SE440774B - PROCEDURE FOR THE PREPARATION OF 5-FLUORO-2-METHYL-1- (R-BENZYL) -INDEN, WHERE R? 711 DESCRIBES P-METHYLTIO OR P-METHYLSULPHINYL - Google Patents

Description

20 of 30 35 40 8107702-6 of the desired compound. Similarly, the Greek patent specification describes the preparation of the present indanon intermediate for the preparation of the indentation materials. However, the preparation of the indanone is completely different from the present preparation and involves the reaction of 3-nitrobenzaldehyde with propionic anhydride to form the appropriate nitrocinnamic acid, which is reduced to the corresponding amino compound and further reacted to form a- methyl 3-fluorohydrocinnamic acid. This compound, in turn, is cyclized to form the indanone. According to one embodiment of the preparation of 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -indene-3-acetic acid, it has been found that this compound can be readily is prepared by a combination of reaction steps, namely by reacting the 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -indene with glyoxylic acid, its ester, salt or other derivatives which may form the free acid or the salt under the reaction conditions to give 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -indenylidene-3-acetic acid, ester or salt thereof, which compound is then isomerized and then oxidized to give the desired product (step H , 6 and 7 in Reaction Scheme I). Alternatively, the indenylidene-3-acetic acid compound may first be oxidized and then isomerized. In another embodiment, the 5-fluoro-2-methyl-1- (p-methylsynfinylbenzyl) -indene is reacted with lead oxylic acid, its ester or salt to directly form 5-fluoro-2-methyl-1- [Yp- methylsulfinyl- or methylthio) -benzyljindenylidene-3-acetic acid, which is then isomerized to the desired product (steps H and 5 in reaction scheme IL V According to yet another embodiment, 5-fluoro-2-methyl-1- (p-methylthiobenzyl) - or (p-methylsulfinylbenzyl) -indene by reaction of 5-fluoro-2-methyl-1-indanone with a p-methylthiobenzyl or p-methylsulfinyl compound under Grignard or Wittig conditions to give 5-fluoro-2-methyl -1 - [(p-methylthio) - or (p-methylsulfinyl) -benzylphidine, which in turn is further reacted as described (steps 3-6 or 3, U, 6 and 7 in the reaction scheme IN.

In yet another embodiment, 5-fluoro-2-methyl-1-indanone is prepared by reacting an appropriate croton under Frieriel-Crafts conditions for lyophilization; of the desired 'i-I'Lu <> r - I'-rn «_-- thyl-1-indanone, which is further reacted as described (steps 2-5 or 2-U, 6 and 7 in the reaction scheme IN). Finally, in yet another embodiment, the ketone is prepared by reacting the fluorobenzene with an appropriate acid content under Friedel-Crafts conditions to form the desired quota and further reacting the gas. as described (steps 1-U 5 or 1-H, 6 and 7 in Reaction Scheme I). In this step, the Friedel -Crafts reaction can be allowed to proceed so that the intermediate ketone formed is cyclized in situ to 5-fluoro-2-methylindanone.

The preparation of 5-fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) indene-3-acetic acid and its many embodiments can be further described by the following reaction scheme: ...___-___ F_. o,; w a___ t 3 <3) ena I E] ål (S) lm F '= CHCOOH O! / -cH l, / 1 ---- e-> “if R1 = 3'CH3 or O + __ š ~ CH3 -----_..-_-_-_ 7 F.": ÉSÉCOOH CH @ I 0e-s-en T (7) C F- Af- -cH coon \ 0113 ll H få? S-CH 3 3 uuAuTv 10. 15. 20. 25. 30. 35.

H0. 'or was used together with the strong base. ^ liga, to be used. walking material. c base used in 'can be used. The condensation reaction between 5-fluoro-2-methyl-1-Rp-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), especially in the presence of a quaternary ammonium halide such as catalyst (eg trialkyl (C 1-6) benzylammonium halide or tetraalkyl (C 1-6) ammonium halide, eg 0.1 0 mol halide per mole of hydroxide), alkali or alkaline earth alkali metal oxide (C1-5) (NaOCH3) Kt-but: oxide), tetraalkyl (C1-6) ammonium hydroxide or benzyltrialkyl (C1-5) ammonium hydroxides (benzyltrimethylammonium hydroxide can be used) Trialkylbenzylammonium hydroxide or tetraalkylammonium hydroxide is preferably used as the strong base. The reaction can be carried out without solvent, but preferably a solvent is used which is either added to the reaction mixture Acanol (c1-5) (methanol, butanol), aromatic solvents such as benzene, pyridine and toluene or dioxane, acetonitrile, dimethylformamide, triglyme, water methylsulfoxide and mixtures of water and organic solvents can be used. In reality, any solvent in which indene and glyoxylic acid are sufficiently soluble Preferably, the solvent is alkanol (C1-5), especially methanol. The molar ratio "bs" to glyoxylic acid should be at least slightly more than 1 mole per 1, but preferably about 1.1 - about 1.0 moles of base per mole of glyoxylic acid, especially 1.2-2.5.

The molar ratio of glyoxylic acid to indene is not critical and may suitably be about 1- 3.0 moles per mole, preferably about 1.5-1.0 moles of indene. Alternatively, alkali or alkaline earth metal salts or the aryl or alkyl ester, especially the alkyl (C 1-5) ester, i.e. the methyl, ethyl or butyl ester, may be used instead of the free glyoxylic acid or other acid salt of a strong base, such as Under these circumstances, the amount of strong reaction with glyoxylic acid salt and ester need not be more than a catalytic amount, although the stated condition is also the order of addition of the reactants is not critical; however, it is convenient to add the glyoxylic acid compound to the reaction mixture of indene and base. The reaction time is not critical, the reaction being carried out to substantial completion.

However, the reaction is preferably carried out for 15 minutes to about 5 hours, especially about 0.5-3 hours. The reaction can be carried out from about 0 ° C up to about 15 ° C, preferably about 10 ° C, especially 35-60 ° C. b UÅLITY 10. 15. 20. 25. 30. 55- H0. a halogenated hydrocarbon as solvent. After completion of the condensation reaction, the isomerization of the 5-fluoro-2-methyl-1-1 (p-methylthio) or (methylsulfinyl) -benzyl-7-indenylidene-3-acetic acid thus formed in the form of its acid addition salt or ester is performed without insulation, ie. the same reaction mixture from the glyoxylic acid reaction can be used for the isomerization. This is especially true when it is desired to carry out the isomerization under basic conditions, since the reaction mixture from the previous step is already basic and only continued reaction will lead to the isomerization product. On the other hand, other stronger bases for the isomerization may be desired. Bases such as those described for the previous reaction can be used. Preferably, however, the isomerization is carried out using acid and, consequently, the reaction product from the previous step is preferably isolated first. Various organic and / or inorganic acids can be used, e.g. alkyl (C1-5) sulfonic acids (methanesulfonic acid), aryl sulfonic acids (toluenesulfonic acid), acidic ion exchange resins, e.g.

Dowex 50, arylcarboxylic acids (p-nitrobenzoic 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 " acids (preferably alkanoic acids having 2 to 5 carbon atoms), such as hydrochloric acid and acetic acid, hydrobromic acid and propionic acid, the ratio of acid to indenylide is not critical and therefore catalytic amounts of the acid can be suitably used. All that is required is that the reaction mixture be made acid in case it is basic, turn about 0.1-50 moles of acid per mole of indenylidene and especially 1.0-20 moles. When solvents are used, preferably those previously indicated. It is convenient, however, that the reaction can be carried out with or without solvent, and for the glyoxylic acid reaction and which are inert, are used as well as halogenated hydrocarbons such as aliphatic halides (ethylene dichloride) or halogen nobensener. Preferably, the reaction is carried out with an acid or When a weak acid is used as the solvent, it is convenient to also use a strong acid, such as aryl sulfonic acids or mineral acids. For example, he could use unsubstituted alkanoic acids (eg acetic acid) as solvent and arylsulfonic acid (toluenesulfonic acid) and especially mineral acids (eg hydrochloric acid). When halogenated hydrocarbons are used as solvents, it is convenient to use mineral acids as catalysts and especially anhydrous mineral acid, such as c, PO0RM ~, WWwW s nuAuTv in 10. 15. 20. 25. 30. 35- HO. 8107702-6 6 as hydrogen chloride. The reaction time and temperature are not critical; the higher the temperature, the shorter the reaction time required for substantially complete reaction. Accordingly, the reaction can be carried out at a temperature of about 0 to about 15,000, preferably about 50-110 ° C. Similarly, the reaction time is preferably at least 30 minutes and may be up to one or more days. After the isomerization reaction is completed, the product can be isolated by standard techniques, such as filtration, extraction or removal of the acid solvent by evaporation.

When using the p-methylthio compound as starting material, the oxidation of methylthio group to the desired methylsulfinyl group can be carried out at any stage of the reaction process, such as immediately after the reaction with glyoxylic acid or after the isomerization, but the oxidation can be carried out by basic periodates preferably after the isomerization. a number of standard methods, such as oxidation with H 2 O 2, or hypohalite, preferably alkali or alkaline earth metal iodate and hypohalite or organic peracids, such as peracetic acid and monoperphthalic acid. However, the oxidizing agent is preferably H 2 O 2. The reaction is preferably carried out in the presence of a solvent. For such purposes, alkanoic acids (having 1 to 5 carbon atoms, eg acetic acid), halogenated hydrocarbons (chloroform, etrafa (dioxan) alkanols (having 1 to 5 carbon atoms, such as isopropanol) or mixtures thereof may be used.

The molar ratio of oxidizing agent to inner compound may be 0.5-10, but is preferably 0.8-1.5. The reaction time and temperature are not critical, the reaction being carried out to substantial completion. However, the reaction time is preferably 1-18 especially 2-6 hours, at a temperature of 10-8000, especially 25-EOOC.

In the event that it is desired to use an ester of glyoxylic acid, the final free acid compound is readily obtained during isomer hours, the riseration, especially if some amount of water is present and when the isomerization is carried out at elevated temperature. The type of ester used is not critical, as it can be easily brought to that reaction. Accordingly, aliphatic aromatic cyclic esters can be used, e.g. alkyl- (methyl, t-butyl, phenyl, alkenyl) or aryl esters (benzyl, phenyl). Glyoxylic acid salts can also be used, such as pharmaceutically acceptable salts, converted to free acid by hydrolysis, e.g. salts, such as alkali or alkaline earth salts (Na, K, Ca, Li), as well as salts of metals, as previously described in the Friedel-Crafts reaction. g 5-fluoro-2-mecyl-11 "xp-mecylthio) - or (methylsulfinyl-b en- fTJÛOR loose un- or hot- as well as others, which QUALITY 10 15 20 25 30 HO 7 81Û77Ü2-6 _ 5-fhkm- Ethyl [((p-methylthio) - or (methylsulfinyl) -benzyl] -indene can be prepared from 5-fluoro-2-methyl-1-indanone by reaction with a p-methylthio- (or methylsulfinyl) benzyl compound under Grignard or Wittig type conditions. This indene contains the double bond in the 1-2 position. However, under certain conditions, a number of tautomeric compounds are present in its formation. When these isomers are reacted in the presence of a base, as in the reaction with glyoxylic acid, the same indenyl anion is formed which reacts with the glyoxylic acid in the same way, the inner compound being obtained. to react with 5-fluoro-2-methyl-1-indanone under Grignard and Wittig conditions, respectively. ignard reaction, the benzyl-indene compound is obtained directly, while in the wíttig reaction the benzylidene-indane compound is largely obtained. In this latter case, the benzylidene is isomerized to benzyl compound under acidic conditions well known for isomerization.

More specifically, the benzyl group is attached to the indanone compound by a Grignard or Wittig reaction under well known conditions.

In the Grignard reaction, for example, suitable benzyl halide (C1, Br, F, I) [p-methylthiobenzyl halide or p-methylsulfinylbenzyl halide] is added to metallic magnesium in absolute ether and the reaction mixture is preferably heated from 25 to 35 ° C. an equivalent amount of magnesium can be used, it is convenient to use 3-6-fold excess relative to the benzyl halide. commonly used as solvents, other eth- Although more or less than Euru diethyl ethers may be similarly used, e.g. di-n-butyl, diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, U-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxytetrahydrofuran. Tertiary amines such as dimethylaniline, hydrocarbons such as benzene and toluene, as well as many other types of solvents described in the literature may also be used. The Grignard reagent thus prepared can be conveniently used in the obtained state for reaction with the indanone. Indanone and Grignard reagent are mixed (preferably indanone to Grignard reagent) at a temperature of about 0 ° C up to the boiling point of the solvent, preferably 20-35 ° C. achieving the best results, however, approximately equimolar- The complex thus formed is brought to the conclusion that the concentration of the reactants is not critical; for up quantities of each. react, as is usually the case with Grignard reactions, with an acid.

Inorganic mineral acids, such as HCl, HZSOH and phosphoric acids, can be used. POURl QUALITY 10. 15. 20. 25. áo. 55- ÄO. m vis at 25-5o ° c. As well as organic or aliphatic acids, such as acetic acid, propionic acid or methanesulfonic acid. At least a 5 to 10% molar excess of acid relative to complexes is used. It is convenient to add the acid to the reaction mixture of complexes, usually as a dilute solution in water, although other solvents for the acid may also be used. , alcohol- The reaction temperature is usually. for example clays, ethers or aromatic hydrocarbons. usually 0-110 ° C, although 20 ° C is suitable.

In the Wittig reaction, for example, triphenylphosphine or a substituted triphenylphosphine is reacted with the appropriate benzyl halide (p-methylthio- or p-methylsulfinylbenzylhalide) in molten or in the presence of suitable solvents to form intermediates. - acetonitrile or dimethyl pea phosphonium salt. nitrobenzene, xylene (ethers) diethyl ether, (aliphatic), nitromethane, formic acid, acetic acid and ethyl acetate can be used. formamide, tat as well as many others described in the literature. The preparation of the phosphonium salt is carried out at known temperatures, e.g. 0-20000, especially 25-75 ° C, at atmospheric pressure or under pressure. The molar concentration of β-phenylphosphine to benzyl halide may suitably vary from 2 moles to 1 molar, preferably 1.2 moles to 1 molar. to Wittig reagent using either the organometallic or alkoxide method. In the former method, phenyllithium or n-butyllithium is the usual proton acceptor and diethyl ether or the phosphonium salt is not necessarily isolated and tetrahydrofuran solvent is transferred. In the latter method, alkali metal alkoxide can be used as the proton acceptor and corresponding alcohols as the solvent. The wittig reagent is usually not isolated, but is instead allowed to react in the same reaction vessel. The reaction of the bases with the phosphonium salt is suitably carried out on an approximately equimolar basis, although an excess of base can be used to advantage. The reaction can be carried out at a temperature of 0 DEG C. up to the boiling point of the solvent, preferably after the addition of the base, the indanone compound is added, suitably approximately equimolar with the wittig reagent, although more or less can be used. The reaction can be carried out at temperatures of DOC up to the boiling point of the solvent, but preferably 25-50 ° C is used, until the reaction is substantially complete. The intermediate product can then be insulated by standard technology. In cases where the wittig reagent is first isolated, the reaction can be with a variety of inert solvents. * øíïññí fi i 'on r fl uÅusïYee indanone is easily carried out in Such solvents as ether, benzene, ethyl acetate, hexane or petroleum ether, may be suitably used. 5-Fluoro-2-methyl-1-indanone is prepared without a ketone of the formula: ßܶ ~ ê ~ OBG wherein A represents methyl or together with G forms the methylidene, B represents hydrogen, methyl or halogen (Cl, Er, F, I ), G represents methyl or CH 2 R or together with A forms the methylidene, wherein R represents halogen (Cl, Br, F, I), hydroxy, its ethers or esters (such as of alkanols, especially alkanols having 1-5 carbon atoms, alkanoic acids (especially with 2-5 carbon atoms, aromatic acids, especially with 7-9 carbon atoms, mineral acids, eg methanol, propanol, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid and the like) or -N- ( alkyl having 1-5 carbon atoms) 2, especially methyl and ethyl, wherein when A and G together represent methylidene, B represents methyl, when A and G each represent methyl, B represents halogen, and when A represents methyl and B represents hydrogen, G represents CH2R, is reacted under Friedel-Crafts conditions to give 5-fluoro-2-methyl-1-indanone.

The ketone starting material is preferably 2-bromo-H'-fluoro-2-methylpropiophenone, (when A and G each represent methyl and B represents halogen), but may suitably also be: 4'-fluoro-2-methylyrylofenone, 5- chloro-U'-fluoro-2-methyl-propicphenone, U'-fluoro-5-hydroxy-2-methylpropiophenone or 3-dimethylaH-n-β'-fluoro-2-methylpropiophenone. grind Friedel-Crafts conditions. react in the presence of such Friedel-Crafts catalysts as Leele Ketone is brought, for example, to the reaction is conveniently carried out under nor- - .. rg acids, metal alkyls and alkoxides, Bronsted acids, acid oxides and sulfides, cation exchange resins, metathetic cation-forming agents and stable carbonium complexes and related complexes.

Lewis acids such as those of acid halide type (metal halides), e.g. aluziniun chloride or bromide, BeCl2, GaBr3, and UClu can be suitably used.

CdCl2, ZnCl2, TiClu, Tißru, ZrClu, SnClu, Snßrn, SbCl5, SbCl3, šiCl5 When the ketone is M- or fi-halo- EFï, ECl5, BBr :, Gafl 7. z 3 ß Peel, .l gene-isobutyrophenone, For example, the metals as such can also be used as catalysts, since during the course of the reaction the halogen compound reacts with the metal to form the corresponding metal halide, which in turn aids in the progress of the reaction. as in This class of Friedel-Crafts catalysts is suitable and especially the use of an aluminum or iron halide.

Metal alkyl and in QUALITY fe 8107702-6 10 10. 15. 20. 25. 50. 35 -alkoxides which may be suitably used are, for example, aluminum or boron alkyls (methyl, ethyl, propyl) or alkoxides (methoxide, ethoxide or propoxide). Bronsted acids which may be suitably used are, for example, sulfuric acid, phosphoric acid, polyphosphoric acid, superchloric acid, chlorosulfonic acid, fluorosulfonic acid, alkyl and aryl sulfonic acids (ethane, p-toluene) and related aromatic sulfonic acids as well as chloroacetic acid and trifluoroacetic acid. Acidic oxides and sulfides, which are useful as catalysts, include a wide variety of solid oxides and sulfides. Of particular utility are aluminum, silica and mixtures of aluminum and silica, although catalysts other than silica-aluminum compositions such as BeO, Cr 2 O 3, P 2 O 5, 11102, Thea, A 12 (so 3), A 12o 3 'x crzoš, Aizoš' Fezoš, A120; leo, Al 2 O 3, MnO, Al 2 O 3, Vl 2 O 3, Cr 2 O 3, Fe 2 O 3, MoS 2 or MOS 3 can also be used; In addition, cation exchange resins, which are solid acids, are useful as catalysts as well as metathetic cation-forming agents, such as anhydrous silver salts (AgClO 3, AgBFu, AgSbF6, AgPP6, AgAsF6 and Ag3POu).

Although the concentration of the Friedel-Crafts catalyst is not critical, it is convenient to use 1.1-2.0 moles of catalyst per 1 mole of ketone, preferably 1.0-1.8 moles per mole of ketone. The reaction is conveniently carried out in a solvent normally used for Friedel-Crafts reaction. Accordingly, such organic solvents as CS2, fluorobenzene, polyhalogenated aromatic hydrocarbons, nitrobenzene, aliphatic hydrocarbons, halogenated, aliphatic hydrocarbons and nitroalkanes are suitable. The reaction is carried out at a temperature of about 150 DEG C., preferably 20 DEG-100 DEG C., for a sufficient time to substantially complete the reaction. The ketone starting material is readily prepared by condensation of a suitable acid halide of the formula: A O | II G - C - C - Z 2 B wherein A, B and G have the meanings indicated and Z represents halogen, with fluorobenzene under Friedel-Crafts conditions as described. The acid halide may optionally be further condensed with the fluorobenzene to form the ketone and in situ directly to 5-fluoro-2-methyl--1-indanone. In the event that this process is desired, additional Friedel-Crafts catalyst was used in sufficient quantity to perform the two steps. i PÛOH HUALIW 10. 15. 20. 25. 30. 35- H0. The invention is described in more detail in the following examples. A mixture of H5.7 g (0.5 mol) of U 'fluoropropiophenone, 9 g (0.5 mol) of paraformaldehyde, M g (0.03 mol) of anhydrous potassium carbonate and 200 ml of methyl alcohol is stirred at 3500 in 2 days. The reaction mixture is quenched in water and acidified with hydrochloric acid.

The product is extracted into benzene. The benzene layer is washed with water and concentrated in vacuo to give E'-fluoro-3-hydroxy--2-methylpropiophenone.

EXAMPLE 2 5-Fluoro-2-methyl-1-indanone from H'-fluoro-3-hydroxy-2-methyleneeneene A mixture of 18.2 g (0.10 mol) of ε'-fluoro-3 -hydroxy-2-methylpropiophenone and 12 g of phosphorus pentoxide in 100 ml of xylene are refluxed for 1 hour. The reaction mixture is cooled, water is added and the xylene layer is washed with aqueous sodium hydroxide and water.

The organic layer is then concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

A slurry of 14 g (1.05 mol) of anhydrous aluminum chloride in 11U, Hg (0.150 mol) of fluorobenzene and 2u ml of carbon disulfide is cooled to 155 ° C. To this is added 23.8 g (0.100 mol) of c-bromoisobutyryl bromide in 10-15 minutes at 15-2000. The reaction mixture is stirred for 5 minutes at 20 ° C and then cooled on ice. roform. The chloroform layer is washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to The product is extracted into chloroformation of 2-bromo-H'-fluoro-2-methylpropiophenone.

EXAMPLE M. 5-Fluoro-2-methyl-1-indanone from 2-bromo-M'-fluoro-2-methylene etherene ______________________________________________ __ A slurry of 120.2 g (0.90 mol) of anhydrous aluminum chloride in 5U ml carbon disulfide was added with 122.6 g (0.50 mol) of fluoro-2-methylpropylphenone at 15-20 ° C in 1 hour. The mixture was heated to 5000 in 1 hour, heated at 5000 for 5 hours and quenched in ice.

The toluene layer is washed with water-2-bromo-10 'The product is extracted into toluene. sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone. §ŠšE3§L_â- El: §luer: ê: @ e§xle5§xl9§en9a A slurry of 29, H g (0.220 mol) anhydrous aluminum chloride in 58, U g (0, U0 mol) fluorobenzene under nitrogen is cooled to 15 ° C.

Methyl acrylate chloride (2.1l, 0.200 mol) is then added dropwise in 50 minutes, keeping the temperature at 15-2000. Mixture POORW "QUALITY 8107702-6 12 10. 15. 20. 25. 50. 35.

H0.

ExEuPEL v.

EXAMPLE 8.

EXAMPLE 9 is heated to 5000 in 10 minutes, heated at 3000 for 10 minutes and quenched on ice. The product is extracted into hexane. The hexane layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give H'-fluoro-2-methyl-acrylophenone.

EXAMPLE 6 5-Fluoro-2-methyl-1-indanone from 4'-fluoro-2-methyl-acrylophase; ______________________________________________ __ 50 g (0.30 mol) of H'-fluoro-2-methyl-acrylophenone are added to a slurry of 60.1 g (0.5 mol) of anhydrous aluminum chloride in 27 ml of carbon disulfide in 1 hour at 20-25 ° C . The mixture is heated to 4500 for 1 hour and stirred at USOC for 1 hour. The reaction mixture is quenched with ice. The oily aqueous layer is extracted with toluene. The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

To a slurry of 22.7 g (0.7 mol) of anhydrous aluminum chloride and 9.6 g (1.0 mol) of fluorobenzene is added 11.1 g (1.0 mol) of 5-chloroisobutyryl chloride in 30 minutes at 20-25. ° c. The mixture is allowed to stand for 50 minutes at 20-2500 and then quickly 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-1H-fluoro-2-methylpropiophenone. 5-fluoro-2-methyl-1-indanone from 3-chloro-H'-fluoro-2-methyl-2r92i9§§§9§ ______________________________________ __ 10 g (0.05 mol) of 3-chloro-H'-fluoro- 2-Methylpropiophenone was added to 20 ml of conc. sulfuric acid at 20-2500 and the mixture is heated to 5000. After stirring for 3 hours at 5000, the mixture is quenched with ice.

The product is extracted into hexane. to form 5-fluoro-2-methyl-1-indanone.

The hexane layer is concentrated in vacuo. A mixture of 15.2 g (0.1 mol) of H'-fluoropropiophenone, 8.2 g (0.1 mol) of dimethylamine hydrochloride, 3.6 g (0.2 mol) of paraformaldehyde in 20 ml of abs alcohol The mixture is stirred at 95 DEG-10 DEG C. for 3 hours. The mixture is cooled and the precipitated product is filtered off. The product is dissolved in water and 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-H'-fluoro-2-methylpropiophenone.

EXAMPLE 10 5-Fluoro-2-methyl-1-indanone from 5-dimethylamino-B'-fluoro-2-ethylene ethylene _______________________________________ - A mixture of 42 g (0.20 mol) of 3-dimethylamino-H'-fluoro-2- 15. 20. 25. 30. 35- HO.

EXAMPLE 12. Methyl propiophenone and 100 ml conc. sulfuric acid is heated to 9000 for 1 hour and stirred at 9000 for 2 hours. The reaction mixture is cooled and quenched with ice and the product is extracted with toluene. the layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.

EXAMPLE ll. 5-fluoro-2-methyl-1-indanone from fluorobenzene and W-bromoiso-Toluene- To a slurry of 120.2 g (0.90 mol) of anhydrous aluminum chloride in 54 ml of carbon disulfide and 5.1 g (0.535 mol fluorobenzene under nitrogen is added 115 g (0.50 mol) of G-bromoisobutyryl bromide. The addition is completed in 75 minutes at 15-20 ° C. The reaction mixture is heated to 50 ° C in 75 minutes, stirred at 50 ° C for 3.5 minutes then rapidly quenched with ice. Toluene is added to extract the product.

The toluene layer is washed with aqueous sodium hydroxide and water and concentrated in vacuo to give 79 g (96%) of 5-fluoro-2-methyl-1-indanone. â: §l! 9 :: ê: me§xl: l: š2: e§§2l§i9ë§n§ill: ànëen 25 g (1.0 U mol) of magnesium turning chips were introduced into a dried flask under nitrogen together with 400 ml ether. 10 ml of 0.05 M p-methylthiobenzylmagnesium chloride in ether was added and the mixture was heated to 3000. About 2-3% of 39.7 g (0; 23 mol) of p-methylthiobenzyl chloride in 75 ml of toluene were added. After stirring for 3-5 minutes, an exoteric reaction to 32-3500 occurs, which indicates the initiation of the reaction.

After standing for 5 minutes, the remainder of the benzyl chloride is added dropwise over 90 minutes. The reaction mixture is allowed to stand for 50 minutes with stirring. 5-Fluoro-2-methyl-1-indanone (32.6 g, 0.199 mol) is added dropwise. After standing for 30 minutes, the milky, supernatant flask and residual magnesium are decanted off in H5 minutes. took the mixture from the magnesia. rinse with toluene. The reaction mixture is then quenched by the addition of 120 ml of 3 N sulfuric acid.

To the organic layer is added 80 ml of a 1:10 mixture of The lower layer is discarded. The sulfuric acid and acetic acid and the two-phase mixture are stirred vigorously for 1 hour and water (100 ml) is added. The bottom layer is discarded and the organic layer is washed with 100 ml of water and 200 ml of 2 K rium hydroxide. After final water washing, the organic layer is concentrated to give 5-fluoro-2-methyl-1% p-methylthiobenzyl) -indene. When p-methylsulfinylbenzyl chloride is used instead of p-methylthiobenzyl chloride in this example, the corresponding p-methylsulfinylbenzylindene is similarly obtained.

EXAMPLE 13. n-Methylthiobenzyltriphenylphosphonium chloride _ _ _ _ _ _ _ _ _ _ _ _ _ _ __u ___-________-___ nun gïjkl fl v 10. 15. 20. 25. 30. 35.

EXAMPLE 15. 8107702-6 N in 80 ml of benzene. The reaction mixture is heated for 4 hours and then cooled; the product, p-methylthiobenzyltriphenylphosphonium chloride, is collected by filtration. 19 g are obtained, m.p. 257-258 ° C.

When p-methylsulfinylbenzyl chloride is used, the product is similarly p-methylsulfinylbenzyltriphenylphosphonium chloride, m.p. 258-262 ° C (during gas formation).

EXAMPLE 14. 169 mg (1.5 mm) of potassium t-butoxide are dissolved in 2 ml of DMSO and treated with 651 mg (1.5 mmol) of p-methylthiobenzyltriphenylphosphonium xloris, dissolved in 1 ml of DMSO. To this solution is added 20 mg (1.65 mmol} of 5-fluoro-2-methyl-1-indanone in 2 ml of DMSO for 15.5 hours. Benzene and water are added and the benzene layer is washed five times with water. The benzene layer is dried over Na2SO3 and in- The residue weighs 915.6 mg.

The solution is heated at 7500 evaporated to dryness under vacuum. This material is eluted through 8 g of silica gel with benzene to remove triphenylphosphine oxide. The eluate wets 372 mg after removal of the reader. This is rechromatographed through 15 g of silica gel using hexane and 95.9 mg of 5-fluoro-2-methyl-1- (p-methylthiobenzidene) -indane is isolated, m.p. 67-70 ° C. §L__5: f; u9 :: š: re§xl:;: íezweëxlëieeešlllzisese 50 mg of benzylidene compound from A is mixed with 1 ml of acetic acid, containing 100 mg of sulfuric acid, and the reaction mixture is stirred for 1 hour at room temperature. The mixture is then diluted with water and extracted with ether. The ether extract is concentrated in vacuo to give the title compound. When p-methylsulinylbenzyl-triphenylphosphonium chloride is used, the corresponding;-ethylsulfinylbenzylindene is similarly obtained. 5: šlëer: š: @ §§xl: l: íe: @ §ëxlëslfiazëäsaëxllzizies 500 mg (1,755 mm) 5-fluoro-2-methyl-1- (p-methylthiobenzyl) -inie: dissolved in 5 ml of chloroform. To this solution is added 30% v peroxide (equivalent to 2.645 mmol). The reaction mixture is allowed to stand for 1 hour at room temperature and then 5 ml are added and the mixture is allowed to stand for a further 1 hour. The reaction mixture is then purged with 25 ml of a 1: 1 mixture of benzene and ether with 6 x 25 ml of 3% aqueous sodium chloride. and extracted. The solution is then dried over sodium sulfate and evaporated in vacuo to give an oil. Recrystallization from ice-cold isopropanol; 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -indene. / j / l i Poon uuAL fl Y i i 10. 20. 25. 30. 35- U0. 8107702-6 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) -indenylidene-3-acetic acid To Ul, 8 g (1H7 mmol) of the preceding indene (from Example 12) was added 150 ml of methanolic solution of Triton B (53.2 g, on a dry basis; 317.5 mmol) and the batch are brought under nitrogen to 3500. 1.63 g of glyoxylic acid (198 mmol) are added and the batch, which is heated to 50-5500, is allowed to stand for 1 hour at 50 ° C. It is then diluted with 250 ml of water. The product obtained in 90 EXAMPLE 16 and acidified with dilute sulfuric acid. percent yield, recrystallized to give pure product, melting at 185.5 ~ 188 ° C.

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

When 5-fluoro-2-methyl-1db-methylsulfinylbenzyl) -indene is used instead of the corresponding methylthio compound in this example, 5-fluoro-2-methyl-1- (p-methylsulfinylbenzyl) -indenylidene-3 is similarly obtained. -acetic acid.

EXAMPLE 17. 5-Fluoro-2-methyl-1- (p-methylthiobenzyl) -indenylene-3-ethylene α A suspension of 34.2 g of 5-fluoro-2-methyl-1- (p-methylthiobenzyl) indenylidene-3-acetic acid (from example 16) in BÄ2 ml glacial acetic acid and 157 ml concise hydrochloric acid is stirred under nitrogen for 10 hours at 9000. The mixture is cooled in 2-5 hours to room temperature and allowed to stand for a further 3 n at 20-25 ° c. the batch is filtered, washed with a To; mixture of acetic acid and water (about 100 ml) and water. 95 Reaction is obtained, then to remove excess acid. ; product, melting at 180-183 ° C.

When 5-fluoro-2-methyl-1- (p-methylsulfinyl) -indenylidene-3-acetic acid is used in this example instead of the corresponding methylthio compound, 5-fluoro-2-methyl is similarly obtained. -1- (p-methylsulfinylbenzylidene) -indene-5-acetic acid. The reaction can be carried out in an aprotic solvent such as 1,2-dichloroethane under an overpressure of 69a kPs hydrogen chloride at 50-100 ° C. 18. 5-Fluoro-2-methyl-1- (p-methylsulfinyltensylidene) -indene- ZÉIÉÉÉEKÉXFÉ _______________________________________- 17 g (50 mmol) of the product from Example 17 are stirred in 95 nl of rryzrifa-.rr Lis-La. .m æJ-J Chloroform and ÄO ml acetic acid under nitrogen and the temperature is cringed to 3000. To this slurry is added 5.5 ml 9.6 N aqueous Nalt HZOZ (51 mm ° 1) In 1 min- The temperature is brought to 3500. The batch is allowed to stand for a total of 6 hours and kept at 3500 internal temperature. After P, 125 ml of water are added and the chloroform layer is concentrated to a The residue is crystallized from 75 nl of ethanol in a small volume under vacuum.

* ,, Eíii- "j_H" fl um fi v 8107702-6 10. 15. 20. 25. 50. 35- HO.

EXAMPLE 20. 16 and the slurry is cooled to 0-5 ° C and allowed to stand at 0 ° C. The filtrate is filtered and washed with 15 ml of cold (0-500) 23A ethanol and (Product dried under vacuum at 80 ° C. The product weighs 16.5 g 922), m.p. 183-185 ° C.

When sodium periodate or potassium hypochlorite is used in place of hydrogen peroxide in this example, the desired compound is similarly obtained. ššEEÉEQ_l2- ______________ __ A slurry of low (0, 105 mol) of anhydrous aluminum chloride in 11U, Bg (0.150 mol) of fluorobenzene and Zü ml of carbon disulphide is cooled to 115 ° C. To this is added 0.100 mol of Gidinethylaminomethyl) -propionyl bromide-nyarobromide in 10 minutes at 15 DEG-20 DEG C. for 5 minutes at 2 ° C and then rapidly cooled on ice.

The chloroform layer is washed with aqueous ..._____..__ .. ~ ._._ ..._-___- The reaction mixture is stirred. The product is extracted into chloroform. sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated to give 2-bromo-U'-fluoro-2-methylpropiophenone. §: §la9§: ê: ma§zl: l: ío: @ §§zl§ieteeoëzll: inden l3,4H g (0,56 mol) magnesium turnings are introduced into a dried flask under nitrogen together with 125 ml of ether and an iodine crystal . 6 ml of a 65 ml solution of 2M, 2 g (0.1 mol) of p-methylthiobenzyl chloride in ether are added. the reaction begins.

After stirring for 3-5 minutes, the iodine color disappears and after standing for 5 minutes, the residue is added. It is rinsed with 1 g of ether 21 g (C, 228, 50 ml of ether), the benzyl chloride is added dropwise at H5 minutes and the reaction mixture is allowed to stand for 2 hours with stirring. nol) 5-fluoro-2-methyl-1-indanone, dissolved in sieve for 30 min. After standing for 1 hour, the milky mixture taken from the magnesia is decanted into 103 ml of acetic acid. The remaining magnesium is rinsed in the acidic solution with Ä x EC 290 ml of water are added, the layers are separated and the organic skirt is washed with 5 x 200 ml of water. drying over Na 2 SO 4. The crude reaction product is crystallized from Bet and evaporated to dryness by Lexan to give pure 5-fluoro-2-: ethyl-1- (p-methylticbenzyl) -indene H + melting point 58-59 ° C.

EXAMPLE 21. 5-Fluoro-2-methyl-1- (p-methylthiobenzylidene) -indene-3-ethylene .......................... ............ _- A suspension of BH g 5-fluoro-2-methyl-1- (p-methylthiohensyl} - indenylidene}} acetic acid in 150 ml of ethylene dichloride is heated to 73 ° C in Anhydrous hydrogen chloride is added until: the jerk reaches 655 kPa. The reaction mixture is stirred under these conditions for 10 hours and the excess base is then deaerated. The slurry product is cooled to 0-5 ° C and filtered after 1 h and washed with (I) s irrifíññí ”uuAuTv freshly prepared ethylene dichloride 8107702-6 17 Product yield is 80%.

Claims (2)

8107702-6 H; _ Patent claims A process for the preparation of 5-fluoro-2-methyl-1- (R 1 -benzyl) -indene, wherein R 1 represents p-methylthio or p-methylsulfinyl, characterized in that an acid halide of the formula: å * f? G ~ C - C - Z 1% wherein A represents methyl or together with G forms the methylidene, B represents hydrogen, methyl or halogen, G represents methyl, CH 2 R or together with A forms the methylidene, wherein R represents halogen, hydroxy, its ethers or esters or -N- (C 1-5 alkyl) 2, Z represents halogen and wherein (1) when A and G together represent methylidene, B represents methyl, and wherein (2) when A and G each represent methyl, B represents halogen and wherein (3) when A represents methyl and B represents hydrogen, G represents CH 2 R, gas is reacted with fluorobenzene under Free-1-Crafts conditions to form 5-fluoro-2-methyl-1-indanone and that -5-fluoro -Z-methyl-1-indanone is reacted with a R1-benzyl compound, wherein R1 is as defined above, under Grignard or Wittig conditions. 2. A process according to claim 1, characterized in that the acid halide is an α-haloisobutyryl halide, preferably u-bromoisobutyryl bromide. 8107702-6 17 freshly prepared ethylene dichloride. The product change is' 80 7D.