IL30426A - 5-aroyl-pyrrole derivatives,their preparation and pharmaceutical preparations containing them - Google Patents

Description

-AROYL-PYRROLB DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM McNBIL LABORATORIES, INCORPORATED 30426/2 Ar represents a phenyl, monosubstituted phenyl or polysubstituted phenyl group, each substituent of said substituted phenyl group being a halogen atom, a lower alkyl, lower alkoxy, nitro, amino, cyano or methylthio group; r^ represents a phenyl, monosubstituted phenyl or pol substituted phenyl group, each substituent of said substituted phenyl group being a halogen atom, a lower alkyl or lower alkoxy group; R represents a hydrogen atom or a lower alkyl group; represents a hydrogen atom, a lower alkyl or benzyl group; R2 represents a CN, C00H, C00-(lower alkyl), COM^, CONH-(lower alkyl) or CON-(lower alkyl)2 group; and represents a COOH, G00-(lower alkyl), C0 2, 00NH-(lower alkyl) or CON-(lower alkyl)2 group; provided that: (i) when Ar is a nitro-substituted phenyl or amino-substituted phenyl group, then R is a hydrogen atom, is a lower alkyl group and 2 is a CN, COOH or C00-(lower alkyl) group; (ii) when Ar is a cyanophenyl or methylthiophenyl group then R.^ is a lower alkyl group and ≥ is a COOH or COO- ( lower alkyl) group; and (iii) when R^ is a hydrogen atom, then R is also a hydrogen atom.

The non-toxic, therapeutically acceptable salts of such acids, such as are obtained from appropriate organic or inorganic bases, are also embraced within the scope of this invention.

As used herein, "lower alkyl" and "lower alkoxy" may be straight or branched chain saturated hydrocarbons having from 1 to about 6 carbon atoms, such as, for example, 30426/2 methyls ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like alkyls, and respectively, the corresponding alkoxys such as methoxy, ethoxy, propoxy, isopropoxy, etc.

She compounds of the present invention may be obtained by means of several synthetic processes. For example, the compounds of formula (I-a), in which is CAT or C00-(lower alkyl), are generally prepared by a friedel-crafts reaction between a benzoyl halide, preferably the chloride (II), and a pyrrole-2-acetic acid derivative of formula (III), wherein R' i3 cyano or lower alkoxy-carbonyl, in the presence of a Lewis acid, preferably a metallic halide such as aluminum chloride. Suitable solvents are those typ ically employed in a Friedel-Crafts reaction, such as, for example methylene chloride, 1,2-dichloroethane, carbon disulfide, nitrobenzene and- the like. The acid derivative (tV) thus obtained can then be converted to the corresponding free carboxylic acid by conventional hydrolysis, for example, by heating a solution of (ΪΥ) in aqueous methanol with an alkali metal hydroxide to form the alkali metal salt of the acid and then acidifying the mixture. The foregoing reactions may be illustrated by the following schematic diagram.

Ar The benzoyl chlorides (II) are generally known and may be obtained by transformation of the corresponding benzoic acid to the acid chloride form according to conventional procedures, such as,. or example, the procedure hereinafter demonstrated in Example LXXXI.

Alternatively, to prepare the nitriles, esters and acids of formula (I~a), wherein R is lower alkyl, a 5-benzoyl-pyrrole^2-acetic acid derivative of the formula : 0 wherein R1 is as previously described, R" is lower alkyl or benzyl, and Ar1 is phenyl or phenyl substituted with halo, lower alkyl, lower alkoxy or cyano, which acid derivative (V) may be obtained in accordance with the aforementioned Friedel-Crafts procedure, is alkylated according to conventional alkylation techniques, e.g., with a lower alkyl halide as .the alkylating agent in the presence of a strong base such as sodium amide o sodium hydride, to yield the corresponding nitriles and esters: from which the corresponding acids are obtained by conventional hydrolysis.

The acetonitriles of formula (VI), in which R" is lower alkyl, are also obtained by conventional N-alkylation of an N-unsubstituted 5-benzoyl-pyrrole-2-acetonitrile of the formula followed by conventional C-alkylation of the thus-Obtained N-alkyl-5-benzoyl-pyrrole-2-acetonitrile using an appropriate lower alkyl halide as the alkylating agent in each step. After the N-alkylation step or the C-alkylation step, . corresponding acids may be obtained by conventional hydrolysis.

The nitriles, esters and acids of formula (I-a), wherein Ar is amino-substituted phenyl, are preferably prepared from the corresponding 5-nitrobenzoyl-l- (lower alkyl)-pyrrole- 2-acetic acid esters or nitriles according to the following · reaction scheme in which the corresponding para-derivatives are exemplified (R1 being as previously described): ■ In- the foregoing reaction sequence, the hitro . function of the 5-nitrobenzoyl-l- (lower alkyl)-pyrrole-2-acetic acid ester or nitrile (obtained by the Friedel-^Crafts type of reaction previously described) is catalytically hydrogenated, for example, with hydrogen and palladium-on-carbon catalyst, to yield the corresponding 5-aminobenzoyl-l- (lower alkyl)-pyrrole-2-acetic acid ester or nitrile which is then hydrolyzed to the corres« ponding free acid form.

. Esterification of the acids of formula (I-a)_ with a slight excess of an appropriate lower alkanol yields the corresponding esters, i.e., wherein R^ equals C00-(lower alkyl). Preferably the methyl esters of formula (l-a) are obtained by the Friedel-Crafts reaction previously described between an appro- The primary amides of formula (I-a) are readily obtained by partial hydrolysis of the corresponding nitriles of formula (I-a). The nitrile-to-arnide transformation is accomplished according to conventional procedures, for example, by treatment of the nitrile with aqueous sodium hydroxide under reflux for a relatively short time, that is, a period sufficient for partial hydrolysis to the amide stage as opposed to complete hydrolysis to the carbox'ylic acid stage. The corresponding lower alkyl-substituted amides are preferably obtained by first transforming the carboxylic function of the formula (I-a). acids into the corresponding acid chloride form, for example, by treatment of the acid or its alkali metal salt with thionyl chloride or oxalyl chloride, and then reacting the thus-obtained acid chloride with an appropriate lower alkyl-amine or di-(low'er alkyl) amine to yield the corresponding N-alkyl or , -dialkyl amides, . respectively, of formula (I-a).

The compounds of formula (I-b), wherein is C00- (lower alkyl), preferably ethoxycarbonyl, and Ar is other than aminophenyl are prepared by a.Friedel-Crafts reaction between an appropriate benzoyl halide, preferably the chloride (VIII), and a lower alkyl 1- (lower alkyl)-pyrrole-2-propionate (IX). Conventional hydrolysis of the thus-obtained lower alkyl 5-benzoyl-l- . (lower alkyl )-pyrrole-2-propionate (X) yields the corresponding free acids of formula (I-b). In turn, the acids may be converted to the corresponding amides of formula (I-b) according to conventional procedures using ammonia, or an appropriate alkyl or dialky amine. 0 II Ar-C-Cl O N -- CH2CH2-C00alkyl AlCl (viii) a{kyl (IX) The formula (i-b) compounds, wherein Ar is aminophenyl, are preferably obtained from the corresponding lower alkyl 5~ nitrobenzoyl-1- (lower alkyl)-pyrrole~2-propionate (obtained by the usual Friedel-Cirafts type of- reaction between nitrobenzoyl chloride and alkyl propionate ΪΧ) by transforming the nitro function to an amino function according to the reaction scheme previously described for the formula (l~a) compounds, i.e., by means of catalytic hydrogenation followed, by hydrolysis.

The alkyl propionates (IX) may be prepared by first treating an. appropriate N-alkylpyrrole-2-carboxaldehyde with an appropriate alkoxyca bonyl-methylene triphenylphosphorane [see R. Jones et al., Canad. Jour. Chem., 18, 883 (1965)] and then hydrogenating the thus-obtained alkyl 2-(l-alkyl-2-pyrrolyl) aerylate, thereby saturating the double bond of the aerylate function, to yield the desired alkyl propionate (IX).

The compounds of formula (I-c) are prepared from an appropriate l-aryl-l,2,3-"butanetrione-2-oxime (XI) and an appropriate dialkyl acetonedicarboxylate (XII) as starting materials. The two are contacted together according, to a Knorr pyrrole synthesis -in glacial acetic acid in the presence of zinc dust to yield thr ring-closed pyrrole, alkyl 5-aroyl-3-alkoxycarbonyl- 4-methylpyrrole-2-acetate (XIII). Hydrolysis of the latter with moderately concentrated alkali, for example 25-50 aqueous sodium hydroxide gives the corresponding free di-acid (XIV) which is then partially reesterified using an acidic solution of a lower alkanol to yield the corresponding alkyl 5-aroyl-3-carboxy- -methylpyrrole-2-acetate (XV). Decarboxylation of the carboxy group in the 3-position is then accomplished ,by heating the latter in a suitable basic organic solvent such as quinoline. The resulting alkyl 5-aroyl- -me hylpyrrole-2-acetate (XVI) is then hydrolyzed in the usual manner to give the desired free, acids (XVII) of formula (I-c). In turn, the acids may be esterified using lower alkanols to the corresponding lower alkyl esters of formula (I-c) or. converted to the corresponding amides of formula (I-c) according to conventional procedures using ammonia, or an appropriate alkyl or dialkyl amine. The foregoing reaction sequence may be illustrated by the following diagrammatic scheme: Me.

Arn-C 0 (xi) (XII) ' (XIII) hydrolysis Ap (XIV) (XV) The compounds of formula (l-d) are prepared from the known pyrrole ester, .ethyl 2, -dimethylpyrrole-3-acetate (XVIII), which is acyiated according to a Friedel-Crafts reaction using an appropriate benzoyl halide, preferably the chloride (XIX), as the acyl ting agent. The methyl group in the 2-position of the thus-obtained ethyl 5- enzoyl-2, -dimethylpyrrole-3-acetate (XX). is then perchlorin ted by treating said ester (XX) with sulfuryl chloride in an inert solvent such as ether to yield the corresponding ethyl 5-benzoyi- -methyl-2-trichloro ethyl- 10 pyrrole-2-acetate (XXI) . Hydrolysis of the latter, for example, by heating at reflux in aqueous dioxane or 1,2-dimethoxyethane, for a few hours, gives the di-acid, 5-benzoyl- -methyl-2-carboxy- pyrrole-3-acetic acid (XXII). The carboxy function on the 2- position is then removed, for example, by heating in a suitable basic organic solvent such as quinoline, to yield the desired free acids (XXIII ) of formula (I-c). Again, the acids may in turn be converted to the corresponding esters and amides of formula (I-c) in the usual manner. The foregoing r.eaction sequence may be illustrated by the following diagrammatic scheme : OOEt CHgCOOH C00H (XXI) (XXII) The corresponding salts of the acids of formulas (I~a, b, c and d) are readily obtained by treatment o the latter with an equivalent amount of appropriate base, for example, a alkali or alkaline earth metal hydroxide, e.g., sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and the like, or with an organic amine base, e.g., a lower aIk lamine such as ethylamine, propylamine and the like,, or other amines such as benzylamine, piperidine, pyrrolidine and the like.

The subject compounds of formulas (I-a, b, c and d) and the therapeutically active salts thereof have useful pharma^ cological properties which make them suitable for incorporation into conventional pharmaceutical forms for administration. These compounds have been found to possess anti-inflammatory activity as demonstrated ' in the standard kaolin-induced rat paw edema and cotton pellet granuloma tests at doses ranging from 5-100 mg/kg body weight. · In the kaolin-induced rat paw edema assay, the ability of a compound, when administered in a single oral dose, to inhibit the swelling of the rat paw injected with a standard amount (0.1 of 10$ kaolin suspension in saline is measured. For comparative purposes, the activity of the compound to be tested is measured against that produced by the known anti-inflammatory agent, phenylbutazone. Male Holtzman rats are used in the assay. For example, in this test, the compound 5- (p_-chlorobenzoyl)~l-methyl-pyrrole-2-acetic acid was found to exhibit an inhibition, of.'about 35$ at 12.5 mg/kg; about 47 at 25 mg/kg; and about · 5-53$ inhibition in doses of 50-100 mg/kg; whereas phenylbutazone exhibited an inhibition of about 30-40$ at 100 mgAg.

In the cotton pellet granuloma assay, the ability of a compound, when administered orally to male Holtzman rats daily for seven days, to inhibit the amount of granuloma tissue formed in or around a cotton pellet implanted beneath the skin in the thoracic region of the animal is measured and compared to v/ater controls. The method is described by Charles A. Winter and coworkers in J. Pharmacol., lk-1, 369 (1963 ) · Analysis, of variance is used to determine the. significance of the results. For exampl in this test, the compound 5- (p-anisoyl )-l-methylpyrrole-2-acetic acid exhibited a granuloma weight of about 71 mg. at a dose of 25 mg/kg as compared to 110 mg. with the water controls ; and. the compound - (p_-chlorobenzoyl)-l-methylpyrrole-2-acetonitrile exhibited a granuloma weight of about 98 mg. at a dose of 100 mg/kg as compared to 115 m . with the water controls.

In the following table, the anti-inflammatory activity of several compounds of formulas (I-a, b, c and d) is listed, it being understood that such compounds are not- listed for purposes of limiting the invention thereto, but only to exemplify the' useful 'properties of all the compounds within the scope of formulas (I-a, b, c and d), including the .pharmaceutically acceptable basic salts thereof.

KAOLIN-INDUCED PAW EDEMA ASSAY DOSE (μο.) .$> INHIBITION (Average 10 ra. - (p_-c lorobenzoyl)-l-methylpyrrole-2-acetic acid 25 . 47 - (m-chlorobenzoyl)-do 25 41 - ( -chlorobenzbyl)-do 25 . 44 - (2 ' , 4 ' -dichlorobenzoyl)-do 25 51 - (p_-bromobenzoyl)-rdo 25 42. - (p_-fluoro enzoyl)-do 25 42 - (p_-methoxybenzoyl)-do 25 42 -(p_-methylbenzoyl )-do 25 • 44 - (p_-nitrobenzoyl)-do 100 35 ~ ( -aminobenzoyl)-do 23 - (pj-cyanobenzoyl)-do 100 20 -benzoyl-do 25 38 - p_-chlorobenzoyl)-a-methyl-l-methylpyrrole-2- acetic acid 50 56 - p_-chlorobenzoyl)-a-ethyl-l-raethylpyrrole-2- acetic acid 25 22 - p_-chlorobenzoyl)-p'yrrole-2-acetic acid 25 32 - p_-chlorobenzoyl)-l-ethylpyrrole-2-acetic acid 100 43 l-benzyl-5-(p_-chlorobenzoyl)-pyrrole-2-acetic acid 50 23 ethyl 5-(p-chlorobenzoyl)-l-methylpyrrole-2- acetate 25 37 methyl 5- (p_-chlorobenzoyl)-l-me hylpyrrole-2- acetate 25 38 -(p_-chlorobenzoyl)-l-methylpyrrole-2-acetamide 50 35 - (p_-chlorobenzoyl )-N-ethyl-l-methylpyrrole-2- acetamide 25 25 - (p_-chlorobenzoyl)-N,N-diethyl-l-methylpyrrole- 2-acetarnide 25 36 \ " (v.-chlorobenzoyl)-l-methylpyrrole-2-propionic acid 25 63 As anti-inflammatory agents, the compounds of formulas (I-a, b, c and d) and salts thereof are of value in reducing inflammation and alleviating the symptoms of rheumatic, arthritic and other inflammatory conditions. The compounds can be admin-istered in therapeutic' dosages in conventional pharmaceutical formulations for oral and parenteral administration, for example, tablets, capsules, solutions, suspensions, elixirs, injectables and . the like .

' As is evident from the previously described methods of forming the subject compounds, many of the compounds of formulas (I-a, b, c and d) are also useful as intermediates in the syntheses of other compounds thereunder. For example, the nitriles and esters represented by formulas (IV, V, VI and VII) j are useful intermediates in the syntheses of corresponding acids. In addition, the 5-nitrobenzoyl compounds of formulas (I-a) and (I-b) are useful intermediates in the transformation procedure to corresponding 5-aminobenzoyl compounds. Moreover, the acids embraced within formulas (I-a, b, c and d) are useful intermediate iii the transformation procedures to corresponding esters, amides and basic salts.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EXAI4PLE I Ethyl 5-(p_-chlorobenzoyl)~l-methylpyrrole-2-acetatc : To a solution of 22.0 g. (0.131 mole) of ethyl N-methylpyrrole-2-acetate and 2 .5 g.. (0.14 mole) of p^-chlorobenzoyl chloride · in 120 ml. of carbon disulfide is added 35.0 g. (0.262 mole) of anhydrous aluminum chloride over a period of 20 minutes with intermittant cooling to keep the temperature at 2 °C.

The mixture is stirred for an additional 20 minutes. The carbon disulfide solvent is then decanted and discarded. The red gummy, residue is washed with hexane and dilute hydrochloric acid and ice is added to the mixture. The mixture is extracted with ether. The ether solution is' shaken with an aqueous solution of dimethylaminopropylamine and washed with, dilute hydrochloric acid followed by brine. The solution is dried over magnesium sulfate and treated with charcoal. After removal of the charcoal, the solvent is evaporated in vacuo leaving a partially crystalline red oil as a residue. This material · is extracted with three 500 ml. portions of boiling pentane.

The combined pentane extracts are evaporated in vacuo and the residue is crystallized from 60 ml. of cold methanol. The resulting solid is collected and washed with cold methanol; there is obtained about 6.3 g. of white crystalline solid, ethyl 5-(lL-chlorobenzoyl)-lHnethylpyrrole-2-acetate, m.p. 7 -7 °C. Recrystallization from methyl cyclbhexane raises the melting point to 78-80°C.

EXAMPLE II -(pj-Chloroben?/oyl)-l-methylpyrrole-2-acetic acid and its sodium salt: A suspension of 3·0δ g. (0.01 mole) of ethyl-5-(p_-chlorobenzoyl)-l-methii'lpyrrole-2-acetate in 25 ml. of 0.5 N sodium hydroxide is refluxed for 39 minutes. About two-thirds of this solution is cooled, washed with ether, and then acidified with dilute hydrochloric acid. The resulting solid precipitate is collected by filtration, dried and re-crystallized from ethanol-water to give the product, 5-(p_-chlorobenzoyl)-l-methylpyrrole-2-acetic acid; m.p. l89-191°C.

Upon recrystallization from ethanol-water, the melting point is I88-I9O°C. The other one-third of the solution is cooled in an ice-bath whereupon the yellow sodium salt of the acid is precipitated and collected by filtration.

Analysis ; Calcd. for C-^H^CINC^ : C, 60.5 ; H, .3β; N, 5-05^ Pound : C, 60.5½ H, 4.37; N, 5.l # EXAMPLE III By following the procedures of the foregoing examples, except that an equivalent quantity of benzoyl chloride is em-ployed in place of the p_-chlorobenzoylchloride used in Example I, there are obtained as respective products, ethyl 5-benzoyl-l-niethyl-pyrrole-2-acetate and 5-benzoyl-i-methyl-pyrrole-2- acetic acid.

EXAMPLE IV ^-Benzoyl-l- ethylpyrrolc-2--acctonitrile ; To a chilled suspension of 9 · 7 g. (0.07 mole) of aluminum chloride in 45 ml. methylene chloride is added 9 Ϊ» · (0.07 mole) benzoyl chloride. The resulting solution is added dropwise to a solu-tion of l-methylpyrrole-2-acetonitrile in 30 ml. methylene chloride while cooling externally with an ammonium chloride ice bath (temperature below 5°C). After the addition is complete, the reaction mixture is stirred at 0 C. for fifteen minutes and then poured into ice acidified with 3N hydrochloric acid. The acidic fraction is extracted three times with methylene chloride. The organic fractions are combined and washed consecutively with' N,N-dimethyl-l, 3-propanediamine and 3N hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated off to yield an oily residue which is column chromatographed on neutral alumina using hexane, benzene and ethylacetate as successive solvents. The first few fractions having ultraviolet absorption in the 240-260 mu, range contain the desired product. These fractions are combined, the solvent evaporated off and the oily residue,, when triturated with methanol, yields the crystalline product, 5-benzoyl-l-methylpyrrole-2-acetonitrile, m.p. 106-108°C.

EXAMPLE V -Benzoyl-l-metbylpyrrole-2-acetlc acid ; A suspension of 2.h2 g. (0.11 mole) of 5~benzoyl-l-methylpyrrole-2-acetonitrile 0.9 g. (0.22 mole) sodium hydroxide, 6 ml. water, and 0.5 ml. ethanol, is stirred and refluxed for one hour. · The resulting solution is cooled and extracted in water and chloroform. The aqueous fraction is made acidic with 3N hydrochloric acid. A white s-olid, 5-benzoyl~l-methylpyrrole-2-acetic acid, precipitates which is filtered and washed with a hexane-ether solution, m.p. 14 -1 5°C.

Analysis ; Calcd. for C-^H-^ O : C, 69.12; H, 5-39; N, 5-7 ^ Found : C, 69. 3; H, 5-^7; ,.5-78 EXAMPLE VI -(m-Chlorobenzoyl)-l-methylpyrrole-2-acetonitrile : To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in 60 ml. 1,2-dichloroethane' is added dropfise 23 g. (0.12 mole) m-chlorobenzoylchloride. The resulting suspension is added dropwise to a cooled solution of .15 g. (0.12 mole) 1-methylpyrrole-2-acetonitrile , in 60 ml. 1,2-dichloroethane.

The reaction mixture is stirred for about twenty minutes at room temperature and then heated and refluxed for three minutes. The reaction is terminated by pouring the mixture into ice acidified with 3N hydrochloric acid. The resulting two fractions are separated. The aqueous fraction is washed with chloroform. The organic fractions · are combined and wached consecutively with N N-dimethyl-l^-propanediamine, 3N hydrochloric, acid and. saturated sodium chloride solution. The organic fraction is then dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is triturated with cold methanbl to yield a precipitate of the desired product which is filtered off and' set aside. The methanol filtrate is concentrated in vacuo and the remaining oily residue is chro- matographed on a column packed with neutral alumina using hexane, benzene and ether as the successive solvents. About 2.5 g. of the desired product are isolated by evaporation of the first few compound- earing (ether) fractions.. The solids are combined and recrystallized from methanol to yield about 3.6 g. of 5-(m-chlorobenzoyl)-l-methylpyrrole-2-acetonitrile m.p. 122-127°C. · Analysis; Calcd. for C^H^Cl^O: N, 10.83 Found : N, 10.5 $ EXAMPLE VII -(m-Chlorobenzoyl)-l-methylpyrrole-2-acetic acid: A mixture of 2.8 g. (0.01 mole) of 5-(m-chlorobenzoyl)-l- methylpyrrole-2-acetonitrile, 22 ml. of IN sodium hydroxide solution and 5 ml. ethanol is stirred at reflux for 15 hours. Some of the ethanol is evaporated. The remaining solution is poured into ice acidified with dilute hydrochloric acid.

A white solid, 5-(m-chlorobenzoyl)-l-methylpyrrole-2-acetic • acid, precipitates which is recrystallized twice from methanol: water, m.p. l65°C.

Analysis : Calcd. for C^H^CINO : C, 60.5K,' H, 4.36; N, 5-05$ EXAMPLE VIII A. The procedure of Example VI is repeated except •that an equivalent quantity of p_-bromobenzoyl chloride and p_-fluorobenzoyl chloride is used in place of the m-chlorobenzoyl chloride used therein to yield, as respective products : -(E.-'b^omobenzoyl)-l-rethylpyrrole-2-acetonitrile, m.p. 139-1^1 °C; 5-(_-fluorobenzoyl)-l-methylpyrrole-2-acetonitrile., m.p. 13^-136 °C B. By following the procedure of Example VII, using an equivalent quantity of the foregoing acetonitriles in place of the 5- (m-chlorobenzoyl)-l-methylpyrrole-2-acetonitrile used therein, the following respective acids are obtained: -(p_-bromobenzoyl)-l-methylpyrrole-2-acetic acid, m.p.- l88°C; and 5- (p- luorobenzoyl)-l methylpy role-2-acetic acid, m.p. l6 -l65°C.

EXAMPLE IX - (o-Chlorobenzoyl)-l-methylpyrrole-2-acetonitrile : To a cooled suspension of 14 g. (0.105 mole) aluminum chloride in 5 ml. dichloroethane is added dropwise, I8.5 g. (0.105 mole) _-chlorobenzoyl chloride.. The resulting solution is added dropwise to a cooled (0°C.) solution of l-methylpyrrole-2-aceto- nitrile in ^5 ml. dichloroethane keeping the temperature at approximately 10°C. The mixture is stirred at room temperature for about twenty minutes, and then refluxed for three minutes. It is poured into ice acidified with 3N hydrochloric acid and is extracted twice with chloroform. The organic fractions are combined and washed twice with I\T,N-dimethyl-l,3~propanediamine, once- with 3N hydrochloric acid and once with saturated' sodium chloride solution. The organic fraction is dried over- anhydrous magnesium sulfate. The solvent is evaporated and the resulting oil is chroinatographed on a column packed with neutral alumina using benzene and ether as successive solvents.. The first compound-bearing fractions contain the desired product . The solvent is evaporated and the resulting oil crystallizes upon 0 treatment . with methanol. The solid product, 5- (o-chlorobenzoyl)- l-methylpyrrole-2-acetonitrile, is purified, by recrystallizafion from benzene :cylcohexane solution, m.p. 80-85°C.

EXAMPLE X -(o-Chlorobenzoyl)-l-methylpyrrole-2-acetic acid: A solution 'of 2.4 g. (0.009 mole) of 5- (o-chlorobenzoyl).-l~ methylpyrrole-2-acetonitrile, 18 mlv of IN sodium hydroxide and 18 ml. 95 ethanol is stirred and refluxed for seven hours.

' The ethanol is evaporated off and the remaining solid residue is dissolved in water and washed with chloroform. The aqueous * ' layer is made acidic with 3N hydrochloric acid. An oil pre-20 cipitates which crystallizes when scratched. The solid is filtered and washed with water and hexane. The solid is' purified by recrystallization from methanol .water and again from ether :hexane, m.p. l40-l4l°C. , Analysis ; Calcd. for C-^H ClNQj, : C, 6θ.?4; Η,· .36 N, 5-05$ 25 Found : C, 60.55; H, 4.43; N, 4. 1$ ' EXAMPLE XI - (2 ' ,K - chlorobenzoyl) -l~methylpy ole--2--acetonitrile : To a suspension of Ιβ.6 g. (0.125 mole) of aluminum chloride in 60 ml. 1, 2-dichloroethane is added 26.2 g. (O. I25 mole) of 2, 4-dichlorobenzoyl chloride. The resulting solution is added slowly to a solution of 15 g. (0.125 mole) of l-methylpyrrole-2-acetonitrile in βθ ml. 1, 2-dichloroethane while cooling externally with an ice bath. After the addition is complete, the mixture is stirred for forty minutes at room temperature followed by heating at reflux for three minutes. It is then poured into ice acidified with dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl-l, 3-propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated. The resulting. red oily residue is chromatographed on a column packed with neutral alumina and eluted with benzene and ether. The first compound-bearing fractions upon evaporation yield a white- solid, 5- (2 ' ,4f-dichlorobenzoyl)-lT.methylpyrrole-2-acetonitrile, vhich is purified by recrystallization from methanol, m.p. 129-130°C. Analysis : Calcd. for Pound : N, 9· 51$ EXAMPLE XII - (2 ' , 1 -Dichlorobenzoyl) -l-methyIpyrrole~2-acetic acid: A solution of 4.3 g. (0.015 mole) of 5- (2 » , » -dichlorobenzoyl)-l-methylpyrrole-2-acetonitrile in 30 ml. IN sodium hydroxide and 30 ml. 9 ethanol is refluxed overnight. The solution is concentrated and poured jnto dilute hydrochloric acid. A white solid, 5~(2l ^'-dichlorobenzoylj-l-methylpyrrole-2-acetic acid precipitates which is recrystallized from iso-propanol and methanol, in. . l65~l66°C.

Analysis : Calcd. for C CI NO : C, 53.86;' K, 3-55; N, .68^ ■*· *■ 11 2 3.

Found : C, 53'.97; H, 3.66; N, h.69& EXAMPLE XIII "5- (p_-Toluoyl)-l-methylpyrrole-2-acetonitrile : To a cooled suspension of 26.6 g. (0.2 mole) aluminum chloride in 80 ml. dichloroethane is added dropwise 30.8 g. (0.2 mole) p_-toluoyl chloride. The resulting solution is added dropwise to a solution of l-methylpyrrole-2-acetonitrile in 80 ml. dichloroethane cooled externally with an ice bath. After the addition, the resulitng solution is stirred at room temperature for twenty minutes and then refluxed for three minutes. The solution is poured into ice acidified with dilute hydrochloric acid. The organic and aqueous fractions are separated. The aqueous fraction is extracted once with chloroform. The organic fractions are combined and vrashed successively with N,N-dimethyl-l,3-propanediamine, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic fraction is dried over anhydrous magnesium sulfate. The solvent is then evaporated off. Upon trituration of the residue with methanol, a solid crystallizes, 5-(p_-toluoyl)-l-methylpyrrole-2-acetonitrile, which is removed by filtration and purified by recrystallization from benzene. Additional product is isolated from the mother liquors which are combined, concentrated in vacuo and the resulting oily residue column chromatographed on neutral alur.iina using hexane, benzene and ether as successive solvents. The product is isolated by concentrating in_ vacuo the first few major compound-bearing fractions (10 ether in benzene).- The solids are combined and recrystallized from methanol and then from benzene-hexane, ra.p. 102-105°C.

EXAMPLE XIV -(p_-Toluoyl)-l-methylpyrrole-2-acetic acid: A solution of 3.67 g. ' (0.015 mole) of 5-(p_-toluoyl)-l-methyl-pyrrole-2-acetonitrile, 2k ml. of IN sodium hydroxide, and 0 ml. of 95$ ethanol is stirred and refluxed for twenty~ our hours .

The resulting solution is poured into ice acidified with dilute hydrochloric acid'. A white solid precipitates which is extracted into ether. The ether phase is washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate'. The solvent is evaporated and a white solid, 5-(p_-toluoyl)-l-methylpyrrole-2-acetic acid, is obtained which' is recrystallized twice from isopropanol, m.p. 155-15 °C.

EXAMPLE XV A. By repeating the procedure of Example XI, except that an equivalent quantity of o-toluoyl chloride, m-toluoyl chloride-, p_-ethylbenzoyl chloride and 3,½- imethyl-benzoyl chloride is used in lieu Qf the 2, ~dichlorobenzoyl chloride used therein, there are obtained as respective products the corresponding 5- (£-toluoyl) , 5- (m-toluoyl) , 5-(n-ethylben oyl) and 5- (31 -dimethylbenzoyl) derivatives of l-methy pyrrole-2-acetonitrile.

B. The procedure of Example XII is repeated, using an equivalent quantity of each of the foregoing acetonitriles in place of the 5-(2',4,-dichlorobenzoyl)- l-methyl-pyrrole-2-acetonitrile used therein, to yield as respective products the corresponding 5- (o_-toluoyl), 5- (m-toluoyl) , 5-(p_-ethylbenzoyl) and 5- (3',^' -dimethylbenzoyl) derivatives of 1-methylpyrrole-2-acetic acid. .

EXAMPLE XVI Methyl 5- (p_-anisoyl)-l-methylpyrrole-2-acetate : A solution of 17.0 g. (0.1 mole) of -anisoyl chloride and 13*3 &' (0.1 mole) of aluminum chloride in 200 ml. o methylene chloride is added over 5 minutes to a solution of methyl 1-methylpyrrole-2-acetate in 100 ml. of methylene chloride at ice bath temperature. . The mixture is stirred for 25 minutes and poured into ice acidified with dilute hydrochloric acid. The organic layer is separated and the aqueous layer is washed with methylene chloride.' The combined organic solutions are washed successively with dimethylaminopropylamine solution, dilute hydrochloric acid and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give a dark oily residue which is crystallized from 0 ml. of cold methanol.. The solid is collected by filtration, washed with cold methanol and recrystallized from methanol to give white crystalline methyl 5-(E-anisoyl)-l-methylpyrrole-2-acetate, m.p. 104-105 °C.

EXAMPLE XVII -(p_-Anisoyl)-l-methylpyrrole-2-acetic acid : A solution of 3.00 g. (0.0105 mole) of methyl 5-(p_-anisoyl)~ l-methylpyrrole-2-acetate in 12 ml. (0.012 mole) of IN sodium hydroxide solution and 5 ml. of 9 ethanol is refluxed for minutes. The solution is diluted with water and the ethanol is evaporated in vacuo. ; The solution is f ltered and the filtrate acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration, dried and recrystallized from ethanol-water to give about 2.4 g. (87 yield) of white 5-(p-anisoyl)-l-methylpyrrole-2-acetic acid, m.p. 170-171°C Analys s : Calcd. for C-,ΕΗ NO. : C, 65.92; H, 5-53; N, 5-13$ Found : C, 66.01; H, 5. 2 N, 5.12# ■EXAMPLE XVIII By repeating the procedures of Examples XVI and XVII successively, except that an equivalent, quantity each of m-anisoyl chloride and p_-ethoxybenzoyl chloride is initially employed in place of p_-anisoyl chloride, there are obtained as ester products, the corresponding 5-(m-anisoyl) and - (p_-ethoxy benzoyl) derivatives of methyl l-methylpyrrole-2-acetate, and as acid products, the corresponding 5~(£].-anisoyl) and 5-(R-ethoxybenzoyl) derivatives of l-methylpyrrole-2-acetic acid, respectively.

EXAMPLE XIX -(3,-Chloro-p_-toluoyl)-l-methylpyrrole-2-acetonitrile: 21.4 Grams (0.114 mole) of 3-chloro~4-methylbenzoylchloride is added to a suspension of 15.2 g. (0.114 mole) aluminum chloride in 50 ml. 1,2-dichloroethane. The resulting solution is added dropwise to" a chilled solution of 13·7 g. (0.114 mole) of l-r methylpyrrole-2-acetonitrile in 0 ml. 1,2-dichloroethane.

After the addition is complete, the mixture is stirred for ten minutes at room temperature and then heated to reflux for three minutes. It is poured into ice acidified with dilute HC1. The organic phase is separated and washed consecutively with N,N-dimethyl-l,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. It is then dried over anhydrous magnesium sulfate and the solvent evaporated off. A white solid, 5-(3,-chl.oro~pj-toluoyl)-l-methylpyrrole-2-acetonitrile, precipitates from the resulting oily residue upon trituration with methanol which is purified by recrystallization from methanol Analysis : Calcd. for C H 01Ν≥0: N, 10.26 Pound : N, 10.38^ EXAMPLE XX - (3 ' -Chloro-p_~toluoyl)-l-metlylpyrrole-2-acetic acid : Λ solution of 3.5 g. (0.0013 mole) of 5- (3'-chlo.ro-p_-tol oyl)- l-methylpyrrole-2-acetonitrile in 18 ml. 9 ethanol and 26 ml. IN sodium liydroxide is heated at reflux overnight. The reaction mixture is then cooled and poured into dilute hydrochloric acid. The resulting white precipitate, 5- (3i-chloro-p_-toluoyl)-l~ methylpyrrole-2-acetic acid, is filtered off and purified by recrystallization once from isopropanol, m.p. 176-178°C.

EXAMPLE XXI By repeating the Friedel-Crafts procedures of Example XVI with an equivalent amount of an appropriately substituted benzoyl chloride, the following 5-aroyl derivatives of methyl l-methylpyrrole-2-acetate are obtained: methyl 5- (3 l , '-diinethoxybenzoyl)-l-methylpyrrole-2-acetate ' methyl 5- (3 ' , 5 ' -dinitrobenzoyl)-l-methylpyrrole-2-acetate; methyl 5- (31 -bromo-4 ' -chlorobenzoyl)-l-methylpyrrole-2-acetate · methyl 5- (2 , , 3 t , 5,-tribromobenzoyl)-l-methjrlpyrrole-2-acetate; and EXAMPLE XXII The transformation of an acetic acid ester function to an acetic' acid function according to the hydrolysis procedure of Example XVII is repeated with an equivalent amount of each of the pyrrole-acetates obtained in Example'. XXI to yield, as respective products, the corresponding 5-aroyl-i-methylpyrrole-2-acetic acids.

EXAMPLE XXIII - (p_-Nitrobenzoyl )-l-methylpyrrole-2-acetonitrile : A solution of 46*4 g. (0.25 mole) of p_-nitrobenzoyl chloride in 100 ml. l,2~dichloroethane is added portionwise to a sus-pension of 32.2 g. (0.25 mole) aluminum chloride in 100 ml. 1,2-dichloroethane. This mixture is added dropwise to a chilled solution of 30.0 g. (0.25 mole) l-methylp3^ role-2-acetonitrile in 100 ml. 1,2-dichloroethane. After the addition is complete, the mixture is stirred for twenty minutes at room temperature and then refluxed for four minutes. It is poured into ice acidified with 3N hydrochloric acid. The organic phase is separated and washed successively with N, -dimethyl-l,3-propanediamine, 3N hydrochloric acid and saturated sodium chloride solution. It is then dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting semi-solid residue is triturated with cold methanol from which the product, 5-(p_-nitrobenzoyl)-l-methylpyrrole-2-acetonitrile, crystallizes . It is removed by filtration and purified by recrystallization EXAMPLE XXIV - (pj-Amlnobenzoyl)-l-methylpyrrole-2-acetonitrile : A solution of 7 g. (0.026 mole) of 5-(pj-nitrobenzoyl)-l~methyl~ pyrrole-2-acetonitrile in 450 ml. of ethyl acetate containing 1 g. palladium-on-carbon catalyst is hydrogenated ,in a Parr shaker under 44 p.s.i. of hydrogen until the theoretical amount of hydrogen is consumed. The catalyst is filtered off and the solvent evaporated in vacuo. About 6.0 g. (97#> yield) of a yellow solid, 5- (p_-aminobenzoyl)-l-methyipyrrole-2-acetonitrile remains, m.p. 137-142°C.

EXAMPLE XXV (P-Aminobenzoyl)-l-methylpyrrole-2-acetic acid: A suspension O 6.0 g. (0.025 mole) of 5~(p_-aminobenzoyli)-l-methylpyrrole-2-acetonitrile, 2 ml. 9 ethanol and 25 ml. IN sodium hydroxide is refluxed overnight. The ethanol is then evaporated in vacuo and the remaining suspension is poured into ice acidified with dilute hydrochloric acid to pH 5. The resulting solid is partitioned ..between sodium bicarbonate solution and chloroform. The insoluble substances are filtered f om the two-phase mixture...The sodium bicarbonate layer is separated and acidified slowly with dilute hydrochloric acid. Solids precipitate at various pHs which are separated by filtration. The desired product, 5- (p_-aminobenzoyl)-l-methyl-pyrrole-2-acetic acid, precipitates at pH 3, m.p. 173-175 °C.

EXAMPLE XXVX Ethyl 5- (p_-Nitrobenzoyl)-l~methylpyrrole-2-acetate : A solution of 5 ·5 g« (° · °3 mole) of p_-nitrobenzoyl chloride in' 60 ml. methylene chloride is added to a. suspension of 3 · 9 β· (0.03 mole) aluminum chloride in 20 ml. methylene chloride.

The resulting suspension is added dropwise to a chilled ( -15°C.) solution of ethyl l-methylpyrrole-2-acetate in 0 ml. methylene chloride. The solution is stirred for 1 minutes at -10°C. and at room temperature for 15 minutes. The reaction mixture is poured into ice-dilute hydrochloric acid. The organic phase is separated and washed successively with N,N-dimethyl- 1, 3-propanediamine, 3N hydrochloric acid and a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo. A solid, ethyl 5-(p_-nitro-benzoyl)-l-methylpyrrole~2-acetate, crystallizes from the re-maining oily residue which is isolated by recrystallization from methanol, m.p. 103 -106°C.

EXAMPLE XXVII -(p_-Nitrobenzoyl)-l-methylpyrrole-2-acetic acid: A solution of 3.2 g. (0.01 mole) of ethyl 5-(p_-nitrobenzoyl)-l-*methylpyrrole-2-acetate and 25 ml. ethanol is brought to reflux. To this is added dropwise 10 ml. of IN sodium hydroxide solution. After the addition is complete, the ethanol is evaporated and the residue is acidified vrith- dilute hydrochloric acid. The resulting solid, 5-(p_-nitrobenzoyl)-l-methylpyrrole-2-acetic acid, is separated by filtration and purified by recrystallization from ethanol, m.p. 192-195°C.

EXAMPLE -XXVIII Ethyl 5-(p_-^yG'nobenzoyl)-l-methylpyrrolo-2-acetG.te : A solution of 5.0 g. (0.03 mole) of jo-c a o en oi'-l chloride in 60 ml. of methylene chloride is added to a suspension of - g.-of aluminum chloride in 30 ml. methylene chloride. The resultin mixture is added dropwise to a chilled solution of 5.0 g. (0.03 mole) of ethyl l-ne h lpyrrole-2-acetate in 15 ml. of methylene chloride. The resulting mixture is stirred at room temperature for 20 minutes, and then poured into ice acidified with dilute hydrochloric acid. The organic phase is separatedj washed successively with Ν,Ν-dimethylaminopropylamine, 3N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate.

The solvent is evaporated in vacuo. The resulting solid, which separates from the oily residue on standing, is recrystallized from methanol to give pure ethyl 5- (p_-cyanobenzoyl)-l-methyl-pyrrole-2-acetate, m.p. 117-120°C.

EXA PLS XXIX -(p_-Cyanobenzoyl)-l-methylpyrrole-2-aceti0 acid : A solution of 0.5 g. (0.0017 mole) of ethyl 5-(j -*-'c anobenzoyl)-l-methylpyrrole-2-acetate in 3 ml. ethanol is brought to reflux and 1.7 ml. of IN sodium hydroxide solution is added dropwise. The mixture is refluxed for 3 minutes and the ethanol is then evaporated in vacuo. The residue is diluted with water and acidified with dilute hydrochloric acid. A whi e solid precipitates, 5- (p_-cyanobenzoyl)-l-methylpyrrole-2-acetic acid, which is collected by filtration and dried, m.p. 196-198°C.

EXAMPLE XXX Methyl 5-(p_-methylthiobenzoyl) -lHraethylpyrrole~2- acetate is obtained b repeating the procedure of Example XVI except that an equivalent quantity of p_-methylthiobenzoyl chloride is used in place of the p_-anisoyl chloride used therein.

EXAMPLE XXXI ' 5- (ρ,-Hethylthlobcnapyl)-I-methylpyrrolo-2-acetic acid is obtained by repeating the hydrolysis procedure of Example XVII except that the hydrolysis is performed on an equivalent amount of the ester obtained from Example XXX.

■ . EXAMPLE XXXII Ethyl 5-(p_-chlorobenzoyl)- -methyl-l-methylpyrrole- 2-acetate ; A solution of 6.68 g. (0.0219 mole) of ethyl 5-(p_- chlorobenzoyl)-l-methylpyrrole-2-acetate in 50 ml. of ether is added to a solution of 0.94 g. (0.024 mole) of sodamide in about I 0 ml., of liquid ammonia at -33 °C. · The mixture is allowed to reflux for 15 minutes and 3.10 g. (0.0219 mole) of methyl · iodide is added. The mixture is stirred for one hour then the ammonia is allowed to boil off. Ether and enough ammonium chloride to neutralize any anion are added. The mixture is poured into dilute hydrochloric acid and the --ether solution is separated and washed with sodium bisulfite solution, sodium magnesium- sulfate and evaporated to give about 6.8 g. of an oily residue which crystallizes upon standing. The solid is recrystallized successively from cyclohexane and methanol to give a white crystalline solid, ethyl 5- (p_-chlorobenzoyl)-a-methyl-l-methylpyrrole-2-acetate, .p. 67-68°C.

EXAMPLE XXXIII - (pj-Chlorobenzoyl) -a-methyl-l-methylpyrrole-2-acetic acid; A 'solution of 4.05 g. (0.0126 mole) of ethyl 5-(_-chlorobenzoyl)-a-methyl-l-methylpyrrole-2-acetate 15 ml. of IN sodium hydroxide solution and 2 ml. of ethanol is refluxed for 3 minutes. The solution is cooled, diluted with water and filtered. The filtrate is acidified with dilute hydrochloric acid. The precipitated solid is collected and recrystallized from methanol-water to give a white crystalline solid, 5-(p_-chlorobenzoyl)-a-methyl-l-methylpyrrole-2-acetic acid, m.p. 135-136°C.

Analysis ; Calcd. for C, ^H^CINO : C, 6l.?6; H, 4.83; N, 4.82$ Found : C, 61.68: H, 4.86; N, ' .89 EXAMPLE XXXIV - (pj-Chloro enzoyl.)«ia~ ethyl-l-methylpyrrole-2-acetonitrxle : To a suspension of sodium hydride (12.2 g. of 50$ w/w NaH in mineral oil) in 1,2-dimethoxyethane is added -(p_-chloro"benzoyl)-l-rethylpyrrole-2-acetonitrile (62.6 g., 0.24 mole) in l,2-dimethoxyetha,ne over a period of 1/2 hr. at room temperature. After the addition is complete, the mixture is stirred for 1 hour and then 35 &· (0.25 mole) of methyl iodide is added. The reaction mixture is stirred for an additional 3 hrs., concentrated under reduced pressure, diluted with water and extracted with chloroform. After drying, the chloroform is removed leaving a brown solid residue which is triturated with cold methanol-..to give yellow crystals of 5- (p_-chlorobenzoyl)~ .a-methyl-l-methylpyrrole-2-acetonltrile, m.p. 1 5-148°C. Two recrystallizations from methanol raises the m.p. to 151.5-152.5°C.

EXAMPLE XXXV -(p_-Chlorobenzoyl)-a-methyl-l-methylpyrrole-2-acetic acid; A 27.1 g. (0.1 mole) sample of 5-(P-chlorobenzoyl)-. a-methyl-l-methylpyrrole-2-acetonitrile is hydrolyzed by reflu -ing for 16 hours with 8 g. (0.2 mole) of sodium hydroxide in 3 O ml. of aqueous ethanol. Upon concentration in vacuo, the sodium salt separates which is filtered off and dissolved in water. After acidification with dilute HCl, the corresponding acid, 5-(p_-chlorobenzoyl)-a-methyl-l-methylpyrrole-2-acetic acid, precipitates. The original basic filtrates are also acidified, extracted with chloroform and concentrated. The residual solid EXAMPLE XXXVI - (p_-Chloroben2;oyl)- -etl l~l-methylpyrrole--2-acetic acid : A solution of. 6.5 g. (0.021 mole) of ethyl 5- (p_-chloro- benzoyl)-l-meth3ripyrrole-2~acetate in 6o ml. of ether is added- to a suspension of 1.25 g. (0.032 mole) of sodamide in 150 ml. of refluxing liquid ammonia. After 10 minutes, .98 g. (0.032 mole) of ethyl iodide is added. The mixture is stirred for 1.5 ' hrs. and an additional 1.0 g. ( .0064 mole) of ethyl iodide is added. Stirring is continued;' for 30 minutes and ammonium chloride is then added to neutralize any anion. The mixture is allowed to warm to room temperature and the ammonia allowed to escape. Ether is added and the mixture poured into dilute' hydrochloric acid. The ether layer is separated and the aqueous layer is washed with ether. The combined ether solutions are washed successively with sodium' bisulfite solution and brine and then dried over anhydrous magnesium- sulfate. The solvent is evaporated in vacuo to give about - 7.'4 g. of a yellow oily residue containing ethyl 5- (pj-chlorobenzoyl)- -ethyi-l-methyl- pyrrole-2-acetate, which is used as such in the following transformation to acid procedure.

A 6.9 g. sample of the oily residue is dissolved in ml. of ethanol and 11.4 ml. of IN sodium hydroxide is added. The mixture is refluxed for 1 hr. The solvent is then evaporated in vacuo and the residue partitioned between ether and water.. The aqueous layer is separated and acidified with dilute hydro- chloric acid. The precipitated oil, which, is separated, crystallizes on scratching to give a solid, 5- ethyl-l-methylpyrrole-^-acetic acid, \tfhich is collected and dried, m.p. 108-112 °C. After successive recrystallizations from ether-metlylcyclohexane, benzene-hexane, methylcyclohexane Analysis: Calcd. for C^H^CINO : C, 62.84$ H, -5.275 N, 4.5¾¾S .

Found ■: C, 63.01; H, 5-36; N, .6l# EXAMPLE XXXVII The alkylation and ester-to-acid trans ormat on procedures of Example XXXVI are repeated except that an equivalen amount o 'an appropriate 5~3-roylr.l-methylpyrrole~2-ace.tic acid alkyl ester and an equivalent amount of an appropriate alkyl halide alkylating agent are employed -to yield the following products : ' -benzoyl-a- (n-butyl)-l-methylpyrrole-2-acetic acid; -(p_-methoxybenzoyl)- -meth3ri-i-methylpyrrole-2-acetic acid; -benzoyl-a- (nj-propyl)-l-methylpyrrole-2-acetic acid and -(_>-cyanobenzoyl)-a-methyl-l-methylpyrrole-2-acetic acid.

EXAMPLE XXXVIII The alkylation and nitrile-to-acid transformation procedures of Examples XXXIV and XXXV, respectively, are repeated except that an equivalent amount of an appropriate 5-aroyl-l-methylpyrrole-2-acetonitrile and an equivalent amount of an appropriate alkyl halide alkylating ¾ent are employed to yield the following products: -(m-chlorobenzoyl)- -methyl-l-methylpyrrole-2-acetic acid; -( -methylbenzoyl)- -ethyl-l-rriethylpyrrole-2-acetic acid; - (2 ' , f -dichlorobenzoyl)- -methyl-l-methylpyrroD-e-2-acetic acid 5 - (31 -chloro- ' -methylbenzoyl)-a-ethyl-l-methylpyrroie-2-acetic ac EXAMPLE XXXIX -(p.-Chlorobenzoyl)-pyrrole-2-acetonitrile : To a chilled suspension of 2β .8θ g. (0.2 mole) of aluminum' chloride in 110 ml. of methylene chloride is added dropwise 35 £ · (0. mole of p_-chlorobenzoyl chloride. The mixture is added dropwise to a solution of 21.22 g. (0.2 mole) of pyrrole-2-acetonitrile in 1 5 ml. methylene chloride which is cooled externally with an ammonium chloride ice bath. After addition is complete, the reaction mixture is stirred for ten minutes at 0°C. and then poured into ice acidified with dilute hydrochloric acid. A solid precipitates, 5- (_-chlorobenzoyl)-pyrrole-2-acetonitrile, which is filtered" off, washed with hot methanol and dried, m.p. 203-20 °C.

EXAMPLE XL -(p_-Chlorobenzoyl)-pyrrole-2-acetic acid: A solution of 3'.6 g. (0.015 mole) of 5- (pj-chlorobenzoyl)-pyrrole-2-acetonitrile, 30 ml. IN sodium hydroxide solution, and 30 ml. $ ethanol. is refluxed and stirred for 6 hours.

The ethanol is evaporated 6ff in vacuo. The resulting solid is dissolved in water and the solution filtered from insolubles The filtrate is acidified with dilute hydrochloric acid. A white solid precipitates, 5- (p-chlorobenzoyl)-pyrrole~2-acetic acid, which is purified by recrystallization from acetone rwater (1:1), m.p. 210°C.

EXAMPLE XLI The procedure of Example XXXIX is followed to prepare 5-aroyl-l-R^-pyrrole-2-acetonitriles wherein is hydrogen, For example, by repeating such procedure, except that an equivalent amount of an appropriate benzoyl chloride is used in place of the p_-chlorobenzoyl chloride used therein, the following pyrrole-acetonitriles are obtained as respective products : -benzoyl-pyrrole-2-acetonitrile - (p_-fluorobenzoyl)-pyrrole-2-acetonitrile - (p_-methylbenzoyl)-pyrrole-2~acetonitrile; -(_-methoxybenzoyl)-pyrrole-2-acetonitrile; -(3' -chloro-^,-methylbenz0yl)-pyrrole-2-acetonitrile5 and - (21 , ' -dichlorobenzoyl)-pyrrole-2-acetonitrile .

EXAMPLE XL1I The procedure of Example XL is repeated using an equivalent a,mount of each pyrrole-acetonitrile obtained in Example XLI in place of 5- (p_-chlorobenzoyl)~pyrrole-2-acetonitrile to yield, as respective products : ' -benzoyl-pyrrole~2-acetic acid; - (p_- luorobenzoyl)-pyrrole~2-acetic acid; -( -methylbenzoyl)-pyrrole-2-acetic acid; -(p_-methoxybenzoyl)-pyrrole~2~acetic acid; -(3'-chloro-4'-metliylbenzoyl)-P3'-rrole-2-acetic ac,id; and -( ' ,4,-dichlorobenzoyl)-pyrrole-2-acetic acid.

EXAMPLE XLIII -(p_-Chlorobenzoyl)-l-ethylpyrrole-2-acetonitrile: A mixture of 24.4 g. (0.1 rnole) 5- (p_-chlorobenzoyl)-pyrrole-acetonitrile, 1.75· (0.3 mole) of potassium carbonate and 16.1 g.' (0.105 mole) of ethyl iodide in 300 ml. of methylethyl-ketone is refluxed overnight. The reaction mixture is then poured. into water and extracted with chloroform. The organic solutions are combined, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue is crystallized from 2-propanol to give about 13 g. of crude solid. The solid s sublimed overnight at l40°C. and 0.025 mm. Hg. The sublimate is successively recrystallized from 2-propanol, benzene and hexan to give 5-(p_-chlorobenzoyl)-l-ethylpyrrole-2-acetonitrile as a wMe solid, m.p. l45-l47°C.

•'EXAMPLE XLIV -(_~Chlorobenzoyl)~l-ethylpyrrole-2-acetic acid: A suspension of 3·52 g. (0.013 mole) of ~ (p-chlorobenzoyl)-!-ethylpyrrole-2-acetonitrile in 2.6 ml. IN sodium hydroxide and · 50 ml. of ethanol is refluxed for six hours. The mixture is then diluted with water and cooled. A solid precipitates which, is filtered off and set aside. The ethanol is evaporated from the filtrate in vacuo. The collected precipitate is added to the concentrated filtrate and the mixture is extracted with chloroform. The aqueous phase is separated, acidified with dilute hydrochloric acid, and the resulting precipitate (A) is collected by filtration and dried." The chloroform phase is evaporated and the residue refluxed with 12 ml. of IN sodium hydroxide and 24 ml. of ethanol for 6 hours. The ethanol is evaporated in vacuo and the remaining solution is diluted with water and washed with chloroform. The aqueous solution is acidified with dilute hydrochloric acid and the precipitated solid (B) is collected and dried. The two samples of acidic material (A. and B) are combined and recrystallized from aqueous isopro-panol to give 5-(p_-chlorobenzoyl)-l-ethylpyrrole-2-acetic acid as a -white solid, m.p. 149-153 °C.

Analysis ; Calcd. for C H C1N0 : C, 6l.?5; H, 4.83; N, 4.80 1514 3 Found : C, βΐ.78; H, 4.94; N, 4.96% EXAMPLE XLV The N-alkylation procedure of Example XLIII is followed to prepare 5-a~royl-l-R-j_-pyrrole-2~acetonitriles wherein is lower alkyl. For example, by repeating such procedure with an equivalent amount of an appropriate N-unsubstituted 5~&royl-pyrrole-2-acetonitrile anc* an equivalent amount of an appropriate alkyl halide as the N-alkylating agents the folloiing respective products are obtained: . -benzoyl-l-ethylpyrrole-2-acetonitrile; - (p_-methylbenzoyl)-1- (n-propyl)pyrrole-2-acetonitrile ; -(p_>-mefchoxybenzoyl)-l-ethylpyrrole-2-acetonitrile; and - (2 * , k 1 -dichlorobenzoyl)-1- (n-butyl)pyrrole~2-acetonitrile.

EXAMPLE XLVI The nitrile-to-acid transformation procedure of Example XLIV is repeated, except that an equivalent amount of each acetonitrile obtained in Example XLV* is used as the starting acetonitrile to yield the following respective product -benzoyl-l-ethylpyrrole-2-acetic acid; ~( -methylbenzoyl)-l-(n-propyl)pyrrole-2-acetic acid; -(p_-methoxybenzoyl)-l-ethylpyrrole-2-acetic acid; and - (2' , 1 -dichlorobenzoyl) -1~ (n-butyl)pyrrole~2-acetic acid.

EXAMPLE XLVII The alkylatio and transformation procedures of Examples XXXIV and XXXV, respectively, are repeated, excep that an equivalent amount of each alk lpyrrole-acetonitrile obtained in Examples XLIII and XLV is used in place of the start-ing acetonitrile used in Example XXXIV, and an equivalent amount of an appropriate alkyl halide is used as the alkylating agent, to yield the following respective products : -(_-chlorobenzoyl)- - ethyl~l-ethylpyrrole-2-acetic acidj · -benzoyl-a-methyl-l-ethylpyrrole-2-acetic acid; , - (p_-methylbenzoyl)- -ethyl-l- (n-propyl)pyrrole-2-acetic acid; an - ( 1 ,4 ' -dichlorobenzoyl)-a-methyl-l- (n-butylpyrrole) -2-acetic ac EXAMPLE XLVI.II l-Benzyl-5~ (p_-chlorobenzoyl)-pyrrole-2-acetonitrile : A solution of 8.43 ml. (0.0663 mole) of p_-chiorobenzoyl chloride and 8.8 g.. (0.0ββ3 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane is added to a solution of 13.0 g. (0.0ββ3 mole) of l-benzylpyrrole-2-acetonitrile in 50 ml. of 1,2-dichloro ethane at 5°C. over a 5 minute period. The mixture is stirred for 1 minutes and then heated quickly to reflux for 3 minutes. The reaction mixture is poured into ice-hydrochloric acid and then filtered. The aqueous layer is separated and washed with chloroform. The combined organic solutions are washed successive with ,Ν-dimethylaminopropylamine solution, dilute hydrochloric acid, and brine and then dried over anhydrous, magnesium sulfate.

The solvent is evaporated and the oily residue dissolved in benzenc~methylcyclohexane and seeded with crystals of 1-benzyl 4~(p_-chlorobenzoyl)-pyrrole~2-acetonitrile . A ter crystalliza tion of the latter substance is complete, the mother liquor is filtered and evaporated and the residue crystallized from methanol. The crystals thus obtained are recrystallized from methanol to give l-benzyl-5-(p_-chlorobenzoyl)-pyrrole-2-aceto-nitrile as a yellow solid, m.p. 104-106°C.

EXAMPLE XLIX l-Benzyl-5~ (p_-chlorobenzoyl)-pyrrole-2-acetic acid : A suspension of 3.0 g. (0.009 mole) of l~benzyl-5- (p_-chloro-benzoyl)-pyrrole-2-acetonitrile in 20 ml. of ethanol and l8 ml. (O.OI8 mole) of IN sodium hydroxide is refluxed for 6 hours.

The mixture is diluted with water and the ethanol evaporated in vacuo. ' The solution is washed with chloroform and ether and acidified with 3N hydrochloric acid. The precipitated solid is collected and dried in vacuo to give about 2.8 g. (91°/ό yield) of l-benzyl-5-(p_-chlorobenzoyl)-pyrrole-2-acetic acid as white crystals, M.P. l62-l63°C.

Analysis ; Calcd. for C^H^CINO : ■ C, 67-70; H, .56 N, -3-9^ Found : C, 67-79; H, 4.65; N, 3.97$ EXAMPLE' L • The procedure of Example XLVIII Is ollowed to prepare 5-aroyl-l-R^~pyrrole-2-acetonitriles wherein ¾ is "benzyl. For example, "by repeating such procedure wit an equivalent amount of an appropriate benzoyl chloride in place o the p_~chlorobenzoyl chloride used therein, the following respective products are obtained : 1~benzyl-5-benzoy1-pyrrole-2-acetoni i1e; l-benzyl-5- ( -bromobenzoyl)-pyrrole-2-acetonitrile; l-benzyl-5- (p_-ethoxybenzoyl)-pyrrole-2-acetonitrile; l-benzyl-5- (2' ,4' -dichlo obenzoyl)-pyrrole-2-acetonitrile; and l-benzyl-5- (3 ' , 1 -dimeth l enzoyl)-pyrrole-2-acetonitrile.

EXAMPLE LI The nitrile-to-acid transformation procedure of Example XLIX is followed using an equivalent amount. of each acetonitrile obtained in Example L to yield, as respective products, the corresponding l-benzyl-5-aroyl-pyrrole-2~acetic acids.

EXAMPLE LII The alkylation and trans ormation procedures of Examples XXXIV and XXXV, respectively, are repeated, except that an equivalent amount of an appropriate l-benzyl-5-a-royl-pyrrole-2-acetonitrile and an equivalent amount of an appro-priate alkyl halide as the alkylating agent are used to yield the following respective products : l-benzyl-5- (p-chlorobenzoyl)~a-methyl-pyrrole-2-acetic acid l-benzyl-5-benzoyl-a~(n-propyl)-pyrrole-2~acetic acid; l-benzyl-5- (p-bromobenzoyl)-a-ethyl-pyrrole~2-acetic acid; l-benzyl-5- (p_-ethoxybenzoyl)-a-methyl-pyrrole-2-acetic acid l-benzyl-5- [2X , t-dichlorobenzoyl)- -ethyl-pyrrole-2-acetic acid; l-benzyl-5- (3,,^'-dimethylbenzoyl)- -methyl-pyrrole~2-acetic acid.

EXAMPLE LIII . ' -(p_-Chlorobenzoyl)-l-methylpyrrole-2-acetonitrile : ■ An acylating solution is prepared by the, slow addition of 278 g. (I.58 moles) of p_-chlorobenzoyl chloride to 210 g. (I.58 moles) of aluminum chloride in 75° ml. of ethylene chloride. The resulting solution is added to a solution of 190 g. (I.58 moles) of N-methylpyrrole-2-acetonitrile in 7 ml. of ethylene chloride. The temperature is maintained at 20-22°C. during the addition; and the solution is further stirred at room temperature for one hour. The solution is then heated rapidly to 7^-76 °C. at which point there is a vigorous evolution of hydrogen chloride gas.

This temperature is maintained about minutes and the solution" is cooled rapidly and poured into ice water. The product is solution of N, N-dimcthylaminopropylamine followed by dilute hydrochloric acid in order to remove any excess p_-chlorobenzoyl chloride. After a final wash with brine, the solution' is dried over anhydrous magnesium sulfate. Distillation of the solvent leaves a residue which crystallizes. Recrystallization from methyl alcohol yields the product, 5- (p-chlorobenzoyl)-l-methyl-pyrroie-2-acetonitrile, m.p. 120-12 °C. After two additional recrystallizatiohs from methanol, the m.p. is 127-131°C EXAMPLE LIV - (p-Chlorobenzoyl)-l-methylpyrrole-2-acetic acid : A mixture of 129 g. (0.52 mole) of 5- (p-chlorobenzoyi) ~1-me hylpyrrole-2-acetonitrile and 88 g. (1.1 moles) of 5 ^ sodium hydroxide solution in 800 ml. of ethanol and 500 ml. of water is stirred and refluxed for about 18 hours with slow evolution of ammonia. The solution is then cooled to about 50°C. and acidified by adding 110 ml. of concentrated hydrochloric acid. The mixture is cooled and the precipitated product, 5-(p_-chlorobenzoyr)-l-methylpyrrole-2-acetic acid, is filtered and recrystallized from methanol, m.p. 193-195 °C. (dec). A. second crop is obtained upon concentration of the. mother liquor for a total yield of about 67 of theoretical. Analysis : Calcd. for C . H C1N0 : N, 5',05$ l^ 11 j Found : N, 5.06g EXAMPLE LV ' · Ethyl 5-(p-chlorobenzoyl)~l-methyl-pyrrole~2-acetate : A suspension of 55 ·4 g« of 5- (pj-chlorobenzoyl)-l-methyl-pyrroles-acetic acid, 44 ml. of absolute ethanol, lg. of p_-toluene-sulfonic acid and 6 0 ml. of "benzene is heated under reflux with azeotropic removal of water for 7 hours. The reaction mixture is filtered, washed with sodium bicarbonate .solution, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The crystalline residue is recrystallized twice from c clohexane to give ethyl 5- (p_-chlorobenzoyl)-l-methyl-pyrrole- . 2-acetate as a yellow solid, m.p. 7.- 6 °C.

EXAMPLE LVI The procedure of Example Ly is repeated except that an equivalent amount of isopropanol and n-butanol are used in place of the ethanol used therein to yield, as respective products, the corresponding isopropyl and ri-butyl esters of -(p_-chlorobenzoyl)-l-methyl-pyrrole-2-acetate.

EXAMPLE LVII A. Methyl l-methylpyrrole-2-acetate ; Pour hundred and fifty ml. of ethereal diazomethane [prepared from 3 g. (0.2 mole) of N-methyl-N-nitroso-p_-toluenesulfonamide by the method described in Organic Synthesis, Vol. IV, John Wiley & Sons p. 25Ο-252, (19S33 is added dropwise to a cooled solution of 18.1 g. (O.13 mole) l-methylpyrrole-2-acetic acid in 100 ml. of anhydrous methanol keeping the temperature at approximatel ' 0°C. When .the evolution of gas ceases, the mixture is washed three times with saturated sodium bicarbonate solution, once with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent is evaporated, yielding about 1 . g. of an oily residue of methyl l-methylpyrrole-2-acetate which is used without further purification in the procedure of Example XLVII.

B. Methyl pyrrole-2-acetate is obtained by repeating the procedure of Example LVII-A, except that an equivalent quantity of pyrrole-2-acetic acid is used in place of the 1-methylpyrrole-2-acetic acid used therein..

EXAMPLE LVIII A. Methyl 5- (P_-chlorobenzoyl)-l-meth lpyrrole-2-acetate: Ten and a half grams of p^-chlorobenzoyl chloride is added dropwise to a chilled suspension of 8 g., (Ο.θβ mole) of aluminum chloride in βθ ml. of methylene chloride. The resulting solution is added quickly but dropwise to a solution of 7.6 g. (O.05 mole) methyl l-methylpyrrole-2-acetate in 30 ml. of methylene chloride keeping the temperature below 10°C. The reaction mixture is stirred for twenty minutes, then poured into 3N hydrochloric acid, and the resulting mixture extracted with ether. The ether fraction is washed successively with N, N~ dimethyl-l,3-p- opanedianrine, with 3N- hydrochloric acid- and with saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo and the resulting solid, methyl 5- (pj-chlorobenzoyl) -l-methylp.yrrole-2-acetate, is purified by recrystallization from methanol,' m.p. 122-125 °C B«» Methyl 5- (p_-chlorobenzoyl)-pyrrole--2~acetate is obtained by repeating the procedure of Example LVIII-A, except that an equivalent quantity of methyl pyrrole-2-acetate is used in place of the methyl l-methylpyrrole-2-acetate used therein.

EXAMPLE LIX By repeating the procedures of Example LVIII (A and B), except that an equivalent quantity of an appropriate benzcy 1 chloride is used in place of the p_-chlorobenzoyl chloride used therein, the following respective products are obtained: methyl- 5-benzoyl-pyrrole-2-acetate; methyl 5-benzoyl~l-methylpyrrole-2-acetate methyl 5-(g_-bromobenzoyl)-l-methylpyrrole-2-acetate; methyl 5-(p_-methoxybenzoyl)-l-methylpyrrole-2-acetatej and methyl 5-(2' , l-dichlorobenzoyl)-pyrrole-2-acetate.

EXAMPLE LX - (p-Chlorob'enzoyl)-l-methylpyrrole-2~acetamide : A mixture of. 12.4 g. (O.05 mole) of 5- (pj-chlorobenzoyl)-l-methyl-pyrrole-2-acetonitrile and 8 g. of 50% sodium hydroxide solution in 5° ml. of water and 75 ml. of methyl alcohol is stirred and refluxed for 5 minutes. The resulting solid is filtered from the hot solution and recrystallized from dimethyl formamide to give about 8.5 g. (62 ) of the product 5-(_~chlorobenzoyl)-l~ methylpyrrole-2-acetamide, m.p. 250-253°C . (dec . ) .

Analysis : Calcd. for C1 H13C1N202 : K> 10.1 3$ ■ Pound : N, 9.97 ■ EXAMPLE LXI The procedure of Example LX is followed to hydrolyze the cyano function of the subject compounds to an amide function (i.e., "Rg")* For example, by repeating said procedure with an equivalent amount of an appropriate 5-aroyl-l-R^-2-alkanonitrile as the starting material, the following respective products are obtained: -benzoyl-l-methylpyrrole-2-acetamidej -(p_-chlorobenzoyl)-pyrrole-2-acetamide - (31 -chloro-p_-toluoyl)-l-methylpyrrole-2-acetamide; -(p_-methoxybenzoyl)-pyrrole-2-acetamide; -(p_-chlorobenzoyl)-l-ethylpyrrole-2-acetamide; and l-"benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetamide.

EXAMPLES LXII ~(p_-Chlorobenzoyl)- -ethyl-l-methylpyrrole-2-acetamide: A suspension of 6.0 g. (0.02.mole) of the- sodium salt of 5- (_-chloro" enzoyl)-l-methylpyrrole-2-acetic acid in 100 ml. of dry benzene is treated with 2.1 ml. (0.025 mole) of oxalyl chloride in 100 ml. benzene. The mixture is stirred for 3 hours, filtered, evaporated in vacuo and the residue taken up in benzene. The benzene mixture is poured into 5 ml. of 70^ ethylamine in 200 ml. of water. The preciix!tated solid is filtered and dried. It is recrystallized from ethanol to give about 2.0 g. of 5-(p_~chlorobenzoyl)>-K-.ethyl-i-methylpyrrole~ 2-acetamide as white needles, m.p. l87-l88°C.

Analys s ; Calcd. for C^H^CII^O : C, 63.05; K, - 62 ; N, 9.20j¾ Pound : C, 63.0β; H, .5.61; N, 9.1*$ EXAMPLE LXIII · -(p_-Chlorobenzoyl)-NiN-diethyl-l-methylpyrrole-2-acetamide: To a solution of 6.1 g. (0.02 mole) of 5- (p_-chloro-benzoyl)-l-metliylpyrrole-2-acetic acid in 100 ml. chloroform is added 3.8 ml. (0.03 mole) thionyl chloride. The mixture . is stirred and refluxed overnight. The solvent is then evaporated and the residue is added quickly to a solution of 22 ml. diethyl-' amine in 50 ml. water while cooling externally with an ice-bath. A solid precipitates, 5- (R~chlorobenzoyl)-N,N-diethyl-l-methyl-pyrrole-2-acetamide, which is collected and purified by recrystal-lization from methylcyclohexane (with charcoal while in solution), m.p. 82-8 °C.

Analysis : Calcd. for c18H icl¾02 : C' ^°^> 11> 6«36; N, -8. ¾£ Found : C, β5· 02; H, 6.38; N, 8.2C# EXAMPLE LXIV By following the respective procedures of Examples LXII and LXIII, except that an equivalent amount of an appro-priate 5-aroyl-pyrrole~2-alkanoic acid or salt thereof and an equivalent quantity of an appropriate primary or secondary allcylamine are used as starting materials, the following respective products are obtained : -benzoyl-N-ethyl-l-raethylpyrrole-2~acetamide; ~benzoyl-N N-diethyl-pyrrole-2-'acetamide; l-benzyl-5- (p-chlorobenzoyl)-N-isopropyl~pyrrole'-2~acetamidej -(p_-toluoyl)-N, -dimethyl-l-methylpyrrole-2-acetamidej - (p_-chlorobenzoyl)-l-ethyl-N-(n-butyl)-pyrrole-2-acetamide and 5- ( -chlorobenzoyl)-N-ethyl-a-methyl-l-methylpyrrole-2-acetamide.

■ EXAMPLE " LXV The procedure described by R. Jones and J. Lindner in -the Canadian Journal of Chemistry, 18, 883 (19&5) , wherein N-alkylpyrrole-2-carboxaldehydes are reacted with ethoxycarbonyl-methylene triphenylphosphorane to yield ethyl 2- (l-alkyl-2-pyrrolyl)-acrylates, is followed to prepare, as respective products, the 1-methyl, l-(n-butyl) and 1-isoamyl derivatives EXAMPLE I.XVI . .■ Ethyl 2- (l-metlyl-2-pyrrolyl) -propion te ; A solution of 62.4 g. (Ο.35 mole) ethyl 2-(l-methyl-2-pyrrolyl)-acrylate in 35Ο ml* 95 ethanol is hydrogenated in a Parr shaker using 3 g. of platinum oxide as the catalyst.' The hydrogenation is continued overnight under 32 p.s.i. of hydrogen. The mixture is filtered and the filtrate concentrated in vacuo. The residua yellow oil is dissolved in ether and washed successively with 3N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The ether solution is . dried over anhydrous magnesium sulfate. 'The ether solvent is then evaporated to yield about 42 g. of a clear oil, ethyl 2-(l-methyl-2-pyrrolyl)-propionate. · EXAMPLE LXVIJ.

Ethyl 5- (p_-chlorobenzoyl) -1-me hylpy role-2-p opionate To a suspension of 26.6 g. (0.2 mole) of aluminum chloride in 100 ml. methylene chloride is added 34.8 g. (0.2 mole) of 'p_-chlorobenzoyl chloride. The resulting solution is added drop-wise to a solution of 3β.8 g. (0.2 mole) of ethyl 2-(l~methyl~ 2-pyrrolyl)-propionate- in 100 ml. methylene chloride while' cooling externally with an ice bath. After the addition is complete, the reaction is stirred for 10 minutes and. poured into ice acidified with dilute hydrochloric acid. The two fractions are separated. The organic fraction is washed success ively with N,N-dimethyl-l,3-propanediamine, 3N hydrochloric acid saturated sodium bicarbonate solution and saturated sodium then dried over anhydrous magnesium sulfate and the solvent evaporated ix vacuo. Λ solid is crystallized in the resulting oily residue which is isolated and purified by recrystallization from methanol, m.p. 71.5-73°C .

■ EXAMPLE LXVIII - (p_-Chloroben.zoyl)-l-methyipyrrole-2-propionic acid: A suspension of 8.0 g. (0.025 mole) of ethyl 5- (pj-chlorobenzoyl)' l-methylpyrrole-2-propionate. in 15 ml. ethanol and 30 ml. IN . sodium hydroxide is refluxed for one hour. The ethanol is then evaporated and the remaining solution is poured into dilute hydrochloric acid. The resulting white precipitate is filtered off and. purified by recrystallization from isopropyl alcohol, 5- (p_-chlorobenzoyl)-l-methylpyrrole-2-propionic acid, m.p. 188-191°C.

EXAMPLE LXIX The successive procedures of Examples LXVI, LXVII . and LXVIII are. repeated, except that an equivalent amount of the l-(n-butyl) and 1-isoamyl derivative of ethyl 2-(2-pyrrolyl)-acrylate is used initially, to yield, as respective products : ethyl 2- (l-n-butyl-2-pyrrolyl)-propionate; ethyl 2-(l-isoamyl-2-pyrrolyl)-propionate; . e hyl 5- (p_-chlorobonzoyl )~I-n-butylpyrrole-2-prop:i.onate ethyl 5- (p-chlorobenzoyl)-l~isoarr lpyrrole-2-propionate - (p_-chlorobenzoyl)-l-n-butylpyrrole~2~propionic acid and - (p_-chlorobenzoyl)-l-isoaraylpyrrole-2-propionic acid .· EXAMPLE LXX A. The acylation procedure of Example LXVII is repeated,, except that an equivalent amount of an appropriate ethyl 2- (l-alkyl-2-pyrrolyl ) -propionate and an equivalent . amount of an appropriate benzoyl chloride acyD.ating agent, are employed, to yield as respective products : ethyl 5- (p_-methylbenzoyl)-l-methylpyrrole-2-propionate ■ ethyl 5- (p-ethoxybenzoyl )-l-n-butylpyrrole-2-propiona te ethyl 5- (21 , ! ~dichlorobenzoyl)-l-methylpyrrole-2-propionate ethyl 5- (p-cyanobenzoyl)-l-isoamylpyrrole-2-propionate j ethyl 5- (p_-methyl.thiobenzoyl)-l-methylpyrrole-2-propionate j ethyl 5- (p_-nitrobenzoyl )-l~methylpyrrole-2-propiozate and ethyl 5- (3 ' , ' , 5' -trimethoxybenzoyl )-l-methylpyrrole-2-propionate .

B. The ester-to-acid transformation procedure of Example LXVIII is repeated using an equivalent amount of each propionate ester obtained from Example LXX-A in place of the ester used therein to yield, as respective products, the corresponding 5-aroyl-l-alkylpyrrole-2-propionic acid.

C. By using an equivalent amount of ethyl 5- (p_-nitrobenzoyl)-l-methylpyrrole-2-propionate in place of 5~(p_-nitrobenzoyl).-l-methylpyrrole-2-acetonitrile in the hydrogenation procedure of Example XXIV, the product, ethyl 5- (p_-aminobenzoyl)-l-methylpyrrole-2-propionate is obtained.

D. By repeating the hydrolysis procedure of- Example LXVIII with an equivalent amount of the ester obtained from Example LXX-C in place of the ester used therein, the product, 5- (p_-aminobenzoyl)-l~methylpyrrole-2-propionic acid is obtained.

EXAMPLE LX I The procedure described by Ceresole in Ber., 17, 8l5 (1884), wherein l-aryl-l,3-butanediones are reacted with nitrous acid to yield the corresponding l-aryl-l,2,3-butanetrione-2~ oximes, is followed to prepare, as respective products: l-phenyl-l,2,3-"b tanetrione-2-oxime, HI.p. 130-131°C; l-p_-chlorophenyl-l,2,3-' tanetrione-2-oxime; l-p_-methylphenyl-l,2,3-'butanetrione-2-oxime and l-p_-methoxyphenyl-l,2,3-t>utanetrione-2-oxime.

EXAMPLE LXXII-- A. Ethy15-benzo 1-3-ethoxycarbony1-4-methylpyrrole-2·-acetate : A solution of 71 g. (0.37 mole) of l-phenyl-1,2,3-butanetrione-2-oxirne in 350 nil. glacial acetic acid and '50 ml. of water is added to 75· β· diethyl acetonedicarboxylate in 3 Ο ml. of glacial acetic acid at 70°C. Concurrently, a mixture of 73 g. (1.12 mole) of zinc dust and 91.5 g. (1.12 mole) of anhydrous sodium acetate is added in portions at such a rate that the temperature is maintained near 100°C.. After the additions are complete (about minutes), the mixture is refluxed for one hour. and poured into iced water. The resulting crude semisolid is collected by filtration and recrystallized twice from methanol to give ethyl 5-¾enzoyl-3-ethoxycarbonyl-4-meth2>'l-pyrrole-2-acetate, m.p. 15 -15 °C.

Analysis : Calcd. for c1^21m^> '' G' K> 6·ιδ; N* 4.08$ Found : C, 66.50; H, 6.20; , 4.17$- B. By repeating the procedure of Example LXXII-A with an equivalent amount of the l-p_-chlorophenyl, l-p_-methylphenyl and l-p-methoxyphenyl derivative of 1,2, 3-butanetrione-2~oxime, there are obtained as respective products, the corresponding ethyl 5~aroyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetates .

A . 5-Benzoy1-3-carboxy- -methyIpyrro c-2-acetlc acid : A mixture of 3·^ &· of ethyl 5-'berizoyl-3-ethoxy-carbonyl- -methylpyrrole-2-acetate, 10 g. of ?ί sodium hydroxide solution and 10 ml. of water is refluxed for 2 hours. The reaction mixture is then diluted with water and acidified with dilute hydrochloric acid. The precipitated solid is collected by filtration, air-dried, and recrystallized from acetone-water -to yield the product, 5~benzoyl~3-carboxy- -methylpyrrole-2-acetic acid, as white crystals, m.p. 250-253 °C.

B. The hydrolysis procedure of Example LXXIII-A is repeated, except that an equivalent amount of each ester obtained in Example LXXII-B is used, to yield, as respective products, the corresponding 5-P_~chlorobenzoyl, 5-P_-^eth lbenzoyl and -p_-methoxybenzoyl derivatives of 3-carboxy- ~methylpyrrole-2-acetic acid.

EXAMPLE LX IV A. Ethyl 5-benzoyl~3-carboxy- -meth lpyrrole-2-acetate : A solution of 8.0 g. (0.028 mole) of 5- enzoyl-3-carboxy- -methylpyrrole-2-acetic acid in 80 ml. of 0.5?ά ethanolic hydrogen chloride is refluxed for 90 minutes. The solution is charcoaled, filtered; and the filtrate evaporated in vacuo to yield a crystalline residue which is recrystallized from acetone to give ethyl 5-benzoyl-3-carboxy- -methylpyrrole-2-acetate, m.p.' I83-I85°C ' B. The partial reesterification procedure of Example CIV-A is repeated using an equivalent amount of the respective acids obtained in Example LXXIII-B. to yield the corresponding ethyl 5-aroyl-3-carboxy-4-methylpyrrole-2-acetatesj respectively.

EXAMPLE Ι,ΧΧΥ A. 5-Benzoyl~ ~methylpyrrole~2-acetic ac d : A solution of 4.13 g. (O.OI31 mole) of ethyl■ 5~benzoyl-3-carboxy-4-methyl-pyrrole-2-acetate in 80 ml. of quinoline in the presence of a trace amount of copper chromite is heated at l80-l83°C. for 5. hours. The mixture is poured into dilute hydrochloric acid and extracted three times with ether. The ether extracts are combined and washed successively with dilute hydrochloric acid, sodium bicarbonate solution and brine and then dried over anhydrou magnesium sulfate. The solvent is evaporated .in vacuo to give about g. of semisolid ethyl 5-benzoyl- -methylpyrrole-2-acetate which is used in the following hydrolysis procedure without further purification.

The entire semisolid is dissolved in 20 ml.. of ethanol and 20 ml. of IN sodium hydroxide solution is added. The mixture is heated under reflux for 30 minutes. The solvent is then evaporated' in vacuo and the residue dissolved in water and washed with ether. The aqueous solution is acidified with dilute hydrochloric acid and the resulting crystalline solid (1.6 g., 50$ yield) is collected by filtration and air-dried. The product, 5-benzoyl- -methylpyrrole-2-acetic acid, is recrystallized three ° B. The procedure of Example IXXV-A is repeated using an equivalent amount of the respective esters obtained in Example LXXIV-B to yield the corresponding 5~p_-chlo obenzoyli 5-p_-methylbenzoyl and 5-Pj-methoxybe zoyl derivatives, respectively, of -methylpyrrole-2~acetic acid.

C. Lower alkyl esters of the acids obtained in A and B of this Example, such as, for example, the ethyl, isopropyl .and n-butyl esters, are prepared by conventional esterification techniques using an appropriate lower alkanol.

D. Primary, secondary and tertiary amides of the acids obtained in A and B of this Example are prepared by conventional procedures, for example, by treatment v/ith thionyl chloride and then contacting the thus-obtained acid chloride with ammonia, a primary lower alkylamine or a secondary lower alkylamine, such as : -benzoyl-N,N-diethyl-4-methylpyrrole-2-acetamide; - (p_-chlorobenzoyl)-4-rnethylpyrrole-2-acetamide; -(_-methylbenzoyl)-N-methyl- -methylpyrrole-2-acetamide; and 5- (p_-methoxybenzoyl)-N-ethyl- -methylpyrrole-2-acetamide.

EXAMPLE LXXVI A. Ethyl 5- (p-chlorobenzoyl)-2, -dimethylpyrrole-3-acetate To a solution of 29 g. (0.17 mole) of p_-chlorobenzoyl chloride and 28.0 g. (0.15 mole) of ethyl 2, -dimethylpyrrole-3-acetate in 100 ml. carbon disulfide, is added 1.23 g. (0.31 mole) of anhydrous aluminum chloride. The reaction mixture is cooled externally with an ice bath. The mixture is stirred for 15 minutes after which the solvent is decanted and the remaining · solid treated with ice acidified with 3N hydrochloric acid.

The acidic mixture is extracted three times with ether. The combined ether extracts are washed successively with N N-dimethylr- l,3~propanediarnine, 3N hydrochloric acid, and a saturated solution of sodium chloride. The solution is dried over anhydrous magnesium sulfate and the solvent evaporated . in vacuo.. The remaining solid is recrystalli ed from methanol to yield, ethyl • 5-(p_-chlorobenzcyl )-2, -dimethylpyrrole-3-acetate, m.p. 126-129°C.

B. By repeating the procedure of Example LXXVI-A, except that an equivalent amount of an appropriate benzoyl chloride is used as the acylating agent, there are obtained as respective products.: ethyl 5-benzoyl-2, -dimethylpyrrole-3-acetate; ethyl 5-(p_-methoxybenzoyl)-2, -dimethylpyrrole-3-acetatej ethyl 5- (2 ' ,k ' -dlchlorobenzoyl)-2, -dimethylpyr ole-3-acetate ethyl 5- (31 -chloro- ' -methylbenzoyl)-2, -dimethylpyrrole-3-acetate EXAMPLE LXXVII A. Ethyl ^~(^-chlOTobenzoyl)~-~m hyl-2-tTlchlor mQt yl~ pyrrole-3-acetate : To a suspension of 9,6 g. (0.03 mole) of ethyl 5- (p_-chloro enzoyl)-2,i|—dimethylpyrrole-3-acetate in 75 ml. ether is added dropwise 7.8 ml. sulfurylchloride, cooling externally with an ice bath. The resulting suspension is stirred at room" temperature for 15 hours. The resulting white solid, ethyl 5- (pj-chlordbenzoyl) - -methyl-2-trichloromethyl- pyrrole-3-acetate, is filtered and purified by recrystallization twice from methylcyclohexane, m.p. 133-137°C.

B. Perchlorination of the 2-methyl group in the esters obtained from Example LXXVI-B is performed by repeating the procedure of Example LXXVII-A.

■ EXAMPLE LXXVIII · A. 5-(p_-Chlorobenzoyl)-il-methyl-2-carboxypyrrole-3- acetic acid; A solution of 1.0 g. (0.0026 mole) of ethyl -(p_-chlorobenzoyl)- -methyl-2-trichloromethylpyrrole-3-acetate in 10 ml. dioxane and 3 ml. water is refluxed for three hours. The resulting solution is cooled and extracted with chloroform. The organic fraction is extracted with a saturated - solution of sodium bicarbonate. The aqueous phase is made acidic with dilute hydrochloric acid and the resulting precipitate of 5-(p_-' chlorobenzoyl)- -methyl-2-carboxypyrrole-3-ace.tic acid is filtered and dried, m.p. 240°C.

B. The procedure of Example LXXVIII-A is repeated using an equivalent amount of the 2-trichloromethyl esters obtained from Example LXXV I-B to yield,' as respective products, the corresponding 5-aroyl- -methyl~2-carboxypyrrole~3--acetic acids .

EXAMPLE LXXIX A. 5- ( -Ch1orobenzqy ) -4-inethyIp rro1e-3~acetic acid: A solution of 1.4 g. (0.004 mole) of 5- (£~chlorobenzoyl) -4-methyl-2-carboxypyrrole-3~ cetic acid in 25 ml. qulnoline is heated overnight at l60°C. under nitrogen. The reaction is poured into ice acidified with hydrochloric acid.. The mixture is extracted with chloroform and the organic phase is extracted with a saturated solution of sodium bicarbonate. The basic solution is made acidic with dilute hydrochloric acid and the resulting solid, ' 5-(p-chlorobensoyl) -4-methylpyrrole-3-acetic acid, is filtered and purified by recrystallization from isopropyl alcohol, m.p. l45-l47°C. Β.· The decarboxylation procedure of Example LXXIX-A is repeated, except that an equivalent amount of the 2-carboxypyrrol 3-acetic acids obtained in Example LXXVIII-B is used as the start ing acid, to yield the corresponding 5-aroyl-4-methylpyrrole-3-acetic acids, respectively. · C. Lower alkyl esters of the acids obtained in A and B of this Example, such as, for example, the ethyl, isopropyl and n_-butyl esters, are prepared by conventional esterification procedures using an appropriate lower alkanol.

D. Primary, secondary and tertiary amides of the acids obtained in Λ and B of this Example are prepared by conventional procedures to yield, for example, the following respective amides - ( j^chloro enzoyl) -4-methylpyrrole-3-acetamide; -benzoyl-K-ethyl- -me'thylpyrrole-3-fi-cetainide - (p_-methoxybenzoyl)-l^n-propyl-4-metlTylpyrrole-3~acetamide; .5- (2f ,4' -dichlorobenzoyl)-I\ W-diethyl-4~methylpyrrole-3-acetamide EXAMPLE LXXX A. 2-Dimethylamlnomethyl-l-benzylpyrrole : A solution of 8.2 g. (0.1 mole) dimethylamine hydrochloride in 8 ml. formalin is added dropwise to 17.12 g. (0.1 mole) of l-benzj^lpyrrole .

The mixture is stirred at room temperature until solution occurs (about 4 hours). The solution is poured into lO sodium hydroxide solution and then extracted into ether.three times. The combined organic fractions are washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent evaporated in vacuo. The product, 2-dimethylaminomethyl-l-benzylpyrrole,' is distilled at reduced pressure, b.p. 73 °C, 0.025 mm. Hg.

B. 2-Dimethylaminomethyl-l-benzylpyrrole methiodide : A solution of 100 g. (0.47 mole) of 2-dimethylaminomethyl-l-benzyl-pyrrole in 200 ml. of absolute ethanol is cooled to 5°C To this is added dropwise 29.4 ml. (0.47 mole) of methyl iodide.

A white, solid precipitates. The suspension is stirred until the precipitate is so thick that additional stirring becomes impossib C. 11-Bsnzy1pyrrole-2-aceton1 r11e: Λ .suspension of 83.9 g. (0.25 mole) of 2~dimcthylaminomethyl~l~bensylpyrrolc methiodido is added to a suspension of 12.8 g. (0.2β mole) of sodium cyanide in ho ml. dimethylrrlfoxide . The mixture is heated under reflux for 3 hours and stirring at room temperature is continued overnight. The reaction mixture is poured into' water and extracted > three times with ether. The combined ether extracts are washed with brine and dried over anhydrous magnesium sulfate. The ether solvent is evaporated in vacuo to give about hi g. of an oily residue which crystallizes upon standing.. Recrystalliz&tion from met ylcyclohexane yields the product, l~benzylpyrrole-2~ ace onitrile, m.p. 62-β3°0.

EXAMPLE LXXXI A. _3~Chloro-^~methylbenzoyl chloride is prepared b reflux'ing together 30 g. (0.175 mole) of 3--chloro- -methyl benzoic acid and 85 ml. thionyl chloride for about 2.5 hours, after which the excess thionyl chloride is distilled off under vacuum. . The aroyl chloride product, 3-chloro~ -methylbenzoyl chloride, distills over at b.p. 70-7¾°C., 10.25 mm. Hg.

B. The procedure .of Example LXXXI-A represents a method for trans orming benzoic acid derivatives to the corresponding acid chloride form. By following such procedure, except that an equivalent amount of an appropriately substituted benzoic acid is initially employed, the following aroyl chlorides are obtained 3, 4-dimethoxybenzoyl . chloride; . 3-bromo-4-chlorobenzoyl chloride; 2, 3, 5-tribromobenzoyl chloride; 3,4-dimethy benzoyl chloride; p_-ethyl e zoyl chloride; p_-ethoxybenzoyl chloride; and p_-methylthiobenzoyl chloride.

EXAMPLE LXXXII Primary, secondary and tertiary amides of the acids obtained in Examples LXVIII, LXIX, LXX-B and LXX-D are prepared by conventional reactions with ammonia or an appropriate alkyl-araine or dialkylamine to' yield, . for example, the following respective amides : - (p_-chlorobenzoyl)-l-methylpyrrole-2-propionamide; - (p_-chlorobenzoyl)-l-n-b tylpyrrole-2-propionamide; - (p-chlorobenzoyl)-l-isoamylpyrrole-2-propionamide; - (p_-methylbenzoyl)-N-ethyl-l-methylpyrrole-2-propionamide; - (3 'At >5 ' -trimethoxybenzoyl)-N, N-diethyl-l-methylpyrrole-2- propionamide - (p_-nitrobenzoyl)-l-methylpyrrole-2-pr0pionamide; and - (p_-aminobenzoyl)-N-n-propyl-l-methylpyrrole-2-propionamide .

EXAMPLE LXXXII1 A. l-Benzyl-5- (p_-chlorobenzoyl)~pyrrole-2~acetor.itrile : A solution o 8. 3 ml. (0.0β'? mole) of p_-chlorobenzoyl chloride and 8.8 g. (0.0o7.mole) of aluminum chloride in- ' 100 ml. of 1, 2-dichloroethane is added to a solution of 13 · 0 g. ( 0.06? mole) of l-benzylpyrrole-2-acetonitrile in 0 ml. of 1 , 2-dichloroethane at 5 °c « over a 5 minute period. The reaction mixture is stirred for 15 minutes and then heated quickly to reflux for 3 minutes. The mixture, is poured into ice-hydrochloric acid and then filtered. The aqueous layer is separated and ' washed. with chloroform. The combined organic fractions are washed successively with N, N~dimeth laminopropylamine solution, dilute hydrochloric acid and brine and then dried over anhydrous, magnesium sulfate. The solvent is evaporated to yield an oily, residue from which the desired compound is isolated by column chromatography on neutral alumina v/ith a 50-50 mixture of benzene- ether as ' the'.eluting solvent. Evaporation of the eluate affords l-benzyl-5- (_-chlorobcnzoyl)-pyrrole.-2-acetonitrile as a yellow solid which is recyrstallized from methanol, m.p. 106-108°C.

B. l-Benzyl- - (_-chlorobenzoyl)-pyrrole-2-aceto'nit.rile : Continued elution of the column in Example LXXXIII-A with ethyl acetate, followed by evaporation of the eluate yields a yellow oil which crystallizes from benzene-methylcyclohexane to yield l-benzyl- -(_-chlorobenzoyl)-pyrrole-2-acetonitrile as a white solid, m.p. 102-104 °C. - 69 30426/2

Claims (1)

1. CLAIMS derivatives of the general and the therapeutically acceptable basic salts of the acids wherein Ar represents a monosubstituted phenyl or polysubstituted phenyl group each substituent of said substituted phenyl group being a halogen a lower lower methylthio or cyano represents a monosubstituted phenyl or substituted phenyl group each substituent of said substituted 70 phenyl group being a halogen a lower l or represents a hydrogen atom or a lower alkyl represents a hydrogen a lower alkyl or benzyl represents a or and represents a a provided that when Ar is a nitrophenyl or group then is a hydrogen is a lower alkyl group and is a COOH or grou when Ar is a cyanophenyl or methylthiophenyl group then is a lower alkyl group and is a COOH or lower and when is a hydrogen then R is also a hydrogen derivatives having the 0 R and the therapeutically acceptable basic salts of the acids wherein and are as defined in Claim derivatives having the 71 and the therapeutically acceptable basic salts of the acids wherein Ar and are as defined in Claim derivatives having the Me H and the therapeutically acceptable basic salts of the wherein and are as defined in Claim derivatives having the Me and the therapeutically acceptable basic salts of the acids wherein and are as defined in Claim h 1 1 2 c 72 h lp acetic acetic Ethyl Methyl h 26 h h A process for preparing derivatives having the general formulae or and the therapeutically acceptable basic salts of the acids as defined in Claim which process comprises reacting a compound of the formula 0 with a compound of the formula L in the presence of acid and a wherein is a cyano or lower alkoxycarbonyl if the product is converted to corresponding free carboxylic acid by or when it is desired to prepare compounds of the formula wherein R is a lower alkyl group and is a or a compound of the wherein is as above is a lower alkyl or benzyl group and is a phenyl group or a phenyl group substituted by a halogen a lower lower alkoxy or cyano with a lower alkyl halide in the presence of a strong if the product is hydrolysed to the corresponding free carboxylic or when it is desired 74 to obtain compounds wherein is a lower alkyl Ar is same as R is a lower alkyl group and is a or ing a compound of the formula followed by of the in each case ing a lower alkyl halide in the presence of a strong base as the alkylating if hydrol sing the product to the corresponding and in the case when Ar is a and is the same as if ically hydrogenating the aitro function to yield the ponding compound wherein Ar is an if hydrolysing the product to the corresponding free acid and in the case when is a if esterifying the said with a lower alkanol to yield a compound wherein is a lower and in the case when is a if partially hydrolysing the said compound to the corresponding amide wherein is a and in the case when is a if converting the said compound to the corresponding acid chloride form followed by reacting the product with a lower or a to yield the corresponding amide wherein is a or or reacting a compound of the formula 75 0 wherein Ar is as defined above and other than with a compound of the formula in the presence of a Lewis acid and a the resultant ester to yield the corresponding free acid of formula and in the instance wherein Ar is a nitrophenyl and is a if catalytically hydrogenating the nitro function to yield the corresponding compound wherein Ar is an phenyl group if hydrol sing the product to the free acid and if converting the said acid to the corresponding amide with ammonia or an appropriate lower alkyl or or and decarboxyl ing a compound of the formula or a compound of the formula 76 by heating in a basic organic solvent to prepare compounds of the respective formulae Me and Me if hydrolysing compound to the ponding and if esterifying compound with a lower alkanol or converting said acids to the corresponding amides with ammonia or an appropriate lower alkyl or if paring therapeutically acceptable salts of the acids of formulae and by treatment with an appropriate process for preparing which comprises reacting ethyl with followed by hydrolysing the product to the free 77 process for which comprises reacting rile with followed by hydrolysing the product to the free process for preparing which comprises reacting with followed by hydrolysing the product to the free A process for preparing which comprises hydrolysing rile to the free A process for preparing which comprises hydrolysing to the free A process for preparing which comprises hydrolysing to the free process for preparing which comprises hydrolysing to the free A process for preparing which comprises hydrolysing to the 78 41 A process for preparing which comprises hydrolysing ethyl to the free A process for preparing which comprises hydrolysing ethyl to the free A process for preparing which comprises hydrolysing ethyl to the free A process for preparing which comprises reacting acetonitrile with benzoyl chloride followed by hydrolysing the product to the free A process for preparing acid which comprises lysing ethyl acetate to the free A process for preparing which comprise hydrolysing ethyl to the free A process for preparing which comprises hydrolysing to the free 79 A process for preparing comprises hydrolysing to the free A process for preparing ethyl which comprises reacting ethyl with A process for preparing methyl which comprises reacting methyl with A process for preparing which comprises partially lysing to the corresponding A process for preparing comprises hydrolysing to the A process for preparing which comprises reacting acid with oxalyl followed by reacting the products with A process for preparing which comprises reacting acetic acid with thionyl followed by reacting the product with A process for preparing 80 which comprises hydrolysing ethyl to the free A process for preparing which comprises acid by heating in A process for preparing which comprises hydrolysing ethyl to the free A process for preparing I which comprises reacting with A process for preparing compounds or as claimed in Claim substantially as inbefore described with reference to any one of the ing A compound as claimed in Claim 1 whenever prepared by the process as claimed in any one of Claims 32 to An agent comprising a compound as claimed in any one of Claims 1 to and a pharmaceutically acceptable carrier For the Applicants AND PARTNERS insufficientOCRQuality