DE2462380C2 - Process for the preparation of 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) - indene-3-acetic acid and its acid addition salts - Google Patents

Description

A O

I Il

G-C-C-Z

in which A forms a methyl group or together with G forms methylidene; B hydrogen, one Methyl group or halogen, G is a methyl group or CHjR group or together with A forms methylidene, where R is halogen, the hydroxyl group, a corresponding ether or esters or the - N- (Ct-5-alkyl) r group, and Z is halogen: and where,

(1) when A and G together are methylidene, B is a methyl group,

(2) when A and G are each methyl groups, B is halogen,

(3) when A is methyl and B is hydrogen, G is CH ₂ Fl,

with fluorobenzene under Friedel-Crafts conditions;

(b) Implementation of the resulting ketone of the formula

10

15th

IF

in which A is the methyl group or together with G forms methylidene; B hydrogen, one Is methyl group or halogen; G is a methyl group or CH.R group or together with A forms methylidene, where R Halogen, the hydroxy group. a corresponding ether or ester or the - N- (Ci v alkyl) »- group mean. and where.

(1) when A and G together are methylidene, B is methyl group.

(2) when A and G are each methyl groups, B is halogen. and

(3) when A is methyl and B is hydrogen. G is a CH? R group,

under Fiedel-Crafts conditions to 5-fluoro-2-methyl-1-indanone;

(c) Conversion of 5-fluoro-2-methyl-1-indanone with a RrBenzylverbindungen, in the Ri is p-methylthio or p-methylsulfinyl. under Grignard ^ or Wiüig »Conditions for 5-fluorine * 2-methyN I - (R ^ benzylJ-indene;

(d) condensation of the inland compound with glyoxylic acid, their ester or salt in the presence of a strong base to form 5-FIüof-2-rnelhyl-1-riberizylinderiylidene * 3-acetic acid, their ester or salt and

(e) if Ri methylsulfinyl lsi: isomerisiereri def indenylidene compounds from step (d) in the presence of a base or an acid to give the desired product, or,
(f) if Ri is methylthio: isomerization of the indenylidene compound from step (d) in the presence of a base or an acid and subsequent oxidation in a manner known per se to the desired product or first oxidation of the product from step (d) in a manner known per se and subsequent isomerization in the presence of a base or acid.

2. The method according to claim 1, characterized in that that after step (d) the isomerization is carried out first.

20 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -inden-3-acetic acid is known from US Pat. No. 3,654,349 and has anti-inflammatory properties. Both in this patent specification and in GR-PS 41 736 different modes of representation for this connection are described. In one of the procedures described in the Greek patent, 5-fluoro-2-methyI-1 - (p-methylsulfinylbenzyl) indene is described as an intermediate. This connection will

JO reacted with a glycolic acid ester; then that will Product of the ester of 5-fluoro-2-methyl-l- (p-methylsulfinylbenzyl) -indenylidene-3-acetic acid oxidized, which then isomerizes to the desired compound and is hydrolyzed. Also in the Greek patent is the manufacture of an indanon intermediate product described as the starting material for indene, the production of indanone being quite different from that in method according to the invention is carried out. According to this Greek patent, 3-nitrobenzaldehyde is used reacted with propionic anhydride to form nitrocinnamic acid. This connection then becomes the corresponding one Amino compound reduced and in a further reaction to the «-Methyl! -3-fluorohydrocinnamic acid implemented. This compound in turn is cyclized to the indanone.

The product obtained according to step a) of the claimed process is known from US-PS 37 32 292, however, this connection is made there in a different way.

From DE-OS 22 02 715 and 22 02 727 are similar processes for the production of a number of substituted indenylacetic acids known. As can be seen from the reaction diagrams I (see p. 8 of these publications) results, starting from a substituted benzaldehyde in a 5-stage Process first produced a / I-arylpropionic acid, which is processed into the desired end product in a further 5-stage process, such as yourself in each case from the reaction diagrams II (each p. 12 of this publication) results.

Thus, in these known processes for producing the desired end products as a whole 10 process steps necessary. In contrast, the inventive method is aimed at a very special product, namely 5 * fluoro'2-methyM- (pmethylsulfonylbenzyliden) -inden-3-acetic acid to be prepared in a process which is as simple as possible and which proceeds in good yields. In fact, it works

claimed process, starting from fluorobenzene tkmssalzen. .

and «-Bromisobulyrylbromid in only a 5-stage In stage a) the Friedel-Crafts reaction can go so far

Procedure. continue that as an intermediate

The invention now relates to a ketone formed in the in situ according to step b) to the

Process defined in the preceding claims 5 S-fluoro ^ -methylindanonzyelisiert. .

for the production of 5-fluoro-2-methyI-1- (p-methyIsulfinylbenzylidene) -inden-3-acetic acid and their acid addi- The invention is explained using the following equation:

Flow sheet I.

Stage c)

CH ₃

Stage d)

CHCOOH

CH ₃

R ₁ = S-CH ₃ or Ot-S-CH ₃

CH

The condensation reaction according to stage a) between the 5-fluoro-2-methyl-l- (p-methyIthio (or methylsulfinyl) benzyl) indene and glyoxylic acid is carried out in the presence of a strong base. Bases can be alkali and alkaline earth hydroxides (NaOH, KOH )

60

especially in the presence of a quaternary Ammonl · umhalogenids as a catalyst (such as CI_ ₆ -Trialkyibenzylammoniumhalogenid or tetra-Ci-6-halide alkylammoniunv 0.1 to 1.0 mole of halide to hydroxide!), alkali or alkaline earth (Ci. ₅₎ - alkoxide (NaOCH ₃ , K-Terti-S-CH ₃

butoxide), tetra-Ci-6-alkylammonium hydroxide or Benzyl-tri-C | _ 5-alkylammonium hydroxide (benzyl trimethylammonium hydroxide) (Triton B) can be used. The preferred strong base is trialkylbenzylammonium hydroxide or tetraalkylammonium hydroxide is used. The reaction can be carried out without a solvent; however, preferably a Solvent used, either added to the reaction mixture or together with the strong Base is used. Q-5 alkanols (methanol, buta-

■ nol), aromatic solvents such as benzene, pyridine and toluene, dioxane, acetonitrile, dimethylformamide, triglyme, dimethyl sulfoxide, water and mixtures of water and organic solvents can be used. In fact, any solvent in which the indene and glyoxylic acid are sufficiently soluble can be used. A Qs-alkanol, in particular methanol, is preferably used as the solvent. The molar ratio of base to glyoxylic acid should be at least slightly greater than 1: 1; it is preferably about 1.1 to about 4.0 mol base to glyoxylic acid and in particular 1.2 to 2.5. The glycol ratio of glyoxylic acid to indene is not critical and can be from about 1 to 3.0 moles to one mole, and preferably about 1.5 to 1.0 moles of indene. Alternatively, the alkali or alkaline earth metal salt or the aryl or alkyl ester, in particular the Ci -5-AlkyIderivate such as the methyl, ethyl, butyl derivatives instead of the free glyoxylic acid or any other acid salt of a strong base can be used as the starting material. Under these circumstances, the strong base need not be used in the reaction with glyoxylic acid salt or ester in greater than catalytic amounts, although the proportions given above can also be used; the order in which the reactants are added is not critical; however, it is preferred to add the glyoxyacid compound to the reaction mixture of indene and base. The reaction time is also not critical, but is carried out until the conversion is practically complete. Preferably, however, the reaction is carried out for 15 minutes to 5 hours, and more preferably for about half an hour to three hours. The reaction can be preferably carried out at temperatures ranging from about 0 ^e C to about 150 ⁰ C. of about 10 ⁰ C to 8O ⁰ C and especially from 35 ° C to 60 ° C.

After completion of the condensation reaction step e) or f), according to the isomerization of the formed 5-fluoro-2-methyl-l * (p-methylthio (or methylsulfinyl) - w benzyl) ndenyliden-3-acetic acid in the form of its acid addition salt or ester without Isolation to be carried out; this means that the same reaction mixture of the glyoxylic acid reaction can be used for isomerization. This is particularly possible if you want to carry out the isomerization under basic conditions because the reaction mixture of the previous stage is already basic; the simple progress of the reaction leads to the isomerization product. On the other hand, it may be possible to want to use stronger bases for isomerization. Bases such as those used for the previous reaction; can be used. However, this isomerization is preferably carried out using acid, so that the reaction product from the previous stage is preferably first isolated. Various organic and / or inorganic acids can be used, such as Ci-5-alkylsulphonic acids (methane sulphonic acid), arylsulphonic acids (toluenesulphonic acid), acidic ion exchange resins (ζ. B. Dowex 50), aryl carbonyl acids (p-nitrobenzoic acid), aÜphatic acids ( Alkanoic acids, such as acetic acid, propionic acid, trichloroacetic acid and trifluoroacetic acid), mineral acids (phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid); however, mineral acids or mixtures of mineral acids and organic acids (preferably C2-5 alkanoic acids), such as hydrochloric acid and acetic acid, hydrobromic acid and propionic acid, are preferably used. The ratio of acid to indenylidene is not critical; appropriate amounts of catalytic acid can be used. All that has to be done is to make the reaction mixture acidic in the event that it is basic. Preferably, however, about 0.1 to 50 moles of acid are used to form indenylidene, and in particular 1.0 to 20 moles. The reaction can be carried out with or without a solvent; If solvents are used, those which have been described in connection with the glyoxylic acid reaction and which are inert, as well as halogenated hydrocarbons, such as aliphatic halides (ethylene dichloride) or halobenzenes, can be used. The reaction is preferably carried out with an acid or a halogenated hydrocarbon as solvent. If a weak acid is used as the solvent, it is also preferred to use a strong acid, such as the arylsulfonic acids or mineral acids. For example, the unsubstituted alkanoic acids (for example acetic acid) and the arylsulfonic acids (for example toluenesulfonic acid) and especially mineral acids (for example hydrochloric acid) can be used as solvents. If halogenated hydrocarbons are used as solvents, preference is given to using mineral acids as catalysts and in particular anhydrous mineral acids such as hydrogen chloride. The duration and temperature of the reaction are not critical; the higher the temperature, the shorter the reaction time until the reaction is complete. The reaction can proceed at temperatures from about 0 ° C to about 150 ⁰ C and preferably from about 50 ⁰ C to 110 ⁰ C. The duration of the reaction is preferably at least 30 minutes and can be up to one or more days. After the isomerization, the product can be isolated in a manner known per se, such as by filtering, extracting or removing the acidic solvent by evaporation. .

The p-methylthio compound is used as the starting material is used, the oxidation of the methylthio group to the desired methylsulfinyl group in any reaction step can be carried out, such as immediately after the reaction with glyoxylic acid or after isomerization, but preferably after isomerization. The oxidation in itself known way, such as by oxidation with H2O2, basic periodates or hypohalites, preferably the alkali or alkaline earth periodates or -hypohalides or organic peracids such as peracetic acid and monoperphthalic acid will. The preferred oxidizing agent, however, is H..O2. The reaction is preferably carried out in the presence a solvent carried out. For this purpose, Ci 5-alkanoic acids (z. B. acetic acid), halogenated hydrocarbons (e.g. chloroform), ether (e.g. dioxane), Ci. vAlcanols (e.g. isopropanol) or their mixtures be used.

The molar ratio of oxidizing agent to indene compound can be from 0.5 to 10, but preferably from 0.8 to 15. The reaction time and temperature are not critical; the reaction is carried out until the implementation is practically complete. Preferably, however, the reaction time is 1 to 18 hours and especially 2 to 6 hours at a temperature vi> n 10-8O ⁰ C and in particular of 25-50 ⁰ C.
If an ester of glyoxylic acid is used; will the

free acid compound easily obtained during isomerization, especially if some water is present, and when the isomerization is carried out at elevated temperatures. It ended Ester itself is not critical; it can be aliphatic, aromatic or heterocyclic esters such as alkyl esters (Methyl, t-butyl, phenyl *, alkenyl ester) or aryl ester (Benzyl-, Phenylestef) can be used. Likewise, glyoxylic acid salts such as the pharmaceutical compatible salts or other salts that are converted into the free acid by hydrolysis » are used, these include the salts of the alkali or alkaline earth metals (Na, K. Ca. Li) as well as the Salts of the metals previously sold by Friedel-Crafts-Re action were described.

The 5-fluoro-2-methyl-1- (p-methylthio (or methylsulfinyl) benzyl) indene according to stage c) can from 5-fluoro-2-methyl-l-indanone by reaction with a n-Methylthio (or methylsulfinyl) benzyl compounds be prepared under Grignard or Wittig conditions. This indene contains the double bond in the I to 2 position. However, under certain conditions in the formation, some of the tautomerized Indene compounds present. Are these isomers in the presence of a base as in the reaction with Glyoxylic acid reacted, forms the same indenyl anion that with glyoxylic acid in the same way to the Indene compound reacts. For example, the Grignard compound is p-methylthiobenzyl chloride or the Wittig compound of p-methylsulfinylbenzyltriphenylphosphonium chloride with 5-fluoro-2-methyl-lindanone under Grignard or Wittig conditions implemented. In the case of the Grignard reaction, the benzyl indene compound is obtained directly; in the Wittig reaction in most cases the benzylidenindane compound is obtained. In the latter case it will Benzylidene isomerized to the benzyl compound under acidic conditions in a manner known per se.

The benyl group is linked to the indanon connection via a Grignard or Wittig reaction under known conditions. For example, in the Grignard reaction to metallic magnesium in absolute ether, the corresponding benzyl halide (Cl. Br. F. I) (p-methylthiobenzyl halide or p-methylsulfinylbenzyl halide) is added and the reaction mixture is preferably heated to 25 to 35 ° C, although more or less can be used as equimolar amounts of magnesium, it is advantageous to use a 3 to 6-fold excess, based on the benzyl halide. Although diethyl ether is normally used as a solvent, other ethers such as di-n-butyl, diisopentyl ether, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-13-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxy tetrahyduran can be used will. Tertiary amines such as dimethylaniline, hydrocarbons such as benzene and toluene, as well as many other types of solvents described in the literature can also be used. The Grignard reagent prepared in this way is suitable for reaction with the indanone. The indanone and the Grignard reagent are mixed at a temperature of about 0 ° C to the boiling point of the solvent and preferably 20 to 35 ° C, the indanone being preferred to which Grignard is added. The concentrations of the reactants are not critical; however, approximately equimolar amounts of each compound are used for best results. The complex formed in this way is reacted, as is normally customary in Grignard reactions with an acid. Both inorganic mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic or aliphatic acids such as acetic acid, propionic acid or methanesulfonic acid can be used. Usually at least a 5-10% molar excess of the acid based on the complex is used. Preferably the acid is added to the reaction mixture of the complex as a dilute solution in water, although other solvents for the acid such as alcohols. Ether or aromatic hydrocarbons can be used. The reaction time is generally 0 to 100 ⁰ C, preferably 20-40 ° C.

In the Wittig reaction, for example, trimphenylphosphine or a substituted triphenylphosphine is reacted with the suitable benzyl halide (p-methylthio- or p-methylsulfinylbenzyl halide) in the melt or in the presence of suitable solvents to form the phosphonium salt as an intermediate. Such solvents include aromatic (e.g. benzene, nitrobenzene, xylene). Ether (e.g. diethyl ether), acetonitrile or dimethylformamide, aliphatic solvents such as nitromethane. Formic acid, acetic acid and ethyl acetate, as well as many other solvents described in the literature. The preparation of the phosphonium salt is carried out at temperatures of from 0 ois 200 ⁰ C and in particular 25 to 75 ° C at normal pressure as well as under reduced pressure. The molar concentration of the triphenylphosphine to benzyl halide can vary from 2 moles to 1 mole, and preferably from 1.2 moles to 1 mole. The phosphonium salt is not necessarily isolated and is converted to the Wittig compound by either the organometallic method or the alkoxide method. In the first procedure, phenylithium or n-butylithium is used as the usual proton acceptor and diethyl ether or tetrahydrofuran as the solvent. In the latter procedure, an alkali metal alkoxide can be used as the proton acceptor and the corresponding alcohols as the solvent.

The Wittig reagent is normally not isolated but reacted further in the same reaction vessel. The reaction of the bases with the phosphonium salt is suitably carried out in approximately equimolar amounts, although an excess of base may be advantageous. The reaction can proceed at temperatures from about 0 ° C to the boiling point of the Solv · * are means of, and preferably in the range of 25 -50 ⁰ C. After adding the base, the indanone compound is then added, suitably in about equimolar amounts with the Wittig reagent, although more or less can also be used. The reaction can be carried out at temperatures from 0 ° C to the boiling point of the solvent, but preferably carried out in the range of 25 to 50 ⁰ C up to complete conversion. The indene intermediate can then be isolated in a manner known per se. In those cases where the Wittig reagent is first isolated, the reaction with the indanone can be carried out in a simple manner in a variety of inert solvents. Solvents such as ether, benzene, ethyl acetate, hexane or petroleum ether are suitable.
The 5-fluorine-2-methyl-1-indanone according to stage b) is

from a ketone of the general formula:

30th

in which A is a methyl group or together with G is a methylene group; B is hydrogen, methyl group or halogen (Cl, Br, F, j); G is a methyl group, CH ₂ R or together with A a methylidene group. where R is halogen (Cl. Br, F, J), hydroxy group. its ethers or esters (such as, for example, of alkanols, in particular of alkanols with 1 to 5 carbon atoms, alkanoic acids (in particular alkanoic acids with 2 to 5 carbon atoms), aromatic acids (in particular aromatic acids with 7 to 9 carbon atoms), mineral acids. Methanol. Piupäriüi Acetic acid, Prcpicr, acid, methanesulfonic acid, 2a p-toluenesulfonic acid, phosphoric acid and the like) or -N- (Ci s-alkyl)?, especially methyl and ethyl: and, if A and G together are methylidene, B is methyl: A and G are each methyl, B is halogen; and when A is methyl and B is hydrogen, G is CH ₂ R. The reaction is carried out under Friedel-Crafts conditions to produce 5-fluoro-2-methyl-1-indanone. The starting ketone used is preferably 2-bromo-4'-fluoro-2-methylpropiophenone (if A and G are each methyl and B is halogen), and 4'-fluoro 2-methylacrylophenone, Z chloro-4 ', can also be used as the starting ketone. -fluoro-2-methylpropiophenone, 4'-fluoro-3-hydroxy-2-methylpropiophenone or 3-dimethylamino-4'-fluoro-2-methylpropiophenone can be used. Suitably the reaction is carried out under normal Friedel-Crafts conditions. For example, the ketone is converted into suitable Lewis acids in the presence of Friedel-Crafts catalysts, such as Lewis acids, metal alkyls and alkoxides, Bronsted acids, acidic oxides and sulfides, cation exchange resin, metathetic cation-forming agents and stable carbonium and related complexes include acid halide types (metal halides) such as aluminum chloride or bromide, BeCl ₂ , CdCl ₂ . ZnCl ₂ . BF ₃ , BCI ₃ . BBr ₃ , GaCl ₃ , GaBr ₃ , TiCl ₄ . TiBr ₄ , ZrCl ₄ , SnCl ₄ . SnBr ₄ , SbCl ₅ , SbCl ₃ . BiCl ₃ . FeCl ₃ and UCl ₄ . If the ketone is the α- or 0-haloisobutyrophenone, the metals themselves can be used as catalysts because in the course of the reaction the halogen compound reacts with the metal to form the corresponding metal halide, which then catalyzes the further reaction. Catalysts are preferred and in particular the use of an aluminum or iron halide. Suitable metal alkyls and alkoxides are, for example, aluminum or boron alkyls (methyl, ethyl, propyl) or alkoxides (methoxide, ethoxide or propoxide).

Suitable BTonsted acids include, for example, sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, chlorosulfonic acid, fluorosulfonic acid, alkyl and aryl sulfonic acids (e.g. ethanesulfonic acids, p-toluenesulfonic acids) and related aromatic sulfonic acids, as well as chloroacetic acids and trifluoroacetic acids. Acidic oxides and sulfides suitable as catalysts include a wide variety of solid oxides and sulfides. Aluminum oxide and silicon oxide and mixtures of aluminum oxide and silicon oxide are particularly suitable, although other catalysts can also be used, such as BeO, Cr ₂ Oi, P2O5, TiO ₂ , ThO ₂ , Ai ₂ (SOi) ₃ . Al ₂ Oi · .VCr ₂ O ₃ , Al ₂ O ₃ · Fe ₂ O ₃ , Al ₂ Oi · CoO. Al ₂ O ₃ , MnO, Al ₂ Oj ■ V ₂ Oi, Cr ₂ Oj · Fe ₂ O ₃ , MoS ₂ or MoSj. In addition, cation exchange resins that are solid acids are suitable as catalysts, as are agents that form metathetic cations such as anhydrous silver salts (AgClO ₄ , AgBF ₄ , AgSbF ₆ , AgPF ₆ , AgAsF ₆ and Ag ₃ PO ₄ ).

Although the concentration of Friedel-Crafts catalysts is not critical, it is preferred to use 1.1 to 2 moles of catalyst and preferably 1.4 to 1.8 moles of catalyst per mole of ketone. The reaction is suitably carried out in a solvent normally used in Friedel-Crafts reactions, including organic solvents such as CS ₂ , fluorobenzene, polyhalogenated aromatic hydrocarbons, nitrobenzene, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and nitroalkanes, nip reaction will suffice ^{carried out at temperatures from about 0} ° C. to about 150 ° C. and preferably from 20 to 100 ° C. for a long time until the reaction is complete.

The starting ketone is obtained according to step a) in a simple manner by condensation of a suitable acid halide the formula

A O

G-C-C-Z

in which A, B and G have the meanings given to them before, and Z is halogen, with fluorobenzene below Friedel-Crafts conditions prepared as described above. In addition, the Acid halide can be condensed with the fluorobenzene to form the ketone and in situ directly to the 5-fluoro-2-methyl-1-indanone are implemented, additional Friedel-Crafts catalyst is used to carry out of the two stages added.

The invention is illustrated in more detail by means of the following examples.

example 1

a) A slurry of 14 g (0.105 mol) of anhydrous aluminum chloride in 14.4 g (0.15 mol) Fluorobenzene and 24 ml of carbon disulfide are cooled to 15 ° C. Then 23.8 g (0.1 mol) of -bromoisobutyryl bromide are added added at 15 to 20 ° C over a period of 13 to 15 minutes. The reaction becomes 5 Stirred for minutes at 20 ° C. and then poured onto ice. The product is extracted with chloroform The chloroform layer is washed with aqueous sodium bicarbonate over anhydrous sodium sulfate dried and concentrated; it becomes 2-bromo-4'-fluoro-2-methylpropiophenone obtained from bp 52 to 53 ° C / 0.08 Torr in a yield of 95%.

b) To a slurry of 120.2 g (03 mol) Anhydrous aluminum chloride in 54 ml of carbon disulfide are 122.6 g (0.5 mol) of 2-bromo-4'-fluoro-2-methylpropiophenone added at 15 to 20 ° C over a period of one hour. The mixture will be over heated to 50 ° C. over a period of 1 hour, stirred at 50 ° C. for three hours and poured onto ice. That Product is extracted with toluene. The toluene layer is made with aqueous sodium hydroxide and water

25th

30th

washed and concentrated in vacuo; it becomes 5-fluor-2-methyl-1-indanone with a boiling point of 75 ° C / 0.1 to 0.2 Torr in 95% yield.

e) 25 g (1.04 mol) of magnesium turnings are placed in a dry flask under nitrogen with 400 ml of ether. Then 10 ml of a 0.05 molar P'-methylthiobenzylmagnesium chloride solution in ether are added; the MisCliung is heated to 30 ⁰ C. About 2 to 3% of 39.7 g (0.23 mol) of p-methylthiobenzyl chloride in 75 ml of toluene are then added. After 3 to 5 minutes of stirring, a temperature increase is observed at 32 to 33 ⁰ C, which indicates that the reaction is initiated. After waiting 5 minutes, the remainder of the benzyl chloride is added dropwise over a period of 90 minutes. The mixture is then stirred for 30 minutes. Then 32.6 g (0.199 mol) of 5-fluoro-2-methyl-1-indanone are added dropwise over a period of 45 minutes. After waiting 30 minutes, the milky supernatant mixture is then decanted from the magnesium. The flask and magnesium are rinsed with toluene. The reaction product is then mixed with 120 ml of 3N sulfuric acid. The lower layer is separated, the organic layer is added 80 ml of 1:10 concentrated sulfuric acid. Acetic acid added; the two-phase mixture is stirred vigorously for one hour and then 100 ml of water are added. The lower layer is separated and the organic layer is washed with 100 ml of water and 200 ml of sodium hydroxide (2N). After a final wash with water, the organic layer is concentrated and gives, in a yield of 85%, 5-fluoro-2-methyl-1- (p-methylthioben / yl) indene with a melting point of 58 to 59 "C. If p-methylsulfinylbenzyl chloride is used instead of p-methylthiobenzyl chloride used in the above reaction step, the corresponding indene obtained is 5-fluoro-2-methyl-1- (pmethylsulfinylbenzyl) indene.

d) 41.8 g (147 mmol) of 5-fluoro-2-methyl-1- (p-methylthiobene ^ H. · .En are mixed with 150 ml of methanolic Trito! B solution (53.2 g dry basis; 317.5 mmol) offset; the reaction product is heated to 35 ° C. under a nitrogen atmosphere. Then 14.63 g Glyoxylic acid (198 mmol) was added and the mixture was heated to 50 to 55 ° C. The product is at 50 ° C for one hour left to itself. Then it is diluted with 250 ml of water and acidified with dilute sulfuric acid. The product obtained in 90% yield is recrystallized and gives pure 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -indenyIiden-3-acetic acid with a melting point of 185.5 to 188 ° C

Instead of Triton B in the above reaction stage, sodium hydroxide and tetramethylammonium chloride are used or tetramethylammonium hydroxide is used; Indenyliden-3-acetic acid is obtained.

If 5-fluoro-2-methyl-1 - (p-methylsulfinylbenzyl) indene is used instead of the corresponding methylene compound 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indenylidene-3-acetic acid obtain.

Q A suspension of 34.2 g of 5-fluorine-2-methyl-1- (pmethylthiobenzyI) -indenyIiden-3-acetic acid (according to stage d) in 342 ml of glacial acetic acid and 137 ml of concentrated hydrochloric acid are stirred under nitrogen at 90 ° C. for 10 hours The reaction is cooled to room temperature over a period of 2 to 3 hours and at 20 to 25 ° C for another 3 hours overcharge itself. Then it is filtered, with a mixture of 70:30 Acetic acid: water (about 100 ml) washed; then-

45

50 ßend was washed with water to remove the excess acid. 5-fluoro * 2 * methyl-1 - (p-methylthiobenzylidene) indene-3-acetic acid with a melting point of 180 to 183 ° C. is obtained in 93% yield.
If 5-fluoro-2-methyl-I - (p-methyIsulfinylbenzyl) -indenylidene-3-acetic acid is used instead of the corresponding methylthio compound in the above reaction, 5-fluoro'2-methyl-1- (p-methylsulfinylbenzyl) -inden-3-acetic acid obtained. The reaction can be carried out in an aprotic solvent such as 1,2-dichloroethane under a pressure of 7.03 atm. HCl gas at 50 to 100.degree. 17 g (50 mmol) of 5-fluoro-2-methyl-1 - (p-methylthiobenzyl) indenylidene-3-acetic acid are stirred in 94 ml of chloroform and 40 ml of acetic acid under nitrogen and brought to a temperature of 30.degree. 5.3 ml of aqueous hydrogen peroxide (9.6N, 51 mmol) are added to this slurry in one minute. The temperature is then brought to 35 ° C and left to stand for 6 hours at 35 ° C internal temperature. Then 125 ml of water are added and the chloroform layer is concentrated to a small volume in vacuo. The residue is recrystallized from 75 ml of ethanol and the slurry is cooled to 0 to 5 ° C. and left to stand. The product is filtered off and washed with 15 ml of cold (0-5 ° C.) 2BA-ethanol and dried at 80 ° C. in a vacuum. 16.3 g of 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) inden-3-acetic acid with a melting point of 183 to 185 ° C. are obtained with a 92% yield.

If sodium periodate or potassium hypochlorite is used instead of hydrogen peroxide in the example above, also becomes the desired connection

^received · example

a) A slurry of 29.4 g (0.22 mol) of anhydrous aluminum chloride in 38.4 g (0.4 mol) of fluorobenzene is cooled to 15 ° C. under nitrogen. Then (0.2 mol 21.9 g.) Is added dropwise over a period of 30 minutes at temperatures of 15 to 20 ^r C N.ethylacrylchlorid added. The mixture is warmed to 30 ° C for 10 minutes, stirred at 30 ° C for 10 minutes and poured onto ice. The product is extracted with hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo; 4'-fluoro-2-methylacrylophenone with a boiling point of 37 to 39 ° C./0.04 Torr is obtained in a yield of 90%.

b) 50 g (03 mol) of 4'-fluorine-2-methylacryIophenon become a slurry of 60.1 g (0.45 mol) anhydrous aluminum chloride in 27 ml carbon disulfide at 20 to 25 ° C for a period of one Hour added. The mixture is heated to 45 ° C. over a period of one hour and at stirred at this temperature for one hour. The reaction product is then poured onto ice. the oily-aqueous layer is extracted with toluene. The toluene layer is extracted with aqueous sodium hydroxide and Washed water and concentrated in vacuo; it was 5-fluoro-2-methyI-l-indanone with a boiling point of 75 ° C / 0.1-0.2 Torr was obtained in a yield of 70%. The further processing to the desired end product takes place according to example 1.

Example 3

a) To a slurry of 22.7 g (0.17 mol) of anhydrous aluminum chloride and 9.6 g (0.1 mol)

Fluorobenzene becomes 14.1 g (0.1 mol) of S-chloroisobufyryl chloride added over a period of 30 minutes at 20 to 25 ° C. The mixture is at 20 to 25 ° C Left to its own devices for 30 minutes and then poured onto ice. The product is extracted with hexane. the The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo; it will 3-chloro-4'-fluoro-2-methylpropiophenone with a boiling point of 65 to 67 ° C./0.04 torr was obtained in a yield of 50%.

b) 10 g (0.05 mole) of S-ChloM'-fluoro ^ -methylpropiophenon is added to 20 ml concentrated sulfuric acid at 20 to 25 ° C and then heated to 50 ⁰ C. After stirring for three hours at 50 ° C., the reaction product is poured onto ice. The product is extracted with hexane. The hexane layer is concentrated in vacuo; 5-fluoro-2-methyl-1-indanone with a boiling point of 75 ° C./0.1-0.2 Torr is obtained in a yield of 50%. The further processing to the desired ΡγϊΛγ »γ / \ ΛιιΙμ» rfnlcjt oAmäft Rpisnipl I

Example 4

a) and b) 115 g (0.5 mol) of Λ-bromoisobutyryl bromide are added under nitrogen to a slurry of 120.2 g (0.9 mol) of anhydrous aluminum chloride in 54 ml of carbon disulfide and 51.4 g (0.535 mol) of fluorobenzene. The addition is carried out over a period of 75 minutes at temperatures of 15 to 20 ^0C is then warmed ahout a period of 75 minutes to 50 ⁰ C, stirred for 3 1/2 hours at this temperature and then added the product on ice. The product is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo; 79 g (96%) of 5-fluoro-2-methyl-1-indanone with a boiling point of 75 ° C./0.1-0.2 Torr are obtained. Further processing to the desired end product takes place according to Example 1.

Example 5

a) A slurry of 14 g (0.105 mol) of anhydrous aluminum chloride in 14.4 g (0.15 mol) of fluorobenzene and 24 ml of carbon disulfide is cooled to 15 ° C. 0.1 mol of a- (dimethylaminoethyl) propionyl bromide hydrobromide are added ^{at 15 to 20 ° C. over a period of 10 to 15 minutes.} It is stirred for 5 minutes at 20 ^° C., then the product is poured onto ice. The product is extracted with chloroform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated; 2-bromo-4'-fluoro-2-methylpropiophenone is obtained. Further processing to the desired end product takes place according to Example 1.

Example 6

Steps a) and b) are carried out according to Example 1.

c) 13.44 g (0.56 mol) of magnesium turnings are in a dry flask under nitrogen together with 125 ml of ether and an iodine crystal introduced 6 ml of 65 ml of a solution of 24.2 g (0.14 mol) p-Methylthiobenzyl chloride in ether are added. After 3 to 5 minutes of stirring, the iodine color disappears and the reaction begins. After 5 minutes the remainder of the benzyl chloride solution is added dropwise over a period of 45 minutes. It will rinsed in with 10 ml of ether; the reaction will be 2 hours stirred 21 g (0.128 mol) S-FIuor ^ -methyl-l-indanone, dissolved in 50 ml of ether are added dropwise over 30 minutes. The reaction mixture will left to its own devices for an hour; then the milky, supernatant mixture of magnesium in tor »ml of acetic acid decanted. Piston and backlog Magnesium are rinsed 4 times with 50 ml of benzene; the rinsing liquid is added to the acidic solution. 200 ml Water is added; the layers are separated and the organic layer is repeated 5 times Washed 200 ml of water. After drying over Na2SÜ4 is concentrated to dryness. The crude product is converted from hexane to pure 5-fluoro-2-methyl-1- (p-methy! Thiobenzyl) indene recrystallized with a melting point of 58 to 59 ° C (yield 90%). The further processing to the desired end product is carried out according to Example 1.

Example 7

Steps a) and b) are carried out according to Example 1.

c) 173 g of p-methylthiobenzyl chloride are added to 28 g of triphenylphosphine in 80 ml of benzene. the The reaction is heated for 4 hours, then cooled and the product is p-methylthiobenzyltriphenylphosphonium chloride obtained by filtration. 19 g with a melting point of 257 to 258 ° C. are obtained.

When using p-methylsulfinylbenzyl chloride becomes p-methylsulfinylbenzyltriphenylphosphonium chloride obtained, which melts at 258 to 262 ° C with release of gas.

A. 169 mg (1.5 mm) potassium tertiary butoxide are dissolved in 2 ml DMSO and treated with 651 mg (1.5 mm) p-methylthiobenzyltriphenylphosphonium chloride dissolved in 1 ml DMSO. 270 mg (1.65 mm) of 5-fluoro-2-methyl-1-indanone in 2 ml of DMSO are added to this solution. The solution is heated at 75 ° C. for 15.5 hours. Benzene and water are added; the benzene layer is washed 5 times with water. The benzene layer is dried over Na2SO4 and concentrated to dryness under vacuum. The product weighs 915.6 mg. The material is passed over 8 g of silica gel with benzene to remove triphenylphosphine oxide. The eluate weighs 372 mg after the solvent is removed. Chromatograph again through 15 g of silica gel using Hexa ^; thereby be 95.5 mg of 5-fluoro-2-methyl-l- (pmethylthiobenzyliden) indan with a melting point of 67 to 7O ⁰ C isolated (yield 20%).

B. 50 mg of the benzylidene compound from A are mixed with 1 ml of acetic acid, which contains 100 mg of sulfuric acid, mixed and stirred for one hour at room temperature. The mixture is then diluted with water and extracted with ether. The ether extract is concentrated in vacuo; it will 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -indene from m.p. 58 to 59 ° C, obtained in a yield of 95%. The further processing to the desired end product is carried out according to Example 1. When using p-methylsulfinylbenzyltriphenylphosphonium chloride the corresponding p-methylsulfinylbenzylindene is obtained.

Example 8

Steps a) to d) are carried out according to Example 1.

f) A suspension of 34 g of 5-fluoro-2-methyl-1- (pmethylthiobenzyl) indenylidene-3-acetic acid in 150 ml

Ethyl chloride is heated to 0 ° C in an autoclave heated with glass inner surface. Hydrogen chloride is supplied up to a pressure of 6.68 atmospheres below this

Conditions, the reaction is stirred for 10 hours; then the excess gas is vented. Daniir is cooled to 0 to 5 ° C and filtered after one hour and washed with fresh ethylene chloride. 5-Fluoro-2.methyl-l- {p-methylthiobenzy-Iidene) indene-3-acetic acid is obtained in 80% yield obtained from 180 to 183 "C. The further processing to the desired end product takes place according to example t.

Claims (1)

Patent claims: 1. Process for the preparation of 5-fluoro-2-methyl-1 - (p-MethyIsuinnyIbenzyliden) -inden-3-acetic acid and their acid addition salts, characterized by (a) Implementation of an acid halide of the formula