DD151307A5 - PROCESS FOR PREPARING ALPHACARBAMOYL-PYRROL-PROPIONITRILENE - 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

V6 79 "^" Berlin, October 17, 1980

AP C 07 D / 221 679 57 607 18

Process for the preparation of alphacarbamoyl-pyrrolpropionitriles

Field of application of the invention

The invention relates to a process for the preparation of Alphaearbamoyl-pyrrolpropionitriles, in particular of novel substituted β-oxo ^ phenylcarbamoyl-pyrrolpropionitriles with valuable pharmacological, in particular antiinflammatory and antiarthritic Wir-? fluctuations. The compounds prepared according to the invention are used as medicaments.

Characteristic of the known technical solutions

Particularly substituted "cyanoacetic acid-anilides" and related "isoxycarbonyl-anilides", e.g. B, those of the formulas

^R 4 is CH 2 -CO-CH-COBH- / K and

³ 'I 4-Re

CN Γ - 5

according to BE-PS 842 688, 842 689, 849 343, 861 500 or US Pat. No. 4,061,767 are "non-ulcerogenic antiphlogistic and analgesic agents".

17. 10. 1980 AP C 07 D / 221 679 57 607 18 - 2 -

Object of the invention

The aim of the invention is the provision of antiinflammatory and antiarthritic compounds.

Show the gist of the invention

The invention has for its object to find compounds with the desired properties and to develop processes for their preparation.

According to the invention, new substituted .beta.-oxo - ^ - phenylearbamoyl-pyrrolpropionitrile of the general formula I.

CU R ι t

Pl-CO-CH-COlT-Ph (I)

wherein Pl is a 2- or 3-Pyp ^ olyl radical which is substituted in the 1-position by alkyl or Ph ~ alkyl and which is unsubstituted in the remaining three positions or substituted by alkyl and / or a carboxy or carboxy-lower alkoxy; R is hydrogen or alkylalkyl, and Ph is phenyl which is unsubstituted or substituted by one to three, identical or different, substituents of the group: mederalkyl, mederalkoxy, alkylthio, hydroxy, halogen, trifluoromethyl, methyl, amino or medico-kanoylamino in their enol form, in the form of their enol-lower alkyl ethers or enol-lower alkanoyl esters, or their salts with bases, especially in the form of their therapeutically acceptable salts with bases in pharmaceutical preparations containing these compounds.

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October 17, 1980

AP C 07 D / 221 679

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Both of said pyrrolyl and phenyl groups P1 and Ph are preferably C ~ unsubstituted, but they can also, in particular by one or zv / ei, identical or different substituents of the group lower alkyl, z · B * methyl, ethyl, n-propyl or i-propyl or butyl. Moreover, the radical Ph can also be replaced by lower alkoxy, z. Methoxy, ethoxy, n ~ or i ~ propoxy or butoxy; Lower alkylthio, e.g. Methylthio or ethylthio; hydroxy; Halogen, e.g. B.'Fluor, chlorine or bromine; trifluoromethyl; ITitro; Amino or lower alkanoylamino, e.g. B · acetylamino or propionylamino. The remainder Pl can also be a carboxy or carbonyl-lower alkoxy group, e.g. Carbomethoxy or Carbethoxy, in particular in the 3- or 4-position.

In the 1-position of the pyrrole ring, the Hiederalkyl- or Ph-Mederalkylgruppen are preferably methyl, but also ethyl, n- or i-propyl or butyl; Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl. The latter radicals may be unsubstituted or substituted as indicated for Ph.

The other H substituent, R, is preferably hydrogen, but also an alkyl group mentioned above.

The term "lower" defines in the organic radicals or compounds mentioned above or below those having at most 7, preferably 4, in particular 1 or 2, carbon atoms.

The β-hydroxy tautomeric 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

16.-. G. ..

October 17, 1980

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Salts are derived from an alkali metal, alkaline earth metal, copper or zinc hydroxide; Ammonia, mono, di-tri (lower alkyl or hydroxy-lower alkyl) amines, lower alkylene amines or lower alkylene diamines. Such salts are for. As sodium, potassium, magnesium, ammonium, mono-, di- or tri- (methyl, ethyl or hydroxyethyl) -ammonium, pyrrolidinium, Äthylendiammonium- or morpholinium salts or their various hydrates »

It has been found, surprisingly, that the said new Pyrrolpropionitrile over said known anilides, but also to the very old analog benzoyl compounds (J. Am. Chem. Soc. ^ I ₉₉₅₉ (1913)) "z. B. in terms of the spectrum of activity and tolerability, provide pronounced therapeutic benefits.

The compounds of the invention exhibit valuable pharmacological properties, primarily antiinflammatory and antiarthritic effects. These can be demonstrated in in vitro or in vivo experiments. In the latter, preferably mammals, e.g. As rats, cats, guinea pigs or dogs, used as test objects. The compounds of the invention may be administered to them enterally, preferably orally, parenterally, for example, subcutaneously or intravenously, or topically, e.g. In the form of solutions in water or oil, or in the form of starch-containing suspensions. The dose used may range from about 0.1 to 100 mg / kg / day, preferably about 1 to 50 mg / kg / day, in the first place

Line about 2 and 25 mg / kg / day. The tests chosen for the above effects are either classical experimental methods such as carrageenin paw edema or adjuvant arthritis test in rat, dog synovitis test or test evaluating ultraviolet light erythema, or modern testing methods , Such are the neutral protease inhibition [described in Arthritis Rheum. _17_, 47 (1974)] or the inhibition of leukocyte chemotaxis [NYAcad. Sci., 256 , 177 (1975)]. Other methods are the decrease in neutrophilic adherence [Amer. Med. 6jL, 597 (1976)] or the inhibition of prostaglandin synthetase, which test in Biochem. 10, 2372 (1971).

Illustrative is the following test method which provides the pertinent data: Male Charles River rats weighing 250-300 g are immunized by intradermal injections of O ₅ ImI Bacillus Calmette Guerin vaccine (BCG). After one week, the animals are injected intraperitoneally with 10 ml of sterile 2% rice starch solution to induce macrophage accumulation. On the eleventh day after immunization, the animals are sacrificed and peritoneal macrophages with 20 ml of Gey ^f shear-buffered saline solution which contains heparin (25 units / ml), collected. The cells are centrifuged for 10 minutes at 1000 revolutions / minute, washed with another 50 ml of Gey ¹ shear solution at the same speed and time and then in Geyser solution containing 0.1% human serum albumin (fraction V, Sigma Co., pH = 7.1) to (suspended.

to reach a concentration of 2 × 10 cells / ml, sus-

-2

With the test substances 1x10 mol solutions in dimethyl

acetamide produced. Subsequent dilutions are made with Gey's solution and this finally to the above cell suspension

4 -5 -6 to achieve appropriate final concentrations of 10, 10, 10 and 10 moles. After the introduction of the suspensions in the

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upper part of modified Boyden chemotaxis chambers, said test substances remain with the cells.

As the chemotactic agent, a rat serum activated with the lipopolysaccharide of Escherichia coli (Difco) (1/10 dilution at pH = 7.1) is used. This serum is filled in the lower parts of said chambers. The cell-containing portion of the chamber is separated from the chemotactic solution by a cellulose filter membrane having pores of 8 microns. The chambers are set up in triplicate and incubated for 5 hours at 37 ° C. As control of cell migration, cell suspensions containing no test compound are used. After incubation, the filters are removed, fixed and stained with Weigert iron hematoxylin. Four fields of the bottom surface of the filter are examined microscopically at a magnification of 320X. The index of the chemotactic activity is the average of the number of neutrophils counted in those four fields. Indomethacin and levamisole are also used as reference compounds in this test procedure.

Thus, in the adjuvant arthritis test, e.g. the 1-methyl-.beta.-oxo-ocphenylcarbamoyl-2-pyrrolpropionitrile, a typical member of the compounds of the invention or said enol ethers or enol esters, salts or their related compounds of formulas I and II highly active in rats at peroral doses down to 2 mg / kg / day. The influence of these compounds on the in vitro chemotactic activity of BCG-immunized macrophages is at concentrations

-5 -f>

down to 10 and 10 moles significantly and it manifests itself in increasing the chemotactic response of the macrophages. In contrast, indomethacin does not affect macrophage chemotaxis, whereas levamisole, a well-known immunopotentiator, does not

-3 -5

increased migration at final concentrations of 10 moles to 10 moles causes.

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The above test methods indicate both the good effect of the compounds according to the invention and a different type of action mechanism, which distinguishes these compounds from other non-steroidal anti-inflammatory agents. The. after all, activity shown in the macrophage chemotaxis assay is similar to that of levamisole, which has been classified as a disease-affecting antirheumatic drug. The compounds of the present invention having both the indomethacin-type activity and the levamisole-type activity are valuable anti-inflammatory and anti-arthritic agents, e.g. for the treatment or control of inflammatory arthritic and / or dermatopathological conditions. The new compounds can also be used as intermediates for the preparation of other valuable, especially pharmacologically active preparations.

Preferred compounds are those of formula I wherein P1 is 1- (lower alkyl or Ph-lower alkyl) -2- or -3-pyrrolyl which is unsubstituted in the remaining positions or by one or two lower alkyl groups, or a carboxy or carbonylalkoxy group Ph is phenyl which is unsubstituted or substituted by one or two identical or different substituents of the group lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino and lower alkanoylamino, and R is hydrogen or lower alkyl; their enol-lower alkyl ethers or enol-lower alkanoyl esters, or theirs. Salts with bases, especially their therapeutically acceptable salts with bases.

Particularly noteworthy are compounds of general formula II

22 1 S 79 -ι -

- I- - CO- V * I R 1 -CH-CONH I CN

^R 5

wherein R _{1 is} lower alkyl, each of R and R is hydrogen or lower alkyl, and each of R and R is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or their salts with bases, especially their therapeutically useful ones Salts with bases.

Preference is further given to compounds of the formula II in which R _{1 is} alkyl having at most 4 carbon atoms, each of the symbols R "and R is hydrogen, and each of the symbols R 1 and R 3 is hydrogen, alkyl or alkoxy, each having at most 4 carbon atoms, Fluorine, chlorine or trifluoromethyl, or their salts with a base, in particular their therapeutically acceptable salts with bases.

Particularly preferred are compounds of general formula II, wherein R is methyl, each of the symbols R and R is hydrogen, and each of the symbols R and R is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl, or their sodium, potassium , Calcium, triethylammonium or trihydroxyethylammonium salts, one of the symbols R 1 and R 1 ', which is different from hydrogen, preferably being in the para position.

The compounds of the invention are prepared by methods known per se, e.g. prepared by a) compounds of the formulas

Pl-CO-CH - CN and OC = N-Ph

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and, ₉ if necessary, a compound obtained by reaction with a reactive ester of R-OH is IT-substituted or

b) compounds of the formulas P1-CO-CH-COX and R-NH-Ph,

CH

wherein X is lower alkoxy, lower alkanoyloxy or halogen, condensed or

c) Compounds of the formulas

Pl-Y and CH ₀ -COlT-Ph

CN R

wherein Y is lower alkoxycarbonyl, halocarbonyl or cyano, condensed and the resulting imines are hydrolyzed or

d) Compounds of the formula P1-C-C-CON-Ph

I II

V ^R

isomerized with a strong base and, if desired, converts a compound of formula I obtained to another compound of the invention, and / or, if desired, converts an obtained enol into an eggiol-lower alkyl ether or enol-lower alkanoyl ester, and / or if desired, converting an obtained enol to a salt with a base or an obtained enol salt into the free enol or to another salt with a base, and / or

17. 10. 1980 AP C 07 D / 221 679 10 57 607 18

desirably separates a resulting mixture of isomers into the individual isomers.

The addition of the isocyanate in process a) is preferably carried out according to the abovementioned Belgian patents or according to US Pat. No. 3,905,997 , ie in the absence or in the presence of an inorganic or organic base, Zc B. sodium hydride, or in the presence or in

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Absence of a polar solvent, e.g. an ether such as diethyl ether or tetrahydrofuran, and / or an amide or sulfoxide, e.g. Dimethylformamide or dimethyl sulphoxide, preferably when

elevated temperatures, e.g. at about 150 ° when no base is used. The reactive ester of the alcohol R-OH is derived from a strong inorganic acid, or an organic sulfonic acid, e.g. derived from a hydrohalic acid or p-toluenesulfonic acid.

The process according to the invention is preferably carried out as follows: the suspension of said nitrile in an aromatic hydrocarbon, e.g. in warm toluene is treated with a slight molar excess of an anhydrous tri-lower alkylamine, preferably triethylamine. Then, one molar equivalent of the phenyl isocyanate Ph-N = CO or its solution in a previously mentioned polar solvent, e.g. Dimethylsulfoxide, given. The reaction mixture is stirred for about 2-12 hours at room temperature and its volume is heated to not too high temperatures, e.g. to 100 °, reduced. The resulting precipitate is dissolved in an alkanol, e.g. Methanol and the solution washed with excess, dilute, aqueous acid, e.g. treated with 0.3 normal hydrochloric acid. The crude product obtained is separated, washed with water, dried, triturated and / or recrystallized from suitable solvents. Such solvents are lower alkanols, lower alkanones, di-lower alkyl ethers and / or lower alkyl lower alkanoates, z.3. Methanol, acetone, diethyl ether and / or ethyl acetate.

The amination according to process b) is also carried out in a customary manner, preferably between room temperature and about 150 °. It works either with equivalent amounts of the reactants, 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, such as a tri-lower alkylamine or pyridine. These are obtained by using halide or anhydride precursors for the neutralization of the acid formed,

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used. The lower alkanol resulting from the reaction of ester precursors is preferably used together with the solvent, e.g. ·

with an aromatic hydrocarbon, e.g. Benzene, toluene or xylene, distilled off.

The condensation in process c) is preferably carried out using alkali metals, their lower alkoxides or, in particular, hydrides, e.g. Natrihydrhydrid, in the said polar solvents, preferably dimethylformamide or dimethyl sulfoxide made. This condensation is analogous to the preparation of said nitrile starting materials for the processes a) and b), which condensation is illustrated in the corresponding examples.

Finally, isomerization in process d) in the presence of strong inorganic or organic bases, e.g. Alkali metal hydroxides or tri-lower alkyl aralkyl ammonium hydroxides, e.g. Trimethylbenzylammonium hydroxide.

The compounds of the formula I obtained can be converted into one another in a manner known per se. Thus, e.g. Snols obtained, preferably with diazoalkanes, etherified, or e.g. with Niederalkansäureanhydriden, esterified. Therapeutically acceptable salts of said enols may be e.g. with aqueous alkali metal hydroxides, preferably in the presence of an ether or alcohol as a solvent, e.g., a lower alkanol. From the alcoholic solutions, the salts with the mentioned ethers, e.g. Diethyl ether or tetrahydrofuran precipitated. One works at moderate temperatures, e.g. below 100 °. Salts obtained can, as mentioned above, be converted into the free compounds by treatment with acids. Also, a nitro group in the radical Ph may be e.g. with catalytically activated hydrogen, such as. Hydrogen in the presence of nickel or palladium catalysts are converted into the amino group. The latter can either like

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as described above or with lower alkanoyl halides or lower alkyl esters.

The starting materials are known or, if new, they can be prepared according to the procedures described for analogous compounds, e.g. those which are described in the prior art for the compounds mentioned there, or are prepared as illustrated in the examples.

Starting materials and final products which are mixtures of isomers can be prepared by methods known per se, e.g. by fractional distillation, crystallization and / or chromatography, are separated into the individual isomers.

The abovementioned reactions are carried out by methods known per se, in the presence or absence of diluents, preferably in those which are inert towards and dissolve the reagents, catalysts, condensing agents or neutralizing agents, and / or in an inert atmosphere, with cooling Room temperature or at elevated temperatures, at normal or ^; increased pressure.

The invention also relates to modifications of the present process, according to which an intermediate product obtainable at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or after which a starting material is formed under the reaction conditions, or in which Starting material in the form of a salt or a reactive derivative, preferably an alkali metal or trialkylammonium salt is used. The said isocyanates can also be prepared starting from corresponding acid azides, and mixed anhydrides from corresponding acids and simple alkanoic anhydrides.

22 16 79

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described above as being particularly valuable, in particular those of the formula II.

The pharmacologically useful compounds of the present invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with excipients suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and V or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or the sodium salt thereof, enzymes of the binders and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions, and suppositories or topical lotions primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical compositions which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. by means of conventional mixing, granulating or coating methods, and containing from about 1% to about 75%, in particular from about 1% to about 50%, of the active substance.

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Execute ungsbei s piel

The invention will be explained in more detail below on some embodiments.

The following examples serve to illustrate the invention, and they should not be construed as limiting it.

Temperatures are given in degrees Centigrade and the parts information refers to parts by weight. Unless otherwise defined, evaporation of solvents is carried out under atmospheric pressure.

16 79 -S-

Example I: A suspension of 12.9 g of 1-methyl-.beta.-oxo-2-pyrrolpropionitrile in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine is mixed with 10.7 g of phenyl isocyanate with stirring. After dissolution of solids, the dark red solution is kept at room temperature for 30 minutes, on the steam bath for 5 minutes and at room temperature overnight. The mixture is evaporated on the steam bath, the residue taken up in methanol and the solution poured into the mixture of 25 ml of 5 N hydrochloric acid and 600 ml of water. The resulting light brown crystals are separated, washed with water, triturated with ethanol and recrystallized from about 2200 ml of methanol. This gives l-methyl-.beta.-oxo-a-phenylcarbamoyl-2-pyrrole-propionitrile of the formula

• - CO - CH - CONH e I I CN CH ..

which melts at 174-175 °.

The starting material is prepared as follows: A solution of 28 g of 1-methylpyrrole-2-carboxylic acid in 20 ml of dimethylformamide is made into 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 is added with stirring and cooling. The reaction mixture is then mixed with 30 ml of methyl iodide and stirred at room temperature. After the initial exothermic reaction subsides, another 10 ml of methyl iodide are added. The reaction mixture is allowed to stand overnight, treated with water and extracted with diethyl ether. The extract is washed with aqueous sodium carbonate solution and water, dried and evaporated. The oily methyl 1-methylpyrrole-2-carboxylate is obtained.

22 18 79 _g_

A solution of 28 g of the latter 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. After the exothermic reaction has subsided, the mixture is heated on the steam bath for 15 minutes with another vigorous bubbling reaction. The viscous, red-brown suspension is diluted with an additional 50 ml of dimethylformamide and allowed to stand overnight at room temperature. The mixture is then reheated on the 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 resulting crystals are separated, washed with water, dried, triturated with cold ethanol and recrystallized from ethanol. This gives the 1-methyl-β-oxo-2-pyrrolpropionitrile, which melts at 107-109 °.

Example 2: By treating equivalent amounts of concentrated aqueous solutions of sodium hydroxide, potassium hydroxide or calcium hydroxide with 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrole-propionitrile, filtering the mixture and evaporating the filtrate to dryness, one obtains the three corresponding metal salts. These do not appear to have well-defined crystalline properties or melting points, although they are made from ethanolic solution by the addition of. Diethyl ether can be precipitated again. The salts are water-soluble and show the following bands in the infrared spectrum:

Nar 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, ·

In each case, the acidic salt solution is acidified with hydrochloric acid to recover the identical free compound (F.174-175 °).

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Example 3 A suspension of 21.4 g of 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile in 100 ml of absolute ethanol is charged with 11.68 ml. Trisäthanolamin added in 25 ml of ethanol and heated until the completion of the dissolution. The solution is filtered hot, allowed to cool with stirring to room temperature, the resulting suspension is cooled to 10 °, filtered and the residue washed with 25 ml of cold ethanol. The corresponding trishydroxyethyl ammonium salt is obtained, which melts at 115-117 °.

EXAMPLE 4 3.8 g of 1-methyl-.beta.-oxo-.alpha.-phenylcarbamoyl-2-pyrrolpropionitrile are added to 500 ml of ethereal diazomethane which consists of 10.3 g of N-nitroso-N-methylurea with 35 ml of 45% aqueous Prepared potassium hydroxide solution and dried over such tablets. After the decay of nitrogen evolution, the solution is filtered and evaporated. The residue is triturated with diethyl ether and recrystallized from ethyl acetate. The corresponding methyl enolate, namely the 1-methyl-.beta.-methoxy-aphenylcarbamoyl-2-pyrrolacrylonitrile, which melts at 121-122 °.

Example 5: A suspension of 4 g of 1-methyl-.beta.-oxo-2-pyrrolpropionitrile 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 the steam bath until the solid material dissolves and the red-brown solution allowed to stand overnight at room temperature. The reaction mixture is on the. Steam evaporated, the residue taken up in methanol and the solution poured into a mixture of 8 ml of 5N hydrochloric acid and 300 ml of water. The precipitated crystals are separated, washed with water, dried, triturated with methanol and recrystallized from ethyl acetate. The resulting 1-methyl-β-oxo-α- (p-fluorophenylcarbamoyl) -2-pyrrolpropionitrile, which melts at 198-199 °.

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Example 6: A mixture of 1.1 g of 1-methyl-β-oxo-α-ethoxycarbonyl-Z-pyrrolpropionitrile, 1.1 g of aniline and 60 ml of xylene is boiled under reflux for 4.5 hours. The reaction mixture is allowed to cool overnight and stand at room temperature.- Then the solution is filtered, evaporated and the residue recrystallized from methanol. The resulting 1-methyl-.beta.-oxo-a-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 173-174 °. The product is identical to that of Example 1.

The starting material is prepared as follows: 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 gradually added with stirring to 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 washed with diethyl ether. The filtrate is evaporated to a smaller volume, filtered again and finally evaporated under reduced pressure. The corresponding acid chloride is obtained.

Its solution in 20 ml of ethylene glycol dimethyl ether is added slowly to a suspension of 7.2 g of 50% sodium hydride in mineral oil (washed with petroleum ether) in 50 ml of dimethylformamide and 20 g of ethyl cyanoacetate with stirring and cooling. The moderately exothermic reaction is accelerated by briefly heating the mixture on the steam bath. The reaction mixture is allowed to stand overnight, treated with water, acidified with 5N hydrochloric acid and extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue triturated and recrystallized from diethyl ether. This gives the 1-methyl-β-oxo-ethoxycarbonyl-2-pyrrolpropionitrile, which melts at 74-77 °.

The same product is obtained by acylation with the mixed anhydride, i. by using the equivalent amount of ethyl chloroformate instead of thionyl chloride in the above reaction step.

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Example 7: A mixture of 5.7 g of 1-methyl-β-oxo-α-ethoxycarbonyl-2-pyrrolpropionitrile, 3.6 g of p-aminophenol and 300 ml of xylene is boiled under reflux for 2 hours and filtered while hot. The filtrate is cooled, the crystals obtained are separated and recrystallized from methanol. The resulting 1-methyl-β-oxo-α- (p-hydroxyphenylcarbamoyl) -2-pyrrolpropionitrile, which melts at 182-184 °.

Example 8: 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 first stirred with 2.9 g of 1-benzyl-β-oxo-2-pyrrolpropionitrile in The reaction mixture is allowed to stand overnight at room temperature, evaporated, the residue taken up in water, the solution filtered and washed with 5 N hydrochloric acid acidified. The resulting yellow precipitate is separated, washed with water, triturated with methanol and recrystallized from ethyl acetate. The resulting 1-benzyl-β-oxo-α- (p-chlorophenylcarbamoyl) -2-pyrrolpropionitrile, which melts at 214-215 °.

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 which consists of 3.4 g of 50% sodium hydride in mineral oil, washed with petroleum ether and suspended in 20 ml Dimethylformamide is produced. The mixture is then treated with 8.5 ml of benzyl chloride and stirred overnight at room temperature. The reaction mixture is treated with water, extracted with diethyl ether, the extract washed with aqueous sodium hydroxide solution and water, dried and evaporated. The 1-benzylpyrrol-2-carboxylic acid methyl ester is obtained as an OeI. (A purified sample of it melts at 31-32 °).

2 2 16 7 9 - »-.

A solution of 9.3 g of the latter compound in 15 ml of acetonitrile and 25 ml of dimethylformamide is added to a suspension under ^: stirring, which is prepared from 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 on the steam bath for 30 minutes, forming a dark red solution. This is allowed to stand overnight at room temperature, treated with water, filtered, washed with diethyl ether and acidified with 5N hydrochloric acid. The resulting crystals are separated, washed with water, dried, triturated with diethyl ether and recrystallized from methanol. This gives the l-benzyl-β-oxo-2-pyrrolpropionitrile, which melts at 119-120 °.

Example 9: A solution of 4 g of phenylcarbamoyl-acetonitrile in 50 ml of dimethylformamide is added with stirring 28 g of potassium tert-butoxide in a nitrogen atmosphere. After 2 hours, the resulting suspension is cooled to 5 ° and 4 g of 1-methylpyrrole-2-carboxylic acid chloride (USP 3,551,571) are added over 10 minutes. The reaction mixture is stirred at room temperature for 18 hours, poured into 300 ml of ice-water and the precipitate obtained is filtered off. This is washed with water, dried and recrystallized from ethanol. The resulting 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 172-174 °. The product is identical to that of Example 1.

The starting material is prepared as follows: a mixture of 42.53 g of cyanoacetic acid, 46.56 g of aniline and. 500 ml of acetonitrile is added with stirring in a nitrogen atmosphere with a solution of 113.7 g of NjN-dicyclohexyl-carbodiimide in 500 ml of acetonitrile within 30 minutes. After 3 hours, the resulting suspension is filtered, the Pöickstand washed with 200 ml of acetonitrile and the filtrates are evaporated. The residue is washed with 500 ml of diethyl

22 1 6 79

Ether and 50 ml of ethyl acetate triturated, filtered and dried. The phenylcarbamoyl-acetonitrile is obtained, which melts at 200-202 °.

EXAMPLE 10 A suspension of 1.135 g of 1-methyl-.beta.-oxo-2-pyrrolpropionitrile in 17,000 ml of dry toluene is first mixed with 913 g of anhydrous triethylamine and then 913 g of phenyl isocyanate with stirring in a nitrogen atmosphere. The resulting dark brown solution is stirred overnight at room temperature and then evaporated at 60-70 ° / 10 mmHg. The residue is taken up in 1400 ml of methanol and the solution is treated with 1400 ml of 6N hydrochloric acid in 4200 ml of water. The suspension is cooled to 15-20 ° for 20 minutes, filtered and the residue washed twice with 1800 ml of water, twice with 1000 ml of isopropanol and 13 times with 1000 ml of diethyl ether. The crude residue is dried at 60 ° and 5 mmHg to constant weight. Dissolve 1960 g of this residue in 44 400 ml of methylene chloride at room temperature. The solution is treated with 400 g of activated charcoal, filtered and the filtrate is evaporated. The residue is triturated with 12000 ml of anhydrous ethanol, the suspension is filtered at 20 °, washed four times with 1000 ml of anhydrous ethanol and dried at 60 ° and 5 mmHg. This gives the l-methyl-.beta.-oxo-a-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 172-174 ° .. The product is identical to those of Examples 1, 6 or 9.

1801 g of the latter compound are suspended in 10500 ml of anhydrous ethanol and 1108 g of triethanolamine are added thereto. The mixture is stirred until the solid material dissolves and heated and then slowly cooled to 20 °. The resulting precipitate is filtered off, washed twice with 1000 ml of cold anhydrous ethanol and dried at 45 ° and 0.1 mmHg. The corresponding tris-hydroxyethylanmonium salt is obtained, which at 115-117 °

- 35 -

melts. The salt is identical to that of Example 3.

The starting material is prepared as follows: A solution of 1325 g of 1-methylpyrrole-2-carboxylic acid in 2400 ml of dimethylformamide is added with stirring in a nitrogen atmosphere and cooling with ice to a suspension consisting of 568.5 g of 50% sodium hydride in Mineral oil and 2400 ml of dimethylformamide is produced. The reaction mixture is then first treated with 1000 ml of dimethylformamide and then with 4316 g of methyl iodide while stirring and at a temperature below 88 °. Stirring is continued overnight at room temperature, then the mixture is cooled to 10 ° and treated with 10600 ml of water. The mixture is extracted three times with 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. The oily methyl 1-methylpyrrole-2-carboxylate is obtained.

A solution of 1604 g of the latter compound in 2650 ml of acetonitrile is added rapidly 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 for 2 hours to 81 ° and then cooled to 10 °, finally treated with 25400 ml of water within 15 minutes.The mixture is washed three times with 9000 ml of diethyl ether, stirred for 45 minutes at 10 mmHg to remove the diethyl ether and with The resulting crystals are separated, washed four times with 2400 ml of water and once with 2400 ml of isopropanol and dried at 60 ° and 5 mmHg to give the l-methyl-β-oxo-2-pyrrolpropionitrile, which melts at 106-108 °.

Example 11: A filtered solution of 4.4 g of 2,6-dichlorophenyl isocyanate in 30 ml of toluene is mixed with 2.5 g of 1-methyl-.beta.-oxo-2-pyrrolpropionitrile and 2.1 g of triethylamine with stirring. The mixture is

221679 _ «

jots'

allowed to stand overnight at room temperature and then filtered. The solid material is washed with toluene and diethyl ether, taken up in 50 ml of methanol and the solution poured into a mixture of 6 ml of 5N hydrochloric acid and 300 ml of water. The resulting crystals are separated, washed with water, dried, triturated with ethanol and recrystallized from methanol. This gives the 1-methyl-.beta.-oxo-a-CZjö-dichlorophenylcarbamoyD ^ -pyrrolpropionitrile, which melts at 196-199 °.

Example 12: '^; A suspension of 2 g of 1-methyl-.beta.-oxo-2-pyrrolpropio nitrile in 50 ml of toluene and 1.6 g of triethylamine is treated with 2.1 g of p-methoxyphenyl isocyanate. The mixture is gently warmed to dissolution of "the solid material and allowed to stand at room temperature overnight." It is then evaporated, the residue taken up in methanol and 10 ml of 10% aqueous sodium hydroxide solution and 250 ml of water added The precipitate is washed with water, dried, triturated with a warm mixture of methanol-ethyl acetate and recrystallized from ethyl acetate to give 1-methyl-.beta.-oxo-α- (m.p. p-methoxyphenylcarbamoyl) -2-pyrrolpropionitrile, which melts at 192-193 °.

In an analogous manner, the 1-methyl-.beta.-oxo-a- (p-methylthio-phenylcarbamoyl) -2-pyrrolpropionitrile is also prepared. F.167-168 °.

Example 13: A solution of 4.9 g of 1-methyl-.beta.-oxo-2-pyrrolpropionitrile in 50 ml of toluene, 5 ml of dimethyl sulfoxide and 4 g of triethylamine is treated with a solution of 5.7 g of p-nitrophenyl isocyanate in a minimal amount of toluene treated under Pvühren. The reaction mixture is allowed to stand overnight, evaporated and the residue

22 1 8 78

- 33 -

taken up in methanol. The solution is filtered, diluted with water and 6 ml of triethylamine, washed with ethyl acetate, and the washing liquid extracted once with 5% aqueous sodium hydroxide solution. The combined aqueous solutions are acidified with 5N hydrochloric acid and the resulting precipitate separated. This is washed with water, triturated with a mixture of methanol-ethanol and recrystallized from dimethylformamide. The resulting 1-methyl-β-oxo-α- (p-nitro-phenylcarbamoyl) -2-pyrrolpropionitrile, which melts at 245-250 ° with decomposition.

A solution of 2 g of the latter compound. 220 ml of ethanol and 2 ml of triethylamine is hydrogenated over 0.5 g of 10% palladium carbon at 3.5 atmospheres and room temperature for 50 minutes. The filtered solution is evaporated, the residue taken up in water, treated with 1 ml of triethylamine and the solution with Essigsäureäthy! Ester, and washed diethyl ether. It is acidified with 5 N hydrochloric acid, the precipitate separated, washed with water, dried and recrystallized from aqueous methanol. The resulting 1-methyl-.beta.-oxo-α- (p-amino-phenylcarbamoyl) -2-pyrrolpropionitrile, which melts with decomposition at 193-195 °.

Dissolve 0.5 g of the latter compound in 10 ml of acetic anhydride id, the solution is refluxed for 10 minutes and evaporated. The residue is triturated with diethyl ether and recrystallized from methanol-ethyl acetate to give the 1-methyl-.beta.-acetoxy-a- (p-acetylamino-phenylcarbamoyl) -2-pyrrolacrylonitrile, which melts at 178-179 °.

Example 14: A mixture of 2.1 g of 1-ethyl-.beta.-oxo-2-pyrrolpropionitrile, 25 ml of toluene and 1.6 g of triethylamine is treated while stirring with 1.6 g of phenyl isocyanate. The mixture is added overnight

22 1 6 79 - »_

Room temperature allowed to stand, then evaporated and dissolved in methanol; The solution is poured into 300 ml of water containing 5 ml of 5N hydrochloric acid, the precipitate separated and dissolved in 5% aqueous sodium hydroxide solution. The solution is filtered, the filtrate acidified again, the solid material separated, washed with water, dried and recrystallized from ethanol. The resulting 1-ethyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 144-145 °.

The starting material is prepared as follows: A suspension prepared from 9.1 g of 50% sodium hydride in mineral oil, by washing with petroleum ether and suspending in 50 ml of dimethylformamide, is gradually treated with 20 g of pyrrole-2-carboxylic acid methyl ester in 50 ml of dimethylformamide , mixed with ice while stirring and cooling. After dissolution, one gives. Add 25 ml of ethyl bromide and gently warm the reaction mixture to initiate the exothermic reaction. When it calms down, add another 5 ml of ethyl bromide and let it stand overnight. It is treated with water and extracted with diethyl ether. The extract is washed with water, dried, filtered and evaporated. The oily ethyl 1-ethylpyrrole-2-carboxylate is obtained.

A solution of 10 g of the latter 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 stirred for 15 minutes on the steam bath heated. It is allowed to stand overnight, added to water, filtered and acidified with 5 normal hydrochloric acid .. The precipitate is separated, washed with water and recrystallized from ethanol. This gives the 1-Aethylß-oxo-2-pyrrolpropionitrile, which melts at 77-79 °.

22 16 79

- 25-

Example 15: A solution of 2.5 g of 1-isobutyl-.beta.-oxo-2-pyrrolpropionitrile in 30 ml of toluene and 1.6 g of triethylamine is mixed with 1.6 g of phenyl isocyanate with stirring. The mixture is allowed to stand overnight, filtered and the residue dissolved in 5% aqueous sodium hydroxide solution. The solution is filtered, acidified with 5 N hydrochloric acid and extracted with a mixture of diethyl ether-ethyl acetate. The organic solution is washed with water, dried and evaporated. The residue is triturated with ethanol and recrystallized from methanol. This gives l-isobutyl-.beta.-oxo-a-phenylcarbainoyl-2-pyrroipropionitrile, which melts at 134-136 °.

The starting material is prepared as follows: 13 g of 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. The mixture is then mixed with 40 g of isobutyl bromide and heated with stirring for 10 minutes on the steam bath. The reaction mixture is allowed to stand overnight, then treated with water and extracted with diethyl ether. The extract is washed with water, dried and evaporated. The oily 1-isobutylpyrrol-2-carboxylic acid ethyl ester is obtained.

A solution of 10 g of the latter compound 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 ether and suspending in 25 ml of dimethylformamide. After the effervescent reaction has subsided, the mixture is heated on the steam bath for 30 minutes. During this time, the sodium hydride is used up. The mixture is allowed to stand overnight at room temperature, it is mixed with water and acidified with 5N hydrochloric acid. The mixture is extracted with diethyl ether, the extract washed with water, dried and evaporated. You get

16 79

the oily isobutyl-β-oxo-2-pyrrolpropionitrile.

Example 16 :. A solution of 1.6 g! ^, S-trimethyl - ^ - athoxycarbonyl-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.8 g of anhydrous triethylamine is added with stirring 0.8 g of phenyl isocyanate. The mixture is heated on the steam bath for 10 minutes and allowed to stand at room temperature overnight. It is then evaporated, the residue taken up in methanol and the solution treated with 2 ml of 5N hydrochloric acid and 200 ml of water. The resulting crystals are separated, washed with water, triturated with a mixture of methanol-ethanol and recrystallized from methanol. The. ^, S-trimethyl ^ -ethoxycarbonyl-.beta.-oxo-a-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 164-166 °.

In an analogous manner, the l, 3,5-trimethyl-4-ethoxycarbonyl-β-oxo-α- (p-fluorophenylcarbamoyl) -2-pyrrolpropionitrile, mp 178-179 ° and l, 3,5-trimethyl- 4-ethoxycarbonyl-β-oxo-α- (p-chlorophenylcarbamoyl) -2-pyrrolopropionitrile, m.p. 238-241 ° (with decomposition).

The starting material is prepared as follows: A suspension of 3.6 g of 50% sodium hydride in mineral oil (washed with petroleum ether) and 50 ml of dimethylformamide is added under stirring with 16 g of diethyl 3,5-dimethylpyrrole-2,4-dicarboxylate 25 ml of dimethylformamide added in portions. The mixture is mixed after the consumption of sodium hydride with 40 ml of methyl iodide and allowed to stand overnight at room temperature. The mixture is then treated with water, the resulting solid material separated, and air dried to remove the excess methyl iodide. The solid material is washed with water, dried and recrystallized from ethanol. The l, 3,5-trimethylpyrrole-2,4-dicarboxylic acid diethyl ester is obtained.

22 16 79 _ *> _

A solution of 13.9 g of the latter 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 suspended in 60 ml of dimethylformamide is. The mixture is heated on the steam bath for 15 minutes and the resulting solution allowed to stand overnight. The mixture is then treated with water, the aqueous solution filtered and acidified with 5N hydrochloric acid. The precipitate is separated, washed with water, trituated with ethanol and recrystallized from ethanol. This gives the l, 3,5-trimethyl-4-ethoxycarbonyl-β-oxo-2-pyrrolpropionitrile, which melts at 105-107 °.

Example 17: A solution of 0.3 g of 5- (1-methyl-2-pyrrolyl) -4-phenylcarbamoylisoxazole in 10 ml of 5% aqueous sodium hydroxide solution and a minimum amount of ethanol is heated on the steam bath for 5 minutes. The solution is then filtered and acidified with 5N hydrochloric acid. The resulting crystals are separated, washed with water and triturated with methanol. This gives 1-methyl-.beta.-oxo-a-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 170-172 °. The product is identical to that of Examples 1, 6, 9 or 10.

The starting material is prepared as follows: A solution of 17 g of 1-methylpyrrole in 400 ml of 1,2-dichloroethane is added first, while stirring and cooling to 10-15 ° with 28 g of anhydrous aluminum chloride in portions. Then add 27 g of malonic acid ethyl ester chloride in 50 ml of dichloroethane in such portions that the temperature remains between 10 and 15 °. The mixture is stirred for 3.5 hours and then allowed to rise slowly its temperature to 32 °. The reaction mixture is allowed to stand at room temperature overnight, treated with water and shaken out. The organic layer is separated, washed twice with water,

7

- 28 -

dried and evaporated. The dark brown OeI obtained as residue is distilled and the fraction boiling at 105-112 ° and 0.25 mmHg collected. This gives the l-methyl-ß-oxo-2-pyrrolpropionsäureäthylester.

A mixture of 3.6 g of the latter compound and 3.9 g of N, N'-diphenylformamidine is heated at 145-165 ° for 2.5 hours. The resulting brittle, glassy mass is pulverized, triturated with diethyl ether and recrystallized from ethanol-ethyl acetate. The 1-methyl-β-oxo-α-anilinomethylene-2-pyrrolpropionsäureanilid, which melts at 178-180 °.

A mixture of 1.4 g of the latter compound, 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 allowed to stand overnight, filtered, evaporated and the residue treated with water. The orange obtained OeI becomes crystalline upon standing. The precipitate is separated, washed with water and recrystallized from ethanol. The 5- (1-methyl-2-pyrrolyl) -4-phenylcarbamoylisoxazole, which melts at 100-103 °, is obtained.

Example 18 A suspension of 1 g, 3,5-trimethyl-.beta.-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.7 g of anhydrous triethylamine is added with stirring 0.75 g of phenyl isocyanate. The mixture is warmed for 5 minutes on the steam bath and allowed to stand at room temperature overnight. It is filtered, the residue taken up in methanol and the solution acidified with 1 N hydrochloric acid. The resulting precipitate is separated, dissolved in 1N aqueous sodium hydroxide, reprecipitated with 5N hydrochloric acid and washed with water. This gives the l, 3,5-trimethyl-.beta.-oxo-a-phenylcarbamoyl-2-pyrrolpropionitrile, which melts at 172-174 °.

221673 -2

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

It is heated for 15 minutes under reflux at 235-240 ° 7.5 g of the latter compound and then cooled. The residue is taken up in petroleum ether, the solution filtered and evaporated to give the l, 3,5-trimethylpyrrole-2-carbonsäureäthylester, which melts at 38-40 °. (The product is described in U.S. Patent 2,479,972, having a boiling point of 102-108V3-4 mmHg).

A solution of 4 g of the latter 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) and suspended in 15 ml of dimethylformamide. The mixture is heated on the steam bath for 25 minutes and allowed to stand at room temperature for 3 hours. The mixture is treated with water, the aqueous solution extracted with diethyl ether and acidified with 5N hydrochloric acid. The crystals are separated, washed with water, dried and recrystallized from ethanol with addition of activated carbon. This gives the 1,3,5-trimethyl-β-oxo-2-pyrrolpropionitrile, which melts at 106-107 °:

221679

In an analogous manner, the l, 3, .5-trimethyl-ß-oxo-a- (pfluorphenylcarbamoyD-2-pyrrolpropionitrile obtained which melts after recrystallization from methanol-ethanol (1: 1) at 184-186 °.

Example 19: A suspension of 1 g, 2,5-trimethyl-β-oxo-3-pyrrolpropionitrile in 40 ml of toluene and 0.7 g of triethylamine is treated with 0.75 g of phenyl isocyanate and 5 minutes on the steam bath until dissolved heated the solid material. The mixture is allowed to stand overnight, the resulting precipitate separated, taken up in methanol and the solution added to a mixture of 3 ml of 5N hydrochloric acid and 250 ml of water. The crude product is separated, washed with water, dissolved in 5% aqueous sodium hydroxide solution, filtered and the alkaline filtrate acidified with 5N hydrochloric acid. The precipitate is separated off, washed with water, dried in air and recrystallized from ethanol. The 1,2,5-trimethyl-β-oxo-α-phenylcarbamoyl-3-pyrrolpropionitrile, which melts at 158-160 °.

In an analogous manner, the crude 1,2,5-trimethyl-ß-oxo-or- (p-fluorophenylcarbamoyl) -3-pyrrolpropionitrile is obtained. It is dissolved in aqueous sodium bicarbonate solution, precipitated with 5 N hydrochloric acid and recrystallized from ethanol. F.171-172 °.

The starting material is prepared as follows: A solution of '7.6 g of ljZjS-trimethylpyrrole-S-carboxylic acid ethyl ester [Ber. _56_, 2374 (1923), melting point after recrystallization from methanol 65-66 °] in 20 ml of acetonitrile is added to a suspension of 4 g of 50% sodium hydride in mineral oil and 11 ml of dimethylformamide. The mixture is heated with stirring for 20 minutes on the steam bath and allowed to cool the resulting suspension to room temperature over 90 minutes. The suspension is poured into 200 ml of ice-water,

2 2 16 79

sb

- yt -

the alkaline aqueous solution was filtered and the filtrate acidified with ice with 18% hydrochloric acid while cooling. The precipitate is separated, washed with water, and dried in air, triturated with diethyl ether and recrystallized from methanol. This gives the l, 2,5-trimethyl-ß-oxo-3-pyrrolpropionitrile, which melts at 140-141 °.

EXAMPLE 20 Starting from equivalent amounts of corresponding starting materials, the following compounds of the formula II in which R "= R_ = H are also prepared according to the processes of the preceding examples, in particular according to Examples 1, 4, 8 and 10:

No. ^R i ^R 4 ^R 5 Recrystallized from F. ⁰ C 1 CH ₃ 2-CH ₃ 6-CH ₃ ethanol 170-171 .2 CH ₃ 3-F H ethyl acetate 191-192 3 CH ₃ 3-Cl H ethyl acetate 192-193 4 ^CH 3 4-Cl H ethyl acetate 205-207 5 CH ₃ 3-CF ₃ H methanol 185-186 6 CH ₃ 2-F 4-F methanol 136-138 7 CH ₃ 4-F 3-Cl ethyl acetate 215-216 8th CH ₃ 2-Cl 4-Cl ethyl acetate 160-162 9 CH ₃ 3-Cl 4-Cl dimethylformamide 217-219 10 benzyl H H ethyl acetate 188-189 11 benzyl 4-F H ethyl acetate 203-204 12 C ₂ H ₅ 4-F H methanol 156-157 13 C ₂ H ₅ 4-Cl H ethanol 160-161 14 i-Butyl 4-F H methanol 162-163

221S7

Example 21 Preparation of 10,000 Tablets Containing 100 mg of the Active Substance

ingredients:

Tris-hydroxyethyl-ammonium-1-methyl-β-oxo

a-phenylcarbamoyl-2-pyrrolopropionitrile 1000 g

Lactose 2535 g

Cornstarch 125 g

Polyethylene glycol 6000 150g

Talcum powder 150 g

Magnesium Stearate 40g

Purified water q.s.

Method:

All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is mixed with lactose, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to the boiling solution of polyethylene glycol in 260 ml of water. The resulting paste is added to the powders and optionally granulated with the addition of another amount of water. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed into tablets of 10.3 mm diameter having a score line.

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

22 16 79 -S-

Example 22: Preparation of 1000 capsules containing 25 mg each of the active substance:

Method:

l-methyl-.beta.-oxo-a- (p-fluorophenylcarbamoyl) -2-

pyrrolpropionitrile. 25 g

Milk sugar 207 g

Corn starch 80 g

Magnesium stearate 3 g

Method:

All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is first homogenized with magnesium stearate and subsequently with lactose and starch in a suitable mixer. Capsules no. 2 are filled with 315 mg each of the mixture with a filling machine.

In an analogous manner, capsules containing 25-100 mg of other named and illustrated compounds, in particular those of the formula II, or of their alkali metal, zinc, tri-lower alkylammonium or tris-hydroxyethyl ammonium salts are prepared.

Claims (16)

17. 10. 1980 AP C 07 D / 221 679 22 16 79 36 57 607 18 Invention claim 1 * Process for the preparation of novel substituted ß-OxooC-phenylcarbamoyl-pyrrolpropionitriles of the general formula I. CIi R I t Pl-CO-CH-CON-Ph (I), wherein Pl represents a 2- or 3-pyrylene-3-olyl radical which is substituted in the 1-position by lower alkyl or Ph-lower alkyl and unsubstituted in the remaining three positions or substituted by lower alkyl and / or a carboxy or carboxy-lower alkoxy group; is hydrogen or lower alkyl, and Ph is phenyl which is unsubstituted or substituted by one to three identical or different substituents of the group lower alkyl, lower alkoxy, alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino or lower alkanoylamino; their enol form, their enol-lower alkyl ethers or enol-lower alkanoyl esters or their salts with bases, characterized in that a) Compounds of the formulas Pl-CO-CH ₀ - CN and OC = N-Ph C. added, and if necessary, a compound obtained by reaction with a reactive ester of R-OH N-substituted or b) Compounds of the formulas Pl-CO-CH-COX and R-NH-Ph,
CN 17. 10. 1980 AP C 07 D / 221 679 22 1S7S 3? "57 607 18 - 55 - in which X mederalkoxy, mediatekanoyloxy or halogen be indicated, condensed or c) Compounds of the formulas Pl-Y and CH ₀ -CON-Ph CN R v / orin Y mederalkoxycarbonyl, halocarbonyl or cyano, condensed and the resulting imines hydrolyzed or ά) compounds of the formula
C = C - CON - Ph ill isomerized with a strong base and, if desired, converts a compound of formula I obtained to another compound of the invention and / or, if desired, converts an obtained snol to an enol-lower alkyl ether or enol-lower alkanoyl ester, and / or if desired, converting an obtained enol to a salt with a base or an obtained enol salt into the free enol or to another salt with a base and / or, if desired, separating a resulting mixture of isomers into the individual isomers. Process according to item 1, characterized in that the reaction a) is carried out in the presence of a base or at elevated temperature and the reactive ester of an alcohol R-OH is derived from a strong inorganic or organic sulphonic acid. 221S7S 17. 10. 1980 AP C 07 D / 221 679 SS 57 607 18 2 2 16 7 9 atoms, fluorine, chlorine or trifluoromethyl, or their salts with bases produces. 2 2 1 6 79 lower alkyl ether or enol-lower alkanoyl ester or their salts with bases, 3 · Method according to item 1, characterized in that the reaction b) is carried out at elevated temperature. 4. The method according to item 1, characterized in that one carries out the reaction c) in the presence of an alkali metal alkoxide or hydride. 5 · Method according to item 1, characterized in that one carries out the reaction d) in the presence of a strong inorganic or organic base. 6. The method according to item 1, characterized in that in a resulting compound which has a Hitrogruppe in the radical Ph as a substituent, this reduced to the amino group. 7- Method according to one of the items 1 to 6, characterized in that acylated in a resulting compound which has the amino group in the radical Ph as substituents, this acylated to a Mederalkanoylaminogruppe. 8. The method according to any one of the items 1 to 7, characterized in that one compounds of the formula I shown in point 1, wherein Pl 1- (lower alkyl or Ph-Mederalkyl) -2- or »3 ~ pyrrolyl means v / elches in the unsubstituted positions are unsubstituted or substituted by one or two lower alkyl groups, or a carboxy or carboxy-lower alkoxy group; Ph is phenyl which is unsubstituted or substituted by one or two identical or different substituents of the group lower alkyl, lower alkoxy, lower alkylthio, hydroxy Halogen, trifluoromethyl, nitro, amino and lower alkanoylamino, and R is hydrogen or lower alkyl; their enol 9 # Method according to item 1 for the preparation of novel substituted β-oxo-of-phenylcarbamoyl-pyrrolpropionitriles of the formula I shown in point 1, in which Pl represents a 2- or 3-pyrrolyl radical which is in the 1-position by lower alkyl or Ph-lower alkyl is substituted in the remaining three positions unsubstituJert or substituted by lower alkyl; R is hydrogen or alkylalkyl, j and Ph are phenyl which is unsubstituted or substituted by one to three identical or different substituents of the group lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, trifluoromethyl, nitro or amino; their enol-lower alkyl ethers or their salts with bases, characterized in that a) starting materials of the formulas given in point 1 and, if necessary, a compound obtained by reaction with a reactive ester of R-OH N-substituted or b) starting materials of the formulas given in point 1 are condensed or c) starting materials of the formulas given in point 1 are condensed and the resulting imines are hydrolyzed or d) isomerizing compounds of the formula given in item 1 with a strong base and, if desired, converting a compound of formula I obtained into another compound of the invention, and / or, if desired, converting an obtained enol into a lower-alkanol ether, and or, if desired, an enol obtained in a salt with a base or an obtained enol sal ζ in the free enol or in another salt 22 1 679 with a base, and / or, if desired, a resulting mixture of isomers separates into the individual isomers. Method according to item 9 », characterized in that the reactions a), b), c) and d) are carried out in accordance with items 2, 3, 4 and 5, respectively. 11. The method according to any one of items 9 and 10, characterized in that in a resulting compound which has a nitro group as substituents in the radical Ph, this reduced to the amino group. 12. The method according to any one of items 9 and 10, characterized in that compounds of the general formula II ^Κ 2 ϊ JTLjL- co-CH-σοΒΗ ϊ ^ J ^ (ΐΐ) wherein R _{1 is} lower alkyl, each of the symbols R _p and R _ is hydrogen or lower alkyl, and each of the symbols R and R represents hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or their salts with bases. 13. Method according to one of the items 9 and 10, characterized in that compounds of the formula II shown in point 12, wherein R 1 is alkyl having at most 4 carbon atoms, each of the symbols R _? and R-, is hydrogen, and each of the symbols R 1 and R 3 is hydrogen, alkyl or alkoxy, each having at most 4 carbon atoms. 17. 10. 1980 AP C 07 D / 221 679 itf 57 607 18 14. The method according to any one of items 9 and 10, characterized by reacting compounds of the formula II shown in point 12, wherein R _{1 is} methyl, each of the symbols R ₂ and Eo is hydrogen, and each of the symbols R. and Rt - means hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, or produces their salts with bases. Method according to one of the items 9 and 10, characterized in that 1-methyl-β-oxo-A-phenylcarbamoyl-2-pyrrolpropionitrile and its salts are prepared with bases. Method according to one of the items 9 and 10, characterized in that 1-methyl-β-oxo-Cp-fluorophenylcarbamoyl-2-pyrrolpropionitrile and its salts are prepared with bases.