SU695558A3 - Method of preparing 5-aroyl-1,2-dihydro-3h-pyrrole-(1,2-a)-pyrrole-1-carboxylic acid derivatives or their salts - Google Patents

Description

(54) METHOD-OBTAINING DERIVATIVES OF 5-AROIL-1,2. -DIGIDRO-ZN-PIRROL 1,2-a PIRROL-1-CARBONOP,. ACIDS or SALTS

brotherly lbdy nyibm during, -, ...- .. about 30 mime. Compounds of formula I, which are racemic mixtures, can be separated to obtain the corresponding individual isomers.

Isomeric () -acids, and (3) -acid-, 5 oty compounds of formula I can be obtained by using known high-pressure liquid chromatography (HPLC) on oi-phenethyl diastereomeric esters of compounds of formula 1 with subsequent acid washing ,

The salts of the resulting compounds of formula I and their isomeric acids are semi-. . They are treated by treating these free 15 acids with an appropriate amount of base. The base representatives are sodium hydroxide, GUID1:) KALY, HYDROXYDY LETTER AT MDRIUM; Ymmoni, hydrous calcium oxide, magnesium hydroxide, iron (II) hydroxide, zinc hydroxide / zinc hydroxide;

manganese (II) hydroxide, hydrodiside al, yumni, iron hydroxide (Ili), manganese hydroxide (III), isopropyl-amine, trimethylamine, diethylamine, triethyl-, tryprpilamip, et anoJamyi, V; 2-dimethylamine.nol, 2-diethidinamineMl7trStamin, lysine, arginine ,,.

 histidine, caffeine ;, Procaine, hydrabamine, holyn, beta: in, ethylenediamine, 3D hl okb8a1j yn, metilglukamin, tebromin,:, purines, pipyorazine, piperidine, N-, and, n Ridan, POLYAMINUM resins, and t. , Ryuktsi is carried out in water v. , or in a mixture of 6D; with mineralized organic-solution mixed with iodine; Rytelvm at temperature :. Z.Tielno from O to, preferable at room temperature. Typical inert, miscible with water and organic solutions of the bodies include methanol, ethanol, isopropanol,. butanol, acetone, dioxane or tetratidrofuran. The molar ratio of the com- pounds – dinyls of the formula (I) or their isomeric acids to the base used is birac), depending on. required. specific salt. For example, to obtain calcium salts or magnesium salts of compounds of formula I, or isomers thereof, starting at 50. The free acid can be treated with a semi-molar equivalent of base to obtain a neutral salt. For 1-liter, and aluminum compounds. jt I or their isomeric. acids npjHMeHHroT. by. at least one 1/3 of -MOjfb equivalent base dp. neutral salt treatment.

Calcium salts and magnes are used according to the preferred method: salt salts of 60 sb. Dienium of formula I and their isomeric acids can be obtained by treating them with the appropriate sodium hydroxide or potassium salts using a minimum of 1/2-mole equivalent chloride. .65

695558

: Calcium or magnesium chloride, respectively, in an aqueous solution or in a mixture with an inert, water-miscible organic solvent at a temperature of from about 20 to. Preferably, the aluminum salts of the compounds described above can be obtained by treating the corresponding free acid compounds with at least 1 / .3 mole equivalent of aluminum alkoxide, for example, aluminum triztoxide, aluminum tripropoxide, and the like, in a hydrocarbon solvent, for example benzene, xylene, cyclohexane, etc., with. from about 20 to 115 ° C. A similar procedure can be used to obtain salts of inorganic bases that are not sufficiently soluble to provide easy flow of light:. . - Isolation of the described compounds can be carried out by any suitable method of separation or purification by Example, Extraction, filtration by evaporation, distillation, crystallization, thin-line or column chromatography, high-pressure chromatography (HPLC): or a combination of these methods. - Method of preparation I. A triple neck is a tight count. the tank, including the bath of the magnetic mesh and the calcium chloride tube, is directly connected (through one of the necks) by the receiver's help. allonzh and short water konden. sator (3 inches, 76.2 mm) With an acetal for pyrolysis. This device. The CO is from a round bulb with a capacity of .100 ml (into which the predvaritel.el. NO is loaded 15.6 g of oxalic acid dihydrate and 11.82T of diethyl acetal bromoacetaldehyde, obtained from .vinyltat.tata) above, which is 6-Inch (152.4 mm) Vigre column, equipped with a thermometer and connected by a condenser. ..; . In a three-necked flask are placed. 3.36 g of ethanolamine cooled; and Ice Noah bath at a temperature from. About to, - and 8.7 gdimethyl-1, 3-acetoNDicarboxylate are added dropwise during stirring. Methyl-3-carbome.toxymet. Methyl-3 (2-hydroxyethyl) aminacrylate is immediately formed. Remove the ice bath and remove .100 ml of dry acetonitrile. Part at (5ora, in which pyrolysis is carried out) is placed in an oil bath, and its temperature is raised to 150-160 ° C. The resulting solution is distilled off (so boiling point 8 p-83 ° C / (580 mmHg) directly into the vinylamine solution stirred by a magnetic stirrer. When the distillation temperature is lowered, the PYROLysis unit is turned off and replaced with a reflux condenser.

equipped with a calcium chloride tube. The solution is heated under reflux for 1 hour and the solvent is removed under reduced pressure, and then 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 in the upper part of the column, filled with 200 g of silica gel in hexane. Then the column was eluted with a mixture of hexane-ethyl acetate (80: 20x500 ml) and hexane-ethyl acetate (1: 1: 9x500 ml),. Fractions 2 and 3 contain an insignificant amount of polar impurities and dimethyl-1, 3-acetone Icarboxylate, fractions 4-8 contain 4.1 g of methyl M- (2-: -oxyethyl) -3-carbomethoxypyrrole-2-acetate, which after recrystallization from a mixture of ether-hexane has a melting point of 52-54 C.

Method II. To a stirred solution of 4.1 g of methyl M- {2-hydroxyethyl) -3-carbomethoxypyrrole-2-acetate in 35 "ml of dry dichloromethane cooled to 2.64 ml of triethylamine is added, then 1 dropwise is added , 46 ml of methanesulfonyl chloride, maintaining the temperature of the reaction mixture in the range from -10 to-5 ° C. The reaction is monitored using those with chloroform-acetone as eluent (90:10) When it is determined that the reaction is over (approximately 30 minutes after 10 ml of water are slowly added to complete the addition of methanesulfonyl chloride) The organic phase is separated, washed with water (3 ml ml), dried over sodium sulfate and evaporated under reduced pressure. After crystallization of the residue from dichloromethane-hexane, 4.75 g (77.7%) methyl-N (2-methyloxyethyl) ) -3-carbomethoxypyrrole-2-acetate; t, pl. 99-101C,

Method III, A solution of 785 mg of methyl-L- (2-methyloxyethyl) -3-carbomethoxypyrrole-2-acetate and 1.83 g of sodium iodide in 10 ml of acetonitrile is heated under reflux for 1 hour. The cooled reaction mixture is evaporated to dryness at reduced pressure and the residue triturated with water. Insoluble materials are separated by filtration, and air dried to obtain 840 mg (97%) methyl -N- (2-iodoethyl) -3-carbomethoxypyrrol-2-acetone; t, pl, 137-138 C,

Procedure IV, Solution of 1 g of methyl-N- (2-iodoethyl) -3-carbomethoxypyrrole acetate with 5 ml of dry dimethylformamgold is stirred under argon with 137 g of 50% sodium hydride in mineral oil, the reaction mixture is maintained for 30 min at room temperature and then cooled by mixing with 100 ml of cold water. The product is extracted with ethyl acetate (3x50 ml), the combined extracts are washed with water,

dried over magnesium sulfate and evaporated to dryness. After chromatography of the residue on 20 g of silica gel with the use of a mixture of hexane-ethyl acetate (4: 1) as eluent, 500 mg (80%) of dimethyl-1,2-dihydro-ZN-pyrrole 1, 2-a) pyrrole-1.7 are obtained - dicarbo. silata; t, pl, 70-71 C,

A solution of 1.80 g of dimethyl-1,2-dihydro-ZN-pyrrole 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 heated, under reflux for 6 hours. The cooled solution is evaporated to dryness and the residue is treated with 50 ml of a saturated solution of sodium chloride. The obtained solution is acidified with 6N hydrochloric acid and extracted with ethyl acetate (3x50 ml). The combined extracts are dried over magnesium sulphate and evaporated dry under reduced pressure, get 1.51 g (95%) 1,2-dihydro-3H-pyr 1,2-ol and pyrrole-1, 7-dicarboxylic acid; t, pl, (without decomposition) ,.

Method Y, A solution of 1.34 g of 1,2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1, 7-dicarboxylic acid in 50 ml of isopropanol, O5 superfluous in an ice bath, saturate the gas: with oxygenated hydrogen chloride maintaining the temperature of the reaction mixtures below 50c. Then the ice bath is removed, the reaction mixture is stirred for 1.5 hours at-room temperature and evaporated to dryness under reduced pressure. 10 mp of benzene is added to the residue and the paipTBOp is evaporated again in vacuo, repeat this procedure three times. to completely remove the excess hydrogen chloride, you get 1.58 g (96) of isopropyl-1,2-dihydro-ZN-pyrrole 1, -2-a irrol-1 -carboxylate-carboxylic acid, which, after crystallization from methanol / ethyl acetate, melts at 144-145 ° C, in a similar way , but replacing isopropanol with methanol, ethanol, propanol and n-butanol, respectively, according to the above method, the following compounds are obtained: -

methyl-1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1-carboxylate-7-carboxylic acid;

ethyl 1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1-carboxylate-7-carboxylic acid;

: propyl-1,2-dihydro-ZN-pyrrole

1,2-a pyrrole-1-carboxylate-7-carboxylic acid;

butyl-1,2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylate-7-carboxylic acid, respectively.

Method YI, 1.054 g of isopropyl-1, 2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylate-7-carboxylic acid is heated up to a temperature of 240-250 with JB dry 10 ml round bottom flask, distilled directly the reaction product from reaction flask. Thus, 745 mg of isopropyl-D, 2-dihydro-3H-pyrrole 1, 2-a pyrrol-1-carboxylate, which is a pale yellow oil with the following physical constants, are obtained. UV spectrum p: Dmax 215 nm (8 6020) T-band max. 1725 cm NMR spectrum: 122 (doublet D 7 Hz, bN); 2.40-2.90 (multiplet, 2H) 3.60 4.2 {) (multiplet, 2H); 4.65-5.2. (multiplet, 1H); 5.73-5.92 (multi pipet, 1H); 6.10 (triplet, J 3 Hz, 1H); 6.43-6.53 ppm (multiplet, 1H). Procedure YII, A 100 ml three-neck round-bottom flask equipped with a condenser, a nitrogen supply tube and a bubbler, will be prepared with 5.0 g of izprpil-1,2-digidro-ZN-pyrrho 1,2-pyrrol-1- carboxylate-7-carboxylic acid. The device is thoroughly purged with nitrogen and then the supply is stopped. The device is immersed in an oil bath heated to a temperature of 270 ° C, and the reaction is monitored by the lip carbon dioxide release rate (gas bubbler) and in the case of silica gel. using shchsch 1syshёst1ё p) 6ShL5Yoshche1 about the solvent mixture of benzene-dioxane-acetic acid (90: 10: 1). After 45 minutes, the reactions almost complete. After 1 hour, the flask is removed from the oil bath, and the contents of the reaction flask are transferred to a round bottom flask containing 500 MP of acetone. The solvent was removed under reduced pressure and was purified using the column method; . chromatography on 100 g silkageL. The fractions are eluted with 1 hexane-: benzene (70:30) and hexane boizole (50:50), which are barely 2, 77 g (68%) isopropyl, 2-dihydro-3H-pyrrole 11,2-pyrrole -1-carboxylate H in the form of an oil7 physical constants. which are given for d1. ., Method vrilw Growth 179 mg; N, I-yy yl yl-p-toluylamide and 0, li ml of phosphorous acid chloride in 2 ml and 1,2-dichloroethane are heated under reflux for 30 minutes. To this solution is added a solution of 193 mg of isopropyl-1, 2-dihydro-3H-pyrol 1,2-a pyrrole-1-carboxy. silt in 2 MP of 1,2-dichloroethane. The reaction mixture is heated under reflux holdyldik in an argon atmosphere for 8 hours, treated with 405 mp sodium acetate and heated under reflux for: another 5 hours. The resulting mixture is evaporated to dryness, and the residue is chromatographed on 12 g of silica gel and eluted with mixture hexane-ethyl acetate (3: 1), the result is 208 mg (66%) of isopropyl-5-p-toluene-1 2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1-carboxylate in the form of an oil that has. The following physical constants. UV spectrum: L.a. 256.312 nm (g 8700, 19500). IR spectrum:. 35, 1620, - - -1 max 1605 cm. NMR: with t1ls1,23 (doublet, J 7 Hz, 6H); 2.38 (singlet, SN); 2.5-3.0 (2H multiplet); 3.75-4.10 (multiplet, 1H); 4.2-4.60 (multiplet, 2NG; 4.85-5.20 (multiplet, 1H); 5.95 (doublet, J 4 Hz, 1H); 6.70 (doublet, J 4 Hz, 1H) ; 7.10 (doublet, J 8 Hz, 2I); 7.60 ppm (doublet, J 8, Hz, 2n); A. A. A solution of 336 mg isopropyl-5-p-toluene-1, 2- dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylate in 10 ml of methanol is treated with a solution of 690 mg of potassium carbonate in 5 ml of water.The reaction mixture is heated under reflux in a nitrogen atmosphere for 30 minutes, cooled and evaporated to dryness. dissolved in .10 ml of a 10% aqueous solution: with 6 ml of acid and 50 ml of water 1, the resulting mixture was extracted with ethyl acetate (2 x 50 ml). the extracts are dried over magnesium sulphate and evaporated to dryness under reduced pressure. After crystallization of the residue, 238 mg (89%) of 5-n-tLuoL-1,2-dihydro-ZN-pyrrole 1, 2-and pyrrol-1- are obtained from ethyl acetate: Carboxylic acid, mp 182-183 C. B. A solution of 25Q mg of isopropyl-5-p-toluene-1, 2-dihydro-3H-pyrrole 1,2-a pyrrolecarboxylate in 8 ml of methanol is treated under nitrogen with a solution .200. mg of sodium hydroxide in 1 MP of water, keeping the reaction mixture at room temperature for 1.5 hours. Methanol is then distilled off under reduced pressure and the remaining alkaline solution is diluted with 5 ml of iodine and extracted with ether to remove all of the crude products. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated under dry pressure, the residue is crystallized from ethyl acetate-hexane to give 5-n-. -toluoyl-1,2-dihydro-ZN-pyrrole 1,2-a irrol-1-carboxylic acid, and the same product obtained in pririe 1:. ; Method 1X. According to the method YI or 11, the remaining compounds were obtained about the method Y, transformed respectively into the following compounds: methyl-1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1-carboxylate; ethyl 1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1-carboxylate; propyl-1,2-dihydro-ZN-pyrrol 1,2-a pyrrole-1-carboxylate, butyl-1,2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylate. .

After condensations of these compounds with N, H-dimethyl-p-toluamide in accordance with method VIII, respectively; .

methyl 5-p-toluoyl-1,2-dihydro-3H -pyrrole 1,2-a pyrrole-1-carboxylate;

ethyl 5-p-toluoyl-1,2-dihydro-3H-pyrrole 1, 2-aIpyrrole-1-carboxylate;

propyl-5-p-toluoyl-1,1,2-dihydro-ZN-pyrrole C1,2-a1 pyrrole-1-carboxyl

butyl-5-p-toluoyl-1,2-hydriro-3H-pyrrole {1, 2-a pyrrole-1-carboxylate.

B. According to the method of preparation of YIII using instead of M, N-dimethyl-p-toluamide from 1.1 to 5 miles-equivalents:

K, N-dimethylbenzamide;

N, K-dimethyl-o-doluolamide; N, N-dimethyl-m-toluamide;

S, S-dimethyl-p-etylbenzamide;

N, N-dimethyl-o-propylbenzamide;

S, S-cimethyl-m-butylbenzamide

S, S dimethyl-o-methoxybenzamide;

N, N-dimethyl-p-methoxybenzo-amide;

N, K-dimethyl-p-ethoxybenzamide;

M, N-dimethyl-p-isopropoxybenzamide; . . ,, -; ; H, N-dimethyl-o-chlorobenzamide;

N, N-dimethyl-m-chlorobenzamide;

N, N-dimethyl-p-chlorobenzamide;

S, H-dimethyl-o-ftbrbenzalo1d;

N, K-dimethyl-p-fluorobenzal 1 d;

11, N-dimethyl-m-bromobenzamide;

N, N-dimethyl-o-bromobenzamide and when controlling the course of the reaction with the help of those obtained, respectively:. . . .

isopropyl-5-benzoyl-1,2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1-carboxylate, light yellow oil, having the following physical constants, meon

UV spectrum of l loox 245.311 nm

(e 7230, 17800) ...

IR spectrum of G ax1735, 1620 cm

NMR: s. 1.24 (doublet, bN, (CH,) „CH); 2.50-3.13 (multiplet, 2H, H-2); 3.97 (doublets, IH, H 1); 4.18-4.70 (multiplet, 2H, H-3);

5.00. (Septet, 1H, (CH5) 2CH); 6.00 (doublet, 1H, H 7); 6.86 (doublet, 1H, Hb); 7.10-7.90 ppm (multiplet 5H, phenyl protons).

Mass spectrometry: m. 287 (M),. Isopropyl-5-o-toluoyl-1,2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1-carboxyl as an oil with the following physical constants.

UV spectrum 2.52, 303 nm

.G 4460. 1910oG.

IR spectrum: 1735, 1720 cm 1.18 (doublet, bN, (CH3) 2CH) 2.28 (singlet, 3N-a-CH,); 2.50-3.13 (multiplet, 2H-H2); 3.92 (doublets, 1H, H 1); 4.17-4.70 (multiplet, 2H, LZ); 4.98 septet (1H, (CH5) 2CH); 5.92 (doublet, 1H, H 7); 6.43 (doublet, 1H-H6); 6, 45 ppm (multiplet, 4H, phenyl protons).

Isopropyl 5-m-toluoyl-1,2-dihydro-3H-pyrrho l 1, 2-a pyrrole-1-carboxylate in the form of an oil with the following physical constants.

UV-spectrum of Limayos 250-251, 310-312 nm (6460, 17400);

IR spectrum GMY; 1735, 1620 cm

NMR: CPTMS 1.25 (doublet, 6H, (CHj) 2: CH); 2.27 (singlet, 3N, CHj); 2.52-3.13 (multiplet, 3N, H2); 3.92 (doublets, 1H, Hi); 4.134, 70 (multiplet, 2Я, NC); 4.95 (septet 1H, (CH3) .2CH); 5.95 (doublet, 1H, H7); 6.67 (doublet, 1H, H6); 7.037, 57 ppm (multiplet, 4H, phenyl protons).

Isopropyl-5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylate;

Isopropyl-5-o-propylbenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylate;

Isopropyl-5-m-butylbenzoyl-1,2-dihydro-3H-pyrrol 1, 2-a Pyrrole-1-carboxylate; .

Isopropyl-5-o-mytoxibenzoyl-1, 2-dihydro-ZN-pyrrole..1,2-a pyrrole-1-carboxylate;

-. Isopropyl-5-p-met6xybenzoyl-1, 2-dihydro-3H-pyrrole 1, -a pyrrol-. -I-carboxylate having the following physical constants.

UV spectrum A mgHE 218, 27D-284 (shoulder); 314 nM (9780, 9320, 22400). .

JK-spectrum. .1730 / 1605 cm .. NMR: CPTM 1.2 (doublet, 6H, J 6 Hz, (CH3) 2.CH); 2.50-3.10 (multiplet, 2H, H 2); 3.78 (singlet, SN,); 3.93 (doublets, –1H, Edh 6 Hz, g 7 Hz, H 1); 4.13-4.60 (multiplet, 2H, H 3); 4.95. (septet., 1H, 6 Hz, (CH3) 2CH); 5.95 (singlet, 1H, J 4 Hz, H 7); 6.68 (ublet, 1H, J 4 Hz, H 6); 6.70-7.90 ppm (multiplet, 4H, - phenyl protons). Mass Spectroscopy. M. 327 (M).

Isopropyl-5-p-ethoxy-6-ene-zoyl-1,2-dihydro-3H-pi. Rrol 1,2-a-pyrrole-1 carboxylate; mp: 94-95 ° C;

isopropyl-5-p-isopropoxybenzoyl-1, 2-dihydro-ZN-pyrrole 1,2-a pyrrol-1 carboxylate; ,

isopropyl-5-o-x) 11Orbenzoyl-1,2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1 carboxylate, an oil that has the following physical constants.

UV spectrum: L 251, 306 nm (8, 16600).

IR Spectrum; 1735, 1625 cm

NMR: (CDCe. 1.22 (doublet, 6H, (.CH5) 2CH) -; 2.55-3., 05 (multiplet, 2H, H 2); 3.97 (doublets, 1H, H 1) ; 4.17-4.70 (multiplet, 2H, I 3); 4.97 (septet), 1H, (CHg) CH) g 5.93 (doublet, 2 / 3N); 6.00 (doublet, 1 / 3N, H 7); 6.42 (doublet, 2 / ЗН); 6.67 (doublet, 1./ZN, H 6) 7.07-7.80 ppm (multiplet, 4H, phenyl protons). Isoprpyl-5-m-hlbrenzojol-1,2-dihydro-ZN-pyrrole 1, 2-a pyrrol-1-carboxylate, an oil that has the following DUAL physical constants. UV spectrum. 211, 313 nm, 6600, 15100). IR spectrum CMCEj 1735, 1620, 1570 cm- NMR: C 1.27 (doublet, 6H, (CH) 2.50-3.18 (multiplet, 2H, H 2); -3.93 (doublets, 1H, H 1), 4.10-4.63 (multiplet, 2H, H3); 4.9 (septe 1H, (CH3) CH); 5.98 (doublet, 1H , H 6.67 (doublet, 1H, H 6); 7.07-7.08 (multiplet, 4H, phenyl protons; Mass spectroscopy, i.e. 331338 (M-) Isopropyl-5-p-chlorobenzoyl-1, 2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1-carbbxylate, mp 80.5-81 ° C; isopropyl-5-o-fluorobenzoyl-1,2-dihydro-ZN-pyrrole 1,2- a pyrrole-1-carboxylate; ---- isopropyl-5-p-fluorobenzoyl-1,2-d hydro-ZN-pyrrole 1,2-a pyrrole-1-car bauxyl; mp 72-72.5 ° C; isopropyl-5-m-bromo-benzoyl-1,2-dihydro-ZN-pyrro l 1, 2-a propanol-l-carboxyl; isopropyl-5-p-bromobenzoyl-1,2-digidro-3H-pyrrole 1, 2-a pyrrole-1-carboxylate., - after hydrolysis of the isopropyl group of complex efry according to the methods 1 or 2, the corresponding acids are obtained with buty acids; 5-benzoyl-1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1-carboxylic acid; mp 160-161 ° C; 5-O- TOLUOIL-1/2-dihydro-3H-pyrrole 2-a pyrrole-1-carboxylic acid, an oil that has the following physical constants. IR spectrum: -g Jf l 1720, 16.20 cm NMR: -jfJ J TMS 2.32 (singlet, 3N, CHj); 2.53-3.03 (multiplet, 2H, H 2); 3.97 (doublet, 1H, H 1), 4, 17-4.67 (multiplet, 2H, H 3); 6.92 (doublet, 1H, H 7); 6.40 (doublet, 1H, H 6); 6.83-7.37 (multiplet, 4H, phenyl protons); 8.60 ppm (broad singlet, 1H, COOH). . . . . 5-m-Toluoyl-1,2-dihydro-3--pyrr-1,2-alpyrrole-1-carboxylic acid 5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrol-1, 2-a pyrr-1- carboxylic acid; 3-o-propylbenzoyl-1,2-dihydro-3H-pyrrrl 1, 2-a pyrrole-1-carbonO-wa acid; -5 m-butylbenzoyl-1, 2-dihydro-3-pyprol. 1, 2-pyrrrl -1-carb6nova kxlbta; J 5-9-methoxybenzoyl-1,2-digidro-3H-pyrrole 1,2-a-pyrrole-1-carbono-kyloslot; ™; g: 2H, xij, I, .5: ---.-- - - 3-DGVe bxibenzoyl-, 2-dihydr-3H-pyrrole 1,2-a1-pyrrole-1-carbono ;; wai acid; - m.p. 187-187.5C 5-p-ethoxybenzoyl-1,2-dihydroZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid; m.p. 169, 5-170С; 5-p-isopropoxybenzoyl-1,2 dihydro-3H-pyrrole 1, 2-a pyrrole-. 1-carboxylic acid; 5-o-chlorobenzoyl-1,2-dihydroZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid has the following physical constants. o UV spectrum. c 250, 307.5 nm 4360, 174000). , IR spectrum: A) 1715, 1620 cm NMR: d TMS 2.60-3.15 (multiplet, H, H 2); 4.02 (doublets, 1H, Hz, Hz, H 1); 4.20-4.70 (multiplet, H, H 3); 5.98 (doublet, 1H, J 4 Hz, {7); 6.42 (doublet, 1H, J 4 Hz, H 6); , 00-1, P (multiplet, 4H, phenyl protons); 8.67 ppm (brilliant inglet, 1H, COOH). . 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylic acid; m.p. 180-l8lC; 5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a PIRROL-1-carboxylic acid; m.p. 201, .5-202,. 5-o-fluorobenzoyl-1,2-diTydro-3H-pyrrole {1, 2-a pyrrole-1-carboxylic acid; 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylic acid; m.p. 179, 5-180, 5 C; 5-m-bromobenzoyl-1, 2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid. . G. To a solution of 300 .mg 5-ben, zoyl-1, 2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carbrnaic acid in 25 ml of dry p-benzene was added 0.58 g of trifluoro-acetic anhydride. The mixture was stirred at room temperature for 10 minutes, the resulting pacTJBop was cooled to 0-5 ° C, 1.4 g of dry triethylamine was added, and 0.5 g of E -ot-phenylethyl alcohol was immediately added. The reaction solution thus obtained is stirred at room temperature for 15 minutes and poured into 20 ml of water containing 1 ml of triethylamine, and then extracted with ethyl acetate. This extract was dried over sodium sulfate, then y solvent and an excess of (i) -o-phenylethyl alcohol in vacuo, yielded 0.42 g of (E) -c6-phenylethyl ether () -5-benzoyl-1, 2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylic acid and (6) -cd-phenylethyl ester (d) -5-benzoyl-1,2-. -dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylic acid, which is separated by high pressure liquid chromatography (using 4% ethyl acetate-hexane mixture in a column of 11 mm x 50 cm, 10 m Lichrozord S 1 -60) and obtain 180 mg of a more polar polar ester; pa; - 145.7 ° and 178 mg of the less polar ester; +128.6 148 mg of the more polar ester is dissolved in 8 ml of dry birch. The solution is cooled to 15-20 seconds. 5 ml of trifluoroacetic acid are added and the solution is stirred at room temperature for 1 hour and 10 minutes. The reaction solution is poured into 60 ml of dry benzene and the solvents are removed in vacuo at ambient temperature. Purification was carried out by high pressure liquid chromatography {using a column similar to the column described above, except that instead of 4% ethyl acetate-hexane mixture, 35% ethyl acetate-hexane in O, 5% acetic acid was used) and get 63 mg (t) -5-benzoyl-1, 2-dihydro-ZN-pyrrole 1,2-pyrrole-1-carboxylic acid, possessing 153.7 ° it.pl. 153155 .С. Similarly, by separating the less polar ester according to the above described method for separating the bolaric ester, 85 mg of (d) -5-benzoyl-1,2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1-carbonic acid, characterized by LTR + 155.1 ° and so pl. 154-156 ° C. - The isomeric (d) -acid obtained in this way can, if desired, be racemized and recycled according to methods known in the art. Similarly, other (de) -connections can be converted into the corresponding (6) -isomers and (d ) Isomers Method X. A 250 ml three-necked round-bottomed flask equipped with a magnetic stirrer and a calcium chloride tube filled with calcium chloride was charged with 3.36 g of rtanolamino cooled in an ice bath to temperature and added dropwise with stirring. , Scientific research institute of 8,7 g dimethyl-1,3-.atse ondi- carboxylate. Methyl-3-carbomethoxymethyl-3- (2 -ox. Ethyl) aminocrylate is instantly formed. At the end of the addition, the next bath is removed and 80 ml of dry acetonitrile are added. Then, 6.75 g of bromoacetaldehyde in 20 ml of acetonitrile is added dropwise to the reaction mixture, and then heated under reflux for 2.4. 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 filled with 200. g of silica gel in hexane, eluting the column with hexane-ethyl acetate mixtures. Infraction, eluted with hexane-ethyl acetate (1: 1), gives methyl-N- (2-hydroxyethyl)

695558

14 -3-carbomethoxypyrrole-2-acetate, identical to the product obtained in Example A. Method XI.- To the solution of 6 mp ethanolamine in 5 ml of water was added 1.74 g of dimethyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to a temperature and over the course of 15 minutes, 1.67 ml of 1-bromoacetone is added dropwise with stirring, keeping the temperature of the reaction mixture no higher than 40 s. After the addition is complete, the dark reaction mixture is stirred for one more hour at room temperature, then poured into a mixture of hydrochloric acid with ice, saturated with solid sodium chloride, and extracted with ethyl acetate (3x100 mp). The combined organic extract is washed with cold water until neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. After chromatography, the residue on 30 g of silica gel using a mixture of hexigexane-ethyl acetate (70:30) as an eluent gives 890 mg of crystalline methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, which after recrystallization from methylene chloride-texane melts at 78 C. Calculated for C, N., N,%: C, 55.45; H 6.72. ° Found,%: 55.41; H 6.73. In a similar way, but using stoichiometric amounts of 1-bromo-2-butanone, 1-bromo-2-pentanone and 1-br6m-2-hexanone instead of 1-bromoacetone, respectively: methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrol-2-acetate, methyl-N- (2-o.xythyl) -3-carbomethoxy-4-propylpyrrol-2-acetate and methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-butylpyrrole-2-acetate. Method XII. According to methods II-YI, methi.n.-K- (2-hydroxyethyl) -3-. -carbomethoxy-4-methylpyrrolt2-acetate, is sequentially converted into: methyl-N- (2-mesyloxyethyl) -3-carbomethoxy-4-methylpyrrol-2-acetate; methyl N- (2-iodoethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, dimethyl-1, 2-dihydr6-5-methyl-ZN-pyrrole 1,2-a pyrrole-1,7-dicarboxylate; 1,2-dihydro-6-methyl-ZN-pyrrole 1,2-a pyrrole-1,7-dicarboxylic acid; isopropyl-1,2-dihydro-6-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxy. path-7-carboxylic acid; isopropyl-1,2-dihydro-6-methyl-3H-propylene 1,2-a pyrrole-1-carboxylate. Similarly, instead of methyl-N- (2-hydroxyethyl) -3-carboxyethoxy-4-methylpyrrole-2-acetamine, methyl-N- (2-hydroxyethyl) -3-carbomethoxy-4-ethylpyrrole-2-acetate, methyl-N- (2 | -oxyethyl) -3-carbrmethoxy-4-propylpyrrole-2-acetate and methyl-M (2-hydroxyethyl) -3-caromethoxy-4-butylpyrrole-2-acetate respectively receive the following final products: isopropyl -1,4-dihydro-6-ethyl-3H-pyrrole 1,2-a-pyrrole-1-carboxylate isopropyl-1,2-dihydro-6-propyl-3-pyrrole 1,2-a pyrrole-1-carboxylate isopropyl -1,2-dihydro-b-ZN-pyrro 1,2-a pyrrole-1-carboxylate. Method XIII. According to Method III, Isopropyl-1, 2-dihydro-b-methyl-3H-pyrrol 1, 2-a, pyrrole-1-carboxylate is subjected to a condensation reaction with N, H-dimethyl-p-toluamide to obtain isopropyl-5-p-toluoyl-1 , 2-dihydro-b-methyl-ZN-pyrrole 1, 2-and pyr} ol-1-carboxylate; -. ---- .- In a similar way, but with the use of H, K-Dim19Tyl-p-tL.uami instead of H, the decythyryl amylases are listed. in method XII, respectively, the floor. they read:. ,,;: - - -:; -., Isopropyl-5-6-benzoyl-1,2-dihydro-b-methyl-3H-pyrrole 1, 2-a pyrrole-1-carboxylate: .... . ,; ; ;; isopropyl-5-o-t6luoyl-1,;; 2-dihydro-b-methyl-3H-pyrr6l 1,2-a Schrrolcarboxylate. .; /.;. - - ..:.; ; izoppbpil-5-m-t6ly yuil-i, 2-da ± yd po-6-methyl-3H-pyropol 1, 2-a pyrrbla-carboxylat; .-:; ..-...; -. . - isopropyl-5-p-ethyl 6-benzoyl-1, .2-dihydro-b-methyl-3H-pyrrole I / 2-a pyrrole-1-carb6, xylate; - ;,,; isopropyl-5-6-proPiLbenzoyl - 1 2 -dihydro-b methyl-3N-pyrrole 1,2-a pyrrol-1-carboxylate; :; isopropyl-5-m-butylbenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1,2-a-pyrr6l-1-carb6xylate; ; :.:,; . i-zopropyl-5-tO-met, hydroxybenzoyl -1,2, 2-dihydro-6-methyl-ZN-pyrrole. , 1, 2-a pyrrole-1-carboxylate, iz6Propyl-5-p-metroxybenz-O.L.-1,2-dihydro-6-methyl-ZN-pyrrole 1,2 pyrrole-1-carboxylate; isopro-1-5-p-ethoxybenzoyl-1,2-dihydro-b-methyl-3H-pyrrole 1,2-a pyrrole-1-carboxylate; :; isopropyl-5-p-ztoxy, benzoyl-1,2-digidro-b-methyl-ZN-pyrrole 1,2-a pyrrole-1-carb-xylate; ..- .. isopropyl-5-p-isopropylbenzene -1,2-dihydro-b-methyl-3H-pyrr6l 1,2-pyrrole-1-carboxylate; .. isopropyl-5-b-hlbrbenzyl-1,2-digidro-b-methyl-3H-pyrrole 1, 2-a pyrrhl-1-carboxylate; isopropyl-5-m-chlorobenzoyl-1; 3-dihydro-b-methyl. -ZH-pyrrole 1,2-a pyrrole-1-carboxylate; isopropyl-5-p-chlorobenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carb 6 xylate; isopropyl-5-o-fluorobenzoyl-1,2 di-Dro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxyl.At; / 816 isopropyl-5-p-fluorobenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1,2-a pyrrole-1-carboxylate, having the following physical constants. UV spectrum: D. j .., - 250, 315 (g 6170, 14 100) L; f-spectrum 1734 ,. 1.605, 1593 cm NMR: cp TM 1.25- (doublet, bN, J b Hz, SND of the DIFFICULT ether group); 1, .83 (singlet, 3N, SN rings); 2, 00 (multiplet, 2H, CHj,) 3.90 (triplet, 1H, J 7.4 Hz, CNSO); 4.10-4.23 (multiplet, 2H, N-CH); 4.98 (septet, 1n, J b Hz, CH complex zfira); 5.84 (singlet, 1H, H 3) j 7.00. (Triplet 2H, 8.4 Hz Hz, H 3); 5.7 5.5 c. Quadruplet, 2H, JOPTO 8.4 Hz, a.dr 5.5 Hz, H 2.6): ..,. Mass spectroscopy: m, e. 329 25 (M-); 242 TOO M -CO-CH (SI.) O; 123 36.. . Isopropyl-5-m-bromobenzoyl-1,2.-Dihydro-b-methyl-ZN-pyrrole 1,2-a pyrrole-1-carboxylate; . isopropyl-5-p-bromobenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylate. .. Similarly, the remaining end products obtained by Ave. Metcdike XII, are converted into the corresponding 5-aroyl-substituted products. ny. Representatives The compounds thus obtained are the following:. from 6propyl-5-benzoyl-1, 2-dihydro-b-ethyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxyl: at; 7 ..: isopropyl-5-benzoyl-1,2-dihydro-b - propyl-3H-pyrrole 1,2-a pyrrole-1-carboxylate ;;.; -. . . . . . . <RTI ID = 0.0> 6, </ RTI> propyl-5-benzoyl 1,2-dihydro-b-butyl-3H-pyrrole 1, 2-a pyrrole-1-carboxylate; isopropyl-3-p-tolu oyl, 2-dihydro-6-ethyl-3H-pyrrole 1, 2-a pyrrole-1-car-ixylate; - .. isopropyl-5-p-methyl-benzryl-1,2-dihydro-b -propyl-3H-pnrR1 1. / pyrrole-1-carboxylate; .- ycc) PrPPil-5-o-methoxybenzRyl-1, 2-dihydro-b-butyl. -3H-pyrrl 1,2-a pyrrole-1-carboxylate; . isopropyl-5-p-ethoxybenzoyl-1,2-di-Dro-b-methyl-3H-pyrrole 1, 2-a pyrrole-1-carboxylate; . . Isopropyl-5-o-chloro. benzoyl-1,2.-diHydrr-b-propyl-3H-pyrrole 1,2-a pyrrole 1-carboxylate; isopropyl-5-m-chlorobenzoyl-1,2-dihydrr-b-butyl-3N-pyrrole 1, 2-a. pyrrole-1-carbrksilat; isrpropyl-5-o-fluorobenzoyl-1,2-dihydro-b-ethyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylate; isopropyl-5-p-fluorobenzoyl-1,2-dihydro-6-propyl-3N-pyrrole 1, 2-a Pyrrole-1-carboxylate; isopropyl-5-p-bromobeneoyl-1,2-dihydro-b-butyl-ZN-pyrrole 1, rol-1-carboxylate. D, A solution of 500 g of isopropyl-5-p-toluoyl-1, 2-dihydro-6-methyl-3N-pyrol 1f2-a pyrrole-1-car6oxylate in 15 ml of methanol is treated with a solution of 1.05 g of potassium carbonate in 8 ml of water. The reaction mixture is heated at reflux under nitrogen for 30 minutes, cooled, and evaporated to dryness. The residue is dissolved in 10 ml of 10% aqueous solution of hydrochloric acid and 50 water and the mixture is extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulphate and evaporated to dryness under reduced pressure; as a result, 5-p-toluoyl-1,2-di-Dpo-b-methyl-3H-pyrpole 1 2-a pyrrole-1-carboxylic acid is obtained. Similarly, or by the method of hydrolysis described in Example 2, the remaining isopropyl esters are converted to free sour. you, namely: 5-benzoyl-1,2-dihydro-b-methyl-ZN -pyrrole 1,2-a pyrrole-1-carboxylic acid; 5-O-toluoyl-1,2-dihydro-6-methyl-3H-pyrpole 1,2-a pyrrole-1-carboxylic acid; 5-m-toluoyl-1,2-dihydro-b-methyl-3H-pyrrole 1,2-a} pyrrole-1-carboxylic acid; 5-p-ethylbenzoyl-1,2-dihydrome-3-pyrrole-1,2-aj pyrrole-1-carboxylic acid; 5-o-propylbenzoyl-1,2-dihydro-6-methyl-ZN-pyrrole 1,2-a pyrrole-1-carboxylic acid; 5-m-butylbenzoyl-1-, 2-dihydro-b-methyl-3H-pyrrole 1, 2-a-pyrrole-1-carboxylic acid; 5-o-metaxybenzoyl-1,2-yyhydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid; 5-p-methoxy-benzoyl-1,2-dihydro-b-methyl-3H-pyrrole 1, -a pyrrole-1-c-1-ebonic acid; 5-p-ethoxybenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrL-1-carboxylic acid; 5-p-isopropoxybenzoyl-1,2-dihydro-b -methyl-3H-pyrrole 1,2-a-pyrrole-1-carboxylic acid; 5-o-chlorobenzoyl-1,2-dihydro-b-Methyl-ZN-pyrrole 1,2-α-pyrrole-1-carboxylic acid; 5-m-chlorobenzoyl-1,2-dihyd: eo-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-ka. bochnovuyu acid; 5-p-x-lorbenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid; 5-o-fluorobenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-aIpyrrole-1-carboxylic acid; 5-p-fluorobenzdil-1, 2-dihydro-: b-methi l-3N-pyrrole 1, 2-a pyrrole-1-carboxylic acid; m.p. . , 5-m-bromobenzoyl-1, 2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid; 5-p-bromobenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid; . 5-benzoyl-1,2-dihydro-b-ethyl-3H-pyrrole 1, 2-a pyrrole-1-carboxylic acid; 5-benzoyl-1,2-dihydro-b-propyl-3N-pyrrole 1., 2-a pyrrole-1-carboxylic acid; . 5-benzoyl-1,2-dihydro-b-butyl-ZNpyrrole 1, 2-a pyrrole-1-carboxylic acid; 5-p-toluoyl-1, 2-dihydro-6-e-methyl-3H-pyrrole 1, 2-a-pyrrole-1-carbonic acid; . 5-p-ethylbenzoyl-1,2-dihydro-b-propyl-3H-pyrrole 1, 2-a pyrrole-1-carboxylic acid; 5-o-methoxybenzoyl-1,2-dihydro-b-butyl-ZN-p11 rrol 1,2-a pyrrole-1-carboxylic acid; 5-p-ethoxybenzoyl-1,2-dihydro-6-ethyl-3N-pyrrol 1, 2-a pyrrole-1-carboxylic acid; . 5-o-chlorobenzoyl-1,2-dihydro-b-propyl-3H-pyrrol 1, 2-a pyrrole-1-carboxylic acid; b-m-chlorobenzoyl-1,2-dihydro-bbutyl-3H-pyrrole I, 2-a pyrrole-1-carboxylic acid; . 5-o-fluorobenzyl-1,2-dihydro-b-ethyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid; 5-p-fluorobenzoyl-i, 2-dihydro-b-propyl-3N-pyrrole 1, 2-a pyrrole-1 -carboxylic acid; 5-p-bromobenzoyl-1,2-dihydro-b-butyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic cYaOH. XIY technique. 710 mg of 50% sodium hydride suspension in mineral oil are washed with anhydrous hexane under a nitrogen atmosphere, then suspended in 50 MP of dimethylformamide. The suspension is cooled to -5 ° C and 4.5 g of methyl N- (2-mesyloxymethyl) -3-carbomethoxypyrrole-2-acetate is added and the reaction mixture is stirred at -5 to 0 ° C for 1 hour. Then poured into ice-cold sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated under reduced pressure. After solidification of the solid residue from ether, dimethyl-1, 2-dihydro-ZN-pyrrole 1,2-a pyrrole-1,7-dicarboxylate, identical to the product obtained by the method of YY, is obtained. XY Method. In a three-neck, 250 ml round-bottomed flask fitted with a valve For pressure equalization. and containing 10.08 g of ethanolamine.

26.1 g of dimethyl-1,3-acetone dicarboxylate are added dropwise with stirring over 30 minutes, keeping the temperature below 30 ° C. The resulting methyl 3-carbomethoxymethyl-3- (2-hydroxyethyl) aminacrylate is diluted 20 ml of acetonitride and chloroacetaldehyde, previously prepared by heating a mixture of 27.4 g of diethylelacetate chloro-acetaldehyde with 46.8 g of oxalic hydride at a temperature of 150-160 ° C and added with stirring for 2 minutes. The reaction mixture is heated to reflux; with a nickname for 5-10 minutes, after which

the reaction is terminated, which is established by thin layer chromatography using acetone-chloroform (10:90) as eluent. The solvent is removed under reduced pressure, .250 ml of benzene and 250 ml of heptane are added to the residue, and distillation is carried out with an understanding. pressure. Oily residue

after yörgrinki, it is suspended in 50 ml of methylene chloride and 20 g of silica gel is added. Methylene chloride mixture

poured into a column containing 200 g of silicate in ethyl acetate at-hexane (20:80), first the column was eluted with 6 liters of ethyl acetate-hexane (20:80), then 4 liters of ethyl acetate-hexan mixture (50:50). Fractions eluted with mixture

ethyl acetate-rejccaH (SO; 50), combined and evaporated. 12.8 g of oil are obtained, from and after grinding it with 20 ml of petroleum ether (SO-SO e) and subsequent removal of the solution at. 11.89 g (32.9% of theoretical yield) of methylgN- (2-hydroxyethyl) -3-carbomethoxypyrrol-2-acetate; . 51-54 s, the same product, obtained by method I.

E. A solution of 200 g 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 chemical reagent are removed at the lowest pressure, the residue is cris. This is obtained from a mixture of ethyl acetate-methanol to give -methyl-b-benzoyl-1, 2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylate.

In a typical way, but with the use of diazoethane and diazopropane instead of diazomethane, etyl-5-benzene-1,2-dihydro-Zn-pyrrole 1,2-a pyrrole-1-carboxyl silate and propyl-5-benzoyl, 1 , 2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylate. .

Similarly, the remaining free acids obtained in Examples B and C, as well as acids, obtained in Example D, are converted into

the corresponding methyl, ethyl and propyl esters.

G. A solution of 300 mg of 5-p-toluoyl-1, 2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours in excess. the alcohol is distilled under vacuum and the residue is purified by chromatography on alumina to give isoamyl-5-p -toluoyl-1, 2-dihydro-3H-pyrrole

 1, 2-a pyrrole-1-carboxylate.

Other esters are prepared in a similar manner. for example, pentyl, hexyl, octyl, nonyl, dodecyl, etc., 5-p-tolu5 oyl-1,2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylic acid by replacing isoamyl alcohol with other alcohols, for example, pentyl, hexyl, OKTIL, H ONIL, DO0 Decyl alcohol, etc.

In the same way, the free acids obtained in Examples B and D with the corresponding 5 alcohol are esterified, the following esters are obtained: isoamyl-5-benzryl-1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1- carboxylate;

pentil-5-m-toluoyl-1,2-digidro .. -ZH-pyrr6l 1,2-a pyrrole-1-carboxylate;

hexyl-5-p-ethylbenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylate; Yzoamyl-5-o-propylbenzoyl-1,2-dihydro-3H-pyrrol-1, 2-a pyrrol-1; carboxylate;

, octyl-5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrole 1, .2-a pyrrole-1-carboxylate;

0 nonyl-5-p-isopropoxybenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylate; .

dodecyl-5-c-chlorobenzoyl-1,2-dihydro-3H-pyrrole 1,2-a pyrrol-1-carbo 5 xylate;

isoamyl-5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxylate;

dodecyl-5-o-fluorobenzoyl-1,2-diQ hydro-3H-pyrrole 1,2-a pyrrole-1-carboxylate;

hexyl-5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1-carboxylate; . . . Yonyl-5-p-bromobenzoyl-1,2-dihyd-. 5 pb-3H-p-irrol 1 g 2-a pyrrole-1-carboxylate; .

isoamine-5-benzoyl-1,2-dihydro-6-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylate; .

0 hexyl-5-p-ethylbenzoyl-1,2-dihydro-6-methyl-ZN-pyrrole 1, 2-a pyrrol-1-carboxylate;

nonyl-5-o-methoxybenzoyl-1,2-dihydro-6-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylate;

21

 dodecyl-5-and-fluorobenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole (1,2-a pyrrole-1-carboxylate;

nonyl-5-benzoyl-1,2-dihydro-6-ethyl-3H-pyrrole 1, 2-a pyrrole-1-carboxylate;

isoamyl-5-p-ethoxybenzoyl-.1,2-dihydro-b ethyl-3H-pyrrole 1,2-a pyrrole-1-carboxylate;

pentyl-5-p-fluorobenzryl-1,2-dihydpb-b-propppyl-3H-pyrpoltl, 2-a pyrrole-1-car-oxoxylate,. .

hexyl-5-m-chlorobenoyl-1,2-dihydro-b-butyl-ZN-pyrrole 1, 2-a pyrrol-1-carboxylate; .

Dodecyl-5-p-bromobenzoyl-1,2-diHydro-b-butyl-ZN-pyrrole 1, 2-a pyrrole-1-carbr xylate,

Example b. To a solution of 300 m of 5-p-toluoyl-1,2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylic acid, 1 mol equivalent of sodium hydroxide in the form of 0.1 n is added to 5 Mji ethanol. solution. The solvent is then evaporated off under reduced pressure, and the residue is dissolved in 2 ml of methanol and is precipitated with ether, and neocomine is obtained; 5-p-toluoyl-1,2-dihydro-3H-pyrrole 1,2-a-pyrrole-1-carboxyl sodium, which is crystallized from sms ethyl acetate-hexane.

Similarly, receive. other salts, for example ammonium and potassium 5-p-toluoyl-If2-dihydro-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid, by replacing sodium hydroxide with ammonium hydroxide and potassium hydroxide. ABOUT.

Similarly, the 5-substituted 1,2-dihydro-3H-pyrrole 1,2-a pyrrole-1-carboxylic acids obtained in Examples B-D, may be converted to the corresponding sodium, potassium and ammonium salts.

The representative compounds of -Noi obtained in this way are the following: .-. . 5-o-toluoyl-1, 2-dihydro-3H-pyrrole {1, 2-a sodium pyrrole-1-carboxylate;

5-benzoyl-1,2-dihydro-3H-pyrrole 1,2-a sodium pyrrol-1-carboxylate;

about -5-benzoyl-1,2-dihydro-3H-pyrrole 1, 2-a sodium pyrrole-1-carboxylate;

. 5-p-ethylbenzoyl-1,2-digidro-3H-pyrrole 1, 2-a pyrrole-1-carboxyxylate potassium ;;

5-o-butylbenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a potassium pyrrole-1-carboxylate;

5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrole 1, 2-a pyrrole-1-carboxyl sodium;

5-p-chlorobenzoyl-1I2-dihydro-3H-pyrrole 1, 2-a ammonium pyrrole-1-carboxylate;

5-o-fluorobenzoyl-1, 2-di.hydro-ZN-pyrrole 1,2-a ammonium pyrrole-1-carboxylate;

22

695558

5-p-bromobenzoyl-1,2-digidro-ZN-pyrrole 1, 2-a potassium pyrrole-1-carboxylate;

5-benzoyl-1, -2-dihydro-6-ethyl-β-3H-pyrrole 11,2-a pyrrole-1-sodium carboxylate;

5-toluoyl-1,2-dihydro-5-methyl-ZN-pyrrole 1, 2-a pyrrol-1-potassium carboxylate;

5-o-methoxybenzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-10-ammonium carboxylate;

5-p-fluorobenzoyl-1,2-dihydro-6prOpil-3N-cyrrol 1, 2-a pyrrol-1-carboxylate sodium;

5-m-chlorobenzoyl-1,2-dihydro-b-butyl-ZN-pyrrole 1, 2-a pyrrole-15

potassium carboxylate.

P p and mer 3. To a solution of 175 mg of 5-p-toluoyl-1,2-dihydro-ZN-pyrrole

, 2-aI pyrrole-1-carbo, of a new acid of 5 MP, methanol are added 1 mol0

{equivalent potassium hydroxide in the form of

jO, n. solution and get a solution

containing 5-p-toluoyl-1,2-dihydro-3H-pyrrole-1, 2-a pyrrole-1-potassium carboxylate. Prepared buffer

5 solution by dissolving 40 mg car: calcium carbonate in a minimum amount of 1 n. srl nry acid, optional. required for the dissolution of carbon monoxide, and 100 mg of solid chloride

0 ammonium and then add 5 ml of water. The calcium buffer solution obtained in this way is added to pac; iop; y 5-p-toluoyl-1,2.-dihydrr-3H-pyrrole 1,2-a pyrrole-1-carbcryl: this is potassium, separated by filtration, and the resulting precipitate is washed. its water is dried in air and: 5-Ptoluoyl-1,2-dihydro-3H-pyrrRl 1,2-a pyrrole-1-carboxylate Xylose is obtained.

0

 In a similar manner, by replacing calcium carbonate with magnesium carbonate, 5-p-toluoyl-1 2-dihydro45 -NH-pyrrole 1,2-a pyrrole-1-carboxylate magnesium is obtained, ....

Similarly to rbraze LM by replacing 5-n-t.6luoyl 1,2-digidro-ZN-pyrrole 1,2-a pyrrole-1-carboxylic acid gl 5-benzoyl-1,2-dihydro-ZN-pyrrole

1,2-a pyrrole-1gcarboxylic acid

ot -5-ben ZOI l-1,2-digidro-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic acid;

5-rt-chlorobenzoyl-l, 2-dihydro-3N -pyrrole 1,2-a pyrrole-1-carboxylic

acid;

5-o-methoxyb. Benzoyl-1, 2-dihydro-ZN-pyrrole 1, 2-a pyrrole-G-carboxylic

acid;

6Q Bn-methoxybenzoyl, 2-dihydro-ZN-pyrrole 1,2-a pyrrole-1-carboxylic

acid;

5-benzoyl-1,2-dihydro-b-methyl-ZN-pyrrole 1, 2-a pyrrole-1-carboxylic H5 acid;