DE2450675B2 - Process for the preparation of N-acyl-4-anilinobutyric acids and their salts - Google Patents

Description

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R ¹ , R ² , R ³ , R ⁴ , R ⁵ independently of one another a hydrogen atom, an alkyl or alkoxy group with up to 4 carbon atoms, a chlorine atom or the trifluoromethyl group,

R ³ additionally the benzyloxy group,

R ^{6 is} an alkyl or cycloalkyl radical having up to 6 carbon atoms or a phenyl radical which is unsubstituted or substituted by chlorine or alkyl having up to 4 carbon atoms

mean, and their salts, by hydrolysis of 1-aryl-pyrrolidones- (2) of the general formula II

Among the alkoxy groups are the methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy and tert-butoxy groups mentioned. Preferred are the corresponding radicals with 1 and 2 carbon atoms, such as the methyl and ethyl groups or the methoxy and

Ethoxy group. There are also such as cycloalkyl radicals

3 to 6 carbon atoms in question, of which those with 5 and 6 carbon atoms are preferred.

The pharmacologically compatible

ο chen salts into consideration, as they are general to the expert are known, for example, the cation equivalents of inorganic ions, such as sodium, potassium, Calcium, magnesium, aluminum, or more organic Ions, such as those derived from glucosamine, N-methylglucosamine, Ethanolamine, diethanolamine, triethanolamine or Ethylenediamine dissipating ammonium ions, called

Process products preferred for the purposes of the invention are N-acyl-4-anilinobutyric acids of the general formula I *

R ²

CH ₂ -CH ₂

R ⁴

(ID

wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meanings given above, in aqueous or aqueous-organic alkaline or alkaline earth solution and subsequent acylation, characterized in that one

A) the hydrolysis with 125 to 500 moles of solvent and 2 to 8 equivalents of base per mole L-Arylpyrrolidon- (2) at temperatures of 75 to 150 ° C and carried out

B) acylated the 4-anilinobutyric acid obtained in each case with a carboxylic acid halide or anhydride containing ^{R 6 in a manner known per se}

and the reaction products are then optionally converted into the salts in the customary manner.

2. The method according to claim 1, characterized in that the hydrolysis with 150 to 400 mol Solvent and 3.5 to 7.5 equivalents of base per mole of 1-arylpyrrolidone- (2).

3. "Process according to claim 1 and 2, characterized in that the hydrolysis is carried out at Temperatures of about 100 ° C performs.

The subject of the invention is the method characterized by the claims.

Suitable alkyl groups are straight and branched chain alkyl groups, of which the methyl, Ethyl, n-propyl, iso-propyl, η-butyl, iso-butyl, tert-butyl, n-atyl and n-hexyl groups may be mentioned.

N-CH, -CH, -CH, -COOH

C = O

wherein

R '", R ² ', R ³ ', R ⁴ *, RS' independently of one another a hydrogen atom, an alkyl or alkoxy group with up to 4 carbon atoms, a chlorine atom or the trifluoromethyl group,

R ³ "additionally the benzyloxy group,

R ⁶ "is an unsubstituted or a phenyl radical substituted by chlorine or alkyl having up to 4 carbon atoms

mean and their salts.

From the compounds obtainable according to the process are N-acyl-4-anilinobutyric acids of the formula I **

R ² ** R ¹ **

N-CH ₂ -CH ₂ -CH ₂ -COOH C = O (I **)

R ⁶ **

R ⁴ **

wherein

R ¹ ", R ² ", R ³ ", R ⁴ ", R ⁵ "independently of one another represent a hydrogen atom, an alkyl or alkoxy group with up to 2 carbon atoms or a chlorine atom,
R ³ "additionally the benzyloxy group,

R ⁶ "is an unsubstituted or a chlorine-substituted phenyl radical

and to emphasize their salts.

The following N-acyl-4-anilinobutyric acids may be specifically mentioned

N- (4-chlorobenzoyl) -4- (3-chloroani-

lino) butyric acid,

N-Benzoyl-4- (4-anisidino) -butyric acid,
b5 N- (4-chlorobenzoyl) -4- (4-anisi-

dino) butyric acid,
N- (4-chlorobenzoyl) -4- (4-pheneti-

dino) butyric acid,

N- (4-chlorobenzoyl) -4- (23-dimethylani-

lino) butyric acid, N- (4-Chlarbeozoyl) -4- (2,4-dimethoxyani-

lino) butyric acid, N- (4-chlorobenzoyI) -4- {3,4-dimethoxyani-

lino) butyric acid, N- (2-chlorobenzoyl) -4- (2,6-dimethylani-

lino) butyric acid, N- (2-chlorobenzoyl) -4- (2,6-diinethylani-

Iino) butyric acid and N- (4-chlorobenzoyi) -4- (4-benzyloxyani lino) butyric acid as well as

10

their salts, of which the

dino) butyric acid and its salts are particularly preferred

DEOS 19 17 936 describes two three-stage processes for the production of cholwetic active substances N-acyl-4-anilinobutyric acids described. Then the active ingredients mentioned can pass through

a) Implementation of 4-halobutyric acid esters with Anilines, reaction of the 4-anilinobutyric acid esters obtained with acyl halides or anhydride crystals and alkaline saponification of the N-acyl-4-anilino-butyric acid esters formed or

b) acidic alcoholysis of l-arylpyrrolidones (2), reaction of the 4-anilino-butyric acid ester obtained N-acyl-4-anilinobutyric acid ester shown with acyl halides and alkaline saponification jo

produce, the yields being 34-85 and 71-76%, respectively.

When transferring the above process variant b) to the industrial scale however, significant difficulties arose. Reaction times were used to carry out the alcoholysis This takes up to 100 hours for alcoholysis The resulting toxic dimethyl sulfate (see Example 5 DE-OS 19 17 036) was extremely hazardous to health. When working up the 4-anilinobutyric acid estCT undesired side reactions (e.g. ring closure reactions) occurred, which reduced the yields 50% and the total manufacturing times were up to 200 hours.

The invention now provides a method with which the disadvantages outlined are avoided, in particular with the method according to the invention higher yields, shorter reaction times on an industrial scale and the avoidance of the formation of toxic dimethyl sulfate

According to the literature (Houben-Weyl 11/2), lactams can easily be saponified to aminocarboxylic acids by alkali or acids. Reppe [Ann. Chem. 596 (1955) 177] points out, however, that N-substituted pyrrolidones are much more difficult to hydrolyze to give the N-substituted 4-aminobutyric acids. The reactions must be carried out either with barium hydroxide or with sodium or potassium hydroxide at elevated temperature in the autoclave (230-240 ⁰ C) [ibidem p 216]. The same reference also shows that acylation of the N-substituted aminobutyric acids formed with acyl chloride or anhydride did not take place, since cyclization to the corresponding pyrrolidone occurred

Surprisingly, it has now been found that 1-Arylpyrrolidone- (2) of the general formula II with strong diluted alkalis at temperatures of around 100 ° C saponify in technically reasonable reaction times to give the 4-anilinobutyric acids, these acylate with acyl derivatives to give the N-acyl-4-anilinobutyric acids and, if necessary, then allowed to convert into the salts.

Table 1 shows the yields and reaction times for the laboratory and operating procedures according to DE-OS 19 71 036 and for the process according to the invention using the example of the production of Clanobutin [N- (4-ChlorbenzoyI) -4- (4-anisidino) -buUersäure] compared to each other. It follows clearly that the inventive method in addition to a chemically new, shorter route to the desired compounds also represents a superior route.

Table 1 Reaction stages

DE-OS 19 17 036 Operating procedure Invention 25 kg according to Laboratory procedure 13 kg procedure 250 g (44.5% of theory) 25 kg 235 g 18 kg (80.5% of theory) (85.4% of theory) 353 g 14.5 kg (92.7% of theory) (83.8% of theory) 310 g 13 kg 43.0 kg (91.3% of theory) (90.3% of theory) (94.6% of theory) 280 g 195-205 38.8 kg (90.3% of theory) hours (90.2% of theory) 58-62 75-85 33 hours hours hours 28-32 28.6% d. Th. 15 hours hours 61.5% d. Th. 85.3% d. Th.

Methyl 1- (4-methoxyphenyl) -pyrrolidone- (2) 4- (4 ^ nisidino) -butyrate

N- (4-chlorobenzoyl) i-4- (p-anisidino) butyric acid methyl ester Crude product N- (4-chlorobenzoyl) -4- (4-anisidino) butyric acid N- (4-chlorobenzoyl] i-4- (4-anisidino) butyric acid pure Response times including working hours working hours

Yield based on the l- (4-methoxyphenyl) -pyrrolidone- (2) used

d. Th .: the theory.

The l-arylpyrrolidones- (2) of the general formula II to be used for the process according to the invention are known to the person skilled in the art or can be prepared by processes known to the person skilled in the art (Belgian patent 6 26 904). Examples of suitable 1-arylpyrrolidones- (2) are:

1-phenyl-pyrrolidone- (2), 1 - (3-chlorophenyl) -pyrrolidone- (2), l- (2 ^ -Dimethylpher, yl) -pyrrolidon- (2), 1 - (2,6-DimeAylphenyl) -pyrrolidon- {2), 1 - £ * -Methoxyphenyi) -pyiTolidon- {2), 1 - (4-ethoxyphenyl) -pyrrolidone- {2), 1 - (4-Benzyloxyphenyl) -pyrrolidone- (2), 1- (2,4-Dimethoxyphenyl) -pyiToIidon- (2), 1 - (3,4 ~ DimethoxyphenyI) -pyrrolidone- (2).

The acyl halides which can be used for the process according to the invention, e.g. B. acyl bromides and preferably chlorides, or acyl anhydrides are those skilled in the art likewise known or can be prepared by processes known to the person skilled in the art. As suitable Examples of acyl halides are:

Acetyl chloride, Propionyl chloride, Butyryl chloride,

iso-butyryl chloride,

n-valeryl chloride,

iso-valeryl chloride,

n-caproyl chloride,

oenanthic acid chloride,

Acetyl fluoride, Acetyl bromide, Acetyl iodide, Cyclopropanecarboxylic acid chloride, Cyclobutane carboxylic acid chloride, Cyclopentanecarboxylic acid chloride, Cyclohexanecarboxylic acid chloride, Benzoyl chloride,

4-chlorobenzoyl chloride,

3-chlorobenzoyl chloride,

2-chlorobenzoychloride, 2-methylbenzoic acid chloride.

Suitable acyl anhydrides are acetic anhydride, propionic anhydride, butyric anhydride, Valeric anhydride, caproic anhydride, benzoic anhydride.

The bases suitable for any subsequent salt formation are known to the person skilled in the art

ίο well known, for example the Hydroxides of the inorganic cations mentioned or the organic bases from which the mentioned derive organic ions.

The reaction is preferably carried out in aqueous

is carried out in a basic solution, but this concludes does not rule out that other water-miscible solvents or solubilizers, such as Alcohols e.g. B. methanol, ethanol, propanol, isopropanol, butanol, or polyols, e.g. B. ethylene glycol, glycerin, or mono- or diethers of polyols, e.g., glyme or diglyme, or cyclic ethers, e.g. B. tetrahydrofuran, or ketones, e.g. B. acetone, the basic solution can be added. Be used as bases in the diluted solutions predominantly the alkalis familiar to the person skilled in the art or their analogues, e.g. B. lithium, sodium, or potassium hydroxide, sodium and potassium carbonate are used. However, the corresponding Alkaline earth metal compounds, e.g. B. Magnesium, Calci um- and barium hydroxide are used. Further come, preferably when working in solvent mixtures, organic bases such as alcoholates, z. B. Sodium methoxide, sodium ethoxide, potassium propoxide, potassium butoxide, potassium tert-butoxide,

Potassium amylate into consideration.

The hydrolysis takes place in dilute solution, with per mole of 1-arylpyrrolidone- (2) 125 to 500, preferably 150 to 400 mol of solvent, and 2 to 8, preferably 3.5 to 7.5, equivalents of base are used will. The results of corresponding hydrolysis tests are shown in Table 2.

Table 2

MoI H ₂ O per mole Moles of NaOH per mole reaction time % not implemented inserted inserted l- (4-methoxy- 1 - (4-Melhoxyphenyl) - 1 - {4-methoxy phenyl) - phenyl) - pyrrolidone- (2) pyrrolidone- (2) pyrrolidone- (2)

400 7.5 8 hours 5% 250 7.5 8 hours 5-6% 200 7.5 8 hours 6-7% 175 7.5 8 hours 8-9% 150 7.5 15 hours 1 -2% 200 5 15 hours 5-6% 125 5 15 hours 7% 125 3.75 15 hours 4-5%

The reaction times for the hydrolysis on an industrial scale are of the order of 5 to 20, preferably 8 to 15 hours. The reaction is carried out at temperatures of 75 to 150 ^° C., preferably at temperatures of about 100 ^° C., which are easy to achieve industrially. Increases in reaction time or temperature cause an improvement in yield or a shortening of the reaction time. The subsequent acylation of the anilinobutyric acids is carried out in a manner known per se. The reaction with the acyl derivatives is expediently carried out in such a way that the

Reaction is carried out in the same reaction vessel, since such a laborious and unnecessary one Isolation of the anilinobutyric acids obtained in the hydrolysis is avoided. Furthermore, the for Hydrolysis used alkalis at the same time to neutralize those released during the acylation Hydrogen halides or carboxylic acids are used, so that only a small amount of hydrogen halides or Carboxylic acid binding bases is required. However, this does not rule out that, if desired, the ι ο Anilinobutyric acids are first isolated and acylated in a separate step, with optionally other neutralization substances known to the person skilled in the art, e.g. B. the released hydrogen halides, can be used. The first and second stages of the procedure are separated from each other carried out, the anilinobutyric acids obtained according to the first process stage are expediently as acid addition salts such as hydrohalides, e.g. B. Hydrochloride, isolated, which take advantage of the have greater chemical resistance.

The reaction products are isolated by methods familiar to the person skilled in the art, for example by neutralizing the solution with acids, and customary work-up of the precipitated N-acyl-4-anilinobutyric acids.

Isolation of the salts of N-acyl-4-anilinobutyric acids can take place directly after the alkaline hydrolysis of the l-arylpyrrolidones- (2) and the acylation. Man but the salts are also obtained by adding the N-acyl-4-ani- 3d linobutyric acids with the stoichiometric equivalent of a corresponding base, or easily soluble Salts converted into sparingly soluble salts by double conversion, or any salts into pharmacological ones compatible salts transferred. r>

The following examples serve to illustrate the invention, temperatures are given in ⁰ C.

Examples example 1

N- (4-chlorobenzoyl) -4- (p-anisidino) butyric acid

25 kg of 1- (4-methoxyphenyl) -pyrrolidone- (2) verden with 30 kg of sodium hydroxide in 7501 of water for 15 hours heated to reflux. After cooling, the pH of the solution is adjusted to about 8 with hydrochloric acid set. For one hour at 20-25 ° with occasional ice cooling 171 4-chlorobenzoyl chloride added dropwise, with the simultaneous addition of 2 η NaOH the pH of the solution between 7.2 and 8 is held. The mixture is stirred for a further 1 hour and the solution is adjusted to pH 7.2, then with Activated carbon cleaned and filtered. By adding hydrochloric acid, 43 kg of N- (4-chlorobenzoy) -4- (4-anisidino) butyric acid are obtained failed; Yield 94.6% of theory.

Recrystallization from ethanol gives 38.8 kg of the pure product with a melting point of 115-116 ". Yield based on the 1- (4-methoxyphenyl) -pyrrolidone- (2) used: 854% of theory. «>

Example 2

N-AcetyM - ^ - anisidinoJ-butyric acid
a) 4- (4-anisidino) butyric acid as hydrochloride 38.25 g of l- (4-methoxyphenyl) pyrrolidone (2) are refluxed with 60 g of sodium hydroxide in 675 ml of water for 12 hours Shaking with trichlorethylene unreacted 1- (4-methoxyphenyl) pyrrolidone extracted. The aqueous solution is acidified to pH 3 by adding concentrated hydrochloric acid while cooling. The deposited precipitate is filtered off with suction and washed with a little ice water. Yield: 39.3 g = 80% of theory. Melting point of the product 195-197 °.

b) acylation

39.3 g of 4- (4-anisidino) butyric acid hydrochloride and 4.8 g of sodium acetate are dissolved in 80 ml of acetic anhydride Heated to boiling under reflux for 6 hours. After the decomposition of the excess acetic anhydride with Water is extracted with chloroform, and after concentration and recrystallization from Benzoi / Peiroiether 36.5 g of N-acetyl-4- (4-anisidino) butyric acid with a melting point of 94 ° -95 ° are obtained. Yield: 90.8% of the Theory.

Example 3

N- (4-chlorobenzoyl) -4- (3-chloroanilino) butyric acid

3.91 kg of 1- (3-chlorophenyl) -pyrrolidone- (2) are mixed with 3 kg of sodium hydroxide in 70 l of water for 25 hours 100 ° heated. After cooling, the pH of the solution is adjusted to about 8 with concentrated hydrochloric acid set. 3.5 kg of 4-chlorobenzyl chloride are added dropwise at 25 ° over the course of 1 hour, with simultaneous Addition of sodium hydrogen carbonate to keep the pH of the solution between 7.2 and 7.8.

It is stirred for a further 1 hour; after the solution has been adjusted to pH 7.2, with Activated carbon cleaned and filtered. By adding hydrochloric acid, 6.5 kg of N- (4-chlorobenzoyl) -4- (3 chloranilino) butyric acid precipitated; Yield 92.2% of theory.

Recrystallization from benzene-light gasoline (1: 1) gives a pure product with 85% yield Melting point 99/100 ° obtained.

Example 4

N- (4-chlorobenzoyl) -4- (4-anisidino) butyric acid
a) 4- (4-Anisidino) butyric acid, as hydrochloride

191 g of 1- (4-methoxyphenyl) -pyrrolidon- (2) are dissolved in 540 ml of 2-ethoxyethanol and 2.5 l of water with 405 g Sodium methylate heated under reflux for 16 hours. Half of the solvent is in vacuo distilled off. The pH of the cooled solution is increased by adding concentrated hydrochloric acid 20-25 ° set to 3. The precipitated 4- (4-anisidino) -butyric acid hydrochloride is filtered off. Yield: 220 g = 89.8% of theory.

b) acylation

220 g of 4- (4-anisidino) butyric acid hydrochloride are used dissolved in 341 of water, the pH value is increased to 7 set at 20-25 °, 160 g are added for 1 hour 4-chlorobenzoyl chloride was added dropwise, with simultaneous Add 10% sodium hydroxide solution to adjust the pH to 74-8. To After stirring for one hour at pH 7.2, the solution is filtered. By adding hydrochloric acid, 278 g are obtained N- (4-chlorobenzoyl) -4- (4-anisidino) butyric acid precipitated Yield 80% based on the 1- (4-methoxyphenyl) -pyrrolidone- {2) used. Recrystallization from toluene gives a product of 90% yield Melting point 115-116 °.

Claims (1)

Patent claims: 1. Process for the preparation of N-acyl-4-amino butyric acids of the general formula 1 R ² N-CH ₂ -CH ₂ -CH ₂ -COOH ₅ C = 0