KR790001641B1 - Process for producing benzensulphonamides - Google Patents

Abstract

Benzenesulfonamide derivs. (I; R1 = H or alkyl ; R3 = alkyl; W1W2 = lower alkylene group), which have antiemetic and psychotropic activities, were prepd. by reaction of salicylic acid derivs. (IV) with sulfonamide derivs. (III; R2 = org. residues) in the presence of trivalent org. p-compd. compd. (III) was prepd. by treating amino compd. (II) with org. disulfide.

Description

Preparation of Benzenesulfonamide Derivatives

The present invention relates to a novel process for the preparation of benzenesulfonamide derivatives of the following general formula (4), useful as analgesics and neurodepressants.

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

R ₃ is an alkyl group,

W ₁ and W ₂ are lower alkylene groups.

Among these derivatives sulfides, ie 1-ethyl-2- (2-methoxy-5-sulfamoylbenzamidomethyl) pyrrolidine, are known compounds.

The present inventors have studied the preparation of such benzenesulfonamide derivatives and found a novel preparation of these compounds for the purpose of the present invention.

The present invention provides a novel sulfenamide derivative of formula (2) obtained by reacting an amino compound of formula (3) with an organic disulfide in the presence of an organic compound of trivalent phosphorus, or a salicylic acid derivative of formula (1) It is to provide a method for producing a benzene sulfonamide derivative of the general formula (4) described above by reacting with a salt in high yield.

Wherein R ₁ , R ₃ , W ₁ and W ₂ are as described above,

R ₂ is an organic residue.

Substituted benzoic acid of formula (1) to be used as starting material is disclosed in U.S. Patent No. 3,342,826, the priority of which is claimed as French Patent No. 1,472,025 corresponding to the present invention.

In the reaction of the present invention, the compound of formula (2) may be reacted with or without separating the new sulfenamide derivative of formula (2) obtained by reacting the amino compound of formula (3) with organic disulfide from the reaction medium. Is carried out by reacting with a salicylic acid derivative of Inban (1) or a salt thereof in the presence of an organic compound of phosphorus.

In the formula (1) sulfene amide derivative of the starting material and the general formula (2), the alkyl group for R ₁ and R ₂ is, for example, and is methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc., W ₁ And lower alkylene groups for W _{2 include} , for example, linear or branched alkylene chains such as methylene, ethylene propylene, 1-methylethylene, methylmethylene and the like. Organic residues R ₂ are all organic groups that can be converted to thio compounds, i.e. aliphatic, cycloaliphatic, aromatic, heterocycle groups such as ethyl, cyclohexyl, phenyl, ortonitrophenyl, 2-pyridyl, 4-pyridyl, 5-nitro-2-pyridyl, pyrimidyl, benzamidazolyl, benzothiazolyl and the like.

Trivalent organophosphorus compounds used in the present invention include, for example, phosphine, arsenic ester, phosphonic acid ester and the like. Suitable phosphines include, for example, primary phosphines such as propylphosphine, isobutylphosphine, phenylphosphine, secondary phosphines such as diethyl phosphine, diisoamylphosphine, diphenylphosphine and trimethylphosphine, Tertiary phosphines such as triethylphosphine, triphenylphosphine and the like.

Examples of arsenic esters are mono- (or di- or tri-) methyl esters, mono- (or di- or tri-) ethyl esters, mono- (or di- or tri-) propyl esters, mono- (or di) Or mono- (or di- or tri-) alkyl esters of arsenic acid, such as tri-) isopropylester, mono- (or di- or tri-) phenyl esters, mono- (or di- or tri-) nitro Mono- (or di- or tri-) aryl esters of arynic acid such as phenyl esters and the like.

Suitable phosphonic acid esters include, for example, mono- (or di-) methyl esters of methyl phosphonic acid, mono- (or di-) alkyl esters of alkylphosphonic acids such as mono- (or di-) ethyl esters of ethyl phosphonic acid and the like. Mono- (or di-) methyl esters of phenylphosphonic acid, mono- (or di-) alkyl esters of arylphosphonic acids such as mono- (or di-) ethyl esters of phenylphosphonic acid and mono- of phenylphosphonic acid (Or di-) phenyl esters and the like. The trivalent organophosphorus compound is not limited to those described above, and other trivalent organophosphonic acids can be oxidized during the reaction and any one can be used in the present invention as long as it does not adversely affect the reaction.

Salts of the starting material (1) are suitable as metal salts capable of removing sulfur atoms from thio compounds, such as salts of copper, mercury, lead, manganese, and chromium, but are not limited to those described above.

Suitable organic disulfide compounds include, for example, diaryls such as dialkyl sulfides such as dimethyl sulfide, diethyl sulfide, methyl ethyl sulfide, dipropyl sulfide and the like, alkylaryl disulfides such as methylphenyl disulfide, ethylphenyl sulfide and the like, diphenyl disulfide, ditolyl disulfide and the like. Diheterocycle disulfides such as disulfide, di (2-pyridyl) disulfide, di (4-nitro-2-pyridyl) disulfide, di (2-benzothiazolyl) disulfide, di (2-benzimidazolyl) disulfide and the like Etc.

The reaction of the present invention can be carried out in the presence of a reagent capable of removing sulfur atoms from the thio compound to obtain benzamide of the general formula (4) as a high yield. The use of such reagents is particularly useful when the R ₂ groups of the sulfenamide derivatives of formula (2) are for example 2-pyridyl groups, 2-benzothiazolyl groups, 2-benzimidazolyl groups or organic disulfides for example di (2-pyrids). Dill) disulfide, di (2-benzothiazolyl) disulfide, di (2-benzimidazolyl) disulfide.

It is not necessary to use these reagents when used in the form of heavy metal salts of the starting material (1) or when the thio compound obtained during the amidation reaction is a stable compound.

Examples of reagents capable of removing sulfur atoms from thio compounds include inorganic acid salts of heavy metals such as mercuric chloride, zinc chloride, cupric chloride, lead sulfate, and manganese sulfate, urea, succinimide, and phthalimide. Organometallic compounds and heavy metals composed of hydrogen donor organic compounds such as P-nitrophenol, 2-4 dinitrophenol, N-hydroxysuccinimide, and P-methoxyphenol; Sulfenic acid esters such as methyl according to Pearson's theory such as methyl or ethyl or tert-butyl ester of 0-nitrophenylsulfenoic acid, methyl or tert-butyl ester of 2-4dinitrophenyl sulfenic acid, and the like; Olefin compounds such as 2-dihydropyran and n-butyl vinyl ether. Such reagents are not limited to those as described above.

The reaction is usually carried out in the presence of a solvent such as dimethylformamide, pyridine, ether, dioxane, methylene chloride, tetrahydrofuran, benzene, toluene or in any other solvent which has no effect on the reaction itself. do.

The reaction may also be carried out in the presence of acids such as pivalic acid N-hydroxysuccinamide, phenol, P-nitrophenol, picric acid, or the like, or in the presence of a base or water such as tertiary amine, N-alkylmorpholine and the like. The reaction temperature is not limited and can be performed at room temperature.

As a target compound of General formula (4) obtained by this invention, it is, for example,

1-methyl-2- (2-methoxy-5-sulfamoylbenzamidomethyl) -pyrrolidine,

1-methyl-2- (2-hydroxy-5-sulfamoylbenzamidomethyl) pyrrolidine,

1-ethyl-2- (2-methoxy-5-sulfamoylbenzamidomethyl) pyrrolidine,

1-ethyl-2- (2-ethoxy-5-sulfamoylbenzamidomethyl) -piperidine,

1-ethyl-2- [3- (2-methoxy-5-sulfamoylbenzamido) -propyl] pyrrolidine,

1-ethyl-2- [2- (2-methoxy-5-sulfamoylbenzamido) -ethyl] piperidine,

1-ethyl-2- [2- (2-ethoxy-5-sulfamoylbenzamido) -ethyl] pyrrolidine and the like.

The desired compound of formula (4) may be optionally prepared with an inorganic acid salt such as hydrochloride, bromate, phosphate, sulfate; Or organic salts such as acetates, propionates, maleates, tartarates, citrates, salicylates and the like.

The present invention will be described in detail based on the following examples.

EXAMPLE

A solution of 0.64 g of 1-ethyl-2-aminomethylpyrrolidine and 1.4 g of triphenyl phosphine in 6 ml of purified dimethyl formamide was stirred at room temperature with stirring of 1.15 2-methoxy-5-sulfamoylbenzoic acid 1.15 in 4 ml of purified dimethylformamide. g and di (2-pyridyl) di sulfide were added to the solution, and the solution was stirred at room temperature for 1 hour, and then dimethylformamide was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and extracted with 1N hydrochloric acid.

The aqueous layer was alkaline with 1N aqueous sodium hydroxide solution under ice cooling, and the solution was saturated with sodium chloride and extracted twice with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and ethyl acetate was distilled off to give quantitatively 1-ethyl-2- (2-methoxy-5-sulfamoylbenzamidomethyl) pyrrolidine. The compound was recrystallized from a mixed solvent of ethyl acetate and N-hexane to give colorless crystals.

Melting Point: 176-178 ℃

Claims (1)

As described above in the text, the novel sulfenamide derivatives of the following general formula (2) produced by reacting the amino compound of the following general formula (3) with organic disulfide in the presence of an organic compound of trivalent phosphorus Reacting with a salicylic acid derivative of to produce a benzenesulfonamide derivative represented by the following general formula (4).

Food, R ₁ is a hydrogen atom or an alkyl group, R ₂ is an organic residue, R ₃ is an alkyl group, W ₁ and W ₂ are lower alkylene groups.