DK155996B - METHOD OF ANALOGUE FOR THE PREPARATION OF SUBSTITUTED BETA-OXO-ALFA-PHENYL CARBAMOYL-PYRROLPROPIONITRILES OR THEIR ENOLFORM OR ENOL-C (1-4) ALKYLETHER OR ENOLYL OR ESTHEROLS OR ENOL-CEREALS OR ENOLE-CEREALS OR ENOLE-CEREALS OR ENOLE-CELLETERS OR ENOLE - Google Patents

Abstract

Antiinflammatory and antiarthritic compounds of the formula I <IMAGE> in which Pl denotes a 2- or 3-pyrrolyl radical, which is substituted in the 1-position by lower alkyl or Ph-lower alkyl and is unsubstituted in the three remaining positions or substituted by lower alkyl and/or a carboxyl or carboxy-lower alkoxy group; R represents lower alkyl and Ph denotes phenyl which is unsubstituted or substituted by one to three identical or different substituents from the group comprising lower alkyl, lower alkoxy, lower alkylthio, hydroxyl, halogen, trifluoromethyl, nitro, amino or lower alkanoylamino; these compounds in their enol form, their enol lower alkyl ethers or enol lower alkanoyl esters, or their salts with bases can be obtained, for example, by condensation of compounds of the formulae <IMAGE> in which X denotes lower alkoxy, lower alkanoyloxy or halogen.

Description

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in

The present invention relates to an analogous process for the preparation of novel substituted (3-oxo-α-phenylcarbamoyl-pyrrole propionitriles of the general formula V \ TtuuJ +

νγ „V

wherein R 1 is C (1-4) alkyl, R 2 represents hydrogen or C (1-4) alkyl, R 3 is hydrogen, C (1-4) alkyl or C (1-4) carbalkoxy, R 4 is hydrogen or O (1-4) -10 alkyl, R5 and Rg are hydrogen, C (1-4) alkyl, C (1-4) alkoxy, C (1-4) alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino or C (1-4) alkanoylamino, these compounds in the enol form, enol-C (1-4) alkyl ethers or enol-C (1-4) alkanoyl esters thereof or salts thereof with bases.

From the specification to BE Patent Nos. 842,688, Nos. 842,689, Nos. 849,343 and No. 861,500, and from the specification to U.S. Patent No. 4,061,767, it is known that certain substituted "cyan acetic anilides" and related 20 "isoxazolyl "carboxylic acid anilides", for example those of the formula // 3 NC-C-CONH- · r 5 II * 2 AN, 5 \ and __ v *

11 l in H

V \ h3 v

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2 has non-ulcerogenic antiphlogistic and analgesic effect.

Surprisingly, it has been found that the compounds prepared by the process of the invention have distinct therapeutic benefits in terms of the spectrum of action and compatibility with the above known anilides.

The two pyrrolyl and phenyl groups of formula I are preferably C-unsubstituted. However, they may also be substituted, especially with 1 or 2, the same or different substituents selected from methyl, ethyl, n-propyl, i-propyl and i-butyl. In addition, R5 and Rg may be methoxy, ethoxy, methylthio, ethylthio, hydroxy, halogen such as fluorine, chlorine or bromine, trifluoromethyl, nitro, amino or acetylamino. R3 can also mean carbomethoxy or carbethoxy, especially in the 4-position.

R 1 preferably means methyl, but also ethyl, n-propyl, i-propyl, n-butyl or i-butyl.

The term "low" in the following organic groups or compounds defines those having at most 7, 20 preferably 4, especially 1 or 2 carbon atoms.

The β-hydroxy-1automeric compounds of formula I are sufficiently acidic to form said enol-lower alkyl ethers, enol-lower alkanoyl esters or salts with bases, especially therapeutically useful salts with bases. These salts are derived from an alkali metal, alkaline earth metal, copper or zinc hydroxide, ammonia of mono-, di- or tri- (low alkyl or hydroxy-1-alkyl) amines, low alkylene amines or low alkylene diamines. Such salts are e.g. the sodium, potassium, magnesium, ammonium, mono-di or tri (methyl, ethyl or hydroxyethyl) ammonium, pyrrolidinium, ethylenediamonium or morpholinium salts or the various hydrates.

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The compounds of this invention have valuable pharmacological properties, primarily anti-inflammatory and anti-arthritic effects. These effects can be detected by 5 in vitro or in vivo tests. In the latter experiments, mammals such as e.g. rats, cats, guinea pigs or dogs as experimental animals. The compounds may be administered enterally, preferably orally, parenterally, e.g. subcutaneously or intravenously or topically, e.g. in the form of solutions in water or oil, or in the form of starchy suspensions. The dose used may vary within a range of from about. 0.1 to 100 mg / kg / day, preferably from ca. 1 to approx. 50 mg / kg / day, primarily from approx. 2 to approx. 25 mg / kg / day. The tests selected to detect the aforementioned effects are either classical test methods, e.g. the carrageenin paw edema test or the adjuvant arthritis test in rats, the synoviitis test on dogs or the test using ultraviolet light induced erythema, or modern test methods. Such are the neutral protease inhibition, cf. Arthritis Rheum. 17, 47 (1974), or the inhibition of leukocyte chemotaxis, cf. N.Y.

Acad. Sci., 256, 177 (1975). Other methods are the reduction of neutrophil adherence, cf. Amer. J. Med. 61, 597 (1976), or the inhibition of prostaglandin synthetase 25 described in Biochem. 10, 2372 (1971).

To further illustrate the anti-inflammatory and anti-arthritic effects of the compounds of the present invention, the following tests are performed: 1. Carrageenin paw edema test for anti-inflammatory effect in rats

One hour after oral administration of the test compounds, 0.1 ml of carrageenin (1%) is injected into the cushion area of a hind paw. The difference in swelling is measured by mercury displacement. The anti-inflammatory effect is expressed as the percentage inhibition of carrageenin production.

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called swelling measured 3 hours after administration of the test compound. The results are given in Table I below.

Table I

Example_% Inhibition Example_% Inhibition (100 mg / kg / p.o.) (100 mg / kg / p.o.).

1 36 20/3 25 5 47 20/4 23 12a 35 20/5 44 10 14 36 20/6 42 15 31 20/7 44 16a 48 20/8 26 18a 25 20/9 42 18b 33 20/10 23 15 19b 43 20/12 11 20/2 46 2. Adjuvant Arthritis Test

The well-known adjuvant arthritis test is performed as described by Perper et al., Proc. Soc. Exp. Biol. & Med., 20 137, 506 (1971). The test compounds are administered orally to the rats. The results obtained are given in Table II below.

Table II

Example No.% protection against arthritic swelling at 12.5 mg / kg p.o.

3 49 5 64 20/1 34 20/2 41 30 20/4 43 20/6 53 5

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Table II (continued)

Example No.% protection against arthritic swelling at 12.5 mg / kg p.o.

5 20/7 29 20/9 41

Illustrative is the test method described below: Male rats (Charles River) weighing 250-300 g are immunized by intradermal injection of 0.1 ml Bacillus 10 Calmette Guerin Vaccine (BCG). After 1 week, the animals are given an intraperitoneal injection of 10 ml of sterile 2% rice starch solution for the purpose of triggering the increase of macrophages. On the 11th day after immunization, the animals are sacrificed and peritoneal macrophages are collected with 20 ml of buffered 15 Geyscher saline solution containing heparin (25 units / ml). Cells are centrifuged for 10 minutes at 1000 rpm, washed with an additional 50 ml of Geyscher solution at the same rate and time, and then suspended in a Geyscher solution containing 0.1% human serum albumin (Fraction V, Sigma Co , pH = 7.1) to a concentration of 2 x 10 6 cells / ml.

With the test compounds, 1 x 10 “2 molar solutions in dimethyl acetamide are prepared. Subsequent dilutions with Geyscher solution are made and these are finally added to the above cell suspensions to obtain suitable final concentrations of 10 °, 10 ° 5, 10 ° ® and 10 ° 7 moles. After introducing the suspensions into the upper part of a modified Boyden chemotaxis chamber, the said test compounds become together with the cells.

30 As a chemotactic agent, a rat serum is activated which is activated with the lipopolysaccharide of Escherichia coli (Difco) (1/10 dilution at pH = 7.1). This serum is introduced into the lower part of said chamber. Part 6

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of the chamber containing the cells is separated from the chemotactic solution by a cellulose filter membrane having pores of 8 μ. Triple 5 is made and incubated for 5 hours at 37 ° C. As a control on cell migration, cell suspensions which do not contain test compound are used. After incubation, the filters are removed and then fixed and stained with iron hematoxylin according to Weigert. Four regions on the lower surface of the filter 10 are examined microscopically at a magnification of 320 times. As the index of the chemotactic effect, the average number of neutrophils is used in each of the four regions. In this test method, indomethacin and levamisole are also used as reference compounds.

In the adjuvant arthritis test, e.g. 1-Methyl-O-oxo-α-phenylcarbamoyl-2-pyrrole propionitrile, which is a typical example of the present compounds or enol ethers or enol esters, salts or related compounds of formula I and II, is highly active in rats at oral doses of down to 2 mg / kg / day. The effect of these compounds on the in vitro chemotactic effect of BCG-immunized macrophages is significant at concentrations as low as 10 "5 and 10" moles, and is manifested by an increase in the chemotactic response of macrophages. In contrast, indomethacin does not affect macrophage chemotaxis, whereas levamisole, a known immunopotentiator, induces increased migration at final concentrations of 10 ″ 3 to 10 ″ 5 moles.

In the experiments described above, the compounds of the present invention exhibit a very good anti-inflammatory effect and, moreover, a mechanism of action other than the usual non-steroidal anti-inflammatory agents, exhibiting a levamisole-like component in the macrophage chemistry test. [Levamisole is a disease-affecting antirheumatic drug, cf. "Arthritis and Rheumatism", 18, 385 7

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(1975) and "The Lancet," February 21, 1976, page 393]. The present compounds, which exhibit the same type of effect as indomethacin as well as the same type 5 as levamisole, are valuable anti-inflammatory and anti-arthritic agents, e.g. for the treatment and control of inflammatory, arthritic and / or dermatopathological conditions.

Compounds of the general formula eβ e / \ e R «- · are preferred. J1 - CO-CH-CONH- (II), 2 V in CN R6 R1 wherein R 1 is C (1-4) alkyl, R 2 is hydrogen or C (1-4) alkyl, R 3 is hydrogen, C (1-4) -alkyl or C (1-4) -carbalkoxy, and R5 and Rg each represent hydrogen, C (1-4) -alkyl, C (1-4) -alkoxy, hydroxy, halogen or trifluoromethyl, or their salts with bases, especially their therapeutically useful salts with bases.

Further preferred are the compounds of formula II wherein R 1 is alkyl having not more than 4 carbon atoms, R 2, R 3 and R 4 are each hydrogen, and R 5 and R 9 are each hydrogen, alkyl or alkoxy, each having at most 2 carbon atoms, fluorine, chlorine or trifluoromethyl, or their salts with bases, especially their therapeutically useful salts with bases.

Particularly preferred are the compounds of the general formula II, wherein R 1 is methyl, R 2, R 3 and R 4 are each hydrogen, and R 5 and R 9 are each hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl, or their sodium , potassium, calcium, triethylammonium or trihydroxyethylammonium salts, one of the symbols R5 and

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Rg, which is different from hydrogen, is preferably in para position.

The process of the invention is characterized in that it a) adds compounds of the formulas R / x f4

R - * - 4— · II | R

3 II -H-GO-CH-CN and OC = N ~ v 5 '! Y h "wherein R], R-2r R3 ^ R4, R5 and Rg have the above meanings, or b) condenses compounds with the formulas, _ J4 * 4 3 II j-CO-CH-COX and ^ \ R2 - \ / * CN II - | --R_ R1 R6 * wherein X means lower alkoxy, lower alkanoyloxy or halogen, and R 1, R 2, R 3, R 4 , R5 and Rg have the above meanings, or c) condenses compounds of the formulas R / v V || | _Y and ra-coJ fR5 rv L2 wherein Y means lower alkoxycarbonyl, halocarbonyl or cyan, and R 1, R 2, R 3, R 4 , R5 and Rg have the above meanings, and hydrolyze the imines formed, or

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D) treating a compound of the formula R / v P 4 \ VV / JL ΕΛ V R6 ri wherein R1, R2, R3, R4, R5 and Rg have the above 5 meanings, with a strong base, and, if desired , converting a formed enol of formula I into an enol-C (1-4) alkyl ether or an enol-C (1-4) alkanoyl ester and / or, if desired, converting a formed enol to a salt with a base or converts a formed enol salt to the free enol or to another salt with a base and / or, if desired, separates a prepared isomer mixture into the individual isomers.

The addition of the isocyanate according to process a) is preferably carried out using the method described in the aforementioned BE patent descriptions or using the process according to the description of US patent 3,905,997, i.e. in the presence or absence of an inorganic or organic base, e.g. sodium hydride, or in the presence or absence of polar solvent, e.g. an ether such as diethyl ether or tetrahydrofuran, and / or an amide or sulfoxide, e.g. dimethylformamide or dimethyl sulfoxide, preferably at elevated temperature, e.g. at about. 150 ° C when no bases are used.

Process a) is preferably carried out as follows: The suspension of the nitrile in an aromatic hydrocarbon, e.g. in hot toluene, is treated with a slight molar excess of anhydrous trilavalkylamine, preferably triethylamine. To the mixture is then added 1 mole equivalent of the phenyl isocyanate or a solution thereof in one of the

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10 above-mentioned polar solvents, e.g. dimethyl sulfoxide. The reaction mixture is stirred for approx. 2-12 hours at room temperature, after which its volume is reduced during heating at not too high temperature, e.g. to 100 ° C.

The resulting precipitate is taken up in an alkanol, e.g. methanol and the solution is treated with excess dilute aqueous acid, e.g. with 0.3 N hydrochloric acid. The crude product obtained is aspirated, washed with water, dried, triturated and / or recrystallized from suitable solvents. Such solvents are low alkanols, low alkanols, dilavalkyl ethers and / or low alkyl alkanols, e.g. methanol, acetone, diethyl ether and / or ethyl acetate.

The condensation according to process b) is carried out in the usual manner, preferably between room temperature and approx.

150 ° C. Either equivalent amounts of the reactants are employed, preferably when an ester is used, or with an excess of amine or in the presence of another base.

Such bases are e.g. tertiary amines, e.g. a trilavalkylamine or pyridine. When using halide or anhydride starting materials, these are used to neutralize the acid formed. The low alkanol formed by the reaction of the ester starting materials is preferably distilled off together with the solvent, e.g. with an aromatic hydrocarbon, e.g. benzene, toluene or xylene.

The condensation according to process c) is preferably carried out using alkali metals, alkali metal-low alkoxides or especially alkali metal hydrides, e.g. sodium hydride, in said polar solvents, preferably dimethylformamide or dimethylsulfoxide. This condensation is analogous to the preparation of said nitrile starting materials for processes a) and b), which condensation is illustrated in the corresponding examples.

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Finally, the isomerization according to process d) is carried out in the presence of strong inorganic or organic bases, e.g. with alkali metal hydroxides or trilavalkylaralkylammonium hydroxides, e.g. trimethylbenzylammonium.

The compounds of formula I prepared can be transferred into each other in a manner known per se. Thus, for example, prepared enols can be etherified, preferably with diazo-alkanes or esterified, e.g. with lower alkanoic anhydrides. Therapeutically useful salts of said enols may be prepared e.g. with aqueous alkali metal hydroxide solutions, preferably in the presence of an ether or alcohol as solvent, e.g. a lower alkanol. From the 15 alcoholic solutions, the salts can be precipitated with said ethers, e.g. diethyl ether or tetrahydrofuran. Work is done at moderate temperatures, e.g. below 100 ° C. The salts prepared can be converted to the free compounds by treatment with acids as indicated above. Furthermore, a nitro group in the group Ph can be transferred into an amino group, e.g. with catalytically activated hydrogen such as hydrogen in the presence of nickel or palladium catalysts. The amino group can be either acylated as described above or with lower alkanoic acid halides or lower alkyl esters.

The starting compounds are known compounds or, if they are novel, can be prepared using the methods described for the analogous compounds, e.g. those described in the prior art for the compounds listed there or as illustrated in the Examples.

Starting compounds and end products which are isomer mixtures can be separated into the individual isomers in a manner known per se, e.g. by fractional distillation, crystallization and / or chromatography.

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The above reactions may be carried out in a manner known per se, in the presence or absence of diluents, preferably in those which are inert to the reactants and which dissolve them, catalysts, condensing or neutralizing agents and / or in an inert atmosphere. under cooling, at room temperature or at elevated temperature under normal or elevated pressure.

The process according to the invention comprises such embodiments in which an intermediate preparation of the process is used as starting material and the remaining process steps are carried out, the process is interrupted at any stage where a starting material is formed under the reaction conditions or where a starting material is used in the form. of a salt or a reactive derivative, preferably an alkali metal or trialkylammonium salt. Said isocyanates can also be prepared from corresponding acidic acids and 20 mixed anhydrides from the corresponding acids and simple alkanoic anhydrides.

In the process of the present invention, preferably, such starting materials listed above are used as particularly valuable compounds, especially those of formula II.

The pharmacologically useful compounds may be used for the preparation of pharmaceutical compositions containing an effective amount of the active substance together with or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active ingredient are used together with diluents such as lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants such as e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate,

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13 and / or polyethylene glycol. The tablets also contain binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidine, and, if desired, disintegrants, e.g. the starch, agar, alginic acid or sodium salt thereof, enzymes for the binder and / or shower mixtures or adsorbents, dyes, flavors and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions and suppositories or topical lotions, primarily fat emulsions or suspensions. The pharmacological compositions may be sterilized and / or contain excipients such as e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The pharmaceutical compositions may, if desired, contain other pharmacological compounds and are prepared in a manner known per se, e.g. using conventional mixing, granulating or coating methods, and containing from ca. 1 to approx. 75, especially from ca. 1 to approx. 50%, active substance.

The following examples serve to illustrate the process of the invention. The quantities indicated are parts by weight. Solvent evaporation takes place at atmospheric pressure, unless otherwise stated.

Example 1

To a suspension of 12.9 g of 1-methyl-β-oxo-2-pyrrolpropionitrile in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine is added with stirring 10.7 g of phenyl isocyanate. After dissolving the solids, the dark red solution is kept for 30 minutes at room temperature, then heated for 5 minutes on a steam bath and then left to stand overnight at room temperature. The mixture is evaporated on a steam bath, the residue is taken up in methanol, and the solution 14

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pour into a mixture of 25 ml of 5 N hydrochloric acid and 600 ml of water.

The light brown crystals formed are isolated, washed with water, triturated with ethanol and recrystallized from ca. 2200 ml of methanol. In this way, 1-methyl- / 3-ω-α-phenylcarbamoyl-2-pyrrole propionitrile of the formula \ CO - CH - CONH

In CN

CH3 melting at 174-175 ° C.

The starting material is prepared as follows: A solution of 28 g of 1-methylpyrrole-2-carboxylic acid in 20 ml of dimethyl formamide is added with stirring and cooling to a suspension prepared from 12 g of 50% sodium hydride in mineral oil by washing with petroleum ether and suspending in 50 ml of dimethylformamide. To the reaction mixture is added 30 ml of methyl iodide and the mixture is still stirred at room temperature. After the initially exothermic reaction is quenched, an additional 10 ml of methyl iodide is added. The reaction mixture is left to stand overnight, then treated with water and extracted with 20 diethyl ether. The extract is washed with aqueous sodium carbonate solution and water, dried and evaporated. In this way, 1-methylpyrro1-2-carboxylic acid methyl ester is prepared in oily form.

A solution of 28 g of the above compound in 50 ml of acetonitrile is added with stirring to a suspension prepared from 19 g of 50% sodium hydride in mineral oil by washing with petroleum ether and suspending in 50 ml of dimethylformamide. When the exothermic reaction is quenched, the mixture is heated to 15

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15 minutes in a steam bath, resulting in a lively, exuberant reaction. The viscous reddish-brown suspension is diluted with an additional 50 ml of dimethylformamide 5 and left overnight at room temperature. The mixture is heated again on a steam bath for 5 minutes, then cooled and diluted with water. The aqueous solution is filtered, washed once with diethyl ether and acidified with hydrochloric acid. The crystals formed are isolated, washed with water, dried, triturated with cold ethanol and recrystallized from ethanol. In this way, 1-methyl-O-oxo-2-pyrrole propionitrile is prepared, which melts at 107-109 ° C.

Example 2

By treating equivalent amounts of concentrated aqueous solutions of sodium hydroxide, potassium hydroxide and calcium hydroxide with 1-methyl-oxo-α: -phenylcarbamoyl-2-pyrrolpropionitrile, filtration of the mixtures and evaporation of the filtrates to dryness, the corresponding metal salts are prepared. These do not appear to have well-defined crystalline properties or melting points, although they can be re-precipitated from ethanolic solutions by the addition of diethyl ether. The salts are water soluble and give the following bands in the IR spectrum:

Na salt: 4.57, 6.17 and 6.29 μ K salt: 4.58, 6.17 and 6.30 μ

Ca salt: 4.55, 6.13 and 6.23 μ.

Acidification of the aqueous saline solutions with hydrochloric acid gives the identical free compound (mp 174-175 ° C).

Example 3 To a suspension of 21.4 g of 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile in 100 ml of absolute ethanol is added 11.68 ml of trisethanolamine in 25 ml of ethanol and

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16 mes until a solution is formed. The solution is filtered hot, allowed to cool to room temperature with stirring, the resulting suspension is cooled to 10 ° C, filtered and the residue washed with 25 ml of cold ethanol.

In this way, the corresponding trishydroxyethyl ammonium salt is prepared which melts at 115-117 ° C.

Example 4 3.8 g of 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile is added to 500 ml of ethereal diazomethane prepared from 10.3 g of N-nitroso-N-methylurea with 35 ml of 45% aqueous potassium hydroxide solution and dried over potassium hydroxide tablets. When nitrogen evolution is stopped, the solution is filtered and evaporated. The residue is triturated with diethyl ether and recrystallized from ethyl acetate. In this way, the corresponding methylenol ether, i.e. 1-methyl- / 3-methoxy-α-phenylcarbamoyl-2-pyrrolacrylonitrile, melting at 121-122 ° C.

Example 5 To a suspension of 4 g of 1-methyl-3-oxo-2-pyrrole propionitrile in 70 ml of toluene and 3.2 g of triethylamine is added with stirring 3.7 g of p-fluorophenyl isocyanate. The mixture is heated on a steam bath to dissolve the solid, and the red-brown solution is left to stand overnight at room temperature. The reaction mixture is evaporated on a steam bath, the residue is taken up in methanol and the solution is poured into a mixture of 8 ml of 5 N hydrochloric acid and 300 ml of water. The precipitated crystals are isolated, washed with water, dried, triturated with methanol and recrystallized from ethyl acetate. In this way, 1-methyl- / 3-oxo-α- (p-fluorophenylcarbamoyl) -2-pyrrole propionitrile is prepared which melts at 198-199 ° C.

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Example 6

A mixture of 1.1 g of 1-methyl- / 3-oxo-G'-ethoxycarbonyl-2-pyrrolpropionitrile, 1.1 g of aniline and 60 ml of xylene is refluxed for 4.5 hours. The reaction mixture is cooled and left to stand overnight at room temperature.

The solution is then filtered and evaporated and the residue is recrystallized from methanol. In this way, 1-methyl-O-oxo-α-phenylcarbamoyl-2-pyrrole-10-propionitrile is prepared, which melts at 173-174 ° C. The product is identical to the product of Example 1.

The starting material is prepared as follows: To a solution of 10 g of 1-methylpyrrole-2-carboxylic acid in 650 ml of dry diethyl ether and 8.5 g of anhydrous triethylamine is added portionwise with stirring a solution of 6 ml of thionyl chloride in 50 ml of diethyl ether. The reaction mixture is filtered after 30 minutes and the residue is washed with diethyl ether. The filtrate is evaporated to a small volume, filtered again and then evaporated under reduced pressure.

In this way, the corresponding acid chloride is obtained.

A solution of the acid chloride in 20 ml of ethylene glycol dimethyl ether is added slowly with stirring and cooling to a suspension of 7.2 g of 50% sodium hydride in mineral oil (washed with petroleum ether) in 50 ml of dimethylformamide 25 and 20 g of cyan acetic acid ethyl ester. The moderately exothermic reaction is accelerated by briefly heating the mixture on a steam bath. The reaction mixture is left to stand overnight, treated with water, acidified with 5 N hydrochloric acid and extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue triturated and recrystallized from diethyl ether. In this way, 1-methyl-β-oxo-Q: -ethoxycarbonyl-2-propylpropionitrile is prepared, which melts at 74-77 ° C.

The same product is prepared by acylation with the intermediate

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18 anhydride, i.e. using the equivalent amount of chloroformic acid ethyl ester instead of thionyl chloride in the above reaction step.

Example 7

A mixture of 5.7 g of 1-methyl-3-oxo-α-ethoxycarbonyl-2-pyrrolpropionitrile, 3.6 g of p-aminophenol and 300 ml of xylene is refluxed for 2 hours, after which the mixture is filtered hot. The filtrate is cooled, the crystals obtained are isolated and recrystallized from methanol. In this way, 1-methyl- / 3-oxo-α- (p-hydroxyphenylcarbamoyl) -2-propylpropionitrile is prepared, which melts at 182-184 ° C.

Example 8

To a suspension of 0.8 g of 50% sodium hydride in mineral oil (washed with petroleum ether) in 10 ml of 1,2-dimethoxyethane is added, with stirring, first 2.9 g of 1-benzyl-3 2-pyrrole propionitrile in 30 ml of 1,2-dimethoxyethane and then 2.7 g of p-chlorophenyl isocyanate. The reaction mixture is allowed to stand overnight at room temperature, then evaporated, the residue is taken up in water, the solution is filtered and acidified with 5N hydrochloric acid. The yellow precipitate formed is isolated, washed with water, triturated with methanol and recrystallized from ethyl acetate. In this way, 1-benzyl-β-oxo-ff- (p-chlorophenylcarbamoyl) -2-pyrrole propionitrile is prepared which melts at 214-215 ° C.

The starting material is prepared as follows. 7.5 g of pyrrole-2-carboxylic acid methyl ester in 25 ml of dimethylformamide are added to a stirred suspension made of 3.4 g of 50% sodium hydride in mineral oil by washing with petroleum ether and suspending in 20 ml of dimethylformamide. 8.5 ml of benzyl chloride is then added to the mixture and stirred overnight at room temperature. The reaction mixture is treated with water, extracted with diethyl ether, extract 19

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The barrel is washed with aqueous sodium hydroxide solution and water, then dried and evaporated. In this way, 1-benzylpyrrole-2-carboxylic acid methyl ester is prepared in the form of an oil. (A purified sample thereof melts at 31-32 ° C).

A solution of 9.3 g of the above compound in 15 ml of acetonitrile and 25 ml of dimethylformamide is added with stirring to a suspension made of 4 g of 50% sodium hydride in mineral oil by washing with petroleum ether and suspending in 25 ml of dimethylformamide. . The mixture is heated for 30 minutes on a steam bath to form a dark red solution. This is left overnight at room temperature, then water is added, the mixture is filtered, washed with diethyl ether and acidified with 5 N hydrochloric acid. The crystals formed are isolated, washed with water, dried, triturated with diethyl ether and recrystallized from methanol. In this way, 1-benzyl-β-οχο-2-pyrrole propionitrile is prepared, which melts at 119-120 ° C.

Example 9 To a solution of 4 g of phenylcarbamoyl-acetonitrile in 50 ml of dimethylformamide, 28 g of potassium tert-butoxide are added with stirring in a nitrogen atmosphere. After 2 hours, the resulting suspension is cooled to 5 ° C and 4 g of 1-methylpyrrole-2-carboxylic acid chloride are added to the suspension over 10 minutes (U.S. Patent No. 3,551,571). The reaction mixture is stirred for 18 hours at room temperature, then poured into 300 ml of ice water and the precipitate formed is filtered off. The precipitate is washed with water, dried and recrystallized from ethanol. In this way, 1-methyl-O-oxo-30 α-phenylcarbamoyl-2-pyrrolpropionitrile is prepared which melts at 172-174 ° C. The product is identical to the product of Example 1.

The starting material is prepared as follows: For a mixture of 42.53 g of cyan acetic acid, 46.56 g of aniline and 500

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20 ml of acetonitrile is stirred in a nitrogen atmosphere over 30 minutes for a solution of 113.7 g of N, N-dicyclohexylcarbodiimide in 500 ml of acetonitrile. After 3 hours, the resulting suspension is filtered, the residue is washed with 200 ml of acetonitrile and the filtrates are evaporated. The residue is triturated with 500 ml of diethyl ether and 50 ml of ethyl acetate, filtered and dried. In this way, the phenylcarbamoyl-acetonitrile is prepared, which melts at 10 200-202 ° C.

Example 10

To a suspension of 1135 g of 1-methyl-O-oxo-2-pyrrole propionitrile in 17,000 ml of dry toluene is added with stirring in a nitrogen atmosphere first 913 g of anhydrous triethylamine and then 913 g of phenyl isocyanate. The dark brown solution formed is stirred overnight at room temperature and then evaporated at 60-70 ° C / 10 mm Hg. The residue is taken up in 1400 ml of methanol and the solution is treated with 1400 ml of 6 N hydrochloric acid in 4200 ml of water. The suspension is cooled for 20 minutes to 15-20 ° C, then filtered and the residue is washed with 2 x 1800 ml water, 2 x 1000 ml isopropanol and 13 x 1000 ml diethyl ether. The crude residue is dried at 60 ° C and 5 mm Hg to constant weight. 1960 g of this residue are dissolved in 44,400 ml of methylene chloride at room temperature. The solution is treated with 400 g of activated carbon, filtered and the filtrate is evaporated. The residue is triturated with 12,000 ml of anhydrous ethanol, the suspension is filtered at 20 ° C, washed with 4 x 1000 ml of anhydrous ethanol and dried at 60 ° C and 5 mm Hg. In this way, 1-methyl-30 (S-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 172-174 ° C, is prepared. The product is identical to the product prepared according to Examples 1, 6 or 9.

1801 g of the above compound is suspended in 10,500 ml of anhydrous ethanol and to the suspension is added 1108 g of triethanolamine. The mixture is stirred and heated to 21

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solution of the solid and then slowly cooled to 20 ° C. The resulting precipitate is filtered off, washed with 2 x 1000 ml of cold anhydrous ethanol and dried at 45 ° C and 0.1 mm Hg. In this way, the corresponding tris-hydroxyethylammonium salt is prepared which melts at 115-117 ° C. The salt is identical to the salt prepared according to Example 3.

The starting material is prepared as follows: A solution of 1325 g of 1-methylpyrrole-2-carboxylic acid in 2400 ml of dimethyl formamide is stirred in one. nitrogen atmosphere under cooling with ice to a suspension made of 568.5 g of 50% sodium hydride in mineral oil and 2400 ml of dimethylformamide. The reaction mixture is then first added with 1000 ml of dimethylformamide and then 4316 g of methyl iodide with stirring at a temperature below 88 ° C. Stirring is continued overnight at room temperature, then the mixture is cooled to 10 ° C and 10,600 ml of water is added. The mixture is extracted with 3 x 5300 ml of diethyl ether, the extract washed with 5300 ml of 10% aqueous sodium carbonate solution and 5300 ml of water, dried and evaporated. In this way, 1-methylpyrrole-2-carboxylic acid methyl ester is prepared in the form of an oil.

A solution of 1604 g of the above compound in 2650 ml of acetonitrile is rapidly added to a suspension prepared from 1017 g of 50% sodium hydride in mineral oil and 2650 ml of dimethylformamide with stirring in a nitrogen atmosphere. The mixture is heated to 81 ° C for 2 hours, cooled to 10 ° C and 25,400 ml of water is added over 30 minutes. The mixture is washed with 3 x 9000 ml of diethyl ether, stirred for 45 minutes at 10 mm Hg to remove the diethyl ether, then acidified with 6400 ml of 6 N hydrochloric acid. The crystals formed are filtered off, washed with 4 x 2400 ml of water and once with 2400 ml of isopropanol, then dried at 60 ° C and 5 mm Hg. In this way, 1-methyl- / 3-oxo-2-pyrrole propylene is prepared.

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22 nitrile, which melts at 106-108 ° C.

Example 11

To a filtered solution of 4.4 g of 2,6-dichlorophenyl isocyanate in 30 ml of toluene is added with stirring 2.5 g of 1-methyl-β-oxo-2-pyrrolpropionitrile and 2.1 g of triethylamine. The mixture is allowed to stand overnight at room temperature and then filtered. The solid is washed with toluene and diethyl ether, taken up in 50 ml of methanol, and poured into a mixture of 6 ml of 5 N hydrochloric acid and 300 ml of water. The crystals formed are isolated, washed with water, dried, triturated with ethanol and recrystallized from methanol. In this way, 1-methyl-β-oxo-ole- (2,6-dichlorophenylcarbamoyl) -2-pyrrole propionitrile is prepared which melts at 196-199 ° C.

Example 12

A suspension of 2 g of 1-methyl-3-oxo-2-pyrrolpropionitrile in 50 ml of toluene and 1.6 g of triethylamine is added 2.1 g of p-methoxy-phenylisocyanate. The mixture is lightly heated to dissolve the solid and left to stand overnight at room temperature. The solution is then evaporated, the residue is taken up in methanol and 10 ml of 10% aqueous sodium hydroxide solution and 250 ml of water are added. The basic solution is filtered, acidified with 5 N hydrochloric acid and the resulting precipitate is isolated. The precipitate is washed with water, dried, triturated with a hot mixture of methanol and ethyl acetate and recrystallized from ethyl acetate. In this way, 1-methyl- / 3-oxo-α- (p-methoxyphenylcarbamoyl) -2-pyrrole propionitrile is prepared, which melts at 192-193 ° C.

Analogously, 1-methyl-O-oxo-ole- (p-methylthiophenylcarbamoyl) -2-pyrrole propionitrile is prepared, which melts at 167-168 ° C.

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23

Example 13

A solution of 4.9 g of 1-methyl-3-oxo-2-pyrrolpropionitrile in 50 ml of toluene, 5 ml of dimethyl sulphoxide and 4 g of triethylamine 5 is treated with stirring with a solution of 5.7 g of p-nitrophenylisocyanate in a minimal amount of toluene. The reaction mixture is left to stand overnight, then evaporated and the residue taken up in methanol. The solution is filtered, diluted with water and 6 ml of triethylamine, washed with ethyl acetate and extracted once with 5% aqueous sodium hydroxide solution. The mixed aqueous solutions are acidified with 5N hydrochloric acid and the resulting precipitate is isolated. The precipitate is washed with water, triturated with a mixture of methanol and ethanol, and recrystallized from dimethylformamide. In this way, 1-methyl-β-oxo-o :-( p-nitro-phenylcarbamoyl) -2-pyrrolpropionitrile is prepared, which melts at 245-250 ° C with decomposition.

A solution of 2 g of the compound prepared above in 220 ml of ethanol and 2 ml of triethylamine is hydrogenated for 50 minutes over 0.5 g of 10% palladium coal at a pressure of 3.5 atm and room temperature. The filtered solution is evaporated, the residue is taken up in water, 1 ml of triethylamine is added and the solution is washed with ethyl acetate and diethyl ether. Acidify with 5N hydrochloric acid, the precipitate is isolated, washed with water, dried and recrystallized from aqueous methanol. In this way, 1-methyl-O-oxo-α- (p-amino-phenylcarbamoyl) -2-pyrrole propionitrile is prepared which melts at 193-195 ° C with decomposition.

30 g of the compound prepared above are dissolved in 10 ml of acetic anhydride, the solution is refluxed for 10 minutes and evaporated. The residue is triturated with diethyl ether and recrystallized from a mixture of methanol and ethyl acetate. In this way, 35 l-methyl- / 3-acetoxy-α- (p-acetylamino-phenylcarbamoyl) -2-

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24 pyrrolacrylonitrile, melting at 178-179 ° C.

Example 14

A mixture of 2.1 g of 1-ethyl-O-oxo-2-pyrrolpropionitrile, 5 ml of toluene and 1.6 g of triethylamine is treated with stirring with 1.6 g of phenyl isocyanate. The mixture is left to stand overnight at room temperature, then evaporated and the residue dissolved in methanol. The solution is poured into 300 ml of water containing 5 ml of 5 N hydrochloric acid, the resulting 10 precipitate is isolated and dissolved in 5% aqueous sodium hydroxide solution. The solution is filtered, the filtrate is acidified, the solid is filtered off, washed with water, dried and recrystallized from ethanol. In this way, 1-ethyl-β-oxo-G1-phenylcarbamoyl-2-pyrrole propionitrile is prepared which melts at 144-145 ° C.

The starting material is prepared as follows: To a suspension made of 9.1 g of 50% sodium hydride in mineral oil by washing with petroleum ether and suspending in 50 ml of dimethylformamide is added portionwise under stirring and cooling with ice 20 g of pyrrole-2-carboxylic acid methyl ester. in 50 ml of dimethylformamide. When a solution is formed, 25 ml of ethyl bromide are added and the reaction mixture is heated slightly to start the exothermic reaction.

When the exothermic reaction is quenched, further 5 ml of ethyl bromide are added and the mixture is left to stand overnight. The mixture is treated with water and extracted with diethyl ether. The extract is washed with water, dried, filtered and evaporated. In this way, 1-ethyl-pyrrole-2-carboxylic acid methyl ester is prepared in the form of an oil.

A solution of 10 g of the above compound in 25 ml of acetonitrile and 25 ml of dimethylformamide is added to a suspension of 5.5 g of 50% sodium hydride (washed with petroleum ether) in 15 ml of dimethylformamide and the mixture is heated with stirring for 15 minutes. minutes in a steam room. Blanchard

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The residue is left overnight, then it is added to water, filtered and acidified with 5N hydrochloric acid. The precipitate is isolated, washed with water and recrystallized from ethanol.

In this way, 1-ethyl / 3-oxo-2-pyrrole propionitrile is prepared which melts at 77-79 ° C.

Example 15

To a solution of 2.5 g of 1-isobutyl / 3-oxo-2-pyrrolpropionitrile in 30 ml of toluene and 1.6 g of triethylamine is added 1.6 g of phenyl isocyanate with stirring. The mixture is left to stand overnight, then filtered and the residue dissolved in 5% aqueous sodium hydroxide solution. The solution is filtered, acidified with 5N hydrochloric acid and extracted with a mixture of diethyl ether and ethyl acetate. The organic solution is washed with water, dried and evaporated. The residue is triturated with ethanol and recrystallized from methanol.

In this way, 1-isobutyl-β-oxo-α-phenylcarbamoyl-2-pyrrole propionitrile is prepared which melts at 134-136 ° C.

The starting material is prepared as follows: 13 g of 20 pyrrole-2-carboxylic acid methyl ester are added with stirring to a suspension prepared from 5.5 g of 50% sodium hydride in mineral oil by washing with petroleum ether and suspending in 70 ml of dimethylformamide. To the mixture is then added 40 g of isobutyl bromide, after which the mixture is heated under stirring for 10 minutes on a steam bath. The reaction mixture is left to stand overnight, then treated with water and extracted with diethyl ether. The extract is washed with water, dried and evaporated.

In this way, 1-isobutylpyrrole-2-carboxylic acid methyl ester is prepared in the form of an oil.

A solution of 10 g of the compound prepared above in 15 ml of acetonitrile is added with stirring to a suspension prepared from 5 g of 50% sodium hydride in mineral oil by washing with petroleum.

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26 ether and suspend in 25 ml of dimethylformamide. A reaction proceeds during the shower and when this reaction is quenched, the mixture is heated for 30 minutes on a steam bath. During this time, the sodium hydride is used up. The mixture is left to stand overnight at room temperature, then water is added and acidified with 5N hydrochloric acid. The mixture is extracted with diethyl ether, the extract washed with water, dried and evaporated. In this way, 1-isobutyl-O-oxo-2-pyrrole propionitrile is prepared in the form of an oil.

Example 16

To a solution of 1.6 g of 1,3,5-trimethyl-4-ethoxycarbonyl-O-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.8 15 g of anhydrous triethylamine is added 0.8 g of phenyl isocyanate with stirring. . The mixture is heated for 10 minutes in a steam bath and allowed to stand overnight at room temperature.

The mixture is then evaporated, the residue is taken up in methanol and the solution is treated with 2 ml of 5 N hydrochloric acid 20 and 200 ml of water. The crystals formed are isolated, washed with water, triturated with a mixture of methanol and ethanol and recrystallized from methanol. In this way, 1,3,5-trimethyl-4-ethoxycarbonyl- / 3-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 164-166 ° C, is prepared.

Analogously, 1,3,5-trimethyl-4-ethoxycarbonyl-O-oxo-α- (p-fluorophenylcarbamoyl) -2-pyrrolpropionitrile is prepared, m.p. 178-179 ° C and 1,3,5-trimethyl-4-ethoxycarbonyl-O-oxo-α- (p-chlorophenylcarbamoyl) -2-pyrrole propionitrile, melting at 238-241 ° C with decomposition.

The starting material is prepared as follows: To a suspension of 3.6 g of 50% sodium hydride in mineral oil (washed with petroleum ether) and 50 ml of dimethylformamide are added portionwise with stirring 16 g of 3,5-dimethylpyrrole-2,4-dicarboxylic acid diethyl ester in 25 ml of dimethylformamide.

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27 When the sodium hydride is used up, 40 ml of methyl iodide are added to the mixture and the mixture is left to stand overnight at room temperature. The mixture is then treated with water, the solid formed is isolated and dried in the air to remove excess methyl iodide. The solid is washed with water, dried and recrystallized from ethanol.

In this way, 1,3,5-trimethylpyrrole-2,4-dicarboxylic acid diethyl ester is prepared.

A solution of 13.9 g of the above compound in 30 ml of acetonitrile and 30 ml of dimethylformamide is added with stirring to a suspension prepared from 5.5 g of 50% sodium hydride in mineral oil (washed with petroleum ether) and suspension in 60 ml of dimethylformamide-15 The mixture is heated on a steam bath for 15 minutes and the resulting solution is left to stand overnight. The mixture is then treated with water, the aqueous solution filtered and acidified with 5N hydrochloric acid. The precipitate is filtered off, washed with water, triturated with ethanol and recrystallized from ethanol. In this way, 1,3,5-trimethyl-4-ethoxycarbonyl-3-oxo-2-pyrrolpropionitrile is prepared, which melts at 105-107 ° C.

Example 17

A solution of 0.3 g of 5- (1-methyl-2-pyrrolyl) -4-phenyl-carbamoylisoxazole in 10 ml of 5% aqueous sodium hydroxide solution and a small amount of ethanol is heated for 5 minutes on a steam bath. The solution is then filtered and acidified with 5N hydrochloric acid. The crystals formed are isolated, washed with water and triturated with methanol. In this manner, 1-methyl-3-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile is prepared which melts at 170-172 ° C. The product is identical to the products made according to Examples 1, 6, 9 or 10.

The starting material is prepared as follows:

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28 solution of 17 g of 1-methyl-pyrrole in 400 ml of 1,2-uichloroethane is first added portionwise with stirring and cooling to 10-15 ° C 28 g of anhydrous aluminum chloride. Then, 27 g of malonic acid ethyl ester chloride in 50 ml of dichloroethane are added in portions such that the temperature is maintained between 10 and 15 ° C. The mixture is stirred for 3.5 hours and then slowly allowed to rise to 32 ° C. The reaction mixture is allowed to stand overnight at room temperature, then treated with water and shaken. The organic phase is isolated, washed twice with water, dried and evaporated. As the residue is obtained a dark brown oil which is distilled and the fraction boiling at 105-112 ° C and 0.25 mm Hg is collected. In this way, 1-methyl-O-oxo-2-pyrrolpropionic acid ethyl ester is prepared.

A mixture of 3.6 g of the above compound and 3.9 g of N, N'-diphenylformamidine is heated for 2.5 hours to 145-165 ° C. The brittle glassy mass formed is pulverized, triturated with diethyl ether and recrystallized from a mixture of ethanol and ethyl acetate. In this way, 1-methyl- (3-oxo-α-ani 1) is prepared in ethyl 1-2-pyrrole propionic acid anilide, which melts at 178-180 ° C.

A mixture of 1.4 g of the compound prepared above, 1.1 g of hydroxylamine hydrochloride, 1.2 g of pyridine and 150 ml of ethanol is refluxed for 7 hours. The reaction mixture is left to stand overnight, then filtered and evaporated and the residue treated with water.

The resulting orange colored oil is recommended for crystallization. The precipitate is isolated, washed with water and recrystallized from ethanol. In this way 5- (1-methyl-2-pyrrolyl) -4-phenylcarbamoylisoxazole is prepared which melts at 100-103 ° C.

Example 18

To a suspension of 1 g of 1,3,5-trimethyl-β-oxo-2-pyrrole-propionitrile in 30 ml of dry toluene and 0.7 g of anhydrous triplet.

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29 ethylamine is added with stirring 0.75 g of phenyl isocyanate. The mixture is heated for 5 minutes in a steam bath and then left to stand overnight at room temperature. Filtration is then carried out, the residue is taken up in methanol and the solution is acidified with 1N hydrochloric acid. The precipitate formed is isolated, dissolved in 1 N aqueous sodium hydroxide solution, precipitated again with 5 N hydrochloric acid and washed with water. In this way, 1,3,5-trimethyl- / 3-oxo-α-phenyl-10-carbamoyl-2-pyrrolpropionitrile, which melts at 172-174 ° C, is prepared.

The starting material is prepared as follows: A mixture of 11.9 g of 1, 3,5-trimethylpyrrole-2,4-dicarboxylic acid diethyl ester and 50 ml of concentrated sulfuric acid is heated for 1 hour on a steam bath. The resulting solution is poured onto ice, the precipitate is isolated and washed with water. The precipitate is then taken up in aqueous sodium carbonate solution, the solution is filtered and the filtrate is acidified with 5N hydrochloric acid. The precipitate formed is isolated, washed with water, dried and recrystallized from ethanol. In this way, 1,3,5-trimethyl-2-carbethoxypyrrole-4-carboxylic acid is prepared, which melts at 197-198 ° C with decomposition.

7.5 g of the above compound is heated under reflux for 25 minutes at 235-240 ° C and then cooled. The residue is taken up in petroleum ether and the solution is filtered and evaporated. In this way, 1,3,5-trimethylpyrrole-2-carboxylic acid ethyl ester is prepared, which melts at 38-40 ° C. (The product is disclosed in U.S. Patent No. 2,479,972 with a boiling point of 102-108 ° C / 3-4 mm Hg).

A solution of 4 g of the above compound in 10 ml of acetonitrile is added with stirring to a suspension prepared from 2 g of 50% sodium hydride in mineral oil (washed with petroleum ether) 35 and suspended in 15 ml of dimethylformamide. The mixture is heated for 25 minutes on a steam bath, then allowed to warm

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30 is set for 3 hours at room temperature. To the mixture is added water, the aqueous solution is extracted with diethyl ether and then acidified with 5N hydrochloric acid. The crystals 5 are isolated, washed with water, dried and recrystallized from ethanol with the addition of activated carbon. In this way, 1,3,5-trimethyl-β-8-oxo-2-pyrrole propionitrile is prepared, which melts at 106-107 ° C.

In an analogous manner, 1,3,5-trimethyl-O-oxo-α- (p-10-fluorophenylcarbamoyl) -2-pyrrolpropionitrile is prepared, which after recrystallization from a mixture of methanol and ethanol in the ratio 1: 1 at 184 -186 ° C.

Example 19

A suspension of 1 µl, 2,5-trimethyl-3-oxo-3-pyrrole propionitrile in 40 ml of toluene and 0.7 g of triethylamine is treated with 0.75 g of phenyl isocyanate and heated for 5 minutes on a steam bath. for dissolving the solid. The mixture is left to stand overnight, the precipitate formed is isolated, taken up in methanol and the solution added to a mixture of 3 ml of 5 N hydrochloric acid and 250 ml of water. The crude product is isolated, washed with water, dissolved in 5% aqueous sodium hydroxide solution, filtered and the basic filtrate acidified with 5N hydrochloric acid. The precipitate is isolated, washed with water, dried in air and recrystallized from ethanol. In this way, 1,2,5-trimethyl- / 3-oxo-α-phenyl-carbamoyl-3-pyrrolpropionitrile, which melts at 158-160 ° C, is prepared.

Similarly, crude 1,2,5-trimethyl-β-oxo-α- (p-fluorophenylcarbamoyl) -3-pyrrole propionitrile is also prepared. It is dissolved in aqueous sodium bicarbonate solution, precipitated with 5N hydrochloric acid and recrystallized from ethanol.

Mp. 171-172 ° C.

The starting material is prepared as follows: A solution of 7.6 g of 1,2,5-trimethylpyrrole-3-carboxylic acid

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31 ethyl ester [Ber. 56, 2374 (1973), melting point after recrystallization from methanol 65-66 ° C] in 20 ml of acetonitrile is added to a suspension of 4 g of 50% sodium hydride in 5 mineral oil and 11 ml of dimethylformamide. The mixture is heated under stirring for 20 minutes on a steam bath and the resulting suspension is cooled over 90 minutes to room temperature. The suspension is poured into 200 ml of ice water, the basic aqueous solution is filtered, and the filtrate is acidified under 10 cooling with ice with 18% hydrochloric acid. The precipitate is isolated, washed with water and dried in air, then triturated with diethyl ether and recrystallized from methanol. On this is prepared 1,2,5-trimethyl-3-oxo-3-pyrrole propionitrile, which melts at 140-141 ° C.

Example 20

From equivalent amounts of the corresponding starting materials are prepared by analogy to the methods of the preceding Examples, in particular of Examples 1, 4, 8 and 10, the following compounds of Formula II wherein R 2 = R 3 20 = R 6 = H:

No. Ri R4 R5 Recrystallized m.p. ° C

1 CH3 2-CH3 6-CH3 ethanol 170-171 2 CH3 3-FH ethyl acetate 191-192 25 3 CH3 3-C1 H ethyl acetate 192-193 4 CH3 4-C1 H ethyl acetate 205-207 5 CH3 3-CF3 H methanol 185-186 6 CH3 2-F 4-F methanol 136-138 7 CH3 4-F 3-C1 ethyl acetate 215-216 30 8 CH3 2-C1 4-C1 ethyl acetate 160-162 9 CH3 3-C1 4-C1 dimethylformamide 217 -219 10 C2H5 4-FH methanol 156-157 11 C2H5 4-Cl H ethanol 160-161 12 i-Butyl 4-FH methanol 162-163

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32

Example 21

Preparation of 10,000 tablets containing 100 mg of active substance per day. tablet: 5 Ingredients

Tris-Hydroxyethylammonium-1-methyl-β-οχο-o: -phenylcarbamoyl-2-pyrrolpropionitrile 1000 g Milk sugar 2535 g

Corn starch 125 g 10 Polyethylene glycol 6000 150 g

Talcum powder 150 g

Magnesium stearate 40 g

Purified water q.s.

All powdered components are sieved through a sieve 15 with a mesh width of 0.6 mm. Then, the active substance is mixed with milk sugar, talc, magnesium stearate and with half the starch in a suitable mixing apparatus. The other half of the starch is suspended in 65 ml of water and the suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The formed paste is added to the powder and optionally granulated with the addition of additional water. The granulate is dried overnight at 35 ° C, pressed through a sieve with a mesh width of 1.2 mm, and then pressed into tablets with split pits and 10.3 mm in diameter.

Analogously, tablets are prepared containing another compound illustrated in the preceding examples.

Example 22

Preparation of 1000 capsules containing 25 mg of active substance per capsule.

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33

Ingredients 1- Methyl-β-οχο-α- (p-fluorophenylcarbamoyl) - 2-pyrrolpropionitrile 25 g 5 Milk sugar 207 g

Corn starch 80 g

Magnesium stearate 3 g

All powdered components are screened through a screen having a mesh width of 0.6 mm. Then, the active substance is first homogenized with magnesium stearate and then with milk sugar and starch in a suitable mixing apparatus. 315 mg of mixture is filled into a No. 2 capsule by means of a filling machine.

By analogy, capsules containing 25-100 15 mg of other mentioned and illustrated compounds, especially those of formula II, or of their alkali metal, zinc, tri-lower alkylammonium or tris-hydroxyethylammonium salts are prepared.

Claims (1)

DK 155996 B Analogous process for preparing substituted / S-oxo-α-phenylcarbamoyl-pyrrole propionitriles of the general formula, Y \ P (I), VY Eé 'wherein R 1 is C (1-4) alkyl / R 2 means hydrogen or C (1-4) alkyl, R3 represents hydrogen, C (1-4) alkyl or C (1-4) carbalkoxy, R4 means hydrogen or C (1-4) -10 alkyl, R5 and Rg represents hydrogen, C (1-4) alkyl, C (1-4) alkoxy, C (1-4) alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino or C (1-4) alkanoylamino, these compounds on the enol form, enol-C (1-4) alkyl ethers or enol-C (1-4) alkanoyl esters thereof or salts thereof with bases, characterized in that a) adding compounds of the formulas VfV Yi _ II Wr -CO-CH-CN and 0C = N- · VY Y wherein R 1, R 5, R 3, R 3, R 4, R 5 and R g have the above meanings, or b) condenses compounds of formulas R -4 1 \. RJ-i-CO-f-OK and Ys are "2 * vi" - + *, wherein X means lower alkoxy, lower alkanoyloxy or halogen, and R 1, R 2, R 3, R 4, R 5 and R 9 have the meanings given above. or c) condenses compounds of the formulas R4N ^ e yjjl · fy5 2. lu A r6 · wherein Y means lower alkoxycarbonyl, halocarbonyl or cyano, and R 2, R 2, R 3, R 4, R 5 and R g the imines formed, or d) treat a compound of formula r4 YV 6 wherein R1, r2, R3, R4, R5 and Rg have the above meanings, with a strong base, and, if desired, convert a formed enol. of formula I to an enol-C (1-4) alkyl ether 15 or an enol-C (1-4) -alkanoyl ester and / or, if desired, converting a formed enol to a salt with a base or converting a formed enol salt to the free enol or to another salt having a base and / or, if desired, separating a prepared isomer mixture into the individual isomers.