DE2462380A1 - PROCESS FOR THE PREPARATION OF 5-FLUORO-2-METHYL-1- (P-METHYL-SULFINYLBENZYLIDES) - INDEN-3-ACETIC ACID AND THEIR ACID ADDITION SALTS - Google Patents

Description

Patent attorneys: 2 A 6 2 3 8

Dr. Ing.Walter Abitz _{1? / September ig? 6}

Dr. Dieter F. Morf _ις ^ r _Yfl

Dr. Hans-Α. Browns

Munich 88, PIenanauerstr. 28

P 2k 62 380. 1

MERCK & CO., INC. Rahway, New Jersey 07065, V.St.A.

Process for the preparation of 5-fluoro-2-methyl-1- (pmethylsulfinylbenzylidene) - indene-3-acetic acid and their

Acid addition salts

The invention relates to a process for the preparation of 5- fluorine-2-methy1-1- (p-methyIsulfinyIbenzylidene) -inden-3-acetic acid.

This indene-3-acetic acid is known from US Pat. No. 3,654,319 and has flame retardant activity. Both in this patent specification and in GR-PS 4l 736 different representation terms are used described for this connection. In one of the procedures described in the Greek patent specification will 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -inden described as an intermediate. This compound is reacted with a Glyko.läurester; then the product becomes an ester 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indenylidene-3-acetic acid oxidized, which then becomes the desired compound

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isomerized and hydrolyzed. Also in Greek The patent specification is the production of an indanone intermediate described as the starting material for indene, wherein the production of indanone is quite different from that of the invention Process is carried out, according to the Greek patent 3- ^ itrobenzaldehyd with propionic anhydride to Mtroziintic acid is applied; this connection becomes the corresponding amino compound and reduced in a further Reaction converted to the eC-methyl-3-fluorohydrocinnamic acid, This compound in turn is cyclized to the indanone.

The invention relates to new processes for the preparation of 5-fluoro-2-ethy1-1- (p-ethy1sulfinylbenzylidene) indene-3-acetic acid as well as the production of the indanone intermediate on a much shorter route and with higher yields than in the procedure described.

According to the invention it was found that indenoacetic acid by Combination of the following reaction steps can be produced:

Implementation of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indene with Glyoxylic acid, its ester, salt or other derivatives which form the free acid or the salt under the reaction conditions can, to 5-fluoro-2-methyl-l- (p-ynethylthiobenzyl) -indenylidene-3-acetic acid, Ester or salt, isomerization and subsequent oxidation to the desired product (steps 4, 6 and 7 in Flow diagram i). Alternatively, indenylidene-3-acetic acid first oxidized and then isomerized. In another embodiment according to the invention, 5-fluoro-2-methyll ~ (p-methylsulfinylbenzyl) indene is used with glyoxylic acid, its ester or salt, with direct formation of 5-fluoro-2-methyl-1- (pmethylsulfinylbenzyl) -indenylidene-3-acetic acid implemented, whereupon this connection to the desired product isoraeri-

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is sated (steps k and 5 in flow diagram i). The 5-fluoro-2-methyl-1- (p-methylsulfinyl (or raethylthio) -benzyl) -indenylidene-3-acetic acids are new compounds and also a subject of the invention. These compounds are suitable intermediates for the preparation of 5-fluoro-2-raethyl-1- (p-methylsulfinylbenzylidene) -inden-3-acetic acid; But they are also suitable end products because it has surprisingly been found that they also have flame-retardant activity and can be suitable for the same purposes as the end product of the process according to the invention.

In addition, according to the invention, 5-fluoro-2-methyl-1- (pmethylthiobenzyl (or p-methylsulfinylbenzyl)) - indene Reaction of 5-fluoro-2-methyl-1-indanone with a p-methylsulfinyl compound or a p-methylthiobenzyl compound under ' Grignard or ¥ ittig conditions, which are then implemented as before (steps 3-5 or 3, 4, 6 and 7 of scheme i)

In a further embodiment according to the invention, 5- Fluoro-2-methyl-1-indanone by reacting a suitable ketone under Friedel € rafts conditions to the desired 5-fluoro-2-methyl-1-indan.one implemented, which is then implemented further as described above (steps 2 to 5 or 2 to 4, 6 and 7 of flow diagram i).

Finally, the invention also relates to the production of the ketone by reacting fluorobenzene with a suitable one Acid halide under Friedel Crafts conditions and its others, previously described implementation (steps 1 to 5 or 1 to 4, 6 and 7 according to formula i). The Friedel Crafts reaction be continued so far that the ketone formed as an intermediate cyclizes in situ to the 5-fluoro-2-methylindanone.

The invention is explained using the following flow diagram:

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Flow diagram I

AO I " + GCCZ

I.
B.

F- / XO A

C-C-G

I B

S-CH ₃ or Οέ- S-CH ₃

CH,

CH ₂ COOH

CH ₂ COOH

NS.

6 0 9 8Γ8 β Π 1 1 B

OHlGiNAL INSPECTED

15576YA j "

The condensation reaction between the 5-fluoro-2-ynethyl-1- (p-methylthio (or methylsulfinyl) benzyl) indene and glyoxylic acid is carried out in the presence of a strong base. Bases such as alkali metal and alkaline earth metal hydroxides (NaOH, KOH), in particular in the presence of a quaternary ammonium halide as a catalyst (such as C ^ r-trialkylbenzylammonium halide or tetra-C., Alkylainmonium halide; 0.1 to 1.0 mol halide to hydroxide), alkali or Alkaline earth (C _1-1 -) - alkoxide (NaOCH_, K-tertiary butoxide), tetra-C, - alkylammonium hydroxide or benzyltri-C ₁ _ ^ - alkylaainioniurahydr oxide (benzyltrimethylammoniuniiiydr oxide) (Triton B) can be used. Trialkylbenzylammonium hydroxide or tetraalkylammonium hydroxide is preferably used as the strong base. The reaction can be carried out without a solvent; however, it is preferred to use a solvent which is either added to the reaction mixture or used together with the strong base. . C 1-4 alkanols (methanol, butanol), aromatic solvents such as benzene, pyridine and toluene or 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 Cc-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; preferably it is about l _f l to about hjo moles of base to glyoxylic acid and in particular from 1.2 to 2 ^. 5 The molar ratio of glyoxylic acid to indene is not critical and can be from about 1 to 30 moles to one mole, and preferably about 1.5 bis; IjO moles indene. Alternatively, the alkali metal or alkaline earth metal _{salt or the aryl or alkyl ester, in particular the C 1} _-- alkyl derivatives such as the methyl, ethyl, butyl _T derivatives can be used as starting material instead of the free glyoxylic acid or any other acid salt of a strong base. Under these circumstances, the strong base at the

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Reaction with glyoxylic acid salt or ester cannot be used 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 glyoxylic acid 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. However, the reaction is preferably carried out for 15 minutes to 5 hours, and in particular for about half an hour to three hours. The reaction may be conducted at temperatures ranging from about ⁰ ° C to about 150 ⁰ C, preferably from about 10 ⁰ C to SO ⁰ C. and especially from 35 ° C to 60 ° C · performed; will.

After the condensation reaction is complete, the isomerization of the 5-fluoro-2-methyl-1- (p-njetliylthio (or niethylsulf inyl) benzyl) -indeny] .iden-3-acetic acid in the form of its acid addition salt or esters are carried out without isolation; this means that the same reaction mixture of the glyoxylic acid reaction can be used for isomerization. This is particularly possible if the isomerization is carried out under basic Wants to perform 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 use stronger bases for isomerization want. Bases as described for the previous reaction can be used. This isomerization is preferred however, carried out using acid, so that: the reaction product from the previous step preferably is first isolated. Various organic and / or inorganic acids can be used, such as C, j -'- ^ l.kyl.su.lfonsäuren (Methanesulphonic acid), arylsulphonic acids (toluenesulphonic acid), acidic ion exchange resins (e.g. Dowex 50), aryl carboxylic acids (p-nitrobenzoic acid), aliphatic acids (alkanoic acids such as acetic acid, Propionic acid, trichloroacetic acid and trifluoroacetic acid), mineral acids (phosphoric acid, sulfuric acid, hydrochloric acid, hydrogen bromide acid);

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however, mineral acids or mixtures of mineral acids and organic acids (preferably C ₂ -C 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; catalytic amounts of acid can suitably be used. All that has to be achieved is that the reaction mixture is made acidic in the event that it is basic. Preferably, however, from about ole to 50 moles of acid are used to form indenylidene, and in particular from 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, a strong acid such as the arylsulfonic acids or mineral acids is preferably used. For example, the unsubstituted alkanoic acids (for example acetic acid) and the arylsulfonic acids (for example toluenesulfonic acid) and in particular mineral acids (for example hydrochloric acid) can be used as solvents. If halogenated hydrocarbons are used as solvents, mineral acids are preferred as catalysts and in particular anhydrous mineral acids. used like 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 may proceed at temperatures of about 0 ⁰ C to about 150 ⁰ C and are preferably carried out from about 5O 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 used in a manner known per se, such as by filtration, extraction or removal.

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isolated removal of the acidic solvent by evaporation will.

When the p-methylthio compound is used as the starting material, the oxidation of the methylthio group to the desired methylsulfinyl group can be carried out in any reaction step, such as immediately after the reaction with glyoxylic acid or after isomerization, but preferably after isomerization. The oxidation can be carried out in a manner known _{per se, such as by oxidation with H 2} O ₉ , basic periodates or hypohalides, preferably the alkali or alkaline earth metal periodates or hypohalides, or organic peracids such as peracetic acid and monoperphthalic acid. However, the preferred oxidizing agent is HpOp. The reaction is preferably carried out in the presence of a solvent. C. _ -alkanoic acids (e.g. acetic acid), halogenated hydrocarbons (e.g. chloroform), ethers ( _{e.g. dioxane), C 1} -alkanoic acids (e.g. isopropanol) or mixtures thereof can be used for this purpose.

The molar ratio of oxidizing agent to indene compound can be from 0.5 to 10, but preferably from 0.8 to 1.5. 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 of 10 80 ⁰ C and in particular of 25 ° - 50 ⁰ C.

If an ester of glyoxylic acid is used, the free acid compound is used easily obtained during the isomerization, especially when some water is present and.when the isomerization is carried out at elevated temperatures. The ester used itself is not critical; it can be aliphatic, aromatic or heterocyclic esters such as alkyl esters (methyl,

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t-butyl, phenyl, alkenyl esters) or aryl esters (benzyl, Phenyl ester) can be used. Glyoxylic acid salts can also be used as the pharmaceutically acceptable salts are used as well as others that are converted into the free by hydrolysis Acid to be converted; these include the salts of alkali or Alkaline earth metals (Na, K, Ca, Li) as well as the salts of the metals previously described for the Priedel Crafts reaction became.

The 5-fluoro-2-methyl-1- (p-methylthio (or methylsulfinyl) benzyl) indene can be made from 5-fluoro-2-methyl-l-indan.one by reaction with a p-methylthio (or methylsulfinyl) benzyl compound be prepared under Grignard or Wittig conditions. This indene contains the double bond in the 1- to 2 position. However, under certain conditions of formation, some of the tautomeric indene compounds are also present. Are these isomers in the presence of a base as in the reaction reacted with glyoxylic acid, the same indenyl anion forms that with glyoxylic acid in the same way as the Indene compound reacts. For example, the Grignard compound of p-methylthiohenzyl chloride or the Wittig compound of p-methylsulfinylbenzyl triphenylphosphonium chloride with 5-fluoro-2-methyl-1-indanone 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 the benzylidene becomes the benzyl compound isoraerized under acidic conditions in a manner known per se.

The benzyl group is with the indanone compound via a Grignard or Wittig reaction under known conditions connected. For example, in the Grignard reaction

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to metallic magnesium in absolute ether the corresponding benzyl halide (Cl, Br, F, J) (p-methylthiobenzyl halide or p-methylsulfinylbenzyl halide) was added and the reaction mixture preferably heated to 25 to 35 g. Although more or less than equiraolar amounts of magnesium can be used, it is advantageous to use a 3 to 6-fold excess based on the benzyl halide. Though diethyl ether usually does is used as a solvent, other ethers, such as, for example, di-n-butyl, diisopentyl ethers, anisole, cyclic ethers Ethers such as tetrahydropyran 4-methyl-l, 3-dioxane., Dihydropyran, Tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxytetrahydrofuran be used. Tertiary amines such as dimethylaniline, hydrocarbons such as benzene and toluene, as well as many other types of solvents described in the literature can be used. The one made in this way Grignard reagent is suitable for reaction with the indanone. The indanone and the Grignard reagent are used in one Temperature from about O C to the boiling point of the solvent and preferably mixed at 20 to 35 ° C., the indanone preferably being added to the Grignard. 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 is. Both inorganic mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid as well as organic or aliphatic acids Acids such as acetic acid, propionic acid or methanesulfonic acid can be used be used. Usually at least a 5 ~ 10% molar excess of the acid, based on the complex, is used. Preferably the acid becomes the reaction mixture of the complex added as a dilute solution in water, although other solvents for the acid such as alcohols, ethers or aromatic Hydrocarbons can be used. The reaction time is usually 0 to 100 C; 20 - 40 C are preferred.

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In the Wittig reaction, for example, triphenylphosphine 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), ethers (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 from 0 to 20O ⁰ C and in particular from 25 to 75 ° C under 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 organo-metal 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 is used as the solvent. In the latter procedure, an alkali metal alkoxide can be used as the proton acceptor and the corresponding alcohols can be used as the solvent.

The Wittig reagent is normally not isolated, but further reacted in the same reaction vessel. The reaction of the bases with the phosphonium salt is suitably carried out in about equimolar amounts, although an excess of base may be advantageous. The reaction may be from ⁰ C to the boiling point of the solvent and preferably in the range of 25 at temperatures of about O - 50 ⁰ C are performed. 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 implementation can

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at temperatures from OC to the boiling point of the solvent, but preferably in the range from 25 to 50 ° C. until the reaction is complete. The indene intermediate can then be isolated in a manner known per se. In those cases where the active 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-fluoro-2-methyl-1-indanone is made from a ketone of the general Formula:

prepared in which A is a methyl group or together with G is a methylidene group; B is hydrogen, methyl group or halogen (Cl, Br, F, J); G. (especially alkanoic acids with 2 to 5 carbon atoms), aromatic acids (especially aromatic acids with 7 to 9 carbon atoms), mineral acids, methanol, propanol, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid and the like) or -N- (C ₁ --alkyl) -, in particular methyl and ethyl; and when A and G together are methylidene, B is methyl; when A and G are each methyl, B is

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15576Y ¹ A "

Halogen; and when A is methyl and B is hydrogen, G is CH ₉ R; the reaction is carried out under Priedel Crafts conditions with formation of 5-fluoro-2-diethyl-1-indanone. Preferably, as a starting ketone, 2-bromo-4'-fluoro-2-methylpropiophenone (when A and G are each methyl and B is halogen) used, as well as the starting ketone can also 4 x - fluoro-2-inethylacrylophenon, 3-chloro-k ¹ -! luor-methylpropiophentjn 2, h '-fluoro-3-hydroxy-2-or 3-Inethylpropiophenon Diraethylamino ^{t-4-fluoro-2-raethylpropiophenon} be used. Suitably the reaction is carried out under normal Friedel Crafts conditions. For example, the ketone is converted 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. Suitable Lewis acids include acid halide types (metal halides) such as aluminum chloride or bromide, BeCl ₉ , CdCl ₉ , ZnCl ₉ , BF-, BCl-, BBr ,, GaCl ,, GaBr ,,, TiCl ^, TiBr ^, ZrCl ^, SnCl ^, SnBr ^, SbCl-, SbCl-, BiCl-, FeCl "and UCl .. If the ketone is the c <- or P-haloisobutyrophenone, the metals themselves can be used as catalysts because in the course of the reaction the halogen compound with the metal reacts to form the corresponding metal halide, which then catalyzes the further reaction. This class of Friedel Crafts catalysts is 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 Bronsted 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. Among the acidic ones suitable as catalysts

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Oxides and sulfides includes 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 O ₃ , P ₂ O ₅ , TiO ₂ , ThO ₂ , Al ₃ (SO ^) ₃ , Al ₃ O ₃ . χ Cr ₃ O ₃ , Al ₃ O ₃ . Fe ₂ O ₃ , Al ₂ O,. CoO, Al ₃ O ₃ , MnO, Al ₃ O ₃ . V ₂ 0, Cr ₃ O ₃ . Fe ₃ O ₃ , MoSg or MoS-. In addition, cation exchange resins that are solid acids are useful as catalysts, as are agents that form metathetic cations such as anhydrous silver salts (AgClO ₄ , AgBF ₄ , AgSbF ₆ , AgPPg, AgAsF ₅ and Ag ₃ PO ₄ ).

Although the concentration of Friedel Crafts Katalysatqren is not critical, preferably 1 _T 1 are catalytic to 2 moles, and preferably 1.4 to used I ₁ S mole of catalyst per mole of ketone. The reaction is suitably carried out in a solvent normally used in Friedel Crafts reactions which include organic solvents such as C5 _Q , fluorobenzene, poly-halogenated aromatic hydrocarbons, nitrobenzene, aliphatic hydrocarbons, halogenated, aliphatic hydrocarbons and nitroalkanes. The reaction is sufficient to complete the reaction at temperatures from about O preferably carried out long ⁰ C to about 150 ° C and from 20 to 100 ⁰ C.

The starting ketone is produced in a simple manner by condensation of a suitable acid halide of the formula

AO j I
GCCZ

t
B.

in which A, B and G have the meanings given to them above, and Z is halogen, with fluorobenzene under Friedel Crafts conditions prepared as previously described. In addition, can

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If necessary, the acid halide can be condensed with the fluorobenzene to form the ketone and in situ directly to the 5-fluoro-2-methyl-l-indanone are implemented. If the implementation is to be carried out in this way, additional Friedel Crafts catalyst was added to carry out the two stages.

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

example 1

A mixture of 45.7 g (0.3 mol) of 4 ^f -fluoropropiophenone, 9 g (0.3 mol) of paraformaldehyde, h g (0.03 mol) of anhydrous potassium carbonate and 200 ml of methyl alcohol are stirred at 35 ° C. for two days. The reaction product is poured into water and acidified with hydrochloric acid and extracted into benzene. The benzene layer is washed with water and concentrated in vacuo; 4 ^l -fluoro-3-hydroxy-2-methylpropiophenone is obtained.

Example 2

A mixture of 15 _f 2 g (ol mol) of V-fluoro-3-hydroxy-2-methylpropiophenone and 12 g of phosphorus pentoxide in 100 ml of xylene is refluxed for one hour. The reaction is cooled and water is added; the xylene layer is washed with aqueous sodium hydroxide and water. The organic layer is concentrated in vacuo; 5-fluoro-2-methyl-1-indanone is obtained.

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Example 3

A slurry of Ik g (0.105 mol) of anhydrous aluminum chloride in lk h _f g (0.15 mol) of fluorobenzene and 2h ml of carbon disulfide was cooled to ⁰ C Ip. Then, 23 ^ 8 g (ol mol) "(.-Bromoisobutyryl bromide were added hot 15 to 20 ⁰ C over a period of 10 to 15 minutes. The reaction is stirred for 5 minutes at 20 C and then placed on ice. The product is chloroform The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated. it is 2-bromo-4-fluoro-2-methylpropiophenone ^t obtained.

example

122.6 g (0.5 mol) of 2-bromo-4'-fluoro-2-methylpropiophenone are added to a suspension of 120.2 g (0.9 mol) of anhydrous aluminum chloride in 5 ^ ml of carbon disulfide at 15 to 20 ^° C. over a period of one hour added. The mixture is heated over a period of 1 hour at 50 ⁰ C, stirred for three hours at 5O ⁰ C and placed on ice. The product is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo; 5-fluoro-2-methyl-1-indanone was obtained.

Example 5

A slurry of 29 j h g (O ₁ 22 mol) of anhydrous aluminum chloride in _38; 4 g (Oj4 mol) of fluorobenzene under nitrogen

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cooled to 15 ° G. Then methyl acrylic chloride (21 _f 9 g, 0.2 mol) is added dropwise over a period of 30 minutes at temperatures from 15 to 20 ^{° C.} The mixture is heated for 10 minutes at 30 ⁰ C, stirred for 10 minutes at 30 ⁰ C and placed on ice. The product is extracted with hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo; 4'-fluoro-2-methylacrylophenone was obtained.

Example 6

50 g (0.3 mol) of 4'-fluoro-2-methylacrylophenon become a slurry of 60 ^ 1 g (0 _# 45 mol) of anhydrous aluminum chloride in 27 al carbon disulfide at 20 to 25 ⁰ C over a period of one Hour added. The mixture is heated to 45 ° C. over a period of one hour and 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 washed with aqueous sodium hydroxide and water and concentrated in vacuo; 5-fluoro-2-methyl-1-indanone was obtained.

Example 7

To a slurry of 22 ^ 7 g (0 ^ 17 mol) of anhydrous aluminum chloride and 9.6 g (0 _T l mol) of fluorobenzene, 14.1 g (oil mol) of ß-chloroisobutyrylelilorid are added over a period of

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Added for 30 minutes at 20 to 23 ° C. The mixture will be at Leave to yourself for 20 to 25 C for 30 minutes and then up Given ice. The product is extracted with hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated under vacuum; it became 3-chloro-V-fluoro-2-methylpropiophenone obtain.

Example 8

10 g (0.05 moles) of 3-chloro-4'-fluoro-2-methylpropiophenone added to 20 ml of concentrated sulfuric acid at 20 to 25 ° C and then heated to 50 C. After three hours Stirring at 50 ° C., the reaction product is poured onto ice. The product is extracted with hexane. The hexane layer will concentrated in vacuo; 5-fluoro-2-niethyl-1-indanone is obtained,

Example 9

A mixture of 15.2 g (0.1 mol) of 4'-fluoropropiophenone, 8.2 g (0.1 mol) of dimethylamine hydrochloride, 3.6 g (0.12 mol) of paraformaldehyde in 20 ml of absolute alcohol were at 95 to 100 C stirred for three hours. The mixture is cooled and the separated product is filtered off. The product is dissolved in water and made alkaline with sodium hydroxide. The free base is extracted with ether. The ether layer is dried over anhydrous sodium sulfate and concentrated in vacuo; 3-dimethylamino-4- ^t -fluoro-2-methylpropioplienone was obtained.

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Example 10

A mixture of k2 g (0.2 mol) of 3-dimethylamino- ⁱ i ^f -fluoro-2-laethylpropiophenone and 100 ml of concentrated sulfuric acid is

/ heated to 90 C over a period of one hour and stirred at this temperature for two hours. It is then cooled and poured onto ice; the product is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo; it became 5-fluoro-2-methyl-1-indanone obtain.

Example 11

To a slurry of 120.2 g (0.9 mol) of anhydrous aluminum chloride in 5 * t ml of carbon disulfide and 51.4 g (0.535 mol) of fluorobenzene under nitrogen are added 115 g (0.5 mol) of bronioisobutyryl bromide. The addition is carried out over a period of 75 minutes at temperatures from 15 to 20 ^° C. ^{The mixture is then heated to 50 °} C. over a period of 75 minutes, stirred at this temperature for 3 1/2 hours and then the product is poured onto 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 were obtained.

Example 12

25 g (l / o'i mol) of magnesia chips were placed in a dry flask

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introduced under nitrogen with 400 ml of ether. Then 10 ml of a 0.05 molar p-methylthiobenzylmagnesium chloride solution in ether are added; the mixture is heated to 30 ° C. Then about 2 to 3 ⁴ ^ of 39.7 g (θ _/ 23 mol) of p-methylthiobenzyl chloride in 75 nil of toluene are added. After 3 to 5 minutes of stirring, an increase in temperature to 32 to 33 ° C is observed, indicating that the reaction has 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 p-fluoro-2-methyl-1-indanone are added dropwise over a period of h5 minutes. After waiting 30 minutes, the milky, supernatant mixture is decanted from the magnesium. The flask and magnesium are rinsed with toluene. The reaction product is then treated with 120 ml of ^3N sulfuric. The lower layer is separated, 80 ml of 1:10 concentrated sulfuric acid, acetic acid are added to the organic layer; 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 5-fluoro-2-methy] -l- (p-methylthiobenzyl) -indene. If p-methylsulfinylbenzyl chloride is used instead of p-methylthiobenzyl chloride in the above example, p-methylsulfinylbenzylindene is obtained as the corresponding indene.

Example 13

17; 3 S p-methylthiobenzyl chloride become 28 g triphenylphosphine

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added in 80 ml of benzene. The reaction is heated for 4 hours, then cooled and the product p-Methylthiobenzyltriphenylphosphoniuraehlorid obtained by filtration. 19 g with a melting point of 257 to 25 ° C. were obtained.

When using p-methylsulfinylbenzyl chloride, p-methylsulfinylbenzyltriphenylphosphoniurachloride becomes obtained, which melts at 253 to 262 ° C with release of gas.

Example 14

A. 169 mg (1.5 πκη) potassium tertiary butoxide are dissolved in 2 ml DMSO and treated with 6f> l mg (l / 5 times) ρ-methylthiobenzyltripheny] phosphoniumiciloride, dissolved in 1 ml DMSO. 270 mg (1.65 nmi) of 5-fluoro-2-methyl-i-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 five times with water. The benzene is layered over Na ₀ SO. dried and concentrated to dryness in vacuo. The product weighs 915/6 mg. The material is poured over ½ 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 hexane; 95/5 nig 5-fluoro-2-methyl-1- (p-methylthiobenzylidene) indane with a melting point of 67 to 70 ° C. is isolated.

B. 50 mg of the benzylidene compound from A are mixed with 1 ml of acetic acid, containing 100 mg of sulfuric acid, mixed and stirred for one hour at room temperature. The mixture is then

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diluted with water and extracted with ether. The ether extract is concentrated in vacuo; it becomes 5-fluorine-2-methyl l- (p-methylthiobenzyl) indene obtained.

When using p-Methylsulfinylbenzyltriphenylphosphoniuinchlorid becomes the corresponding p-methylsulfinylbenzylindene obtain.

Example 15

500 mg (1.755 ram) of 5-fluoro-2-methyl-1- (p-niethylthiobe.ijzyl) -indene are dissolved in 5 ml of chloroform. 30 5 »hydrogen peroxide (equivalent to 2.6 ^ 5 mra) are added to this solution. The reaction mixture is left to stand for one hour at room temperature and then 5 nil glacial acetic acid is added and again left to stand for one hour. The Reaktionsniischung is then treated with 25 ml of a 1: 1 mixture of benzene and ether, and extracted with 6 times 25 nil of a follow aqueous Natriumehloridlösung. The solution is then dried over sodium sulfate and concentrated in vacuo to an oil. Recrystallization from ice-cold isopropanol leads to 5-fluoro-2-niethyl-1- (p-niethylsulfinylbenzyl) indene.

Example 16

41.8 g (1 ^ 7 inMol) of the indene according to Example 12 are mixed with 150 ml of methanolic Triton B solution (53 _f 2 g dry basis; 317 »5 mmol); the reaction product is

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substance atmosphere heated to 35 ° C. Then I * Ij63 g of glyoxylic acid (198 mmoles) are added and the mixture is heated to 50 to 55.degree. The product is left to its own devices at 50 ° C for one hour. It is then diluted with 250 ml of water and acidified with dilute sulfuric acid. The in 90% yield resulting product is recrystallized to yield pure \ 5-fluoro-2-methyl-l- (p-methylthiobenzyl) -indenyliden-3-acetic acid having a melting point of 185 ^ 5-188 ⁰ C.

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

In the above example, 5-fluoro-2-methyl-1- (p-niethylsulfinylbenzyl) indene is used Used instead of the corresponding methylthio compound, 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) indenylidene-3-acetic acid is used obtain.

Example 17

A suspension of 34.2 g of 5-fluoro-2-raethyl-l- (p-methylthiobenzyl) indenylidene-3-acetic acid (according to Example 16) in 3 ^ 2 ml of glacial acetic acid and 137 ml of concentrated hydrochloric acid are added for 10 hours under nitrogen 90 ⁰ C stirred. The reaction is cooled to room temperature over a period of 2 to 3 hours and left to stand at 20 to 25 C for a further 3 hours. It is then filtered, washed with a mixture of 70:30 acetic acid: water (about 100 ml); it was then washed with water in order to remove the excess acid. 5-Fluoro-2-methyl-1- (p-methylthiobenzylidene) indene-3r-acetic acid with a melting point of 180 to 183 ° C. is obtained in 93% yield.

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76YA

Is used in the previous case. : .ρΐ.Ί 5-fluoro-2-. _; ; 'ithyl-l- (p-iue tliylsul f inylbonzyl) -indenylide:] - 3-acetic acid used instead of the corresponding methyl tliLo compound, 5-fluoro-2-: aethyl-l- (p-methylsul f inylbonzyl. iden) is used -inden-3-acetic acid obtained. The reaction can be carried out in an aprotic solvent, λνΐβ for example 1,2-dichloroethane under a pressure of 7.03 a LU HCl gas at 50 to 100.degree.

Example 1S

17 g (50 nmol) of the product from Example 17 is dissolved in 94 ml of chloroform and ^; 10 ml of acetic acid were stirred under nitrogen and brought to a temperature of 30.degree. _{5 f} 3 nil cracked water peroxide (9.6 n, 51 μmol) are added to this slurry in one minute. The TeniperaLur is then brought to 33 ° and left to stand for 3 hours at an internal temperature of 33 ° C. Then 125 ml of I. water are added and the chloroform layer is concentrated to a small volume in vacuo. The residue is made up of 75% of ethanol urakristallisiert and the suspension is cooled to 0 to 3 ° 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 50 ° C. in vacuo l6 _t 3 g of 5-fluoro-2 - ;: iethyl-IB (p -. / ie thylsulf inylbenz3'liden) indene-3-acetic acid having a melting point of 135 ⁰ C to 1S3.

Sodium periodate is used instead of hydrogen peroxide in the above example or potassium hypochlorite is also used desired connection obtained.

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Example 19

A slurry of 1h g (0.15 mol) of anhydrous aluminum chloride in 1'ij-'ig (0.15 mol) of fluorobenzene and 2-Ί ml of carbon disulfide is cooled to 15 ° C. There are 0.1 MoIcC- (dimethylaminoethyl) propionylbromidhydrobroraid over 10 to 15 minutes at 13 ο is 20 ⁰ C added. It is stirred for 5 minutes at 20 C; then the product is placed on ice. The product is extracted with chloroform. The chloroform layer is washed with aqueous NatriUiHOiearbonat over anhydrous sodium, ¹ -. sulfate dried and concentrated; there is obtained 2-bromo-4 ^r -f1uor-2-methyl propiophenone ·.

Example 20

13.Vi g (O _t 56 mol) magnesium shavings are placed in a dry flask under nitrogen together with 125 nil ether and an iodine crystal. 6 ml of 63 ml of a solution of 2-'i _f 2 g _(θ? 14 mol) of p-methylthiobenzyl chloride in ether are added. After 3 to 5 hours 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 is rinsed in with 10 ml of ether; the reaction is stirred for 2 hours. 21g (0.12S mol) of 5-fluoro-2-ynethyl-lindanone, dissolved in 50 ml of ether, are added dropwise over 30 minutes. The reaction mixture is left to stand for one hour; then the milky, supernatant mixture of magnesium is decanted in 100 ml of acetic acid. Flask and residual magnesium are rinsed with k times 50 ml of benzene; the rinsing liquid is added to the acidic solution. 200 ml of water

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are admitted; the layers are separated and the organic layer is washed with 5 times 200 ml of water. After drying over Na ₀ SO, Trocl-IUE is concentrated to. The crude product is crystallized from hexane to give pure 3-fluoro-2-diethyl-1- (p-n3ethylthiobenzyl) indene with a melting point of 58 to 59 ° C.

Example 21

A suspension of 3 ^! i g 5-Pluor-2-never thyl ~ l- (p-me thylthiobenzyl) -indenyliden-3 - & 3sigsäure in 150 ml of ethylene dichloride is heated to 70 C in an autoclave with glass inner surface. Hydrogen chloride is fed in up to a pressure of 6.68 atii. Under these conditions the reaction is stirred for 10 hours; then the excess gas is vented. The mixture is then cooled to 0 ° to 5 ° C. and, after one hour, filtered and washed with fresh ethylene electrolyte. 3-Fluoro-2-ynethyl-1- (p - ;;] e fchylthiobenzyliden) -inden- 3-acetic acid is obtained in 80% yield.

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Claims (1)

576 YA * Patent claims 1. Process for the preparation of 5-fluoro-2-methyl-1- (pmethylsulfinylbenzylidene) -inden-3-acetic acid or their acid addition salts, characterized by (a) Reaction of 5-5 ¹ luoro ~ 2-methyl-1-indanone with a FL-benzyl compound in which R ^ is p-methylthio or p-methylsulfinyl, under Grignard or Wittig conditions to give 5-fluoro-2 -methyl-1- (R ..- benzyl) -indene; (b) Condensation of the indene compound with glyoxylic acid, its ester or salt to give 5-fluorine-2-methyl-IR ₁ -benzylindenylidene-3-acetic acid, its ester or salt; (c) when R. is methylsulfinyl: isomerizing the indenylidene compound from step (c) to the desired product; or, (d) when R 1 is methylthio: isomerizing the indenylidene compound from stage (c) and subsequent oxidation to the desired product or first oxidation of the product from stage (c) and subsequent isomerization. 2. The method according to claim 1, characterized in that the reaction in step (a) is carried out under Grignard conditions, R. being p-methylthio. 3. The method according to claim 2, characterized in that after step (b), the isomerization is first carried out will. - 27 - 0 9 8 8 6/1115 576 YA Process for the preparation of 5-fluoro-2-methyl-1- (pmethylsulfinylbenzylidene) -inden-3-acetic acid or their salts, characterized by (a) Implementation of a ketone of the formula in which A is the methyl group or together with G forms methylidene; B is hydrogen, a methyl group, or halogen; G is a methyl group or CH ₂ R group or together with A forms methylidene, where R is halogen, the hydroxy group, a corresponding ether or ester or the -N- (C ^^ - alkyl) group, 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, and (3) when A is methyl and B is hydrogen, G is CH ₂ R group, under Friedel-Crafts conditions to give 5-fluoro-2-methyl-1-indanone; (b) Reaction of 5-fluoro-2-methyl-1-indanone with an R ₁ -benzyl compound in which R _{1 is} p-methylthio or p-methylsulfinyl, under Grignard or Wittig conditions to give 5-fluoro-2- methyl- _{1- (R 1} -benzyl) indene; - 28 - Θ09886 / 1115 576 YA $ 3 (c) Condensation of the indene compound with glyoxylic acid, its ester or salt to give 5-fluorine-2-methyl-IR ₁ -benzylindenylidene-3-acetic acid, its ester or salt; (d) when R _{1 is} methylsulfinyl: isomerizing the indenylidene compound from step (c) to the desired product; or, (e) xif R ^ methylthio is: isomerizing the indenylidene compound from stage (c) and subsequent oxidation to the desired product or first oxidation of the Product from stage (c) and subsequent isomerization. 5. The method according to claim 4 ,. characterized in that as a ketone in step (a) .4 '-fluoro ^ -halogen ^ -methylpropiophenone and glyoxylic acid is used in step (c). 6. The method according to claim 4, characterized in that a p-methylthiobenzyl compound is used in step (b), and that after stage (c) isomerization is first carried out. 7. Process for the preparation of 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -inden-3-acetic acid or their salts, characterized by (A) conversion of 4 ^f -fluoro-2-halo-2-methylpropiophenone under Friedel-Crafts conditions to 5-fluorine-2-methyl-1-indanone; (b) Reaction of 5-fluoro-2-methyl-1-indanone with a p-methylthiobenzyl compound under Grignard or Wittig conditions for 5-fluoro-2-methyl-1- (p-methylthiobenzyD-indene; - 29 - 609886/1 1 15 15 576 YA (c) condensation of the indene compound with glyoxylic acid in the presence of a base to give the corresponding 3-indenylideneacetic acid compound; (d) Isomerizing the 3-indenylideneacetic acid compound in the presence of a base or acid to form 5-fluoro-2-methyll- (p-methylthiobenzylidene) indene-3-acetic acid compound; and (e) Oxidation of the indene-3-acetic acid compound to the desired one Product or, if required, first oxidation of the product from stage (c) and subsequent isomerization. 8. The method according to claim -7, characterized in that 4 ^f -fluoro-2-bromo-2-methylpropiophenone is used and the isomerization is carried out in the presence of an acid. 9. Process for the preparation of 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) indene-3-acetic acid or their salts, characterized by (a) Implementation of an acid halide of the formula A O I - G-C-C-Z in which A forms a methyl group or together with G forms methylidene; B hydrogen, a methyl group or halogen, G is a methyl group or CH-R group or together with A forms methylidene, where R is halogen, the hydroxyl group, a corresponding ether or ester or is the -N- (C 1 -C 4 -alkyl) group and Z is halogen and where, (1) when A and G together are methylidene, B is a methyl group, 6 0 9 θ δ 6 Ά 1 Ϊ S 576 YA ^ (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 R, with fluorobenzene under Friede1-Crafts conditions to give 5-fluorine-2-methyl-1-indanone; (b) Reaction of 5-fluoro-2-methyl-1-indanone with a FL-benzyl compound, where R _{1 is} p-methylthio or p-methylsulfinyl, under Grignard or Wittig conditions to give 5-fluoro-2-methyl- 1- (R ₁ -benzyl) indene; (c) Condensation of the indene compound with glyoxylic acid, its ester or salt to form 5-fluoro-2-methyl-1-R benzylindenylidene-3-acetic acid, their ester or salt; (d) when R _{1 is} methylsulfinyl: isomerizing the indenylidene compound from step (c) to the desired product; or, (e) if R _{1 is} methylthio: isomerization of the indenylidene compound from step (c) and subsequent oxidation to the desired product or first oxidation of the product from step (c) and subsequent isomerization. Process according to claim 9, characterized in that the acid halide used is an od-haloisobutyryl halide, where R _{1 is} a p-methylthio compound, and step (c) is carried out under Grignard conditions. 11. The method according to claim 9, characterized in that glyoxylic acid is used in step (c) and the isomerization is first carried out after step (c). - 31 - 80988671 1 15 576 YA 3! L 12. Process for the preparation of 5-fluoro-2-methyl-1- (pmethylsulfinylbenzylidene) -inden-3-acetic acid or their salts, characterized by (a) Reaction of an α-haloisobutyryl halide under Friedel-Crafts conditions with fluorobenzene to give 5-fluoro-2-methyl-1-indano; (b) Reaction of 5-fluoro-2-methyl-l-indanone with a p-methylthiobenzyl compound under Grignard or Wittig conditions to give 5-fluoro-2-methyl-1- (p-methyIthiobenzy1) -indene; (c) Condensation of the indene compound with glyoxylic acid in Presence of a base to the corresponding 3-indenylideneacetic acid compound; (d) Isomerizing the 3-indenylideneacetic acid compound in Presence of a base or acid to give the 5-fluoro-2-methyll- (p-methyIthiobenzylidene) indene-3- acetic acid compound; and (e) Oxidation of the indene-3-acetic acid compound to the desired product or, if necessary, oxidation first of the product from stage (c) and subsequent isomerization. 13. The method according to claim 12, characterized in that oC-bromo-isobutyrylic acid bromide is used and the Carries out isomerization in the presence of an acid. - 32 - 609886/1115