FR2558465A1 - PROCESS FOR THE PREPARATION OF A BENZAMIDE DERIVATIVE AND DERIVED DERIVATIVE - Google Patents

Abstract

THE PRESENT INVENTION RELATED TO A PROCESS FOR PREPARING A BENZAMIDE DERIVATIVE. BENZAMIDE, KNOWING 2-HYDROXY-5-1-HYDROXY-2- (1-METHYL-3-PHENYLPROPYL) AMINOETHYLBENZAMIDE, OF FORMULA: (CF DRAWING IN BOPI) IS OBTAINED BY HYDROGENATION OF 2-HYDROXY-5 -1-HYDROXY-2- (1-PHENYL-BUT-1-ENE-3-YLIDENE) IMINOETHYLBENZAMIDE. APPLICATION: HYPOTENSING AGENT A- AND B- BLOCKING.

Description

The present invention relates to a process

  for preparing a benzamide derivative. More specifically

  it concerns a new and improved process for the preparation of

  2-hydroxy-5- {1-hydroxy-2- (1-methyl-3-phenyl)

  propyl) amino / ethyl benzamide and its acid addition salts

  pharmaceutically acceptable.

  It is known that 2-hydroxy-5- {1-hydroxy-2- / (1-

  methyl-3-phenylpropyl) aminoethyl] benzamide is an agent

  a- and E-blocking hypotensive agent useful and widely used.

  The prior art provides a number of

  procedures for the preparation of 2-hydroxy-5- {1-hydroxy-2- / (1-

  methyl-3-phenylpropyl) -amino7éthyl} benzamide. According to DOS No. 2,032,642, 2-hydroxy-5-acetylbenzamide is brominated and then the resulting β-bromoacetyl derivative is reacted with N-benzyl-N- (1-methyl-3-phenylpropyl) amine and one

  reduces the ketone group of 2-hydroxy-5- {2- / N-benzyl-N- (1-

  methyl-3-phenylpropyl) -amino-acetylbenzamide by hydro-

  catalytic interference, while the N-group is detached

  benzyl protecting agent to obtain 2-hydroxy-5- (1-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

  many stages and with low yields.

  In addition, the N-benzyl-N- (1-methyl-3-phenylpropyl) amine component can only be produced by a multiple synthesis.

  steps and complicated way too.

  According to another method described in DOS No. 2 032 642 of 2-hydroxy-5 (bromoacetyl) benzamide is

  treated with N, N-dibenzylamine and 2-hydroxy-5- (N, N-)

  dibenzylglycyl) benzamide represented by the formula

after:

255846 5

CONH 2 C

H 4 CH 2t (IV)

H COCH2 - N

2H

  obtained is treated with 1-phenyl-3-butanone in

  reducing conditions. The yields obtained are average.

  This method offers another disadvantage in that the

  1-phenyl-3-butanone is not available on the scale

  and no method of manufacture is described

  on an industrial scale of this compound in Art

prior.

  According to another process described in this DOS, 5- (2-amino-1-hydroxyethyl) salicylamide is reacted with 1-phenyl-3-butanone in an ethanolic solution,

  under reducing conditions to obtain 2-hydroxy-

  5- {1-hydroxy-2- (1-methyl-3-phenylpropyl) amino] ethyl} ben-

  zamide. However, in the corresponding example, no yield is indicated. This process has a disadvantage already mentioned above, the starting lphenyl-3-butanone is not

  not available on an industrial scale.

  Belgian Patent No. 840,779 and DOS No. 2,616,403 provide a process for the preparation and separation of

  diastereoisomers of 2-hydroxy-5- {1-hydroxy-2-Z- (1-methyl)

  3-phenylpropyl) amino7éthyl} benzamide. The number of steps is increased as a result of the formation of the chiral center in the processes described above and the total yield of the

synthesis is rather weak.

  2-Hydroxy-5- {1-hydroxy-2 can be prepared

  / - (1-methyl-3-phenylpropyl) aminoethyl] benzamide according to

  general formulas of Hungarian Patent N 165 291, in accordance with

  2-hydroxy-5-glyoxylylbenzoic acid ester with 1-phenyl-3-butylamine and subjecting the base of

  Schiff thus obtained to a catalytic hydrogenation. How-

  no example of the preparation of 2-hydroxy-5- {1hydroxy-2- (1-methyl-3-phenylpropyl) amino

  ethyl} benzamide in the specification of the patent.

  The present invention aims to provide a

  process for the preparation of 2-hydroxy-5- {1-hydroxy-2-

  - (1-methyl-3-phenylpropyl) aminoethyl] benzamide, which

  undermines the above disadvantages of the known methods,

  higher yields, is easily achieved on an industrial scale and uses

departure readily available.

  It has been found that 2-hydroxy-5- (1-hydroxy-2-

  t (1-methyl-3-phenylpropyl) aminoethyl] benzamide

  with formula (I) below: CONH2

- HO CH - CH2

, H3 l l / C5

OH NH- CH

OH; 2- CH 2

  can be prepared simply and economically from

  2-hydroxy-5- {1-hydroxy-2 - (1-phenyl-but-1-ene-3)

  ylidene) imino7ethyl} benzamide of formula

CONH2

HO \ C-H -2 C (V) C

-35 255846

  According to the present invention, it is

  a process for the preparation of 2-hydroxy-5- (1-hy-

  hydroxy-2- (1-methyl-3-phenylpropyl) aminoethyl] benzamide of formula I and its pharmaceutically acceptable acid addition salts thereof, wherein

  2-hydroxy-5- {1-hydroxy-2 - (1-phenyl-but-1-en-3-yl)

  dene) imino7ethyl} benzamide of formula V and if this is

  desired, the compound of formula (I) thus obtained is converted into

  naked in an acid addition salt acceptable from the point of view

1a pharmaceutical.

  The reduction of the formula Schiff base

  (V) can be carried out by catalytic hydrogenation.

  The catalyst used in this connection may be palladium,

  platinum, nickel or a catalyst Adams. Catalytic

  it can also be applied on a support (for example, coal, barium sulphate). The hydrogenation can be carried out at a temperature between 10 and 40 C, preferably at a temperature between 20 and 30 c, at a pressure of 1 to 10 atm, preferably 2 to 4 atm. It is particularly advantageous to work at C and under a pressure of 3 atm. The reduction can be

  made in an inert organic solvent. This medium of reaction

  is preferably an ether (for example, diethyl ether).

  ethyl, dioxane or tetrahydrofuran) or an alcohol

  cool (eg methanol or ethanol) and in particular

  bind tetrahydrofuran. Two equivalents of hydrogen are consumed during the reaction and both the azomethine bond and the carbon-carbon double bond

  are saturated. This reaction can be accomplished by

  of a small amount of an organic acid (eg

  for example, glacial acetic acid). The yields obtained

nudes are almost theoretical.

  The reaction mixture can be treated according to

  methods known per se. We can preferably

  yield by separating the catalyst by filtration and

  poranting the filtrate. The hydrochloride can be isolated by the addition of anhydrous ethanolic dilhydric acid or a relaunch.

  of concentrated hydrochloric acid and ethanol to the hydrogenated filtrate.

  The starting material of formula (V) is a novel

  compound and can be prepared by the reaction of 2-hydroxy-5- (1-hydroxy-2-aminoethyl) benzamide represented by the formula below:

CONH2 (II)

HO 'H - CH2

-I!

OH NH2

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

CH = CH - COCH3 (III).

  The reaction can be carried out in an inert organic solvent. The reaction medium is preferably an ether

  (for example diethyl ether, dioxane or tetra-

  hydrofuran), an alcohol (for example, methanol or ethanol) or an aromatic hydrocarbon (for example, benzene, toluene or xylene) and in particular tetrahydrofuran can be used. The reaction can be carried out at a temperature of between 25 and 100 C,

  preferably at a temperature close to 40 C. The reaction

  may possibly be carried out in the presence of a

  base (for example, triethylamine or morpholine).

  The compound of formula (V) thus obtained can be either isolated or subjected to a catalytic hydrogenation

in situ, without prior isolation.

  In accordance with one embodiment of the

  In accordance with the present invention, the compound of formula (II) prepared by catalytic hydrogenation of the compound of the following formula is used: CONH2 m ,, C: ':

HO H / - (VI)

  OH c2 It is preferable to work by subjecting a compound

  of formula (VI) to a catalytic hydrogenation, in

  reacting the compound of formula (II) thus formed in situ with the compound of formula (III) and hydrogenating the compound of formula (V) thus obtained, without isolating it beforehand. According to another embodiment of the method

  according to the present invention, the com-

  layer of formula (II) prepared by catalytic hydrogenation of the compound of formula (IV). It is preferable to proceed by subjecting the compound of formula (IV) to a catalytic hydrogenation, by reacting the compound of formula (II) thus formed, in situ with a compound of formula (III) and by hydrogenating the compound of formula ( V) thus obtained,

without isolating it first.

  These last two implementations of

  The present invention may be formed preferably at an elevated temperature, preferably between about 70 ° C and a pressure of from about 1 to about 100 atmospheres, preferably about 50 atmospheres. The reaction can be carried out in an inert organic solvate. This reaction medium may be preferably an alcohol (by 255846y

  for example, methanol or ethanol). The reaction environment

  it may also contain an acid (eg glacial acetic acid). The catalyst may be palladium,

  platinum, nickel or a catalyst Adams. Catalytic

  may be applied to a medium, for example

  good, barium sulfate, etc., if desired.

  The main advantage of the process according to the

  The present invention resides in the fact that

  used for the preparation of the compound of formula (V) may be prepared from materials (eg

  benzal acetone) are readily available on the scale

  industrially, the process is easily feasible and economical on an industrial scale as well and the yields are high. It is believed, without limiting the scope of the present invention, that this is due to the fact that the group

  ketone of 1-phenyl-but-1-ene-3-one (benzal acetone)

  In the process of the present invention, it is more reactive because of the conjugation than the ketone group of 1-phenyl-butan-3-one applied in the process described in DOS No. 2,032,642. is for this

  the compound of formula (III) reacts with 2-hy-

  droxy-5- (1-hydroxy-2-amino-ethyl) -benzamide of formula (II)

  to give 2-hydroxy-5 - {- hydroxy-2- (1-phenyl-but-1)

  3-ene-3-ylidene) imino7ethyl} benzamide corresponding more

  that the corresponding intermediate is formed in the process described in DOS No. 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) imino7éthyl} benzamide.

  In addition to the foregoing, the invention also includes other arrangements which will be apparent from

the following description.

  The invention better understood by means of the supplement

  description which will follow, which refers to

  examples of implementation of the method object of the present invention.

  It should be understood, however, that these examples

  implementation plans are given solely for the purpose of

  lustration of the object of the invention, of which they do not constitute

  in no way kill a limitation.

EXAMPLE 1

  Preparation of 2-hydroxy-5- (1-hydroxy-2- (1-phenyl-but-1-yl)

  ene-3-ylidene) imino7éthyl} benzamide. 2.30 g (10 millimoles) of 2-hydroxy-5- (1-hydroxy-2-aminoethyl) benzamide hydrochloride and 1.46 g (10 millimoles) of 1-phenyl-but-1-ene-3 are mixed. -one with 10 ml of

  tetrahydrofuran and, with further stirring and cooling,

  In ice, 1.20 ml of triethylamine are added dropwise at a temperature of 10-15 ° C. After the end of the addition, the reaction mixture is stirred at room temperature for an additional 5 hours and the precipitated triethylamine hydrochloride is separated by

  filtration. 2-hydroxy-5- {1-hydroxy-2 - [(1-phenyl-but-1-yl)}

  en-3-ylidene) iminoethyl] benzamide is isolated from

  filtrate by column chromatography on silica gel.

  1.56 g of the desired compound are thus collected, with a

  48% yield, m.p. 142 - 1460C.

EXAMPLE 2

  Preparation of 2-hydroxy-5- {1-hydroxy-2- (1-phenyl-but-1-yl)

  ene-3-ylidene) imino7éthyl} benzamide. 2.30 g (10 millimoles) of 2-hydroxy-5- (1-hydroxy-2-aminoethyl) benzamide hydrochloride and 1.46 g (10 millimoles) of 1-phenyl-but-1-ene-3 are mixed. -one with 10 ml of

  tetrahydrofuran and, with further stirring and cooling,

  with ice, 4 ml of water are added dropwise

  morpholine at a temperature of 10-15 C. The reaction mixture

  is stirred at room temperature for an additional 5 hours, the precipitated morpholine hydrochloride is

  filtered off and the filtrate is heated to boiling.

255,846!

  for 3 hours. The desired compound is isolated at

  extraction of the filtrate by chromatography on a column of silica gel. There is thus obtained 2.05 g of the desired compound, with a

  63% yield, m.p. = 142 - 145 C. -

EXAMPLE 3

  Preparation of 2-hydroxy-5- (1-hydroxy-2-hydrochloride

  (1-methyl-3-phenylpropyl) amino / ethyl} benzamide.

  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 the procedure of Example 1 or 2 are dissolved in 25 ml of tetrahydrofuran and then 0.5 g of a catalyst. consisting of 10% palladium on charcoal, is added and the mixture is hydrogenated at 25 C under

  a pressure of 3 atm. At the end of the reduction, the

  The lysine is filtered off and the filtrate is added.

  5 ml of ethanol containing 20% hydrochloric acid.

  than. The precipitated white crystals are separated by

  and washed with ethanol. Thus, 3.46 g of

  desired compound, with a yield of 95%, m.p. = 188 -

189 C.

EXAMPLE 4

  Preparation of 2-hydroxy-5- (1-hydroxy-2-hydrochloride

  N - (1-methyl-3-phenylpropyl) aminoethyl] benzamide.

  A solution of 3.74 g (10 mmol) of 2-hydroxy-5- (N, N-dibenzylglycyl) -benzanilide, 1.46 g (10 mmol) of 1-phenyl-but-1-en-3-one

  ml of methanol is added with 1.0 ml of acetic acid.

  1.0 g of a catalyst consisting of 10% palladium on carbon and 0.1 g of platinum oxide (Adams catalyst). The reaction mixture is hydrogenated

  at a temperature of 601C and a pressure of 50 atm.

  The catalyst is filtered off and the filtrate is evaporated to a small volume. The residue is supplemented with 3 ml of propanol saturated with hydrochloric acid and 5 ml of ethyl acetate. Crystals precipitate at rest, then they are separated by filtration and washed. We obtain

  2.62 g of the desired compound; yield 72%, m.p. = 187 -

 C.

EXAMPLE 5

  Preparation of 2-hydroxy-5- (1-hydroxy-2-hydrochloride

  (1-methyl-3-phenylpropyl) aminoethyl] benzamide.

  A solution of 3.76 g (10 millimoles) of 2-hydroxyethyl

  5- (1-hydroxy-2- (dibenzylamino) ethyl) benzamide and 1.46 g (10 millimoles) of 1-phenyl-but-1-en-3-one in

  50 ml of methanol is added with 1.0 ml of acetic acid.

  1.0 g glacial tick of a catalyst consisting of 10% palladium on carbon and 0.1 g of platinum oxide (Adams catalyst) and the reaction mixture is hydrogenated

  at a temperature of 60 C, under a pressure of 50 atm.

  The reaction mixture is treated and the product isolated according to the procedure of Example 4.

  2.77 g of the desired compound, 76% yield, m.p. = 188 -

189 C.

  As is apparent from the foregoing, the invention

  tion is not limited to those of its modes of implementation and implementation that have just been

  described more explicitly; it embraces

  milk all variants that may come to the mind of the technician in the field, without departing from the framework, nor

  of the scope of the present invention.

Claims (10)

  1.- Process for the preparation of 2-hydroxy-5- {1-hy-   hydroxy-2- (1-methyl-3-phenylpropyl) aminoethyl] benzamide represented by the formula below: CONH2 HO CH - CHH2 I CH3 OH NH-CH CH2- CH2   and its pharmaceutically acceptable acid addition salts, characterized in that 2-hydroxy-5- (1-hydroxy-2-yl) -phenyl-but-1-en-3-ylidene is hydrogenated. ) imino7ethyl} benzamide represented by the following formula: CONIH HO C'H -O (y) OH N = C HO <> CH C- (V) OI 2 =   and if desired, converting the compound of formula (I) thus obtained into an acceptable acid addition salt from the pharmaceutical point of view.   2. A process according to claim 1, characterized   in that the hydrogenation is carried out in the presence a catalyst.   3. A process according to claim 2, characterized   in that a palladium catalyst is used, in   platinum or nickel or a mixture thereof.   4. A process according to any of the claims   cations 1 to 3, characterized in that the reaction is carried out at a temperature between 10 and 40 C, preferably at a temperature of about 20 to 30 C, under a pressure of   1 to 10 atm and preferably 2 to 4 atm.   5. A process according to claim 1, characterized in that a compound is used as the starting material.   of formula (V) prepared by the reaction of 2-hydroxy-5- (1-   hydroxy-2-aminoethyl) benzamide represented by the formula below: CONH2 -HO / CH-CH2) OH 1; (2   2   with 1-phenyl-but-1-en-3-one of the formula below: / CH = CH - C0C3 (III)   6. A process according to claim 5, characterized   in that the reaction is carried out in an organic solvent. inert nique.   7. Process according to claim 6, characterized   rised by using an ether, an alcohol or a hydro- aromatic carbide as a solvent.   8. Process according to claim 1 or 5,   characterized by the use of 2-hydroxy-5- (1-hydroxy-   2-aminoethyl) benzamide of formula (II) prepared in situ by   catalytic hydrogenation of 2-hydroxy-5 - / 1-hydroxy-2-   (N, N-dibenzylamino) ethyl / benzamide represented by the following formula: C A2 C / H2 (vi), HO CH - C 42 -N I \ H OH C2   in that the compound of formula (II) is reacted without prior isolation in situ with the compound of formula (III) and in that the compound of formula (V) is subjected to   obtained in a hydrogenation, without isolating it beforehand.   9.- Method according to one of claims 1 or   5, characterized in that 2-hydroxy-5- (1-hydroxy) is used.   xy-2-aminoethyl) benzamide of formula (II) prepared in situ   by catalytic hydrogenation of 2-hydroxy-5- (N, N-dibenzyl)   glycyl) benzamide represented by the formula below (IV), CONH2 C H2 HO CO - CH2 -N   In that the compound of formula (II) is reacted in situ without isolating it with the compound of formula (III) and in that the compound of formula (V) and   formed without isolating it from hydrogenation.   10. 2-Hydroxy-5- {1-hydroxy-2 - [1-phenyl-but-   1-en-3-ylidene) imino / ethylbenzamide represented by the formula below: HoOCH - CH C (v). CH3 OH N = C - N CH.:j