JPS6015616B2 - Method for producing N-2-(pyrrolidinylmethyl)-substituted benzamide derivative or salts thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel N-(2-pyrrolidinylmethyl)-substituted penzamide derivative and a method for producing its pharmaceutically acceptable acid salts or quaternary ammonium salts. .

The target penzamide derivative of the present invention is represented by the following general formula.

[In the formula, A is a hydrogen atom or a lower alkyl group x is a hydrogen atom or a lower alkoxy group, Y is a hydrogen atom or an amino group, Z is hydrogen Fujiko, a halogen atom, a lower alkoxy group,
Lower alkylsulfonyl group or S02NR, R2 group (
Here, R and R2 are the same or different and are hydrogen or a lower alkyl group.

) respectively]] The reaction according to the present invention is as follows. A compound represented by the general formula [wherein B is a halogen atom or a hydroxy group, and A, By reacting an amine or a reactive derivative thereof, the target substance N1 (2
-pyrrolidinylmethyl) substituted penzamide derivative (1)
and, if necessary, convert it into pharmaceutically acceptable acid salts or quaternary ammonium salts thereof.

In the definitions of A, X and Z in the above compounds (1) and (b), examples of lower alkyl and lower alkoxy include C, -5 alkyl and C, -5 alkoxy. The reactive derivatives of are reactive derivatives at the carboxy group, such as carboxylic acid esters such as methyl ester, ethyl ester, propyl ester, butyl ester, isobutyl ester, benzyl ester, cyanomethyl ester, methoxymethyl ester, N- reactive esters such as hydroxyimide esters, substituted or unsubstituted aromatic esters, acid hydracides, acid azides, symmetrical acid anhydrides, mixed acid anhydrides such as lower alkyl haloformates, triazolides, tetrazolides or imidazolides; Examples include azolides and isocyanates, but the present invention is not limited to these derivatives.

In the present invention, reactive derivatives of the amine (m) include phosphorus chlorides, phosphorus oxychlorides, dialkyl or diaryl or orthophenylenechlorophosphites, alkyl or aryl dichlorides of the amine.

A reaction product with a phosphite or an isothiocyanate of an amine can be used. These reactive derivatives can be reacted as such or after separation with an acid. It is also possible to react the free acid and the free amine in the presence of a condensing agent such as silicate tetrachloride, phosphoric anhydride or a carbodimide such as dicyclohexylcarbodimide.

The amidation reaction of the present invention is carried out in the presence or absence of a solvent. Examples of inert solvents that can be used in the amidation reaction include alcohols, polyols, benzene,
Examples include toluene, dioxane, chloroform, diethylene glycol dimethyl ether, and the like. Moreover, an excess amount of the amine used as a starting material can also be used as a solvent. The amidation reaction is preferably carried out by heating to the boiling point of the solvent, for example. The compounds obtained by the method of the present invention may be combined with pharmaceutically acceptable inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, methanesulfonic acid, etc., if necessary. It can be converted into a salt with an acid, and can also be converted into a quaternary ammonium salt by reacting with an alkyl sulfuric acid, an alkyl halide, etc., if necessary.

The penzamides obtained according to the invention have significant therapeutic activity and are particularly useful as antiemetics, antiulcer agents and central nervous system improving agents. Its toxicity is low and it can be used for human treatment without the risk of exhibiting side effects. Examples are shown below to demonstrate the technical features of the present invention, but the present invention is not limited thereto.

Example 1 N-(Z-pyrrolidinylmethyl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 2-methoxy-
Methyl 4-acetamido-5-chlorobenzoate 51.5
Evening, water 20 [and 2-amino/methylpyrrolidine 40
The mixture is introduced into a round bottom flask equipped with a thermometer and thermometer.

The mixture is heated to reflux for 7 hours and then cooled. To this was added 50 parts of water and 50 parts of 40% sodium hydroxide solution, and the mixture was heated under reflux for 2 hours. After cooling, the resulting crystals are washed with water and dried at 50 quarts in a dryer to obtain the desired penzamide 32 as a free salt. This hot alcoholic solution of the base is filtered in a hot oven and hydrochloric acid (d=1.18) is added to precipitate the hydrochloride.

After cooling, the formed crystals were taken in a furnace, washed with ethanol, and dried at 50 qo in a dryer to give N-(2-pyrrolidinylmethyl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride at 24.2 qq. obtained (melting point: 1670
). Example 2 N-(2'-pyrrolidinylmethyl)-2-methoxy4
-Amino-5-sulfamoylbenzamide 2-methoxy-4-amino-5-sulfamoylbenzoate methyl 1
After 40 minutes, 48.5 parts of water and 80 parts of 2-aminomethylpyrrolidine are introduced into a flask equipped with a condenser.

The resulting suspension is heated on a water bath. After cooling, the reaction mixture is diluted with 540 °C of water and the resulting solid is taken off, washed with water and dried at 460 °C. The generated base is converted into hydrochloride, and 2
Re-precipitate with 0% ammonia water, take out the furnace, wash thoroughly and
When dried at ℃, N-(2-pyrrolidinylmethyl)-2
-Methoxy4-amino-5-sulfamoylbenzamide 97% is obtained (yield: 54.8%, melting point 205
~206°C).

Example 3 N-(2-pyrrolidinylmethyl)-2-methoxy5-
Ethylsulfonylbenzamide N-penzyl-2-aminomethylpyrrolidine 130%, methyl ethyl ketone 62
0 and 2-methoxy-5-ethylsulfonylbenzoyl chloride 16 while maintaining the temperature between 5 and 10.
2.6 hours is introduced into a flask equipped with a strainer, condenser and thermometer.

Let this sit for an hour without heating. The resulting crystals are filtered, washed with a small amount of methyl ethyl ketone, and then dissolved in hot ethanol. After cooling, the crystals formed are taken out in a furnace, washed and dried, and then mixed with 500 g of water and 150 g of Raney nickel.
Put it in the autoclave with the mixture and reduce the pressure to 17.
Hydrogen is introduced until the temperature reaches 0k9. Heat the mixture to 10°C for 4 hours. After cooling, the nickel is washed with water taken from the furnace. The solvent was distilled off under reduced pressure, and the residue was treated with a mixture of 25% 36% hydrochloric acid and water until the liquid volume reached 500%. After heating to 80°C, it is filtered and made alkaline with 40% sodium hydroxide solution.

After cooling, the crystals formed are taken out in a furnace, washed with water, and dried.
111.5 ml of -(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide is obtained (yield: 70.3%, melting point: 150q○). Example 4 N-(2-pyrrolidinylmethyl)-2-methoxy-4-aminobenzamide 2-aminomethylpyrrolidine In a solution of 2 parts of pyridine, 1.4 parts of phosphorus trichloride was added to 8 parts of pyridine.
The solution dissolved in the solution is dropped into the fly bath while maintaining the temperature at 0 to 5°C.

Further heating is continued at 0 to 5°C and then at room temperature. After adding 1.6 g of 2-methoxy-4-aminobenzoic acid to this, the mixture was heated for several hours. After the reaction mixture is cooled and the solvent is removed, the residue is dissolved in chloroform, this solution is washed with an aqueous sodium carbonate solution, and dried over anhydrous magnesium sulfate.

Concentration under reduced pressure yields N-(2'-pyrrolidinylmethyl)
1.5 times of -2-methoxy 4-aminopenzamide is obtained (yield: 62.8%, melting point: 98°C). Example 5 N-(2-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonylbenzamide In a round bottom flask equipped with a column vessel and a thermometer, methyl ethyl ketone 750
, N-benzyl-2-aminomethylpyrrolidine 103 ml was added, and then 2 ml was added while maintaining the temperature at 15-20 pm.
-Methoxy-5-methylsulfonylbenzoyl chloride 133 is introduced.

The reaction mixture was allowed to stand at room temperature for 2 hours. The resulting solid is filtered, treated with ice-cold methyl ethyl ketone, and dissolved in ethanol. The crystals obtained on cooling are filtered, rinsed and dried, and then introduced into an autoclave with 1 night of water and 20 nights of Raney nickel. After sealing, hydrogen was introduced at a pressure of 130 k9 and the mixture was heated to 10
Heat to 0°C for 4 hours. After cooling, the nickel is filtered through a furnace and washed.

Next, the solvent is distilled off under reduced pressure. Treat the residue with water and add hydrochloric acid to make 500 ml. The resulting solution is heated to 80° C., heated and made alkaline with sodium hydroxide.
After cooling, the crystals formed are filtered, washed with water, and dried. N
-(2'-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonyl benzamide was obtained (yield: .9%, melting point: 152.500). Example 6 N-(2'-pyrrolidinylmethyl)-2-methoxy-5
-Ethylsulfonylbenzamide 7.3 hours of 2-methoxy-5-ethylsulfonylbenzoic acid, 200 hours of Z of tetrahydrofuran, and 7.3 hours of carponyldimidazole are introduced into a round bottom flask equipped with a steamer and a condenser.

After the mixture was incubated at room temperature for 3 females, 4.8 hours of 2-aminomethylpyrrolidine was added.

After continuing Nada-azusa at room temperature, the solvent was distilled off under reduced pressure. The residual bamboo is dissolved in hydrochloric acid, the resulting solution is filtered, and sodium hydroxide is added to form the shaft 12-13. This mixture is extracted with chloroform. Dry, filter and remove the solvent under reduced pressure. Purification with ethanol yields 6.5% of N-(2'-pyrrolidinylmethyl)-12-methoxy-5-ethylsulfonylbenzamide (yield: 665%, melting point: 150°C). Example 7 N-(2-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide hydrochloride Acetone 1 and N-benzyl-2
200 mg of aminomethylpyrrolidine are introduced into 4 flasks equipped with a flask and a thermometer.

The mixture was cooled to 0°C and 2,3-dimethoxy-5-
280 mg of sulfamoylbenzoyl chloride is added and the temperature of the reaction system is maintained below 10°C. The mixture was allowed to coagulate for 4 hours, the resulting precipitate was filtered off, purified on a furnace with acetone, and mixed with 1200 parts of water, hydrochloric acid (d=1.
18) Introduce into an autoclave with 40 ml and 5 tsp.

After sealing, hydrogen is introduced to bring the pressure to 140k9. The mixture is heated at 100° C. for 4 hours. After cooling, the nickel is filtered through a furnace, and 150 ml of ammonia is added to the reaction solution to make it alkaline. The resulting precipitate was taken off in an oven, dried, dissolved in 150' of absolute ethanol at boiling temperature, and diluted with 4 ml of ethanolic hydrochloric acid.
Make it acidic with [0]. After cooling, the obtained crystals are collected in a furnace,
Wash thoroughly and dry at 50°C. 95% of N-(2-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide hydrochloride is obtained (melting point: 195-1 pseudo°C). Example 8N-(2-pyrrolidinylmethyl)-2
-Methoxy5-sulfamoylbenzamide ethyl 2-methoxy5-sulfamoylbenzoate 51.8 minutes,
2-aminomethylpyrrolidine and butanol
00' is introduced into the flask.

The mixture is heated to reflux for 7 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was recrystallized from dimethylformamide to obtain the desired penzamide 51 (yield: 73%).
). By further repeating the recrystallization, N-(2'-pyrrolidinylmethyl)-12-methoxy-5-sulfamoylpenzamide 43 was obtained (yield: 61.5%, melting point: 185
afternoon C).

Claims (1)

[Claims] 1 General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, A is a hydrogen atom or a lower alkyl group, B is a halogen atom or a hydroxy group, X is a hydrogen atom or a lower alkoxy group, Y is a hydrogen atom or an amino group, Z is a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkylsulfonyl group, or an SO_2NR_1R_2 group (where R_1 and R_2 are the same or different and are hydrogen or a lower alkyl group). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A dextro-, levorotatory-, or racemic-type amine or its reactive derivative represented by ▼ is reacted with a compound represented by [respectively meaning] or its reactive derivative, and the general formula is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Obtain the N-(2-pyrrolidinylmethyl) substituted benzamide derivative represented by [In the formula, A, X, Y and Z are the same as above], and if necessary, 1. A method for producing an N-(2-pyrrolidinylmethyl)-substituted benzamide derivative or a salt thereof, which is characterized by leading to a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof.