CH647782A5 - 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids, their esters and salts - Google Patents

Abstract

(d) Compounds of the formula: <IMAGE> can be converted to racemates in a polar solvent by heating in the presence of an acid, and the racemic compounds can be used in therapy as such or after conversion into alkyl esters or into pharmaceutically permissible salts. The racemic compounds can also be resolved into the (d) and (l) isomers in order to recover the therapeutically effective (l) isomers. In the formula A, R denotes hydrogen or C1-C4-alkyl, R<1> denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine or bromine and R<2> denotes hydrogen, C1-C12-alkyl or a pharmaceutically permissible cation.

Description

The present invention relates to new pyrrole-1-carboxylic acid compounds, namely the (d) -5-aroyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-l-carboxylic acids, esters and salts of the formula :

in which R represents the hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and R1 represents the hydrogen atom, an alkoxy radical having 1 to 4 carbon atoms or the chlorine atom, the fluorine atom or the bromine atom, the substituent R1 being in the o-, m- or p Position of the aroyl group, and R2 represents a hydrogen atom, a C1-c12-alkyl radical or a pharmaceutically acceptable cation.

Typical alkyl ester groups are, for example, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, iso-decyl, 6 -Methyldecyl and dodecyl esters.

Salts derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium, magnesium, ferro, zinc, copper, mangano, aluminum, ferric and manganese salts, etc. Particularly preferred are the ammonium, potassium, sodium, calcium and 10 magnesium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines, including the naturally occurring substituted amines, cycloamines and basic ion exchange resins such as e.g. Isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betamine, methylamine, gluaminamine , Theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Organic non-toxic bases such as isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine are particularly preferred. 25 The (d) acid isomer of formula (A) and its esters and pharmaceutically acceptable salts are valuable as intermediates for the preparation of (d, 1) acids of formula (A), as will be described in more detail below.

30 The racemization can be carried out as follows. A solution of the (d) acid isomer of formula A in a polar organic or organic aqueous solvent, e.g. Ethanol-water or methanol, is heated to about 60 to 100 ° C and mixed with an acid such as e.g. Hydrochloric acid or sulfuric acid, acidified. The mixture is heated for a period of about 15 minutes to 24 hours or until racemization is complete. The racemate can then be isolated by customary methods and the carboxylic acid obtained as a residue can be converted into corresponding esters or pharmaceutically acceptable salts as described below.

The racemate can then be separated and the (l) isomer isolated as described below. The isolated (l) isomer can be converted to corresponding esters or salts in 4s in the same manner as described for the (d, l) form.

The (l) acid isomers and (d) acid isomers of the compounds of formula A can be obtained by using the known technique of high pressure liquid chromatography (HPLC) on the diastereoisomeric a-phenylethyl esters of the compounds of the Formula A applies and then causes the splitting with an acid. For example, the compounds of the formula A, in which R and R1 are each hydrogen atoms, can be further treated in accordance with the following diagram:

3rd

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COOH

«

several levels

Mixture / (l) -a-phenylethyl ester of the (l) acid isomer of the formula (A) of the \ (l) -a-phenylethyl ester of the (d) acid isomer of the formula (A)

Separation using HPLC

(A) - (l) acid isomer (1) phenyl ethyl ester

M /

(A) - (l) acid isomer

(A) - (d) -acid-isomer- (l) -phenylethyl ester n! /

(A) - (d) Acid Isomer —I

A detailed description of this workflow 40 and preferably at room temperature. Typical, inert ones can be found in Example 1 below. Water-miscible, organic solvents are metha-

The free acids of formula A can in alkyl esters with 1 noi, ethanol, isopropanol, butanol, acetone, dioxane or up to 12 carbon atoms in a manner known per se, e.g. Tetrahydrofuran. The molar ratio of the compounds of the base used by treatment with (a) the desired ester corresponding to formula A or the (l) acid isomers thereof, based on speaking alcohol in the presence of a strong mineral, is selected such that depending on the acidity, (b) with an ethereal diazoalkane or (c) the salt used, the right ratio is available. To desired alkyl iodide in the presence of lithium carbonate, for example the calcium salts or magnesium salts of the be converted. The (l) acid isomers can be prepared according to the methods according to (b) and (c) in the corresponding compounds of formula A or the (l) acid isomers thereof, the one used as the starting material

Alkyl esters are transferred. so free acid with at least 1/2 mol equivalent of pharma-

Treat the salts of the compounds of formula A and the table base to make a neutral salt

(I) acid isomers thereof are obtained by obtaining them. The aluminum salts of the compounds of the free acids are to be treated with an appropriate amount of a pharmaceutical formula A or the (l) acid isomers thereof prepared from the table base. Suitable, pharmaceutically, so used at least 1/3 mol equivalent of permissible bases are sodium hydroxide, potassium hydroxide, ss the pharmaceutically acceptable base, if you want to obtain a neutral lithium hydroxide, ammonium hydroxide, calcium hydroxide, salt.

Magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper. According to the preferred embodiment, the ferhydroxide, manganese hydroxide, aluminum hydroxide, ferrous calcium salts of the compounds of the formula A and the rihydroxide, manganese hydroxide, isopropylamine, trimethyl (l) acid isomers thereof can be prepared by that the amine, diethylamine, triethylamine, tripropylamine, ethanol- corresponding sodium or potassium salts thereof with min-amine, 2-dimethylaminoethanol, 2-diethylaminoethanol, at least 1/2 molar equivalent of calcium chloride or magnesi-tromethamine, lysine, arginine, histidine, Caffeine, procaine, umchloride in an aqueous solution alone or in verbin-hydrabamine, choline, betaine, ethylenediamine, glucosamine, manure with an inert, water-miscible organic methylglucamine, theobromine, purines, piperazine, piperidine, solvents at a temperature of about 20 ° C to N-ethyl piperidine, polyamine resins, etc. The reaction 65 treated about 100 ° C. The aluminum can preferably be prepared in water alone or in combination with a minium salt of such compounds by inert, water-miscible, organic solvents, the corresponding free acids with at least 1/3 at a temperature of about 0 ° C to about 100 ° C molar equivalent of an aluminum alkoxide, e.g. Aluminum-

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triethoxide, aluminum tripropoxide or the like in a hydrocarbon solvent such as e.g. Benzene, xylene, cyclohexane, or the like, treated at a temperature between about 20 ° C and about 115 ° C. Similar measures can be taken to produce salts of inorganic bases which are not sufficiently soluble for easy implementation.

Of course, the isolation of the compounds described in the present specification can, if desired, be carried out using any suitable separation and purification methods, e.g. Extraction, filtering,

Evaporation, distillation, allowing to crystallize, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or by a combination of these measures. Suitable

Separation and isolation methods can be found in the examples below. Of course, you can also use other equivalent separation and isolation methods.

The inventive (d) isomers of the formula A can be prepared as follows:

wherein R and R1 have the above meanings and R2 'is a lower alkyl radical having 1 to 4 carbon atoms, e.g. is the methyl, ethyl, isopropyl or n-butyl radical.

In carrying out the present process in practice, equimolecular amounts of ethanolamine of the formula I and dimethyl 1,3-acetone-dicarboxylic acid of the formula II are used at a temperature of approximately 0 ° for the preparation of the compound of the formula IV in which R is the hydrogen atom React C to about room temperature in order to easily obtain a solution of the vinylamine of the formula III, which is then preferably in situ in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at one Treated temperature from about 40 ° C to about 100 ° C for a period from about 30 minutes to about 16 hours. Suitable solvents for this reaction are aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform, dichloromethane, etc. In the preferred embodiments, the reaction in acetonitrile solution at reflux temperature takes about 1 hour. The compounds used as reactants, i.e. 2-bromoacetaldehyde and 2-chloroacetal dehyde are known compounds. They can be obtained by pyrolysis of the corresponding diethylacetals in the presence of oxalic acid dihydrate.

To the compounds of formula IV, wherein R is a lower alkyl radical having 1 to 4 carbon atoms, which is preferably a straight-chain radical, is an aqueous mixture of ethanolamine of the formula I and 1,3-aceto-dicarboxylic acid dimethyl ester of the formula II with a compound of the following formula:

O

II

r3-c-ch2x wherein X is bromine or chlorine and R3 is a lower alkyl group of 1 to 4 carbon atoms, which is preferably a straight chain group, at about 40 to about 100 ° C for about 30 minutes to about 16 hours. Preferred compounds for this are 1-bromoacetone, l-bromo-2-butanone, l-bromo-2-pentanone and l-bromo-2-hexanone. In a preferred embodiment, the reaction is carried out at a temperature of from about -10 ° C to about room temperature for about 1 hour to about 6 hours. The compounds of the formula:

O

II

R3_c-cmx are known.

The esterification of a compound of formula IV with methanesulfonyl chloride in the presence of a tertiary amine, e.g. Triethylamine, pyridine or the like is preferably carried out in the presence of a cosolvent such as e.g. Dichloromethane at a temperature in the range of about -10 ° C to about room temperature for about 10 minutes to about 2 hours to give a corresponding mesylate of formula V which is then reacted with sodium iodide in acetonitrile solution at reflux temperature for a period of about 1 hour to about 10 hours is converted into a corresponding N- (2-iodoethyl) pyrrole.

After the reaction of the iodomethyl compounds of the formula VI with sodium hydride in a suitable, inert,

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organic solvents, e.g. Dimethylformamide, a 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l, 7-dicarboxylic acid dimethyl ester and derivatives thereof in the 6-position alkyl-substituted derivatives thereof of the formula VII are obtained. This cyclization takes place in an inert Atmosphere, ie in an argon or nitrogen atmosphere, at temperatures in the range of about 15 ° C to about 40 ° C for a period of about 15 minutes to about 4 hours. The best results are obtained if the reaction is carried out at room temperature for about 30 minutes, provided that the radical R represents the hydrogen atom.

On the other hand, the compounds of formula VII can also be obtained by direct cyclization of a mesylate of formula V using sodium hydride in dimethylformamide solution at a temperature from about -10 ° C to about room temperature for about 30 minutes to about 2 hours.

Basic hydrolysis of a compound of formula VII with an alkali metal hydroxide or alkali metal carbonate, e.g. Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., in an aqueous, lower aliphatic alcohol, e.g. Methanol or ethanol, at a temperature between room temperature and reflux temperature for about 4 hours to about 24 hours results in a free diacid of Formula VIII, i.e. 1,2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l, 7-dicarboxylic acid and 6-alkyl derivatives thereof. The hydrolysis is preferably carried out using aqueous methanolic potassium hydroxide at the reflux temperature for about 10 hours.

The carboxylic acid group at the C-1 position in a compound of formula VIII is then removed by treatment with a lower aliphatic alcohol, e.g. Methanol, ethanol, isopropanol, n-butanol or the like, selectively esterified in the presence of hydrogen chloride, using a 1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-7-carboxylic acid 1 - car-bonsäurealkylester of formula IX receives. The reaction is carried out at a temperature between about 0 ° C and about 50 ° C for about 1 hour to about 4 hours.

The decarboxylation of the monoesterified compounds of the formula IX to give corresponding compounds of the formula X, which are the key intermediates in the process for the preparation of the compounds according to the invention, is carried out by heating a compound of the formula IX to an elevated temperature of about 230 ° C. to about 280 ° C. for a sufficiently long period of time to effect full implementation. The course of the reaction can be determined based on the extent of evolution of carbon dioxide and by thin layer chromatography, the decarboxylation generally being completed in about 45 to about 90 minutes. The reaction products, namely the 1,2-di-hydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid alkyl esters and the 6-alkyl derivatives thereof, which correspond to formula X, can be purified by chromatographic methods . On the other hand, especially in the decarboxylation of small amounts of compounds of the formula IX, the reaction product of the formula X can be obtained directly from the reaction vessel by distillation.

The condensation of a compound of formula X with an amide of the following formula:

£ VcoN (CH, -),,

where R1 has the above meaning leads to corresponding ones

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5-Aroyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carbon-acidic alkyl esters of the formula XI. This reaction is carried out in an inert, organic, aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for about 1 hour to about 175 hours in an inert atmosphere, followed by refluxing in the presence of sodium acetate for about 2 to about 10 hours. Instead of phosphorus oxychloride, other acid chlorides, e.g. Use phosgene or oxalyl chloride.

According to preferred embodiments, this condensation is carried out by adding a solution of a compound of the formula X in a suitable solvent to a mixture of 1.1 to 5 molar equivalents of both the desired amide and the phosphorus oxychloride which has previously been heated under reflux in the same solvent, the resultant product being obtained in this way The reaction mixture is refluxed for about 6 to about 72 hours in an argon atmosphere and then about 3 to about 10 molar equivalents of sodium acetate are added. The mixture is then heated to boiling under reflux for about 4 to about 6 hours.

Adequate solvents for this reaction are halogenated hydrocarbons, e.g. Dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc., also dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Examples of suitable N, N-dimethylarylamides that can be used are:

N, N-dimethylbenzamide,

N, N-dimethyl-o-toluamide,

N, N-dimethyl-m-toluamide,

N, N-dimethyl-p-toIuamid,

N, N-dimethyl-p-ethylbenzamide,

N, N-dimethyl-o-propyl-benzamide,

N, N-dimethyl-m-butyl-benzamide,

N, N-dimethyl-o-methoxy-benzamide,

N, N-dimethyl-m-methoxy-benzamide,

N, N-dimethyl-p-ethoxy-benzamide,

N, N-dimethyl-p-isopropoxy-benzamide,

N, N-dimethyl-o-chloro-benzamide,

N, N-dimethyl-m-chlorobenzamide,

N, N-dimethyl-p-chloro-benzamide,

N, N-dimethyl-o-fluoro-benzamide,

N, N-dimethyl-p-fluoro-benzamide,

N, N-dimethyl-m-bromo-benzamide and

N, N-dimethyl-p-bromo-benzamide.

These amides are known, commercially available compounds. You can in the usual way from the corresponding acids, i.e. by conversion to the acid chlorides and by subsequent treatment with dimethylamine.

After the alkali hydrolysis of the alkyl ester group in a compound of the formula XI, the corresponding free acid of the formula A is obtained. This hydrolysis is carried out in a manner known per se using an alkali metal hydroxide or alkali metal carbonate, e.g. Sodium hydroxide, potassium hydroxide, sodium carbonate, etc., in an aqueous, lower aliphatic alcohol, e.g. Methanol, ethanol, or the like, at a temperature ranging from about room temperature to reflux temperature for about 15 minutes to about 2 hours, in an inert atmosphere. According to the preferred embodiments, this hydrolysis is carried out by means of aqueous, methanolic potassium carbonate at reflux temperature for approximately 30 miputes.

The compounds of the formula A can be broken down by methods known per se for the preparation of the corresponding individual isomers.

Production of the starting products a) A 250 ml three-necked round-bottom flask, which has a magnetic stirrer and is equipped with a drying tube filled with calcium chloride, is directly (via one of the outer openings) with a feed line and a short (3 ") water condenser with the acetal pyrolyzer The latter consists of a 100 ml round-bottomed flask which has previously been treated with 15.6 g of oxalic acid dihydrate and 11.82 g of bromoacetaldehyde diethyl acetal, prepared from vinyl acetate as described by PZ Bedoukian, J. Am. Chem. Soc. 66,651 (1944), with a 6 "Vigreux column, which has a thermometer, attached to this device, which is connected to the aforementioned condenser.

The three-necked flask is charged with 3.36 g of ethanolamine, cooled to 0 ° to 10 ° C. in an ice bath, and treated dropwise with 8.7 g of dimethyl-1,3-acetone-dicarboxylate while stirring. This spontaneously forms methyl-3-carbometh-oxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III). When the addition is complete, the ice bath is removed and 100 ml of dry acetonitrile are added. The pyrolysis part of the device is placed in an oil bath and the temperature of the latter is allowed to rise to 150 to 160 ° C. The bromoacetaldehyde solution formed is distilled directly into the magnetically stirred solution of vinylamine III (boiling point 80 to 83 ° C./580 mm). As soon as the distillation temperature has dropped to less than 80 ° C., the pyrolysis device is interrupted and replaced by a reflux condenser equipped with a drying tube containing calcium chloride. The solution is then heated at reflux temperature for 1 hour, the solvent is removed under reduced pressure and then 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is evaporated to dryness in vacuo and fed to a column which contains 200 g of silica gel and contains hexane. The column is then eluted with a mixture of hexane and ethyl acetate (mixing ratio 80:20) (500 ml) and a mixture of hexane and ethyl acetate (mixing ratio 1: 1; 9 x 500 ml). Fractions 2 and 3 contain less polar impurities and dimethyl 1,3-acetone dicarboxylate; fractions 4 to 8 yield 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H), which after recrystallization from a mixture of ether and hexane has a melting point of 52 up to 54 ° C.

b) 2.65 ml of triethylamine are stirred into a solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate in 35 ml of dry dichloromethane, cooled to -10 ° C., after which Add 1.46 ml of methanesulfonyl chloride dropwise while maintaining the temperature of the reaction mixture from -10 ° C to -5 ° C. The course of the reaction is observed by thin layer chromatography analysis using a mixture of chloroform and acetone (mixing ratio 90:10). As soon as the reaction can be regarded as complete (30 minutes after the addition of methanesulfonylchloride has ended), 10 ml of water are slowly added. The organic phase is separated off, washed three times with 30 ml of water each time, dried over sodium sulfate and evaporated to dryness under reduced pressure. Allowing the residue to crystallize out from a mixture of dichloromethane and hexane gives 4.75 g (77.7%) of methyl N-

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(2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), mp 99-101 ° C.

c) A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodidine in 10 ml of acetonitrile is heated to boiling under reflux for 1 hour. The reaction mixture is then cooled and then evaporated to dryness under reduced pressure and the residue is triturated with water. The insoluble material is separated off by filtration and air-dried, 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), mp. 137 to Receives 138 ° C.

d) A solution of 1 g of methyl-N- (2-iodoethyl) -3-carbo-methoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred in an argon atmosphere with 137 mg of 50% sodium hydride in mineral oil. Then the reaction mixture is kept at room temperature for 30 minutes and then treated with 100 ml of water. The product is extracted three times with 50 ml of ethyl acetate each time and the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue over 20 g of silica gel using a mixture of hexane and ethyl acetate (mixing ratio 4: 1) as the eluent gives 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a ] -pyrrole-l, 7-dicarboxylate (VII, R = H), mp 70-71 ° C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylate in 20 ml of methanol is mixed with a solution of 4.48 g of potassium hydroxide treated in 20 ml of water and the reaction mixture was then heated to boiling under reflux for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of saturated sodium chloride solution. The resulting solution is acidified with 6N hydrochloric acid and extracted three times with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, giving 1.51 g (95%) 1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H), mp. 220 ° C (decomposition).

e) A solution of 1.34 g of 1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylic acid in 50 ml isopropanol, cooled in an ice bath, is maintained with gaseous hydrogen chloride a temperature of the reaction mixture of less than 50 ° C saturated. The ice bath is then removed and the reaction mixture is stirred at room temperature for 1 V2 hours and evaporated to dryness under reduced pressure. Then the residue is mixed with 10 ml of benzene. The solution is then evaporated once more in vacuo, repeating this procedure three times in total to remove the excess hydrogen chloride. In this way, 1.58 g (96%) of isopropyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R2 '= ÌC3H7), which has a melting point of 144 to 145 ° C after crystallization from a mixture of methanol and ethyl acetate.

f) 1.054 g of isopropyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate-7-carboxylic acid are in a dry round-necked flask with a capacity of 10 ml to 240 to 250 ° C heated, the reaction product being distilled off directly from the reaction vessel. In this way, 745 mg (87%) of isopropyl-1,2-dihydro-

3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate (X, R = H,

R2 '= ÌC3H7), pale yellow oil with the following physical

Constants:

s U.V .:? Cex0H 215 nm (s = 6020);

I.R .: 1725 cm- ';

NMR: 5? JSs'31.22 (d, J = 7 Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H), 4.65- 5.2 (m, 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3 Hz, 1H), 6.43-6.53 ppm (m, 1H).

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g) A 100 ml three-necked round bottom flask equipped with a condenser, a nitrogen inlet tube and a gas inlet tube is charged with 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l- carboxylate-7-carboxylic acid is loaded. The device is flushed out thoroughly with nitrogen and the nitrogen supply is then stopped. The device is then immersed in an oil bath heated to 270 ° C and the reaction as a result of the carbon dioxide evolution (gas inlet nozzle) and by thin layer chromatography over silica gel using a mixture of benzene, dioxane and acetic acid (mixing ratio 90: 10: 1) Developer solvent observed. The reaction is practically complete after 45 minutes. After 1 hour, the container is removed from the oil bath and the contents of the reaction flask are placed in a round bottom flask which is provided with 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography over 100 g of silica gel. The fractions eluted using a mixture of hexane and 30 benzene (mixing ratio 70:30) and a mixture of hexane and benzene (mixing ratio 50:50) yield 2.77 g (68%) isopropyl-1,2-dihydro-3 H- pyrrolo- [l, 2-a] -pyrrole-l-carboxylate (X, R = H, R2 '= ÌC3H7), an oil whose physical constants are identical to those according to 35 section f).

h) A solution of 179 mg of N, N-dimethyl-p-toluamide and 0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes

40 heated. Then a solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane is added to this solution. The reaction mixture is then refluxed for 8 hours in an argon atmosphere, then treated with 405 mg of sodium acetate for 45 hours and then refluxed for a further 5 hours. The mixture obtained is then evaporated to dryness and the residue is chromatographed over 12 g of silica gel, eluting with a mixture of hexane and ethyl 50 acetate (mixing ratio 3: 1). This gives 208 mg (66%) of isopropyl-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate (Xl, R = H, R1 = p-CH3, R2 '= ÌC3H7), an oil with the following physical constants:

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U.V .:? I ^ x0H 256.312 nm (e = 8700.19 500);

I.R .: vïï ™ 1735, 1620.1605 cm "1;

NMR: 5tms'3 1.23 (d, J = 7 Hz, 6H), 2.38 (s, 3H), 2.5-3.0 (m, 2H), 3.75-4.10 (m , 1H), 4.2-4.60 (m, 2H), 4.85-5.20 (m, 1H), so 5.95 (d, J = 4Hz, 1H), 6.70 (d, J = 4Hz, 1H), 7.10 (d, J = 8Hz, 2H), 7.60ppm (d, J = 8Hz, 2H).

i) A solution of 336 mg isopropyl-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate in 10 ml

65 methanol is treated with a solution of 690 mg potassium carbonate in 5 ml water. The reaction mixture is then heated to reflux in a nitrogen atmosphere for 30 minutes, cooled and dried

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evaporated. The reflux is taken up in 10 ml of a 10% aqueous hydrochloric acid solution and 50 ml of water and the resulting mixture is extracted twice with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. By allowing the residue to recrystallize from a mixture of ethyl acetate and hexane, 238 mg (89%) of 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid [ (A), R = H, R1 = p-CHs], mp 182 to 183 ° C.

j) A solution of 250 mg of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate in 8 ml of methanol is mixed with a solution of 200 in a nitrogen atmosphere mg of sodium hydroxide in 1 ml of water, keeping the reaction mixture at room temperature for 1 Vi hours. The methanol is then removed under reduced pressure and the remaining basic solution is diluted with 5 ml of water and extracted with ether to remove any unsaponified product which may be present. The aqueous solution is then acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure. The residue is crystallized from a mixture of ethyl acetate and hexane to give 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] pyrrole-l-carboxylic acid, which is obtained with the Product according to section i) is identical.

k) Following the same procedure as described above, the following compounds are obtained:

Isopropyl-5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, light yellow oil with the following physical constants:

U.V .:; CX0H 245.311 nm (e 7230.17 800); I.R .: VmaxC'31735.1620 cm-1;

NMR: SÇJEk 31.24 [d, 6H, (CHs ^ CH], 2.50-3.13 (m, 2H; H-2); 3.97 (dd, 1H, H-1), 4.18 -4.70 (m, 2H, H-3), 5.00 (sept., IH, (CH3) 2CH), 6.00 (d, IH, H-7), 6.86 (d, IH, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons);

M.S .: m / e 297 (M +).

Isopropyl-5-o-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate, an oil with the following physical constants:

Isopropyl-5-o-propylbenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] -py rrol-1-carboxylate,

Isopropyl-5-m-butylbenzoyl-l, 2-dihydro-3H-pyrrole [l, 2-a] pyrrole-l-carboxylate, s isopropyl-5-o-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo - [1,2-a] pyrrole-1 carboxylate,

Isopropyl-5-p-methoxybenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate with the following physical constants:

10th

U.V .: CX0H 218.270-284 (shoulder), 314 nm (e 9780.9320, 22 400);

I.R .: v ™ cl3 1730, 1605 cm "1;

N.M.R .: 5? Ss'3 1.24 [d, 6H, J = 6 Hz; (CH3) 2CH-], 2.50-3.10 is (m, 2H; H-2), 3.78 (s, 3H; CH3O), 3.93 (dd, 1H, Jax = 6 Hz, Jbx = 7 Hz; H-1), 4.13-4.60 (m, 2H; H-3), 4.95 [sept., IH, J = 6 Hz; (CH3> CH], 5.95 (s, IH, J = 4 Hz; H-7), 6.68 (d, IH, J = 4 Hz; H-6), 6.70-7.90 ppm (m, 4H; phenyl protons); MS: m / e 327 (M +).

20th

Isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, mp. 94-95 ° C,

Isopropyl-5-p-isopropoxybenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate, 2s isopropyl-5-o-chlorobenzoyl-l, 2-dihydro- 3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate, an oil with the following physical constants:

U.V .:? .Iex0H 251.306 nm (e 5750.16 600);

301.R .: v ™ CIJ 1735, 1625 cm "1;

NMR: 5? Ss "1.22 [d, 6H, (CH3> CH], 2.55-3.05 (m, 2H; H-2), 3.97 (dd, 1H, H-1), 4.17-4.70 m, 2H, H-3), 4.97 [sept., IH, (CH3) 2CH], [5.93 (d, 2 / 3H), 6.00 (d, 1 / 3H) H-7], [6.42 (d, 2 / 3H), 6.67 (d, 1 / 3H), H-6], 7.07-7.80 ppm (m, 4H; phenyl -35 protons).

Isopropyl-5-m-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-l-carboxylate, an oil with the following physical constants:

40

U.V .:? Cex0H 241.313 nm (e 6600, 15 100);

I.R.:v:00c "1735,1620,1570 cm-1,

N.M.R .: 8 ™ s'! 1.27 [d, 6H, (CH3) 2CH], 2.50-3.18 (m, 2H, H-2), 3.93 (dd, 1H, H-1), 4.10-4, 63 (m, 2H, H-3), 4.98 [sept., 45 IH, (CH3) 2CH], 5.98 (d, 1H, H-7), 6.67 (d, 1H, H- 6), 7.07-7.78 ppm (m, 4H, phenyl protons);

M.S .: m / e 331-333 (M +),

U.V .: 252.303 nm (e4460.19 100); Isopropyl-5-p-chlorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-

I.R .: v ™ ci31735, 1620 cm-1; so a] -pyrrole-l-carboxylate, mp. 80.5-81 ° C,

NMR: SMS3 M8 [d, 6H, (CH3) 2CH], 2.28 (s, 3H, 0-CH3), isopropyl-5-o-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l , 2-

2.50-3.13 (m, 2H, H-2), 3.92 (dd, 1H, H-1), 4.17-4.70 (m, 2H, a] -pyrrole-l-carboxylate ,

H-3), 4.98 [sept. IH, (CH3) 2CH], 5.92 (d, 1H, H-7), 6.43 isopropyl-5-p-fluorobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-

(d, 1H, H-6), 6.97-7.45 ppm (m, 4H, phenyl protons). a] -pyrrole-l-carboxylate, mp 72-72.5 ° C,

55 isopropyl-5-m-bromobenzoyl-1,2-dihydro-3H-pyrrolo- [l, 2-

Isopropyl-5-m-toluoyl-1,2-dihydro-3 H-pyrrolo- [l, 2-a] - a] pyrrole-1-carboxylate and pyrrole-1-carboxylate, an oil with the following physical isopropyl-5- p-bromobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-

Constants: a] pyrrole-1 carboxylate.

U.V .: 250-251,310-312 nm (e 6460.17 400); so

I.R .: 1735.1620 cm-1; By hydrolysis of the isopropyl ester group according to the in

NMR: 8 ™ ch 1.25 [d, 6H, (CH3) 2CH], 2.27 (s, 3H, CH3), the sections i) and j) mentioned, 2.52-3.13 (m , 2H, H-2), 3.92 (dd, 1H, H-1), 4.13-4.70 (m, 2H, the corresponding free acids, namely:

H-3), 4.95 [sept, IH, (CH3) 2CH], 5.95 (d, 1H, H-7), 6.67 (d,

1H, H-6), 7.03-7.57 ppm (m, 4H; phenyl protons). 65 5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-car-

bonic acid, mp. 160-161 ° C,

Isopropyl-5-p-ethylbenzoyl-1,2-dihydro-3 H-pyrrolo- [l, 2- 5-oT oluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole- 1 -car-

a] -1-carboxylate, bonic acid, an oil with the following physical constants:

9

647 782

U.V .: A ^ X0H 253.307 nm (e 3310.16 980);

I.R.vvc "1720.1620 cm" 1;

NMR: 8ÇJSP 2.32 (s, 3H, CHs), 2.53-3.03 (m, 2H, H-2), 3.97 (dd, 1H, H-1), 4.17-4, 67 (m, 2H, H-3), 6.92 (d, 1H, H-7), 6.40 (d, 1H, H-6), 6.83-7.37 (m, 4H, phenyl protons) ), 8.60ppm (bs, IH, COOH).

5-m-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-car-bonic acid,

5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-o-propylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-m-butylbenzoyl-1,2-dihydro-3 H-pyrrolo-1,2-a] pyrrole-1-carboxylic acid,

5-o-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-p-methoxybenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, mp. 187-187.5 ° C,

5-p-ethoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid, mp. 169.5-170 ° C,

5-p-isopropoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -py rrol-1-carboxylic acid,

5-o-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -py rrol-1-carboxylic acid, with the following physical constants:

U.V .: A, lex0H 250.307.5 nm (s 4360.17 400);

I.R.:v.00c "1715, 1620 cm" 1

NMR: SfSP 2.60-3.15 (m, 2H; H-2), 4.02 (dd, 1H, Jax = 6 Hz, Jbx = 7 Hz; H-1), 4.20-4.70 (m, 2H; H-3), 5.98 (d, IH, J = 4 Hz; H-7), 6.42 (d, 1H, J = 4 Hz; H-6), 7.00- 7.77 (m, 4H; phenyl protons), 8.67 ppm [s, (br), 1H; COOH].

5-m-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid, mp. 180-181 ° C,

5-p-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, mp. 201.5-202.5 ° C,

5-o-fluorobenzoyl-1,2-dihydro-3 H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

5-p-fluorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, mp. 179.5-180.5 ° C,

5-m-bromobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid and

5-p-bromobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid.

1) A 250 ml three-necked round bottom flask, which contains a magnetic stirrer and is equipped with a drying tube filled with calcium chloride, is charged with 3.36 g of ethanolamine, cooled to 0 to 10 ° C. in an ice bath and added dropwise with stirring with 8.7 g Dimethyl

1,3-acetone dicarboxylate treated, being spontaneous

Methyl-3-carbomethoxymethyl-3- (2'-hydroxyethyl) amino acrylate (III) is obtained. When the addition is complete, the ice bath is removed and 80 ml of dry acetonitrile are added to the reaction mixture. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated under reflux for 2 hours. Then the solvent is removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is then evaporated to dryness in vacuo and introduced at the top into a column of 200 g of silica gel in hexane, the column being eluted with a mixture of hexane and ethyl acetate. The fractions eluted with the mixture of hexane and ethyl acetate in a mixing ratio of 1: 1 yield methyl-N- (2-hydroxyethyl) -3-carbomethoxy-pyrrole-

2-acetate (IV, R = H), which is identical to the product obtained according to section a).

m) A solution of 6 ml of ethanolamine in 5 ml of water is mixed with 1.74 g of dimethyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and then treated dropwise within 15 minutes while stirring 1.67 ml of 1-bromoacetone while maintaining the reaction mixture at a temperature not exceeding 40 ° C. After the addition has ended, the dark reaction mixture is stirred for a further 60 minutes at room temperature and then poured into a mixture of hydrochloric acid and ice, which is saturated with solid sodium chloride, and then extracted three times with 100 ml of ethyl acetate each time. The combined organic extracts are washed neutral with cold water, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue over 30 g of silica gel using a mixture of hexane and ethyl acetate in a mixing ratio of 70:30 as the eluent gives 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methyl-pyrrol-2- acetate, which melts at 78 ° C after recrystallization from a mixture of methylene chloride and hexane and provides the following analytical values:

Analysis for C12H17NO5:

Calculated: C 56.45; H 6.71.

Found: C 56.41; H 6.73.

n) According to the same procedure as described above, this is obtained

Isopropyl-5-p-fluorobenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate, which has the following physical constants:

U.V .: C? X0H 250.315 nm (e 6170.14100);

I.R .: v ™ c'3 1734.1605, 1593 cm "1

NMR: 8 ^ s'3 1.25 (d, 6H, J = 6 Hz; ester CH3), 1.83 (s, 3H; ring CHs), 2.49-3.00 (m, 2H; CH2) , 3.90 (t, 1H, 2 J = 7.4 Hz; CHCO), 4.10-4.23 (m, 2H; N-CH2), 4.98 (sept., IH, J = 6 Hz ; EsterCH), 5.84 (s, IH, H-3), 7.00 (t, 2H, Jonho = 8.4Hz, Jhf = 8 Hz; H-3 ', 5'), 7.55 (q , 2H, Jortho = 8.4 Hz, Jhf = 5.5 Hz;

H-2,6 ');

M.S .: m / e 1%, 329: 25 M +, 242: 100 + -C02CH (CH3>, 123: 36 F-C6H4CO,

o) A solution of 500 mg of isopropyl-5-p-toluoyl-l, 2-dihydro-6-methyl-3 H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate in 15 ml of methanol is with a Treated solution of 1.05 g of potassium carbonate in 8 ml of water. The reaction mixture is then heated to boiling under reflux in a nitrogen atmosphere for 30 minutes, cooled and evaporated to dryness. The residue is taken up in 10 ml of a 10% aqueous hydrochloric acid solution and 50 ml of water and the resulting mixture is extracted three times with 50 ml of ethyl acetate each time. The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, giving 5-p-toluoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [1,2-a] pyrrole-1 - carboxylic acid [(A), R = CH3, R1 = p-CH3].

5-p-Fluorobenzoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid, mp. 204 ° C.

p) 710 mg of a 50% suspension of sodium hydride s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

647782

10th

in mineral oil are washed with anhydrous hexane in a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension thus obtained is cooled to -5 ° C. and 4.5 g of methyl-N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate are added, the reaction mixture being stirred at -5 ° C. to 0 ° for 1 hour ° C stirs. The mixture is poured into ice-cooled sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The solid residue is made to crystallize from ether, giving dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1,7-dicarboxylate (VII, R = H), that is identical to the product obtained according to section d).

q) A 250 ml three-necked round bottom flask, which is equipped with an inlet and outlet nozzle suitable for dry nitrogen, a magnetic stirring rod and a funnel with pressure compensation, which contains 10.08 g of ethanol, is added dropwise with stirring with 26.1 g of dimethyl 1,3-acetone dicarboxylate charged within 30 minutes, keeping the temperature below 30 ° C. The methyl-3-carbomethoxymethyl-3- (2'-hydro-xyethyl) aminoacrylate (III) formed is mixed with 20 ml of acetonitrile and chloroacetaldehyde, which was previously heated by heating a mixture of 27.4 g of chloroacetaldehyde diethyl acetal with 46.8 g of oxalic acid dihydrate was obtained at 150 to 160 ° C, added within 2 minutes with stirring. The reaction mixture is then heated to boiling under reflux for 5 to 10 minutes, after which the reaction can be regarded as complete, as can be determined by thin layer chromatography analysis using a mixture of acetone and chloroform (mixing ratio 10:90) as eluent. The solvent is then removed under reduced pressure and the residue is mixed with 250 ml of benzene and 250 ml of heptane and then distilled under reduced pressure. The oily residue obtained after distillation is suspended in 50 ml of methylene chloride and 20 g of silica gel are added to the suspension. The methylene chloride mixture is poured into a column containing 200 g of silica gel and, as the eluent, a mixture of ethyl acetate (mixing ratio 20:80). The column is first eluted with 6 liters of a mixture of ethyl acetate and hexane (mixing ratio 20:80) and then with 4 liters of a mixture of ethyl acetate and hexane (50:50). The fractions eluted with the mixture of ethyl acetate and hexane in a mixing ratio of 50:50 are combined and concentrated to give 12.8 g of an oil which is triturated with 20 ml of petroleum ether (30 ° C to 60 ° C). The solvent is then evaporated off under reduced pressure. In this way, 11.89 g (32.9% of theory) of methyl N- (2'-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H) of melting point 51 to 54 ° C. It is the same product as that obtained in section a).

example 1

0.58 g of trifluoroacetic anhydride are added to a solution of 300 mg of 5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 25 ml of dry benzene. Then the mixture is stirred for 10 minutes at room temperature and the resulting solution is cooled to 0 to 5 ° C and then 1.4 g of dry triethylamine and then immediately mixed with 0.5 g of (l) -a-phenylethyl alcohol. The reaction solution thus obtained is stirred at room temperature for 15 minutes and then poured into 20 ml of water containing 1 ml of triethylamine and then extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and the solvent and the excess (l) -a-phenylethyl alcohol are removed in vacuo. In this way, 0.42 g of a mixture 5 of (l) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid- (l) -a is obtained -phenylethyl ester and (d) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid- (l) -a-phenylethyl ester, which can be determined by high pressure liquid chromatography (using of 4% EtOAc / hexane io on an 11 mm x 50 cm, 10 ^ m Lichrosord S1-60 column) is separated, whereby 180 mg of a more polar ester [aMe ° H _ J45 70J uncj 178 mg of a less polar ester [aoeOH + 128.6 °].

The splitting of the less polar ester by the ls method, as described below in Example 3 for the splitting of the more polar ester, leads to 85 mg (d) -5-benzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid, [a ™ cl + 155.1 °], mp. 154 to 156 ° C. If desired, the (d) acid isomer obtained in this way can be racemized and recycled by methods known per se.

Example 2

A solution of 200 mg (d) -5-benzoyl-l, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-f-carboxylic acid is dissolved in 50 ml of ethanol-25 water and the solution is heated to boiling. 2 ml of concentrated hydrochloric acid are then added and the mixture is heated under reflux for 30 minutes. The resulting (d, l) -5-benzoyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-l-carboxylic acid is isolated by a conventional method; m.p. 160 to 161 ° C.

In a similar way, other (d) -carboxylic acids are race-mized and give the following (d, 1) compounds of formula A:

35 5-p-toluoyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-l-car-bonic acid, mp. 182 to 183 ° C;

5-o-toluoyl-1,2-dihydro-3 H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, oil;

5- (4-methoxybenzoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] -40 pyrrole-1-carboxylic acid, m.p. 187-187.5 °;

5- (4-ethoxybenzoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid, mp 169.5 to 170 ° C;

5- (3-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid, mp. 180 to 181 ° C; 45 5- (4-chlorobenzoyl) -1.2 dihydro-3 H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp. 201.5 to 202.5 ° C;

5- (4-fluorobenzoyl) -1, 2-dihydro-3H-pyrrolo [1,2-a] -pyrrole-1-carboxylic acid, mp 179.5 to 180.5 ° C;

5-p-toluoyl-6-methyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] -50 pyrrole-1-carboxylic acid, mp 187 ° C;

5-benzoyl-6-methyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid, mp 169 ° C;

5- (4-methoxybenzoyl) -6-methyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-l-carboxylic acid, mp 182 ° C;

55 5- (4-chlorobenzoyl) -6-methyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-l-carboxylic acid, mp. 204 ° C;

6-propyl-6-methyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] -pyrrole-1-carboxylic acid, mp 172 ° C; and

5- (4-fluorobenzoyl) -6-ethyl-1,2-dihydro-3H-pyrrolo [l, 2-60 a] pyrrole-l-carboxylic acid, mp 196 ° C.

Example 3

0.58 g of trifluoroacetic anhydride are added to a solution of 300 mg of 5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 25 ml of dry 65 benzene. Then the mixture is stirred for 10 minutes at room temperature and the resulting solution is cooled to 0 to 5 ° C and then with 1.4 g of dry triethylamine

and then immediately mixed with 0.5 g (l) -cc-phenylethyl alcohol. The reaction solution thus obtained is stirred at room temperature for 15 minutes and then poured into 20 ml of water containing 1 ml of triethylamine and then extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and the solvent and the excess (l) -a-phenylethyl alcohol are removed in vacuo. In this way, 0.42 g of a mixture of (l) -5-benzoy 1-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid- (l) - a-phenylethyl ester and (d) -5-benzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid- (1) -a-phenylethyl ester, which by High pressure liquid chromatography (using 4% EtOAc / Hexane on an 11 mm x 50 cm, 10 µm Lichrosord S1-60 column)

is separated, giving 180 mg of a more polar ester [aMe ° H_145 JO] and 178 mg of a less polar ester [aïf0 "+ 128.6 °].

148 mg of the polar ester are dissolved in 8 ml of dry benzene. The solution is cooled to 15 to 20 ° C and then mixed with 5 ml of trifluoroacetic acid. The solution is then stirred at room temperature for 70 minutes. The reaction solution thus obtained is poured into 60 ml of dry benzene and the solvents are removed in vacuo and at room temperature. Purification is done by high pressure liquid chromatography (using a column as described in Example 1 with the difference that 35% EtOAc / hexane in 1/2% acetic acid is used instead of 4% EtOAc / hexane), whereby 63 mg (l) -5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid, [a ™ cl! -153.7 °], mp. 153 to 155 ° C.

Example 4

A solution of 200 mg of d-5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane and the reaction mixture during Maintained at room temperature for 30 minutes. The solvents and the excess reactant are eliminated under reduced pressure and the residue is crystallized from a mixture of ethyl acetate and methanol. In this way, methyl d-5-benzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate is obtained.

Similarly, using diazoethane and diazopropane instead of diazomethane, the ethyl d-5-benzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -1-carboxylic acid or d- 5-Benzoyl-1,2-dihydro-3 H-pyrrolo- [l, 2-a] pyrrole-1-carboxylic acid propyl ester.

The free acids obtained according to Example 1 can be converted into the corresponding methyl, ethyl and propyl esters in a similar manner.

Example 5

A solution of 300 mg of d-5-p-tolyol-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue is purified by chromatography on aluminum oxide. In this way, isoamyl-d-5-p-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] -py rrol-1-carboxylate is obtained.

Similarly, other esters, e.g. the pentyl, hexyl, octyl, nonyl, dodecyl ester etc. the d-5-p-toluoy 1-1,2-dihydro-3 H'-pyrrolo- [1,2-a] pyrrole-1 -Carboxylic acid if, instead of isoamyl alcohol other alcohols, for example the pentyl, hexyl, octyl, nonyl or dodecyl alcohol, etc. used.

Using the same method, the free acids, as obtained in Example 1, with the corresponding

647 782

Alcohols esterified, which leads to the following esters, e.g .:

Isoamyl-d-5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Pentyl-d-5-m-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Hexyl-d-5-p-ethylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isoamyl-d-5-o-propylbenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Octyl-d-5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Nonyl-d-5-p-isopropoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Dodecyl-d-5-o-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Isoamyl-d-5-m-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Dodecyl-d-5-o-fluorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Hexyl-d-5-p-fluorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Nonyl-d-5-p-bromobenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isoamyl-d-5-benzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Hexyl-d-5-p-ethylbenzoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Nonyl-d-5-o-methoxybenzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Dodecyl-d-5-o-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Nonyl-d-5-benzoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Isoamyl-d-5-p-ethoxybenzoyl-l, 2-dihydro-6-ethyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Pentyl-d-5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3 H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylate,

Hexyl-d-5-m-chlorobenzoyl-l, 2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate and

Dodecyl-d-5-p-bromobenzoyl-1,2-dihydro-6-butyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate.

Example 6

1 mol equivalent of sodium hydroxide in the form of a 0 is added to a solution of 300 mg of d-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 5 ml of methanol , ln solution. The solvent is then evaporated under reduced pressure and the residue is taken up in 2 ml of methanol and then precipitated with ether. In this way, sodium d-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylate is obtained, which is crystallized from a mixture of ethyl acetate and hexane can be.

Similarly, other salts, e.g. produce the ammonium and potassium salts of d-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylic acid if ammonium hydroxide or potassium hydroxide is used instead of sodium hydroxide .

In a similar manner, the 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylic acids obtained in the 5-position substituted according to Example 1 can be converted into the corresponding sodium, potassium and ammonium salts.

Examples of such connections are the following:

Sodium a-5-o-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

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Sodium a-5-benzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Potassium d-5-p-ethylbenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Potassium d-5-o-butylbenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylate,

Sodium a-5-p-methoxybenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Ammonium d-5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Ammonium d-5-o-fluorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Potassium d-5-o-bromobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-1-carboxylate,

Sodium a-5-benzoyl-1,2-dihydro-6-ethyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Potassium d-5-toluoyI-1,2-dihydro-6-methyl-3 H-pyrrolo- [1,2-a] -pyrol-l-carboxylate,

Ammonium d-5-o-methoxybenzoyl-1,2-dihydro-6-methyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate,

Sodium d-5-p-fluorobenzoyl-l, 2-dihydro-6-propyl-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate and

Potassium d-5-m-chlorobenzoyl-1,2-dihydro-6-butyl-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate.

Example 7

1 mol equivalent of potassium hydroxide in the form of a 0 is added to a solution of 175 mg of d-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-l-carboxylic acid in 5 ml of methanol , In solution, to obtain a solution which contains potassium d-5-p-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate. A solution of 40 mg of calcium carbonate, which has been dissolved in the smallest possible amount of hydrochloric acid in order to be able to dissolve the calcium carbonate, is buffered with 100 mg of solid ammonium chloride, after which 5 ml of water are added. The buffered calcium solution thus obtained is then added in a solution of potassium d-5-p-toluoy 1-1,2-dihydro-3 H-pyrrolo- [l, 2-a] pyrrole-1-carboxylate and the precipitate formed is collected by filtration, washed with water and air-dried to give calcium-d-5-p-toluoyl-dp-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a ] pyrrole-1 carboxylate.

Magnesium d-5-p-toluoyl-l, 2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylate is similarly obtained if magnesium carbonate is used instead of calcium carbonate.

The corresponding calcium and magnesium salts are obtained in a similar manner if d-5-benzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carbonic acid,

d-5-p-chlorobenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid,

d-5-o-methoxybenzoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid,

d-5-p-methoxybenzoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid,

d-5-benzoyl-l, 2-dihydro-6-methyl-3H-pyrrolo- [l, 2-a] -pyrrole-1-carboxylic acid and d-5-o-fluorobenzoyl-l, 2-dihydro-6- ethyl 3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid instead of d-5-pT oluoyl-1,2-dihy dro-3 H-pyrrolo- [1,2-a] -pyrrole- 1-carboxylic acid used.

Example 8

1 mol equivalent of potassium hydroxide in the form of a 0 is added to a solution of 200 mg of d-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 5 ml of methanol , Add in solution. The solvent is removed and the residue is dissolved in 5 ml of water. The aqueous solution of potassium d-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate thus obtained is a solution of 150 mg cuprinitrate trihydrate in 5 ml of water added. The precipitate thus formed is collected, washed with water and air-dried, copper-d-5-p-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole- 1-carboxylate receives.

The free acids, as obtained in Example 1, can be converted into the corresponding copper salts in a similar manner.

Example 9

A solution of 200 mg of d-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution is then allowed to cool to room temperature and the product is filtered off, washed with ether and dried, giving the isopropylamine salt of d-5-p-toluoyl-1,2-dihydro-3 H-pyrrolo- [1,2-a ] -pyrrole-1-carboxylic acid.

Similarly, other amine salts, e.g. receive the diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts of d-5-p-toluoyl-l, 2-dihydro-3H-pyrrolo- [l, 2-a] -pyrrole-l-carboxylic acid if you use other corresponding amines instead of isopropylamine.

In a similar manner, the free acids as obtained according to Example 1 can be converted into the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine salts.

Example 10

A solution of 770 mg of d-5-o-toluoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] -pyrrole-l-carboxylic acid in 10 ml of benzene is treated with 580 mg of dicyclohexylamine. The reaction mixture is then stirred for 10 minutes and the solid product formed is separated off by filtration and washed with anhydrous ether, giving 965 mg of the dicyclohexylamine salt of d-5-o-toluoyl-l, 2-dihydro-3H-pyrrolo - [1,2-a] pyrrole-1 carboxylic acid obtained.

Similarly, the free acids so obtained as obtained in Example 1 can be converted into the corresponding dicyclohexylamine salts, e.g. convert the dicyclohexylamine salt of d-5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylic acid.

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Claims (2)

647782 PATENT CLAIMS 1. (d) -5-Aroyl-l, 2-dihydro-3H-pyrrolo [l, 2-a] pyrrole-l-car-bonic acids, their esters and salts of the formula: wherein R is the hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, R1 is the hydrogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1 to 4 carbon atoms or the chlorine, fluorine or bromine atom and R2 is the hydrogen atom, an alkyl radical with 1 to 12 carbon atoms or a pharmaceutically acceptable cation, the substituent R1 being in the ortho, metha or para position of the aroyl group. 2. Use of the compounds of the formula A reproduced in claim 1 for the preparation of the corresponding racemic compounds, characterized in that said (d) -carboxylic acids or their pharmaceutically acceptable salts are racemized.