• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Novel 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid compounds represented by the formula <IMAGE> and the pharmaceutically acceptable, non-toxic esters and salts thereof, wherein R is hydrogen or a lower alkyl group containing from 1 to 4 carbon atoms and R1 is hydrogen, a lower alkyl group having from 1 to 4 carbon atoms, a lower alkoxy group of 1 to 4 carbon atoms, chloro, fluoro or bromo, the R1 substitution being at the ortho, meta or para positions of the aroyl group and process for the production of such compounds; 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid is representative of the class. These compounds, as the racemic mixture or the (1)-isomer, are useful as anti-inflammatory, analgesic and antipyretic agents and as smooth muscle relaxants.
    公开号:SU946403A3
    申请号:SU772558802
    申请日:1977-12-28
    公开日:1982-07-23
    发明作者:М.Маковски Джозеф；Ф.Клюге Артур
    申请人:Синтекс (Ю.С.А.)Инк (Фирма)；
    IPC主号:
    专利说明:

    in the desired ester, in the presence of a strong mineral acid; ether diazoalkane; alkyl iodide in the presence of lithium carbonate. Salts are obtained by treating free acids with an appropriate amount of a base. Examples of bases are sodium, potassium, lithium, ammonium, calcium, magnesium, iron II, zinc, copper, manganese II, aluminum, iron III, manganese III, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylamine methanol hydroxides. , 2-di-ethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine.Holine, betaine, ethylenediamine, glucosamine, methylglucamine, theo-bromine, purines, piperazine, piperidine N-ethylpiperidine, polymethyne resin, resin, phosphines, purines, piperazine, piperidine N-ethylpiperidine, polyamine resin, resin, phosphines, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resin, resin, purines, piperazine, piperidine, ethylenediamine, polyamine resin, purines, piperazine, piperidine, ethylenediamine, polyamine resin, purine, piperazine, piperidine held in water or in a mixture of water with inert mixing with water, an organic solvent at 0-10Sg C, preferably at room Melting. Typical inert, water-miscible, organic solvents include methanol, ethanol, isopropiol, butanol, acetone, dioxane, or tetrahydrofuran. The molar ratio of acids to the base used is selected depending on the particular salt required. For example, to obtain calcium or magnesium salts, the starting free acid can be treated with at least a semi-polar equivalent of base to form a neutral salt. For the preparation of aluminum salts, at least one third mole equivalent of base is used to form a neutral salt. Isolation of the described compounds can be carried out by any suitable method of separation or purification, for example, extraction, filtration, evaporation, distillation, crystallization, thin-layer or column chromatography at high pressure (HPLC), or a combination of these methods. Example 1. A solution of 200 mg of 5-benzoyl-1,2-dihydro-ZN-pyrrole (1,2-a pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ether diazomethane and the reaction mixture is kept at room temperature for 30 minutes. Solvents and the excess reagent is removed under reduced pressure, the residue is crystallized from ethyl acetate-methanol and methyl 5-benzoyl-1,2-dihydro-3H-pyrrole {1,2-o) pyrrole-1-carboxylate. In a similar way but using diazoethane and diazopropane instead of diazomethane, ethyl-5 benzoyl-1,2-dihydro-3H-py are obtained, respectively ol (1,2-a) pyrrole-1-carboxylate and propyl-5, 7benzoyl-1,2-dihydro-ZN-pyrrole (1,2Q) pyrrole-1-carboxylate; Similarly, the remaining free acids are converted into the corresponding methyl, ethyl and propyl esters. Example 2. A solution of 300 mg of 5-P-toluoyl-, 2-dihydro-ZN-pyrrole (1) pyrrole-1-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 alumina. Isoamyl-5 C1-toluoyl-1, 2-dihydro-ZN-pyrrole (1,2-c () pyrrole-1-carboxylate is obtained. Other esters, for example, pentyl, hexyl, octyl, ionyl, dodecyl 5 and -toluoyl-1,2-dihydro-ZN-pyrrole (1, 2-o () pyrrole-1-carboxylic acid by replacing isoamyl alcohol with other alcohols, for example pentyl, hexyl, octyl, nonyl, dodecyl). In the same way, free esterification acids with the corresponding alcohol, the following esters are obtained: Isoamyl-5 benzoyl-1,2-dihydro-ZN-pyrrole (1,2-0) pyrrole-1- carboxylate; Pentyl-5-M-toluoyl-1,2-dihydro-ZN-pyrrole (1, 2-a) pyrrol-1-carboxyl-r. Hexyl-5-I-ethylbenzoyl-1,2-dihydro-3JH- pyrrole (1, 2-O) pyrrole-1-carboxylate; Isoamyl-5 o-propylbenzoyl-1,2-dihydro-3H-pyrrole (1,2-Oupirrole-1-carboxylate; Octyl-5-I-methoxybenzoyl-1 , 2-dihydro-ZN-pyrrole (1, 2-a) pyrrole-1.-carboxylate; Nonyl-5-vi-isopropoxybenzoyl-1,2-dihydro-ZN-pyrrole (1,2-Q) pyrrole-1 carboxylate; Dodecyl-5O-chlorobenzoyl-1,2-dihydro-ZN-pyrrole {1, 2-a) pyrrole-1-carboxylate;
    Isoamyl-5-M-chlorobenzoyl-1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylate;
    Dodecyl-5 C-fluorobenzoyl-1,2-dihydro-3H-pyrrole (1,2-O) pyrrole-1-carboxylate;
    Hexyl-5-I-fluorobenzoyl-1,2-dihydro-ZN-pyrrole (1,2-0) pyrrole-1-carboxylate;
    Nonyl-5-I-bromobenzoyl-1,2-dihydro-ZN-pyrrl (1,2-c |) pyrrole-1-carboxylate
    Isoamyl-5-benzoyl-1,2-dihydro-6-methyl-ZN-pyrrole (1,2-o1) pyrrole-1-carboxylate
    Hexyl-5- -ethylbenzoyl-1, 2-dihydro-6-methyl-ZN-pyrrole (1,2-Q) pyrrole-1 -carboxylate;
    Nonyl-5-o-methoxybenzoyl-1,2-dihydro-6-methyl-ZN-pyrrole (1,2-O) pyrrole-1-carboxylate; ,
    Dodecyl-5-o-fluorobenzoyl-1,2-dihydro-6-methyl-ZN-pyrrole (1,2-a) pyrrole-1-carboxylate;
    Nonyl-5 benzoyl-1,2-dihydro-6-ethyl-ZN-pyrrole {1, 2-a) pyrrole-1-carboxylate;
    Isoamyl-5 and-ethoxybenzoyl-1,2-dihydro-6-ethyl-3H-pyrrole- (1, 2-c |) pyrrole-1-carboxylate;
      Pentyl-5-m-fluorobenzoyl-1, 2-dihydro-b-propyl-3N-pyrrole- (1, 2-a) pyrrole-1-carboxylate;
    Hexyl-5-M-chlorobenzoyl-1,2-dihydro-6-butyl-ZN-pyrrole (1,2-a) pyrrole-1 -carboxylate;
    Dodecyl-5-rhombenzoyl-1, 2-dihydro-6-butyl-ZN-pyrrole (1, 2-O |) pyrrole-1-carboxylate.
    Example 3. To a solution of 300 mg of 5-11-toluoyl-1,2-dihydro-ZN-pyrrole (1,2-CI) pyrrole-1-carboxylic acid in 5 ml of ethanol was added 1 mole equivalent of sodium hydroxide as O , 1 n solution. The solvent is then evaporated off under reduced pressure and the residue is dissolved in 2 ml of methanol, precipitated with ether and the crude 5-I-toluoyl-1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-sodium carboxylate is obtained, which crystallized from a mixture of ethyl acetate - hexane.
    Other salts, for example, the ammonium and potassium salts of 5-U-toluoyl-1, 2-dihydro-3-pyrrole (1,2-o) 1-carboxylic acid, are prepared in a similar way by replacing sodium hydroxide with ammonium and potassium hydroxide.
    Similarly, 5-substituted-1,2-dihydro-ZN-pyrrole (1,2-) pyrrole-1-carboxylic acids MAY be converted to the corresponding sodium, potassium, and ammonium salts.
    Examples of the compounds thus obtained are as follows:
    5 o Toluoyl 1,2-dihydro-3H-pyrrole (1,2-a) sodium pyrrole-1-carboxylate;
    5-Benzoyl-1,2-dihydro-3H-pyrro) 1 (1,2-o) sodium pyrrole-1-carboxylate;
    () -5 Benzoyl-1,2-dihydro-ZN-pyrrole-1-sodium carboxylate;
    5-U1-ethylbenzoyl-1,2-dihydro-3H-pyrrole (1,2-cj) pyrrole-1-potassium carboxylate;
    5 o-Butylbenzoyl 71,2-dihydro-ZN-pyrrole (1,2-Q) pyrrole-1-potassium carboxylate;
    5-ti-methoxybenzoyl-1,2-dihydro-3H-pyrrole (1,2-a) sodium pyrrole-1-carboxylate;
    5-I-Chlorobenzoyl-1,2 - dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylate ammonium;
    G Fluorobenzoyl-, 2-dihydro-ZN-pyrrole {1, 2-O) ammonium pyrrole-1-carboxylate;
    5-1-Bromobenzoyl-1, 2-dihydro-3Npyrrole (1,2-O) potassium pyrrole-1-carboxylate;
    5-Benzoyl-1,2-dihydro-6-ethyl-3H-pyrrole (1,2-a) sodium pyrrole-1-carboxylate;
    5 Toluoyl-1,2-dihydro-6-methyl-3H-pyrrole (1,2-CI) pyrrole-1-potassium carboxylate;
    ZO-Methoxybenzoyl-, 2-dihydro-6-methyl-ZN-pyrrole (1,2-c |) ammonium pyrrole-1-carboxylate;
    5-Fluorobenzoyl-1,2-dihydro-6-propyl 3H-pyrrole (1,2-a) sodium pyrrole-1-carboxylate;
    B-Chlorbe. Nzoyl-, 2-dihydro-6-butyl-ZN-pyrrole (1,2-c () pyrrol-1-carboxylate potassium.
    权利要求:
    Claims (1)
    [1]
    An example. To a solution of 175 mg of B-toluoyl-1,2-dihydro-ZN-pyrrole (1,2-01) pyrrole-1-carboxylic acid in 5 ml of methanol was added 1 mole equivalent of potassium hydroxide in the form of a 0.1 N solution and get a solution containing 5I-toluoyl-1,2-dihydro-ZN-pyrrho (1,2-Q) pyrrole-1-potassium carboxylate. Buffer solution is prepared by dissolving 40 mg of potassium carbonate at the minimum, to dissolve it in an amount of 1N. hydrochloric acid, 100 mg of solid ammonium chloride and the subsequent addition of 5 ml of water. The calcium buffer solution thus obtained is added to a solution of 5-toluoyl-1, 2-dihydro-ZN-pyrrole (1, 2-C () pyrrole-1-potassium carbonate, separated by filtration, the resulting precipitate, washed with water, dried in the air, 5-M-toluoyl-1,2-dihydr-3H-pyrrole (1,2-0) pyrrole-1-carboxyl calcium is obtained. Similarly, by replacing calcium carbonate with magnesium carbonate, 5-I-toluoyl-1 is obtained , 2-dihydro-ZN-pyrrole (1, 2-0.) Pyrrole-1-carboxylate magnesium. Similarly, by replacing 5-I-toluoyl-1,2-dihydro-ZN-pyrrole (1, 2-CI) pyrrole -1-carboxylic acid 5-benzoyl-1,2-di idro-ZN-pyrrole (1, 2a) pyrrole-1-carboxylic, (d) -5-benzoyl -1,2-dihydro-3H-pyrrole (1,2-a) pyrrole-1-carboxylic, 5-I- Chlorobenzoyl-1,2, -dihydro-ZN-pyrrole (1, 2-c1) pyrrole-1-carboxylic, 5-O-methoxybenzoyl-1,2-dihydrOZN-pyrrole (1,2-O) pyrrole-1 -carboxylic , 5-I-methoxybenzoyl-1,2-dihydro-ZN-pyrrole (1,2-a) pyrrole-1-carboxylic, 5-benzoyl-1,2-dihydro-6-methyl-ZN-pyrrole (1, 2 -C () pyrrole-1-carboxylic, 5-O-fluorobenzoyl-1,2-dihydro-6-ethyl-3H-pyrrole (1, 2-e) pyrrole-1-carboxylic acids get the corresponding calcium and magnesium salts. Example 5 - To a solution of 200 mg C-K-toluoyl-1, 2-dihydro-ZN-pyrrole (1,2-0) -n Irrol-1-carboxylic acid. In 1 ml of methanol, 1 mole equivalent of potassium hydroxide is added in the form of 0.1N. of the solution .. The solvent is distilled off and the residue is dissolved in 5 ml of water. The solution of 5-1-toluoyl-1, 2-dihydro-3H-pyrrole (1,2-O) pyrrole-1-potassium carboxylate thus obtained is added to the solution 150 mg of copper II nitrate trihydrate in 5 ml of water. The resulting precipitate is separated, washed with water, dried in air and 3H-toluoyl-1, 2-dihydro-3H is obtained. -Pyrrole (1,2-O) pyrrole-1-copper carboxylate. Similarly, free acids can be converted to the corresponding copper salts. Example 6. A solution of 200 mg of 5-M-TOLUOIL-1, 2-dihydro-ZN-pyrrole (1,2-0) pyrrole-1-carboxylic acid in 15 ml of hot benzene is treated with 60 mg of isopropylamine. The solution was allowed to cool at room temperature, the product was filtered, washed with ether, dried, and the salt of Isopropylamine and 5-I-toluoyl-1,2-dihydro-ZN-pyrrole (1, 2-C |) pyrrole-1-carboxylic acid was obtained. Similarly, salts of other amines, for example ethylamine, ethanolamine, piperidine, tromethamine, choline and caffeine and 5-1-toluoyl-1,2-dihydro-ZN-pyrrole (1,2-a) pyrrole-1-carboxylic acid, are obtained by replacing isopropylamine corresponding amine. Similarly, the free acids can be converted to the corresponding isopropylamine, diethylamine, ethanolamine, piperidino, tromethamine, choline and caffeine salts. Example 7- A solution of 770 mg of 5 -0-toluoyl-1,2-dihydro-ZN-pyrrole (1,2-O) pyrrole-1-carboxylic acid in 10 ml of benzene is treated with 580 mg of dicyclohexylamine. The reaction mixture is stirred for 10 minutes, the resulting solid is separated by filtration, washed with anhydrous ether and receive 9b5 mg dicyclohexylamine salt of the 5-O-toluoyl-1,2-dihydro-ZN-pyrrole (T, 2-a) pyrrole-1- carboxylic acid, so pl. 1b1-1bz C. Similarly, the remaining free acids can be converted into the corresponding dicyclohexylamine salts, for example, the 5 o-chlorobenzoyl-1,2-dihydro-3H-pyrrole (1, 2-C1) pyrrole-1-carboxylic acid dicyclohexylamine salt, m.p. 173-175 ° C. Formula of the invention. A method for producing esters or salts of 5-aroyl-1,2-dihydro-3H-pyrrolo (1,2-0} - pyrrole-1-carboxylic acid of the general formula P G1 K, II, O IJ where R is hydrogen or lower alkyl hydrogen, lower alkyl lower alkoxy, chlorine, fluorine or bromine, and the substituents are in the ortho, para or meta position of the aroyl ring; R, 2. is an alkyl. Inorganic residue or 9 9 "640310 characterized in that where R and Ry have the indicated meanings, 5-aroyl-1,2-dihydro-3H-pyrrolo- (1,2 is converted to an ester or salt in d) - pyrrol-1 -carboxylic acid of the general form of (d) - or (1) -isomers by the known formulas, IR aj 1Г T1 Sources of information, Jtv.-xXLuylk rli / taken into account in the examination of j J, 1. Bühler K. Pearson D. Organic I-syntheses Part 2, Chapter F, 1973
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    申请号 | 申请日 | 专利标题
    US70490976A| true| 1976-07-14|1976-07-14|
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