DK152652B - ANALOGY PROCEDURE FOR PREPARING 5- (2-FUROYL) -, 5- (2-THENOYL) -, 5- (3-FUROYL) - AND 5- (3-THEONYL) -1,2-DIHYDRO-3H-PYRROLOOE1,2 -AAAPYRROL-1-carboxylic acid esters - Google Patents

Description

The present invention relates to an analogous process for the preparation of novel 5- (2-furoyl) -, 5- (2-thenoyl) -, 5- (3-furroyl) - and 5- (3-thenoyl) -1 , 2-dihydro-3H-pyrrolo-11,2-aj-pyrrole-1-carboxylic acid esters of the general formula:

wherein X represents oxygen or sulfur, R represents hydrogen or an alkyl group of 1-4 carbon atoms which may be in position 3, 4 or 25 represents hydrogen, methyl, chlorine or bromine, and R is an alkyl group of 1- 4 carbon atoms, the process being characterized by the characterizing part of the claim.

The compounds prepared by the process of the present invention, described above and more fully described below, exert an anti-inflammatory, analgesic and antipyretic effect and are thus useful in the treatment of mammalian inflammation, pain and / or pyrexia as described below. They are also smooth muscle relaxants.

The term "pharmaceutically acceptable, non-toxic esters" is used herein to mean "alkyl esters" derived from straight or branched chain hydrocarbons having 1-4 carbon atoms.

Typical alkyl ester groups are methyl, ethyl, propyl, isopropyl, butyl and t-butyl esters.

The present novel compounds of formulas (XI) and (XII) exist as pairs of optical isomers (or enantiomorphs), viz. a (dl) mixture.

The novel (dl) compounds and starting materials for use in the preparation thereof of the present invention can be prepared by a process which can be illustrated by the following reaction scheme:

Wherein X, R and R are as defined above and R is an alkyl group of 1-4 carbon atoms, e.g. methyl; ethyl isopropyl or h-butyl ·.

When the above process is carried out to prepare the compound of formula (IV) wherein R is hydrogen, equimolar amounts of ethanolamine (I) and dimethyl-1,3-acetonedicarboxy = lat (II) are reacted at a temperature of about 0 ° C to about room temperature to readily form a solution of the vinylamine of formula (III) which is then, preferably in situ, treated in a suitable inert organic solvent under anhydrous conditions with 2-bromoacetaldehyde or 2-chloroacetaldehyde at a temperature of about . 40 ° C to approx. 1 0 0 ° C for a period of approx. 30 minutes to approx. 16 hours. Suitable solvents for this reaction are the aprotic solvents such as acetonitrile, tetrahydrofuran, dimethoxyethane, chloroform or dichloromethane. In the preferred embodiments, the reaction is carried out in acetonitrile solution at reflux temperature for approx.

1 hour. The 2-bromo (chloro) acetaldehyde reagents are known compounds or can be obtained by pyrolysis of the corresponding diethyl acetals in the presence of oxalic acid dihydrate.

To prepare the compounds of formula (IV) wherein R is a preferably straight chain lower alkyl group of 1-4 carbon atoms, an aqueous mixture of ethanolamine (i) and dimethyl-1,3-acetone dicarboxylate (II) is treated with a compound of the formula R--C-CH «X wherein X is bromine or chlorine and R- is a lower alkyl group, preferably straight-chain of 1-4 carbon atoms, and especially 1-bromoacetone, 1-bromo-2-butanone, 1- bromo-2-pentanone and 1-bromo-2-hexanone at a temperature of ca. 40 ° C to approx. 100 ° C for a period of approx. 30 minutes to approx. 16 hours. In the preferred embodiment, the reaction is carried out at a temperature of from about -10 ° C to about room temperature for from 1 hour

3 V

to approx. 6 hours. The R-C-CEy reagents are known compounds.

Esterification of compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine, e.g. triethylamine slidepyridine, optionally in the presence of a co-solvent such as dichloromethane, at a temperature of about -10 ° C to about room temperature for approx. 10 minutes to approx. 2 hours, the corresponding mesylate of formula (V) which is converted to the corresponding N- (2-iodoethyl) pyrrole of formula (VI) by reaction with sodium iodide in acetonitrile solution yields at reflux temperature for from ca. 1 to approx. 10 hours.

After reaction of iodoethyl compounds of formula (VI) with sodium hydride in a suitable inert organic solvent such as dimethyl = formamide, dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7 di = carboxylate and the 6-alkyl-substituted derivatives thereof (VII). This ring closure is carried out under an inactive atmosphere, i.e. under an argon or nitrogen atmosphere at temperatures of the order of ca. 15 ° C to approx. 40 ° C for a period of approx. 15 minutes to approx. 4 hours. The best results are obtained by conducting the reaction at room temperature for approx. 3 minutes when R is hydrogen.

Alternatively, the compounds of formula (VII) may be prepared by direct cyclization of the mesylate (V) with sodium hydride in dimethyl form = amide solution at a temperature of ca. -10 ° C to about room temperature from approx. 30 minutes to approx. 2 hours.

Basic hydrolysis of a compound of formula (VII) with an alkali metal hydroxide or alkali metal carbonate, e.g. sodium hydroxide, sodium carbonate or potassium carbonate in an aqueous lower aliphatic alcohol, e.g. methanol or ethanol at a temperature between room temperature and the reflux temperature for from ca. 4 to approx.

24 hours, the corresponding free diacid of formula (VIII), i.e.

The 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid and the 6-alkyl derivatives thereof. The hydrolysis is preferably carried out under the use of aqueous methanolic potassium hydroxide at the reflux temperature for approx. 10 hours.

The carboxylic acid group at the C-1 position of the compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol, e.g. methanol, ethanol, isopropanol or n-butanol, in the presence of hydrogen chloride to produce the corresponding alkyl-1,2-di = hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid with formula (IX). The reaction is carried out at a temperature of approx. 0 ° C to approx. 50 ° C, for approx. 1 to approx. 4 hours.

Decarboxylation of the mono-esterified compounds (IX) to the corresponding compounds of formula (X), the main intermediates of the process for obtaining the compounds of the present invention, is achieved by heating (IX) at an elevated temperature of the order of about 100 ° C. 230 ° C to approx. 280 ° C for a time sufficient to cause the reaction to terminate. The course of the reaction can be followed by the extent of carbon dioxide evolution and thin-layer chromatographic analysis, the decarboxylation usually being completed over approx. 45 to approx. 90 minutes. The reaction product, namely alkyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate and the 6-alkyl derivatives thereof (X), can be purified by chromatographic methods. Alternatively and especially for the decarboxylation of small portions of compound (IX), the reaction product (X) can be distilled directly from the reaction vessel.

The condensation of the process according to the invention. a compound (X) down an amide of the formula

wherein X and R have the meanings set forth above, the corresponding alkyl-5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylates of formulas (XI) or ( XII).

This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for a period of about 1 to approx. 72 hours under an inactive atmosphere followed by further reflux in the presence of sodium = acetate for from ca. 2 to approx. 10 hours. Alternatively, instead of phosphorus oxychloride, other acid chlorides such as phosgene or oxalyl chloride may be used.

In the preferred embodiments, this condensation is carried out by adding a solution of compound (X) in a suitable solvent to a pre-refluxed mixture of 1.1-2 molar equivalents of both the desired amine and phosphorus oxychloride in the same solvent, refluxing the reaction mixture thus obtained. i from approx. 2 to approx. 30 hours under an argon atmosphere and thereafter set from approx. 3 to approx. 10 molar equivalents of sodium acetate, followed by a further reflux period of approx. 4 to approx. 6 hours.

Suitable solvents for this reaction are the halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, or carbon tetrachloride, dimethoxyethane and tetrahydrofuran. The preferred solvent is 1,2-dichloroethane.

Representative examples of the Ν, Ν-dimethylamides that can be used as starting materials are: N, N-dimethylthiophene-2-carboxamide, N, N-dimethylfuran-2-carboxamide, N, N-dimethyl-3-methylthiophene-2-carboxamide, N, N-dimethyl-4-methylthiophene-2-carboxamide, N, N-dime thyl-5-methylthiophene-2-carboxamide, N, N-dime thyl-4-chlorothiophene-2-carboxamide, N, N- dimethyl-5-chlorothiophene-2-carboxamide, N, N-dimethyl-3-bromothiophene-2-carboxamide, N, N-dimethyl-5-bromothiophene-2-carboxamide, N, N-dimethyl-3-methylfuran-2 -carboxamide, N, N-dimethyl-4-methylfuran-2-carboxamide, N, N-dimethyl-4-chlorofuran-2-carboxamide, N, N-dimethyl-5-chlorofuran-2-carboxamide, N, N- dimethyl-4-bromofuran-2-carboxamide, N, N-dimethyl-5-bromfuran-2-carboxamide, N, N-dimethylthiophene-3-carboxamide and N, N-dimethylfuran-3-carboxamide.

These amides can be prepared in the usual manner from the corresponding thiophene or furan 2- (3) carboxylic acids, i.e. by conversion to the acid chlorides followed by treatment with dimethylamine.

It is to be understood that, if desired, isolation of the compounds described herein may be effected by any suitable separation or purification method, such as e.g. extraction, filtration, evaporation, distillation, crystallization, thin layer chromatography or column chromatography, high pressure liquid chromatography (HPLC) or a combination of these methods. Examples illustrate suitable separation and isolation methods. Of course, other equivalent separation or isolation methods can also be used.

The compounds of formulas; (XI) and (XII) are useful as anti-inflammatory agents, analgesics, platelet aggregation inhibitors, fibrinolytic agents, and as smooth muscle relaxants. These compounds can be used both prophylactically and therapeutically.

On the basis of these compounds, products which are thus useful in the treatment and elimination of inflammation, such as inflammatory conditions of the muscular skeletal system, skeletal joints and other tissues, may be prepared. in the treatment of inflammatory conditions such as rheumatism, concussion, laceration, arthritis, fractures, post-traumatic conditions and arthritis. In the cases where the above conditions include pain and pyrexia in connection with inflammation, the present compounds are useful in alleviating these conditions, as well as the inflammation.

The preferred mode of administration for the conditions described above is the oral one, using an appropriate daily dose amount that can be adjusted according to the nature and extent of the disorder. A daily dose of 25 mg to 500 mg of said active compound is used. Most disorders respond to a treatment comprising a dose amount of the order of 0.5 mg to 6 mg per day. kg body weight per day.

The compounds of the invention, as described above, are also smooth muscle relaxants and are thus useful as agents for maintaining pregnancy in pregnant women and pregnant mammals for the benefit of the mother and / or fetus until termination of pregnancy from a medical point of view is found favorable or more favorable for the mother and / or the fetus.

The following preparation methods and examples illustrate the preparation of starting materials and the process according to the invention respectively. All mixing ratios used with regard to liquids refer to volume ratios. Where necessary, examples are repeated to prepare additional material for the following examples, and unless otherwise stated, the reactions are carried out at room temperature (20-30 ° C).

Preparation method 1

A mixture of 23 g of 4-chlorothiophene-2-carboxylic acid (J. Iriarte et al., J. Heterocyclic Chem. 13, 3931 and 80 ml of thionyl chloride is heated to reflux under anhydrous conditions for 4 hours. The excess thionyl chloride is removed and the residue distilled under reduced pressure (60 ° C / 2 mm Hg) to give 18 g of 4-chlorothiophene - 2-carboxylic acid chloride.

A solution of 10.5 g of 4-chlorothiophene-2'-carboxylic acid chloride in 500 ml of anhydrous benzene is cooled in an ice-water bath and dimethylamine is slowly bubbled through the solution for 30 minutes. The ice-water bath is removed, maintaining the dimethyl = amine stream for a further 15 minutes. The reaction mixture is then diluted with 100 ml of 10% sodium chloride solution and stirred for 5 minutes at room temperature, the organic phase is separated, washed with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. There is thus obtained N, N-dimethyl-4-chlorothiophene-2-carboxamide.

Similarly, the thiophene and furan-2-carboxylic acids listed below under I, are converted to the Ν, Ν-dimethylamides listed under II:

I II

Thiophene-2-carboxylic acid NjN-dimethylthiophene-2-carboxamide furan-2-carboxylic acid Ν, Ν-dimethylfuran-2-carboxamide 3-methylthiophene-2-carboxylic acid N, N-dimethyl-3-methylthiophene-2-carboxamide 4-methylthiophene 2-carboxylic acid N, N-dimethyl-4-methylthiophene-2-carboxamide 5- methylthiophene-2-carboxylic acid NrN-dimethyl-5-methylthiophene-2-carboxamide 5-chlorothiophene-2-carboxylic acid NfN-dimethyl-5-chlorothiophene 2-carboxamide 3-bromothiophene-2-carboxylic acid N, N-dimethyl-3-bromothiophene-2-carboxamide 4-bromothiophene-2-carboxylic acid N / N-dimethyl-4-bromothiophene-2-carboxamide 5-bromothiophene-2-carboxylic acid N, N-dimethyl-5-bromothiophene-2-carboxamide 3-methylfuran-2-carboxylic acid N, N-dimethyl-3-methylfuran-2-carboxamide 4-methylfuran-2-carboxylic acid N, N-dimethyl-4-methylfuran 2-carboxamide 5-methylfuran-2-carboxylic acid N, N-dimethyl-5-methylfuran-2-carboxamide 3-chlorofuran-2-carboxylic acid N, N-dimethyl-3-chlorofuran-2-carboxamide 4-chlorofuran-2-carboxylic acid N, N-dimethyl-4-chlorofuran-2-carboxamide 2-carboxylic acid N, N-dimethyl-5-chlorofuran-2-carboxamide-4-bromfuran-2-carboxylic acid N, N-dimethyl-4-bromfuran-2-carboxamide-5-bromfuran-2-carboxylic acid N, N-dimethyl-5 bromfuran-2-carboxamide thiophene-3-carboxylic acid N, N-dimethylthiophene-3-carboxamide furan-3-carboxylic acid N, N-dimethylfuran-3-carboxamide.

Preparation Method 2

A 250 ml 3-necked, round-bottomed flask with magnetic stirring and fitted with a calcium chloride-filled drying tube is connected directly (via one of the external necks) by means of an adapter and a short (3 ") water cooler to the acetal pyrolysis apparatus. This latter apparatus consists of a 100 ml straight-linked flask (pre-loaded 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 at the top, with a thermometer connected to the above swallow.

The 3-neck flask is charged with 3.36 g of ethanolamine, cooled in an ice bath to 0-10 ° C and treated dropwise with stirring with 8.7 g of dimethyl-1,3-acetone dicarboxylate. Methyl 3-carbomethoxymethyl-3 (2'-hydroxyethyl) aminoacrylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 100 ml of dry acetonitrile. The pyrolysis part of the apparatus is placed in an oil bath and its temperature is raised to 150 to 160 ° C. The bromoacetaldehyde solution formed distills (boiling point 80-83 ° C / 580 mm Hg) directly into the magnetically stirred solution of the vinylamine (III). When the distillation temperature drops below 80 ° C, the connection to the pyrolysis apparatus is disconnected and a reflux condenser fitted with a calcium chloride drying tube is instead. The solution is heated at reflux for 1 hour, the solvent is removed under reduced pressure, then 200 ml of methanol and 20 g of silica gel are added to the residue. The mixture is evaporated to dryness under vacuum and placed on top of a column of 200 g of silica gel packed in hexane. The column is then eluted with hexane / ethyl acetate (80:20, 500 mL) and hexane / ethyl = acetate (1: 1, 9 x 500 mL). Fractions 2 and 3 contain minor polar impurities and dimethyl-1,3-acetone dicarboxylate, fractions 4-8 give 4.1 g of methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H ), which after recrystallization from ether / hexane has a melting point of 52-54 ° C.

Method of preparation 3

To a stirred solution of 4.1 g of methyl N- (2-hydroxyethyl) -3-carboxy methoxypyrrole-2-acetate in 35 ml of dry dichloromethane cooled to -10 ° C, add 2.65 ml of triethylamine and then drop by drop. 1.46 ml of methanesulfonyl chloride, keeping the temperature of the reaction mixture at -10 - -5 ° C. The course of the reaction is followed by thin layer chromatographic analysis using chloroform / acetone (90:10). When the reaction turns out to be complete (about 30 minutes after the methane = sulfonyl chloride addition has ceased) slowly add 10 ml of water.

The organic phase is separated, washed with water (3 x 30 ml), dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from dichloromethane / hexane gives 4.75 g (77.7%) of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), mp 99-101 ° C.

Preparation Method 4

A solution of 785 mg of methyl N- (2-mesyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is refluxed for 1 hour. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is decomposed with water. The insoluble material is filtered off and air dried. Thus, 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), m.p. 137-138 ° C is obtained.

For cooking method 5

A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred under an argon atmosphere with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is kept at room temperature for 30 minutes and then cooled rapidly with 100 ml of water. The product is extracted with ethyl acetate (3 x 50 ml), the combined extracts washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue on silica gel (20 g) using hexane / ethyl acetate (4: 1) as the eluant gives 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 7-dicarboxylate (VII, R = H), m.p. 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 treated with a solution of 4.48 g of potassium hydroxide in 20 ml of water. and the reaction mixture is refluxed 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 with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure. There is thus obtained 1.51 g (95%) of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid (VIII, R = H), m.p. 220 ° C with decomposition.

Preparation Method 6

A solution of 1.34 gl, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-di-carboxylic acid in 50 ml of isopropanol is cooled in an ice bath, saturated with hydrogen chloride gas, the temperature of the reaction mixture kept below 50 ° C. The ice bath is then removed and the reaction is stirred for 1 1/2 hours at room temperature and evaporated to dryness under reduced pressure, 10 ml of benzene is added to the residue and the solution is evaporated again under vacuum, repeating a total of three times for complete treatment. removing hydrogen chloride excess. Thus, 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, R = iso-C H₂) which, after recrystallization from methanol / ethyl = acetate, has a melting point of 144-145 ° C.

Similarly, but using methanol, ethanol, propanol and n-butanol in place of isopropanol by the above process, respectively, is obtained: methyl 1,2-dihydro-3 H -pyrrolo [1,2-a] pyrrole-1- carboxylate-7-carboxylic acid, ethyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid, propyl-1,2-dihydro-3H-pyrrolo [1,2- a] pyrrole-1-carboxylate-7-carboxylic acid, and butyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid. Preparation Method 7 1.054 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid is heated to 240-250 ° C in a dry 10 ml round bottom flask, the reaction product being distilled directly from the reaction vessel.

In this way, 745 mg (87%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] o-pyrrol-1-carboxylate (X, R = H, R = iso-C 1), a pale yellow oil with the following physical constants: DV,: 215 nm (ε 6020), IR: v (Nuclear Magnetic Resonance): δ 3.22 (d, J = 7 Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (in, 2H), 4 , 65-5.2 (m, 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3 Hz, lfi), 6.43-6.53 (m, 1H) ).

Preparation Method 8

A 100 ml three-necked round bottom flask provided with a cooler, nitrogen supply tube and a gas bubbler is supplied with 5.0 g of isopropyl-1,2-di-hydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid . The apparatus is completely blown with nitrogen and then the nitrogen flow is stopped. The apparatus is immersed in an oil bath, heated to 270 ° C, and the reaction is monitored by the extent of carbon dioxide evolution (gas bubbles) and by thin layer chromatography on silica gel using benzene / dioxane / acetic acid (90: 10: 1) as the developing agent. After 45 minutes, the reaction is almost complete. After 1 hour, the vessel is removed from the oil bath and the contents of the reaction flask are transferred to a round bottom flask with 500 ml of acetone. The solvent is removed under reduced pressure and the residue is purified by column chromatography on 100 g of silica gel. The fractions eluted with hexane / benzene (70:30) and hexane / benzene (50:50) give 2.77 g (68%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = H, R 2 = iso-C 2 H 2), an oil whose physical constants are identical to those specified in Preparation Method 7.

Method 9 910 mg of a 50% suspension of sodium hydride in mineral oil is washed with anhydrous hexane under a nitrogen atmosphere and then suspended in 50 ml of dimethylformamide. The suspension is cooled to -5 ° C and 4.5 g of methyl N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate is added, stirring at 5 ° C to 0 ° C for 1 hour. The reaction mixture is then poured into ice-cold 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 crystallized from ether. There is thus obtained dimethyl-1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1,7-dicarboxylate (VII, R = H) identical to the product obtained by: Preparation Method 5.

Preparation Method 10

Following methods 7 or 8, the residues obtained by method 5 are converted into: methyl 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil, ethyl-1,2- dihydro-3H-pyrrole [1,2-a] pyrrole-1-carboxylate, propyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, and butyl-1,2-dihydro -3H-pyrrolo [1,2-a] pyrrole-l-carboxylate,

Preparation Method 11

A 250 ml 3-neck round bottom flask with magnetic stirring and fitted with a calcium chloride-filled drying tube is charged with 3.36 g of ethanolamine, cooled in an ice bath to 0-10 ° C and treated dropwise with stirring with 8.7 g of dimethyl-1. 3-acetonedicarboxylate. Methyl 3-carbomethoxymethyl-3- (2, -hydroxyethyl) aminoacrylate (III) is formed immediately. After the addition is complete, remove the ice bath and add 80 ml of dry acetonitrile. The reaction mixture is then treated dropwise with 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile and then heated at the reflux temperature for 2 hours. The solvent is then removed under reduced pressure and 200 ml of methanol and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness under vacuum and placed on top of a column of 200 g of silica gel packed in hexane, eluting with the column with hexane / ethyl acetate mixtures. Fractions eluted with hexane / ethyl acetate (1: 1) give methyl N- (2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate (IV, R = H) identical to the product obtained in Preparation Method 2.

Preparation Method 12

To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of di-methyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and treated dropwise over a 15 minute period with stirring with 1.67 ml of 1-bromoacetone while maintaining the reaction mixture at a temperature not exceeding 40 ° C. After completion of the addition, the dark reaction mixture is stirred for a further 1 hour at room temperature and then poured into a hydrochloric acid / ice mixture saturated with solid sodium chloride and extracted with ethyl acetate (3 x 100 mils).

The total organic extract is washed with cold water for neutral reaction, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue on 30 g of silica gel using hexane / ethyl acetate (70:30) as the eluent gives 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, which by recrystallization from methylene chloride / hexane melts at 78 ° C and has the following analysis;

Calculated for ci2H17N05i C '56'45' H '

Found: C, 56.41; H, 6.73.

Similarly, but using a stoichiometric equivalent amount of 1-bromo-2-butanone, 1-bromo-2-pentanone and 1-bromo-2-hexanone instead of 1-bromoacetone is obtained respectively: methyl-N- (2 -hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-propyl-pyrrole-2-acetate, and methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-butyl-pyrrole-2-acetate.

Release to Method 13

Following method 3, methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R = CH3) is converted to methyl N- (2-mesyloxyethyl) -3-carbomethoxy-4 -methylpyrrole-2-acetate and then cyclized with sodium hydride in dimethylformamide according to the method of Preparation Method 9 to prepare dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7 -dicarboxylate.

By hydrolysis of the latter compound with potassium hydroxide according to the method of Preparation Method 5 followed by selective esterification at C1 and decarboxylation at C-7 according to the methods of Preparation Methods 6 and 8 respectively, 1,2-dihydto-6-methyl-3H is successively obtained. -pyrrolo [1,2-a] pyrrole-1,7-di-carboxylic acid, isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7 carboxylic acid and isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = CH 2, R = iso-C 2 H).

Similarly using methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-propylpyrrole-2-acetate and methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate instead of methyl N- (2-hydroxy = ethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate are available as final products respectively; isopropyl-1,2-dihydro-6-ethyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, isopropyl-1,2-dihydro-6-propyl-3H-pyrrolo [1,2-a ] pyrrole-1-carboxylate, and isopropyl-1,2-dihydro-6-butyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate.

Example 1

By analogy with the following procedure:

A solution of 232.5 mg of N, N-dimethylthiophene-2-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane was refluxed for 30 minutes. To this solution is added a solution of 181 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and refluxed for an additional 5 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel eluting with hexane / ethyl acetate (3: 1). Thus, isopropyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R and R = H, R = iso C ^H ^, X = S) is obtained by condensation of ethyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo- [1,2-a] pyrrole-1-carboxylate with N, N -dimethylthiophene-2-carboxamide: ethyl 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, Me H 265 328 nm (7580 17780) < max '

Example 2

Following the procedure of Example 1 and using 1.1-2 molar equivalents N, N-dimethylfuran-2-carboxamide, N, N-dime thyl-5-methylthiophene-2-carboxamide, N, N-dimethyl-4-chlorothiophene -2-carboxamide, N, N-dimethylthiophene-3-carboxamide, and N, N-dimethylfuran-3-carboxamide, instead of N, N-dimethylthiophene-2-carboxamide and follow the course of the reaction by thin layer chromatography are obtained, respectively: isopropyl-5- (2-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate an oil having the following physical constants:

isopropyl 5- (5-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 82 ° -82.5 ° C, isopropyl-5 - (4-chloro-2-thenoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil,

isopropyl-5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 67-68 ° C, isopropyl-5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, oil,

Example 3 In accordance with the procedure of Example 1, iso = propyl ~ 1,2-dihydro-6-methyl'-3H '' pyrrolo [1,2 ~ a] pyrrole-1'-carboxylate is condensed with N, N-dimethylthiophene -carboxamide to prepare isopropyl 5- (2-thenoyl) -1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R = CH = H, R 2 = iso-C 2 Hy, X = S), mp 102.5 ° C.

Example 4

A solution of 232.5 mg of N, N-dimethylthiophene-3-carboxamide and 0.15 ml of phosphorus oxychloride in 2 ml of lf2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 181 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane.

The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 450 mg of sodium acetate and refluxed for an additional 5 hours. The resulting mixture is then evaporated to dryness and the residue is chromatographed on 12 g of silica gel eluting with hexane / ethyl = acetate (3: 1). Thus, isopropyl 5- (3-thenoyl) -1,2-dihydro-3H- Λ pyrrolo [1,2-a] pyrrole-1-carboxylate (XII, R = H, R = iso-C X = S), m.p. 67-68 ° C.

Similarly, N, N-dimethylfuran-3-carboxamide is used in place of N, N-dimethylthiophene-3-carboxamide, and isopropyl-5- (3-furoyl) -1,2-dihydro-3H-pyrrolo [1 2-a] pyrrole-1-carboxy = lat, an oil having the following physical constants:

Test for anti-inflammatory effect using Carrageenin-induced protein inflammation in rat.

Protocol: Simonsen female rats weighing 80-90 g are used. The compounds to be tested are administered hourly orally by administration in 1 ml

Claims (1)

aqueous carrier. One hour later, 0.05 ml of a 1% solution (0.9% NaCl) of carrageenin is injected into the right hind paw. This injection causes inflammation of the paw. The rats are sacrificed 4 hours after the start of the experiment, during which time both hind legs are removed and weighed separately. End point:% increase in paw size calculated as follows: Weight of right leg - weight of left leg Weight of left leg Using the above protocol, it is determined that 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid has an anti-inflammatory effect of 48 (95% confidence limits: 32-72) times phenylbutazone. Compound-Activity dl methyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate dioctyl-5- (2-thenoyl) -1,2-dihydroxy dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate di dodecyl-5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole -1-Carboxylate Patent Claims. Analogous Process for Preparation of 5- (2-Furoyl) -, 5- (2-thenoyl) -5- (3-furoyl) - and 5- (3-thenoyl) -1,2-dihydro-3H-pyrrolo- [1 2-a] pyrrole-1-carboxylic acid esters of the general formula: wherein X represents oxygen or sulfur, R represents hydrogen or an alkyl group of 1-4 carbon atoms, R 4 which may be in position 3, o 4 or 5 represents hydrogen or "methyl, chlorine or bromine" and R is one. alkyl group having i-4 carbon atoms, characterized by condensing a compound of the formula: wherein R and R 2 have the meaning defined above, with an amide of the formula wherein X and R1 have the meaning defined above.