DK151886B - METHOD OF ANALOGUE FOR THE PREPARATION OF (DL) OR (1) 5-BENZOYL-1,2-DIHYDRO-3H-PYRROLOOE1,2-AAAPYRROL-1-CARBOXYL ACID ESTERS - Google Patents

Description

DK 151886 B

The present invention relates to an analogous process for the preparation of hitherto undefined (dll or (II 5-benzoyl * l) 2T ^ ihydro ^ 3HT · pyrrolo [1,2-a] pyrrole 1'K2arBoxylic acid esters of the general formula r1_CXDtX / coos2 · • ti I ΙΟ 3J_J2 2

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wherein R represents hydrogen or an alkyl group of 1-4 carbon atoms, R "* represents hydrogen, an alkyl group of 1-4 carbon atoms, an alk = 2 oxy group of 1-4 carbon atoms, chlorine, fluorine or bromine, and R is an alkyl group having the 1-4 carbon atoms which are characterized by the characterizing part of the claim. The compounds prepared by the process of the present invention, as described above and more fully described below, exert anti-inflammatory, analgesic and antipyretic action and are thus useful in the treatment of inflammation, pain, and / or pyrexia in mammals, as described in more detail below, They are also 10 smooth muscle relaxants.

The novel compounds of formula (XX) described below exist as pairs of optical isomers (or enantiomorphs), i.e. However, as will be seen, the present invention relates to the preparation of both the (1) form and (dl) mixtures thereof.

The novel (dl) compounds can according to the present invention. is prepared by a process which can be illustrated by the following reaction scheme; it should be noted that only the last step of the reaction scheme illustrates the process of the present invention. The diagram further illustrates possible synthetic pathways in the preparation of the starting material (X) for the process of the invention.

25 30 35

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HH,. COOCH, fcOOCHj [+ R * H || C «2 I coocH, ~" J COOCH 2 3 J (III)

CH, O vA HN

I ΧΛ, H0C ~ CH- OH (II)> sffc. 2. 2

. ·. No.® OH

(I).

COOCHj N ^ R COOCH3 \ KjCcoocH3 * 'XX / c ° and3ch2 \ i I 2 \ H-C-CH, CH ~ (V) \ · I (IV).

I 2 \ OH

r 0S02CH3 \ __ ^ cooch3 * Rv ^ _ ^ cooch3 ^ iNX / coocH3? H2 ,. (VII) I (vi)

IH2C

R _ ^ COOH R jCOOH

T ^ IycooR2 "TjX cooh ^ - (IX) (VIII) t Rv XX / COOP'2, -

i_J 0 I — I

(X) (XI) 4

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Wherein R and R are as defined above and R is a lower alkyl group of 1-4 carbon atoms, e.g. methyl, ethyl, isopropyl and n-butyl.

By carrying out the above process for preparing a compound of formula (IV) wherein R is hydrogen, equilibrium amounts of ethanolamine (I) and dimethyl-1,3-acetone dicarboxylate (II) are formed to form a vinylamine. of formula (III) which can then be treated under anhydrous conditions with a 2-haloaldehyde.

10

To prepare the compounds of formula (IV) wherein R is lower alkyl group, an aqueous mixture of ethanolamine (I) and dimethyl-1,3-acetone dicarboxylate (II) is treated with a compound of formula

ISLAND

15 3 "

R -C-CH2X

3 wherein X is bromine or chlorine and R is a lower alkyl group.

Esterification of compound (IV) with methanesulfonyl chloride in the presence of a tertiary amine results in a corresponding mesylate 'of formula (V) which is then converted to the corresponding N- (2-iodoethyl) pyrrole of formula (VI) by reaction with sodium iodide in acetonitrile solution. The compounds of formula (VII) are obtained from the compounds of formula (VI) by treatment with sodium hydroxide in a suitable inert organic solvent such as dimethylformamide.

The compounds of formula (VII) may alternatively be prepared by direct cyclization of mesylate (V) with sodium hydride in dimethylformamide solution.

The compound of formula (VIII) is derived from the compound (VII) by hydrolysis under basic conditions. The carboxylic acid group of the C-position of compound (VIII) is then selectively esterified by treatment with a lower aliphatic alcohol to give the corresponding mono = 35 carboxylate of formula (IX) which is then decarboxylated to the corresponding compounds of formula (X). which are the starting materials for the process according to the invention.

5 DK 151886 Β τ

Decarboxylation of the mono-esterified compounds (IX) to the corresponding compounds of formula (X), the key intermediates of the process for the preparation of the compounds of the present invention, is obtained by heating (IX) at an elevated temperature of the order of about 230 ° C to approx. 280 ° C for a time sufficient to complete the reaction. The course of the reaction can be followed by the carbon dioxide development rate and thin layer chromatographic analysis, with decarboxylation usually completed in about 10 minutes. 45 to approx. 90 minutes. The reaction product, namely alkyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate and its 6-alkyl derivatives (X), can be purified by chromatographic methods. Alternatively and especially for decarboxylating 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 comprises a compound (X) having an amide of the formula CON (CHg) g R1 in which R R has the meaning given above, giving the corresponding alkyl-5-benzoyl-1,2-dihydro-3H -pyrrolo [1,2-a] pyrrole-1-carboxylate (XI).

This reaction is carried out in an inert organic aprotic solvent and in the presence of phosphorus oxychloride at reflux temperature for from ca. 1 to approx. 175 hours under an inert 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 previously refluxed mixture of 1.1-5 molar equivalents of both the desired amide and phosphorus oxychloride in the same solvent, refluxing the thus obtained reaction mixture for from ca. 6 35 to approx. 72 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 from approx. 4 to approx. 6 hours.

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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.

The N, N-dimethylarylamides used in the following examples are: N, N-dimethyl-o-toluamide, N, N-dimethyl-m-toluamide, N, N-dimethyl-p-toluamide, N, N- dimethyl-p-methoxy-benzamide, N, N-dimethyl-p-ethoxy-benzamide, N, N-dimethyl-o-chloro-benzamide, N, N-dimethyl-m-chloro-benzamide, N, N- dimethyl-p-chloro-benzamide, N, N-dimethyl-p-fluoro-benzamide and N, N-dimethyl-m-ethoxy-benzamide.

These amides are known, commercially available compounds or can be prepared in the usual manner from the corresponding acids, i.e. by about- | formation to the acid chlorides followed by treatment with dimethylamine.

The compounds of formula (XI) may be cleaved in accordance with known methods in the art to obtain the corresponding single isomers thereof.

To illustrate this, it should be mentioned that (11-acid isomers Qg (d) -s-acid isomers of the acids corresponding to compounds (XI) of formula (A) can be obtained by using the prior art high-pressure liquid chromatography (HPLC) for 7 '. :

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on α-phenethyl diastereoisomeric esters of the compounds of formula (A) followed by acid cleavage. Thus, the compounds of formula (A) wherein R and both are hydrogen may e.g. is subjected to further treatment in accordance with the following diagram: COOII ^ - several steps.

. Φ i'iA1) - (1) - ^ acid isomer- '(1) -oc-phenethyl ester - ix (Ax) - (d) - acid isomer- (1) -α-phenethyl ester j [' separation using .. ·. · '. High pressure liquid- *.

. · 'Kroma ^ jgrafi · • (a ^) - (1) - ^ acid & somei ^. [. : λ \ · (A ^) - (d) - / acid isomer - (1) -phenethyl ester t V '' in (A) - (l) -isomer. (A) - (d) acidomer.

It is to be understood that, if desired, the isolation of the compounds described herein may be accomplished 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.

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. The 8 (dl) and (1) compounds of formula (XI) are useful as antiinflammatory agents, analgesics, platelet aggregation inhibitors, fibrinolytic agents, and as smooth muscle relaxants. !

These compounds can be used both prophylactically and therapeutically.

Thus, the products containing these compounds are useful in the treatment and elimination of inflammation, such as inflammatory conditions in the muscular skeletal system, skeletal joints and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, concussion, laceration, arthritis, fractures, post-traumatic conditions and arthritis. In cases where the above conditions include pain and pyrexia in the prevention of inflammation, the present compounds are useful in alleviating these conditions as well as the inflammation.

The preferred mode of administration for the above-described conditions 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 uterine muscle relaxants and 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. The following manufacturing methods and examples illustrate, respectively, the preparation of starting materials or intermediates en route to starting materials for the process of the invention and the process of the invention. All mixing conditions used with! for liquids, refer to volume ratio. Where necessary, examples are repeated to prepare additional material for subsequent examples, and unless otherwise stated, the reactions are carried out at room temperature (20-30 ° C).

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Preparation method 1

A 250 ml 3-necked, round bottom flask containing a magnetic stirring rod and fitted with calcium chloride-filled drying tube is connected directly (via one of the external necks) by means of a publishing beaker and a short (3 ") water cooler to the acetal pyrolysis apparatus. 5 rat consists of a 100 ml round bottom flask (pre-loaded with 15.6 g of oxal = 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 provided with a thermometer connected to the above swallow.

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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 (21-hydroxyethyl) aminoacrylate (III) is formed immediately. After completion of addition 15, the ice bath is removed and 100 ml of dry acetonitrile is added. The pyrolysis part of the apparatus is placed in an oil bath and the temperature of the bath is raised to 150-160 ° C. The bromoacetaldehyde solution formed is distilled (boiling point 80-83 ° C / 580 mm Hg) directly to the magnetically stirred solution of the vinylamine (ill). When the distillation temperature falls below 80 ° C, the pyrolysis apparatus is discontinued and a back swallower fitted with a drying tube containing calcium chloride is replaced. The solution is heated to reflux for 1 hour, the solvent is removed under reduced pressure and then 200 ml of methanol and 20 g of silica gel are added to the residue. This mixture is evaporated to dryness in vacuo 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-carbomethoxypyr = 30-roll-2-acetate (IV, R = H) which, after recrystallization from ether / hexane, has a melting point of 52%. 54 ° C.

Forward method 2

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 is added 2.65 ml of triethylamine and then added dropwise. 1.46 ml of methane = sulfonyl chloride keeping the temperature of the reaction mixture at -10 ° C

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to -5 ° C. The reaction is followed by a thin layer chromatographic analysis using chloroform / acetone (90:10). When the reaction turns out to be complete (about 30 minutes after the end of methanesulfonyl chloride seeding), add 10 to 10 times water slowly. Drain 5 organic phases are 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-mesyl = oxyethyl) -3-carbomethoxypyrrole-2-acetate (V, R = H), m.p. 99-101 ° C.

10

Forward t o ll i ng its t o d e 3

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 15 l. The cooled reaction mixture is evaporated to dryness under reduced pressure and the residue is decomposed with water. The insoluble material is separated by filtration and air dried. There is thus obtained 840 mg (97%) of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-acetate (VI, R = H), mp 137-138 ° C.

20 For Reaming Method 4 '

A solution of 1 g of methyl N- (2-iodoethyl) -3-carbomethoxypyrrole-2-ace = | tat in 5 ml of dry dimethylformamide is stirred under an argon atmosphere with | 137 mg 50% sodium hydride in mineral oil. The reaction mixture is kept | ZO (for 30 minutes at room temperature and then rapidly cooled with 100 ml in water. The product is extracted with ethyl acetate (3 x 50 ml), the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. g of silica gel, using 3Q of hexane / ethyl acetate (4: 1) as eluent, gives 500 mg (80%) of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1 7-dicarboxylate (VII, R = H), mp 70-71 ° C.

A solution of 1.80 g of dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate in 20 ml of methanol is treated with a solution of 4.48 g of potassium hydroxide in 20 ml. 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 4Q 50 mL). The combined extracts are dried over magnesium sulfate and concentrated by evaporation.

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steam 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 during decomposition.

Preparation Method 5 A solution of 1.24 g of 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid in 50 ml of isopropanol, cooled in an ice bath, is saturated with hydrogen = chloride gas keeping the temperature of the reaction mixture below 50 ° C. The ice bath is then removed and the reaction mixture is stirred for 1 1/2 hours at room temperature and evaporated to dryness under reduced pressure. 10 ml of 10 benzene is added to the residue and the solution is evaporated again under vacuum, repeating this process a total of three times to completely remove excess hydrogen chloride. Thus, 1.58 g (96%) of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid (IX, R = H, p R = iso -C1 Hy) which, after recrystallization from methanol / ethyl acetate 15, has a melting point of 144-145 ° C.

Similarly, but using methanol, ethanol, propanol and n-butanol instead of isopropanol by the above process, the following starting materials are obtained, respectively: O Π methyl-1,2-dihydro-3H-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 pc butyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid.

For example, the method of measuring 6 1,054 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-30 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] p pyrrol-1-carboxylate (X, R = H, R = iso-C a pale yellow oil with the following physical constants: UV : 215 nm (e 6020); I.R. : V ^^ p3 1725 cm -1; N.M.R. : 1.22 (d, J = 7Hz, 6H), 2.40-2.90 (m, 2H), 3.60-4.20 (m, 2H), 4.65-5.2 (m, 1H), 5.73-5.92 (m, 1H), 6.10 (t, J = 3Hz, 1H), 6.43-6.53 ppm. (m, 1H).

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Method of preparation 7

A 100 ml 3-necked, round mouth flask is provided with a cooler, nitrogen supply tube and a gas bubbler is provided with 5.0 g of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7 carboxylic acid. The apparatus is purged with nitrogen and the nitrogen flow is then stopped. The apparatus is immersed in an oil bath heated to 270 ° C and the reaction is monitored by the rate of carbon dioxide evolution (gas bubbles) and by thin layer chromatography on silica gel using benzene / di = oxane / acetic acid (90: 10: 1) as the developing agent. After 45 minutes of 10 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, = iso-C- Hy), an oil whose physical constants are identical to those obtained in Preparation Method 6.

Preparation Method 8

A 250 ml 3-necked, round bottom flask with magnetic stir bar and fitted with a calcium chloride-filled drying tube is provided with 3.56 g of ethanolamine, cooled in an ice bath to 0-10 ° C and treated dropwise with stirring with 8.7 g dimethyl-l, 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 1.75 g of bromoacetaldehyde in 20 ml of acetonitrile, and then refluxed 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 in vacuo and placed on top of a column of 200 g of silica gel packed in hexane, eluting with the mixture of hexane and ethyl acetate. The fractions eluted with hexane / ethyl acetate (1: 1) gave methyl N- (2-hydroxyethyl) -3-carbomethoxypyr = 35-2-acetate (IV, R = H) identical to that of Preparation Method 1 product obtained.

1 '"13

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Preparation Method 9

To a solution of 6 ml of ethanolamine in 5 ml of water is added 1.74 g of dimethyl-1,3-acetone dicarboxylate. The resulting mixture is rapidly cooled to -10 ° C and treated dropwise over a period of 15 minutes with stirring with 1.67 ml of 1-bromoacetone while maintaining the temperature of the reaction mixture at a maximum of 40 ° C. After completion of the addition, the dark reaction mixture is stirred for an additional hour at room temperature and then poured into a mixture of hydrochloric acid and ice, saturated with solid sodium chloride and extracted with ethyl acetate (3 x 100 ml). The combined extracts are washed with cold water for neutral reaction, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography the residue on 30 g of silica gel using hexane: ethyl acetate (70:30) as the eluent to give 890 mg of crystalline methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, which after recrystallization from methylene chloride / hexane melts at 78 ° C and has the following analysis:

Calcd for C 21 H 17 O: C 56.45, H 6.71

Found: C 56.41, H 6.73.

Similarly, but using a stoichiometric equivalent amount of 1-bromo-2-butanone instead of 1-bromoacetone, there is obtained: methyl N- (2-hydroxyethyl) * 3 ^ carbomethoxy-4-ethylpyrrole-2-acetate, mp. 61-62 ° C

Preparation Method 10 2g Following Methods 2, 3, 4, 5 and 7, methyl N- (2-hydroxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate (IV, r = CH 2) is successively converted to: methyl -N- (2-mesyloxyethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, m.p. 81 ° C, methyl N- (2-iodoethyl) -3-carbomethoxy-4-methylpyrrole-2-acetate, m.p. 103 ° C,

dimethyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylate, m.p. 71 ° C

1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1,7-dicarboxylic acid, m.p. 200-203 ° C, 14

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isopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate-7-carboxylic acid, m.p. 160 ° C and in sopropyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (X, R = CH 2, = iso-C 2 Hy) * oil.

Preparation Method 11 D 1 710 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 the reaction mixture at -5 ° C - 0 ° C for 1 hour. . It is then poured into ice-cooled sodium chloride solution and extracted several times with benzene. The combined extracts are washed with water, dried and evaporated to dryness under reduced pressure. The solid residue is crystallized from ether to give dimethyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1,7-15 dicarboxylate (VII, R = H) identical to that of Preparation method 4 obtained product with m.p. 70-71 ° C.

Preparation Method 12 To a 250 ml 3-necked, round bottom flask equipped with a nitrogen addition and relief valve, a magnetic stir bar and a pressure equalized addition funnel containing 10.08 g of ethanolamine are added while stirring 26.1 g of dimethyl-1,3-acetonedicarboxylate. for a period of 25 minutes, while keeping the temperature below 30 ° C. The resulting methyl 3-carbomethoxymethyl-3- (2'-hydroxyethyl) aminoacrylate (III) is diluted with 20 ml of acetonitrile and chloroacetaldehyde, pre-prepared by heating a mixture of 27.4g of chloroacetaldehyde diethylacetal with 46.8g of oxalic acid dihydrate at 150 -60 ° C, is added with stirring for 3q over a 2 minute period. The reaction mixture is refluxed for 5-10 minutes, after which the reaction by thin layer chromatographic analysis using acetone / chloroform (10:90) as the eluent is found to be complete. The solvent is removed under reduced pressure, and to the residue are added 250 ml of benzene and 250 ml of heptane, and distillation is then carried out under reduced pressure.

The oily residue remaining after distillation is suspended in 50 ml of methylene chloride and to this is added 20 g of silica gel. Me- 15

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The thylene chloride mixture is poured onto a column containing 200 g of silica gel made in ethyl acetate trhexane (20:80). The column is first eluted with 6 liters of ethyl acetate hexane (20:80) and then with 4 liters of ethyl acetate: hexane (50:50). The fractions eluted with ethyl acetate: hexane (50:50) are combined and concentrated to give 12.8 g of an oil which is decomposed with 20 ml of petroleum ether (30-60 ° C) followed by removal of the solvent under reduced pressure to prepare of 11.89 g (32.9% of theory) of methyl N- (2, -hydroxyethyl) -3-carbomethoxy = pyrrole-2-acetate (IV, R = H), m.p. 51-54 ° C, the same product obtained by Preparation Method 1.

Example 1

A solution of 179 mg of N, N-dimethyl-p-toluamide and 0.11 ml of phosphorus oxychloride in 2 ml of 1,2-dichloroethane is refluxed for 30 minutes. To this solution is added a solution of 193 mg of isopropyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate in 2 ml of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 8 hours, treated with 405 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, 208 mg (66%) of isopropyl-5-p-toluoyl-1,2-dihydro-3H-pyrrolo 20 · [1,2-a] pyrrole-1-carboxylate (XI, R = H, R1 = p -CH₂, R2 = iso-C CH H), an oil having the following physical constants: UV256, 312 nm, (e 8700, 19500); 1735, 1620, 1605 cm -1; NMR: δ 1.23 (d, J = 7Hz, 6h), 2.38 (s, 3H), 2.5-3.0 (m, 2H), 3.75 -4.10 (m, 1H), 4.2-4.60 (m, 2H), 4.85-5.20 (m, 1H), 5.95 (d, J = 4Hz, 1H), 6 , 70 (d, J = 4Hz, 25H), 7.10 (d, J = 8Hz, 2H), 7.60 ppm (d, J = 8Hz, 2H).

Example 2

Following the procedure of Example 1 using 1.1-5 molar equivalents N, N-dimethylbenzamide, N, N-dimethyl-o-toluamide, JN, N-dimethyl-m-toluamide, Γ DK 151886Β 16 Ν, N-dimethyl-p-methoxybenzamide, Ν, N-dimethyl-p-ethoxybenzamide, Ν, N-dimethyl-o-chlorobenzamide, Ν, N-dimethyl-m-chlorobenzamide, 5 Ν, Ν-dimethyl-p-chlorobenzamide, N , N-dimethyl-p-fluorobenzamide, and N, N-dimethyl-m-ethoxybenzamide in place of N, N-dimethyl-p-toluamide and monitoring the reaction process by thin layer chromatography are obtained respectively: isopropyl-5-benzoyl-1, 2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, a pale yellow oil having the following physical constants: UV: 245, 311 nm (e 7230, 17800); IR: δ 3 1735, 1620 cm "1; NMR: 124 (d, 6H, (CH3) ₂CH), 250-3.13 (m, 2H; H-2); 3.97 (dd, 1H, H1), 4.18-4.70 (m, 2H, H-3), 5.00 (sept, 1H, (CH 3) 2CH), 6.00 (d, 1H, H-7), 6 , 86 (d, 1H, H-6), 7.10-7.90 ppm (m, 5H, phenyl protons); MS: m / e 297 (M +), isopropyl-5-o-toluoyl-1,2 dihydro-3H-pyrrolo [1,2-a] pyrrole-l-carboxylate,

- QTI

an oil having the following physical constants: U.V .: Åma 25 cs, 303 nm 20 (e 4460, 19100): 1735, 1620 cm -1; NMR: 1.18 (d, 6H, (CH3) 2CH), 2.28 (s, 3H-, o -CH2), 2.50-3.13 (m, 2H, H-2), 3, 92 (dd, 1H, H1), 4.17-4.70 (m, 2H, H-3), 4.98 (Sept. 1H, (CH3) 2CH), 5.92 (d, 1H, H- 7), 6.43 (d, 1H, H-6), 6.97-7.45 ppm. (m, 4H, phenyl = protons), isopropyl-5-m-toluoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, an oil having the following physical constants: U.V. : Amak.s 250-251, 310-312 nm (e 6460, 17400); I.R.i ^ S 1735, 1620 cm -1; NMR: 1.25 (d, 6η, (CH 3) 2 CH), 2.27 (s, 3H, CH 3), 2.52-3.13 (m, 2H, H-2), 3.92 (dd, 1H, H1), 4.13-4.70 (m, 2H, H-3), 4.95 (Sept. 1H, (CH3) 2CH), 5.95 (d, 1H, H-7), 6.67 (d, 1H, H-6), 7.03-7.57 ppm. (m, 4H; phenyl = protons),

DK 151886B

17 isopropyl-5-p-methoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having the following physical constants: UV: 218, 270-284 (shoulder), 314 nm (e 9780, 9320, 22400); I.R. : 1717, 1605 cm -1; NMR: 1.24 (d, 6H, J = 6Hz; (CH3) 2CH-), δ 2.50-3.10 (m, 2H; H-2), 3.78 (s, 3H; CH 2 O), 3.93 (dd, 1H, = 6Hz, JBX = 7Hz; H1), 4.13-4.60 (Μ, 2H; H-3), 4, 95 (sept; 1H, J = 6Hz; (CH 3) 2CH), 5.95 (s, 1H, J = 4Hz; H-7), 6.68 (d, 1H, J = 4Hz; H-6) , 6.70-790 ppm (m, 4H; phenyl protons); MS: m / e 327 (M +), 3'-isopropyl-5-nitroethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2 a] pyrrole --- 1-carboxylate mp 50-51 ° C, isopropyl-5-p-ethoxybenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 95 ° C, isopropyl-5-o-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-ΜθΜ carboxylate, an oil having the following physical constants: UV: 251, 306 nm (e 5750, 16600); IR: δ 5 1735, 1625 cm -1; N.M.R. : 6TMs < 1 > 22 (d < β > (CH2) 2ch), 2.55-3.05 (m, 2H; H-2), 3.97 (dd,.

1H, H1), 4.17-4.70 (m, 2H, H-3), 4.97 (Sept., 1H, (CH3) 2CH), [5.93 (d, 2 / 3H), 6.00 (d, 1 / 3H) H-7], [6.42 (d, 2 / 3H), 6.67 (d, 1 / 3H), H-6], 7.07-7.80 ppm. (m, 4H; phenyl protons), isopropyl-5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carb = oxylate, an oil having the following physical constants: U.V. : ^ 241 ,. CWH wd.ft.b_-.

313 nm (e 6600, 15100); IR: δ ks3 1735, 1620 '1570 cm-1 NMR: δ ™ 13 1.27 (d, 6H, (CH3) 2CH), 2.50-3.18 (m, 2H, H-2), 3, 93 (dd, 1H, H1), 4.10-4.63 (m, 2H, H-3), 4.98 (sept, 1H, (CH3) 2CH), 5.98 (d, 1H, H -7), 6.67 (d, 1H, H-6), 7.07-7.78 ppm.

(m, 4H, phenyl protons); MS: m / e 331-333 (M +), isopropyl-5-p-chlorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-3q carboxylate, m.p. 80.5-81 ° C, is propyl 5-p-fluorobenzoyl-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 72-72.5 ° C.

18

DK 151886B

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-dimethyl-p-toluamide to preparation of isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate (XI, R = CH 2, R 1 = p-CH 3, R 2 = iso-C ^ Hy), m.p. 72 ° C ~ Similarly, but using the Ν, Ν-dimethylarylamides listed in Example 3. instead of N, N-dimethyl-p-toluamide, there is obtained -1Q respectively: isopropyl-5-benzoyl-1,2. -dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 75 C, isopropyl 5-p-methoxybenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 89 ° C, isopropyl 5-p-chlorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate, m.p. 88 ° C, isopropyl 5-p-fluorobenzoyl-1,2-dihydro-6-methyl-3H-pyrrolo [1,2-a] pyrrole-1-carboxylate having the following physical constants: 20 U.V. 250, 315 nm (e 6170, 14100); I.R. ^ SSs3 1734 »16 ° 5» 1593 cm ”1; N.M.R. 1.25 (d, 6H, J = 6Hz; ester CH3), 1.83 (s, 3H; ring CH3), 2.49-3.00 (m, 2H; CH2), 3.90 (t, 1H, EJ = 7.4Hz; CHCO), 4.10-4.23 (m, 2H; N-CH2), 4.98 (sept., 1H, J = 6Hz; ester CH), 5.84 (s , 1H, H-3), 7.00 (t, 2H, Jortho = 8.4Hz, Jm = 8Hz; H-3 ', 5'), 7.55 (q., 2H, 5Ϊ0Γ , 4Hz, J · = = 5 »5Hz; H-2.6 ') MS m / e 1% 329 25 M + 242 100 M + -CO 2 CH (CH 3) 2 123 123 36 F-C 6 H 4 CO,

Claims (1)

Wherein R represents hydrogen or an alkyl group having 1-4 carbon atoms, R1 represents hydrogen, an alkyl group having 1-4 carbon atoms, R1 represents (fT'l) * "| j-Π ^ JL JL JL COOR2 (XI) an alk = oxy group having 1-4 carbon atoms, chlorine, fluorine or bromine, and R2 is an alkyl group having 1-4 carbon atoms, characterized by condensing a compound of formula DK 151886 BR wherein R and R have the meaning defined above, with a qmid of the formula Έ> - CON (CH 3). 2 'ii wherein R 1 has the meaning defined above.