IL43570A

IL43570A - Aroyl-substituted phenylacetic acids and derivatives thereof their preparation and pharmaceutical compositions containing them

Info

Publication number: IL43570A
Application number: IL43570A
Authority: IL
Original assignee: Janssen Pharmaceutica Nv
Priority date: 1972-10-24
Filing date: 1973-11-05
Publication date: 1977-05-31
Also published as: JPS4993346A; LU68666A1; YU37106B; BG25209A3; NO141651C; DE2353357C2; NL179583C; JPS5940811B2; IE38402B1; FI66369C; DD110044A5; CA1007643A; NL7314629A; NO141651B; CS183719B2; ES419871A1; IL43570A0; AU6176573A; YU275973A; FR2203635A1

Description

—S—SS—¾B—-*—«—SB—J3—CS»--S— — so—es—«s«t- Aroy -s bstttuted phenylacetic acids and derivatives thereof* their preparation and pharmaceutical . compositions containing them C:-41702 The invention pertains to the field of aroyl-phenylacetic acids, and to esters, amides and hydroxamic acids thereof, which demonstrate anti-inflammatory activity. The sulgect compounds differ mainly from those of the prior art by the nature of the aroyl function.

The prior art may be represented by the following references: French Spec. Med. Pat. 8.440M; French Pat. No. 1, 589.691; French Spec. Med. Pat. 7, 956M; Chem. Abstr. , 7 , 91097s; Chem. Abstr. , 73» 66268g; French Pat. No. 1,516, 775; French Spec. Med. Pat. 5, 903M; Chem. Abstr., 73, 77035e; and French Spec. Med. Pat. 6, 444M.

This invention relates to novel aroyl-substituted phenylacetic and certain esters, amides and hydroxamic acids thereof. Said novel compounds may be represented by the following formula: whe ein: is an aroyl substituent the Ar function of which is a member t selected from the group consisting of 2-thienyl, 5-loweral_ yl-2 thienyl, preferably 5-methyl-2-thienyl, 5-halo- 2-thienyl, preferably 5-chloro- 2-thienyl, 2-naphthyl and 3-pyridyl, said ArCO being in the meta- or para-position relative to the acetic ncid function. 43570/3 is a member selected from the group consisting of hydrogen, halo, preferably chloro, and loweralkyl, preferably methyl, provided t that, when said R is halo or loweralkyl, then said ArCO is in the aforementioned para-position, and provided that, when said R is halo, then -said Ar is 2-thienyl, 5-loweralkyl- 2-thienyl or 5-halo-2-thienyl; ^ is a member selected from the group consisting of hydrogen, halo, preferably chloro and loweralkyl, preferably methyl, provided that, when said R^ ie halo or loweralkyl, then said ArCO is in the meta-position; and provided that when said j is halo, then eaid Ar is 2-thienyl, 5-loweralkyl-2-thienyl or 5-halo-2-thienyl; either of R2 and R3 is a member selected from the group consisting of hydrogen, allyl and loweralkyl, the other being ■ a member selected from the group consisting of hydrogen and loweralkyl, provided that, when either of said R2 and R3 is allyl, the other is hydrogen, and when either of said and is loweralkyl, the other is a member selected from the group consisting of hydrogen, and loweralkyl; and Y is a member selected from the group consisting of hydroxy, alkoxy having from 1 to 8 carbon atoms, diloweralkylamino-loweralkyloxy and aminoradicals of the class consisting of -NH^, ariilino, halo-substituted anilino, preferably chloro-anilino, loweralkyl- anilino, such as methylanilino, loweralkyloxy- anilino, preferably methoxyanilino, piperidino, -NH-C^-C^OH, 2-(2-thiazolinyl)amino, -NHOH; when Y stands for the radical -NHOH, the tautomeric hydroxamic acid form is intented to be within the scope of the invention.

As used herein, "loweralkyl" may be straight or branch chained and have from 1 to 5 carbon atoms, such as for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like. The term "halo" is generic to fluoro, chloro, bromo and iodo.

The para-aroyl-substituted phenylacetic acid derivatives of formula (I), wherein R3 is hydrogen, are conveniently prepared by reacting an appropriate aryl-ketone of formula ( II ) wherein Ar and R are as previously defined, and Z is an appropriate leaving group, preferably a fluorophenyl-arylketone, with an appropriate diloweralkyl-Z-R^-malonate of formula ( III ), preferably the diethyl ester, in a suitable reaction-inert organic solvent. It is advantageous to displace the active hydrogen in the 2-poeition of (III ) with alkali metal, preferably sodium, by treatment with an appropriate base, for example, an alkali metal hydride such as sodium hydride, prior to reaction with ( II ). As employed herein, the term "reaction-inert organic solvent" is meant to include any organic liquid which will solubilize or disperse the reactants ( II) and (HI) and not interfere with their interaction, for example, hexame thy lphoephor amide, nitromethane, dimethyls lf oxide, dimethylformamide and the like.

The thus-obtained di-ester ( IV ) is then hydrolyzed, preferably utilizing alkaline hydrolysis conditions, for example, by heating a mixture of ( IV ) with alkali metal hydroxide solution to form the corresponding alkali metal salt of the corresponding acid and then acidifying the resultant salt to yield the desired phenylacetic acids ( I-a The latte may then be subjected to standard eB te r if i cation procedures, for example, (a) by treatment with an appropriate alcohol (R^OH) in acid medium, or (b) by first converting the acid to the corresponding alkali metal salt form by treatment with an appropriate alkali metal base, e. g. , sodium hydride, and then reacting said salt with an appropriate R^-halide in an appropriate polar solvent; or (c) by converting the acid to the acid-halide and then reacting said acid-halide with the appropriate alcohol to yield the desired esters ( I-b ) wherein Ar, R and are as previously defined and R^ is alkyl or dilower-alkylaminoloweralkyl. The foregoing reactions may be illustrated by the following schematic diagram: (Π) (HI) (IV) Moreover, esters of formula (I-b) may also conveniently be prepared by transesterification of a loweralkylester with a higher alkanol or with the appropriate dialkylaminoalkanol for example in the presence « of a alkaline reaction promotor.

It has been found that the aforementioned reaction between (II) and (III) can yield a mixture of the di-ester (IV) and the mono-ester (IV- a), said mono-ester proceeding from decomposition of the di-ester: R Ar-CO COOalkyl (IV-a) 43570/2 The mono-ester, which can be isolated by conventional means, for example, by distillation, is then subjected to standard cster-to-acid hydrolysis to yield the desired phenylaeetic acid derivative of formula (I The instant invention also comprises reacting a compound of with a compound reaction conditi la preferably using 43570/2 the chloride, of the formula: Ar-CO-Cl, wherein Ar is as previously defined.

Several of the fluorophenyl aryl ketones of formula (Il-a) are also deemed to be novel. These novel ketones may be represented by the following generic formula: (Il-a) wherein ArCO is an aryl carbonyl substituent the Ar function of which is a member .selected from the group consisting of 2-thienyl, 5-chloro-2-thienyl, 5-methyl-2-thienyl, and 3-pyridyl; R is a member selected from the group consisting of hydrogen, halo and loweralkyl; provided that, when said Ar is 2-thienyl, then said R is halo or loweralkyl, and provided that when said R is halo, then said Ar is 2-thienyl,.5-halo-2-thienyl or 5-loweralkyl- -thienyl.

The compounds of formula (i) wherein Y stands for an aminoradical are easily obtained by known methods for the preparation of amides or hydroxamic acids. For example, they are obtained by treating a loweralkylester of formula (I-b) with an appropriate amine or acid addition salt thereof in alkaline medium, „or by reacting an acylhalide of formula (V) with an appropriate amine in a suitable solvent. eta- and para-aroylphenylacetic acids of formula (i) wherein Y is OH; and ArCO, R, R^, ^ and R^ are as previously defined, may be prepared by conventional nitrile-to- acid hydrolysis of the corresponding aroyl phenylacetonitriles of formula (VI), for example by tetrahydropyran ( IX ), which can be isolated by conventional techniques, is then converted into a Grignard complex by standard treatment with magnesium in a suitable solvent, such as, for example, tetrahydrofuran, and said Grignard complex is reacted with an appropriate aryl nitrile of formula ( X ), wherein Ar is as previously defined, to yield the resultant ketone of formula ( XI ). The hydroxy function of the latter ketone is transformed into a reactive ester function ( XIl ) by treatment . with an appropriate agent, preferably a chlorinating or brominating agent, such as thionyl chloride, phosphorous tribromide and the like, in a suitable solvent, for example, aromatic hydrocarbons, such as benzene, toluene, xylene and the like, ethers , such as diethyl ether, dioxane and the like, and halohydrocarbons, such as chloroform and the like. In turn, the reactive ester function is transformed into a nitrile function ( Vl-a ), for example by treating ( XIl) with sodium cyanide in a suitable solvent, such as dimethyl sulfoxide. Slightly elevated temperature s (50-60° C) may be employed to enhance the rate of reaction. me ium, for example, in a 50 -aqueous sodium hydroxide solution with an equivalent amount of a suitable alkylhalide in the presence of a quaternary ammonium salt, preferably N-benzyl-triethylammonium (lower) ι ( Vl-b ) ( VI-c ) onoalkylation of ( Vl-b ) may also be carried out by reacting ( Vl-b ) with an alkylhalide, in liquid ammonia, in the presence of an equivalent amount of sodiumamide.

Monoalkylation is also achieved by reacting ( Vl-b ) with an alkylhalide in the pre sence of a s uitable metallating agent, such as sodium hydride in a s uitable polar solvent, provided that the alkyl group sterically prevents dialkylation, as is the case for example with a. branched alkyl group, such as isopropyl, isobutyl and the like. a-Diloweralkyl aroyl phenylacetonitrile s of formula ( Vl-d ), are conveniently prepared by di-alkylation of ( Vl-b ). Di-alkylation may be carried out by reacting a phenylacetonitrile of formula ( Vl-b ) with an appropriate alkylhalide, prefe rably an alkyliodide, in a suitable organic solvent, such as for example, hexamethylphosphoramide, nitromethane , dimethylformamide, dimethylsulfoxide and the like , in the pre sence of an appropriate base, preferably a metal hydride, such as sodium hydride .

Alte rnatively when an a- alkyl aroylphenylacetonitrile is alkylated under similar conditions, an a-dialkyl aroyl phenylacetonitrile ( Vl-f ) is obtained wherein may be a different loweralkyl radical.

I I 43570/2 (VI-c) (VI-f) Aroylbenzylhalides of formula (ΧΙΙ-a) wherein Ar is 2-thienyl, 5-halo-2-thienyl, 5-loweralkyl-2-thienyl or 2-naphthyl; R and Rj are hydrogen or halo and R£ is hydrogen or loweralkyl, may be prepared by brominating a suitable meta- or para-alkylphenyl aryl ketone of formula (XIII) with a convenient brominating agent, such as N-bromosuccinimide in an appropriate reaction-inert organic solvent, such as for example, carbon-tetrachloride in the presence oi a peroxide, such as benzoyl peroxide.

The reaction is preferably carried out at elevated temperatures.

(XIII) (Xll-a) It is under stood that the bromide s of formula ( Xll-a ) may easily be converted to the corresponding nitrilee by conventional means .

Said alkylphenyl aryl ketones of formula ( XIIl ) may be prepared for example by reacting a meta- or para- alky 1 benzoyl halide ( XIV ) with The compounds of formula ( Xll-b ), wherein *8 as previously defined, Ar is 2-thienyl, 5-halo- 2-thienyl or 5-loweralkyl-2-thienyl and X is halo, may be prepared by reacting a o- haloalkyl benzoyl halide of formula ( XV ) with an ArH compound in mild Friedel- Crafts conditions whe reby acylation of the aryl compound selectively occurs.

( XV ) ( Xll-b ) Another method for" the preparation of the meta- and para-aroyl benzylalcohols of formula ( XI-a ), wherein Ar, R and R j are as previously defined and is hydrogen or loweralkyl consists in a selective reduction of a ketone of formula ( XVI ) with an equivalent amount of a suitable hydrogenating agent, such as a metal borohydride, preferably sodium boro-hydride or sodium cyanoborohydride in a suitable organic solvent, for example a lower alkanol, such as methanol, ethanol, isopropanol and the like, or with lithium aluminum hydride - tert. butoxide preferably in an ether, such as for example diethyl ether, tetrahydrofUran, dioxane and the like .

Ar (XVI) (Xl-a) Compounds of formula (XVI) wherein Ar is as previously defined and R, R^ and are hydrogen or loweralkyl, may be prepared starting from m- or p-bromobenzoyl derivatives of formula ( XVII ), the carbonyl function of which is previously protected by a suitable protecting group for example by ketalization. The resulting cyclic acetal or ketal of formula (XVIII) is then converted into a Grignard complex by standard treatment with magnesium in a suitable solvent and said Grignard complex is reacted with an appropriate arylnitrile.

(XVII) ( XVIII ) (XVI) The o-unsubstituted aroyl phenylacetic acids of formula (i-d) may also be prepared from acetophenones of formula (XVI-a) by application of the Willgerodt reaction.

Esters of aroyl phenylacetic acids ( I-g ), wherein Ar, R, Rj and R^ are as previously defined, may also be mono- or di-alkylated in the a-position.

In one method the ester is first treated with an appropriate amount of a metailating agent such as for example sodiumhydride in a suitable reaction-inert organic solvent such as for example, dimethylformamide, dime thylsul oxide, hexamethylphosphoramide and the like and then reacted with an appropriate amount of an appropriate alkylhalide to form the a- alky 1 substituted compounds.

An alternative method for the preparation of p-aroyl hydratropic acids wherein Ar is as herebefore defined; R, Rj and R3 are hydrogen and R^ is methyl is given in the following reaction sequence .

A p-formylhydratropic acid alkylester of formula ( XIX ) is converted into the corresponding di-carboxylic acid monoester of formula ( XX ) by oxidation, preferably under neutral conditions such as for example with hydrogen peroxide in acetone, with silver oxide in water or dioxane or with oxygen in the presence of finely divided silver in a suitable reaction-inert organic solvent, such as dioxane, benzene, toluene, xylene and the like. The carboxyl group is then selectively converted into an halocarbonyl group by known methods such as for example, by treatment with thipnyl chloride in chloroform in the presence of a trace of pyridine as reaction promotor.

JAB 123 -17b- (XXVIII) (vi-c) e f The subject compounds ( I) possess useful anti- inflammatory properties as demonstrated by their activity in the HOAc- induced writhing test and/or in the mycobacterium butyricum test. In these tests, the subject compounds have been found to be potent antagonists of acetic acid induced writhing in rats and/or of mycobacterium butyricum induced arthritis in rats.

According to the acetic acid induced writhing test, female Wis tar rats (body weight 100+ 5g) are fasted overnight and injected intraperitoneal^ with 0. 5 ml of a 1 % acetic acid solution. Rate with at least 10 writhes within the first 10 minutes following the acetic acid injection are selected and treated five minutes later with an oral dose of the compound under investigation or with the vehicle (control).

The number of writhes, i. e. the backward extension of the hind limbs, are counted during a 15 minute Experimental session 45 to 60 minutes after the oral treatment. A minimum of three rats are used for each dose level tested. A significant drug effect is said to occur if the number of writhes counted during the experimental session of 1 5 minutes is lee 8 than 15 since this is significantly (P < 0. 05) different from controls.

The data given below show the lowest effective oral dose expressed as (mg/kg), of the preferred compound A, p- (2-thenoyl)-o-methyl-phenylacetic acid, compared with the corresponding phenyl compound B, p-benzoyl-o-methylphenylacetic acid, calculated on the all-or-none basis of less than. 15 writhes per animal per session. Under the 8 e experimental conditions, the former compound is shown to be 16 times more active than the latter compound.

Oral ED50 Compound (mg/kg) Potency Ratio 0. 08 ® 1. 25 1/16 ArCO R Rl R2 R 3 p -( 5- chloro - 2 - thenoyl) H H Me H OH p- (2 -thenoyl) H H Me H NHOH in - (2 - thenoyl) H Me H H OH p- (2 -thenoyl) H H Me H NH-^~^»OCH3 p-(2-thenoyl) H H Me H N- ' As was already demonstrated with other anti- inflammatory agents, the compounds' of formula ( Ϊ ) were found to inhibit platelet aggregation.

The following examples are intended to illustrate, to limit, the scope of the present invention.

Unless otherwise stated, all parts are by weight. -22- JAB 123 Condensed form for foreign filing.

Corres. Ex.

• U. S. -filing Example I To a stirred mixture of 25. 25 parts of thiophene, [ 58. 1 parts of 2-chloro-4-fluorobenzoyl chloride and 200 parts of anhydrous benzene are added drop ise 78. 16 parts of stannic chloride (fuming) at room temperature (slightly exothermic reaction: the temperature is kept for 3 hours at 25e C). The reaction mixture is poured onto a mixture of crushed ice and concentrated hydrochloric acid solution.

The whole is stirred for a few minutes and the layers are separated. The Organic layer is diluted with 80 parts of toluene, washed successively with 200 parts of sodium hydroxide solution 5% and with 200 parts of water, dried and evaporated. The residue is distilled, yielding 2-chloro-4 -fluorophenyl 2-thiertyl ketone; bp. 129- 130" C at 0. 5 mm. pressure. IV.

Example II To a stirred mixture of 29. 5 parte of 2 -methyl thiophene, 39. 65 parts of p-fluorobenzoyl chloride and 280 parts of methylene chloride are added portipnwise 40 parts of aluminium chloride while keeping the temperature at 20° C (water-bath). Upon completion, stirring is continued for 4 hours at room temperature . The reaction mixture is poured onto crushed ice and 50 parts of hydrochloric acid, while stirring vigorously. The layers are separated and the aqueous phase is washed with chloroform. The organic layers are dried and evaporated. The re sidue is taken up j n benzene and the latter is evaporated again. The residue · Corres. Ex: U. S. -filimfr solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from ethanol at. -20° C,. yielding p -fluorophenyl 5-methyl-2-thienyl ketone; mp. 68 ° C.

Example III To a stirred mixture of 29. 2 parts of 2-thenoyl chloride, 22 parts of m-fluorotoluene and 200 parts of methylene chloride are added portionwise 37. 4 parts of aluminum chloride (exothermic reaction: temperature rises to 30° C). Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is poured onto crushed ice while stirring. The product is extracted with methylene chloride. The organic layer is washed successively with a sodium hydrogen carbonate solution and with water, dried and evaporated. The residue is distilled twice, yielding 4-fluoro-o-tolyl 2-thienyl ketone; bp. 105- 1 06C C at 0. 2 mm. pressure.

Example IV To a stirred and cooled (ice -bath) mixture of 88 parts of nicotinoyl chloride hydrochloride in 400 parts of fluorobenzene are added portionwise 165 parts of aluminium chloride at a temperature between 5° and 1 0° C. Upon completion, the cooling -bath is removed and the mixture is stirred and refluxed for 6 hours. The reaction mixture is allowed to stand overnight at room temperature and is then poured onto a mixture of crushed ice arid hydrochloric acid. After cooling, the layers are separated.

The aqueous phase is extracted three times with ether. The combined organic layers are discarded and the aqueous phase is alkalized with a 40% sodium hydroxide solution. The product is extracted several times with chloroform. The extracts are washed twice with water, dried and evaporated. The residue is dissolved in ether. The solution is filtered from insoluble matter and the filtrate is allowed to crystallize upon dilution with petroleumether at -20° C, yielding p-fluorophenyl 3-pyridyl ketone; mp. 74. 5° C.

Example V 9. 6 parts of sodium hydride dispersion 55% are suspended three times in anhydrous benzene and the latter is each time decanted. Then there are added successively 200 parts of hexamethylphosphoramide and dropwise 34. 8 parts of diethyl 2-methylmalonate . The mixture is warmed gently, whereupon a vigorous reaction takes place. When the reaction ceases, the mixture is cooled and 41 . 2 parts of p-fluorophenyl 2- thienyl ketone are added. The whole is heated to 1 00° C and stirred at this temperature for 1 0 hours . The reaction mixture is diluted with 400 parts of benzene, washed twice with water, dried and evaporated. The oily residue is distilled, yielding diethyl 2 -methyl- 2 - p- (2-thenoyl)phenyl7malonate; bp. 205-21 0° C at 0. 4 mm. pressure. I By repeating the procedure of Example V and replacing p-fluorophenyl 2-thienyl ketone by an appropriate amount of an appropriate p-fluorophenyl afyl ketone and replacing diethyl 2 -methylmalonate by an equivalent amount of an appropriate diethyl malonate, the following compounds are obtained: diethyl 2 - me thy 1 - 2 - ¾ - ( - the noy 1) - m .- toly l7ma lona te ; - ° · ' '"":· diethyl 2-/3-chloro-4- (2-thenoyl)phenyl7-2-methylmalonate; bp. 225-235° C at 0.6-0.8 mm. pressure; diethyl 2-methyl-2- p-(5-methyl-2-thenoyl)pheny] malonate; bp. 235-240° C at 1 mm. pressure; diethyl 2-methyl-2- p- (2-naphthoyl)phenyi7malonate; diethyl 2-methyl-2- -(3-pyridylcarbonyl)phenyl7malonate; diethyl 2-ethyl-2- p-(2-thenoyl)phenyl7malonate; bp. 175-199°C at 0.1 mm. pressure; and diethyl 2-allyl-2- p-(2-thenoyl)phenyl7malonate; bp. 215-220° C at 0.2 mm. pressure. ■' Example VI A mixture of 30.3 parts of diethyl 2-methyl-2- p-(2-thenoyl)-phenyl/malonate and 200 parts of sodium hydroxide solution 5% is stirred and refluxed for 6 hours. The reaction mixture is allowed to cool while stirring. The whole is filtered and the aqueous phase is separated. The latter is washed with benzene, acidified with concentrated hydrochloric acid solution and stirred for 15 minutes. The product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The oily residue is triturated twice in petroleumether. The solid product is filtered off and crystallized twice from aceto-nitrile: first at -20° C and then at 0°C, yielding pr (2-thenoyl)-hydratropic acid; mp. 124.3°C; also named p- (2-thenoyl)-a-methyl-phenylacetic. acid.

Example VIII 60 parts of diethyl 2-methyl-2- p-(3-pyridylcarbonyl)-phenyl/malonate (residue of previous reaction) are distilled* : yielding about 20.3 parts of ethyl p-(3-pyridylcarbonyl)-hydratropate, also named ethyl p- (3-pyridylcarbonyl)-a-methyl-phenylacetate; bp. 235-244 °C at >- mm. pressure.

A mixture of 10 parts of ethyl p- (3-pyridylcarbonyl)-hydratropate and 50 parts of sodium hydroxide solution 4% is stirred and refluxed for 6 hours. The reaction mixture is allowed to stand overnight at room temperature. The whole is extracted with ether. The organic layer is discarded and the aqueous phase is acidified with hydrochloric acid solution. The precipitated product is filtered off, washed with ethe and suspended in acetone. The suspension is acidified with an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The salt is washed with acetone and dried, yielding p-(3-pyridylcarbonyl)hydratropic acid hydrochloride; mp. 210°C; also named p-(3-pyridylcarbonyl)-a-methyl- .· ■ '. ■ phenylacetic acid HGl.

Example IX A mixture of 269 parts of p-bromo-a-methylbenzyl alcohol ai d 225 parts of 2H-3, 4-dihydropyran is stirred and cooled to 0°C. .Then there are added dropwise 10 drops of concentrated hydrochloric acid solution and the whole, is stirred in an ice -bath . (room temperature is reached). After stirring for 24: hours,1 the reaction mixture is poured onto.1200 parts of ether.' The organic phase is washed twice with . a sodium hydrogen carbonate solution and twice with water, dried/ filtered- and evapo '1 eel. The residue is distilled, yielding 2- (p-br mo-a'-methylbenzylbxy) G o r re s . ϋ. S. ■-·£{ is poured onto a mixture of 20 parts of hyd o-chloric c'id solution and 100 parts of crushed ice. The product is extracted with methylene chloride. The organic phase is washed with alkaline water, dried and evaporated. The solid residue is triturated with hot petroleumether. The product is filtered off and crystallized from ethanol, yielding a-bromo-p-tolyl 2-thienyl ketone; mp. 85.6°C (dec. ). . . X II, When the procedure of Example XIII is repeated except that p- (bromomethyl)benzoyl chloride is replaced by an equivalent amount of p- (1 -chloroethyl)benzoyl chloride, the following compound is obtained: p-(l -chloroethyl)phenyl 2-thienyl ketone. :. ΧΧΧΙΓ..

Example XIV To a stirred mixture of 26.7 parts of p-ethylbenzoyl chloride, 13.3 parts of thiophene in 80 parts of methylene chloride are added 41.1 parts of stannic chloride in 40 parts of methylene chloride at 30°C. Upon completion, stirring is continued for 3h.30 at reflux temperature. The reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid. The layers. are separated and the aqueous phase is extracted- with .methylene. . chloride. The combined organic phases are washed with water,' . - . dried, filtered and evaporated. The residue is evaporated once more from benzene.' The latter residue is distilled, yielding '' . '·.-:¾.'. p-ethylphenyl 2-thienyl ketone; bp. 200-205° C at 1 mm. .'·:■'''/' 'Ί...-pressure., · XX VIII By repeating the procedure of Example XIV and replacing ,· p-ethylbenzoyl chloride by an equivalent amount of 2-chloro-ra- '·,· toluoyl chloride the following compound is obtained: . ;r : . - 'i ' 2-chloro-m-tolyl 2-thienyl ketone; bp. 197 - 19.9° C at , : :; :'; >Y'-12 mm. pressure. XLII.

Example XV A mixture of 23.5 parts of p-ethylphcnyl 2-thienyl ketone, 19.5 parts of N-bromosuccinimide, 220 parts of carbon tetra -chloride, 1.1 parts of benzoyl peroxide and one drop of toluene is stirred and refluxed for 2 hours. The precipitated succinimide is filtered off and the carbon tetrachloride filtrate is dried and; . evaporated. The oily residue solidifies on cooling., The solid product is dissolved in 2-propanol and the product is allowed ; to crystallize. It is filtered off and dried in vacuo, yielding . α-bromo-a-methyl-p-tolyl 2-thienyl ketone; mp. 71.1°C.

Example XVI A mixture of 26 parts of 5-chloro-2-thienyl p-ethyl-phenyl ketone, 350 parts of carbon tetrachloride, 1 part of benzoyl peroxide and 18.5 parts of N-bromosuccihimide isV stirred and refluxed. When the reaction ceased, the formed precipitate is filtered off and the carbon tetrachloride phase, is dried and evaporated. The lesidue solidifies on cooling on ice. The solid product is crystallized from 2-propa.nol (activated charcoal), yielding, after drying in vacuo, Q-brom.o-a-methyl-p-tolyl 5- chloro- 2-t.hienyl ketone; mp. 69.4°C.

Corres . Ex.

U.S. -filing.

By repeating the procedure of Example XVI except that an equivalent amount of 2-chloro-m-tolyl 2-thienyl ketone is employed instead of 5-chloro-2-thienyl p-ethylphenyl ketone, the following compound is obtained: q-bromo-2- chloro-m-tolyl 2-thieriyl ketone as a residue. XLII.

Example XVII A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60° C. Then there are added at once 8.5 parts of p-(l-chloroethyl)phenyl 2-thienyl ketone and stirring at 60° C is continued for 4h.30. The reaction mixture is poured onto water and the^product is extracted with ether. The organic layer is washed with water, dried, filtered and evaporated, yielding p-(2-thenoyl)hydratroponitrile, as a residue. XXIX.

By repeating the procedure of Example XVII and replacing p-(l -chloroethyl)phenyl 2-thienyl ketone by an equivalent amount of an appropriate chloroalkylphenyl 2-thienyl ketone, the following compounds are obtained: m- (2-thenoyl)hydratroponitrile as a residue; VIII. 2- ji- (2-thenoyl)phenyl/acetonitrile as a residue; and XVIII. 2-methyl- 3- (2-thenoyl)hydratroponitrile as a residue. XXX. -3.5-- - V Corrcs. Ex.

U. S. -filing Example XVI.II To a stirred mixture of 5.5 parts of sodium hydride dispersion 78% in 150 parts of hexamethylphosphoramide are added drop ise 14 parts of 2- p-(2-thenoyl)pheny7-acetonitrile over a period of 30 minutes at a temperature of 15°C. Upon completion, stirring is continued for 3 hours at room temperature. Then there are added dropwise 34 parts of methyl iodide (strong exothermic reaction) and upon completion, the whole is stirred overnight. The reaction mixture is poured onto water and the product is extracted three times with 200 parts of benzene. The combined extracts are washed five times with water, dried, filtered and evaporated, yielding a-methyl-p- (2-thenoyl)hydratroponitrile as a residue. XVIII Example XIX 11.4 parts of 2- p-(2-thenoyl)phenyl7acetonitrile, 4.9 parts of methyl bromide and 0.13 parts of benzyl triethyl ammonium chloride are added to 30 parts of a 50% sodium hydroxide solution. The whole is stirred vigorously for 5 hours * at 35°C. Distilled water is added. The organic layer is separated, washed with distilled water and evaporated.. The oily residue is distilled, yielding p-(2-thenoyl)hydratropo-nitrile. ΧΧΧί Example XX A suspension of 4.9 parts of sodium cyanide in 55 parts of dimethyl sulfoxide is stirred while heating to 60°C. Then there are added at once 10 parts of a-bromo-a-methyl-p tolyl .2-thi-enyl ketone and stirring at 60°C is continued for 4h.30.

Th reaction mixture is poured onto water and the product is extracted with ether. The organic layer is washed with water, By repeating the procedure of Example XX and by replacing α-bromo-a-methyl-p-tolyl 2-thienyl ketone by an equivalent amount of a-bromo-2-chloro-m-tolyl 2-thienyl ketone or an equivalent amount of a-bromo-p-tolyl 2-thienyl ketone, the following compounds are obtained as respective products: 2- 2-chloro-3-(2-thenoyl)phenyl acetonitrile; and - p- (2- thenoyljphenyl/acetonitrile .

Example XXI A mixture of 9.9 parts of a-bromo-a-methyl-p-tolyl 5-chloro- 2-thienyl ketone, 1.96 parts of sodium cyanide, 12 parts of water and 48 parts of dioxane is stirred for 17 hours while heating at 90 °C. The reaction mixture is evaporated and 36 parts of water are added to the residue.

The product is extracted with ether. The extract is dried and evaporated. The residue is purified by column-chromatography over silicagel, using chloroform as eluent.

The pure fraction is collected and the eluent is evaporated.

The residue is triturated in h-hexane;, yielding p-(5-chlpro-2-thenoyl)hydratropOnitrile; mp. 90° C.

Example XXII A mixture of 7.3 parts of p-(2-thenoyl)hydratroponitrile, 18 parts of. sulfuric acid, 10 parts of water and 10 parts of acetic acid is stirred and refluxed for 2 hours. The reaction mixture is poured onto crushed ice and the product is extracted with ether. The organic layer is washed with diluted sodium hydroxide solution. The aqueous phase is acidified with hydrochloric acid solution and the product is extracted with ether. The organic layer is dried, stirred with activated charcoal, filtered and evaporated in vacuo.

The re sidue solidifie s on triturating in petroleumether.

The solid product is filtered off and crystallized from acetonitrile , yielding p- (2-thenoyl)hydratropic acid; mp. 121 . 1 ° C.

By repeating the procedure of Example XXII and replacing p- (2-thenoyl)hydratroponitrile by an equivalent amount of and appropriate aroyl phenylacetonitrile, the following compounds are obtained: p- (5-chloro-2-thenoyl)hydratropic acid; mp. . 137. 4 ° C; m- (2-thenoyl)hydratropic acid as a residue; 2- p- (2-thenoyl)phenyl7acetic acid; mp. 126- 129° C; a-methyl-p- (2-thenoyl)hydratropic acid; mp. 138. 8 ° C; and 2- 2- chloro- 3-.(2-thenoyl)phenyl7acetic acid; mp. 1 12. 2 ° C.

Example XXIII When the procedure of Example X is repeated except that an equivalent amount of an appropriate aryl nitrile is used instead of 2-thiophenecarbonitrile and when the re sulting aroylbenzylic alcohol is used as a starting material for consecutively repeating the procedures of Examples XII, XVII and XXII, the following compounds of formula (i) are obtained: m-(2-naphthoyl)hydratropic acid; m- (5-methyl-2-thenoyl)hydratropic acid; and m- (3-pyridylcarbonyl)hydratropic acid.

Example XXIV ■ A mixture of 6 parts of 2-methyl-3-(2-thenoyl)hydratropo-nitrile, 2.7 parts of potassium hydroxide, 28 parts of ethanol and 3.5 parts of water is stirred and refluxed for 44 hours. The reaction mixture is evaporated. The residue is taken up in water and washed twice with 80 parts of ether. The aqueous phase is acidified with concentrated hydrochloric acid solution. The separated oily product is extracted with ether. The latter is dried and evaporated. The oily residue solidifies on triturating in petroleumether. The product is crystallized from acetonitrile at -20°C, yielding a first fraction of 2-methyl-3- (2-thenoyl)hydratropic acid; mp. 118.7°C.

The mother -liquor is evaporated. The residue solidifies on triturating iri petroleumether, yielding a second fraction of 2-methyl-3- (2-thenoyl)hydratropic acid; mp. 100°C.

Example XXV A mixture of 14.7 parts of V -methyl-3' - (2-thenoyl)aceto-phenone, 4.3 parts of sulfur and 33 parts of morpholine is stirred and refluxed for 3 hours. The reaction mixture is cooled, diluted with '45.0 parts of chloroform and shaken Corres . Ex.

U. S. -filiiyg. succe s sively twice with diluted hydrochloric acid solution and t ice with wate r. The organic layer is dried and evaporated .

The oily residue is boiled in a mixture of 200 parts of glacial acetic acid and 1 50 parts of a 50% sulfuric acid solution for 2 hours. After cooling, the mixture is poured onto 700 parts of ice -water and the product is extracted twice with ether.

The combined extracts are washed with water, dried, stirred with activated charcoal, filtered and evaporated. The re sidue is taken up in 200 parts of water, alkalized with diluted sodium hydroxide s olution and washed twice with ether. The aqueous phase is acidified with concentrated hydrochloric acid solution and the product is extracted twice with ether. The extracts are dried and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The re sidue is dissolved in ether and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The re sidue is crystallized from acetonitrile at -20° C, yielding 2-/3- (2 -theno o-tolyl/acetic acid; mp. 136 ° C.

Example XXVI To 400 parts of liquid ammonia are added a trace of ferric chloride and 3 parts of sodium. The mixture is stirred for 30 minute s, after which 14. 8 parts of 2- p- (2-thenoyl)phenyl7- · acetic acid are added slowly during 30 minutes, and the mixt ire is furthe s tirred for 45 minutes . 13. 6 parts of methyl iodide are added dropwis e and the reaction mixture is stirred for 2h. 30. 400 parts of diethyl ether are then added and the mixture -40, U. S. -filing is stirred overnight. The ammonia is evaporated and the resulting solution is acidified with diluted hydrochloric acid.

The ethereal layer i s separated and extracted with 1 0% sodium hydroxide solution. The extract is washed with ether, acidified and extracted with ether. The ethereal solution is dried on sodium sulfate and the ethe r is evaporated in vacuo. The residue is triturated in petroleumether, filtered off and crystallized twice from acetonitrile , first at -20° C and then at 0 ° C, yielding p- (2 -thenoyl)hydratropic acid.

Example XXVII A mixture of 5. 2 parts of p- (2-t"henoyl)hydratropic acid, 40 parts of absolute denatured ethanol and 0. 5 parts of hydrochloric acid solution is stirred and refluxed for 24 hours .

The reaction mixture is evaporated and the residue is taken up in ether . The ethereal solution is shaken with alkaline water, separated and shaken twice with water. The ether phase is dried, filtered and evaporated, yielding ethyl p- (2-thenoyl)hydratropate, also named ethyl · ' p- (2-thenoyl)- a-methyl-phenylacetate, as a residue.

The following ester s of formula ( I ) are obtained as re spective products by repeating the e sterification procedure of Example XXVII, except that an equivalent amount of an appropriate aroyl- substituted phenylacetic acid is used: ethyl p- (2-thenoyl) -a-allyl-phenylacetate; XI ethyl p- (2 - thenoyl) - a-ethyl-phenylacetate ; ' XI ethyl m- (2- thenoyl) -q-methyl-phenylacetate XI ethyl p- (2-naphthoyl) -a -me thyl-ph.enylacetate; XT ethyl p- (5-mcthyl- 2-thenbyl) - a-inethyl-phenylacetate; and XI Corrcs. Ex.

U. S. -filing To a stirred mixture of 5.2 parts of p-(2-thenoyl)-hydratropic acid in 50 parts of dry hexamethylphosphor-amide are added 0.86 parts of sodium hydride dispersion 55.3% and the whole is stirred for 1.5 hours. Then there are added 3.86 parts of octyl bromide and 0.01 parts of potassium iodide. Upon completion, stirring is continued for 18 hours at room temperature. The reaction mixture is poured onto benzene and the whole is shaken successively twice with water, twice with sodium hydroxide solution and again twice with water. The organic phase is dried, filtered and evaporated. The residue is taken up in ether and stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated again. The residue is purified by column- chromatography with chloroform over silicagel. The pure fractions are collected!' and the solvent is evaporated, yielding octyl p- (2-thenoyl)-hydratropate as a residue.

By repeating the esterification procedure of Example XXVIII, except that an equivalent amount each of an appropriate aroyl- substituted phenylacetic acid and an appropriate alkyl halide are utilized, the following esters of formula (I) are obtained as respective products: propyl p- (2 -thenoyl)-a-allyl-phenylacetate; . XII butyl p- (2-thenoyl)-a-ethyl-phenylacetate; XII octyl m- (2-thenoyl)-a-methyl-phenylacetate; XII propyl p-(2-naphthoyl)-a-methyl-phenylacetate; and XII pentyl 3-chloro-4-(2-thenoyl)-a-methyl-phenylacetate. . XII Cor res . Ex.

U . S. -filing Example XXIX A mixture of 1 part of sodium hydroxide in 96 parts of 2-propanol is heated to reflux and stirred till a homogenous mixture is obtained. Then there are added 6. 25 parts of p- (2 -thenoyl)hydratropic acid and the whole is stirred at reflux for one hour. The mixture is treated with 0. 5 parts of activated charcoal and filtered over diatomaceous earth.

After stirring the filtrate for 24 hours at room temperature, the product is filtered off and dried in vacuo over calcium chloride at 70° C, yielding p- (2-thenoyl)hydratropic acid, sodium salt; mp. 187. 4° C. XXXIII, To a stirred mixture of 28. 2 parts of p- (2-thenoyl) -hydratropic acid, sodium salt and 2 50 parts of hexamethyl-phosphoramide are added 56. 8 parts of methyl iodide at room temperature (slightly exothermic reaction) . The whole is stirred at room temperature for one hour. The reaction mixture is poured onto 1 000 parts of water and the product is extracted three time s with 140 parts of diisopropylether. The combined extracts are washed with 200 parts of water, dried , filtered and evaporated. The residue is crystallized from 35 parts of diisopropylether at 0° C, washed with cooled ether and dried, yielding methyl p- (2-thenoyl)hydratropate; mp. 62 XXXIII.

By repeating the procedure of Example XXIX and by replacing methyl iodide by an equivalent amount of 1 -bromo propane, the compound propyl p- (2 -thenoyl)hydratropate is obtained as a yellow oil. XXXIV Corres . Ex.

U. S. -filing Example XXX . ,·_ . ' 1.3 parts of sodium hydride dispersion 78% are suspended three times in anhydrous benzene and the latter is decanted each time. Then there are added 75 parts of hexamethylphosphor-amide, followed by the addition of 10.4 parts of p-(2-thenoyl)-hydratropic acid. The whole is heated to 50° C and when the reaction is ceased (formation of sodium salt), the mixture is cooled to room temperature. 7 parts of N-(2-chloroethyl)-N, N -dime thy lamine are added and the whole is stirred for 18 hours at 50° C. The reaction mixture is cooled and extracted with 240 parts of benzene. The organic layer is washed successively with 100 parts of water, with diluted sodium hydroxide solution and again with 100 parts of water, dried, filtered and evaporated. The residue is purifie column- chromatography over silicagel, using as eluent chloroform the first time and further a mixture of chloroform and 5% of methanol. After evaporation of the eluent, the residue is converted into the oxalate salt in 2-propanol. The crude salt is filtered off and crystallized from 2-propanol (activated charcoal) at -20° C, yielding 2-(dimethylamino)ethyl p- (2-thenoyl)hydratropate oxalate; mp. 117.4° C. XXIV By repeating the esterification procedure of Example XXX and by replacing N- ( -chloroethyl)-N, N-dimethylamine by an equivalent amount of N- (3-chloropropyl)-N, N-dimethylamine or an equivalent amount of N-(2-chloroethyl)-N, N-diethylamine, the following compounds are obtained: 3-(dimethylamirio)propyl p- (2-thenoyl)hydratropate oxalate; mp. 135-145°C; and XXV 2- (diethylamino)ethyl p- (2-thenoyl)hydratropate hydrochloride; mp. 126.4° C. . XXVI Corres . Ex.

U. S. -filinfi Example XXXI A mixture of 4. 27 parts of lithium diisopropylamide and 50 parts of tetrahydrofuran is cooled to - 78 ° C. Then there are added 1 0. 4 parts of methyl 2 - p- (2-thenoyl)phenyl7acetate and the mixture is stirred for 40 minutes . 6. 25 parts of methyl iodide dissolved in 2. 1 5 parts of he amethylphos -phoramide are added at -78 ° C and the mixture is further stirred for one hour after which it is allowed to warm up to room temperature . The whole is poured onto water. The resulting mixture is extracted with diisopropylether. The organic phase is washed with water, dried and evaporated. The residue is crystallized from diisopropylether at 0° C, yielding methyl p- (2-thenoyl)hydratropate .

Example XXXII A mixture of 5. 2 parts of p- (2-thenoyl)hydratropic acid, 4. 8 parts of thionyl chloride and 32 parts of anhydrous benzene is stirred, and refluxed for 3h. 30. The reaction mixture is evaporated and the re sidue is evaporated once more from benzene, yielding p- (2 -thenoyl)hydratropoyl chloride as a residue. XI^ To a solution of 3. 7 parts of p-methoxyaniline in 20 parts of dioxane, is added a solution of 4. 2 parts of p- (2-thenoyl) -hydratropoyl chloride in 25 parts of dioxane. Upon completion, another 30 parts of dioxane are added and the whole is stirred and refluxed for one hour. The reaction mixture is allowed to cool to room temperature. After filtration, the filtrate is treated with activated charcoal, filtered and evaporated in vacuo. The oily re sidue solidifie s on triturating in ether . The solid product is filtered off, stirred twice in ether and filtered again. The product is crys tallized from 2 -propanol, yielding, after. drying in vacuo, p- (2 - thenoyl)hydratropo-p-anisidide; mp. 149 ° C. I2 By repeating the procedure of Example XXXII and by replacing p- me thoxy aniline by an equivalent amount of an appropriate amine, the following compounds are obtained: N-(2-thiazolin-2-yl)-p-(2-thenoyl)hydratropamide; mp. 186.4° XXII p-(2.-thenoyl)hydratropanilide; mp. 139.8°C XXXVII p-(2-thenoyl)hydratropo-p-toluidide; mp. 158.3eC; XXXIX 4'-chloro-4-(2-thenoyl)hydratropanilide; mp. 169.4°C; and XXXVIII 1 - p- (2-thenoyl)hydratropoyl7piperidine; mp. 70.3°C. XL Example XXXIII To a stirred solution of 2.44 parts of 2-aminoethanol in 15 parts of chloroform is added dropwise a solution of 5.6 parts of £- (2-thenoyl)hydratropoyl chloride in 15 parts of chloroform at room temperature (highly exothermic reaction).

Upon completion, the whole is stirred and refluxed for one hour.

The reaction mixture is cooled and washed with a IN hydrochloric acid solution. The organic layer is separated, washed twice with water, dried, filtered and evaporated. The oily residue solidifies on triturating in potroleumether . The solid product is filtered off and crystallized from boiling ether, yielding N-(2-hydroxyethyl)-p-(2-thenoyl)hydratropamide; mp. 87.1°C. -46V Corres. Ex.

U. S. A. - filine Example XXXIV Gaseous ammonia is introduced through a solution Of 5. 8 parts of p- (2-thenoyl)hydratropoyl chloride in 80 parts of ether; the product is precipitated as an oil. The solvent is decanted and the oil is stirred twice in petroleumether.

The solvent is decanted each time. The oily residue is dissolved in 2-propanol and the solvent is evaporated. The residue is dissolved in ether and upon the addition of petroleumether, the product is precipitated. It is filtered off and purified by column- chromatography over silicagel, using a mixture of chloroform, methanol and acetone (8 : 1. : 1 by volume) . The pure fractions are colle cted and the solvent is evaporated. The oily residue is triturated in ether. The solid product is filtered off and dried, yielding p- (2-the oyl) -hydratropamide ; mp. 108- 124 ° C.

Example XXXV To a stirred solution of 1 2. 6 parts of ethyl p- (2-thenoyi) -hydratropate in 35 parts of methanol is added successively and while coolingj first a solution of 6. 05 parts of hydroxyl amine hydrochloride in 35 parts of methanol and .then a solution of 7. 3 parts of potas sium hydroxide in 35 parts of methanol. Upon completion, the whole is stirred for 30 minutes. The mixture is filtered and the filtrate is stirred for 3 days at room temperature .

The reaction mixture is evaporated and the residue is taken up in water. The aqueous solution is acidified with hydrochloric acid solution and the product is extracted with ether. The extract is washed with water, dried, filtered and evaporated.

The re sidue is taken up in water, alkalized with sodium hydroxide solution, washed with ether and the aqueous phase is a c idified with concentrated hydrochloric acid solution; The product is extracted with ether. The latter is washed with water, dried, Corres . Ex; U. S. -iilins: V-filtered and evaporated. The residue is pui'ified by column-chromatography over silicagel, using a mixture of chloroform and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in a. mixture of petroleumether and diisopropylether. The solid product is filtered off and crystallized from 2-propanol, yielding p- (2-thenoyl)hydratropohydroxamic acid; mp. 143.5°C.

Example XXXVI To a stirred mixture of 20 parts of p- (2-thenoyl)hydratropic acid and 9.3 parts of ( - )-a-methylbenzylamine in 200 parts of ethanol are added 50 parts of water. The precipitated salt is filtered off and. crystallized from a mixture of ethanol and water (10 : 2 by volume), yielding the crude salt form. This fraction is recrystallized several times till constant rotation, from a mixture of ethanol and water (10 : 2 by volume) j to yield ( - )-p- (2-thenoyl)hydratropic acid a-methylbenzylamine; mp. 170.5° C; j (1.98% Me OH) = -13.74°. 1.5 Parts of ( - )-p- (2-thenoyl)hydratropic acid a-methylbenzylamine are suspended in water and acidified with hydrochloric acid. The product is extracted with ether. The organic layer is washed with water, dried and evaporated. The oily residue solidifies on triturating in petroleumether. The solidified product is filtered off and dried in vacuo at 50° C, yielding ( +)-p-(2-thenoyl)hydrc.tropic acid; ~

Claims

CLAIMS A process for preparing am aroyl subs tituted α-ϊ^' α-R^-phenylacetic acid derivative having the formula: wherein: ' ArCO is an aroyl substituent the Ar function of which is a member selected from the group consisting of 2 -thienyl, 5-loweralkyl- 2-thienyl, 5 -halo- 2-thienyl, 2-naphthyl and 3-pyridyl; said ArCO being in the meta- or para-position relative to the acetic acid function; R is a member selected from the group consisting of hydrogen, halo and lowcralkyl, provided that when said R is halo or lower- alkyl, then said Ar CO is in the aforementioned para-position, and provided that when said R is halo, then said Ar is 2 -thienyl, 5-lower alkyl -2 -thienyl or 5-halo-2-thienyl; j is a member selected from the group consisting of hydrogen, halo and lowcralkyl, provided that, when said ^ is halo or lower- alkyl, then said Ar CO is in the aforementioned meta-position, and provided that when said R , is halo, then said Ar is 2-thienyl, 5-loweralkyl-2- thienyl or 5-halo-2- thienyl; - 50 - s 43.570/ 3 \ ' either of I¾2 and R3 is a member selected from the group consisting of hydrogen, allyl and loweralkyl, the other being a member selected from the group consisting of hydrogen and loweralkyl, provided that, when either of said 1*2 and R3 is allyl, the other is hydrogen, and when either of said and R- is loweralkyl, the other is a member selected from the group consisting of hydrogen, and loweralkyl; and Y is a member selected from the group consisting of hydroxy, alkoxy, having from 1 to 8 carbon atoms, diloweralkylamino-lower- alkyloxy, and aminoradicals of the class consisting of amino, anilino, halo- substituted anilino, lower alkylanilino, lower- alky loxyani lino, piperidino, hydroxyethylamino, 2- (2-thiazolinyl) - -s amino, and hydroxylamino, characterized by (IV ) preferably under a lka line hydrolysis condi tions in order to prepare a cc mpound of the formula : - 51 - PROCESS CLAIM 1 cont ' d JAB 123 and, if desired, esterifying said compound I-a by known esterification methods in order to prepare a compound of the formula (i-b) wherein is alkyl or diloweralkylamino lower alkyl and, if desired, converting said compound of formula I-a to the acid halide of the formula (V) and further, if desired, replacing the OR^ group in said compound 1-b, or the halide in compound (V), with an amino group, or substituted amino group, by known methods, or (b) hydrolysing a compound of the formula wherein the ArCO-group is in the meta o:: para position, by conventional nitrile-to-acid hydrolysis in order to prepare a compound of the formula JAB 123 PROCESS CLAIM 1 cont ' d (I-c). or (c) subjecting a compound of the formula to the Willgerodt reaction in the presence of sulfur and morpholine in order to prepare a compound of the formula (I-d) τ· ......... . JAB 123 PROCESS CLAIM 1 cont'd or (d) subjecting a compound of the formula to a modified Willgerodt reaction in the presence of rhodanine in order to prepare a compound of the formula • (I-e) or (e) mono alkylating ε compound of the formula Pflge5 -54- JAB 123 PROCESS CLAIM 1 cont ' d preferably by metallating one of the a-hydrogen atoms and thereafter treating with an alkyl halide in order to prepare a compound of the formula or (f) mono or dialkylating esters of the formula preferably by first metallating the a-hydrogen atom followed by reacting with an alkyl halide in order to prepare a compound of the formula (I-h) JAB 123 PROCESS CLAIM 1 cont'd

1. (I-i) or transforming a compound of the formula (I-g) into a metal enolate and then reacting with an alkylating agent in order to prepare a compound of the formula JAB 123 PROCESS CLAIM 1 cont'd or (g) reacting a compound of the formula with a compound of the formula ArH under Friedel-Crafts conditions in order to prepare a compound of the formula hydrolysing and decarboxylating a compound of the formula PROCESS CLAIM 1 cont'd JAB 123 in order to prepare a compound of the formula (i-f)' or (i) and, if desired, resolving, by standard methods, the (+) or (-) stereochemical isomers from compounds of formula (I); or (j) reacting a compound of the formula with a compound of the formula ArCO halide, under Friedel-Craft reaction conditions i rmula preferably using carbon disulfide as a solvent. PROCESS CLAIMS JAB 123 2. A process for preparing £- (2-thenoyl)hydratropic acid according to claim 1, characterized by hydrolysing diethyl 2-methyl-2-[p- (2-thenoyl) phenyl] malonate. *v 3. A process for preparing ethyl £- (2-thenoyl)hydratropate characterized by esterifying the product of claim 2 with ethanol. 4. A process for preparing o ctyl p-(2-thenoyl)hydratropate characterized by esterifying the product of claim 2 with octyl bromide. 5. A process for preparing 3-chloro-4-(2-thenoyl)hydratropic acid according to claim 1, characterized by hydrolysing diethyl 2- . [3-chloro-4- (2-thenoyl) phenyl ]- 2-methylmalonate . 6. A process for preparing £- (3-pyridylcarbonyl)hydratropic acid according to claim 1, characterized by hydrolysing ethyl, p-(3-pyridylcarbonyl)hydratropate . 7. A process for preparing £- (5-m ethyl-2-thenoyl)hydratropic acid according to claim 1, characterized by hydrolysing diethyl 2-methyl-[p- (5-methyl-2-thenoyl) phenyl J alonate. . 8. A process for preparing p-(2- n aphthoyl)hydratropic acid according to claim 1, charaterized by hydrolysing diethyl 2-methyl -2- [ p- (2-naphthoyl) phenyl jmalonate . PROCESS CLAIMS JAB 123 9. A process for preparing m-(2- thenoyl)hydratropic acid according to claim 1, characterized by hydrolysing m- (2-thenoyl) hydratroponitrile. 10. A process for preparing P- (2- thenoyl)-a-ethyl-phenylacetic ac according to claim 1, characterized by hydrolysing diethyl 2-ethyl- 2- [p- (2-thenoyl) phenyl ]malonate. 11. A process for preparing p-(2- thenoyl) -a - allyl-phenylacetic a according to claim 1, characterized by hydrolysing diethyl 2-allyl- 2- [p-( 2-thenoyl) phenyl ]malonate. 12. A process for preparing ( + )-p-(2- thenoyljhydratropic acid according to claim 1, characterized by resolving same from a mixture of the (+) and (-) forms, utilizing (-)-cc-methylbenzylamine. 13. A process for preparing ( - )-p-(2-t henoyl)hydratropic acid according to claim 1, characterized by resolving same from a mixture of the (+) and (-) forms utilizing (+)-a-methyl-benzylamine. 14. A process for preparing 3- ( dimetKylamino)propyl p-(2-thenoyl)hydratropate oxalate f characte.-. ized by reacting the sodiu salt of p- (2-thenoyl)hydra tropic acid with N- -chloropropy^-l^N-dimethylamine and then preparing the oxalate salt of the product. -60- pagB 11 JAB 123 PROCESS CLAIMS 15. A process for preparing 2- (d iethylami no) ethyl p-(2-thenoyl)hydratropate hydrochloride, characterized by reacting the sodium salt of p- (2-thenoyl)hydratropic acid with N- (2-chloroethyl)-N,N-diethylamine arid then preparing the hydrochloride salt of the product. 16. A process for preparing 3- m ethyl-4-(2-thenoyl)hydratropic ac according to claim 1, characterized by hydrolysing diethyl 2-methyl-2- [4· (2-thenoyl)-m-tolyl]malonate. 17. A process for preparing a-.methyl-p-(2-thenoyl)hydratropic a according to claim 1, characterized by hydrolysing a-methyl-p- (2-thenoyl)hydratroponitrile. 18. A process for preparing 2- (dimethylamino)ethyl p- (2 -thenoyl) hydratropate oxalate according to claim 1, characterized by reacting the sodium salt of p- (2-thenoyl)hydratropic acid with N-(2-chloro-ethyl)-N,N-dimethylamine, and then preparing the oxalate salt of the product . 19. A process for preparing p-(5- Chloro-2-thenoyl)hydratropic aci according to claim 1, characterized by hydrolysing p- (5-chloro-2-thenoyl)hydratroponitri le . 43570/2 PROCESS CLAIMS 20. A process for preparing p-(2- Thenoyl)hydratropohydroxamic acid according to claim 1, characterized by reacting ethyl p-(2-thenoyl) -hydra tropate with hydroxylamine . "v 21. A process for preparing 2-/3- (2-Thenoyl)-o-tolyl7acetic acid according to claim 1, characterized by subjecting 2' -methyls' - (2-thenoyl)acetophenone to the Willgerodt reaction in the presence of sulfur and morpholine. 22. A process for preparing p-(2- Thenoyl)hydratropo-p-anisidide according to claim 1, characterized by reacting p- (2- thenoyl) hydratropyl chloride with p-methoxyaniline. 23. A process for preparing N-(2-thiazolin-2ryl)-p-(2- thenoyl) hydratropamide according to claim 1, characterized by reacting 2-amino-2-thiazoline with p- (2- thenoyl)hydratropoyl chloride. - 62 - . * ·' . . .: · .. .. . · 43570/2 ■ . . '··* ' · ■ *· 24. An aroyl substituted o-R^, α-R^-phenylacetic acid derivative having the formula: wherein: ' ArCO is an aroyl substituent the Ar function of which is a member selected from the group consisting of 2-thienyl, 5-loweralkyl- 2-thicnyl, 5-halo-2-thienyl, 2-naphthyl and 3-pyridyl; said ArCO being in the meta-.or para-position relative to the - acetic acid function; R is a member selected from the group consisting of hydrogen, halo and loweralkyl, provided that when said R is halo or loweralkyl, then said ArCO is in the aforementioned para-position, and provided that when said R is halo, then said Ar is 2-thienyl, 5-loweralkyl-2-thienyl or 5-halo-2-thienyl; Rj is a meml.er selected from the group consisting of hydrogen, halo and loweralkyl, provided that, when said is halo or lower- alkyl, then said ArCC is in the aforementioned meta-position, and provided that when said is halo, then said Ar is 2-thienyl, 5-loweralkyl-2-thicnyl or 5-halo-2- thicnyl; - 63 - 43570/3 \ . · . . . ·■ either of R2 and R3 is' a member selected from the group consisting of hydrogen, allyl and loweralkyl, the other being a member selected from the group consisting of hydrogen and loweralkyl, provided that, when either of said R2 and R3 is allyl, the other is hydrogen, and when either of said R and -j "is loweralkyl, the other is a member selected from the group consisting of hydrogen, and loweralkyl; and Y is a member selected from the group consisting of hydroxy, alkoxy, having from 1 to 8 carbon atoms; diloweralkylamino-lower- alkyloxy, and aminoradicals of the clas s consisting of amino, anilino, halo- substituted anilino, lower alkylanilino, lower- alkyloxyanilino, piperidino, hydroxyethylamino, 2- (2-thiazolinyl) - amino, . and hydroxylamino, ■ and the pharmaceutically acceptable salts of such compounds. - 64 - * 25. p-(2-Thenoyl)hydratropic acid. 26. Ethyl p-(2-thenoyl)hydratropate. . . ^ ' · 27. .Octyl p-(2-thenoyl)hydratropate. 28. 3-Chloro-4-(2-thenoyl)hydratropic acid. 29. p- (3-Pyridylcarbonyl)hydratropic acid. 30. p-(5-Methyl-2-thenoyl)hydratropic acid. 31. . p-(2-Naphthoyl)hydratropic acid, ί 32. m- (2-Thenoyl)hydratropic acid. 33. p-(2-Thenoyl)-a-ethyl-phenylacetic acid. ' . 34. p- (2-Thenoyl)-a-allyl-phenylacetic acid. 35. ( ) — p-(2-Thenoyl)hydratropic acid. 36. ( - )-p-(2-Thenoyl)hydratropic acid. 37. 3- (Dimethylamino)propyl p- (2-thenoyl)hydratropate oxalate. 38. 2-(Diethylamino)ethyl p-(2-thcnoyl)hydratropate hydrochloride. - 65 - 39. 3-Methyl-47 (2-thenoyl)hydratropic acid. 40. ·' 41. oxalate. p-(5-Chloro-2-thenoyl)hydratropic acid. p- (2 - The noy l)hydr atr opohydr oxamic acid .

2. -

3. -(2-Thenoyl)-o-tolyl7acetic acid. p-(2-Thenoyl)hydratropo-p-anisidide. N-(2-thiazolin-2-yl)-p-(2-thenoyl)hydratropam ! · - 47. A process for preparing a compound of formula I herein, substantially as hereinbefore described and. 'with reference to the accompanying examples. ' '■ 48. A compound of the formula I herein whenever prepared according to the process of claim 47. - 49. An anti inflammatory agent characterized by the fact that the active ingredient has the formula I herein.