized in that the reaction between the compounds of formulas II and III is carried out in an ether, preferably tetrahydrofuran. Process according to claim 1, characterized in that 2-hydroxy-5- (1-hydroxy-2-aminoethyl) -benzamide of the formula II is prepared in situ by catalytic hydrogenation of 2-hydroxy-5- [1-hydroxy-benzamide]. 2 (N, N-dibenzylamino) -ethyl] benzamide of the formula VI A / - -OH ° \ / ~ CH - CH- - N r.-λ ίνχ) reacts with the compound of formula II without isolation in situ Formula III and subject to the acid-poured compound of Formula V hydrogenation without isolation In situ. Process according to claim 1, characterized in that 2-hydroxy-5- (1-hydroxy-2-aminoethyl) benzamide of formula II is prepared in situ by catalytic hydrogenation of 2-hydroxy-5- (N, N dibenzylglycyl) benzamide of formula IV Γ? CH, J ~, reacts the compound of formula II without isolation in situ with the compound of formula III and submits the compound of formula V thus formed with hydrogenation without isolation in situ. 6. 2-Hydroxy-5- {1-hydroxy-2 - [(1-phenyl-but-1-en-3-ylidene) -imino] ethyl} benzamide of the formula V. CONH- \ 2 <v) OH - \ CH - CH_ \ = JII / 3