FI62287C - PROCEDURE FOR FRAMSTATION OF AV 5-FLUOR-2-METHYL-1- (P-METHYLSULPHINYL BENZENYL) -INDEN-3-ACETYXYRA - Google Patents

Description

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Patent · och registerstyrelsen '' AmBkan uttafd oeh utl. »Krlft # n pgbikarad (32) (33) (31) Pyr»> «« r «« uoikau * —Bajtrd prior · »· * 20.12.73 05.07-74, 30.09 · 74 US A (us) 426864, 486031, 509602 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey, USA (72) Roger James Tull, Metuchen, New Jersey, Robert Francis Czaja, Scotch Plains, New Jersey, Richard Ferriss Shuman, Westfield, New Jersey,

Seemon Hayden Pines, Murray Hill, New Jersey, USA.

(7 * 0 Oy Kolster Ab (54} Process for the preparation of 5-fluoro-2-methyl-1- (p-methylsulfinyl-benzylidene) -indene-3-acetic acid - Preparation of 5-fluoro-2-methyl-1-acetic acid - (p-metylsulfinyl bensyliden) inden-3-acetic acid

The invention relates to a new process for 5-fluoro-2-methyl-1- (p-methylsulfinyl-benzylidene) -indene-3-acetic acid of general formula I

0

F-j / N-j-CH 2 -C-OH

1 „3

A

V

0 <- S - CH, ¢ 2287 or its acid addition salts.

Indene-3-acetic acid is a known compound having anti-inflammatory activity, as disclosed in U.S. Patent 3,645-3,9. The compound has been prepared by a number of methods, such as those disclosed in U.S. Patents 3,65-3 * + 9 and 3,732,292. U.S. Patent 3,732,292

In the process, 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene is shown as an intermediate. This intermediate is reacted with a glycolic acid ester and the resulting product is oxidized to 5'-fluoro-2-methyl-1- (p-methylsulfonylbenzyl) -indenylidene-3-acetic acid ester, which is then isomerized and hydrolyzed to the desired compound. According to another known method, 5-fluoro-2-methylindanone is condensed with cyanoacetic acid, after which a p-methylsulfinylbenzylidene side chain is attached to the compound.

The present invention relates to a new process for the preparation of 5-fluoro-2-methyl-1- (p-methylthio- or methylsulfinyl-benzylidene) -indene-3-acetic acid, which is more advantageous than the above-mentioned processes and which achieves higher yields than known processes. . The process according to the invention is characterized in that it comprises the following steps: a) 5-fluoro-2-methyl-1-benzylindene of the formula II

f2 Ä

containing methylthio or methylsulfinyl is condensed in the presence of a strong base with glyoxylic acid, its salt or ester to give the corresponding 5-fluoro-2-methyl-1- (p-methylthio or methylsulfinylbenzyl) indenylidene-3-acetic acid of formula III

62287

O

F— - v = CH-C-OH

L 111 λ

V

wherein R 1 '"is as defined above, a salt or ester thereof, and b) the indenylidene compound is isomerized to the desired indene-3-acetic acid compound when R 1 is p-methylsulfinyl; when R 1 is methylthio, the indenylidene compound obtained from step (a) The 3-acetic acid compound is isomerized to the 5-fluoro-2-methyl-1β-methylthiobenzylidene-3-indene acetic acid compound and the 3-indeneacetic acid is oxidized, or alternatively the 3-indenylideneacetic acid is first oxidized to the corresponding 1-p-methylsulfinylmethylisulfinyl after this.

When R · * · is p-methylthio, the compound of formula I is prepared by reacting 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indene with glyoxylic acid, its salt or ester to give the corresponding indenylidene-3-acetic acid, its to a salt or ester, which compound is then isomerized and oxidized to give the desired product, (steps k, 6 and 7 in Scheme I). Alternatively, the indenylidene-3-acetic acid compound may be first oxidized and then iso-merized.

When R 1 is p-methylsulfinyl, a compound of formula I is prepared by reacting 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene with glyoxylic acid, its salt or ester directly with 5-fluoro-2-methyl 1- (p-methylsulfinylbenzyl) -indenylidene-3-acetic acid, which compound is then isomerized to the desired product (steps * + and 5 in Scheme I).

It is surprising that the reaction according to the invention with glyoxylic acid takes place selectively and in high yield without the methyl group participating in the reaction. It is also unexpected that the reaction can be carried out without isolating the intermediate.

62287

The process according to the invention is simpler than the process known from U.S. Pat. No. 3,732,292 in that by reacting the indene compound with glyoxylic acid, its salt or ester (compare step H) instead of glycolic acid ester, no oxidation is required with 5-fluoro-2-methyl-1- -methyl-sulfinyl-benzyl) -indenylidene-3-acetic acid. In a more preferred embodiment, the process according to the invention has two steps, namely condensation with glyoxylic acid and subsequent isomerization.

The new process is substantially better than the known process in which the condensation of indanone with cyanoacetic acid is first performed and then a p-methylsulfinylbenzylidene side chain is added to the compound. The yield in these two reaction steps is about 65% ·> so the total yield is about k2%. In addition, the starting p-methylsulfinylbenzaldehyde prepared from p-chlorobenzaldehyde by a two-step reaction in a total yield of 38-39%

When the condensation is carried out according to the invention with glyoxylic acid, the yield is 95% and the yield of the subsequent isomerization is 90. The possible oxidation of the p-methylthio group takes place in 92% yield. In addition, the starting 5-i'-fluoro-2-methyl-1- (p-methylthiobenzyl) indene is obtained in 88% yield from the corresponding 5-fluoro-2-methyl-1-indanone. The process according to the invention thus gives a substantially better yield than the known methods.

The method according to the invention is described by the following flow chart:

J

5 '' 62287

Flowchart I

. AO / v

p A j «F— / NO A

IVn I + G-C-c-z -> Oli /.

Ig1 t ©

B

'"Τ§0- · ^ _Θ_ Τ§ζ ^"> CH ~ 0 έ

v F __ / ^ \ rCH ^ COOH

Ri y is; Θ @ // v / / n / X / o [Oji.CKj / 0 <s-s-ch3 <* 2 j ©

p) -> F1te00H

* 1 | h,, φ

R 1 is S-CHO or O-S-CH-I

13 3 S ~ CH3 6 62287

The condensation reaction between 5-fluoro-2-methyl-1- (p-methylthio- or methylsulfinylbenzyl) -indene and glyoxylic acid is carried out in the presence of a strong base. In this case, bases such as alkali and alkaline earth metal hydroxide (NaOH, KOH) can be used, in particular in the presence of a quaternary ammonium halide, as a catalyst (such as C 1-6 trialkylbenzylammonium halide or tetra-C 1-6 alkylammonium halide, e.g. 0.1-1.0 mol). halide / mole hydroxide), alkali or alkaline earth metal C 1-6 alkoxide (NaOCH 2, K-tert-butoxide), tetra-C 1-6 alkylammonium hydroxide or benzyl tri-C 1-4 alkylammonium hydroxides (benzyltrimethylammonium hydroxide); Triton (S) B · Preferably, trialkylbenzylammonium hydroxide or tetraalkylammonium hydroxide is used as the strong base. The reaction can be carried out without a solvent, but preferably a solvent which is either added to the reaction mixture or used in combination with a strong base is used. Alkanols (methanol, butanol), aromatic solvents such as benzene, pyridine and toluene or dioxane, acetonitrile, dimethylformamide, triglyme, dimethyl sulfoxide, water and mixtures of water and an organic solvent can be used. In fact, any solvent in which the indene and glyoxylic acid are sufficiently soluble can be used. The preferred solvent is a C 1-4 alkanol, especially methanol. The molar ratio of base to glyoxylic acid should be at least slightly higher than the ratio of one mole to one mole, but preferably 1.1 to 4.0 moles of base per mole of glyoxylic acid, and especially 1.2 to 2.5 moles. The molar ratio of glycoxylic acid to indene is not critical and may suitably be a ratio of about 1-3 to 0 moles per mole, and preferably about 1.5-1.0 moles per mole of indene. Alternatively, an alkali or alkaline earth metal salt or an aryl or alkyl ester, in particular a C 1-4 alkyl, i. instead of methyl, ethyl, butyl free glyoxylic acid or a salt of another acid with a strong base as starting material. Under these conditions, the amount of strong base used in the reaction with the salt or ester of glyoxylic acid need not be greater than the catalytic amount, although the above ratios may also be used. The order of addition of the reactants is not critical; however, it is preferable to add the glyoxylic acid compound to the mixture of indene and base. The reaction time is also not critical, it is continued until it is approximately complete. However, the reaction is preferably carried out for a period of about 15 minutes to 2 hours, and the reaction time is preferably about 1/2 to 3 hours. The reaction can be carried out at a temperature of about 10 ° C, preferably at about 10-80 ° C and especially at 35 ° C to 60 ° C.

The isomerization of the 5-ol-fluoro-2-methyl-1- (p-methylthio- (dimethylsulfinyl) -benzyl) -indenylidene-3-acetic acid τ 62287 formed after completion of the condensation reaction as its acid addition salt or ester can be carried out without isolation. the same reaction mixture obtained from the glyoxylic acid reaction can be used for ieomerization. This is especially the case if it is desired to carry out the isomerization under basic conditions, since the reaction mixture obtained from the previous step is already basic and the mere continuation of the reaction leads to the isomerized product. On the other hand it may be desirable to use other strong bases isomerization. In this case, the bases mentioned in connection with the above reaction can be used. However, the isomerization is preferably carried out using an acid, in which case the reaction product obtained from the previous step is preferably isolated first. Various organic and / or inorganic acids can be used, such as C 1 -C 4 alkylsulfonic acids (meta-sulfonic acid), arylsulfonic acids (toluenesulfonic acid), acidic ion exchange resins (e.g. Dove 3® 50), arylcarboxylic acids (p-nitrobenzene). acid), aliphatic acids (alkanoic acids such as acetic acid, propionic acid, trichloroacetic acid and trifluoroacetic acid), mineral acids (phosphoric acid, hydrochloric acid, hydrobromic acid and sulfuric acid), but preferably mineral acids or mineral acids, or mineral acids or mineral acids such as hydrochloric acid and acetic acid, hydrobromic acid and propionic acid. The ratio of acid to indenylidene is not critical and therefore a catalytic amount of acid can be suitably used. It is only necessary to acidify the reaction mixture in case it is basic. However, it is preferred to use about 0.1 to 50 moles of acid per mole of indenylidene, and especially 1.0 to 20 moles of acid. The reaction can be carried out with or without a solvent, and when solvents are used, the same solvents can be used as in the reaction of glyoxylic acid, which are inert as well as halogenated hydrocarbons such as aliphatic halides (ethylene chloride) or halobenzenes. Preferably, the reaction is performed using an acid or a halogenated hydrocarbon as a solvent. When a weak acid is used as a solvent, it is also preferable to use a strong acid such as arylsulfonic acids or mineral acids. For example, unsubstituted alkanoic acid (e.g. acetic acid) can be used as the solvent, and arylsulfonic acid (toluenesulfonic acid) and especially mineral acid (e.g. hydrochloric acid) can be used. When halogenated hydrocarbons are used as solvents, it is recommended to use mineral acids as catalysts and especially anhydrous mineral acid such as hydrochloric acid. The reaction time and its temperature are not critical, the higher the temperature, the shorter the reaction time required to complete the reaction. Accordingly, the reaction can be carried out at temperatures of about 0 ° to 150 ° C, and preferably at temperatures of about 50 to 110 ° C.

Temperatures. Likewise, the reaction time is preferably at least 30 minutes and may be one day or several days. After completion of the isomerization reaction, the product can be isolated by normal procedures such as filtration, re-filtration or removal of the acidic solvent by evaporation.

If the p-methylthio compound is used as a starting material, the oxidation of the methylthio group to the desired methylsulfinyl group can be carried out at any stage of the reaction, such as immediately after the glyoxylic acid reaction or isomerization, but is preferably carried out after isomerization. The oxidation can be carried out by one of a number of standard procedures, such as oxidation with H 2 O 2, alkaline periodates or hypohalites, preferably alkali or alkaline earth metal periodates and hypohalites, or organic peracids such as peracetic acid and monoperphthalic acid. However, the oxidizing agent is preferably HgOg. The reaction is preferably carried out in the presence of a solvent. C 1-4 alkanoic acids (acetic acid), halogenated hydrocarbons (chloroform), ethers (dioxane), C 1-4 alkanol (isopropanol) or mixtures thereof can be used for this purpose.

The molar ratio of oxidizing agent to indene compound may be 0.5 to 10, but is preferably 0.8 to 1.5. The reaction time and temperature are not critical, the reaction is continued until it is approximately complete. Preferably, however, the reaction time is 1 to 18 hours, and especially 2 to 6 hours at temperatures between 10 and 80 ° C, especially at 25 to 50 ° C.

In the case where it is desired to use a glyoxylic acid ester, the final free acid compound is easily obtained by isomerization, especially if some water is present and if the isomerization is carried out at elevated temperatures. The type of ester used is not critical because it is easily decomposed in the reaction. Aliphatic, aromatic or heterocyclic esters, such as alkyl (methyl, t-butyl), alkenyl or aryl (benzyl, phenyl) esters, can be used. Salts of glycoxylic acid can also be used, such as pharmaceutically acceptable salts as well as others which are converted to the free acid by hydrolysis, such as salts of alkali and alkaline earth metals (Na, K, Ca, Li) and Be, Cd, Zn, B , Ga-, Ti, Zr, Sn, Sb,

Bi, Fe and U salts.

5-Fluoro-2-methyl-1- (p-methylthio- or methylsulfinyl-benzyl) -indene can be prepared from 5-fluoro-2-methyl-1-indanone by reaction with the p-methylthio (or methylsulfinyl) benzyl compound according to Grignard or Vittig. in type conditions. This indene contains a double bond from position 1 to position 2. However, under certain conditions, some tautomeric indene compounds are present when it is formed. When these isomers react in the presence of a base, such as by reaction with glyoxylic acid, the same indenyl anion is formed, which reacts with glyoxylic acid in a similar manner to form an indene compound. For example, the Grignard reagent of p-methylthiobenzyl chloride or the Vittig reagent of p-methylsulfinylbenzyltriphenylphosphonium chloride is reacted with 5'-fluoro-2-methyl-1-indanone under Grignard or Vittig conditions, respectively. In the case of the Grignard reaction, the benzyl compound is obtained immediately; while the Vittig reaction yields most of the benzylidene-indane compound. In the latter case, the benzylidene is isomerized to the benzyl compound under acidic conditions by well-known isomerization methods.

More specifically, the benzyl group is attached to the indanone compound by a Grignard or Vittig reaction under well-known conditions. For example, in the Grignard reaction to metallic magnesium in absolute ether, the appropriate benzyl halide (Cl, Br, F, j) - (p-methylthiobenzyl halide or p-methylsulfinylbenzyl halide) is added and the reaction mixture is preferably heated to 25-35 ° C. Although magnesium may be used in more or less than an equimolar amount, it is preferable to use it in a 3-6 fold excess over the benzyl halide. Although diethyl ether is usually used as a solvent, other ethers such as di-n-butyl, diisopsnyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, t-dihydrofurfuryl, ethyl ether, furan and 2-stoxytetrahydrofuran. Tertiary amines such as dimethylaniline, hydrocarbons such as bentene and toluene can also be used, as well as several other types of solvents reported in the literature. The Grignard reagent thus prepared is suitable for use as such for the reaction with indanone. The indanone and Grignard's reagent are mixed together (preferably indanone with Grignard's reagent) at temperatures ranging from 0 ° C to the boiling point of the solvent, preferably 20-35 ° C. Reactant concentrations are not critical; however, for best results, approximately equimolar amounts of each are used. The complex thus formed is reacted as usual with Grignard's reagent using an acid. Inorganic mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid can be used, as can organic or alpha-acid acids such as acetic acid, propionic acid or methanesulfonic acid. Usually a molar excess of at least 5-10-6 of acid relative to the complex is used. It is preferable to add the acid to the complex reaction mixture, usually diluted with water, although mold solvents may be used for the acid, such as alcohols, ethers or aromatic hydrocarbons. The reaction temperature is usually 0 to 100 ° C, although 20 to 40 ° C is preferred.

10 62287

For example, in the Vittig reaction, triphenylphosphine or substituted triphenylphosphine is reacted with a suitable benzyl halide (p-methylthio or p-methylsulfinyl-benzyl halide) in the melt or in the presence of suitable solvents to form the intermediate phosphonium salt. Solvents such as (aromatic) benzene, nitrobenzene, xylene, (ethers) diethyl ether, acetonitrile or dimethylformamide, (aliphatic) nitromethane, formic acid, acetic acid and ethyl acetate, and many others reported in the literature can be used. The preparation of the phosphonium salt is carried out at temperatures well known in the art, such as 0-200 ° C and especially 25-75 ° C * at normal atmospheric pressure as well as under pressure. The molar concentration of triphenylphosphine with respect to the benzyl halide suitably ranges from 2 moles to 1 mole and preferably from 1.2 moles to 1 mole. The phosphonium salt need not be isolated and converted to Vittig's reagent using either the organometallic or alkoxide method. In the first method, phenyllithium or n-butyllithium is a conventional proton acceptor and a diethyl ether or tetrahydrofuran solvent. In the latter method, an alkali metal alkoxide can be used as a proton acceptor and the corresponding alcohol as a solvent.

Vittig's reagent is not usually isolated but rather reacted in the same reaction vessel. The reaction of the bases with the phosphonium salt is conveniently carried out on an equimolar basis, although an excess of base may be advantageously used. The reaction can be carried out at temperatures ranging from 0 ° C to 8 ° C to the boiling point of the solvent, preferably at 25 to 50 ° C. After the addition of the acetone, the indanone compound is added, suitably approximately equimolarly with Vittig's reagent, although it may be used more or less.

The reaction can be carried out at temperatures ranging from 0 ° C to the boiling point of the solvent, but preferably at 25-50 ° C until the reaction is approximately complete. The indene intermediate can then be isolated by standard methods. In cases where the Vittig reagent is isolated first, the reaction with indanone can be readily performed in various inert solvents. Suitably solvents include ether, benzene, ethyl acetate, hexane or petroleum ether.

5-Fluoro-2-methyl-1-indanone can be prepared from the formula

1 C-C-G

M t

0 B

a ketone according to IL 62287, wherein A is methyl or together with G forms methylenedene; B is hydrogen, methyl or halogen; G is methyl, CH 2 R or together with A forms methylidene, where R is halogen (Cl, Br, F, J), hydroxy, its ether or ester (such as from alkanol (especially C 1-4 alkanols), alkane acids (especially C 2-4 alkanoic acids), aromatic acids (especially C 1-4 aromatic acids), mineral acids, i.e. methanol, propanol, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid and the like) (C 1-4 alkyl) g wherein in particular alkyl is methyl and ethyl * and when A and G together form methylidene, B is methyl * when A and B are methyl, B is halogen; and when A is methyl and B is hydrogen, G is CHgR * which ketone is reacted under Friedel Crafts conditions to form 5 'fluoro-2-methyl-1-indanone. Preferably the ketone starting material is 2-bromo-4'-fluoro-2-methylpropiophenone (when A and G are both methyl and B is halogen) but may also be 4'-fluoro-2-methylacrylophenone, 3-chloro-4 '-fluoro-2-methylpropiophenone, 4'-fluoro-3-hydroxy-2-methylpropiophenone or 3-dimethylamino-4'-fluoro-2-methylpropiophenone. The reaction is conveniently carried out under standard Friedel Frafts conditions. For example, the ketone is reacted in the presence of Friedel Crafts catalysts such as Levis acids, metal alkyls and alkoxides, Bronsted acids, acid oxides and sulfides, cation exchange resins, metathetic cation-forming agents, and stable carbonium, and the like. Levis acids (metal halides) of the acid halide type can be suitably used, e.g. aluminum chloride or bromide, BeCl 2, CdCl 2, ZnCl 2, BF 2, BCl 2, BBr 2, CaCl 2, CaBr 2, TiCl 2, TiBr 2, ZrCl 2, SnCl 2 , SnBr ^, SbCl ^, BiCl ^, FeCl ^

And UCl ^. Also, If the ketone is an α- or β-halo-isobutyrophenone, the metals as such can be used as catalysts because during the reaction the halogen compound reacts with the metal to form the corresponding metal halide, which in turn continues the reaction. This class of Friedel Crafts catalysts is recommended and in particular the use of aluminum and iron halide. Suitable metal alkyls and alkoxides for use are, for example, aluminum and boron alkyls (methyl, ethyl, propyl) or alkoxides (methoxide, ethoxide or propoxide). Suitable Bronsted acids for use include, for example, sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, chlorosulfonic acid, fluorosulfonic acid, alkyl and arylsulfonic acids (ethane, p-toluene) and the corresponding aromatic sulfonic acids, as well as chloroacetic acid. Acid oxides and sulfides suitable as catalysts include a very large number of solid oxides and sulfides. Particularly useful are aluminum, quartz, and alloys of aluminum and quartz, although non-quartz-aluminum compositions such as BeO, Cr 2 O 2 PgO 2, TiO 2,

ThO 2, Al 2 (SO 4) 3, Al 2 O 3, Cr 2 O 3, ΑΙ ^, Ρβ ^, ΑΙ ^, ΟοΟ, ΑΙ ^, ΜηΟ, Al ^, VlgOy Cr203, Pe203 »MoS2 or MoSj, can also be used. In addition, cation exchange resins which are solid acids are suitable catalysts as well as metathetic cation-forming agents such as anhydrous silver salts (AgC104, AgBF4, AgSh? 6, AgPFg, AgAsFg and AgPO4).

Although the concentration of Friedel Crafts catalyst is not critical, it is recommended to use 1.1 to 2.0 moles of catalyst per mole of ketone, and preferably 1.4 to 1.8 moles of catalyst per mole of ketone. The reaction is conveniently carried out in a solvent commonly used in the Priedel Crafts reaction. These include organic solvents such as CS2, fluorobenzene, polyhalogenated aromatic hydrocarbons, nitrobenzene, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and nitroalkanes. The reaction is carried out at a temperature of 0 to 150 ° C, and preferably 20 to 100 ° C * for a time sufficient to substantially complete the reaction.

The ketone starting material is readily prepared by condensing the appropriate formula A 0 »lt

G - C - C - Z

B

an acid halide according to the above, wherein A, B and G are the same as above and Z is halogen, with fluorobenzene under Friedel Crafts conditions as described above. If desired, the acid halide can be condensed with fluorobenzene to form a ketone and further in situ directly to 5-fluoro-2-methyl-1-indanone. If this procedure is to be used, an additional amount of Priedel Krafts catalyst sufficient to carry out the two steps is used.

The following examples are intended to illustrate the invention.

Example 1 4'-Fluoro-5-hydroxy-2-methylpropiophenone

A mixture of 45 * 7 g (0.3 mol) of 4'-fluoropropiophenone, 5 g (0.3 mol) of paraformaldehyde, 4 g (0.03 mol) of anhydrous potassium carbonate and 200 ml of methyl alcohol is stirred at 35 ° C for two days. . The reaction mixture is cooled with water and acidified with hydrochloric acid. The product is extracted with bentee. The bentene layer is washed with water and concentrated in vacuo to give 4'-fluoro-3-hydroxy-2-methylpropiophenone.

62287

Example 2 5-Fluoro-2-methyl-1-indanone from 4'-fluoro-3-hydroxy-2-methylpropophenone

A mixture of 18.2 g (0.10 mol) of 4'-fluoro-3-hydroxy-2-methylpropiophenone and 12 g of phosphorus pentoxide in 100 ml of xylene is heated under reflux for one hour. The reaction mixture is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide solution and water. The organic layer is then concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

Example 3 2-Bromo-4'-fluoro-2-methylpropiophenone

The slurry containing 14 g (0.105 moles) of anhydrous aluminum chloride in 14.4 g (0.150 moles) of fluorobenzene and 24 ml of carbon disulfide is cooled to 15 ° C. To this is added 23.8 g (0.100 mol) of α-bromoisobutyryl libromide over 10-13 minutes at 13-20 ° C and then cooled with ice. The product is extracted into chloroform. The chloroform layer is washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated to preach 2-bromo-4'-fluoro-2-methylpropiophenone.

Example 4 5-Fluoro-2-methyl-1-indanone from 2-bromo-4'-fluoro-2-methylpropiophenone

To a slurry containing 120.2 g (0.90 moles) of anhydrous aluminum chloride in 34 mL of carbon disulfide is added 122.6 g (0.50 moles) of 2-bromo-4'-fluoro-2-methylpropiophenone at 13-20 ° C. in an hour. The mixture is heated to 30 ° C over one hour, stirred at 30 ° C for three hours and cooled with ice. The product is extracted into toluene. The toluene layer is washed with aqueous sodium hydroxide solution and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

Example 3 4'-Fluoro-2-methyllacrylphenone

A slurry containing 29.4 g (0.220 moles) of anhydrous aluminum chloride, 33.4 g (0.40 moles) of 38.4 g (0.40 moles) of fluorobenzene under nitrogen is cooled to 15 ° O. Methyl acrylic chloride (21.9 g, 0.200 moles) is then added dropwise over 30 minutes, maintaining the temperature at 15-20 ° C. The mixture is heated to 30 ° C over 10 minutes, stirred at 30 ° C for 10 minutes and cooled with 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.

111 62287

Example 6 5-Fluoro-2-methyl-2-indanone from 41-fluoro-2-methylacrylophenone 50 g (0.30 mol) of 4'-fluoro-2-methylacrylophenone are added to a slurry containing 60.1 g (0, 45 moles) of anhydrous aluminum chloride in 27 ml of carbon disulfide, at 20-25 ° C for one hour. The mixture is heated to 45 ° C over one hour and stirred at 45 ° C for one hour. The reaction mixture is cooled with ice, the oily aqueous layer is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide solution and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

Example 7 3-Chloro-4'-fluoro-2-methylpropiophenone

To a slurry containing 22.7 g (0.17 moles) of anhydrous aluminum chloride and 9.6 g (0.10 moles) of fluorobenzene is added 14.1 g (0.10 moles) of β-chloroisobutyryl chloride over 30 minutes at 20- 25 ° Csssa. The mixture is aged for 30 minutes at 20-25 ° C and then cooled with ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-chloro-4'-fluoro-2-methylpropiophenone.

Example 6 5-Fluoro-2-methyl-1-indanone from 3-chloro-4'-fluoro-1-methylpropiophenone 10 g (0.05 mol) of 3-chloro-4'-fluoro-2-methylpropiophenone are added in 20 ml. concentrated sulfuric acid at 20-25 ° C and the mixture is heated to 50 ° C. After stirring for 3 hours at 50 ° C, the reaction mixture is cooled with ice. The product is extracted into hexane. The hexane layer is concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

Example 9 3-Dimethylamino-4'-fluoro-2-methylpropiophenone

A mixture of 15.2 g (0.10 moles) of 4'-fluoropropiophenone, 8.2 g (0.10 moles) of dimethylamine hydrochloride, 3 * 6 g (0.12 moles) of para-formaldehyde in 20 ml of absolute alcohol , stirred at 95-100 ° C for three hours. The mixture is cooled and the precipitated product is filtered off.

The product is dissolved in water, made alkaline with sodium hydroxide. The free base is extracted into ether. The ether layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-dimethylamino-4'-fluoro-2-methylpropiophenone.

Example 10 5-Fluoro-2-methyl-1-indanone from 3-dimethylamino-41-fluoro-2-methylpropiophenone 62287

A mixture of 42 g (0.20 mol of 3 * dimethylamino-4, -fluoro-2-methylpropiophenone and 100 ml of concentrated sulfuric acid) is heated to 90 [deg.] C. over 1 hour and stirred at 90 [deg.] C. for two hours. The toluene layer is washed with aqueous sodium hydroxide solution and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

Example 11 5-Fluoro-2-methyl-1-indanone from fluorobenzene and α-bromoisobutyryl bromide

To a slurry containing 120.2 g (0.90 moles) of anhydrous aluminum chloride in 54 mL of carbon disulfide and 514 g (0.553 moles) of fluorobenzene under nitrogen is added 115 g (0.50 moles) of e-bromoisobutyryl bromide. The addition is complete at 15-0 ° C in 75 minutes. The reaction mixture is heated to 50 ° C over 75 minutes, stirred at 50 ° C for 3/2 hours and cooled with ice. Toluene is added to extract the product. The toluene layer is washed with aqueous sodium hydroxide solution and water and concentrated in vacuo to give 79 g (96 n) of 5-fluoro-2-methyl-1-indanone.

Example 12 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) indene 25 g (1 * 04 moles) of magnesium turning chips are placed in a dried vessel under Ng with 400 ml of ether. 10 ml of 0.05 molar p-methylthiobenzylmagnesium chloride in ether are added and the mixture is heated to 50 ° C. About 2-5 [mu] l of 59 * 7 g (0.23 mol) of p-methylthiobenzyl chloride in 75 ml of toluene are added. After stirring for 5 * 5 minutes, an exotherm to 32-33 ° C occurs, clearly indicating the onset of the reaction. After 5 minutes of aging, the rest of the benzyl chloride is added dropwise over 90 minutes. The reaction mixture is aged for 50 minutes with stirring. 5-Fluoro-2-methyl-1-indanone (52.6 g, 0.199 mol) is added dropwise over 45 minutes. After aging for 30 minutes, the milky mixture at the top is decanted from the magnesium. The vessel and the 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 Θ0 ml of concentrated sulfuric acid and acetic acid in a ratio of 1:10 and the two-phase mixture is stirred vigorously for one hour, after which water (100 ml) is added. The base layer is discarded and the organic layer is washed with 100 ml of water and 200 ml of 2N aqueous sodium hydroxide solution. After the last water wash, the organic layer is concentrated to give 5 'fluoro-2-methyl-1- (p-methylthiobenzyl) indene. Similarly, if p-methylsulfinylbenzyl chloride is used instead of p-methylthiobenzyl chloride in the above example, 16,628,77 p-methylsulfinylbenzyl indene is obtained.

Example 13 p-Methylthiobenzyltriphenylphosphonium chloride 17 * 3 g of p-methylthiobenzyl chloride are added to 28 g of triphenylphosphine in 60 ml of benzene. The reaction mixture is heated for 4 hours, then cooled and the product, p-methylthiobenzyltriphenylphosphonium chloride, is collected by filtration. Yield 19 g * m.p. 257-258 ° C.

Similarly, when p-methylsulfinylbenzyl chloride is used, the product is p-methylsulfinylbenzyltriphenylphosphonium chloride, m.p. 258-262 ° C with gas evolution.

Example 14 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) indene A. 5-Fluoro-2-methyl-1- (p-methylthiobenzylidene) indane 169 g (1 * 3 nm) of potassium -butoxide is dissolved in 2 ml of DMSO and treated with 63I mg (1 * 3 mmol) of p-methylthiobenzyltriphenylphosphonium chloride dissolved in 1 ml of DMSO. To this solution is added 270 mg (1.63 mmol) of 5-fluoro-2-methyl-1-indanone in 2 ml of DMSO. The solution is heated at 75 ° C for 13 * 3 hours. Benzene and water are added and the benzene layer is washed five times with water. The beechene layer is dried over Na 2 SO 4 and evaporated to dryness in vacuo. The weight is 915 * 6 mg. This material is eluted through an 8 g silica gel with benzene to remove triphenylphosphine oxide. The eluate weighs 372 mg after removal of the solvent. This is rechromatographed through 13 g of silica gel using hexane and 95 * 9 mg of 5-fluoro-2-methyl-1- (p-methylthiobenzylidene) indan, m.p. 67-70 ° C.

B. 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) indene 30 mg of the benzylidene compound from A above are mixed with 1 ml of acetic acid containing 100 ml 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 ether extract is concentrated in vacuo to give the title compound.

Similarly, if p-methylsulfinyltriphenylphosphonium chloride is used, the corresponding p-methylsulfinylbenzylindene compound is obtained.

Example 13 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene 500 mg (1.755 mmol) of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indene are dissolved in 5 ml of chloroform. . To this solution is added 30 hydrogen peroxide (corresponding to 2.645 mmol). The reaction mixture is aged 1T 62287 for one hour at room temperature, after which 5 ml of glacial acetic acid are added and aging is continued for one hour. The reaction mixture is then diluted 1: 1 with 25 ml of benzene ether and extracted with 6 x 25 ml of 5% aqueous sodium chloride solution. The solution is then dried over sodium sulfate and evaporated in vacuo to give an oily product. Recrystallization from ice-cold isopropanol gives 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene.

Example 16 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid To 41.8 g (147 mmol) of the above indene (from Example 12) is added 150 ml of a methanolic Triton B solution (53.2 g, dry; 317.5 mmol) and the bath is brought to 35 ° C under a nitrogen atmosphere. 14.65 g of glyoxylic acid (198 mmol) are added and the bath, which is heated to 50-55 ° C, is aged for one hour at 50 ° C. The solution is then diluted with 250 ml of water and acidified with dilute sulfuric acid. The product obtained in 90-6 yield is recrystallized to give the title product in pure form, m.p. 185.5 "188 ° C.

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

Similarly, when 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indene is used in place of the corresponding methylthio compound in the above example, 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -indenylidene-3 is obtained. -yes still acid.

Example 17 5-Fluoro-2-methyl-1- (p-methylthiobenzylidene) -indene-3-acetic acid

A suspension of 34.2 g of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid (from Example 16) in 342 ml of glacial acetic acid and 157 ml of concentrated hydrochloric acid is stirred under a nitrogen atmosphere. At 90 ° C for 10 hours. The reaction mixture is cooled to room temperature over 2-5 hours and further aged for 3 hours at 20-25 ° C. The mixture is filtered, washed with acetic acid-water (70:30) (about 100 ml) and then washed with water to remove excess acid. 93% of product are obtained, m.p. 180-183 ° C.

Similarly, when 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -indenylidene-3-acetic acid is used in the above example instead of the corresponding 18,628,7-methylthio compound, 5-fluoro-2-methyl-1- (p-methylsulfyl) is obtained. -nyylibentsylideeni) indene-l-acetic acid. The reaction can be carried out aprotically in a solvent such as 1,2-dichloroethane at a pressure of 7 kp / cm 2 HCl in 50-100 ° C.

Example 18 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -inden-3-acetic acid 17 g (50 mmol) of the title compound of Example 17 are stirred in 94 ml of chloroform and 40 ml of acetic acid under nitrogen and the temperature of the reaction mixture is raised to 30 ° C. * C. To this slurry is added 3.3 mL of 9 / 6N aqueous hydrogen peroxide (51 mmol) per minute. The temperature is raised to 33 ° C. The mixture is aged for a total of 6 hours while maintaining an internal temperature of 33 ° C. After the aging period, 123 ml of water are added and the CHCl 3 layer is concentrated to a small volume in vacuo. The residue is crystallized from 73 ml of ethanol and the slurry is cooled to 0-3 ° C and aged to 0-3 ° C.

The product is filtered and washed with 13 ml of cold (0-3 ° C) 2BA ethanol and dried in vacuo at 80 ° C. The product weighs 16.3 g (92 56), m.p. 183-185 ° C.

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

Example 19 2-Dimethylaminomethyl-4'-fluoropropiophenone

A slurry containing 14 g (0.103 moles) of anhydrous aluminum chloride, 14.4 g (0.150 moles) of fluorobenzene and 24 ml of carbon disulfide is cooled to 13 ° C. * To this is added 0.100 moles of α- (dimethylaminomethyl) -propionyl bromide hydrobromide over 10-13 minutes. -20 ° C sea. The reaction mixture is stirred for 5 minutes at 20 ° C. The reaction is quenched with ice. The product is extracted into chloroform. The chloroform layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated to give 2-dimethylaminomethyl-4'-fluoropropiophenone.

Example 20 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) indene 13.44 g (0.56 moles) of magnesium lathes are placed in a dried flask under Ng with 125 ml of ether and iodine crystal. Six milliliters of a 65 milliliter solution containing 24-2 g (0.14 moles) of p-methylthiobenzyl chloride in ether is then added. After stirring for 3-3 minutes, the color formed by the iodine disappears and the reaction begins. After aging for 5 minutes, the remainder of the benzyl chloride is added dropwise over 43 minutes. It is rinsed with 10 ml of ether and the reaction is allowed to proceed for 2 hours with stirring. 21 g (0.128 mol) of 5-fluoro-2-methyl-1-indanone dissolved in 50 ml of ether are added dropwise over 30 minutes. After aging for one hour, the milky supernatant of the mixture is decanted from magnesium into 100 ml of acetic acid. The vessel and the residual magnesium are rinsed into an acid solution with 4 x 50 ml of hensene. 200 ml of water are added, the layers are separated and the organic layer is washed with 3 x 200 ml of water. After drying over Na 2 SO 4, it is evaporated to dryness. The crude reaction product is crystallized from hexane to give pure 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indene, m.p. 58-59 ° C.

Example 21 5-Fluoro-2-methyl-1- (p-methylthiobenzylidene) indene-3-acetic acid

A suspension of 34 g of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid in 150 ml of ethylene dichloride is heated to 70 ° C in a glass-lined autoclave. Add anhydrous hydrogen chloride

O

until the pressure reaches 6,7 kp / cm. The reaction mixture is stirred under these conditions for 10 hours and the excess gas is vented. The resulting slurry is cooled to 0-5 ° C and filtered after 1 hour and washed with fresh ethylene dichloride. The yield of the product is 80 96.

Claims (5)

20 62287 A process for the preparation of 5-fluoro-2-methyl-1- (p-methylsulfinyl-benzylidene) -indene-3-acetic acid of the general formula I 0 -p-CHg-C-OH CH X Ύ 0 <-S-CH3 or for the preparation of its acid addition salts, characterized in that it comprises the following steps: a) condensing a 5-fluoro-2-methyl-1-benzylindene of the formula II 'YYi CH II Λ V in which R 1 is methylthio or methylsulfinyl with a strong base in the presence of glyoxylic acid, its salt or ester to give the corresponding 5-fluoro-2-methyl-1- (p-methylthio- or methylsulfinyl-benzyl) -indenylidene-3-acetic acid of formula III 21 62287 o F-^-p-CH -C-OH I III V wherein R 1 is as defined above, as a salt or ester thereof, and b) the indenylidene compound is isomerized to the desired indene-3-acetic acid compound when p-methylsulfinyl; when R is p-methylthio, the indenylidene-3-acetic acid compound obtained from step (a) is isomerized to the 5-fluoro-2-methyl-1p-methylthiobenzylidene-3-indene acetic acid compound and the 3-indene acetic acid is oxidized or alternatively the 3-indenylideneacetic acid is first acidified The 1-p-methylsulfinyl compound and the 1-p-methylsulfinyl compound are then isomerized. Process according to Claim 1, characterized in that it comprises the following steps: a) 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indene is condensed in the presence of a strong base with glyoxylic acid, its salt or ester to give 3 -indenylideneacetic acid compound, b) the 3-indenylideneacetic acid compound is isomerized with a base or in the presence of an acid to 5-fluoro-2-methyl-1- (p-methylthiobenzylidene) indene-3-acetic acid compound and c) the indene-3-acetic acid halide compound Process according to Claim 2, characterized in that glyoxylic acid is used and the isomerization is carried out in the presence of an acid. 22 62267 A compound for the preparation of 5 "fluoro-2-methyl-1- (p-methylsulphinyl-benzylidene) -inden-3-acetic acid with the formula I 0 F __ _ CH2-C-OH i 3 CH Γ A 0 <- S - CH 2 or a hydrogenation moiety which, after conversion, comprises: a) 5-fluoro-2-methyl-1-benzylates of formula II 'YYi ch3 XV color R1 and methylthio or methylsulfinyl, condenser and a starch based on glyoxylic acid, the ester or ester of the compound 5 ~ fluoro-P-motyI_l "(p-methylthio-or-methylsulfinyl-benzyl) -indenylidene-3-acetic acid :: is given in the form of an ITI