FI59088B - NYTT FOERFARANDE FOER FRAMSTAELLNING AV BENSENSULFONAMIDDERIVAT - Google Patents

Description

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France-Frankrike (FR) 73 / ^ 2266 (71) Societe d'fitudes Scientifiques et Industrielles de 1'Ile-de-France, - U6, Boulevard de Latour-Maubourg, 75 Paris 7, France-Frankrike (FR) (72) ) Yoshinari Sato, Tokyo, Japan-Japan (JP) (7I +) Oy Kolster Ab (5I +) New method for the preparation of benzenesulfonamide derivatives -Now for the preparation of benzenesulfonamides

The invention is a new process for the preparation of benzenesulfonamides which have interesting pharmacological properties when used as psychotropic drugs and antidotes for emesis.

Of these derivatives, "sulpiride" or 1-ethyl-2- (2-methoxy-5-sulfamyl-benzamidomethyl) pyrrolidine is one of the known compounds.

It has now been found that these compounds can be prepared in maximum yields by applying the new process which is the subject of the invention.

The invention relates to a new process for the preparation of benzenesulfonamides of the formula -f 2 Π:; γ h? No2s wherein R1 and R1 represent an alkyl group.

2 59088

The invention is characterized in that the amine compound of formula

- CH

H N-CH --- I (III) “2 wherein is as defined above is reacted with di (2-pyridyl) disulfide to give a sulfenamide derivative of the formula -O 2. S-NH-CH-— J (II)

J

R2 wherein is as defined above and that the compound of formula (II) is reacted with a salicylic acid derivative of formula

H2N02S

wherein is as defined above, or with a salt thereof, in the presence of triphenylphosphine.

It is known from the patent applications 27 ^ 3/7 ^, 1076/71 *, 3553/73, 3361/71 and 25 ^ 9/72 to prepare N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzene. amide in the presence of a phosphorus compound from compounds of formula III and I in 59%, 20%, 82.7%> 7.3% and 3% yields, respectively. With the new process according to the invention, this compound can be prepared in practically quantitative yields.

The saccharified benzoic acid of formula (I) used as a starting material is described in U.S. Patent 3,3 ^ 2,826.

The new sulfenamide derivative (II) can be isolated from the reaction mixture or not isolated.

In the starting compound (i) and the novel sulfenamide derivative (II), the alkyls represented by Rgt can be, for example, methyl, 3,59088 ethyl, propyl, isopropyl, butyl, pentyl, etc.

The reaction according to the invention is generally carried out in a solvent such as dimethylformamide, pyridine, ether, dioxane, methylene chloride, tetrahydrofuran, benzene, toluene, etc., i.e. all solvents inert to the reaction.

The reaction of the invention may be carried out in the presence of an acid, for example pivalic acid, N-hydroxysuccinimide, phenol, p-nitrophenol, picric acid, etc., or a base such as triethylamine, n-alkylmorpholine, etc., or water.

The reaction temperature is not limited, and the reaction can be carried out at room temperature.

According to the invention, for example, the following benzamides (N) can be prepared: 1-methyl-2- (2-methoxy-5-sulfamylbenzamidomethyl) -pyrrolidine 1-methyl-2- (2-hydroxy-5-sulfamylbenzamidomethyl) -pyrrolidine 1-ethyl- 2- (2-Methoxy-5-sulfamylbenzamidomethyl) -pyrrolidine 1-Ethyl-2- (2- (2-methoxy-5-sulfamylbenzamido) -4-propyl) -4-pyrrolidine-1-ethyl-2- [2- (2- ethoxy-5-sulfamyylibentsamido) -etyylj7-pyrrolidine.

The benzamides (IV) formed according to the process of the invention can, if necessary, be converted into salts with mineral acids, e.g. hydrochlorides, hydrobromides, phosphates, sulphates, etc., or salts of organic acids, e.g. acetate, propionate, maleate, tartrate, citrate, citrate, , and so on.

The following example illustrates the invention.

Example 6 ml of a solution of 0.6 kg of 1-ethyl-2-aminomethylpyrrolidine and 1.0 μg of triphenylphosphine in purified dimethylformamide were added at room temperature with stirring to a solution of 1.15 g of 2-methoxy-5-sulfamylbenzoic acid and 1.2 ml of g of di- (2-pyridyl) disulfide in 1 ml of purified dimethylformamide.

The mixture was kept under stirring for 1 hour at room temperature, after which dimethylformamide was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and then extracted with 1N hydrochloric acid.

The aqueous layer was basified with 1 N aqueous sodium hydroxide solution and cooled with ice. The solution was saturated with sodium chloride and then extracted twice with ethyl acetate. The organic base was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the ethyl acetate was removed by distillation.

1-Ethyl-2- (2-methoxy-5-sulfamylbenzamidomethyl) -pyrrolidine was quantified.

This material was recrystallized from a mixture of ethyl acetate and normal hexane to give colorless crystals of m.p. was 176-1T8 ° C.

Claims (2)

h 59088 Claim: A new process for the preparation of benzenesulfonamides of the formula I-CHo CO-NH-CH -L | 2 LT i (IV> H 2 NO 2 S 2 wherein R 1 and R 2 represent an alkyl group, characterized in that the amine compound of the formula -CH HpN-CH ---- 12 2 2 (III> wherein the same as above is reacted with di ( 2-pyridyl) disulfide to give a sulfenamide derivative of the formula I-CH 0 aS-NH-CH-J ---- I 2 (II) R 2 wherein R 2 is as defined above, and that the compound of formula (II) is reacted with a salicylic acid derivative with a woman of formula co2h T u) h2no2s wherein R is as defined above, in the presence of triphenylphosphine.