FI73412C - 2-methoxy-4-amino-5-alkylthio (or alkylsulfonyl) benzoic acid derivative. - Google Patents

Description

1,73412 2-Methoxy-4-amino-5-alkylthio (or alkylsulfonyl) benzoic acid derivatives

Separated by application 790182 5

The invention relates to 2-methoxy-4-amino-5-alkylthiobenzoic acid derivatives of formula II.

jc \

COOH

10 OCH

I XIA

nh2 wherein R2 is a methyl, ethyl, propyl or isopropyl group.

The invention also relates to 2-methoxy-4-amino-5-alkylsulfonylbenzoic acid derivatives of formula II_

B

COOH

20 (O '^ -OCH- I ΙΙβ R2 ° 2S “" V / nh2 25 where R2 is the same as in formula IIA ·

Compounds of formula IIA and ΙΙβ are useful as intermediates in the preparation of therapeutically active 4-amino-5-alkylsulfonyl-ortho-anisamides of formula I

30 _

Jonh-CH-_L

V0CH3

Ij Rj 1

35 R202S

nh2 2 73412 having a methyl, ethyl, propyl or allyl group and R2 has the same meaning as in formulas IIA and ΙΙβ ·

The 4-amino-5-alkylsulfonyl-ortho-anisamides of the formula (I) are new, valuable compounds with antiemetic and antiulcer activity, as shown by the following results of the comparative experiments: The compounds of the formula (I) studied 1: N- (ethyl 2-Pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide 2: N- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide 3: N- (1- Allyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide 7: N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-propylsulfonylbenzamide 8: N- (1 -ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide 9: N- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide.

10: N- (1-propyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide 11: N- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5- isopropyylisulfonyylibentsamidi

Reference compound: N- (1-ethyl-2-pyrrolidylmethyl-2-methoxy-5-sulfamoylbenzamide (sulpiride)

The results are shown in the following table.

fsxrX-

Compound 12 3 7 8 9 10 11 pyride 30 ED50 anti-0.29 0.8 0.65 1.6 2.7 7 1.5 7.5 3.5 emetic (μg / kg) ED wound 1 0.4 0.65 3.2 3 1.14 2 7.5 110 35 Antimony (mg / kg) | |

II

3,73412

The process for the preparation of the compounds of formula I involves the treatment of 2-methoxy-4-amino-5-mercaptobenzoic acid with alkyl sulphate, the oxidation of the 2-methoxy-4-amino-5-alkylthiobenzoic acid of formula II thus obtained with hydrogen-5 peroxide to give 2-methoxy-4 -amino-5-alkylsulfonyl-benzoic acid, or an active derivative thereof (such as its acid halide, alkyl ester, reactive ester, for example methoxymethyl ester or cyanomethyl ester, aromatic ester, N-hydroxyimide-10 ester, symmetrical anhydride anhydride formed, for example, from a carboxylic acid ester or haloformic acid ester, azide, hydrazide, azolid, acid isothiocyanate, trichloroacetophenone or triphenylphosphine derivative) is then treated with an amine of formula III

III

h2n to ch2 -k N2 is as defined in formula I, or with a reactive derivative thereof, such as a derivative obtained by reacting an amine with phosphorus chloride, phosphorus oxychloride, dialkyl, diaryl or orthophenylene-2 chlorophosphite, with an alkyl or aryl dichlorophosphite with an amine isothiocyanate or a substituted urea or sulfamide.

The amidation reaction can be carried out in situ or after the reactive derivative formed as an intermediate has been isolated.

It is equally possible to react the free acid and the free amine in the presence of a condensing agent such as silicon tetrachloride, trichlorophenylsilane, phosphoric anhydride, carbodiimide or alkoxyacetylene.

4,73412

Compounds of formula I may be similarly prepared by reacting an acid of formula II or an active derivative thereof as defined above with a dihaloalkylamine of formula IV

5

/ \ IV

H2N - CH2 __ \ 1V

x Hai Hai '

In 10 j, Hai is a chlorine or bromine atom, followed by administration of the resulting compound of formula V

/ \ CONHCH „~~~ \ / ^ x Hai Hai 15 / 0CHo Y 3 v

R2 2S °

nh2 to react with an amine of formula: h2n - rx VI, 25 as defined above.

The amidation reaction can be carried out with or without a solvent.

Solvent-neutral systems for the amidation reaction include, for example, alcohols, polyols, ketones, benzene, toluene, dioxane, chloroform or diethylene glycol dimethyl ether. The amine used as a raw material can be similarly used as a solvent by using this in excess. Heating the reaction mixture during amidation, e.g. at the boiling temperature of the above-mentioned solvents, may be advantageous.

To illustrate the essential features of the invention, a few examples are given below.

Il 5 73412

Example I

N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide 2-methoxy-4-amino-5-ethylthiobenzoic acid 5,159 g of 2-methoxy-4-amino-5-mercaptobenzoic acid , 3 3 355 cm of water and 160 cm of caustic soda solution are placed in a flask fitted with a condenser. The mixture is heated until the solid dissolves, then 123 g of ethyl sulfate are added. The mixture is heated to boiling, 10 cm 10 of 30% caustic soda solution is added and then boiled for 3 hours. After cooling, 800 cm of water 3 are added and the solution is filtered. The precipitate obtained by adding 100 cm of concentrated hydrochloric acid in the presence of ether is filtered off, washed with water and dried.

162 g of 2-methoxy-4-amino-5-ethylthio-benzoic acid are obtained (yield 88%).

2-Methoxy-4-amino-5-ethylsulfonyl-benzoic acid 123 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid are dissolved hot in 542 cm of acetic acid. The resulting solution is cooled to 35 ° C, then a small portion of 185 cm -1 131 vol is added. hydrogen peroxide as the temperature rises to 80 ° C.

The temperature is lowered to 40 ° C and the mixture is kept at this temperature for a few hours, and then cooled to 10 ° C.

The precipitate formed is filtered off, washed with acetic acid and dried, then dissolved in 600 cm 3 of water and 100 cm of 20% ammonia.

The precipitate formed on addition of 70 cm @ 2 concentrated hydrochloric acid is cooled, filtered off, washed with water and dried.

61.5 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid hydrate are obtained (yield 42%, m.p. 95-100 ° C).

N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide 35 81 g of 2-methoxy-4-amino-5-ethylsulfonyl-benzoic acid 3a 297 cm of acetone are placed in a flask. , to which a stirrer, a thermometer and a dropping funnel are attached, and then 6 73412 33 g of triethylamine are added. The solution is cooled to 0 ° C, then 30 g of ethyl chloroformate are added dropwise at 0-5 ° C.

At 5-10 ° C, 51 g of 1-ethyl-2-aminomethylpyrrolidine are added dropwise with stirring. The mixture is stirred at 10 ° C and then at ambient temperature. The precipitated triethylamine hydrochloride is filtered off, after which the acetone is distilled off. The residue is dissolved in 600 cm @ 4 of water in the presence of a caustic soda solution. The base crystallizes after seeding and is filtered off, washed with water and dried.

After purification of the crystals by hydrochloride treatment and recrystallization from acetone, 66 g of, ΛΙ-ethyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonyl-15-benzamide are obtained (yield 61%, m.p. 126-127 ° C). .

Example II

N-N-methyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonyl-benzamide 144 g of 2-methoxy-4-amino-5-ethylsulfonyl-benzoic acid, 440 cm of acetone and 44.5 g of the triethylamine is placed in a flask equipped with a stirrer, a thermometer and a dropping funnel. The solution is cooled to 0 ° C, then 48 g of ethyl chloroformate are added dropwise at 0-15 ° C.

The mixture is stirred for 30 minutes at 0-5 ° C, after which 67 g of 1-methyl-2-aminomethylpyrrolidine are added dropwise at 5-10 ° C. The mixture is then stirred first at 10 ° C and then at room temperature. The product 3 obtained is filtered off, washed with acetone, treated with 500 cm <3> of water, then filtered, washed with water and dried.

The material obtained is recrystallized from absolute alcohol and purified by hydrochloride. Recrystallization from absolute alcohol gives 101 g of 35 N, N-methyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonylbenzamide (yield 65%, m.p. 157-158 ° C).

v 73412

Example III

N-N-allyl-2-pyrrolidylmethyl 17-2-methoxy-4-amino-5-ethylsulfonyl-benzamide 132 g of 2-methoxy-4-amino-5-ethylsulfonyl-benzoic acid-3 5 poa, 510 cm of acetone and 51.5 g of triethylamine are placed in a flask equipped with a stirrer, a thermometer and a dropping funnel. The resulting solution is cooled to 0 ° C, then 55.5 g of ethyl chloroformate are added dropwise at 0-5 ° C.

The mixture is stirred for 30 minutes at 5 ° C, then 96 g of 1-allyl-2-aminomethylpyrrolidine are added dropwise at 5-10 ° C. The mixture is stirred at 10 ° C and then at room temperature.

The precipitated triethylamine hydrochloride is filtered off and washed with acetone, after which the acetone is distilled off. The residue is dissolved in water and 60 cm of concentrated hydrochloric acid, after which the resulting solution is filtered and treated with 30% caustic soda solution. The resulting oil is extracted with methylene chloride, then the organic solution is dried over potassium carbonate and the methylene chloride is distilled off.

After purification, 131 g of N- [T.-allyl-2-pyrrolidylmethyl] -2-methoxy-4-amino-5-ethylsulfonylbenzamide are obtained (yield 67%, m.p. 110-112 ° C).

25 Example IV

N-Ethyl-2-pyrrolidylmethyl-147-2-methoxy-4-amino-5-ethylsulfonylbenzamide dextrorotatory tartrate

Right-rotating N - [(1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide Following the same procedure as in Example I, 95 grams of 2-methoxy-4-amino-5-ethylsulfonyl-benzoic acid are treated Dissolved in 370 ml of acetone, in the presence of a 37 gram portion of triethylamine, with 40 grams of ethyl chloroformate and then with 57 grams of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine.

115 g of dextrorotatory N- [T.-ethyl-2-pyrrolidylmethyl] -2-methoxy-4-amino-5-ethylsulfonyl-β 73412 benzamide are obtained (yield 84%).

N-Z1-ethyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonylbenzamide dextrorotatory tartrate 133 g of dextrorotatory N-ZT1-ethyl-2-pyrrolidyl-5-methyl-2-methoxy-4-amino-5 -ethylsulfonyl-benzamide is dissolved in 500 money of methanol, followed by the addition of 54 g of dextrorotatory tartaric acid dissolved in 80 ml of methanol. The crystals formed after seeding are filtered off, washed with methanol and dried.

After recrystallization from methanol, 106 g of N- (3-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide dextrorotatory tartrate are obtained (yield 56%, m.p. 98-108 ° C,? .I7 20 ° C in 5% aqueous solution = +7 °, 5).

15 Example V

N-E-L-ethyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonylbenzamide levorotatory tartrate

Left-turning N-ZT.-ethyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonyl-benzamide Following the same procedure as in Example I

104 grams of 2-methoxy-4-amino-5-ethylsulfonylbenzic acid, dissolved in 380 ml of acetone, are treated, in the presence of a 38 gram portion of triethylamine, with 41 grams of ethyl chloroformate followed by 58 grams of levorotatory 1-ethyl -2-aminomethyl-pyrrolidine.

140 g of levorotatory N-ε-ethyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulphonylbenzamide are obtained (yield 100%).

N- [3-ethyl-2-pyrrolidylmethyl] -2-methoxy-4-amino-30-ethylsulfonylbenzamide levorotatory tartrate 136 g levorotatory NZR] L-ethyl-2-pyrrolidylmethyl-2-methoxy 4-Amino-5-ethylsulfonyl-benzamide is dissolved in 500 ml of methanol, then 58 g of levorotatory tartaric acid dissolved in 70 ml of methanol are added.

The crystals formed are filtered off, washed with methanol and dried.

After recrystallization from methanol, 103 g of 103 g of N, N-ethyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulphonylbenzamide levorotatory tartrate are obtained (yield 54%, m.p. 100 ° C, 20 ° C 5%). - in aqueous solution = -6 °, 3).

5 Example VI

N-ZJ-methyl-N-pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonylbenzamide

Following the same procedure as in Example I, 115 grams of 2-methoxy-4-amino-5-ethylsulfonyl-benzoic acid-10a po are treated with 450 g of any acetone dissolved in the presence of a 46 g portion of triethylamine, 49 grams of ethyl chloroformate and then 69 grams to the right. circulating 1-methyl-2-aminomethylpyrrolidine.

69 g of dextrorotatory N-ZZ1-methyl-2-15 pyrrolidylmethyl-2-methoxy-4-amino-5-ethylsulfonylbenzamide are obtained (yield 44%, m.p. 125-126 ° C, C in 1% dimethylformamide solution = + 35.3 °). Example VII

N- (L-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-20-propylsulfonylbenzamide 2-Methoxy-4-amino-5-propylthiobenzoic acid Following the same procedure as in Example I and using as starting material 2 -methoxy-4-amino-5-mercapto-benzoic acid, 2-methoxy-4-amino-5-propylthio-benzoic acid-25 poa is obtained (m.p. 104-105 ° C).

2-Methoxy-4-amino-5-propylsulfonyl-benzoic acid Following the same procedure as in Example I, 137 g of 2-methoxy-4-amino-5-propylthio-benzoic acid are dissolved in 570 ml of acetic acid dissolved in 233 ml of 30,110 vol. . hydrogen peroxide. 108 g of 2-methoxy-4-amino-5-propylsulfonyl-benzoic acid are obtained (yield 69%, m.p. 165-166 ° C).

N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-propylsulfonyl-benzamide 35 Following the same procedure as in Example I

160 grams of 2-methoxy-4-amino-5-propylsulfonylbenzoic acid are treated with 590 g of any acetone dissolved in the presence of a 2 gram portion of triethylamine, 64 grams of ethyl chloroformate and then 101 grams of 1-ethyl-2-aminomethylpyrrolidine.

After purification, 151 g of N- [1-ethyl-2-5-pyrrolidylmethyl] -2-methoxy-4-amino-5-propylsulfonyl-benzamide are obtained (yield 67%, m.p. 105-106 ° C).

Example VIII

N-Z-Methyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-methylsulfonyl-benzamide 10-Methoxy-4-amino-5-methylthio-benzoic acid

Following the same procedure as in Example I and starting from 2-methoxy-4-amino-5-mercapto-benzoic acid, 2-methoxy-4-amino-5-methylthio-benzoic acid (m.p. 151-152 ° C) is obtained.

15 2-Methoxy-4-amino-5-methylsulfonyl-benzoic acid

Following the same procedure as in Example I, 159 grams of 2-methoxy-4-amino-5-methylthiobenzoic acid are treated with 7 ml of acetic acid dissolved in 310 ml of 110 vol. hydrogen peroxide.

114.5 g of 2-methoxy-4-amino-5-methylsulphonylbenzoic acid are obtained (yield 63%, m.p. 178-180 ° C).

N- (l-methyl-2-pyrrolidyylimetyyli) -2-methoxy-4-amino-5-methylsulfonyl-benzamide

Following the same procedure as in Example I

25,131 grams of 2-methoxy-4-amino-5-methylsulfonylbenzoic acid dissolved in 538 ml of acetone in the presence of a 54 gram portion of triethylamine are treated with 58.5 grams of ethyl chloroformate and then with 73 grams of 1-methyl 2-aminomethylpyrrolidine. .

After purification, 114 g of N, N-methyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-methylsulfonylbenzamide are obtained (yield 62%, m.p. 190-191 ° C).

Example IX

35 N- [1-ethyl-2-pyrrolidylmethyl] -2-methoxy-4-amino-5-methylsulfonylbenzamide

Following the same procedure as in Example I

I! n 73412 129 grams of 2-methoxy-4-amino-5-methylsulfonyl-benzoic acid dissolved in 526 ml of acetone are treated, in the presence of a 53 gram portion of triethylamine, with 57 grams of ethyl chloroformate and then with 81 grams of 1-ethyl-2 -5 aminonethyl pyrrolidine.

After purification, 96 g of N, N-ethyl-2-pyrrolidylmethyl-2-methoxy-4-amino-5-methylsulfonylbenzamide are obtained (yield 52%, m.p. 151-151.5 ° C).

10 Example X

258.3 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide N-oxide are placed in a 2-liter flask equipped with a stirrer and a thermometer. -2-pyrrolidyl-15-methyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide and 875 ml of absolute ethanol, and 142 ml of a 110 vol. hydrogen peroxide. The mixture is heated at 45 ° C for a few hours, then cooled to 40 ° C and 2 g of manganese dioxide are gradually added.

After addition of charcoal and filtration, the solvent is removed in vacuo. The residue obtained is dissolved in 200 ml of ethanol and 150 ml of acetone, after which the solution is filtered and the filtrate is poured into 2 l of ethyl ether. The crystals formed are filtered off, washed with ether and dried.

140 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide are obtained (m.p. 190 DEG C. with decomposition, yield 52%).

Example XI

N-oxide of N- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide A 24-liter flask equipped with a stirrer and a thermometer is charged with 248.5 g of N- (1- methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide and 35,875 ml of absolute ethanol, followed by the addition of 142 ml of 110 vol. hydrogen peroxide. The mixture is heated for a few hours at 45 [deg.] C., then cooled to 72 [deg.] C. and 40 g, and 2 g of manganese dioxide are gradually added.

The solution is filtered, then the solvent is removed in vacuo and the residue is dissolved in 500 ml of acetone. The crystals formed are filtered off and dried, and then dissolved in a liter of hot ethanol. After adding a 20 gram portion of charcoal, the solution is cooled and then poured into one liter of ethyl ether. The formed crystals are filtered off, washed and dried.

190 g of N-oxide of N- (1-methyl-2-pyrrolidylmethyl) -2-10-methoxy-4-amino-5-ethylsulphonyl-benzamide are obtained (m.p. 200-210 ° C with decomposition, yield 73%).

Example XII

N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide Mixed anhydride of ethyl hydrogen carbonate and 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid

77.7 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and 500 ml of dry dioxane are placed in a flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel, and 30.3 g of triethylamine are added dropwise.

The mixture is cooled to 20 ° C and then 32.5 g of ethyl chloroformate are added dropwise keeping the temperature at 20 ° C. The mixture is stirred and filtered, and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 500 ml of carbon tetrachloride, after which crystallization is initiated by seeding.

The crystals formed on cooling the mixture are filtered off, washed and then dried.

74 g of anhydride are obtained (m.p. 77 ° C, yield 74.5%).

N- (2,5-diklooripentyyli) -2-methoxy-4-amino-5-ethyl-sulfonyl-benzamide

A flask equipped with a stirrer, thermometer and condenser is charged with 4.33 g of 2,5-dichloropentyl-35-lamine hydrochloride, 65 ml of dimethylformamide and 2.27 g of triethylamine, followed by 7.47 g of ethyl hydrogen carbonate and 2-methoxy- 4-Amino-5-ethylsulfonyl-benzoic acid mixed

II

13 7341 2 anhydrides.

The mixture is stirred at room temperature for one hour, then 100 ml of water and 10 ml of hydrochloric acid are added.

The suspension obtained is evaporated to dryness in vacuo, after which time the residue is dissolved in 100 ml of water. The formed crystals are filtered off, washed with water and then dried in an oven at 50 ° C.

6.5 g of N- (2,5-dichloropentyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide are obtained (m.p. 109 ° C, yield 73%).

N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide 5.95 g of N- (2,5-dichloropentyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide and 22 ml of a 56% aqueous solution of ethyl-15 amine is placed in a flask equipped with a stirrer.

The mixture is stirred until the solids are completely dissolved, then the solution is heated in an oven at 40-45 ° C until the reaction is complete.

The solvent is evaporated off and the residue is taken up in 100 ml of water and 5 ml of caustic soda solution.

After extraction twice with methylene chloride, the organic phase is dried over magnesium sulphate and filtered, after which the solvent is evaporated off under vacuum.

The residue is dissolved in 10 ml of acetone at the boiling point, after which the crystals formed on cooling are filtered off and dried in an oven at 50 ° C.

3 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide are obtained (m.p. 125 ° C, yield 54%).

Claims (6)

1. Intermediates used in the preparation of therapeutically active 4-amino-5-alkylsulfonyl ortho-anisamides of the formula I CONH - CH1 - 2 N , ethyl, propyl or allyl group and R 2 is a methyl, ethyl, propyl or isopropyl group, characterized in that they are 2-methoxy-4-amino-5-alkylthiobenzoic acid derivatives of the formula IIft COOH 20A. (s' A-AND, JIA R2S- ^ y ^ nh2) where R2 is as defined above. 2. Intermediates used in the preparation of 4-amino-5-alkylsulfonyl ortho-anisamides of formula I - CONH - CH, L i R „09S — J 35 2 2 nh2 li