DD228245A5 - PROCESS FOR PREPARING A BENZAMIDE DERIVATIVE - Google Patents

Abstract

The invention relates to a process for the preparation of 2-hydroxy-5- (1-hydroxy-2- (1-methyl-3-phenyl-propyl-amino) -ethyl) -benzamide of the formula I and its pharmaceutically suitable acid addition salts thereof in that 2-hydroxy-5- (1-hydroxy-2- (1-phenylbut-1-en-3-ylidene-imino) ethyl) benzamide is hydrogenated and the compound of the formula I obtained, if desired, is hydrogenated converted into a pharmaceutically acceptable acid addition salt. The advantage of the process according to the invention is that it can be carried out in an economical manner, with high yields, using starting materials which are readily available even in large amounts. The compound of formula I is a known and valuable a- and b-receptor-blocking hypotensive agent. formula 1

Description

16 280 53

Process for the preparation of a benzamide derivative

Field of application of the invention:

The invention relates to a process for the preparation of a benzamide derivative, namely of 2-hydroxy-5- / ~ 1-hydroxy-2- (1-methyl-3-phenyl-propyl-amino) -ethyl / -benzamide and pharmaceutically suitable Acid addition salts thereof.

characteristics the known technical solutions:

2-Hydroxy-5 - ^ / l -hydroxy-2- (1-phenyl-3-phenyl-propyl-amino) -ethyl / benzyltiide is a valuable and widely used .76 and beta-receptor blocking hypotensive agent ,

Several processes for the preparation of 2-hydroxy-5- / 1-hydroxy-2- (1-methyl-S-phenyl-propyl-amino) -ethyl / -benz3mid are already known. According to DE-OS 2,032,642, 2-hydroxy-5-acetyl-benzamide is brominated, the resulting ui Srom-acetyl derivative with N-benzyl-N- (l-methyl-3-phenyl-propyl) -amin urngesetzt and catalytically hydrogenating the obtained 2-hydroxy-5-f 2 - / - N -benzyl-N- (1-ethyl-3-phenyl-propyl) -amino-7-acetyl-benzamide, thereby reducing the keto group and cleaving off the N-senzyl protecting group becomes. This method has several disadvantages. The final product 2-hydroxy-5-yl-i-hydroxy-2- (1-methyl-3-phenylpropylamino) -

Ethyl 7-benzamide is obtained in many process stages with a low yield. The N-3-benzyl-N- (1-methyl-3-phenyl-propyl) -amine used as starting material can also be prepared only in several steps by a complicated process.

According to another method described in DE-CS 2 032 642, 2-hydroxy-5-bromo-acetyl-benzamide is reacted with N, N-dibenzyl-amine and the resulting 2-hydroxy-5- (N, N-dibenzyl-amine) Glycyl) benzamide of formula IV with 1-phenyl-3-butanone under reductive conditions to the reaction. The yields obtained are mediocre. Another disadvantage of this method is that the l-phenyl-3-butanone used as starting material is not accessible in large quantities. The literature does not describe any process which is also economical in operation for the preparation of this compound.

In DE-OS 2,032,642 a further process for the preparation of 2-9ydroxy-5 - </ l-hydroxy-2- (1-methyl-3-phenylpropylamino) ethyl / benzamide is described. In this method, 5- (2-amino-l-hydroxyethyl) -salicylamid reacted with 1-phenyl-3-butanone in ethanol as a medium under reductive conditions, In the preparation of the compound 2-hydroxy-5- / l-hydroxy-2 - (l-methyl-3-phenyl-propylamino) ethyl / benzamide no yield is given. The disadvantage of this method lies in the use of 1-phenyl-3-butanone (see above).

In BE-PS 840 779 and DE-OS 2 616 403, the preparation and separation of the diastereomers of 2-hydroxy-5 - / _ i-hydroxy-2- (in et hy 1-3-phenyl-p ropy I- amino) ethyl-7-benzamide. According to these methods, as a result of the formation of the chiral center, the number of process steps is increased and the overall yield of the synthesis is reduced.

According dsn in the general formula given in the HU-PS 15b 291 2-γγαι ~ οχγ-5 -, / 1-hydroxy-2- (1-methyl-3-phenyl-propyl-amino) ethyl 7-benzamide by condensation of 2 -Hydroxy-5-glyoxyl-benzoic acid esters and 1-phenyl-3-butyl-amine, and subsequent catalytic hydrogenation of the Schiff's base formed. However, the patent does not contain an example of the preparation of 2-hydroxy-5 -, / - 1-hydroxy-2- (1-methyl-3-phenyl-propylamine.o) ethyl / benzyl chloride.

Aim of the invention:

The aim of the invention is to overcome the above disadvantages of the known methods and to provide a process according to which the 2-hydroxy-5- / 1-hydroxy-2- (1-methyl-3-phenyl-propyl-amino) -ethyl benzamide in high yields, can be prepared in a simple to operate manner using readily available starting materials.

Presentation of the essence is Invention:

It has been found that the 2-hydroxy-5- ^{/: r} l-hydroxy-2- (1-methyl-3-phenyl-propyl-amino) -ethyl / -benzamide from the 2-hydroxy-5 - / _ l Hydroxy-2- (1-phenyl-but-l-en-3-ylidene-imino) ethyl / benzamide of the formula V is easy and economical to produce.

The invention is therefore a method for Her-. Preparation of 2-hydroxy-S- / l-hydroxy-2- (1-methyl-3-phenylpropyl-amino) -ethyl / benzamide of the formula I and eat pharmaceutically acceptable acid addition salts, which is characterized in that the 2- Hydroxy-5- / ~ l-hydroxy-2- (1-phenyl-but-l-en-ylidene-imino) ethyl / benzamide of the formula V is hydrogenated and the resulting compound of formula I.

-A-

if desired, converted into a pharmaceutically acceptable acid addition salt.

The reduction of Schiff's 3ase of Formula V can be accomplished by catalytic hydrogenation. The catalyst used may advantageously be palladium, platinum, nickel or an Adams catalyst. The catalyst can also be applied to a support (eg, carbon, barium sulfate, etc.). The hydrogenation may be at a temperature of 10-40 ⁰ C, preferably at 20-30 C, and under a pressure of 1-10 atm., Preferably at 2-4 atm,.. It is preferably at 25 ⁰ C under a pressure of 3 atm. work. The reduction can be carried out in an inert organic solvent. The reaction medium may preferably ether (eg diethyl ether, dioxane or tetrahydrofuran) or alcohols (eg methanol or ethanol), in particular tetrahydrofuran serve. During hydrogenation, two equivalents of hydrogen are taken up and both the azomethine bond and the carbon-carbon double bond become saturated. The reaction can also be carried out in the presence of a small amount of an organic acid (eg glacial acetic acid). The yield obtained corresponds almost to the theoretical value.

The reaction mixture can be worked up in a manner known per se. The final product can z.3. be isolated by filtering off the catalyst and concentrating the filtrate. The hydrochloride may be isolated by adding to the hydrogenated filtrate anhydrous ethanolic hydrogen chloride or a mixture of concentrated hydrochloric acid and ethanol.

The starting material of the formula V is a new, unknown compound and can be prepared by reacting a 2-hydroxy-5- (1-hydroxy-2-amino-ethyl) -benzamide of the formula II with a

1-phenyl-but-1-en-3-one of formula III. The reaction can be carried out in an inert solvent. As the reaction medium may advantageously ether (eg diethyl ether, dioxane or tetrahydrofuran), alcohols (eg methanol or ethanol) or aromatic hydrocarbons (eg 3enzol, toluene or xylene), in particular tetrahydrofuran serve. The reaction can be carried out at a temperature of 25-100 ⁰ C, preferably at about 40 C. It is possible to work all in the presence of a 3ase (eg triethylamine or morpholine).

The resulting compound of formula V can either be isolated or catalytically hydrogenated in situ without isolation.

According to one embodiment variant of the process according to the invention, use is made of a compound of the formula II which has been prepared by catalytic hydrogenation of a compound of the formula VI.

It is advantageous to proceed by catalytically hydrogenating the compound of the formula VI, reacting the compound of the formula II thus obtained without isolation in situ with the compound of the formula III and hydrogenating the resulting compound of the formula V without isolation in situ.

According to a further embodiment of the process according to the invention, use is made of a compound of the formula II which has been prepared by catalytic hydrogenation of the compound of the formula VI. The procedure may preferably be such that the compound of the formula IV is catalytically hydrogenated, the resulting compound of the formula II is reacted without isolation in situ with the compound of the formula III and the resulting compound of the formula V is hydrogenated in situ without isolation.

-c

The above two embodiments of the method according to the invention can with heating, preferably at a temperature of 50-7O ⁰ C and under a pressure of 1-100 atm., Preferably about 50 atm. To be performed. It is advantageous to work in an inert solvent. The reaction medium can advantageously be alcohols (eg methanol or ethanol). An acid (for example glacial acetic acid) may be added to the reaction mixture. The catalyst used may be, for example, a palladium, nickel or Adams catalyst. The catalyst can also be applied to a support (eg, carbon, barium sulfate, etc.).

The main advantages of the process according to the invention are that the compound of the formula V used as starting material can be prepared from readily available substances (benzalacetone), and the process can also be carried out simply, economically and with high yields during operation.

Without limiting the scope by theoretical considerations, this is apparently attributable to the fact that the keto group of the invention used 1-phenyl-but-l-en-3-one (benzalacetone) of the formula III as a result of the conjugation more reactive than the keto group of the after DE-OS 2 032 642 used l-phenyl-3-butanone.

Accordingly, the compound of formula III reacts with the 2-hydroxy-5- (1-hydroxy-2-amino-ethyl) -benzamide of formula II to give the 2-hydroxy-5 - / _ l -hydroxy-2- (1 -phenylbut-l-en-3-ylidene-imino) ethyl / benzamide of the formula V considerably easier than in the formation of the intermediates of DE-OS 2,032,642 (ie 2-hydroxy-5 - / _ ~ l-hydroxy -2- (1-phenyl-but-3-ylidene-imino) -ethyl / -benzamide or 2-hydroxy-5- / i-keto-2- (1-phenyl-but-3-ylidene-imino) -äthy ! / - benzamide)

EXAMPLES

Further details of the method according to the invention can be found in the following examples, without limiting the scope of protection to these examples.

example 1

Preparation of 2-hydroxy-5- (1-hydroxy-2- (1-phenyl-3-ylidene-imino) -thyl) -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-phenylbut-1-en-3-one mixed with 10 ml of tetrahydrofuran, followed by dropwise addition to the reaction mixture with stirring and ice cooling at a temperature of 10-15 C, 1.20 ml of triethylamine. After completion of the addition, stirring is continued at room temperature for five hours. The precipitated triethylamine hydrochloride is filtered and the desired product is isolated from the filtrate by chromatography on a silica gel column. There are obtained 1.56 g of the title compound.

Yield: 48%, m.p .: 142-146 ⁰ C.

Example 2

Preparation of 2-hydroxy-5- / ~ 1-hydroxy-2- (1-phenyl-but-len-3-yl ide n-imo) -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-phenylbut-1-en-3-one with 10 ml of tetrahydrofuran, whereupon 4 ml of morpholine are added dropwise with further stirring and ice cooling at a temperature of 10-15 ° C.

-S

will give. The Reaktionsgemisc'n is stirred at R a to t em pe temperature for 5 hours, filtered, the precipitated morpholine hydrochloride and the filtrate was heated to boiling for 3 hours. The desired product is isolated from the filtrate by chromatography on a silica gel column. There are obtained 2.05 g of the titled compound.

Yield: 63 %, mp .: 142-145 ° C.

Example 3

Preparation of 2-hydroxy-5 -, / 1-hydroxy-2- (1-methyl-2-phenyl-propyl-amino) -ethyl / -benzamide hydrochloride

3.24 g (10 millimoles) of 2-hydroxy-5- ^ 1-hydroxy-2- (1-phenylbut-1-en-3-ylidenimino) ethyl / benzamide prepared according to Example 1 or 2 are dissolved in Dissolved 25 ml of tetrahydrofuran, whereupon 0.5 g of a 10% palladium-carbon catalyst are added and the mixture at a temperature of 25 C under a pressure of 3 atm. is hydrogenated. After completion of the reduction, the catalyst is filtered off. To the filtrate is added 5 ml of 20 % hydrochloric acid-containing ethanol. The precipitated white crystals are filtered and washed with ethanol. There are obtained 3.46 g of the titled compound.

Yield: 95 %, mp .: 188-189 ° C.

Example 4

Preparation of 2-hydroxy-5- / 1-hydroxy-2- (1-methyl-3-phenyl-propyl-amino) -ethyl-7-benzamide hydrochloride

To a solution of 3.74 g (10.0 millimoles) of 2-hydroxy-5- (N, N-dibenzyl-glycyl) -benzamide and 1.45 g (10.0 millimoles) of 1-phenyl-but-1-ene To 1 ml of glacial acetic acid, 1.0 g of a 10 g palladium-carbon catalyst and 0.1 g of a platinum oxide (Adam) catalyst are added to 3-one in 50 ml of methanol. The mixture is heated at 60 C under a pressure of 50 atm. hydrogenated. The catalyst is filtered off and the filtrate is concentrated to a small volume. To the residue is added 3 ml of hydrochloric acid-saturated propanol and 5 ml of ethyl acetate. The mixture is allowed to stand, the precipitated crystals are filtered and washed. 2.62 g of the title compound are obtained.

Yield: 72 %, mp .: 137-190 ⁰ C.

Example 5

Preparation of 2-hydroxy-5- / 1-i-hydroxy-2- (1-methyl-3-phenyl-propyl-amino) -ethyl / -benzamide hydrochloride

To a solution of 3.76 g (10.0 millimoles) of 2-hydroxy-5- / ~ lhydroxy-2- (dibenzylamino) -ethyl / -benzamide, 1.46 g (10.0 millimoles) of 1-phenyl- but-l-en-3-one and 50 ml of methanol are added 1.0 ml of glacial acetic acid, 1.0 g of a 10% palladium-carbon catalyst and 0.1 g of a platinum oxide (Adams) catalyst. The mixture is at 6O ⁰ C under a pressure of 50 atm. hydrogenated. The reaction mixture is worked up in the manner described in Example 4.

- 10 -

There are obtained 2.77 g of the title compound. , ''

Yield: 76% m.p .: 183-189 ⁰ C.

- 11 -

- 13 -

CH - CH.

OH NH CH

CONH ₂

.CH.

CH ₂ - CH

CH CH.

OH NH ₂ IE

CH = CH - COCH ₃

CONH ₂

CH-

CO-CH ₂ - N

CONH,

CH - CH,

OH N = C CH CH = CH

CONH

CH - CH ₂ - N

OH

CH,

Claims (10)

Claims: 1. Process for the preparation of 2-hydroxy-5 -, / l-hydroxy-2 (1-methyl-3-phenyl-propyl-amino) -ethyl-benzamide of the formula I and of its pharmaceutically acceptable acid addition salts, characterized in that a 2-hydroxy-5- / -l-hydroxy-2- (l- phenyl-but-1-en-3-ylidene-imino) ethylbenzamide of the formula V is hydrogenated and the compound of formula I thus obtained, if desired, converted into a pharmaceutically acceptable acid addition salt. 2. The method according to claim 1, characterized in that one carries out the hydrogenation in the presence of a catalyst. 3. The method according to claim 2, characterized in that one comprises a palladium, platinum or nickel catalyst or a
Mixture of it used. 4. The method according to any one of claims 1 to 3, characterized in that one carries out the reaction in the presence of an inert organic solvent. 5. The method according to claim 4, characterized in that one uses an ether or alcohol as a solvent. 6. The method according to any one of claims 1 to 5, characterized in that the reaction at a temperature of 10 to 40 ⁰ C - preferably from 20 ⁰ C and 30 ⁰ C and under a
Pressure of 1-10 atm. preferably from 2-4 atm. performs. 7. The method according to claim 1, characterized in that the starting material used is a compound of formula V,
obtained by reaction of 2-hydroxy-5- (l-hydroxy-2-aminoethyl) -benzamide was represents formula II cer with the 1-phenyl-but-l-en-3-one Formula III prepared. · - 12 -. P. Process according to claim 7, characterized in that the reaction is carried out in an inert organic solvent. 9. The method according to claim 8, characterized in that the solvent used is an ether, an alcohol or an aromatic solvent. 10. The method according to claim 1 or 7, characterized in that one uses a compound of general formula II, which by catalytic hydrogenation of a 2-hydroxy-5- (1-hydroxy-2-N, N-dibenzyl-amino-ethyl) benzamide of the formula VI, the resulting compound of the formula II is reacted in situ without isolation with a compound _{s of} formula III and hydrogenating the resulting compound of formula V in situ without isolation. 11. The method according to claim 1 or 7, characterized in that one uses a compound of formula II, which was prepared by catalytic hydrogenation of the 2-hydroxy-5- (N, N-dibenzylglycyl) benzamide of formula IV, the thus obtained Reacting compound of formula II in situ without isolation with the compound of formula III and hydrogenating the resulting compound of formula.V in situ without isolation. - For this 1 sheet formulas-