SU793400A3 - Method of preparing 5-heteroyl-1,2-dihydro-3h-pyrrolo-(1,2a)-pyrrol-1-carboxylic acid esters or salts - Google Patents

Abstract

Carboxylic acid esters of the formula <IMAGE> are prepared by condensation of a compound of the formula <IMAGE> with an amide of the formula <IMAGE> In the formulae, X represents oxygen or sulphur, R represents hydrogen or C1-C4-alkyl, R<1> represents hydrogen, methyl, chlorine or bromine and R<2> represents C1-C4-alkyl. Hydrolysis of the carboxylic acid esters results in the corresponding carboxylic acids and their salts. The compounds are novel and exhibit an anti inflammatory, analgesic and antipyretic action. They are suitable in particular for treating inflammations, pain and febrile conditions.

Description

(54) METHOD FOR OBTAINING COMPLEX ETHERS OR SALTS

5-GETKROIL-1, 2-DIHYDRO-ZN-PIRROLO l, 2-a G IRROL-1 -CARBONIC ACID

12

This invention relates to the field of the preparation of new heterocyclic compounds that can be used in the pharmaceutical industry.

A method for producing esters from flj carboxylic acids is widely described in the literature.

The purpose of the present invention

COOR

where X is oxygen or sulfur;

R is hydrogen or lower

an alkyl group; R is hydrogen, methyl, chlorine or bromine, and the substituent is in the 3.4 or 5 positions of the ring;

mr

soon

is the development, based on the well-known reactions of the method of obtaining new compounds with high pharmacological activity.

This goal is achieved by the described method of preparing esters or salts of 5-heteroyl-1,2-dihydro-3H-pyrroloG1, 2-a} pyrrole-1-carboxylic acid of the general formula

ten

R.

N -COOJR2

Uj

II

g 15

l

,

 alkyl with C - C / g or an inorganic or organic residue of a salt, concludes that 5-heteroyl-1, 2-dihydro-3H-pyrrole 1,2-aJ pyrrole-1-carboxylic acid of the general formula

25

soon

30 where R, Ry and X are as defined above, are converted into a salt or ester in the form of d or C isomers by known methods. Typical alkyl ether groups are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isoamyl, pentyl, isopentyl, hexyl, octyl, nonyl, isodepyl, o-methyldecyl and dodecyl ethers. Salts derived from inorganic bases include sodium potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ferrous; manganese. Particularly preferred salts are the amg / lonium potassium, sodium, calcium, and magnesium salts. Salts derived from organic bases include salts of primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, for example, isrpropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2 -dimethylaminoethanol, 2-diethylaminoethanol, promethamine dizine, arginine, histodine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, pyridine, N-ethylmine, purine, piperazine, N-ethylmine, N-ethyridine. s. Particularly preferred organic bases are isopropylamine, diethylamine, ethanols piperidine, tromethamine, choline, and caffeine. The esters can be obtained from the corresponding acid by treatment with: an alcohol corresponding to the desired ester in the presence of a strong mineral acid: an ester diazo-alkylide iodide in the presence of lithium carbonate. Salts are obtained by treating free acids with an appropriate amount of base. Representative of bases include hydroxide - sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, kgshtsi magnesium hydroxide, iron hydroxide, zinc hydroxide, copper hydroxide, .gidrookis manganese hydroxide alu mini hydroxide divalent same Lez, dvuhvalentnozg March manganese hydroxide, isopropylamine , trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethane nol, 2-diethylthylaminoethanol, arginine trometry, caffeine, procaine, gibrabamine, zolin, betaine, ethylene diamine, glucose N, methylglucamine, those Romijn, purines, piperazine, piperidine, N-ztilpiperidin, polyamine resins and the like The reaction is carried out in water or in its combinations with an inert water-miscible organic solvent at a temperature from 0 to, better at room temperature. Typical inert water-miscible organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane, or tetrahydrofuran. The molar ratio of the compounds of the formulas 1 or I or their C-acid isomers to the base is chosen so as to provide the desired ratio for any desired salt. To obtain, for example, calcium salts or magnesia salts of the compounds of the formulas / or // or their c-acid isomers, the starting free acid can be treated with a semi-polar equivalent of the salt to form a neutral salt. If aluminum salts of the compounds of Formula 1 or a or theirs are obtained (f-acid isomers, then one third of the molar equivalents of the base must be used to obtain the neutral salt. The isolation of the described compounds can be carried out by a suitable separation method or purification, for example by extraction, filtration, evaporation, distillation, crystallization by thin layer chromatography or column chromatography, high pressure liquid chromatography or a combination of these methods. Example 1. Solution 200 mg 5- {2-furoyl ) -1,2-Dihydro-3H-pyrrolo-fl, 2-aJ pyrrol-1-carboxylic acid in 5 MP of dichloromethane was treated with an excess of ether diazomethane and the reaction mixture was kept at room temperature for 30 minutes. Solvents and excess reagents were distilled off under reduced pressure, and the residue was crystallized from ethyl acetate-methanol, methyl 5- (2-furoyl) -1, 2-dihydro-3H-pyrrolo 1,2-a} pyrrole-1-carboxylate was obtained . In the same way, but instead of diazomethane, diazoethane and diazopropane, respectively, ethyl 5- (2-furoyl) -1,2-dihydro-ZN-pyrrolo 1,2-a pyrrole-1-carboxylate and propyl 5- (2- furoyl) -1,2-dihydro-3H-pyrrolo. 1, 2-a} pyrrole-1-carboxylate. Similarly, free acids were converted to the corresponding methyl ethyl and propyl esters. Representatives of the compounds thus obtained are: methyl 3- - tenoyl) -1, 2-dihydro-3H-pyrrolo fi, 2-a pyrrole-1-carboxylate J ethyl 5- (2-thenoyl) -1 , 2-dehydro-3Npyrrolo 1,2-aJpyrrole-1-carboxylate; propyl 5- (2-tenoyl) -1, 2-ligidro-ZN-pyrrolo 1, 2-aJ pyrrol-carboxyl, and methyl; ethyl and propyl esters -5 - (2-thenoyl) -1,2-dihydro-3H-pyrrolo 1, 2-aJ pyrrole-1-carboxylic acid. Example 2 / A solution of 300 mg of 5- (2-tenoyl) -1,2-dihydro-ZN-pyrrolo l, 2-aj pyrrole-1-carboxylic acid in 5 ml of isoamyl alcohol was saturated with hydrogen chloride. After 14 h, the excess alcohol was distilled off in vacuo, the residue was purified by chromatography from alumina, and isoamyl 5- (2-thenoyl) -1,2-dihydro-ZN-pyrrolo, 2-a pyrrole-1-carboxylate was obtained. In the same way, but replacing iso-amyl alcohol with other alcohols, for example, pentyl, hexyl / ryl, nonyl, dodecyl and other alcohols, other esters have been obtained, for example, pentyl, hexyl, octyl, nonyl, dodecyl, and the like. 5- (2-tooyl) -1, 2-dihydro-3H-pyrrolo esters, 2-aJ pyrrole-1-carboxylic acid. By the same procedure, the free acids were esterified with the appropriate alcohol and the corresponding esters were obtained, for example: isoamyl 5- (2-furoyl) -1,2-dihydro-3H-pyrrolo 1, 2-a pyrrole-1-carboxylate, pentyl 5 - (4-methyl-2-tooyl) -1,2-dihydro-3H-pyrrolo 1, 2-a pyrrole-1-carboxylate; hexyl-5- (5-chloro-2-thenoyl) -1,2-di hydro-3H-pyrrolo l, 2-a pyrrole-1-car bauxyl; isoamyl-5- {4-bromo-2-thenoyl) -1,2-dihydro-3H-pyrrolo 1,2-a pyrrole-1-carboxylate, octyl-5- (2-furoyl) -1,2-dihydro- 3N-pyrrolo 1,2-a pyrrol-1-carboxylate nonyl-5- (3-methyl-2-furoyl) -1,2-dihydro-3H-pyrrolo 1,2-a} pyrrole-1-carboxylate; dodecyl-5- (3-chloro-2-furoyl) -1,2-dihydro-ZN-pyrrolo 1, 2-a pyrrole-1-carboxylate / hexyl-5- (4-chloro-2-thenoyl) -1, 2-dihydro-6-methyl-ZN-pyrrolo 1, rol-1-carboxylate, isoamyl-5- (2-thenoyl) -1,2-dihydro-6-ethyl-ZN-pyrrolo 1, 2-a pyrrol-1 carboxylate, octyl-5- (3-furoyl) -1,2-dihydro-ZN-pyrrolo 1,2-a pyrrol-1.-carboxylate. Froze To a solution of 300 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo-fl, 2-a-pyrrole-1-carboxylic acid in 5 ml of methanol was added 1 molar equivalent of sodium hydroxide in the form of 0.1 and. solution. The solvent was evaporated under reduced pressure and the residue was washed with 2 ml of methanol, then it was precipitated. ether and obtained crude 5- (2-thenoyl -1,2-dihydro-3H-pyrrolo 1,2-a pyrrole -1-carboxylate sodium, which can be crystallized from isopropanol. In the same way, other salts were obtained, for example, ammonium and potassium salts 5- (2-thenoyl) -1,2-dihydro-ZN-pyrrolo tl, 2-aJ pyrrole-1-carboxylic acid salts, replacing sodium hydroxide with potassium hydroxide and ammonium hydroxide. Similarly, 5-substituted 1,2-dihydro compounds -ZN-pyrroloG1,2-a pyrrole -carboxylic acid can be converted into the corresponding sodium, potassium, and amg / 1 nium salts. In this way, the compounds are: -5 -. (2-thenoyl) -1, 2-dihydro-3H-pyrrolexY, 2-a-pyrrole-1-sodium carboxylate; 5- (2-furoyl) -1,2-dihydro- 3N-pyrrolo-1,2a sodium pyrrol-1-carboxylate, 5- (4-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo-1,2-a-pyrrole-1-sodium carboxylate; 5- (4-chloro-2-tenoyl) -1,2-dihydro-3H-pyrrolo 1, 2-a pyrrol-1-potassium carboxylate; 5- (b-bromo-2-thenoyl) -1,2-dihydro-3H -pyrrolo 1, 2-a potassium pyrrol-1-carboxylate, 5- (3-methyl-2-furoyl) -1,2-dihydro-, -3H-pyrrolo Cl / 2-a sodium pyrrole-1-carboxylate, 5 - (2-furoyl) -1,2-dihydro-3H-pyrrolo 1,2-a ammonium pyrrole-1-carboxylate; 5- (3-chloro-2-furoyl) -, 2-dihydro-ZN-pyrrolo 1,2-a ammonium pyrrole-1-carboxylate; 5- (4-methyl-2-thenoyl) -1,2-dihydro-b-ethyl-3H-pyrrolo Ll, 2-aJ pyrrol-1-carboxylate sodium; 5- (5-chloro-2-tenoyl) -1,2-dihydro-b-methyl-3H-pyrrolo l, 2-aJ potassium pyrrole-1-carboxylate 5- (3-thenoyl) -1,2-dihydro- 3H-pyrrolo f 1,2-a pyrrol-1-carboxylate ammo-5- (3-furoyl) -1,2-dihydro-3H-pyrroloG / 2-aJ pyrrole-1-carboxylate sodium. Example4. To a solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-ZN-pyrrolo fl, 2-ajpyrrole-1-carboxylic acid in 8 ml of methanol was added 1 molar equivalent of potassium hydroxide as .0.1 n. solution and obtained a solution containing 5- (2-tenoyl) -1,2-dihydro-3H-pyroloyl l, 2-a} pyrrole-1-potassium carboxylate. A solution of 50 mg of calcium carbonate in the minimum amount of 1 g of hydrochloric acid needed to dissolve calcium carbonate was buffered with 100 mg of solid ammonium chloride, then another 5 ml of water was added to it. A solution of 5- (2-tenyl) -1, 2-dihydro-3H-pyrrolo 1,2-a pyrrol-1-carboxyl potassium was added to the buffer solution of calcium thus obtained.

The precipitated precipitate was separated by filtration, washed with water and dried in air, to obtain 5- (2-thenoyl) -1,2 dihydro-3H-pyr6, 2-aj calcium pyrrole-1-carboxylate.

In the same way, replacing calcium carbonate with magnesium carbonate, 5- (2-thenoyl) –1,2-dihydro-3Npyrrolo {1,2-a) pyrrole-1-carboxylate of magnesium was obtained.

Similarly, replacing 5- (2-tenoyl) -l, 2-dihydro-3H-pyropros 1, 2-a pyrrole-1-carb6nova acid -5- (2-thenoyl) -1 g 2 dihydro-3N-pyrr6lo, 2 - aJ pyrrole-1-carboxylic acid,

5- (2-furoyl) -1,2-dihydro-3H-pyrrolol; 2-a pyrrole-1-carboxylic acid;

5- {4-chloro-2-thenoyl) -1,2-dihydro-3H-pyrrolo fl, 2-a pyrrole-1-carboxylic acid; .

5- {3-methyl-2-thenoyl) -1,2-dihydro-3H-pyrrolo tl, 2-a} pyrrole-1-carboxylic acid;

5- (5-bromo-2-furoyl) -1,2-dihydro-b-methyl-3H-pyrrol-1, 2-aJ pyrrol-1-carbonic acid or

5- (3-chloro-2-furoyl) -1,2-dihydro-6-ethyl-ZN-pyrrolo 1,2-aJ pyrrol-1-carboxylic acid, the corresponding calcium and magnesium salts were obtained.

Froze To a solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolol, 2-a} pyrrole-1-carboxylic acid in 8 ml of methanol was added 1 molar equivalent of potassium hydroxide as 0.1 n. solution. The solvent was distilled off and the residue was dissolved in 5 ml of water. The aqueous solution of 5- (2-thenoyl) -1,2-dihydro-ZNpyrrolo 1, 2-a} pyrrole-1-carboxylate potassium thus obtained was added to a solution of 110 mg of trgidrate of copper nitrate in 5 ml of water. The precipitate formed was collected, washed with water and dried in air, and 5- (2-thenoyl) -1,2-digi. Dro-3H-pyrrolo 1,2-a pyrrole-1-carboxylate copper was obtained.

In this way, the free acids can be converted to the corresponding copper salts.

Example A solution of 237 mg of 5- (2-thenoyl) -1,2-dihydro-ZN-pyrrolo 2-a7-pyrrole-1-carboxylic acid in 15 ml in hot benzene was treated with 59 mg of isopropylamine. The solution was given

Hrl- I I |,

 sm H-soonLh /

cooled to room temperature and the product was filtered, washed with water and dried to give the isopropylamine salt of 5- (2-thenoyl) -1,2-dihydro-3H-pyrrolo G1,2-aJ pyrrole-1-carboxylic acid.

In the same way, other amine salts can be obtained, for example, diethylamine, ethanolamine, piperidine tromethamine, choline, and caffeine 5- (2-tenoyl) -1,2-dihydro-3H-pyrrolo C1,2-pyrrole-1-carboxylic acid, if instead isopropylamine use the appropriate amines.

In the same way, the free acids can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, choline or caffeine salts.

Claims (1)

Invention Formula The method of producing esters or salts of 5-heteroyl-1,2-dihydro-3H25-pyrrol-1,2-ay-pyrrole-1-carboxylic acid of the general formula R , 4 i ii. R, ABOUT W SOOE, II II X - oxygen or sulfur, R is hydrogen or lower Cj-C-alkyl /  hydrogen, methyl, chlorine or bromine with the substituent in 3.4 or 5 positions of the ring, galkyl with C - C, or inorganic residue or organization. base characterized in that 5-heteroyl-1, 2-dihydro-3H-pyrrolo1,2 azpyrol-1 carboxylic acid total formulas m v / 79 where X, R and R have the above values, are converted into esters or salts (especially in the form of Y or f-isojus by known methods. Priority by feature: 14.07-.76 with R = hydrogen or low Ci-Cd alkyl) R / is hydrogen, methyl, chlorine or bromine, 0010 and is in the 3.4 and 5-positions of the ring; X - oxygen or sulfur. 02.23.77 - the target product is isolated in the form of d or α-acid isomers. Sources of information taken into account in the examination 1. Buhler K., Pearson D. Organic syntheses, Part 2, Ch. 14, 1973.