DE2008692A1 - Process for the preparation of indole-3carboxylic acid derivatives and new compounds obtainable by the process - Google Patents

Description

The present invention relates to a new process for the preparation of derivatives of indole-3-carboxylic acid as well as new derivatives which can be prepared by this process.

The indole-3-carboxylic acid derivatives which can be prepared by the process according to the invention have the following formula (I) in which R [deep] 1 and R [deep] 2, which can be the same or different, represent hydrogen or optionally substituted alkyl, aralkyl or aryl radicals or, together with the nitrogen atom, a 5-, 6- or 7- form a membered ring, which can optionally have a 2nd heteroatom, in particular a further nitrogen atom, and in which X and Y, which can be identical or different, hydrogen, halogen atoms, alkyl or alkoxy radicals with 1-5 carbon atoms, aralkoxy radicals, the trifluoromethyl group Represent, hydroxyl, amino, carboxyl, or sulfonic acid groups or their functional derivatives.

The process according to the invention is characterized in that a derivative of 2-aminophenylcyanoacetic acid of the formula (III)

in which R [deep] 1, R [deep] 2, X and Y have the above meaning, subjected to hydrogenolysis.

To carry out the process, a derivative of 2- (2-nitrophenyl) cyanoacetic acid of the following formula II, in which R [deep] 1 and R [deep] 2 have the above meanings, while X 'and Y' have the meanings of X and Y, but can also represent nitro groups, reduce: (II)

Compound III is obtained as an intermediate product, which is generally not isolated, but is directly subjected to hyrogenolysis, giving indole I with loss of ammonia.

If X 'or Y' are NO [deep] 2 or aralkoxy groups in a compound of the formula II, these can be changed during the reduction, an amino group or hydroxyl group being obtained. Even if X 'or Y' represent a halogen atom, this can be replaced by hydrogen.

The reduction can be carried out in the presence of a hydrogenation catalyst. It is possible to interrupt this in the stage of intermediate III by working at temperatures below 50 ° C. If the hydrogenation is then carried out at temperatures between 50 and 150 ° C., the hydrogenolysis of the compound III takes place with the formation of the end product I. The nitriles of the nitroaryl compounds II can also be reduced with reducing compounds, in particular iron (II) salts, and in this case the aminoarylnitriles of the formula III obtained in this way are then subjected to hydrogenolysis with hydrogen in the presence of a catalyst.

The compounds of the formula II which can be used as intermediates for the synthesis of the compounds I include new compounds. These are the dimethylamides of the following acids:

2-cyano-2- (2-nitrophenyl) acetic acid,

2- (4-chloro-2-nitrophenyl) acetic acid,

2- (6-chloro-2-nitrophenyl) acetic acid,

2- (4-trifluoromethyl-2-nitrophenyl) acetic acid,

2- (4-methyl-2-nitrophenyl) acetic acid,

2- (4-methoxy-2-nitrophenyl) acetic acid

2- (6-methoxy-2-nitrophenyl) acetic acid

2- (2,4-Dinitrophenyl) acetic acid

2- (2,6-Dinitrophenyl) acetic acid and

2- (4-Dimethylamidosulfonyl-2-nitrophenyl) -2-cyano-acetic acid,

the pyrrolidide, piperidide and 4-methyl-piperazide (as well as the chlorohydrates) of 2-cyano-2-nitrophenyl-acetic acid, the 2-cyano-2- (4-trifluoromethyl-2-nitrophenyl) -acetanilide, the 1-methyl- 4-piperazide of 2-cyano-2- (4-chloro-2-nitrophenyl) acetic acid, the 1-methyl-4-piperazide of 2-cyano-2- (4-trifluoromethyl-2-nitrophenyl) acetic acid and its Chlorohydrate.

The dimethylamide of 2-cyano-2- (2-aminophenyl) acetic acid is also a new compound.

The indole-3-carboxylic acid derivatives obtainable as described below are new compounds. These are the dimethylamides of indole-3-carboxylic acid, 6-trifluoromethyl-indole-3-carboxylic acid, 6-methyl-indole-3-carboxylic acid, 6-methoxy-indole-3-carboxylic acid, 6-amino-indole-3 carboxylic acid and 6-dimethylamidosulfonyl-indole-3-carboxylic acid, the pyrrolidide and piperidide of indole-3-carboxylic acid, the anilide and 4-methyl-piperazide of 6-trifluoromethyl-indole-3-carboxylic acid.

The new compounds can be used as herbicides as well as intermediates in the synthesis of other compounds.

The most important new compounds according to the present invention are 1-methyl-piperazide- (4) of 6-trifluoromethyl-, 6-fluoro-, 5-methoxy-, 6-methoxy- and 6-dimethylaminosulfonyl-indole- (3) -carboxylic acid as well as 1- (2-methoxyphenyl) -piperazid- (4) and 1-phenyl-piperazid- (4) of 6-trifluoromethyl-indole- (3) -carboxylic acid. These compounds are therapeutically valuable; they have an oxytoxin effect, a local anesthetic, anti-inflammatory, hypotensive effect and a tranquilizer effect.

Example 1:

Dimethylamide of indolecarboxylic acid-3.

A. It is hydrogenated at 50 atmospheres and room temperature for 30 minutes, then for 4 hours at 80 ° C. 17.5 g (0.075 mol) of the dimethylamide of 2-cyano-2- (2-nitrophenyl) acetic acid in 400 ml Ethyl acetate in the presence of 8 g of charcoal with 10% palladium. The catalyst is filtered off hot, the filter is washed with hot dimethylformamide, then the filtrate concentrated in vacuo. The crude product is recrystallized from methanol. This gives 6.2 g (yield 44%) of the expected amide in the pure state (melting point 236 ° C.).

The dimethylamide used as the starting material was prepared as follows:

A solution of 59 g (0.52 mol) of 2-cyanoacetic acid dimethylamide (Bowman et Cavalla, J. Chem. Soc. , (1954), 1171) in 200 ml of dimethylformamide are added, then 79 g (0.5 mol) of 2-nitrochlorobenzene in 200 ml of dimethylformamide are added to the solution thus obtained, and the mixture is stirred at 20 ° C. for 15 hours. After filtration, the filtrate is diluted with 1000 ml of water, then acidified with 60 ml of concentrated hydrochloric acid. As a result, the amide is precipitated in quantitative yield (melting point 123-124 ° C). After recrystallization from 150 ml of a mixture of methanol and water, 95 g (yield 81%) of the pure product with a melting point of 125 ° -126 ° C. are obtained.

B. Two-step production

At room temperature, 58.5 g (0.25 mol) of 2-cyano-2- (2-nitrophenyl) -acetic acid dimethylamide are hydrogenated in 200 ml of ethyl acetate in the presence of 6 g of palladium-carbon in the course of 30 minutes. The catalyst is then filtered off and the filtrate is cooled to 0 ° C. In the process, 0.5 g of the dimethylamide of indole-3-carboxylic acid is precipitated. After this product has been separated off, the solution is concentrated and the dimethylamide of 2-cyano-2- (2-aminophenyl) acetic acid is obtained quantitatively (melting point 110-112 ° C.). After recrystallization from 25 ml of methanol, 39 g (yield 77%) of the pure product with a melting point of 114 ° C. are obtained.

20.3 g (0.1 mol) of the product prepared as above in 150 ml of dimethylformamide are hydrogenated in the presence of 4 g of carbon with 10% palladium at 50 atmospheres and 80 ° C. in the course of 5 hours. The catalyst is filtered off while hot. When the filtrate cools, part of the expected indole carboxamide crystallizes out. This portion is separated off and the filtrate is concentrated in vacuo and a further portion of the desired amide is obtained. When the crude product is recrystallized from methanol, 14.3 g (yield 76%) of the pure product with a melting point of 236 ° C. are obtained.

C. Manufacture by hydrogenolysis of a halogenated intermediate.

26.7 g (0.1 mol) of the dimethylamide of 2-cyano-2- (4-chloro-2-nitrophenyl) acetic acid in 150 ml of dimethylformamide are in the presence of 5.4 g of carbon with 10% palladium under 50 atmospheres Hydrogenated first for 1 hour at room temperature, then for 5 hours at 80.degree. The catalyst is filtered off while hot. When the filtrate is cooled, 5.9 g of crystalline, pure indolecarboxamide are obtained. When water is added to the mother liquor, a further amount (5.3 g) of the amide is precipitated, so that the product with a melting point of 236 ° C. is obtained in an overall yield of 50%.

To prepare the dimethylamide used as the starting material, you can proceed as follows:

To a suspension of 9.8 g (0.4 mol) of sodium hydride in 150 ml of dimethylformamide, a solution of 22.7 g (0.2 mol) of dimethylamide is slowly added with stirring at a temperature below 50 ° C. and under a stream of nitrogen 2-cyanoacetic acid in 150 ml of dimethylformamide was added. 38.5 g (0.2 mol) of 2,5-dichloro-nitrobenzene are then added and the mixture is stirred at 20 ° C. for 18 hours. After filtration, the filtrate is diluted with 800 ml of water and acidified with 25 ml of concentrated hydrochloric acid. 51.6 g (yield 95%) of the amide with a melting point of 122-124 ° C. After recrystallization from methanol, 44 g (yield 82%) of the pure amide with a melting point of 124-125 ° C. are obtained.

Example 2 Dimethylamide of 6-methoxy-indole-3-carboxylic acid

Under 50 atmospheres 13.15 g (0.05 mol) of the dimethylamide of 2-cyano-2- (4-methoxy-2-nitrophenyl) acetic acid in 100 ml of dimethylformamide in the presence of 2.5 g of carbon with 10% palladium hydrogenated, initially working for 30 minutes at room temperature, then for 3 hours at 75.degree. The catalyst is filtered off hot, then the filtrate is cooled in order to initiate the crystallization of the indolecarboxamide. Evaporation of the mother layers gives a further amount of the product which is recrystallized from dimethylformaid. A total of 6.8 g (yield 62%) of the pure product with a melting point of 270 ° C. is obtained. After a further recrystallization from dimethylformamide, the melting point no longer changes.

The production of the dimethylamide used as the starting material can be carried out as follows:

To a suspension of 9.6 g (0.4 mol) of sodium hydride in 200 ml of hexamethylphosphoramide, a solution of 25 g (0.225 mol) of dimethyl cyanoacetamide (for preparation see Bowman) is gradually added at a temperature below 50 ° C. with stirring and under a stream of nitrogen and Cavalla, J. Chem. Soc., (1954), 1171) in 100 ml of hexamethylphosphoramide. A solution of 37.5 g (0.2 mol) of 4-methoxy-2-nitrochlorobenzene in 100 ml of hexamethylphosphoramide is slowly added to the mixture thus obtained, with stirring, the temperature being kept at 50.degree. After 4 hours under these reaction conditions, the mixture is filtered, then the filtrate is diluted with 800 ml of water and acidified with 20 ml of concentrated hydrochloric acid in order to precipitate the amide formed.

After cooling to 0 ° C., the solid is filtered off with suction, washed with water and dried. 47.5 g (yield 90%) of the product with a melting point of 90 ° -91 ° C. are obtained in this way. After recrystallization from methanol, the pure amide with a melting point of 94 ° C. is obtained.

Example 3 Dimethylamide of 6-amino-indole-3-carboxylic acid.

13.9 g (0.05 mol) of the dimethylamide of 2-cyano-2- (2,4-dinitrophenyl) acetic acid in 150 ml of dimethylformamide are in the presence of 2 g of carbon with 10% palladium at 50 atmospheres, initially for 45 minutes hydrogenated for 2 hours at room temperature, then at 80 ° C. The catalyst is filtered off while hot, the solvent is evaporated off and the residue is then caused to crystallize by trituration with a little methanol. The solid obtained in this way is recrystallized from 30 ml of methyl ethyl ether. This gives 4 g (yield 40%) of the pure product with a melting point of 260.degree.

The dimethylamide used as the starting material can be produced as follows:

To 4.8 g (0.2 mol) of sodium hydride in 100 ml of dimethylformamide, a solution of 12.3 (0.11 mol) of dimethyl cyanoacetamide in 60 ml of dimethylformamide is slowly added with stirring. A solution of 20.5 g (0.1 mol) of 2,4-dinitrochlorobenzene in 60 ml of dimethylformamide is slowly added to the solution obtained in this way, while cooling to 15-20 ° C. After stirring for 3 hours at 20 ° C., the mixture is filtered, then the filtrate is diluted with 450 ml of water and acidified with 12 ml of concentrated hydrochloric acid. In this way, the amide is precipitated, filtered off with suction, washed with water and dried. The expected amide is obtained in quantitative yield in pure form. It melts at 161 ° C; after further recrystallization from acetone, the melting point remains unchanged.

Example 4 1-Methyl-piperazid- (4) of indole-3-carboxylic acid

10 g (0.03 mol) of the hydrochloride of 1-methyl-piperazide- (4) of 2-cyano-2- (2-nitrophenyl) acetic acid in 100 ml of dimethylformamide are in the presence of 2 g of carbon with 10% palladium under Hydrogenated at 50 atmospheres at room temperature, initially for 30 minutes, then for 2 hours at 80 ° C. After the catalyst has been filtered off, the filtrate is concentrated in vacuo. The filter is washed with dilute hydrochloric acid and this filtrate is added to the concentrated residue. Then the base is precipitated by adding potassium carbonate. After recrystallization of the base from 70% ethyl alcohol, 4.8 g (57% yield) of the pure product with a melting point of 206 ° C. are obtained. (F = 194 ° according to Wormser, Elkin, J. Pharm. Sci. 50, (1961), 976).

The following procedure can be used to produce 4-methylpiperazide, which is used as the starting material in the form of the chlorohydrate:

35 g (0.21 mol) of 1-cyanoacetyl-4-methyl-piperazine (F = 115 °; F = 113-114 ° according to US Pat. No. 3,138,592, Chem. Abstr., 61, 7027) have a value of 9.6 g (0.4 mol) of sodium hydride reacted in 300 ml of dimethylformamide. Then gradually 31.5 g (0.2 mol) of 2-nitrochlorobenzene in 100 ml of dimethylformamide are added and the mixture is stirred at 50 ° C. for 2 hours. Then it is filtered and the filtrate is diluted with dry ether, then it is acidified with hydrochloric acid ethanol. A mixture of the chlorohydrate of the expected piperazide and sodium chloride is precipitated. The hydrochloride is purified by extraction with 400 ml of boiling dimethylformamide, then filtered to remove the sodium chloride and cooled to 0.degree. The pure chlorohydrate crystallizes out and in this way 30 g (46%) of the product with a melting point of 270-275 ° C. (decomposition) are obtained.

Example 5 Anilide of 6-trifluoromethyl-indole-3-carboxylic acid

10 g (0.029 mol) of the anilide of 2-cyano-2- (4-trifluoromethyl-2-nitrophenyl) -acetic acid in 150 ml of dimethylformamide are initially in the presence of 2.5 g of carbon with 10% palladium at 50 atmospheres for 1 hour hydrogenated at room temperature, then at 80 ° C. for 8 hours. The catalyst is filtered off hot, then the filtrate is concentrated in vacuo and the residue is recrystallized from methanol. 4.3 g (yield 50%) of the expected product are obtained. It is pure and melts at 224 ° C.

The anilide used as the starting material can be produced as follows:

8 g (0.05 mol) of cyanoacetanilide (melting point 198-200 ° C.) are reacted with 2.4 g (0.1 mol) of sodium hydride in 100 ml of dimethylformamide, then a solution of 11.25 g (0 , 05 mol) of 4-trifluoromethyl-2-nitrochlorobenzene in 25 ml of dimethylformamide was added. The mixture is stirred at 20 ° C. for 4 hours, then filtered and the filtrate is diluted with 400 ml of water. When 10 ml of concentrated hydrochloric acid is added, the amide formed precipitates, it is dried and recrystallized from 80 ml of methanol. 15 g (yield 85%) of the pure product with a melting point of 182 ° C. are obtained.

Examples 6-11

Using the above process conditions, the compounds of the formula I summarized in the table below are prepared.

The intermediates of the formula II are also obtained under the conditions described above:

Example 12 1- (2-Methoxyphenyl) -piperazid- (4) of 6-trifluoromethyl-indole-3-carboxylic acid

9 g (0.02 mol) of 1- (2-methoxyphenyl) piperazid- (4) of 2-cyano-2- (2-nitro-4-trifluoromethylphenyl) acetic acid are dissolved in 100 ml of dimethylformamide in the presence of 4 g of carbon Hydrogenated with 10% palladium first for 2 hours at room temperature, then for 4 hours at 80.degree.

After the catalyst has been filtered off, the filtrate is diluted by adding 3 times the volume of water, with crystallization of the piperazide occurring. In this way, 5 g (yield 62%) of the pure product with a melting point of 211-212 ° C. are obtained. On further recrystallization from methyl ethyl ether (3 ml per g) the melting point is not changed.

The preparation of the piperazide used as the starting material can be carried out as follows:

1- (2-Methoxyphenyl) piperazine is reacted with ethyl cyanoacetate in the presence of sodium ethylate for 1 week at 20 ° C., then the product is recrystallized from benzene. Then 10 g (0.04 mol) of the 1-cyanoacetyl-4- (2-methoxyphenyl) piperazine thus obtained are reacted with 2 g (0.08 mol) of sodium hydride in 100 ml of dimethylformamide. A further 9 g (0.04 mol) of 2-nitro-4-trifluoromethylchlorobenzene in 20 ml of dimethylformamide are slowly added, the temperature being kept at 20.degree. C., then the mixture is maintained for a further 4 hours while stirring this temperature. It is then filtered, 300 ml of water and then aqueous hydrochloric acid are added to the filtrate until a pH of 3-4 is reached. The expected piperazide crystallizes out. It is filtered off with suction, dried and recrystallized from 50 ml of methanol, 12 g (yield 70%) of the pure product having a melting point of 125 ° -126 ° C. being obtained.

Example 13 1-Methyl-piperazid- (4) of 6-fluoro-indole-3-carboxylic acid

17.1 g (0.05 mol) of the hydrochloride of 1-methyl-piperazid- (4) of 2-cyano-2- (4-fluoro-2-nitrophenyl) -acetic acid (in a mixture with 3 g of sodium chloride) in 100 ml of dimethylformamide are hydrogenated in the presence of 4 g of carbon with 10% palladium under 50 atmospheric pressure, initially for 1 hour at room temperature, then for 4 hours at 80 ° C. The catalyst is filtered off, the filtrate is concentrated in vacuo, then the residue is taken up in 50 ml of 2 molar potassium carbonate solution (0.1 mol) in order to liberate the base. This crystallizes out, is filtered off, washed with water and dried in vacuo. 7 g (yield 54%) of the pure piperazide with a melting point of 192 ° C. are obtained. After recrystallization from methanol (4 ml per g), the melting point is no longer changed.

The preparation of the piperazide used as the starting material can be carried out as follows:

16.8 g (0.1 mol) of 1-cyanoacetyl-4-methyl-piperazine (see Example 4) are reacted with 5 g (0.2 mol) of sodium hydride in 150 ml of dimethylformamide. Then gradually 16 g (0.1 mol) of 2,5-difluoronitrobenzene (for preparation see F. Swartz, Bull. Academie Royale de Belgique, (1913) p. 227) in 25 ml of dimethylformamide are added, the temperature at 20 ° C is maintained; then the mixture is kept at this temperature for a further 20 hours with stirring. It is then filtered, a solution of hydrochloric acid in ether is added to the filtrate until the pH is acidic, then anhydrous ether is added. The precipitate formed is filtered off with suction and washed with ether. 43 g (yield 97%) of the piperazide chlorohydrate, which contains 3.5 g of sodium chloride, are obtained. This product is used for hydrogenation without further purification.

Examples 14-17

Using similar conditions, the compounds listed in the following table are established:

Tabel

In the same way, the chlorohydrates of 1-methyl- (4) -piperazide of 2-cyano-2- (5-methoxy-2-nitrophenyl) acetic acid (Example 14), of 1-methyl- (4) -piperazide of 2-cyano-2- (4-methoxy-2-nitrophenyl) -acetic acid (Ex. 15) and the 1-methyl- (4) -piperazide of 2-cyano-2- (4-dimethylaminosulfonyl-nitrophenyl) -acetic acid ( Ex. 16), and also the 1-phenyl-4-piperazide of 2-cyano-2- (4-trifluoromethyl-2-nitrophenyl) acetic acid (melting point 115 ° -120 °, Ex. 17), which serve as intermediates .

+) Base: no melting point; NMR spectrum in CDCl [low] 3; CH [deep] 3 (piperazide) 2.33; CH [deep] 3 (methoxy) 3.81; CH [deep] 2 (adjacent CO group in the piperazine ring) 3.80; CH [deep] 2 (removed from the CO group in the piperazine ring) 2.45; H (the indole-NH group) 10.4 ppm.

Claims (9)

1. Derivatives of indole-3-carboxylic acid of the formula I. in which R [deep] 1 and R [deep] 2, which can be the same or different, represent hydrogen or optionally substituted alkyl, aralkyl or aryl radicals or together with the nitrogen atom, a 5-, 6- or 7- form a membered ring, which can optionally contain a further hetero atom, in particular a nitrogen atom, and X is hydrogen, halogen, an alkyl or alkoxy group with 1-5 carbon atoms, aralkoxy group, the trifluoromethyl group, a hydroxyl, amino, carboxylic acid or sulfonic acid group or a functional derivative thereof and Y represents halogen, an alkyl or alkoxy radical having 1-5 carbon atoms, aralkoxy radical, trifluoromethyl group, hydroxyl, amino, carboxylic acid or sulfonic acid group or a functional derivative thereof. 2. Dimethylamides of indole-3-carboxylic acid, 6-trifluoromethyl-indole-3-carboxylic acid, 6-methyl-indole-3-carboxylic acid, 6-methoxy-indole-3-carboxylic acid, 6-amino-indole-3-carboxylic acid and 6-dimethylaminosulfonyl-indole-3-carboxylic acid. 3. Pyrrolidide and piperidide of indole-3-carboxylic acid, anilide, 1-methyl- (4) -piperazide, 1-phenyl- (4) -piperazide and 1- (2-methoxyphenyl) - (4) -piperazide of 6- Trifluoromethyl-indole-3-carboxylic acid. 4. 1-methyl- (4) -piperazide of 6-fluoro-6-indole-3-carboxylic acid, 5-methoxy-, 6-methoxy- and 6-dimethylaminosulfonyl-indole-3-carboxylic acid. 5. Process for the preparation of derivatives of indole-3-carboxylic acid of the formula I. in which R [deep] 1 and R [deep] 2, which can be identical or different, represent hydrogen or optionally substituted alkyl, aralkyl or aryl radicals or together with the nitrogen atom form a 5-, 6- or 7-membered ring , which can optionally comprise further heteroatoms, in particular a further nitrogen atom, and X is hydrogen, halogen, an alkyl or alkoxy radical with 1 - 5 carbon atoms, aralkoxy radical, the trifluoromethyl group, a hydroxyl, amino, carboxylic acid or sulfonic acid group or a functional derivative thereof and Y halogen, an alkyl or alkoxy radical having 1-5 carbon atoms, aralkoxy radical, the trifluoromethyl group, a hydroxyl, amino, carboxylic acid or sulfonic acid group or a functional derivative thereof, characterized in that one is a derivative of 2-aminophenylcyanoacetic acid the formula subjected to hydrogenolysis. 6. The method according to claim 5, characterized in that a derivative of 2- (2-nitrophenyl) -cyanoacetic acid of the formula II, in which R [deep] 1 and R [deep] 2 have the above meaning, while X 'and Y 'have the same meaning as X and Y, but can also be nitro groups, II reduced to form an intermediate of formula III (III) which is preferably subjected to hydrogenolysis without isolation, which leads to the indole of the formula I with loss of ammonia. 7. The method according to claim 5 or 6, characterized in that the hydrogenation is carried out with hydrogen in the presence of a catalyst. 8. The method according to any one of claims 5-7, characterized in that one hydrogenates at 50-150 ° C for hydrogenolysis. 9. The method according to any one of claims 6-8, characterized in that the reduction of the compound II is carried out at a temperature below 50 ° C.