IE41529B1 - Indene-acetic acids - Google Patents

Abstract

5-Fluoro-2-methyl-1-(p-methylsulphinylbenzylidene)indenyl-3-acetic acid or its salts are prepared. The said acid is obtained by condensing 5-fluoro-2-methyl-1-R1-benzylindene, where R1 is p-methylthio or p-methylsulphinyl, with glyoxylic acid, its salt or ester to give the corresponding 5-fluoro-2-methyl-1-(p-methylthio- (or methylsulphinyl)benzyl)indenylidene-3-acetic acid, its salt or ester. If R1 is p-methylsulphinyl, the indenylidene compound is isomerised to indenyl-3-acetic acid. If R1 denotes methylthio, then the resulting indenylidene-3-acetic acid is isomerised to 5-fluoro-2-methyl-1-(p-methylthiobenzylidene)indenyl-3-acetic acid and the p-methylthio radical is then oxidised to the p-methylsulphinyl group. However, the oxidation can also be carried out first and the isomerisation subsequently. The said compounds can be used as active agents in anti-inflammatory medicaments.

Description

-Fluoro-2-methyl-l- (£-methylsulfinylbenzylidene) -.indene-3acctic acid is a known compound having anti-inflammatory activity, as described in U.S. Patent No. 3,654,349. It has been prepared by a number of methods as disclosed in the above-mentioned patent as well as in Greek Patent No. 41,736. In one of the methods described in the Greek patent, 5-fluoro-2-methyl-l-(p-methylsulfinylbenzyl) -indene is reacted with a glycolic acid ester and the product is subsequently oxidized to an ester of 5-fluoro-2methyl-1-(p-methyl-sulfinylbenzyl)-indenylidene-3-acetic acid, which is then isomerized and hydrolysed to obtain the desired compound. The methods in the Greek patent are quite different from the methods of the present invention.

In accordance with one aspect of this invention, 5-fluoro-2methyl-1-(p-methylsulfinylbenzylidene)-indene-3-acetic acid is readily prepared by condensing 5-fluoro-2-methyl-1-(R^-benzyl)indene, where is p-methylthio or p-methylsulfinyl, with glyoxylic acid or a salt or ester thereof to form the corresponding -fluoro-2-methyl-l-(p-methylthiobenzyl or methylsulfinylbenzyl)indenylidene-3-acetic acid or its salt or ester; and when R^ is p~ methylsulfinyl, isomerizing the indenylidene compound to form the desired indene-3-acetic acid compound in which R^ is p-methylsulfinyl; and when is methylthio, oxidizing to produce the said compound in which R^ is p-methylsulfinyl; or alternatively first oxidizing the 5-fluoro-2-methyl-l-(p-methylthiobenzyl)-indenylidene3-acetic acid or its salt or ester to form the corresponding 1-pmethylsulfinyl compound and subsequently isomerizing that compound.

The 5-fluoro-2-methyl-l-(p-methylsulfinylbenzyl or methylthiobenzyl)-indenylidene-3-acetic acids (the products of Step 4 in Plow Sheet I below) are novel compounds and constitute another aspect of this invention. They are useful intermediate compounds in the preparation of 5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)indene-3-acetic acid. Moreover, it has been found that they also possess anti-inflammatory activity and could be useful for the same purpose as described for the final product of this process.

The 5-fluoro-2-methyl-l-(p-methylthiobenzyl or p-methylsulfinylbenzyl)-indene is preferably prepared by reaction of 5fluoro~2-methyl-l-indanone with a p-methylthiobenzyl or p-methylsulfinyl compound under Grignard or Wittig conditions; the 5fluoro-2-methyl-1-indanone is preferably prepared by reaction of an appropriate ketone under Friedel Crafts conditions; and the said ketone is preferably prepared by reaction of fluorobenzene with an appropriate acid halide under Priedel-Crafts conditions. In this step, the Friedel Crafts reaction may be allowed to continue such that the intermediate ketone formed is cyclized in situ to the 5fluoro-2-methyl indanone.

The invention, including the preferred methods of preparing the starting material, are further described in the following Flow Sheet.

Flow Sheet I S - CH More specifically, the condensation reaction between the 5fluoro-2-methyl-l-[(p-methylthio or methylsulfinyl)benzyl]-indene and glyoxylic acid is carried out in the presence of a strong base. Such bases include alkali metal and alkaline-earth metal hydroxides (e.g. NaOH and KOH), especially in the presence of a quaternary ammonium halide (e.g. a C^_g trialkylbenzyl ammonium halide or tetra alkyl ammonium halide) as catalyst, preferably using 0.1 to 1.0 mole of halide to 1 mole of hydroxide); alkali metal and alkaline-earth metal C alkoxides (e.g. NaOCH^ and K-tertbutoxide); tetra(C^ alkyl)ammonium hydroxides, and benzyl tri-(C, _ alkyl)ammonium hydroxides (e.g. benzyltrimethyl 1-5 ammonium hydroxide). Preferably, a tri(C^ alkyl)benzyl ammonium hydroxide or tetra(C^ θ alkyl)ammonium hydroxide is used as the strong base. The reaction can be carried out without a solvent, but a solvent is preferably used: it is either added to the reaction mixture or used in conjunction with the strong base. alkanols (e.g. methanol and butanol), aromatic solvents such as benzene, pyridine and toluene, dioxane, acetonitrile, dimethylformamide, triglyme, dimethylsulfoxide, water and mixtures of water and organic solvents may be used. Xn fact, any solvent in which the indene and glyoxylic acid are sufficiently soluble can be used. The preferred solvent is a 5 alkanol, especially methanol. The mole ratio of base to glyoxylic acid should be at least slightly more than one mole to one, but preferably from 1.1 to 4.0 and especially 1.2 to 2.5 moles of base to one mole of glyoxylic acid. The mole ratio of glyoxylic acid to indene is not critical and may conveniently be from 1 to 3.0, preferably 1.5 to 1.0, moles of glyoxylic acid to one mole of indene.

Alternatively, one may use a salt with a strong base, e.g. an alkali metal or alkaline-earth metal salt, or an aryl or alkyl ester, especially a C^_5 alkyl, e.g. methyl, ethyl or butyl,ester, in place of the glyoxylic free acid. Under these circumstances, the amount of strong base used in the reaction with glyoxylic acid salt or ester need be no more than a catalytic amount, although the ratio indicated above is also suitable. The order of addition of the reactants is not critical; however, it is preferred to add the glyoxylic acid compound to the reaction mixture of indene and base. The time of reaction is not critical, the reaction being carried out until it is substantially complete. Preferably, however, the reaction is carried out for from 15 minutes to 5 hours, and especially from 30 minutes to 3 hours. The reaction may be carried out from 0°C to 150°C, preferably 10°C to 80°C and o o especially 35 C to 60 C.

After the condensation reaction is complete, the isomerization of the thus formed 5-fluoro-2-methyl-l-(p-methylthiobenzyl or methylsulfinylbenzyl)-indenylidene-3-acetic acid, in the form of its acid-addition salt or ester, may be carried out without isolation; that is, the same reaction mixture from the glyoxylic acid reaction can be used for the isomerization. This is particularly true when it is desired to carry out the isomerization under basic conditions, since the reaction mixture from the previous step is already basic and merely continuing the reaction will lead to the isomerization product. On the other hand, other strong bases for the isomerization, such as those described for the previous reaction, may be used. Preferably, however, the isomerization is carried out with the use of acid, and accordingly the reaction product from the previous step is preferably first isolated. Various organic and/or inorganic . acids may be used such as C. ,- alkylsulfonic acids (e.g. methanesulfonic acid), aryl1-5 sulfonic acids (e.g. toluene sulfonic ncidti), acidic ion-oxchange resins (e.g. that sold under the trade mark Dowex 50), arylcarboxylic acids (e.g. jq-nitrobenzoic acid), aliphatic acids (e.g. alkanoic acids such as acetic acid, propionic acid, trichloroacetic acid and trifluoroacetic acid) and mineral acids (e.g. phosphoric acid, hydrochloric acid, hydrobromic acid and sulfuric acid). It is preferable to use mineral acids or mixture of mineral acids and organic acids (preferably C_ alkanoic acids) ' 2—5 such as hydrochloric and acetic acid, hydrobromic and propionic acid. The ratio of acid to indenylidene is not critical and catalytic quantities of acid can be used. All that is necessary is that the reaction mixture be kept acid if there is any likelihood of its becoming basic. It is preferred, however, to use 0.1 to 50 and especially 1.0 to 209 moles of acid to 1 mole of indenylidene. The reaction may be carried out with or without a solvent, and when solvents are used those previously mentioned for the glyoxylic acid,reaction, which are inert, may be used, as well as halogenated hydrocarbons such as aliphatic halides (ethylene dichloride) or halobenzenes. Preferably the reaction is carried out with an acid or a halogenated hydrocarbon as solvent. When a weak acid is used as solvent it is preferred to also use a strong acid such as arylsulfonic acid or mineral acid. For example, one could use an unsubstituted alkanoic acid (e.g. acetic acid) as solvent together with an arylsulfonic (e.g. toluenesulfonic acid) or especially, a mineral acid (e.g., hydrochloric acid). When halogenated hydrocarbons are used as solvents, it is preferred to use mineral acids as catalysts and especially an anhydrous mineral acid such as hydrogen chloride. The time and temperature of reac7 tion are not critical: the higher the temperature the shorter the time needed to substantially complete the reaction. Accordingly, the reaction may be carried out at a temperature of °C to 150°C o o and preferably from 50 C to 110 C. Similarly, the reaction time is preferably at least 30 minutes and may be up to one or more days. After completion of the isomerization reaction, the product may be isolated by standard techniques such as filtration, extraction or removal of the acid solvent by'evaporation.

When the p-methylthio compound is used as the starting material, oxidation of the methylthio group to the desired methylsulfinyl group may be carried out at any stage of the process such as immediately after reaction with glyoxylic acid or after isomerization, but preferably after isomerization. The oxidation may be carried out by any number of standard techniques such as oxidation with hydrogen peroxide, basic periodates or hypohalites, preferably the alkali metal or alkaline-earth metal periodates and hypohalites or organic peracids such as peracetic acid and monoperphthalic acid. Preferably, however, the oxidizing agent is hydrogen peroxide. The reaction is preferably carried out in the presence of a solvent. For such purposes alkanoic acids (e.g. acetic acid), halogenated hydrocarbons (e.g. chloroform), ethers (e.g. dioxane), C alkanols (e.g. isopropanol) or mixtures thereof may be used.

The mole ratio of oxidizing agent to indene compound may be from 0.5 to 10 but is preferably from 0.8 to 1.5. The reaction time and temperature are not critical, the reaction being carried out until substantial completion. Preferably, however, the time of reaction is from 1 to 18 hours and especially 2 to 6 hours at o o . o o a temperature of 10 C to 80 C and especially 25 C to 50 C. - 8 41539 If the use of an ester of glyoxylic acid is desired, the final free acid compound is readily obtained during the isomerization, especially if some water is present and when the isomerization is carried out at elevated temperatures. The type of ester used is not critical since it can be made to readily come off during the reaction. Accordingly aliphatic, aromatic or heterocyclic esters may be employed such as alkali (e.g. methyl or tbutyl), alkenyl, aralkyl (e.g. benzyl) or aryl (e.g. phenyl). Glyoxylic acid salts, such as the pharmaceutically acceptable salts as well as others converted to the free acid by hydrolysis, may also be used. Such salts include those of alkali metals and alkaline-earth’methls (e.g. Na, K, Ca and Li), as well as salts of the metals previously described with respect to the Friedel Crafts reaction.

The 5-fluoro-2-methyl-l-(p-methylthiobenzyl or methylsulfinylbenzyl)-indene may be prepared from 5-fluoro-2-methyl-l-indanone by reaction with a p-(methylthio or methylsulfinyl)benzyl compound under Grignard or Wittig type conditions. This indene contains the double bond in the 1 or 2 position. However, under certain conditions in its formation, some tautomeric indene compounds are present. When these isomers are reacted in the presence of a base, as in the reaction with glyoxylic acid, the same indenyl anion is formed: this reacts with glyoxylic acid in the same way, giving the indene compound. For example, the Grignard of p-methylthiobenzyl chloride or the Wittig reagent of p-methylsulfinylbenzyl triphenylphosphonium chloride is reacted with 5fluoro-2-methyl-l-indanone under Grignard or Wittig conditions, respectively. In the case of the Grignard reaction, the benzyl indene compound is obtained directly, whereas with the Wittig reaction, there is obtained for the most part the benzylidene indane compound, in this latter case, the benzylidene is isomerized to the benzyl compound under acid conditions by well known means for isomerization.

More specifically, the benzyl group is attached to the indanone compound via a Grignard or Wittig reaction under well known conditions. For example, in the Grignard reaction, to metallic magnesium in absolute ether is added the appropriate p-methylthiobenzyl halide or p-methylsulfinylbenzyl halide (e.g. Cl, Br, F, I) and the reaction mixture is heated to a temperature preferably in the range 25 to 35°C. Although more or less than an equimolar amount of magnesium may be used, it is advantageous to use 3—6 fold excess relative to the benzyl halide. Although diethyl ether is usually used as the solvent, other ethers may be similarly used such as di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-l,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxy-tetrahydrofuran. Tertiary amines such as dimethylaniline, hydrocarbons such as benzene and toluene, and many other types of solvent described in the literature can be also used. The Grignard reagent thus prepared may be suitably used without purification for reaction with the indanone. The indanone and Grignard are admixed (preferably indanone is added to Grignard) at a temperature of from about 0°C to the boiling point of the solvent and preferably 20 to 35°C The concentrations of reactants are not critical ; however for best results, about equimolar quantities of each are used.

The complex thus formed is reacted, as is usual with Grignard reactions, with an acid. Inorganic mineral acids such as IIC1, HjSOj and phosphoric acids may be used as well as organic or aliphatic acids such as acetic, propionic or methanesulfonic.

Usually, at least a 5—10% molar excess of acid to complex is used. It is preferred to add the acid to the complex reaction mixture usually as a dilute solution in water, although other solvents for the acid may also be used such as alcohols, ethers or aromatic hydrocarbons. The reaction temperature is usually 0 to 100°C, although 20 to 40°C is preferred.

In the Wittig reaction, for example, triphenylphosphine or a substituted triphenylphosphine is reacted with the appropriate (pmethylthio or p-methylsulfinyl)benzyl halide in the melt or in the presence of a suitable solvent to form the intermediate phosphonium salt. Such solvents as aromatic liquids (e.g. benzene, nitrobenzene and xylene), ethers (e.g. diethyl ether), acetonitrile, dimethylformamide, nitromethane, formic acid, acetic acid and ethyl acetate as well as many others described in the literature may be used. The preparation of the phosphonium salt is conveniently carried out at temperatures from 0 to 200°C and especially 25 to 75°C, at atmospheric pressure as well as under elevated pressure. The molar concentration of the triphenylphosphine to the benzyl halide may suitably vary from 2 moles to 1 mole and preferably 1.2 moles to 1 mole. The phosphonium salt is not necessarily isolated and is converted to the Wittig reagent by either the organometallic or alkoxide method. In the former method, phenyl lithium or n-butyl lithium is the usual proton acceptor and diethyl ether or tetrahydrofuran the solvent. In the latter method an alkali metal alkoxide may be used as the proton acceptor and corresponding alcohols as the solvent.

The Wittig reagent is usually not isolated but rather is allowed to react in the same reaction vessel. The reaction of the bases with the phosphonium salt is suitably carried out on about an equimolar basis, although an excess of base may be advantageously used. The reaction may be carried out at a temperature of from 0°C to the boiling point of the solvent and preferably from 25 to 50°C. After addition of the base, the indanone compound is then added, suitably in about equimolar quantity with the Wittig reagent, although more or less may be used. The reaction may be carried out at temperatures of from 0°C to the boiling point of the solvent but preferably 25 to 50°C until the reaction is substantially complete. The indene intermediate may then be isolated by standard techniques.

In those cases where the Wittig reagent is first isolated, the reaction with the indanone may be readily carried out in a variety of inert solvents. Solvents such as ether, benzene, ethylacetate^ hexane or petroleum ether may be suitably used.

The 5-fluoro-2-methyl-l-indanone is prepared by reacting a ketone of the formula: under Friedel-Crafts conditions. In the formula, A and G are both methyl and B is halo, or A and G together form a methylene radical and B is methyl; or A is methyl, B is hydrogen, and G is CH^R where R is a halogen atom, a hydroxy group or an ether or ester of hydroxy, or a difc^ 5 alkyl) amino group. The term halogai, in both R and B, means Cl, Br, F or I. When R is di(C., _ alkyl)amino it is preferably dimethylamino or diethylamino. When R is an ether or ester of hydroxy, it may be derived from alkanols, especially alkanols, alkanoic acids, especially alkanoic 41539 acids, aromatic acids, especially C aromatic acids, or mineral 7—y acids, examples of which are methanol, propanol, acetic acid, propionic acid, methane sulfonic acid, ja-toluenesulfonic acid and phosphoric acid. Z is a halogen atom.

Preferably, the ketone starting material is 2-bromo-41-fluoro2-methylpropiophenone (when A and G are each methyl and B is halogen) but it may suitably also be 41-fluoro-2-methylacrylophenone, 3-chloro-4'-fluoro-2-methylpropiophenone, 4'-fluoro-3hydroxy-2-methylpropiophenone or 3-dimethylamino-4'-fluoro-2methylpropiophenone. The reaction is suitably carried out under normal Priedel Crafts conditions. For example, the ketone is reacted in the presence of such Friedel Crafts catalysts as Lewis acids, metal alkyls and alkoxides, Bronsted acids, acidic oxides and sulfides, cation-exchange resins, metathetic cation-forming agents and stable carbonium and related complexes. Lewis acids such as those of the acid halide type (metal halides), e.g. aluminium chloride or bromide, BeCl2, Cdcl2, Zncl^BF.^, BCl^, BBr3, Gacl3, GaBr_, TiCl., TiBr., ZrCl., SnCl., SnBr., SbCl , SbCl , BiCl , 344444333 FeCl3 and UCl^ may be suitably used. Also, when the ketone is the a or β-haloisobutyrophenone, the metals per se may be used as catalysts, since in the course of the reaction the halo compound reacts with the metal forming the corresponding metal halide, which in turn assists in furthering the reaction. This class of Friedel-Crafts catalysts is preferred and particularly the use of an aluminium or iron halide. The metal alkyls and alkoxides that can be suitably used are, for example, aluminium or boron alkyls (e.g. methyl, ethyl or propyl) or alkoxides (e.g. methoxide, ethoxide or propoxide). Bronsted acids which can be suitably used are, for example, sulfuric, phosphoric, polyphosphoric. perchloric, chlorosulfonic, fluorosulfonic, alkylsulfonic and arylsulfonic {e.g. ethane sulfonic and p-toluene sulfonic) and related aromatic sulfonic acids, as well as chloroacetic and trifluoroacetic acids. The acidic oxides and sulfides useful as catalysts include a great variety of solid oxides and sulfides.

Of particular usefulness are alumina, silica and mixtures of alumina and silica, although catalysts other than silica-alumina compositions such as BeO, Cr2O3, p2°5» TiO2 The ketone starting material is readily prepared by condensing an appropriate acid halide of the formula; A 0 T B where A, B and G are as previously described and Z is halo, with fluorobenzene under Friedel-Crafts conditions as described previously. Further, if desired, the acid halide may be condensed with the fluorobenzene to form the ketone and in situ go directly to the 5-fluoro-2-methyl-l-indanone. If this procedure is desired, additional Friedel Crafts catalyst is used sufficient to carry out the two steps. The acid halide is preferably an a-haloisobutyrylhalide.

The following examples and preparations are given by way of illustration. The abbreviations mm andmmole mean millimole.

Preparation 1 4'-Fluoro-3-hydroxy-2-methylpropiophenone A mixture of 45.7 g. (0.3 mole) of 4'-fluoro-propiophenone, g. (0.3 mole) of paraformaldehyde, 4 g. (0.03 mole) of anhydrous potassium carbonate and 200 ml. of methyl alcohol is stirred at 35°C for two days. The reaction mixture is quenched in water and acidified with hydrochloric acid. The product is extracted into benzene. The benzene layer is washed with water and concentrated in vacuo to give 4'-fluoro-3-hydroxy-2-methylpropiophenone.

Preparation 2 -Fluoro-2-methyl-l-indanone from 4'-fluoro-3-hydroxy-2-methylpropiophenone A mixture of 18.2 g. (0.10 mole) of 4'-fluoro-3-hydroxy-2methylpropiophenone and 12 g. of phosphorus pentoxide in 100 mi. of xylene is refluxed for one hour. The reaction mixture is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide and water. The organic layer is then concentrated in vacuo to give 5-fluoro-2-methyl-l-indanone.

Preparation 3 2-Bromo-4'-fluoro-2-methylpropiophenone A slurry of 14 g. (0.015 mole) of anhydrous aluminium chloride in 14.4 g. (0.150 mole) of fluorobenzene and 24 ml. of carbon disulfide is cooled to 15°C. To it is added 23.8 g. (0.100 mole) of α-bromoisobutyryl bromide over lo—15 minutes at 15~—20°C, The reaction mixture is stirred for five minutes at 20°C and then quenched on ice. The product is extracted into chloroform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give 2-bromo-41 fluoro-2-methylpropiophenone.

Preparation 4 -Fluoro-2-methyl-l-indanone from 2-bromo-4'-fluoro-2-methylpr opiopher .one To a slurry of 120.2 g. (0.90 mole) of anhydrous aluminium chloride in 54 ml. of carbon disulfide is added 122.6 g. (0.50 mole) of 2-bromo-4'-fluoro-2-methylpropiophenone at 15—20°C over one hour. The mixture is warmed to 50°C over one hour, stirred at 50°C for three hours and quenched in ice. The product is extracted into toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5fluoro-2-methyl-l-indanone.

Preparation 5 41-Fluoro-2-methylacrylophenone A slurry of 29.4 g. (0.220 mole) of anhydrous aluminium chloride in 38.4 g. (0.40 mole) of fluorobenzene under nitrogen is cooled to 15°C. Methylacryl chloride (21.9 g., 0.200 mole) is then added dropwise over 30 minutes while holding the temperature at 15—2o°C The mixture is warmed to 30°C over 10 minutes, 41539 stirred at 30°C for 10 minutes and quenched in ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 4'fluoro-2-methylacrylophenone.

Preparation 6 -Fluoro-2-methyl-l-indanone from 4'-fluoro-2-methylacrylophenone g. (0.30 mole) of 4'-fluoro-2-methylacrylophenone is added to a slurry of 60.1 g. (0.45 mole) of anhydrous aluminium chloride in 27 ml. of carbon disulfide at 20—25°C over one hour. The mixture is heated to 45°C over one hour and stirred at 45°C for one hour. The reaction mixture is quenched in ice. The oily aqueous layer is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-l-indanone.

Preparation 7 3-Chloro-4'-fluoro-2-methylpropiophenone To a slurry of 22.7 g. (0.17 mole) of anhydrous aluminium chloride and 9.6 g. (0.10 mole) of fluorobenzene is added 14.1 g. (0.10 mole) of β-chloroisobutyrylchloride over 30 minutes at 20— 25°C. The mixture is aged for 30 minutes at 20—25°C and then quenched in ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-chloro-41-fluoro-2-methylpropiophenone.

Preparation 8 -FluorO’-2-methyl-l-indanone from 3-chloro-4'-fluoro-2-methylpropiophenone g. (0.05 mole) of 3-chloro-4'-fluoro-2-methylpropiophenone is added to 20 ml of concentrated sulfuric acid at 20—25°C and the mixture is warmed to 50°C. After being stirred for three ο hours at 50 C, the reaction mixture is quenched in ice. The product is extracted into hexane. The hexane layer is concentrated in vacuo to give 5-fluoro-2-methyl-l-indanone.

Preparation 9 3-Dimethylamino-4'-fluoro-2-methylpropiophenone A mixture of 15.2 g. (Q.10 mole) of 4'-fluoropropiophenone, 8.2 g. (0.10 mole) of dimethylamine hydrochloride and 3.6 g. (0.12 mole) of paraformaldehyde in 20 ml. of absolute alcohol was stirred at 95—100°C for three hours. The mixture is cooled and the precipitated product is filtered. The product is dissolved in water and made alkaline with sodium hydroxide. The free base is extracted into ether. The ethereal layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-dimethylamino4'-fluoro-2-methylpropiophenone.

Preparation 10 -Fluoro-2-methyl-l-indanone from 3-dimethylamino-41-fluoro-2- J methylpropiophenone A mixture of 42 g. (0.20 mole) of 3-dimethylamino-41-fluoro-2methylpropiophenone and 100 ml. of concentrated sulfuric acid is warmed to 90°C over one hour and stirred at 90°C for two hours.

I The reaction mixture is cooled and quenched in ice and the product extracted into toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5fluoro-2-methy1-1-indanone.

Preparation 11 -Fluoro-2-methyl-l-indanone from fluorobenzene and a-bromoisobutyryl bromide To a slurry of 120.2 g. (0.90 mole) of anhydrous aluminium chloride in 54 ml. of carbon disulfide and 51.4 g. (0.535 mole) of fluorobenzene under nitrogen is added 115 g. (0.50 mole) of abromoisobutyryl bromide. The addition is accomplished at 15—20°C over 75 minutes. The reaction mixture is warmed to 50°C over 75 minutes, stirred at 50°C for 3¾ hours and then quenched in ice. Toluene is added to extract the product'. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 79 g. (96%) of 5-fluoro-2-methyl-l-indanone.

Preparation 12 -Fluoro-2-methyl-l-(p-methylthiobenzyl)-indene g. (1.04 moles) of magnesium turnings is placed in a dried flask under N2 with 400 ml. of ether, 10 ml. of 0.05 molar pmethylthiobenzyl magnesium chloride in ether is added and the mixture is warmed to 30°C. About 2—3% of 39.7 g. (0.23 moles) of pmethylthiobenzyl chloride in 75 ml. of toluene is added. After 3—5 minutes of stirring an exotherm to 32—33°C occurs signifying initiation of the reaction. After the reaction mixture has aged for 5 minutes, the rest of the benzyl chloride is added dropwise to it over 90 minutes. The reaction is aged for 30 minutes with stirring. 5-Fluoro-2-methyl-l-indanone (32.6 g., 0.199 mole) is added dropwise over 45 minutes. After aging for 30 minutes, the milky supernatant mixture is decanted from the magnesium.

The flask and residual magnesium are rinsed with toluene. The reaction is then quenched by the addition of 120 ml. of 3N sulfuric acid. The lower layer is discarded. To the organic layer is added 80 ml. of a 1:10 by volume mixture of concentrated sulfuric acid and acetic acid, the two-phase mixture is stirred vigorously for one hour and water (100 ml.) is added. The bottom layer is discarded and the organic layer is washed with 100 ml. of water and 200 ml. of 2N sodium hydroxide. After a final water wash the organic layer is concentrated to give 5 -fluoro-2-methyl · -(p-methylthiobenzyl)-indene. Similarly, when p-methylsulfinyl benzyl chloride is used in place of p-methylthiobenzyl chloride in the above example, the corresponding p-methylsulfinylbenzyl indene is obtained.

Preparation 13 p-Methylthiobenzyltriphenylphosphonium chloride. 17.3 g. of p-methylthiobenzyl chloride is added to 28 g. of triphenylphosphine in 80 ml. of benzene. The reaction mixture is heated for 4 hours, then cooled, and the product, p-methylthiobenzyltriphenylphosphonium chloride, is collected by filtration. There is obtained 19 g., melting point 257—258°C.

In a similar manner, when p-methylsulfinylbenzyl chloride is used, the product is p-methylsulfinylbenzyltriphenylphosphonium chloride, melting point 258—262°C with gassing.

Preparation 14 -Pluoro-2-methyl-l-(p-methylthiobenzyl)-indene A. 5-Fluoro-2-methyl-l-(p-methylthiobenzylidene)-indane 169 mg. (1.5 mm) of potassium t-butoxide is dissolved in 2 ml. of DMSO and treated with 651 mg. (1.5 mm) of p-methylthiobenzyltriphenylphosphonium chloride dissolved in 1 ml. of DMSO.

To this solution is added 270 mg. (1.65 mm) of 5-fluoro-2-methylo « 1-indanone in 2 ml.of DMSO. The solution is heated at 75 C for ' .5 hours. Benzene and water are added and the benzene layer is washed five times with water. The benzene layer is dried over Na^SO^ and evaporated to dryness under vacuum. The weight is 915.6 mg. This material is eluted through 8 g. of silica gel with benzene to remove triphenylphosphine oxide. The eluate weights 372 mg. after removal of solvent. This is rechromato20 41529 graphed through 15 g. of silica gel using hexane and 95.9 mg. of -fluoro-2-methyl-l-(p-methylthiobenzylidene)-indane is isolated, melting point 67—70°C.

B. 5-Fluoro-2-methyl-l-(js-methylthiobenzyl)-indene mg. of the benzylidene compound from A above is mixed with 1 ml. of acetic acid containing 100 mg. of sulfuric acid and the reaction mixture is stirred for 1 hour at room temperature. The mixture is then diluted with water and extracted with ether. The ethereal extract is concentrated in vacuo to give the desired compound.

Similarly, when the £-methylsulfinylbenzyl triphenylphosphonium chloride is used, the corresponding p-methylsulfinylbenzyl indene compound is obtained.

Preparation 15 -Fluoro-2-methyl-l-(p-methylsulfinylbenzyl)-indene 500 mg. (1.755 mm) of 5-fluoro-2-methyl-l-(p-methylthiobenzyl)indene is dissolved in 5 ml. of chloroform. To this solution is added 30% hydrogen peroxide (equivalent to 2.645 mm). The reaction mixture is aged for one hour at room temperature followed by the addition of 5 ml. of glacial acetic acid and aged for an additional hour. The reaction mixture is then diluted with 25 ml. of 1:1 by volume benzene-ether and extracted with 6X25 ml. of 3% aqueous sodium chloride. The solution is then dried over sodium sulfate and evaporated in vacuo to yield an oil. Recrystallization from ice-cold isopropanol gives 5-fluoro-2-methyl-l-(jg-methylsulfinylbenzyl)-indene.

EXAMPLE 1 -Fluoro-2-methyl-l-(jg-methylthiobenzyl)-indenylidene-3-acetic acid To 41.8 g. (147 mmole) of the preceding indene (from Example 12) is added 150 ml. of methanolic Triton B solution (53.2 g. , dry basis; 317.5 mmole) and the batch, under a nitrogen atmosphere, is brought to 35°C. 14.63 g. glyoxylic acid (198 mmole) is added and the batch, which warms to 5O-55°C, is aged one hour at 50°C. It is then diluted with 250 ml. of water and acidified with dilute sulfuric acid. The product obtained in 90% yield is recrystallized to give the pure desired product, melting point 185.5-188°C. Triton is a trade mark.

When sodium hydroxide and tetramethylammonium chloride or tetramethylammonium hydroxide are used in place of Triton B in the above example, the indenylidene-3-acetic acid is obtained.

Similarly, when 5-fluoro-2-methyl-l-(p-methylsulfinylbenzyl) indene is used in place of the corresponding methylthio compound in the above example, there is obtained 5-fluoro-2-methyl-l(p-methylsulfinylbenzyl)-indenylidene-3-acetic acid.

EXAMPLE 2 A. 5-Fluoro-2-methyl-l-(p-methylthiobenzylidene)-indene-3acetic acid A suspension of 34.2 g. of 5-fluoro-2-methyl-l-(]3methylthiobenzyl)-indenylidene-3-acetic acid (from Example 1) in 342 ml. of glacial acetic acid and 137 ml. of concentrated HCl is stirred under a nitrogen atmosphere at 90°C for 10 hours.

The reaction is cooled over 2 to 3 hours to room temperature and aged an additional 3 hours at 2O-25°C. The batch is filtered, washed with a 70:30 by volume mixture of acetic acid and water (ca. 100 ml.) then water-washed to remove excess of acid. There is obtained 93% of product, melting point 18O-183°C.

Similarly when 5-fluoro-2-methyl-l-(£-methylsulfinylbenzyl)indenylidene-3-acetic acid is used in the above example in place of the corresponding methylthio compound, there is obtained 5- 22 fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-indene-3-acetic acid. The reaction may be conducted in an aprotic solvent such as 1,2-dichloroethane under 100 p.s.i.g. of HCl gas at 50—100°C.

B. 5-Fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-indene-35 acetic acid g. (50 mmole) of the product from Step A is stirred in 94 ml. of chloroform and 40 ml.of acetic acid under nitrogen and the temperature brought to 30°C. To this slurry is added 5.3 ml. of 9.6H aqueous (51 mmole) over one minute. The temperature is lo brought to 35°C. The batch is aged for a total of 6 hours, maintaining 35°C internal temperature. After the age period, 125 ml. of water is added and the CHC1, layer concentrated to a small volume in vacuo. The residue is crystallized from 75 ml. of ethanol and the slurry cooled to 0—5°C and aged at 0—5°C. The product is filtered and washed with 15 ml. of cold (0—5°C) ethanol and dried in vacuo at 80°C. The product weighs 16.3 g. (92%), melting point 183—185°C.

Similarly, when sodium periodate or potassium hypochlorite is used in place of hydrogen peroxide in the above example, there is obtained the desired compound.

Preparation 16 2-Dimethylaminomethyl-4'-fluoropropiophenone A slurry of 14 g. (0.015 mole) of anhydrous aluminium chloride in 14.4 g. (0.150 mole) of fluorobenzene and 24 ml. of carbon disulfide is cooled to 15°C. To it is added 0.100 mole of a-(dime thylaminomethyl)propionyl bromide hydrobromide over 10—15 minutes at 15—20°C and then quenched on ice. The product is extracted into chloroform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give 2-dimothylaminoethyl-41-fluoro-2-methylpropiophenone.

Preparation 17 -Fluoro-2-methyl-l-(p-methylthiobenzyl)-indene 13.44 g. (0.56 mole) of magnesium turnings are placed in a dried flask under with 125 ml. of ether and a crystal of iodine, ml. of 65 ml. solution of 24.2 g. (0.14 mole) of p-methylthiobenzyl chloride in ether is added. After 3 to 5 minutes of stirring the iodine color disappears and the reaction begins. After the reaction mixture has aged for 5 minutes, the rest of the benzyl chloride is added dropwise over 45 minutes. It is rinsed in with 10 ml. of ether and the reaction aged for 2 hours with stirring. 21 g. (0.^.28 mole) of 5-fluoro-2-methyl-l-indanone dissolved in 50 ml. of ether is added dropwise over 30 minutes. After aging for 1 hour, the milky supernatant mixture is decanted from the magnesium into 100 ml. of acetic acid. The flask and residual magnesium are rinsed into the acid solution with 4X50 ml. of benzene. 200 ml. of water is added, the layers are separated and the organic layer is washed with 5X200 ml. water.

It is stripped to dryness after drying over Na^SO^. The crude reaction product is crystallized from hexane to give pure 5fluoro-2-methyl-l-(p-methylthiobenzyl)-indene, melting point 58— 59°C.

EXAMPLE 3 -Fluoro-2-methyl-l-(p-methylthiobenzylidene)-indene-3-acetic acid A suspension of 34 grams of 5-fluoro-2-methyl-l-(p-methylthiobenzyl) -indenylidene-3-acetic acid in 150 ml. of ethylene dichloride is heated to 70°C in a glass-lined autoclave. Anhydrous hydrogen chloride is admitted until the pressure reaches 95 psig. The reaction mixture is stirred under these conditions for 10 hours and the excess of gas is then vented. The product slurried is cooled to 0—5°C and after one hour is filtered and washed with fresh ethylene dichloride. The yield of product is 80%

Claims (20)

1. A cis or trans compound of the formula: where R^ is methylthio or methyIsulfinyl, or a salt or ester 5 thereof.

2. A method of preparing a compound as claimed in Claim 1 that comprises condensing 5-fluoro-2-methyl-l-(R^-benzyl)indene, where is £-methylthio or p-methylsulfinyl, with glyoxylic acid or a salt or ester thereof. 10

3. A method as claimed in Claim 2, in which 5-fluoro-2methyl-(1-p-methylthiobenzyl)indene and glyoxylic acid are used.

4. A method as claimed in Claim 2 or 3, including the step of preparing the 5-fluoro-2-methyl-l-(R^-benzyl)indene by reacting 5-fluoro-2-methyl-l-indanone with an R^ benzyl compound, in which 5. Or Λ and G together form a methylene radical and B is methyl; or A is methyl, B is hydrogen, and G is CIl^R where R is a halogen atom, a hydroxy group or an ether or ester of hydroxy, or a di(C^_5 alkyl)amino group.

5. A method as claimed in Claim 4, in which R^ is p-methylthio and Grignard conditions are used.

6. A method as claimed in Claim 4 or 5, including the step 20 of preparing the 5-fluoro-2-methyl-l-indanone by reacting a ketone 41539 of the formula: under Friedel-Crafts conditions to form 5-fluoro-2-methyl-l-indanone; where, in the formula, Λ and G are both methyl and B is halo;

7. A method as claimed in Claim 6, in which the ketone is

8. A method as claimed in Claim 6 or 7, in which the ketone is prepared by reacting an acid halide of the formula: A 0 G I j z B in which A, B and G are as defined in Claim 6 and Z is a halogen

9. A method as claimed in Claim 8, in which the acid halide is an α-haloisobutyryl halide.

10. A method as claimed in Claim 9, in which the halide is tt-bromoisobutyryl bromide. 20 11. A method as claimed in any one of Claims 2 to 10, in which R^ is p-methylthio and the product is then oxidized to the corresponding compound in which R^ is p-methylsulfinyl. 10 4'-fluoro-2-halo-2-methylpropiophenone.

11. , including the further step of isomerizing the resulting product where R^ is p-methylsulfinyl to produce 5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)indene-3-acetic acid.

12. A method as claimed in any one of Claims 2 to 10, in which is p-methylthio and the product is isomerized to form 5-fluoro-2methyl-1-(p-methylthiobenzylidene)indene-3-acetic acid.

13. A method as claimed in Claim 12, including the further step of oxidizing the 5-fluoro-2-methyl-l-(p-methylthiobenzylidene)indene-3-acetic acid to produce 5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene) indene-3-acetic acid.

14. A method as claimed in any one of Claims 2, 4, and 6 to

15. A method of producing a compound as claimed in Claim 1, substantially as hereinbefore described in Example 1. 15 atom with fluorobenzene under Friedel-Crafts conditions. 15 R 1 is p-methylthio or p-methylsulfinyl, under Grignard or Wittig conditions.

16. A compound as claimed in Claim 1 when prepared by a method as claimed in any one of Claims 2 to 10 and 15.

17. A method of producing 5-fluoro-2-methyl-l-(p-methylthiobenzylidene) indene-3-acetic acid, substantially as hereinbefore described in Example 2 or 3.

18. 5-Fluoro-2-methyl-l-(p-methylthiobenzylidene)indene-3acetic acid when prepared by a method as claimed in Claim 12 or 17.

19. A method of producing 5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)indene-3-acetic acid, substantially as hereinbefore described in Example 2.

20. 5-Fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)indene3-acetic acid, when prepared by a method as claimed in Claim 13, 14 or 19.