KR790001910B1 - Process for the preparation of sallcylamides - Google Patents

Abstract

Salicylamide derivs. (I; R1 = H, alkyl, alkenyl, R2 = H, amino, a group can be converted to amino, R4 = tert-aminoalkyl, X = H, halogen atom, alkylsulfonyl), useful as digestive modifier, were prepd. Thus, salic ylic acid derivs. (II; R1,R2, X are given) were reacted with amine (III; R3 and R4 are given) in the presence of organic phosphor compd. and organic disulfide to give I.

Description

Preparation of Salicylate Derivatives

The present invention relates in particular to a novel process for the preparation of salicylic amide derivatives represented by the following general formula (1), which has an effective pharmacological action as a modulator of digestion. Among these derivatives are known compounds, metoclophamide, ie N- (2-diethylaminoethyl) -2-methoxy-4-amino-5-chlorobenzamide.

The present inventors have conducted a number of studies and found a novel method for obtaining this compound in high yield.

Food,

R ₁ is a hydrogen atom or an alkyl or alkenyl group,

R ₂ represents a hydrogen atom, an amino group or a group convertible to an amino group, R ₄ is a tertiary amino alkyl group,

X is hydrogen or a halogen atom or an alkyl sulfonyl group.

The process of the present invention comprises reacting a salicylic acid derivative of the following general formula (2) or a salt thereof with sulfenamide of the following general formula (3) or a salicylic acid derivative of the following general formula (2) The salt is reacted with the amine of the following general formula (4) in the presence of a trivalent organic compound or organic disulfide to prepare the desired compound of the general formula (1).

Food,

R ₁ , R ₂ , R ₄ and X are as described above,

R ₃ represents an organic residual.

Substituted benzoic acid of the general formula (2) to be used as a raw material is prepared by the methods described in French Patent Nos. 1,472,025 and 1,476,925.

The reaction according to the present invention is carried out by reacting an amino compound of the general formula (4) with an organic disulfide to obtain a sulfenamide derivative of the general formula (3), with or without separating the compound in the presence of a trivalent organic compound. It reacts with the salicylic acid derivative of Formula (2).

In the basic compound of formula (2) and the sulfenamide derivative of formula (3), R ₁ represents an alkyl group including, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, or the like. Kenyl is indicated and R ₂ represents a group convertible to an amine such as, for example, nitro, acylamino.

Acyl groups are all residual groups of aliphatic, aromatic, bicyclic, carboxylic acids in ester acids, amides or sulfonic acids, such as acetyl, propionyl, acryloyl, butyryl, isobutyryl, vareryl, isovare Alkanoyls such as reel, caproyl, enanthoyl, heptanoyl, octanoyl and the like; Cycloalkanecarbonyl, such as cyclopentanecarbonyl and cyclohexanecarbonyl; Arylyl such as benzoyl, toluoyl, naphthoyl and the like; Aryloxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and the like; Aralcoxicarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, nicotinoyl, piperazine-1-carbonyl, morpholine-4-carbonyl, pyrrole-2-carbonyl, furan-2- Heterocycle carbonyl such as carbonyl and the like; Succinyl, malonyl, maleoyl, phthaloyl, benzenesulfonyl, carbamoyl and the like having a substituent such as halogen (eg, chlorine, bromine, iodine and the like); Alkoxy (such as methoxy, ethoxy, propoxy, etc.); Alkylthio (eg, methylthio, ethylthio, propylthio, butylthio, etc.); Aryloxy (eg, phenoxy, tolyloxy, naphthyloxy, etc.); Aryl (eg, phenyl, tolyl, naphthyl, etc.); Alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.); Acyloxy (eg, acetyloxy, propionyloxy, butyryloxy, benzoyloxy, etc.); Acylthio (eg, acetylthio, propionylthio, butyrylthio, benzoylthio, etc.); Acylamino (e.g. formamide, acetamide, propionamide, butylamide, benzamide, tert-butoxycarbonylamino, allyloxycarbonylamino, cyclohexyloxycarbonylamino, phenoxycarbonylamino, allyloxy Carbonylamino, cyclohexyloxycarbonylamino, phenoxylcarbonylamino, phenylthiocarbonylamino, benzyloxycarbonylamino, toluenesulfonylamino, etc.); Heterocycle groups such as thienyl, furyl, pyrrolyl, indoryl, 2-oxo-benzothiazolin-3-yl, imidazolidinyl and the like.

The organic residual R ₃ includes all organic residuals which can be converted to mercaptan compounds. These groups are aliphatic, cycloaliphatic, aromatic or bicyclic groups such as ethyl, cyclohexyl, phenyl, 0-nitrophenyl, 2-pyridyl, 4-pyridyl, 5-nitro-2-pyridyl, pyrimidyl, benz Imidazolyl, benzothiazolyl and the like.

The tertiary aminoalkyl group R ₄ is, for example, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-dipropylaminoethyl, 2- (or 3-, or 4-) diethylaminobutyl, 2- (pyrroli) Dill) ethyl, 2- (piperidino) ethyl, 2- (piperazinyl) ethyl, 2- (4-methylpiperazinyl) ethyl, 3- (piperazinyl) propyl, and the like.

As a salt of the said General formula (4), For example, Inorganic acid salts, such as hydrochloride and sulfate; Organic acid salts such as acetates, maleates, tartarates and the like.

When X is an alkylsulfonyl group, alkyl represents methyl, ethyl, propyl, butyl, and for example, phosphine and phosphoric acid are included as compounds which are trivalent organic in the present invention.

Suitable phosphines include, for example, primary phosphines such as propylphosphine, isobutylphosphine, phenylphosphine and the like; Secondary phosphines such as diethyl phosphine, diisoamyl phosphine and diphenyl phosphine; Tertiary phosphines such as trimethylphosphine, triethylphosphine, triphenylphosphine and the like.

Suitable phosphate esters are, for example, mono (or di- or tri-) methyl esters, mono (or di- or tri-) ethyl esters, mono (or di- or tri-) propyl esters, mono (or di) Mono (or di-, or tri-) alkyl esters such as-or tri-) isopropyl esters; Phosphoric acid mono (or di- or tri-) aryl esters such as mono (or di- or tri-) phenyl esters, mono (or di- or tri-) nitrophenyl esters and the like.

Examples of the phosphonoic acid esters include mono (or di) methyl esters of methylphosphonoic acid and mono (or di) alkylesters of alkylphosphonoic acids such as mono (or di) ethylesters of ethylphosphonoic acid; Mono (or di) alkyl esters of aryl phosphono acids such as mono (or di) methyl esters of methyl phosphono acids and mono (or di) ethyl esters of ethyl phosphono acids; Mono (or di) methyl ester of phenylphosphonoic acid, mono (or di) ethyl ester of phenylphosphonoic acid, and mono (or di) phenyl ester of phenylphosphonoic acid.

The trivalent organophosphorus compound is not limited to the above, and any compound that is a trivalent organophosphate that can be oxidized during the reaction without adversely affecting the reaction of the method of the present invention can be used in the present invention.

As a salt of the basic compound of the said General formula (2), the metal salt which can remove sulfur from the tooth compound, such as copper salt, mercury salt, lead salt, manganese salt, and chromium salt, is suitable, for example.

As an organic sulfide compound used for this invention, For example, Dialkyl sulfides, such as dimethyl sulfide, diethyl sulfide, methyl ethyl sulfide, dipropyl sulfide, etc .; Alkyl aryl disulfides such as methyl phenyl disulfide and ethyl phenyl disulfide; Diaryl disulfides, such as a diphenyl disulfide and a tolyl disulfide; Diheterocycle disulfides such as di (2-pyridyl) disulfide, di (4-nitro-2-pyridyl) disulfide, di (2-benzothiazolyl) disulfide, di (4-benzimidazolyl) disulfide, and the like. have.

The reaction for achieving the object of the present invention can be carried out in the presence of an agent capable of removing sulfur of the thio compound to obtain the desired benzamide of the general formula (1) in high yield.

Such agents may be used when the group of the sulfenamide derivative of general formula (3) is, for example, 2-pyridyl, 2-benzothiazolyl, 2-benzimidazolyl, or the like or disulfide, for example, di (2-pyridyl) disulfide , Di (2-benzothiazolyl) disulfide, di (2-benzimidazolyl) disulfide and the like are very effective.

Such agents cannot be used when the base material of Formula (2) to be used is a heavy metal salt or when the thio compound obtained by the amidation reaction is a stable compound.

Agents capable of removing sulfur from thio compounds include, for example, inorganic acid salts of heavy metals such as mercuric chloride, manganese sulfate, zinc chloride, cupric chloride, and lead sulfate; Organic with organic compounds that donate hydrogen such as urine, succinimide, phthalimide, P-nitrophenol, 2-4-dinitrophenol, N-hydroxysuccinimide, P-methoxyphenol, etc. Metal compounds; For example, acids by Pearson's theory such as sulfenic acid such as methyl or ethyl or tert butyl ester of 0-nitrophenylsulfenoic acid, methyl or tertiary butyl ester of 2-4-dinitrophenylsulfenoic acid and the like; 2-3 dihydropyran, an olefin compound such as n-butyl-vinyl ether, and the like. Such agents are not limited to those described above.

The reaction of the present invention is generally carried out in solvents such as dimethylformamide, pyridine, ether, dioxane, methylene chloride, tetrahydrofuran, benzene, toluene or solvents which have no effect on the reaction.

The reaction of the present invention may also be carried out in the presence of an acid such as pivalic acid, N-hydroxysuccinimide, phenol, P-nitrophenol, picric acid and the like.

The reaction temperature is not limited and the reaction may be carried out at an environmental temperature.

When the basic compound of formula (2) or a salt thereof is reacted with an amine of formula (4) in the presence of a trivalent organic compound and an organic disulfide compound, the desired benzamide of formula (1) is represented by Obtained via the sulfenamide derivative of 3).

Benzamide of formula (1) can be converted to inorganic acid salts such as hydrochloride, bromate, phosphate, sulfate, or organic acid salts such as acetate, propionate, maleate, tartarate, citrate, salicylate and the like.

When explaining the method of the present invention in detail as follows.

Example 1

N- (2-diethylamino) ethyl-2-methoxy-4-amino-5-chlorobenzamide

6 ml of a solution of 1.0 g of 2-methoxy-4-amino-5-chlorobenzoic acid dissolved in dimethylformamide was dissolved in 2- (diethylamino) ethylamine (0.6 g), 1.4 g of triphenylphosphine and di- (2 -Pyridyl) was added to 5 ml of purified dimethylformamide containing disulfide (1.2 g), and the solution was stirred at ambient temperature for 1 hour, and then the dimethylformamide was distilled off under reduced pressure to dissolve the residue in ethyl acetate. After extracting with standard hydrochloric acid, the aqueous layer is alkaline with standard sodium hydroxide solution, saturated with sodium chloride, and extracted twice with ethyl acetate. The organic base is washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and distilled ethyl acetate. The resulting N- (2-diethylamino) ethyl-2-methoxy-4-amino-5-chlorobenzamide was recrystallized from benzene to give colorless crystals (melting point: 145-146 ° C). . Melting point, red line spectrum and thin layer chromatography are consistent with the true sample.

The following compounds were prepared in the same manner as in Example 1.

N- (2-diethylamino) ethyl-2-methoxy-4-acetamide-5-chlorobenzamide Melting Point: 99.5-101 占 폚

N- (2-diethylamino) ethyl-2-methoxy-4-nitro-5-chlorobenzamide Melting Point: 70-72 ° C

N- (2-diethylamino) ethyl-2-methoxy-4-amino-5-chlorobenzamide was hydrolyzed with caustic soda solution under heating to give N- (2-diethylamino) ethyl-2-methoxy Obtained from -4-acetamide-5-chlorobenzamide. (Melting point: 145-146 ° C) In addition, to reduction of N- (2-diethylamino) ethyl-2-methoxy-4-nitro-5-chlorobenzamide) metoclopramide (Raney Nickelo in alcohol) (Melting point: 145-146 ° C)

Example 2

N- (2-diethylamino) ethyl-2-methoxy-4-amino-5-chlorobenzamide

6.2 g of 0, 0'-desulfurized dinitrophenyl, 25 ml of dimethylformamide and 2.3 g of N, N-diethylethylenediamine were placed in a 250 ml flask with a stirrer and thermometer, and the solution was allowed to stand for 30 minutes at ambient temperature. It must be stirred. Next, 5.2 g of triphenylphosphine and 4.9 g of 2-methyl-4-acetamino-5-chlorobenzoic acid were added to 30 ml of dimethylformamide, the solution was stirred for 1 hour, the solvent was distilled off under vacuum, and the residue was ethyl acetate. Dissolve in 50 ml, extract the organic solution with dilute hydrochloric acid, filter the aqueous solution, add 20 ml of caustic soda solution, heat the solution under reflux for 1 hour, cool it, filter the crystals, wash with water, and dry at 50 ℃. Dried at.

Preparation yield: 3.3g (55.1%)

Melting Point: 142-144 ℃

The IR spectrum is similar to a true sample but indicates the presence of low impurities.

Example 3

N- (2-diethylamino) ethyl-2-methoxy-4-amino-5-chlorobenzamide

The preparation of this compound is similar to that of Example 2 except for a few differences below.

The acid used was 2-methoxy-4-amino-5-chloro benzoic acid (4.0 g),

There is no need to heat in the presence of caustic soda, and the crude product is recrystallized from benzene to give a pure product.

Yield after recrystallization: 0.2g (3.3%)

Melting Point: 144 ℃

Example 4

N- (2-diethylamino) ethyl-2-methoxy-5-methylsulfonylbenzamide

The preparation of this compound is similar to that of Example 3.

The basic starting material used is 2-methoxy-5-methylsulfonylbenzoic acid (4.6 g).

Preparation yield: 3.8g (57.9%)

Melting Point: 112 ℃

The IR spectrum is similar to a true sample but indicates the presence of low impurities.

Example 5

N- (2-diethylamino) ethyl-2-methoxy-4-aminobenzamide

The preparation of this compound is similar to that of Example 2.

The basic raw material is 2-methoxy-4-acetaminobenzoic acid (4.2 g),

The acetylation product is extracted from caustic soda aqueous suspension with methylene chloride and the evaporated residue of the organic phase is deacetylated by heating under reflux for 8 hours in 50 ml of a propanol solution containing 5 ml of 40% caustic soda solution. After evaporation of the propanol under vacuum, N- (2-diethylamino) ethyl-2-methoxy-4-aminobenzamide was extracted with methylene chloride and the organic solution was evaporated to dryness in vacuo to give the residue as a brown oil. Lose.

Formulation Yield: 1.6g (30.2%)

The NMR spectrum is consistent with the expected structure but indicates the presence of low impurities.

Example 6

N- (2-diethylamino) ethyl-2-methoxy-4-amino-5-bromobenzamide

The preparation of this compound is similar to that of Example 2.

As the basic starting material, 2-methoxy-4-acetamino-5-bromobenzoic acid (5.8 g) is used.

Preparation yield: 3.5g (50.9%)

Melting Point: 147 ℃

Example 7

N- (2-diethylamino) ethyl-2-allyloxy-4-amino-5-chlorobenzamide

The preparation of this compound is similar to that of Example 2, and 2-allyloxy-4-acetamino-5-chlorobenzoic acid (5.4 g) is used as the basic starting material.

The crystals obtained by saponification with caustic soda are dissolved in dilute hydrochloric acid, and the solution is filtered to further alkaline with caustic soda to precipitate the product.

Purification Yield: 3.35g (51.5%)

Melting Point: 128 ℃

The NMR spectrum is consistent with the expected structure, but indicates low impurities.

Example 8

N- (2-diethylamino) ethyl-2-allyloxy-4-amino-5-chlorobenzamide

The preparation of this compound is similar to that of Example 7. The only difference is the choice of disulfide. For example, 2, 2'-dithiodipyridine is used (4.4 g).

Preparation yield: 2.2g (33.8%)

Melting Point: 128 ℃

NMR spectrum is similar to that of Example 7.

Example 9

N- (2-diethylamino) ethyl-2-methoxy-5-methyl sulfonylbenzamide

The preparation of this compound is similar to that of Example 4. The difference is in the choice of disulfide. For example, 2, 2'-dithiodipyridine is used (4.4 g)

Formulation yield: 3.1g (48.4%)

Melting Point: 117 ℃

The IR spectrum is similar to a true sample.

Claims (1)

As described above in the text, the salicylic acid derivative of the following general formula (2) is reacted with the amine of the following general formula (4) in the presence of a trivalent organophosphorus compound and an organic disulfide: How to prepare.

Wherein R ₁ is a hydrogen atom or an alkyl or alkenyl group, R ₂ represents a hydrogen atom, an amino group, or a group convertible to amino, R ₄ is a tertiary aminoalky group, X is a hydrogen or halogen atom or an alkylsulfo It is a nil group.