PL102696B1 - METHOD OF PRODUCTION OF 5-FLUORO-2-METHYL-1- / P-METHYLSULFINYLBENZYLIDENO / -INDENYL-3-ACETIC ACID - Google Patents

Description

The subject of the invention is a process for the preparation of 5-fluoro-2-ime'-ethyl-1- '(p-methylsulfinyl-benzylidene) -indenyl-3-acetic acid. The above-mentioned acid is a known anti-inflammatory compound described in the patent specification. 5-tier St. US Am. No. 3,654,349. Hitherto, the above compound has been prepared by the Glaisen reaction by condensing an appropriately substituted benzaldehyde with an acetic acid ester or by using the Reformatsky reaction to condense benzaldehyde with an α-halopropionic acid ester. The obtained unsaturated ester was subjected to reduction and hydrolysis to obtain / arylpropionic acid, and then after closing the ring, indanone was obtained, to which the side chain was substituted in the Reformatsky or Wittig reaction. The idenoacetic acid or ester thereof is obtained, to which the substituent at position 1 is introduced by reaction of the above acid or ester with an aromatic aldehyde or ketone, and then, after dehydration, the desired iidene acetic acid is obtained. is a new method for the production of 5-fluoro-2-methyl-1-acid. According to the process according to the invention, the said compound can easily be obtained by treating the 3,3'-O-ethylene ketai 6 fluoro-2-methylin- The 1,3-danedione is reacted with the factor introducing at the 3-position acetic acid residues, and then in situ cleaves the protective ketal group and gives 5-fluoro-2-methylind-2-en-1-one-3 acid acetic acid which is isolated from the reaction mixture. The end product is obtained by the nuMeophilic addition of a p-methylsulfinylbenzyl derivative to the carbonyl group of 3-fLuoro-2-metholind-2-en-l-one-3-acetic acid or its ester and, if necessary, after hydrolysis of the ester group Condensation to introduce into the 3-position as acetic acid side-chain in the 3,3'-O-ethylene ketal of 6-fluoro-2-methylindandione-1,3 can be carried out using a number of well-known reactions, such as the reaction Reformatsky, Wittig, Knosvenagel modification, Stobbe reaction, reaction with cyanoacetic acid, Watermelon reaction or reaction with organolithium compound. For example, condensations can be carried out using the Reformatsky reaction, in which the ketone in question is reacted with chloroacetate in the presence of zinc dust and iodine in an inert solvent such as benzene, ethyl ether, tetrahydrofuran, dioxane or hexane. San, at a temperature of about 0-100 ° C for 1-6 hours. Preferably, the process is carried out with an alkyl bromoacetate having 1-5 carbon atoms, e.g. methyl or ethyl, or alkenyl bromoacetate with 2-5 carbon atoms. in diethyl ether or tetrahydrofuron at 20-40 ° C for 6-18 hours. The concentration of the reactants is not critical, but it is preferable to use 2 to 4 moles of the Reformatant. The obtained product is dehydrated by using any of the known dehydrating agents such as phosphorus pentoxide, phosphorus pentachloride, polyphosphoric acid or p-toluenesulfonic acid at 50-120 ° C for 0.1-5 hours in an inert solvent such as (benzene, toluene or xylene). However, it is preferable to dehydrate by using polyphosphoric acid in benzene or toluene at a temperature of 80-90 ° C. for 0.25-2 hours. The amount of the dehydrating agent is not critical, but it is preferable to use 10-W moles for one mole of the suffosit. Condensations can also be carried out under the conditions of the Wittig reaction. To this end, a phosphonium halide is reacted with a strong base to give a phosphate which treats the 3,3'-O-ethylene ketal of 6-fluoro-2-methylindanedione-1,3 to give the 5-fluoro-2-methylindione acid ester -2-en-l-one-3-acetic. The phosphonium halide can readily be obtained by reacting a trisubstituted phosphine such as triphenylphosphine, tricycloexylphosphine, or tribenzylphosphine with an alkyl, aryl or aralkyl haloacetate. The process is carried out in a closed vessel for 1-48 hours at a temperature of 0-100 ° C. The haloacetate ester fragment is not critical, as it serves only as a protective group and is cleaved in the last stage. process pie. It may therefore be any organic ester group, such as an alkyl, preferably with 1-5 carbon atoms, e.g. methyl, ethyl or butyl, aralkyl, such as phenylethyl with 7-12 carbon atoms. for example benzyl or phenethyl, aryl such as phenyl or alkenyl having 2 to 5 carbon atoms. An alkyl group having 1-5 carbon atoms is preferred, especially methyl or benzyl. Chloroacetate or ibromoacetate can be used as the chloroacetate. An alkyl chloroacetate of 1-5 carbon atoms is preferred, especially methyl chloroacetate or methyl bromoacetate. The phosphonium halide is first reacted with a strong base such as, for example, n-phthyllithium in hexane. or diethyl ether, sodium amide in liquid ammonia, or sodium hydride in ether or tetrahydrofuran. It is preferable to use n-butyllithium in ether or tetrahydrofuran at a temperature of - <80 - + SO ° C, and to carry out the reaction for as long as it is needed to proceed, for example 0.5 to 6 hours. . The concentration of the base and the phosphonium halide is not critical, e.g. 1 to 1.5 moles of the base can be used per mole of phosphonium halide, but it is preferable to use 1.1-1.2 moles of Wittig's reagent for higher yields. . The phosphate obtained in this reaction can be isolated and used as described hereinafter, but it is preferable to use 6-fluoro -2-methylindione-1,3-dione-1,3'-01-ethylene directly without isolation. . or 5-fluoro-2-methylin-4-dione-1,3-dione. The process is carried out in an inert solvent at a temperature of -80 - + £ 0 ° C. preferably -80 (-50 ° C, within) 0.5-24, preferably 0.5-6 hours, the 5-fluoro-2-methylindan-1-one-3-acetic acid ester is obtained, if necessary, it is isolated using known methods. The concentration of the reactants is not critical, but it is preferable to use 1.1-2 moles of pho- and phosphonium compound per mole of 1,3-indanedione in order to obtain a higher yield. In another condensation process, the 3,3'-O-ethylene 6-fluoro-2-methylindanedione-1, S or 5-fluoro-2-methylindanedione-1,3 ketal is reacted with cyanoacetic acid in neutral solvent, at an elevated temperature of 100-200 ° C., preferably at a temperature close to the boiling point of the solvent. The water that evolves in the reaction can be easily removed using known methods, for example by azeotropic distillation with a solvent. Although the reaction time is not critical and may be 12 to 36 hours, it is preferable to run the process until all water is removed. The ratio of cyanoacetic acid and 1,3-indandione concentrations may be approximately molar, but it is preferable to use 1.1-1.7, especially 1.1-1.5 moles of cyanoacetic acid per 1 mole of indanedione. -1.3. Obtained 3,3'-O-ethylene ketal of 6-fluoro-2-methylind--2-eri-l-one-3-acetic acid or 5-fluoro-2-methylind-2-en-l-one -3-acetic acid is esterified to protect the carboxyl function during a step nucleophilic reaction. low, ethyl, butyl; aralkyl, for example phenylalkyl having 7 to 12 carbon atoms, such as benzyl or phenethyl; aryl, e.g. phenyl alkenyl of 2 to 5 carbon atoms. An alkyl group with 1-5 carbon atoms is preferred, especially a methyl group or a benzyl group. The esterification process is carried out by reacting 3-acetic acid with a suitable alcohol, preferably aliphotic with 1 to 6 carbon atoms, such as methanol, ethanol, T-butanol and the like in the presence of a strong organic or inorganic acid, for example concentrated sulfuric acid, gaseous hydrogen chloride or p-toluenesulfonic acid, or in the presence of dicyclohexylcarbodiimide. The ratio of alcohol to acetic acid may be 1-100, preferably 10-20, moles of alcohol per 1 mole of acid. toluene or xylene, or using an alcohol as a solvent. In another other condensation method, the 3,3'-O-ethylene 6-fluoro-2-methylindanedione-1,3r ketal is reacted with a malonic acid ester * 60 in the presence of strong base and gives the corresponding arylidenemalonic acid diester. or 1H-tibutyl, phenyl, e.g. benzene or phenethyl or another phenyl group substituted alkyl group with 1-5 carbon atoms. , tetrahydrofuran, liquid ammonia In the case of a sodium midide or III-th. butanol in the case of using potassium tert-butaxylate. A strong base is used as a base, such as an alkali metal or alkaline earth metal alkoxide, alkali metal hydroxide, sodium amide, sodium hydride, potassium tert-oxyate or sodium metal, preferably an alkali metal alkoxide of 1 to 5 carbon atoms, e.g. sodium ethophysylate or methoxide. The process is carried out at a temperature of -80 HlMO, preferably 60-80 ° C. The concentration of suffostrates and base is not of essential concentration, therefore 1 to 2 moles of ester per 1 mole of dione, preferably 1-1.5 moles, and 1.0-5.0 moles of base per 1 mole of ester, preferably 1, may be used. 0 → 1.1 mol. The obtained aryiidene compound is decarboxylated using known methods such as heating in the presence of an organic or inorganic acid, e.g. . Benzene, toluene and Hub xylene can be used as inert solvents. However, it is preferable to carry out the reactions in the presence of an aqueous solution of an inorganic acid, e.g. hydrochloric acid, which acts as both an acid and a solvent. The concentration of the acid is not critical, but its quantity (it should be sufficient to acidify the mixture). is carried out near or at the boiling point of the solvent until the evolution of carbon dioxide ceases. The resulting 5-fluoro-2-methylind-2-eh-1-one-3-acetic acid is esterified using the methods described above. also before the decarbofcsylation process, carry out the reactions with the malonate under the conditions of the Grignard or Wittig reaction and only then decarfoxylation. 1,3-methylindanedione-1,3-or 5H-fluoro-5-imethylindanedione-1,3 is treated with a trialkoxy anion by reacting a tralkoxy or monoalkoxydiaryl oxyphosphonoacetate with a very strong base in an inert solvent at. The temperature of the process is between 0 and 100 ° C, preferably between 2 and 30 ° C. The solvent used is benzene, hexane, heptane, ethyl ether or tetrahydrofuran. The phosphonate used is a trialkoxyphosphonoacetate at 1-6 carbon atoms in the alkoxy group, such as methyl, ethyl, propyl, methophenyl, ethdxyl or Alkali metal hydrides such as sodium or potassium hydride, alkali metals in benzene, butyimite, sodium amide in liquid ammonia and similar substances capable of producing anion. The reaction time is 1-12 hours, preferably up to 4 hours. The concentration of phosphonoacetate, strong base and indanedione-1,3 are not critical values. 0.5-2 moles of phosphonoacetate per 1 mole of indanedione, especially 1-11.2 moles per mL. The obtained 3,3'-ethylene ketal ester of 6-fluoro-2-methylindenyl-3-acetic acid is reacted with an aqueous solution With an inorganic acid to give the 5-fluoro-2-methylind-2-en-1-one-3-ocuic acid ester and the ester group serves only as a protection of the carboxylic function during subsequent reactions and may be one of many forming an ester of groups, such as alkyl, preferably with 1-5 carbon atoms, e.g. methyl, ethyl or butyl, arylalkyl, such as phenylalkyl with 7-12 carbon atoms, e.g. benzyl or phenethyl, alkenyl with J21-6 atoms carbon or acrylic, e.g. phenyl. An alkyl group with 1 to 5 carbon atoms is preferred, in particular methyl benzyl alba. the reaction with the p-methylsulfinylbenzyl derivative is not essential. They may be alkyl, alkenyl, aryl, arylalkyl or heterocyclic esters. However, alkyls with 1-5 carbon atoms, such as methyl, propyl and tert-butyl, aralkyl esters, such as e.g. benzyl or alkenyl with 2 to 5 carbon atoms, for example vinyl or ip-tri-phenyl. The nucleophilic attachment of the p-methylsulfinylbenzyl derivative is readily accomplished under Grignard or Wittig reaction conditions. In yet another condensation method, the dione or ketal is reacted with a lithium compound in the formula given in the figure where X is a pe-COOR group. -ON or a group of the formula —CON in which R 2 is hydrogen, an alkyl group * preferably 1 to 5 carbon atoms, an alkali metal or alkaline earth metal atom or an aralkyl group, preferably phenyl substituted with 45 alkyl groups with 1-5 carbon atoms, especially benzyl; Rj and R2 represent an alkyl group, preferably with 1-5 carbon atoms, aryl, arylalkyl, preferably phenyl (substituted alkyl group with 1-5 carbon atoms) , or substituted alkyl, aryl or aralkyl, or Rx and R * together form a cycloalkyl group, preferably of 4-6 carbon atoms; Y is a hydrogen atom, a group of the formula MOR, or a group of the formula -Si-J * IIO $ 5 wherein R4 is an alkyl group with 1 to 5 carbon atoms, phenyl or benzyl, or a substituted alkyl, phenyl or benzyl group, especially methyl. Preferably, if Y is hydrogen, x has the meaning given above, especially is a group of formula - "COOR" and R represents an alkyl group of 1-5 carbon atoms, an alkali metal or alkaline earth metal, and in particular a tert-tutyl group, alpha sodium or es lithium; if Y represents a group of formula COOM and M is a hydrogen, alkali metal or alkaline earth metal group, and if Y is a group of formula -SiCR, X is a group of formula -COOR, wherein R represents (alkyl, especially methyl or ethyl. The lithium compounds are readily prepared as described in the following publications: J. Am. Chem. Soc., 89, 2600- ^ 2501 (1967); J. Org. Chem., 36, Il51 <1971); J. Am. Chem. Soc, 92, 1396-1397 (11970); J. Am. Ohem. Soc, 95,3050O973); Tetrahedron Letters, Nos. 9, 711-7131 (1974) and J. Am. Ohem. Soc., 96, 5 (1974). Compounds of the formula Li-CH2-X are obtained e.g. as follows. One equivalent of acetic acid is added to a suspension of sodium, potassium or lithium alpha amide hydride in tetrahydrofuran, heated to 40 ° C., cooled and 1 equivalent of lithium butyl at 10 ° C. is added to obtain lithium enolate. The suspension of the lithium compound obtained can be used without isolation for the reaction with the appropriate indanone. Likewise, lithium tertiary butyl acetate, lithium methyl acetate, lithium benZyl acetate, lithium acetonitrile or lithodimethylacetate can be obtained. The n-foutyl lithium and diisopropylamine in nexane are cooled in a bath with dry ice and acetone, the appropriate acetic acid derivative is added and the mixture is stirred for minutes. The product obtained can be used without isolation for the reaction with indanone. The compound of formula I, in which Y is a group of formula -P-II with -OOOH, is obtained by treating at -80 ° C on the substituted Mb with unsubstituted dialkyl or diphenzyl phosphorus, especially for the latter, with methyllithium in tetrahydrofuran followed by the addition of methyl iodide "** carbon dioxide. The dubenzylphosphonoacetic acid is obtained. X represents a group of the formula hOOOR, in which R is an alkyl group, by treatment with a tri-alkyl, phehyla or benzylsilyl acetate, preferably trimethylsilyl acetate, lithium dicyclohexylamide in anhydrous tetrahydrofuran at -70 ° C. The condensation of the dione or ketal with the lithium compound is carried out in an inert solvent such as an aromatic hydrocarbon having 6-12 carbon atoms or an aliphatic hydrocarbon having 5-15 carbon atoms, e.g. benzene, toluene, hexane, nonane, and similar, or in pos with up to 10 carbon atoms such as tetrahydrofuran, diethyl ether, diethoxyethane and the like, or in solvents used to prepare enols. The process is carried out by mixing the lithium compound f. injdione in an inert solvent at a temperature of -80 - + and GUQC, preferably -10-4-40 ° C. Although the molar ratio of lithium to indanodicm is not critical, it is preferable to use a slight volatile excess of lithium of 1-1.2 moles. • S If a compound of the formula Li-CH2-COORv is used, a strong base is added after the reaction has started to effect complete dehydration. strong bases are alkali metal and alkaline earth metal hydroxides, e.g. sodium or potassium hydroxide, alkoxides with 1-5 carbon atoms, e.g. sodium methoxide or potassium tert-butoxide, tetrabutoxides - alkylammonium with 1 to 6 carbon atoms or benzyl trialkylammonium hydroxides, for example benzyltrimethylammonium hydroxide. Preferred is tetraalkyl ammonium hydroxide or benzyl trialkyl ammonium hydroxide. The concentration of the base is not critical and may be 0.1-2 moles per mole of indanone, but it is preferable to use 0.5-1 mole of the base. The dehydration process is carried out at 25-100 ° C, preferably 50-75 ° C, until the reaction is complete. The resulting ester, nitrile, amide or dndeneacetic acid salt is converted into the free acid by conventional hydrolysis. In the case of the tertiary butyl ester, it is possible to use pyrolysis and in the case of the benzyl ester hydrogenolysis. Hydrolysis is carried out in the usual way using a strong organic or inorganic acid, such as p-toluenesulfonic, dinitrobenzenesulfonic, methanesulfonic, sulfuric and especially hydrochloric acid. Hydrolysis can also be carried out under basic conditions. [The nucleophilic attachment of the 1-ibenzylideronic group to acetic acid is carried out under the conditions of the Grignard or Wittlg reaction. The 2-en-1-one-3-acetic acid is reacted with a Grignard reagent made up of, for example, p-methylsulfinyl benzyl halide (chloride or bromide) and magnesium. The reactions are carried out at 0-100 ° C. for 1-24 hours, preferably at 30-50 ° C. for 5-8 hours. The solvent is ethyl ether; ozterohydrofuran lyb 1,4-diocoane. The reaction product can be isolated using known methods and then reacted in an inert solvent such as benzene, ether, tetrahydrofuran at 0 ° to 100 ° C for 1-15 hours, and a dehydrating agent is then added, preferably an acidic agent such as phosphorus pentoxide or pentachloride, or p-toluenesulfonic acid, leading. reactions at 20 ° C to 0 ° C. It is preferable, however, to carry out the reactions between the Grignard reagent and the acetic acid ester * in an inert solvent such as ethyl ether or tetrahydrofuran at 0 ° - -20 ° C for 1-- 12 hours, then add phosphorus pentoxide or p-toluenesulfonic acid to the reaction mixture and heat at 60- * 80 ° C for 15 minutes to 2 hours. Nucleophilic attachment can also be carried out using the known Wittig reaction . In this case, the 5-Huoro-2-imethylind-2-en-1-one-3-acetic acid ester is reacted with a suitable aralkylidate phosphate, in particular p-methytesulfinylphenzylidene phosphate. in an inert solvent such as benzene, toluene, ihexane, ethyl ether or tetrahydrofuran within 1-8 hours. The concentration of suffostrates is not critical and can be 1-1 5 mole of phosphate per mole of ketone. The obtained ester of 5-fluoro-2-methyl-Mp-β-methylsulfinylbenzy, lidene) -indenyl-3-acetic acid is subjected to alkaline hydrolysis using known methods. for this purpose, organic or inorganic bases in aqueous or hydroalcoholic solutions, such as hydroxides of alkali metals or alkaline earth metals, pyridines, carbonates or acid carbonates of alkali metals or alkaline earth metals or tnorpholine, for example calcium hydroxide lufo sodium, sodium or calcium carbonate, acid sodium carbonate and tfoujofone. It is preferred to use alkali metal hydroxides, for example sodium or potassium hydroxide, at a temperature of p1220 ° C, preferably G0 to 80 ° C. The concentration of the substrates is not has an essential z however, for best yield, it is preferable to use 2-3 moles of base or acid per mole of acetate. The reactions can be carried out in various solvents, preferably in aqueous or hydroalcoholic solutions, for example in an aqueous solution of carbonate or sodium hydroxide, or in a mixture of water and an organic base, for example pyridine or morpholine. The reaction time is not critical, it is preferable to proceed until complete ester hydrolysis is achieved, which is usually achieved within 0.5-1 hour. methylindandione-1,3 of the nucleophilic coupling reaction of the benzylidene group as previously described using the Crignard or Lufo Wittig reaction. The resulting 3,3'-O-ethylene 5-fluoro-2-methyl-Mp-methylsulfinyl-phenzylidene) indane ketal is hydrolyzed to give 5--fluoro-2-methyl-Hp-methylsulfinylphoenzylide) indanone-3. Grignard reaction 3 -O-ethylene ketal 5-fluoro-2-imethylindanedione-1,3 or diethone is reacted with p-methylsulfinylbenzyl halide (chloride or bromide) and magnesium at 0 ° -100 ° C C, preferably 20 ° -60 ° C., for 1-3 hours, preferably 1-1.5 hours. The process is carried out in an inert solvent such as diethyl ether, tetrahydrofuran, dioxane, cyclonexane or hexane. The Orignard reagent can, if necessary, be isolated using known methods and then reacted with a ketal in an inert solvent such as benzene, toluene, xylene or cyclonexane at 0 ° to 100 ° C for 1–100 ° C. 5 hours. The next step is to react with a dehydrating agent such as phosphorus pentachloride or pentoxide, polyphosphoric acid or p-toluosulfonic acid, or digital hexyl naphthoimide at 20 to 100 ° C. However, it is preferable to carry out the reactions between the Grignard compound and ketal using diethyl ether or tetrahydrofurran, at a temperature of 0-20 ° C and a time of 1-2 hours. For dewatering, it is preferable to use phosphorus pentoxide or phosphorus pentachloride in benzene and the process is carried out at a temperature of 50-100 ° C for 0.25-2 hours. In the case of wittig reatotion, the process is carried out. by treating the 3,3'-O-ethylene ketal, 5-luoro-2-n-methylindanedione-1,3 or ditone, with a suitable arylalkylidene phosphate, especially or dioxane within 1-12 hours. The concentration of suffostrates is not essential and may be 1.1-2 moles of Wittig's reagent per mole of ketal. - Methyl-Mp-methylsulfinylphoenzyldene) indan is hydrolyzed to 5-fluoro-2-methyl-1- [The hydrolysis process is carried out under mild acidic conditions. Depending on the conditions under which the nucleophilic attachment is carried out in the previous step, the product may be hydrolyzed in situ during isolation from the reaction mixture. Dilute acids are used, such as sulfuric, p-toluenesulfonic acid, preferably aqueous hydrogen chloride. The reactions are carried out at 0 ° -100 ° C, preferably 20 ° -3K) ° C, until complete hydrolysis is achieved. Since the hydrolysis takes place in the presence of a catalytic amount of acid, it is not necessary to use excess acid. According to the invention, the 3,3'-O-ethylene ketal 6H-1,3-fluoro-2-methylindandione is obtained by reacting 1,3-5-fluoro-2-methylindanedione with ethylene glycol. The reaction product is a mixture of 6- and 5-fluoro isomers which are separated and used in the process according to the invention. 5-fluoro-2-methylindanedione-1,3 is obtained by reducing-4-nitrophthalic acid to 4-aminophthalo- in the presence of platinum on activated carbon, zinc and acetic acid or iron and hydrochloric acid, carrying out the reactions in an inert solvent such as ethyl acetate, methanol, or ethanol at a temperature of 20-60 ° C, preferably at near room temperature, under c between 1 and 30 atmospheres, preferably between 1 and 2 atmospheres, until the desired amount of hydrogen has been consumed. The 4-aminophthalic acid is then converted to 4-fluorophthalic acid using known methods of replacing the amino group with a fluorine atom. For example, the process is carried out by dissolving 4-amino phthalic acid in fluorotaric acid and adding sodium nitrite at 0-10 ° C. The obtained diazonium salt decomposes at an elevated temperature and gives 4-ffluorophthalic acid, which in turn (transforms into a diester, talcs such as alkyl with 1-5 carbon atoms, e.g. diethyl, using known procedures). 4-Fluorophthalic acid is heated to reflux for a suitable period of time with ethanol and a small amount of concentrated sulfuric acid. 1,3. For this purpose, the compound is mixed with methanol and sodium, and then a 1-5-carbon alkyl ester of propionic acid, e.g. ethyl propionate, is slowly added and the mixture is heated to reflux for 2 hours. -6 hours. The invention is illustrated by the following examples: Example IA 4-aminophthalic acid. 0.2 mole of 4-nitrophthalic acid (Caz., Anin et al. 87, 329-341, 1957) is hydrated in 1 liter of ethyl acetate at room temperature, more than 10% palladium on activated carbon m, under a pressure of about 3 atm., until the theoretical amount of hydrogen is consumed, equal to 2 moles. The catalyst is filtered off and the filtrate is evaporated to dryness, giving 4-amino-phthalic acid. B. 4-fluorophthalic acid. 0.2 mole of 4-amino-phthalic acid is dissolved in 200 ml of 48% fluoroboric acid and cooled to 0-5 ° C, then keeping the temperature below 1 ° C, it is doubled by adding, while stirring, in small portions of 14.7 g ( 0.211 mol) of sodium nitrite. It is left to stand at 10 ° C for 1 hour and then heated to room temperature to destroy the diazonium salt. After the evolution of nitrogen has ceased, the solution is extracted with three 200 ml portions of acetate, ethyl and dried over magnesium sulfate. After filtration and evaporation, the acid obtained is recrystallized from ethyl alcohol. Diethyl 4-fluorophthalate. 0.2 mole of 4-fluorophthalic acid is dissolved in 200 ml of ethanol, 0.5 ml of concentrated sulfuric acid is added and the mixture is heated to reflux for 3 hours and then concentrated to 1/10 volume. The residue is dissolved in 200 ml of diethyl ether, washed thoroughly with 3 × 100 ml of a saturated solution of sodium carbonate acid, 100 ml of water and dried over magnesium sulfate. After filtering, the slurry is concentrated to dryness and the title compound is obtained in a liquid form. 5-fluoro-2-methylindanedione-1,3. To a mixture of 0.2 mole of the above ester and 0.4 mole of metallic sodium, 0.4 mole of ethyl propionate is slowly added with stirring and cooling. The whole is refluxed for 4 hours, then washed with 500 ml of ethyl ether. The precipitate is filtered off, dissolved in 300 ml of water, washed with 100 ml of ether and acidified with sulfuric acid until the evolution of carbon dioxide ceased. The mixture is extracted with three 200 ml portions of methylene chloride. The combined organic extracts were washed twice with 100 ml of water, dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness to give an oily product which crystallized on cooling. . '¦. Example II. A. 3,3'-O-ethylene ketal 6-fluoro-2-methylindanedione-1,3. A mixture containing 0.5 mole of 5-fluoro-T 2 -methylindanedione-1,3 and 0.52 mole of ethyl glycol in 600 ml of benzene, heated in a continuous manner; 18 hours at boiling temperature with 2.1 g of prtoluenesulfonic acid. - The solution is dissolved four times with 20O, 12 ml of 5% sodium hydroxide solution, twice with 100 ml of water and dried and then evaporated to dryness. The crude product is chromatographed on the column. with silica gel, dimensions 610 X X62.5 mm, eluting with a mixture of n-hexane and diethyl ether. In this way, the pure title compound is obtained from a mixture containing 3,3'-O-ethylene ketal 6-fluoro-2H-methylindane and dione-1,3,14 -S4-di-O-ethylene 5-fluoro ketal. -2-methylindanedione-1,3,3,3,0-O-ethylene 5-fluoro-2-methylindanedione-1,3 and the slightly original 5-fluoro-2-methylindanedione-1,3 (B. 3,3′-O-ethylene ketal of 6-fluoro-2-methylindane-3-acetic acid methyl ester Mixture containing 0.2 mole of dichone from A, 0.24 mole of methyl bromoacetate, 0.25 mole of pyl of zinc and iodine crystals in 300 ml of anhydrous benzene, heated gently to initiate the reaction, and then heated carefully while boiling for 5 hours. saturated ammonium chloride solution, dried over magnesium sulphate and the benzene is evaporated. The crude product obtained is dehydrated by heating to reflux and stirring for one hour with phosphorus pentoxide. in 200 ml of benzene. The benzene layer is decanted, washed with 50 ml of a saturated solution of sodium carbonate acid and with water, dried over magnesium sulphate, filtered and evaporated. A crude product containing the 5 and 6-fluorine isomers of the title compound and the starting compound is obtained. All the components of the mixture are separated on a silica gel column measuring approximately 1000 × 50 mm, eluting with a mixture of n-nexane and diethyl ether. The title compounds 40 are obtained in the form of an oil. Lower alkyl brornoethanes are used in the same way to obtain lower alkyl esters. 'Instead of benzene, other hydrocarbon solvents can be used, boiling at 45 80-100 ° C. Other dehydrating agents may also be used. ¬ce such as p-toluenesulfonic acid, polyphosphoric acid, concentrated sulfuric acid, thionyl chloride, phosphorus oxychloride or p-toluenesulfonyl chloride. The product mixture is separated using a gas chromatograph or a rotating-plate column • C. 5-Fluoro-2-methyl-ind--2-en-1-acetic acid methyl ester. 0.2 mole of the compound of Example IIB was dissolved in 200 ml of ethanol-aqueous (1: 1) hydrochloric acid (2N) and stirred at room temperature for 6 hours. After evaporation of the alcohol at 20 ° C., the crude methyl ester of 5 * -fluoro-2-methylind-60 -2-en-1-one-3-acetic acid is extracted with 200 ml of ethyl ether and dried over magnesium sulphate. and she does. After evaporation of the solvent, the title compound is obtained, which can be used for further reactions without further purification. S5 * E. P-methylsulfinyiobenzyl bromide. To a solution of 0.1 mole of p-methylthiotoluene in 200 ml of carbon tetrachloride, 0.1 mole of N-bromosuccinimide is added and the mixture is heated to reflux for 2 hours. The mixture was filtered, the filtrate evaporated to dryness and applied to silica gel columns 450 × 25 mm, eluting with a mixture of n-hexane and diethyl ether. Pure p-methylthiobenzyl ibromide is obtained in the form of an oil. A solution containing 0.1 mole of the above compound in 200 ml of a 10: 1 mixture of acetone and water is oxidized by adding 0.4 mole of sodium metaperiodate. The course of the reaction was monitored by thin layer chromatography to prevent excessive oxidation. - The mixture is evaporated to 1/3 of its volume, added with 100 ml of diethyl ether and washed thoroughly with water. After drying the ether solution over magnesium sulfate, filtering and evaporating the solvent, solid p-methylsulfinylbenzyl bromide is obtained. Instead of N-bromosuccinimide, molecular bromine can be used and the reactions carried out in the presence of light. , cold aqueous hydrogen peroxide solution, hypochlorite solution, ruteh tetroxide, peracetic acid or peraeric acid. E. 5-Fluoro-2-methyl-1- - (p-methylsulfinylbenzylidene) -indenyl-3-acetic acid methyl ester. To a solution of 0.1 mole of 5-fluoro-2-methylind-2-en-1-one-3-acetic acid methyl ester, obtained according to Example IIC, in 300 ml of benzene is added over 30 minutes. while stirring under nitrogen, a Grignard reagent made up of 0.15 mole of p-methylsulfinylbenzyl bromide, 0.2 mole of magnesium and 100 ml of tetrahydrofuran. The mixture is stirred for 18 hours at room temperature, washed thoroughly with 200 ml of saturated ammonium chloride solution and the benzene layer is separated. The benzene solution is dried over magnesium sulfate, filtered and 5 g of phosphorus pentoxide are added. The mixture is stirred and refluxed for 2 hours, then filtered, washed thoroughly twice with 50 ml of a saturated acid sodium carbonate solution, 50 ml of water, dried over magnesium sulphate and filtered. The benzene solution is evaporated to dryness and gives 5-fluoro-2-methyl-1- (p-methylsulfinyl-benzylidene) -indeny-3-oic acid methyl ester. 5-fluoro-2-methyl-li (p-methylsulfinyl-benzylidene) -iridene-3-acetic acid 0.1 mol of the ester is dissolved in 100 ml of 1: 3 1 in ethanol-aqueous sodium hydroxide solution and stirred under nitrogen for 2 hours at room temperature. The ethanol is evaporated at ° C., the residue is cooled, vigorously stirred and acidified with 1N hydrochloric acid, the precipitate is filtered off and dried at 20 ° C. over phosphorus peroxide. The product obtained can be recrystallized from a mixture of ethyl acetate and n-hexane. G: 5-Fluoro-2-mefcyl-1- (p-methylsullylbenzylidene) -indenyl-3-acetic acid methyl ester. A mixture of 0.1 mole of benzyl bromide from Example IID, 0.1 mole of triphenylphosphine and 20 ml of tetrahydrofuran in a sealed tube is left for 2 days at room temperature, and p-methylsulfinylbenzyltriphenylphosphine bromide is then filtered off. .To a solution containing 0.05 ml of the above phosphine bromide in 50 ml of liquid ammonia cooled to -80 ° C, 0.05 ml of freshly prepared sodium amide and 50 ml of benzene are added while stirring. After the ammonia has evaporated, the sodium bromide is filtered off and the filtrate is added over 20 minutes, while stirring at room temperature, to a solution of 0.045 ml of the 5-fluoroketone of Example 2C in 60 ml of dimethoxyethane. - The precipitated triphenylphosphine oxide is filtered off, the filtrate is evaporated and chromatographed on a silica gel column 610 × 37.5 mm, eluting with a mixture of chloroform and ethanol. The cis isomer of 5-fluoro-2-methyl-l-indenyl-3-acetic acid methyl ester free from the trans isomer is obtained. The ester is hydrolyzed as described in Example II F. Example III. A. 6-Fluoro-2-methylindane-3-acetic acid methyl ester, ketal 3,3'-O-ethylene (Wittig reaction). A mixture of 0.2 mole methyl bromoacetate and 0.2 mole triphenylphosphine in benzene is allowed to stand in the a period of 3 days at 50 ° C in a closed tube and the precipitated phosphonium bromide is used directly in the next reaction step. To a suspension of 0.15 mol of phosphonium bromide in 100 ml of tetrahydrofuran is added over 20 minutes, while stirring, 21, A 9% solution of 0.15 mol n-butyllithium in hexane. 0.12 mol of 3,3′-O-ethylene ketal of 6-fluoro-2-methylindanedione-1 3 in 50 ml of tetrahydrofuran. The reaction mixture is poured into 200 ml of saturated ammonium chloride solution, extracted three times with 150 ml of diethyl ether, the combined extracts are washed twice with 50 ml of water and dried over magnesium sulphate. After evaporation of the ether, the compound is obtained. title Example IV A. A, 0.27 mole of cyanoacetic acid, 14 ml of acetic acid, 4 g of ammonium acetate in anhydrous toluene, stirred and refluxed for 12 hours in a flask fitted with a Dean-Stark trap to separate water. The toluene is evaporated off, the residue is dissolved in 100 ml of a 15% aqueous solution of sodium hydroxide and heated to temperature. from 60 boil in 12 hours. The aqueous solution is washed thoroughly with 2 × 50 ml. Ethyl acetate and acidified with 5 N hydrochloric acid. After "2 hours, the precipitate of 5-fluoro-2-methyl-1-oxoindene-3-acetic acid is filtered off. 65 The acid obtained can be esterified and heated under reflux with methanol" and a few drops of concentrated sulfuric acid. O- is 5-fluoro-2-methyl-ind-2-en-1-one-3-acetic acid methyl ester.B. 5-Fluoro-2-methyl, lO-ind--2-en-l-one-3-acetic acid, methyl ester. A mixture consisting of 0.3 mole of indanone from Example IIA, 0.26 mole of diethylmaloniain, 0.3 mole of tert-1-butoxide potassium and 400 ml of tert-butanol is heated with stirring under nitrogen to room temperature. within 2 hours and then within 6 hours at boiling point. The reaction mixture is then acidified with 2.5 N hydrochloric acid, heated to reflux and stirred until no more precipitation of WEEF Dioxide ceases. The mixture is extracted three times with 200 µl of ethyl acetate, the combined extracts are washed with water and dried over sulfate. magnesium, succinate and evaporate to dryness. The residue is refluxed for 2 hours with 200 ml of methanol and 0.5 ml of concentrated sulfuric acid. The methanol is evaporated to 1/10 of its volume and the ester is extracted with 100 × A of ethyl acetate from the mixture after extraction with 2 × 50 ml of saturated acidic sodium carbonate solution. The organic solution is dried over magnesium sulfate, filtered and the filtrate is evaporated to dryness. This gives 5-fluoro-2-methyl | lind-2-en-1-one-3-acetic acid methyl ester. Example V. 3,3'-ethylene ketal 5-fluoro -2-methyl-1 {p- 1,3-methylsilifnylbenzilidene) -indedione. To a solution of 0.1 mole of 3,3-O-ethylene ketal 5-fluoro-2-methylindanedione-1,3, prepared according to Example IIA, in 300 ml of benzene is added for 30 minutes, while stirring under nitrogen at 10 ° C., a Grignard reagent made of 0.15 mole of p-methylsulfinylbenzyl bromide, 0.2 mole of magnesium and 100 ml of tetrahydrofuran. The mixture is then stirred for 18 hours at room temperature, and washed thoroughly with 200 ml of saturated ammonium chloride solution. The benzene solution is dried over magnesium sulphate, filtered and 5 g of phosphorus pentoxide are added, the whole is stirred at the boiling point for 2 hours, filtered, washed carefully with 2 × 50 ml of saturated sodium carbonate acid solution and 50 ml of water, dried over sulfur. With magnesium and sucrose. The filtrate is evaporated to dryness to give the 3,3, -O-ethylene 5-fluoro-2-methyl-1-i (pH-methylsulfinylbenzylidene) -indanone-1,3-indanone ketal. Example VI. 5-fLuoro-2-methyl-1- (p-methylsulfinylbenzylidene) -indanon-3. The compound of Example V (0.2 mol) is dissolved in 200 ml of a 2N aqueous-ethanol solution (1: 1) of hydrogen chloride and stirred for 6 hours at room temperature. The ethanol is evaporated at 20 ° C and the crude product is extracted with 200 ml of diethyl ether, dried over magnesium sulfate and filtered. After evaporation of the ether, the title compound is obtained, which can be used for further reactions without additional purification. Example VII. 5-Fluoro-2H-methyl-nyl-benzylidene-Mndenyio-3-acetic acid. 2 696 U A mixture containing; 0.25 mole of 5-fluoro-2-methyl-1-n-3-3, 0.27 mole of cyanoacetic acid, 14 ml of acetic acid and 4 g of ammonium acetate in anhydrous toluene are stirred and heated for 12 hours to at boiling point, in a flask fitted with a Dean-Stark trap for water separation. After the toluene has been evaporated, the residue is dissolved in 100 ml of a 15% aqueous solution of sodium hydroxide and heated to reflux for 12 hours. The aqueous solution is washed; with 2 x 50 ml of ethyl acetate and acidified with 5 N hydrochloric acid. After 2 hours, the resulting product is filtered off, for example VIII. 3,3′-O-ethylene ketal 5-phai-o-2-methyl-Mp-raethylsulfinylbenzylsenylene) indane A mixture of 0.1 mole benzyl thyme from the HD example, 0.1 mole triephenylphosphine and 20 ml 580 of tetrahydrofuran in a sealed tube is left for 2 days at room temperature, after which the gate of p-methylsulfinylbenzyltriphenylphosphine is drained. To 0.05 ml of the above phosphine bromide in 50 ml of liquid ammonia is added slowly with stirring at temperature. -80 ° C, 0.05 ° C freshly prepared sodium amide and 50 ml of benzene. After the ammonia has evaporated, the sodium bromide is filtered off and the filtrate is added over 210 minutes, while stirring at room temperature to 0.045 ml of the 3.3 'ketal. 1,3-O-ethylene 5-fluoro-2-methylindanedione in 60 ml of dimethoxyethane The precipitated triphenylphosphine oxide is filtered off and the filtrate is concentrated and chromatographed on a silica gel column of dimensions 610 × 37.5 mm, eluting with a mixture chloroform and ethonol to give compound t ytulium. Example IX. 5-Fluoro-2-methyl-Mp-methylsulfinylabenzylidene) -40-iradenyl-3-acetic acid methyl ester. - A mixture of 0.2 mole of methyl ibromoacetate, 0.2 mole of triphenylphosphine and benzene is left for 3 days in a closed tube at 50 ° C and the precipitated phosphonium bromide is used directly for further reactions. 15 mole of phosphonium bromide W (0 ml of tetrahydrofuran is slowly added over 20 minutes, with stirring, to 0.15 mole of a 21.9% solution of n-butylite in hexane. The resulting clear solution is cooled to 0-6 10 ° G and 0.12 mole of 5-fluoro-2-methyl-1H (p-methylsulfinylbenzylidene) -indanone-3 in 50 ml of tetrahydrofuran is added thereto over 30 minutes. 55 ml of saturated ammonium chloride solution, the product is extracted with 3 × 150 ml of diethyl ether, washed with 2 × 50 ml of water, dried over magnesium sulfate. After evaporation of the ether, the titanium compound is obtained. -. ^ methyiosulfinyl benzylidene) • * indenyl-3-acetic acid. 0.1 mol of the ester from example IX is dissolved in 100 ml of a mixture of 1 N aqueous sodium hydroxide solution in ethanol # M * and the whole mixture is stirred at room temperature for 2 hours under nitrogen A10269617. After evaporation of the alcohol at 20 ° C., the residue is cooled, stirred vigorously and acidified with 1N hydrochloric acid. The precipitate is filtered off and dried over phosphorus pentoxide at 20 ° C. The product obtained can be crystallized from a mixture of ethyl acetate and n-hexane. Example XI. 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -indenyl-3-acetic acid methyl ester Mixture containing 0.2 mole of indan-3 from Example VI, 0.24 mole of methyl bromoacetate, 0.25 grams of zinc dust, iodine crystals and 300 ml of anhydrous benzene are gently heated to initiate the reaction and then carefully heated to reflux for 5 hours. After cooling, the benzene layer is washed thoroughly with 2 × 100 ml of water and dried over magnesium sulphate and then the benzene is evaporated. The crude product obtained is dehydrated by heating to reflux and stirring for one hour with 5 g of phosphorus pentoxide in 200 ml of benzene. The benzene layer is decanted, washed with 50 ml of a saturated solution of acid carbonate carbonate and 50 ml of water, dried over magnesium sulfate, filtered and evaporated to give the crude product. Lower alkyl esters are obtained in the same way by using lower alkyl bromoacetates. Instead of benzene, any other solvent may be used. Other dehydrating agents such as p-toluenesulfonic acid, polyphosphoric acid, concentrated sulfuric acid, dicyclohexylcarbodiimidi, thionyl chloride, phosphorus oxychloride and p-thiiuenesulfonyl chloride can also be used. The eighth shelf Example XII 5-Fluoro-2-methyl-1- {p-methylsulfinylbenzylidene) -indenyl-3-acetic acid. 0.1 mole of the ester of Example 11 is dissolved in 100 ml of a 1N mixture of sodium hydroxide and ethanol (3: 1) in water, and the mixture is stirred under nitrogen at room temperature for 2 hours. After evaporation of the alcohol at 20 ° C., the residue is cooled, stirred vigorously and acidified with 1N hydrochloric acid. The precipitate is filtered off and dried over phosphorus pentoxide at 20 ° C. The product obtained can be crystallized from a mixture of acetate and ethyl and n-thiexane. Example XIII. 5-Fluoro-2-methyl-1- (p-Hmjetylsulfinyiobenzylidene) -indenyl-3-acetic acid. Mixture containing 0.3 mol of 5-fluoro-2-methyl-Mp-methylsulfinylbenzylidene) -indanone T3, 0.25 mol of diethylmalonate, 0.025 mole of potassium tert-butoxylate and 400 ml of tert-butanol are stirred for 2 hours under nitrogen at room temperature and then refluxed for 6 hours. The reaction mixture is acidified with 2.5 hydrochloric acid and stirred at reflux for a further 3 hours until the evolution of carbon dioxide ceases. The mixture is extracted three times 18 times with 200 ml of ethyl acetate, washed with water and dried over magnesium sulfate. After filtering, the solution is evaporated to dryness to give the title compound. Example XIV. 5-Fluoro-2-methyl-1- (p-methylsulfinyl-benzylidene) -indenyl-3-acetic acid methyl ester. 0.1 mole of methyl bromoacetate is boiled for 2 hours with 0.1 mole and triethyl phosphite in 250 ml of dimethoxyethane. All is evaporated to dryness and the residue is fractionated under reduced pressure. This gives diethoxymethoxyphosphonic acetate (diethylphosphonoacetic acid methyl ester). To a solution of 0.1 mole of the above product in 100 ml of dimethoxyethane, 0.1 mole of a 50% suspension of sodium hydride in paraffin oil is added and the mixture is stirred for one hour. at room temperature. Rp track. the above is added at 15 ° C to a solution of 0.1 mol of 5-fluoro-2-methyl-Mp-methylsulifnylbenzylidene) -indanone-3 in dimethoxyethane. After 3 hours, 20 ml of water are added and the methyl ester is separated by chromatography on a silica gel column measuring 1000 x 50 m / m. Example XV. 5-Fluoro-2-methyl-1- (p-methylsulfinylbenzylidene) -indenyl-3-acetic acid. <0.1 mole of the ester of Example 14 is dissolved in 100 ml of a 1N mixture of sodium hydroxide and ethanol (3: 1) in water and the whole is stirred under nitrogen for 2 hours at room temperature . After the alcohol is evaporated at room temperature, the residue is cooled, vigorously stirred and acidified with 1N hydrochloric acid. The resulting precipitate is filtered off and dried at 20 ° C. over phosphorus pentoxide. The product obtained can be recrystallized from a mixture of ethyl acetate and n-hexane. 40 iExample XVI. 5-Fluoro-2-methyl-ind-2-en-1-one-3-acetic acid methyl ester e.g. A mixture of 0.25 mol 5-fluoro-2-methylindan-1,3-dione, 0.27 mol Cyano-acetic acid, 14 ml of acetic acid and 4 g of ammonium acetate in anhydrous toluene, heated to the boiling point and stirred for 12 hours in a Dean-Stark flask. The toluene was evaporated and the residue dissolved in 50 100 ml of a 15% aqueous sodium hydroxide solution and refluxed for 12 hours, then washed thoroughly twice with 50 ml of ethyl acetate and acidified with 5N hydrochloric acid. After 2 hours, the precipitated 5-fluoro-2-methylind-2-en-1-tertiary-3-acetic acid is filtered off. The above acid can be esterified by heating for 2 hours under reflux with methanol and a few drops of concentrated sulfuric acid. This gives 5'-fluoro-2-methyl-ind-2-en-1-one-3-acetic acid methyl ester e.g. Example XVII. 5-Fluoro-2-methyl-1- (p-methylsulfinyl benzylidene) -indenyl-3-acetic acid methyl ester. 65 To a solution of 0.1 mol of methyl ester of 182 693 19-fluoro-2-methylind-2-en-1-one-3-acetic acid in 300 ml of benzene, the Orignard reagent was added over 30 minutes while stirring under nitrogen. made from 0.15 mol of p-methylsulfinylbenzyl bromide, 0 µmol of magnesium and 100 ml of tetrahydrofuran. The mixture is stirred for 16 hours at room temperature, washed thoroughly with 200 ml of saturated ammonium chloride solution and the gasoline layer is separated. The benzene solution is dried over magnesium sulfate, filtered and added with% phosphorus pentoxide. The mixture is stirred and refluxed for 2 hours, then filtered, washed thoroughly twice with 50 ml of a saturated acid sodium carbonate solution, 50 ml of water, dried over magnesium sulphate and filtered. The {benzene layer is evaporated to dryness and gives 5-fluoro-2-methyl-1-indenyl-3-ootic acid methyl ester. -indenyl-3-acetic. 0.1 mole of 1-methylsulfinylbenzyl bromide is mixed with 0.1 mole of triphenylphosphine in 20 ml of tetrahydrofuran and left in a closed tube for 2 days at room temperature, and then p-methylsulfinylbenzyltriphenylphosphonium bromide is filtered off. To a solution of 0.05 ml of the above phosphonium bromide in 50 ml of liquid ammonia is slowly added, while stirring at -H80 ° C, freshly prepared 0.05 ml of sodium amide and 50 ml of benzene. [After evaporation of the ammonia, the sodium bromide is filtered off and the salt-free solution is added at room temperature to 0.045 aul of 5-fluoro-2-lmethylind 2-en-1-one-3 acid methyl ester with stirring. acetic acid in 60 ml of dimethoxyethane. The precipitate of triphenylphosphine oxide is filtered off, a concentrate filter and a chromatograph on a 610 × 37.5 mm column packed with silica gel. A mixture of chloroform and ethanol is used for elution. In this way, the cis-isomer of the benzylidene derivative is separated from the contaminating trans isomer. The cis-isomer of 5-fluoro-2-methyl-1- (p-methylsulfylbenzylidene) -indenyl-3-acetic acid is obtained. The ester can be hydrolyzed as described in Example XV. Example XIX. 5--Fluoro-2-methyl-ind-2-en-1-on-3-acetic acid methyl ester. A mixture of 0.3 mole 5-fluoro-2-methylindanedione-11.3, 0.25 mole diethylmalonate, 0.6 moles of anhydrous potassium tert-butoxide and 400 ml of tert-butanol are stirred for 2 hours under nitrogen at room temperature and then for 6 hours at reflux. The mixture is acidified with 2.5 N hydrochloric acid, then stirred at the boiling point for a further 3 hours until the release of carbon dioxide ceases. The mixture is extracted with 3 × 200 ml of ethyl acetate, washed with water and the organic solution is dried over sulfate. magnesium. After filtration and evaporation to dryness, the residue is refluxed for 2 hours with 200 ml of methanol and 0.5 ml of concentrated hydrochloric acid. The methanol is evaporated to 1/10 volume, added with 100 ml of ethyl acetate and washed twice with 50 ml of a saturated solution of acidic sodium carbonate. After drying the organic solution over magnesium sulphate, filtering and concentrating to dryness, 5-fluoro-2-methyl-ind-2-en-1-one-3-acetic acid methyl ester is obtained. Example XX. 5-Fluoro-2-methyl-ind-i2-en-1-one-3-acetic acid methyl ester and 6-fluoro-2-l-one-3-acetic acid methyl ester. 0.2 mole of methyl bromoacetate and 0.2 mole of triphenylphosphine are kept for 3 days in gasoline in sealed tube at 50 ° C. The recovered foaphonium bromide is used directly for further processing. 15 moles of phosphonium bromide in 100 ml of tetrahydrofuran are slowly added over 20 minutes, with stirring, 0.15 mole, 21.99% of a solution of n-butylolipho in n-foexane. To the resulting clear solution, 0.12 mole of 1,3-5-fluoro-2-methylindanedione in 50 ml of tetrahydrofuran is added over 30 minutes at 0 ° -10 ° C. The reaction mixture is poured into 200 µl of saturated ammonium chloride solution. The crude product is extracted with 3 × 150 ml. Of ethyl ether, washed with 2 × 50 ml. Of water and dried over magnesium sulfate. After the filtration and concentration of the ethereal solution, a mixture of 5- and 6-fluoro derivatives is obtained. The 5-fluoro compound is obtained by separating the mixture on a 1 mu m column and eluting with a mixture of n-hexane and diethyl ether. Example XXI. 5-Fluoro-2-methyl-ind-2-en-1-one-3-acetic acid methyl ester and 6-fluoro-2-methyl-ind-2-en-1-one-acetic acid methyl ester . 40 0.2 mole of dichone of Example ID, 0.24 mole of methyl bromoacetate, 0.25 mole of zinc dust and iodine crystals in 300 ml of benzene are warmed gently to initiate the reaction, and then the MB is not heated carefully while boiling. 45 - within 5 hours. After cooling the solution, the benzene is washed thoroughly twice with 100 ml of saturated ammonium chloride solution, dried over magnesium sulfate and the benzene is evaporated off. The crude product obtained is dehydrated by heating to reflux and stirring for one hour with 5 g of phosphorus pentoxide in 200 ml of benzene. The benzene layer is decanted, washed with 50 ml of a saturated solution of acid sodium carbonate and 50 ml of water, dried over magnesium sulphate, filtered and evaporated to give a crude product containing the impurity starting compound and some 5-dimethyl ester. fluoro-2-methylindene-1,3, diacetic-6.gO- All four components of the mixture are separated on calum with silica gel measuring 1000 × 50 mm, using a mixture of n-hexane and diethyl ether for elution. The title compounds are obtained in the form of an oil.21 Lower alkyl esters are obtained in the same way using lower alkyl bromoacetates. Any other hydrocarbon solvent can be used instead of benzene. Other dehydrating agents such as p-acid can also be used. toluenesulfonic acid, polyphosphoric acid, concentrated sulfuric acid, thionyl chloride, phosphorus oxychloride or p-toluenesulfonyl chloride. The product mixture is separated by means of gas chromatography or column and a rotating plate. Example XXII. 5-fluoro-2-methyl-ind-2-en-1-one-3-acetic acid methyl ester. 0.1 mole of methyl bromoacetate is refluxed for 2 hours with 0.1 mole of triethyl phosphite in 250 ml of dimethoxyethane. All is evaporated to dryness and the remainder of the ppcV- is fractionated under reduced pressure. This gives triethoxyphosphonoacetic acid methyl ester (diethylphosphonoacetic acid methyl ester). To a solution of 0.1 mole of the above compound in 100 ml of dimethoxyethane, 0.1 mole of a 50% sodium hydride suspension in paraffin oil is added and the mixture is stirred for 1 hour at a time. room temperature. The above solution is added at 15 ° C to a solution of 0.1 mole 5-fluoro-2-methylindanedione-1,3 in dimethoxyethane. After 3 hours, 20 ml of water are added and the methyl ester is distilled off by extraction and chromatography on a 1000 × 50 mm silica gel column, thus separating the isomer. * Example XXIII. Lithium-sodium acetate. 300 mmoles of n-butyl lithium are added to a suspension of 300 millimoles of anhydrous sodium acetate in 500 ml of tetrahydrofuran containing 500 millimoles of diisopropylamine, cooled to -20 ° C. The mixture is stirred for 2 hours at room temperature. This gives lithium sodium acetate suitable for use in a condensation reaction. Example XXIV. Dilitic acetate. To 300 mmoles of acetic acid in 500 ml of tetrahydrofuran are added at 0 ° C. 600 millimoles of diisopropyl lithiumamide. The mixture is stirred for 3 hours at room temperature to obtain two-liter acetate. Example XXV. Lithiumacetonitrile. 300 millimoles of diisopropyl lithiumamide are added to 300 millimoles of acetonitrile in 500 ml of tetrahydrofuran at 0 ° C to 5 ° C. The mixture is stirred for 3 hours at room temperature. The reaction mixture contains lithium acetonitrile. Similarly, replacing acetonitrile with dimethylacetamide or methyl acetate produces lithium dimethylacetamide or lithium acetate. Example XXVI. 5-fluoro-2-methylindenyl-3-acetic acid tert-butyl ester. 1.1 mole of a monomolar acetate solution is added to 1 mole of 6-fluoro-2-methylindanone-1 dissolved in H volumes of toluene. lithium tertiary butyl in toluene. The mixture is stirred for 1 hour at room temperature, after which 0.5 mole of TritoniL B is added and the mixture is heated for 2 hours at 65 ° C. After washing with water and concentration, the T-ester is obtained. 5-fluoro-2-methylindenyl-3-acetic acid butyl. 'Example XXVII. 5-Fluoro-2-methyl-indenyl-3-acetic acid. To the lithium sodium acetate obtained according to Example XXIII, 300 mmoles of 6-fluoro-2-methylindanone are added at 0 ° C and -20 ° C. for 1 hour at room temperature, then 150 millimoles of Triton B are added, and the mixture is acidified with dilute hydrochloric acid and the solvent is evaporated off. The title compound is extracted with chlorophyll and the solution is concentrated to dryness. In a similar manner, replacing lithium-sodium acetate with ditium acetate obtained according to example XXIV, or lithiumacetonitrile, lithium-distimethylacetamide, or lithomethyl acetate according to the pphosphyl chloride XXV, - oro-2-methylindenyl-3-acetic acid, 5-fLuoro-2-methyl-indenyl-3-acetonitrile, 5-fluoro-2-methyl-indenylH3-acetic acid N-dimethylamide or 5-fluoro methyl ester -2-methylindenyl -3-acetic acid. Example XXIX. 5-Fluoro-2-methylindenyl-3-acetic acid. To a solution containing one equivalent of 33-dubenzylphosphonoacetic acid in 200 ml of tetrahydrofuran is added at -80 ° C a solution of two equivalents of diisopropyl polyamide in 100 ml of tetrahydrofuran. The mixture is mixed for 20 minutes and then one equivalent of 6-fluoro-2-methylindanone-1 is added, keeping the temperature below -70 ° C. After 30 minutes, the temperature was gradually raised and the mixture was allowed to stand at 4 (0 ° C) overnight, then water was added and the tetrahydrofuran was evaporated under reduced pressure. The aqueous solution was extracted with toluene. discarding the organic extract The title compound crystallizes by carefully adding hydrochloric acid to a pH of 2. The precipitate is filtered off, washed with water and dried. EN EN

Claims (1)

Patent claim 1. Process for the production of 5-fluoro-2-methyl-1-50 tonic acid, characterized in that 6-fluoro-2-methylindanedione-1,3'-O-ethylene ketal is reacted with capable of introducing an acetic acid residue such as by reacting with a haloacetic acid in the presence of zinc dust and iodine, under gradual dehydration, or with a phosphate produced by the reaction of a trisubstituted phosphine and a haloacetate, or with cyanoacetic acid or with a malonic ester in the presence of a strong base or with tri (alkoxy or acryloxy) phosphonoacetate or with an acidic lithium compound, yielding the 3,3'-ethylene ketal of 6-fluoro-2-methylindenyl-1-acetic acid, which is hydrolyzed and the resulting 5-fluoro-2-methylind-2-en-1-one-3-acetic acid is reacted with p-65-methylsulfinylbenzyl halide and magnesium, and the resulting the product is a dehydrating agent or reacted with an alkylene phosphate in an inert solvent to give 5-fluoro-2-24-methyl-1- (p-methylsulfinylbenzylidene) -indenyl-3-acetic acid ester is used, from which, after hydrolysis, 5-fluoro-2-methyl-1- (p-methylsulifinyl- benzylidene) indenyl-3-acetic. Li®-GCH-X Y LZG Z-d 3 in Pab. Zam, 472-79 Nakl. 95 + 20 copies Price PLN 45 PL PL