PL93421B1 - - Google Patents

Description

The subject of the invention is a method for the production of nova indanoacetic acid derivatives of formula 1, where Rt is lower alkyl and R3 is a hydrogen atom or a lower alkyl radical, R3 is A total hydrogen atom or a lower alkyl radical, R4 is a hydrogen atom or a lower alkyl radical, R5 is hydrogen, chlorine or a lower alkyl radical, and R6 and R7 are hydrogen or when R5 is atom hydrogen, R6 also represents a chlorine atom or a lower radical alkyl and R7 is chloro or a lower alkyl radical acid and salts of acids of formula 1.

According to the invention, the new compounds of formula I and their the salts are obtained in that the compounds are reduced of Formula 2, wherein R13, R2, R3, R5, R6 and R ' may know The above description, and R8 and R9 together are oxygen nu or a lower alkylidene group, or R8 is an atom hydrogen or a lower alkyl radical and R9 is a group hydroxyl, and the optionally obtained acids of the formula where R15, R2, R4, R5> R6 and R? they matter given above, optionally converted to salts.

In compounds of formula 1, symbolized by Rt lower than The first alkyl radical preferably contains 1 to 4 carbon atoms and is, in particular, a methyl or ethyl radical. He is If R3 is a lower alkyl radical it contains a co-radical Preferably 1-4 carbon atoms. Preferably R2 is an atom hydrogen or a methyl radical. R3 is preferably a hydrogen atom. If R3 is a lower alkyl radical, it preferably has 1 to 4 carbon atoms and is Na for example a methyl, ethyl, isopropyl or radical IH-before. butyl. If R4 is the lower alkyl radical It preferably contains 1 to 4 carbon atoms. Ko¬ Preferably R4 is a methyl radical or a hydrogen atom. Ko¬ Preferably R6 and R7 are hydrogen and R5 is hydrogen or chlorine. Where R5, R6 and R7 represent a lower alkyl radical, these are the alkyl groups contain 1-4 carbon atoms and are especially rhodium methyl nickel. Compounds, for example, are particularly advantageous ki in which Rj is a methyl, ethyl or radical isopropyl and R3 represents a hydrogen atom or a metal radical rear, R3 is hydrogen, R4 is methyl rear or hydrogen, and R5, R6 and R7 are atoms hydrogen.

The reductions of the compounds of the formula II are carried out in the known manner way. Preferably, the reductions are carried out, for example method of catalytic hydrogenation. Hydrogenation can be lead, for example, in the presence of a catalyst in dilution an inert solvent under the reaction conditions under pressure with hydrogen gas of 1 to 5 atm and at a temperature of 10-100 ° C.

Platinum or catalysts are used as catalysts palladium or Raney nickel.

Solvents used are, for example, lower alcohols cohols or alcohol / water mixtures, or in the case of for the preparation of acids of formula I, preferably α-acid thats you. Hydrogenation is preferably carried out with the additive a strong mineral acid such as sulfuric acid or perchloric acid.

Acids of formula 2 (R3 = H), wherein R8 and R9 are zem forms an alkylidene group, and R5, R6 and R7 are 93 42 193 421 no other than chlorine, can also be reduced for example clade by treatment with sodium in liquid ammonia either in a lower alcohol such as propanol, n-butanol or methyl isobutyl carbinol to give the corresponding acids Formula 1 wherein R3 is hydrogen and R4 is lower alkyl radical.

For the reduction of compounds of formula 2 in which R8 and R * together they represent the oxygen atom, the method is also suitable Wolff-Kishner and modifications thereof, obtained these are acids of formula I in which R3 is a hydrogen atom hydrogen and R4 is hydrogen. So the Wolff method- -Kishner, the compounds of formula 2 can first be reconstructed putting in hydrazones and then treating them with strong ones bases such as metal hydroxides or alkoxides alkaline. Wolff-Kishner reductions are done in a horse preferably according to the Huang-Minlon variant, surrendering to an example of a compound of formula II by reaction with hydrate hydr gins in the presence of an alkali metal hydroxide, such as sodium or potassium hydroxide and obo under reaction conditions, high boiling, polar, a water-miscible organic solvent at a temperature of about 20-220 ° C. As solvents for example, polyalcohols such as di- or triethylene, or dimethyl sulfoxide.

The duration of the reaction may be 1/2 to 40 hours.

The obtained compounds of formula I can be isolated from the reaction mixture and purify in a known manner.

Acids of formula Ia can optionally be converted into salts with inorganic or organic bases and vice versa.

The starting compounds can be produced for example in as follows: a) Compounds of formula 2a, wherein R 1, R 2 * Ra> Rs> Re and R7 are as defined above, can be manufactured for example, so that the compounds of formula III in which R15 R2, Rs, R * and R7 have the meaning given above, reacts with monoalkyl ester chlorides oxalic acid of formula 4, wherein R * is lower alkyl radical in the presence of acid catalysis tora and the obtained alkyl esters of the acid ct-ketoindane acto- it is optionally hydrolyzed. Relationship reactions of formula III with acid monoalkyl ester chlorides of oxalic acid is preferably carried out under the reaction conditions Friedel-Crafts, for example in the presence of trichloride aluminum, in the presence of an inert dilution under the reaction conditions an organic solvent such as carbon disulfide or a halogenated hydrocarbon, for example chloride of methylene at about 0 ° to the boiling point reaction mixture. b) Compounds of formula 2b, wherein R ', R2, R3, Rs, R6 and R7 have the meanings given above, for example to prepare by reducing the compounds of formula IIa by the strength of sodium borohydride. The reductions are carried out preferably in a lower alcohol such as methanol or ethanol. c) Compounds of formula 2c, wherein R15, R2, R3, R5, Rs and R7 are as defined above and R * is lower an alkyl radical, for example, can be produced by this the way that esters of formula 2a (R3 is lower alkyl) reacts with the relationship. Grignard formula 5, wherein R * is as defined above and X1 is of a chlorine, bromine or iodine atom, under inert conditions under the re action in a solvent, for example an ether such as ethyl ether or tetrahydrofuran at temperature around 0-50 ° C, hydrolyzes the resulting meta complex Organo and the resulting esters of formula 2c (R3 is lower alkyl) is optionally hydrolyzed. d) Compounds of formula 2d, wherein R19, R2, R3, R5, R5 and R7 are as defined above and R10 is a group alkylidene, can be obtained, for example, by grafting water from compounds of formula 2c, for example in such a way that the compounds of formula 2c are treated as and a lytic amount of a strong acid, such as meta-acid nosulfonic acid or p-toluenesulfonic acid, in neutral under the reaction conditions of a solvent such as carbon hydrogen, for example benzene or toluene, at elevated levels temperature, preferably at reflux temperature, 13 reaction shifts. e) Compounds of formula 3 can be obtained, for example cyclization path of compounds of formula 6, where R15 R * R5, R6 and R7 are as defined above, or their reaction derivative acid derivatives and reductions of the obtained other compounds of formula 7, wherein R13, R2, R5, B1, and R7 have the meaning given above. Cyclization of the compounds of Fr. Formula 6 is preferably carried out in the presence of a strong acid a catalyst, such as a strong mineral acid, for example preferably hydrogen fluoride, polyphosphoric acid or sulfuric acid, possibly with the addition of an inert " under the reaction conditions of an organic solvent, ta such as a hydrocarbon, for example benzene, toluene or tetralin. For cyclization, instead of the acids of formula VI, it is also use, for example, reactive derivatives of these 80 acids. The reactive derivatives are, for example, acid halide clade. You can proceed on the occasion for example, acids of formula VI are converted, for example, clade first with inorganic acid chloride such as thionyl chloride to acid chlorides and these then cyclize under Friedel-Crafts conditions in the presence of a Friedel-Crafts catalyst such as aluminum chloride, in an inert dilution under the reaction conditions organic solvent. Reduction of compounds by the formula The death 7 can be carried out, for example, with hydrogen 40 in statu nascendi, for example by treating compounds with a formula 7 Clemmensen's method with amalgamated zinc / concentrated hydrochloric acid. f) Compounds of formula 3a, wherein R 1? R5, R6 and R7 May the meaning given above may also be obtained, for example, mac in such a way that compounds of formula 8, where R5, Ra and R7 are as defined above, and are reacted with the Grignard compound of formula 9, where Rx has as defined above, the resulting complex is subjected to hydrolysis, then splits off the water and thus obtained a compound of formula 10, wherein R5, R5, R5 and R7 are as defined The above combination is subject to reduction. Compound reductions The compounds of formula 10 are preferably carried out by the catalytic route tic hydrogenation. 55 g) Compounds of formula 6a, wherein Rw R5, R6 and R7 may the meaning given above can be obtained, for example so that aldehydes of formula 11, where R5, R6 and R7 have the meaning given above, they are condensed with compounds of formula 12, in which Rj is 60 below, with the addition of a strong base such as al alkali metal alcoholate and hydrogenates the resulting pellets derivatives of cinnamic acid. Dual reductions. the bonding can be carried out by catalytic convolution of water, or if R5, Re and R7 are not 65 of the chlorine atom, also with the help of hydrogen in statu 45 5093 421 uascendi, treating these compounds with metallic sodium in al koholu. h) Compounds of formula 6b, wherein R19, R *, R6 and R7 may as defined above, and R * is the lower radical al the keel, for example, can be obtained that compounds of formula 13, wherein R 6 and R | they matter as defined above, and Rn is a lower alkyl radical, con- is densified with halo compounds of formula 14, where R5, Re, R7 and X1 have the meanings given above, as hereinbefore carry a strong base such as sodium hydride or amide in an inert organic solvent such as kim like ether, for example tetrahydrofuran, and got many ester saponifies in a known way.

Compounds of the formula I and their pharmacologically acceptable usable salts have not yet been described. They show interesting pharmacodynamic properties and one can therefore use them as medications. They have their own anti-inflammatory properties, as can be shown in studies on animals. They inhibit the formation of fringes in the rat ku in the lap cardgenin edema test in doses about 20-100 mg / kg body weight.

Due to their action, these substances may know lie use as anti-inflammatory agents relatively inhibiting exudates in inflammatory conditions or rivers. The doses used can be varied naturally depending on the type of substance, method of treatment and condition on the patient. In general, however, a satisfactory performance is achieved However, at a dose of 20-100 mg / kg body weight. Te dose it may be given in 2 to 4 parts or in pos extended life taci. For larger mammals the daily dose is about 200-2000 mg. Particulate doses for oral administration, they can include, for example about 50-1000 mg of compounds of formula I in addition to solids or liquid media.

The compounds of formula 1 also have an inhibitory effect arthritis. So, for example, in the period study Freund-Adjuvans latent arthritis in rat they show an effect that inhibits the formation of edema in doses of about 30-100 mg / kg body weight.

Due to the anti-arthritis effect the compounds of formula I can be used for prevention and treatment treatment of arthritic and rheumatic diseases. Applicable important doses vary naturally depending on the growth the type of substance, treatment and condition of the patient. On overall, however, satisfactory results are achieved with doses —100 mg / kg body weight. This dose may be administered optionally in 2 to 4 parts or in an extended form effective operation. Daily dose for larger mammals is about 200-2000 mg. For oral administration the partial dose can be, for example, about 50-1000 mg of compounds of formula 1.

The new compounds were relatively physiologically acceptable These salts can be used as medicaments alone or as appropriate the form of the drug together with the pharmacologically acceptable other auxiliary substances.

If the output production is not described, they are known, or may be made in the sense of the word a different method or analogous to those described herein or analogously to known methods.

The following examples are more illustrative process according to the invention, all temperature data cycles are given in degrees Celsius.

Example I. 2-isopropyl-α-methyl-5-inda acid aoacetic. 6 A solution of 15 g of a-hydroxy-2-isopropyl-a-me- acid tly-5-indane acetic acid in 300 ml of glacial acetic acid and 4 ml of 70% perchloric acid is hydrogenated with the addition of 400 mg of platinum oxide IV catalyst -value at 80 °, stirring continuously hours. The solution is then filtered to add the solution gives 6 g of anhydrous sodium acetate and the solvent is evaporated off teapot. The remainder is distributed between the ether and the water, the ether phase is washed with water, dried over sodium sulphate he sucks and hesitates. Acid obtained as residue 2-isopropyl-α-methyl-5-indane acetic acid is purified from yeast chromatography on silica gel and crystalline Lyses from hexane to give a product at temperature mp 83-86 °.

Obtained by reaction with 2-amino-2-hydroxy-me- Tylyl-1,3-propanediol salt (1,3-dihydroxy-2-hydroxy- 2-isopropyl-a-mc- methyl-2-propyl) -ammonium acid tylo-5-indane acetic acid crystallizes from methanol / ether and it has a melting point of 140-141 °.

The output product can be produced in a nasal manner stabbing: a) 36 g of indan-2-carboxylic acid (prepared by of a, a ', -dibromo-o-xylene and dimethyl ester of malonic acid) is dissolved in 500 ml of tanol and added to the solution within 5 hours, while stirring, gaseous hydrogen chloride at 20-35 °.

The solution is concentrated and the resulting residue is dried tine indane-2-carboxylic acid methyl ester purified by distillation in a distillation apparatus tions with ball tube. ^ The boiling point is 150— —170 ° / 11 mm Hg. b) To a solution of methylmagnesium iodide (prepared by made from 142 g of methyl iodide and 24.0 g of magnesium filings a solution of 37.3 g in 1.2 liters of ether is added dropwise indan-2-carboxylic acid methyl ester v 200 ml of ether and boil it under a chiller for 2 hours feedback. The reaction mixture is then mixed with a little 500 ml of a 10% ammonium chloride solution and extract he buzzes with ether. The ether extract is washed with water and dried 40 over sodium sulfate and evaporated. Raw received 2- (2-indanyl) -2-ptopanol is taken up in 1 liter of t luen and cook for 24 hours with 1 g of p-toluene sulfonyne under a reflux condenser. Chilled solution the product is washed with a solution of acid sodium carbonate 45 g, dried over sodium sulfate and concentrated. Received the remaining oil is taken up in 500 ml of eta nol and hydrogenated with the addition of 1 g of 10% palladium on carbon under pressure at room temperature jowa. The solution is filtered and concentrated. Received as 50 residue 2-isopropylindane melts at 40- —41 °. c) For a suspension of 55 g of aluminum chloride in 400 ml of chloride methylene is added dropwise at 0-5 °, while stirring, a solution of 33 g of 2-isopropyl-indan and 27.8 g of ester chloride 55 of monomethyl oxalic acid in 400 ml of chlorine to methylene within 60 minutes. The red solution was measured continues in 3 hours at room temperature, then poured into ice water. The mixture was extracted is boiled with methylene chloride, the extract is filtered with talc, washed with water, dried over sodium sulfate and concentrated.

The remainder of the acid methyl ester 2- -isopropyl-α-keto-5-indane acetic acid is purified by road distillation in a ball tube. The boiling point of 65 of the duct is 200 ° / 0.2 mmHg. $ 3121 d) For a solution of methylmagnesium iodide, prepare made from 9.6 g of magnesium filings and 25 ml of iodide 100 ml of ether, a solution of 41 g of methanol is added dropwise 2-isopropyl-α-keto-5-ine & noacetic acid v 400 ml of ether and stirred for 2 hours in the refrigerator feedback. 400 ml of sfc was added dropwise to the cooled mixture % ammonium chloride solution, then extracted with ether rem. The ether extract is washed with water, dried over sodium sulfate and evaporated. Received as remainder crude acid methyl ester α ^ hydroxy- Working up the -2-propyl-tt-methyl-5-indane acetic acid was possible funnel without cleaning. e) To a solution of 41.5 g of the crude methyl ester a-hydroxy-2-isopropyl-a-methyl-5-indanoacetic acid- to 500 ml of methanol, a solution of 26.6 g of hydrogen is added of potassium oxide in 50 ml of water and the mixture is boiled under feedback within 1.5 hours. Solution for thesis itself, diluted with water and to remove indifferent ingredients are extracted with ether. The water phase becomes acidic With hydrochloric acid, extracted with ether, the ether extract went through washed with water, dried over sodium sulfate and evaporated uncle. The a-hydroxy- acid obtained as residue -2-propyl-α-methyl-^ -indane acetic acid recrystallized they are eaten from the ether / hexane system to give a product of temperature mp 126-130 °.

Example II. 2-isopropyl-α-methyl-5-inda acid nocturnal, A solution of 1.7 g of 2-isopropyl-α-methylene-5-kidan- acid of acetic acid in 300 ml of ethanol is hydrogenated with the addition 50 mg of IV-valent platinum oxide at temperature room. The catalyst is then filtered off and dissolved the solvent is evaporated and the remaining oil of the chromatograph is them, yielding 2-isopropyl-α-methyl-5-indanoac- mp 83 ° -86 °. Temperature salt melting (1,3-dihydroxy-2-hydroxymethyl-2-pro of the pyl) ammonium of the title compound is 140-141 ° (from methanol / ether).

The starting material can be made in a nasal way tepujacy: Solution 3.8 g of a-hydroxy-2-isopropyl- -α-methyl-5-indane acetic acid in 300 ml of toluene was retained in boil under reflux with 0.5 g p-toluenesulfonic acid for 5 hours; jac water separator. The cooled solution is washed water, dried over sodium sulfate and concentrated. Received as residue 2-isopropyl-α-methylene-5-indanoac- this is recrystallized from toluene / hexane to give having a product, mp 158-159 °.

Example III. 2-ethyl-2, a-dimethyl-5-in- acid daoacetic. 2-ethyl-a-hydroxy-2, a-dimethyl-5- acid the indane acetic acid is hydrogenated analogously to example I.

Melting point of the cyclohexylammonium salt of the compound titanium is 165-167 ° (from ether).

The exit relationship can be made as follows; a) For a suspension of 44 g of sodium hydride in 1.3 liters 202.7 g of methyl ester are added dropwise of α-methylbutyric acid, followed by stirring keeps boiling under reflux during 16 hours. A solution of 204 ml of chloride is then added dropwise benzyl in 500 ml of tetrahydrofuran and the reaction mixture It cooks under a reflux condenser for 70 hours.

The tetrahydrofuran is then distilled off Shanine is cooling, 600 ml of petroleum ether and 30 ml are added methanol and washed with 300 ml of 5% acetic acid and sat tap water. Obtained as a residue after evaporation In the absence of a solvent, crude oily acid methyl ester The α-ethyl-α-methyl dihydrocinnamic acid distils at 15 mm Hg and the fractions boiling at 13 ° C -140 ° is used without further purification in ha * St§p- reaction step. b) For a solution of 101.5 g of kfcsu methyl ester a- -ethyl-α-methyldihydrogen cinnamic 1.5 liters of methanol tanol, a solution of 100 g of potassium hydroxide is added in 200 ml of water and the mixture is kept to a boil under a reflux condenser within 20 hours. Solution solution thesis to a volume of about 300 ml, diluted with water and ob¬ it extracts any by-products with ether. Next the aqueous phase is acidified with hydrochloric acid and extracted with ether rem, ether extract washed with water, dried over sulfur sodium hydroxide and evaporated. Obtained as after remains oily crude acid a-ethyl-a-methyldihydrate rocinnamon can be purified by chromatography fic. c) To 700 g of polyphosphoric acid is added dropwise, szajac, at a temperature of 150 ° 69 g of a-ethyl-a-me- tylo-dihydroxy cinnamon within 5 minutes. Have Shanine is then mixed for 10 minutes at a temperature temperature 160 °, cooled to 100 ° and dropwise 100 ml of water. Then the mixture is poured over the ice, extracted with ether, the ether extract washed with water and dry lower over sodium sulfate. Obtained by the answer the solvent 2-ethyl-2-methyl-1-indanone o- the distillation route is cleaned. The boiling point is it is 137-140 ° / 20 mm Hg. d) 335 g of tin dust is quickly dropped into the mixer and 33.5 g of mercuric acetate and a solution of 330 ml concentrated hydrochloric acid in 280 ml of water. Mixture boils under reflux and a solution of 63 g of 2-ethyl-6-methyl-1-indanone is added dropwise in 525 ml of ethanol, stirring for 10 minutes. Stir Nine is then mixed for 28 hours under the cold reflux, cools and sucks, and rinses the residue water / petroleum ether system. The slope extracts Aug with petroleum ether, the petroleum ether extract is washed water and dried over sodium sulfate. After removal, dissolve of the solvent, an oily crude 2-ethyl-2-methyl- -indane which is purified by chromatography at using alumina and petroleum ether. e) 2-Ethyl-α-keto-2-methyl-5- acid methyl ester -indanoacetate is prepared analogously to the example du Ic) and processed further in the raw form. f) 2-ethyl-α-hydroxy-2, α-dimethyl-5-indanoac- acid this is produced by analogy to the example Id) and Te) and in its raw form it processes further.

Example IV. 2-ethyl-2,6-dimethyl-5-in- acid daoacetic.

For a solution of 6.2 g of methyl 2-ethyl ester -2,6-dimethyl-a-keto-5-indanoacetic acid in 50 ml of glycine In a diethylene column, 10 g of hydroxide are added tasu, the mixture is stirred for 1 hour at the temperature of the turn 100 °, then left for 12 hours. Us 12 ml of hydrazine water are added, with a mixture while stirring, it is heated for 1 hour under cool With a reflux system, the excess is distilled off with hydro and the water formed during the reaction, and the temperature the boiling point of the reaction mixture will rise to 180 °, then continues to cook under reflux for 2 hours in temperature of 180 °. The reaction mixture is cooled to 65 room temperature, diluted with water, acidified with acid 40 4591421 - ^ 9 salt and extracted with ether. The extract is washed with water, dried over sodium sulfate and evaporated. Received no residue 2-ethyl-2,6-dimethyl-5- -indane acetic acid is recrystallized from petroleum ether at -30 °, the melting point of the prop the yield is 40-42 °. The melting point of cy- clohexylammonium of the title compound is 154— —156 °.

The starting point can be obtained in the manner of us stabbing: a) α-Ethyl-α, 4-dimethyl-diacid, methyl ester of hydrogen cinnamon is prepared analogously to example clade Ilia) from methyl ester of α-methyl-butyl- and α-bromo-p-xylene, the boiling point of of the product is 135-152 ° / 13 mm Hg. b) α-ethyl-α, 4-dimethyl dihydrogen cinnamon acid y is produced by analogy to example Illb). Oily the raw product is processed directly further. c) 2-ethyl-2,6-dimethyl-1-indanone gives the ana logically for the example of Hic), the melting point is it is 25.5-27 °. d) 2-ethyl-2,5-dimethylindane is prepared analogously for example Md). The oily crude product was converted into he rabies directly on. e) 2-Ethyl-α-keto-2,6-dimethyl ester tly-5-indane acetic acid is prepared analogously to example clade Ic). The boiling point of the product is 195 ° / / 0.1 mm Hg.

Example 5 2-isopropyl-5-indanoacetic acid 2-Isopropyl-α-keto-5-indanoacetic acid is reduced analogously to example IV by reaction with hydrogen potassium oxide and hydrazine hydrate. Temperature the melting point of the title compound is 83-86 °.

A starting material is produced as follows who: a) 2-isopropyl-α-keto-5-indano-acid ethyl ester acetic acid is prepared by analogy to Example Ic).

The oily crude product is processed directly further. b) To a solution of 24.5 g of crude acid ethyl ester of 2-isopropyl-α-keto-5-indaneacetic acid in 300 ml. of ethanol A solution of 10 g of sodium hydroxide is introduced into the nol in 20 ml of water and the mixture is boiled under a chiller feedback within 1.5 hours. The solution is concentrated and dissolved thin water and extracts inert by-products ether. The aqueous phase is then acidified with hydrochloric acid is extracted with ether, and the ether extract is washed with water da, dried over sodium sulfate and evaporated. As the remainder gives 2-isopropyl-a-keto-5- acid indanoacetic acid in the form of an oil which can be processed funnel without cleaning. The melting point of salt (1.3- - dihydroxy-2-hydroxymethyl-2-propyl) ammonium 2-isopropyl-α-keto-5-indanoacetic acid is 145- —147 °.

P r z y k l a d VI. 2-ethyl-6-chloro-5-indanbacetic acid.

2-Ethyl-6-chloro-a-keto-5-inda acid methyl ester the acetic acid is reduced analogously to example IV.

Melting point of the cyclohexylammonium salt of the compound the titanium is 145-147 °.

The starting material can be produced in a nasal way stabbing: a) To sodium ethoxide solution prepared from 27 g of sodium, in 450 ml of ethanol, a solution of 126 g of ethyl ester is added dropwise α- (diethylphosphono) -butyric acid in 130 ml ethanol while stirring at a temperature of 0-5 °. It mixes up further at 0-5 ° for 1 hour, dropwise solution of 70 g of 4-chlorobenzaldehyde in 140 ml of ethanol and stirring was continued for 2 hours at room temperature in. A solution of 140 g of hydroxide is then added dropwise of potassium in 280 ml of water, warm the mixture while stirring, under reflux within 18 hours, cool down, dissolve thin water and inert by-products are extracted ether. The alkaline water phase becomes acidic, cooling, concentrated hydrochloric acid, the colorless precipitate was filtered off io teases and rinses with water. Crude a-ethyl-4- acid -chlorocinnamon is recrystallized from methanol.

The melting point of the product is 138-140 °. b) A solution of 44.5 g of a-ethyl-4-chlorocinnamic acid in 750 ml of ethanol it is hydrogenated with the addition of 0.4 g of the platinum oxide IV catalyst under pressure 1 atm of hydrogen and at a temperature of 25 °. After the arrival combining the calculated amount of hydrogen is sipped and the solution thesis. The a-ethyl-4-chloro acid obtained as residue Hydrogen cinnamon rhodium recrystallizes from ether oil. The melting point of the product is 59-61 °. c) 2-ethyl-6-chloro-1-indanone is prepared analogously not for example IIIc). The boiling point of the product is 135-145 ° / 0.1 mm Hg. d) 2-ethyl-5-chloroindane is prepared analogously for example Md). The boiling point of the product was it is 122-127 ° / 14 mm Hg. e) 2-ethyl-6-chloro-a-keto acid methyl ester -5-indane acetic acid is prepared analogously to clade Ic). The boiling point of the product is 176- —180 ° / 0.15mmHg.

Example VII. ~ 2-ethyl-6-methyl-5-indano- acid acetic.

2-Ethyl-α-keto-6-methyl-5-in- acid methyl ester The acetic acid is reduced analogously to example IV.

The melting point of the title compound is 103- —104 °.

The starting material can be produced in a manner 40 stabbing: a) α-Ethyl-4-methylcinnamic acid is prepared analogous to the example Via) from an acid ethyl ester α- (diethylphosphono) butyl and 4-methylbenzaldehyde.

Mp 156-158 ° (from methanol). 45 b) To 100 g of sodium in 250 ml of toluene dribbled over the course 1 hour at 130 °, with good stirring, vialine 91 g of α-ethyl-4-methylcinnamic acid w 1.5 liters of methyl isobutyl carbinol. After the follow-up hours, no more sodium is found, then 50 of the mixture is cooled and 500 ml of water are carefully added.

The aqueous phase is separated and the methyl isobutyl carbin phase Water is extracted twice more in the nol. Connected the aqueous phases are acidified with concentrated hydrochloric acid and extract scuffs with ether. The ether extract is washed with water, 55 is dried over sodium sulfate and evaporated. Crude α-Ethyl-4-methyldihydrogen cinnamic acid is obtained form an oil and can be purified by chromatography graphia. c) 2-ethyl-6-methyl-1-indanone is prepared analogously 60 not for example Hic). Product melting point is 50-52 ° (from hexane). d) 2-ethyl-5-methylindane is prepared analogously for example Md). The oily product cleans up the road aluminum oxide chromatography using petroleum ether. E) 2-Ethyl-α-keto-6-methyl-5-03421 acid methyl ester AT -indane acetic acid is prepared analogously to Example du Ic). The boiling point of the product is 185- —190 ° / 0.1mmHg.

Example VIII. 2-methyl-5-indanoacetic acid.

A-keto-2-methyl-5-iudanoacetic acid methyl ester this reduction is reduced analogously to example IV. Tem¬ the melting point of the cyclohexylammonium salt of the compound the titanium is 175-178 °.

A starting material is produced as follows: a) .alpha.-Methiccinaronic acid is prepared analogously for example Via) from an acid methyl ester Β - (diethylphilone) propionic acid and benzaldehyde. Tem¬ the melting point of the product is 78-80 °. b) α-Methylhydrogen cinnamic acid and * awy are produced analogously to the example VHb) in the form of an oily pro raw product. c) 2-methyl-1-indanone is prepared analogously to of Example IIIc) in an oily form with a boiling point 170—1909 / 11 mm Hg- d) A solution of 28.7 g of 2-methyl-1-indanone in 500 ml ethanol is hydrogenated with the addition of 2.5 g of palladium and precipitates coal (10%) and 20 rot of concentrated hydrochloric acid for 4 hours at room temperature under pressure German. The solution is concentrated to a volume of about 100 ml thin water and extracted with petroleum ether. Extract washed with water, dried over sodium sulfate and evaporated evaporates. Obtained as residue 2-methylindane o- it is purified by chromatography on 200 g of alumina using petroleum ether, e) a-keto-2-in-ethyl-5-mdanooeth- acid methyl ester is produced analogously to example Ic. Tem¬ The boiling point of the product is 170 ° / 0.1 mm Hg.

Example IX, 2-ethyl-5-ittanoacetic acid.

2-Ethyl-α-keto-5-indanoacetic acid is reduced by ana logically for example IV. Compound melting point of the title is 48-50 °,% The starting material can be produced in a nasal way stabbing: a) .alpha.-ethyl cinnamic acid is prepared analogously not for example Via) from ethyl ether of α- (di- ethylphosphono) butyl and benzaldehyde. Temperature the melting point of the product is 105-180 °. b) [alpha] -ethyldihydrogen cinnamic acid is prepared analogous to example VIIb. It gets oily product with a boiling point of 136 ° -140 ° / 0.02 mm Hg. c) 2-ethyl-1-indanone is prepared analogously to example IIIc). An oily product with a temperature of boiling point 127-129 ° / U mm Hg. d) 2-ethylindane is obtained analogously to example clade VIIId). The oily crude product is processed without indirectly on. e) 2-Ethyl-α-keto-5-indano-acto-acid methyl ester is produced by analogy to the example Ie). Tem¬ The boiling point of the product is 170-190 ° / 0.05 mm Hg. f) 2-Ethyl-α-keto-5-indanoacetic acid is prepared analogously to example Vb) and in the raw form Rabbi on.

Example X. 2-ethyl-63a-dimethyl-5-in- acid daoacetic.

Z-ctyl-α-hydroxy-eight-vumethyl-S-indanoacetic acid my, prepared analogously to example 14) and Ie from an ester 2'et7lQ-6-methyl-a-keto-5-indanooc- methyl acid 12 18 50 this is hydrogenated by analogy to example I, Tem the melting point of the product is 106-108 °.

Example XI. 2-Ethyl - "- Methyl-5-indanoic acid" thats you.

2-ethyl-α-hydroxy-α-methyl-5-indaacetic acid, formed analogously to the example Id) and Ie) from the meter's ester 2-ethyl-α-keto-5-indanoacetic acid, tuft is obtained by analogy to example I. Temperature, melting of the cyclohexyl ammonium salt of the title compound It is 182-184 °.

Example XII. 23a-dimethyl-5-indanooc- acid thats you.

Α-hydroxy-2, α-dimethyl-5-indane acetic acid, and $ formed analogously to the example Id) and Ie) from the meter ester of α-keto-2-methyl-5-indanoacetic acid is obtained by analogy to example I. Temperature melting of the cyclohexylammonium salt of the title compound it is 190-193 °. 88 Example XIII. 2-ethyl-6-chloro-α-methyl- acid -5-indanoacetic acid.

2-ethylH6- chbro-a-hydroxy-a-methyl-5-indanoac- acid made by analogy to the example Id) and Ie) from 2-ethyl-6-chloro-a-keto-5-in- acid methyl ester of the acetic acid is hydrogenated analogously to example I.

The melting point of the product is 113-115 °.

Example XIV. 2-ethyl-2-methyl-5-indano- acid acetic. 2Q 2-Ethyl-α-keto-2-methyl-5-in- acid methyl ester dacetic acid is reduced analogously to example IV.

The melting point of the cyclohexylammonium salt of the compound for the title is 149 ° -151 ° and the mp of the sodium salt of the title compound 184-188 °. 3 * Example XV. 2,2-diethyl-5-indanoac- acid thats you.

2,2-Diethyl-α-keto-5-inda-acid methyl ester the acetic acid is reduced analogously to example IV.

The melting point of the salt (1,3-dihydroxy-2-hydro 40 of the xymethyl-2-propyl) ammonium compound of the title compound it is 116-119 °.

The starting material can be produced analogously for example Ula) —Ule): a) α, α-diethyldihydrogentin acid methyl ester 45 monic acid is prepared from 2-ethylbutyric acid and chlorine towards benzyl. The boiling point of the product is 140- —154 ° / 14mmHg. b) α, α-diethyldihydrogen cinnamic acid the face is made by boiling 85 g of the above-mentioned ester and 85 g of potassium hydroxide in 300 ml of sulfoxide to dimethyl and 120 ml of water for 20 hours under a reflux condenser and in its raw form is processed further. c) 2,2-diethyl-1-indanone is purified by des- 55 aeration in a ball tube (air bath 200 ° / 13 mm Hg). d) 2,2-diethylindane, b.p. 140-150 ° / / 14 mm Hg (air bath temperature). e) 2,2-Diethyl-α-keto-5-inda-acid methyl ester aA noacetic acid is further processed raw. 60 Example XVI, 2,2-Dimethyl-5-indanoic acid new.

2,2-Dimethyl-a-keto-5-indano- acid, methyl ester acetic acid is reduced by analogy with example IV 65 The melting point of the cyclohexylammonium salt of the compound the title is 155-156 ° 93,421 13 14 The starting material can be produced analogously not for example Ilia) -Ule): a) α, α-dimethyldihydrogen, methyl ester cinnamon is made from benzyl chloride and an ester methyl isobutyric acid. The temperature boils at 5 The product is 112-126 ° / 14 mm Hg. b) α, α-dimethyl dihydrogen cinnamic acid, tem Melting point 58.5-59.5 °. c) 2,2-dimethyl-1-indanone, m.p. 42-43 °. ' io d) 2,2-dimethylindane is processed further as raw. e) 2,2-Dimethyl-a-keto-5-in- acid methyl ester The acetic acid is processed further raw.

Example XVII. 6-chloro-2,2-dimethyl- acid -5-indanoacetic acid.

6-Chloro-2,2-dimethyl-a-ke- acid methyl ester to-5-indanoacetic acid is reduced analogously to e.g. clade IV. Title compound melting point 20 is 143-145 °.

The starting material can be produced similarly for example Ilia / —Me /: a) Acid methyl ester, α, α-dimethyl-4-chloro Dihydrocinnamon is prepared from a methyl ester of isobutyric acid and 4-chlorobenzyl chloride.

The boiling point of the product is 127-145713 mm Hg. b) α, α-dimethyl-4-chlorodihydrogen cinnamon acid mp 90-92 ° (from hexane). . thirty c) 6-chloro-2,2-dimethyl-1-indanone, m.p. a temperature of 40-42 °. d) 5-chloro-2,2-dimethylindane, reflux 105-108 ° / 13 mm Hg. e) 6-Chloro-2,2-dimethyl-α-35 acid methyl ester -keto-5-indanoacetic acid is processed further as raw.

Example XVIII. Acid 2-ethyl-6-chloro-2-methyl- -5-indanoacetic acid.

2-ethyl-6-chloro-2-methyl-α- acid methyl ester -keto-5-indane acetic acid is reduced analogously to example IV. The melting point of the title compound temperature is 87-89 °.

The starting material is produced in the same way as for 45 kladu'Ilia) —Ule). a) α-Ethyl-α-methyl-4-chloro acid methyl ester Dihydric cinnamon is prepared from a methyl ester α-methylbutyric acid and 4-chloro chloride benzyl. The boiling point of the product is 148-168 ° / 50 / 15 mm Hg. b) acid a-ethyl-4-chloro-a-methyldihydrogentin- monic, mp 35-36.5 °. c) 2-ethyl-6-chloro-2-methyl-1-indanone, oily, they continue to rob in their raw form. 55 d) 2-ethyl-5-chloro-2-methylindane oil, work up still in raw form. e) 2-ethyl-6-chloro-2-methyl- acid methyl ester The -a-keto-5-indane acetic acid is processed further as raw. 60 Example XIX. 2,2,6-trimethyl-5-indanoac- acid thats you.

2,2,6-Trimethyl-α-keto-5-indano- acid, methyl ester acetic acid is reduced by analogy with example IV.

The starting material is produced analogously to example Ilia) —Ule): a) Methyl ester of α, α, 4-trimethyl dihydrogen The mononic acid is prepared from a-bromo-p-xylene and an ester methyl isobutyric acid, boiling point is 120-145,713 mm Hg. b) a, ct, 4-trimethyl dihydrogen cinnamic acid, temp mp 51-53 ° (from petroleum ether / ether). c) 2,2,6-trimethylindan-1-one is processed further as shown in FIG raw tart. d) 2,2,5-trimethylindane, boiling point 120- —130,714 mm Hg. e) 2,2,6-Trimethyl-α-keto-5-in- acid methyl ester The acetic acid is processed further raw.

Similarly to example IV can also be produced the following relationships: 2-Ethyl-4,7-dichloro-5-indanoacetic acid, start from 2-ethyl-4,7-dichloro-α-keto-5-indanoacetic acid, 2-ethyl-7-chloro-4-methyl-5-indanoacetic acid, yielding using 2-ethyl-7-chloro-4-methyl-a-keto-5-indano- acid vinegar, 2-ethyl-4,7-dimethyl-5-indanoacetic acid, temp mp 103-105 °, starting from 2-ethyl 4,7-dimethyl-α-keto-5-indanoacetic acid.

Example XX. 2,2, a-trimethyl-5-indano-acid acetic.

2,2, α-Trimethyl-α-hydroxy-5-indane acetic acid, yield prepared analogously to Examples Id) and Ic), hydrogen is similar to Example I. Temperature melts The ratio of the cyclohexylammonium salt is 180-183 ° (z ethanol).

Analogously to example I can also be produced the following relationships: 2-ethyl-4,7-dichloro-α-methyl-5-indanoacetic acid, starting from 2-ethyl-4,7-dichloro-a-hydroxy-a- -methyl-5-indanoacetic acid; 2,2,6, α-tetraiomethyl-5- acid -indane acetic acid, starting from α-hydroxy-2,2,6, a_ - tetromethyl-5-indane acetic acid; 2-ethyl-4,7, a-trie, methyl-5-indacetic acid, m.p. 98-100 °.

Example XXI. 2-ethyl-6- acid methyl ester -chloro-2-methyl-5-indane acetic acid.

A solution of 5.2 g of 2-ethyl-6-chloro-acid methyl ester -2-methyl-α-keto-5-indane acetic acid in 100 ml of methanol and 10 ml. concentrated sulfuric acid is hydrogenated with the with the addition of 1.0 g of valence platinum oxide at 45 ° turn and under a pressure of 4 atm of hydrogen. After joining the theoretical amount of hydrogen is filtered off the catalyst, solution The product was diluted with a 5% solution of acid sodium carbonate it is extracted with ether. The extract is washed with water, dried over sodium sulfate and evaporated. Received as the remainder of the title compound is purified by chroma tography. Thin layer chromatogram: Rf value 0.60, adsorbent: silica gel, eluent: chloroform.

By analogy with example XXI you can also get the following derivatives of 5-indano-acid alkyl esters acetic acid catalytic hydrogenation route appropriate h derivatives of alkyl esters of a-keto-5-indano- vinegar: 2-ethyl-5-indanoacetic acid methyl ester, temp boiling point 145 70.01 mm Hg.

2-Ethyl-5-indanoacetic acid ethyl ester, temp boiling point 102-10670.01 rnm Hg. 93 421 2-ethyl-2,6-dimethyl-5-indanoac- acid methyl ester this, 2-isopropyl-5-indanoacetic acid ethyl ester, 2-ethyl-6-chloro-5-indanoacetic acid, methyl ester, 2-ethyl-6-methyl-5-indanoacetic acid methyl ester, 5 2-methyl-5-indanoacetic acid methyl ester, 2-ethyl-5-indanoacetic acid methyl ester, 2-ethyl-2-methyl-5-indanoacetic acid methyl ester 2,2-diethyl-5-indanoacetic acid methyl ester, 2,2-dimethyl-5-indanoacetic acid methyl ester, 10 6-chloro-2,2-dimethyl-5-inda acid methyl ester noacetic, 2,2,6-trimethyl-5-indanoacetic acid methyl ester, 2-ethyl-4,7-dichloro-5-indano-acid n-butyl ester vinegar, 15 2-ethyl-7-chloro-4-methyl-5- n-propyl ester -indane acetic acid, 2-ethyl-4,7-dimethyl-5-indanoac- acid ethyl ester this.

Example XXII. 2-ethyl-2, α- 'acid methyl ester -dimethyl-5-indane acetic acid.

A solution of 8 g of 2-ethyl-α-hydroxy-acid methyl ester -2, α-dimethyl-5-indane acetic acid in 100 ml of methanol and 8 ml. concentrated sulfuric acid is hydrogenated with the with the addition of 0.8 g of valence platinum oxide at 25 bend 40-45 ° under 3 atm of hydrogen. After connecting In order to obtain the theoretical amount of hydrogen, the solution is sucked and diluted with a 5% solution of acidic sodium carbonate and extract he buzzes with ether. The extract is washed with water, dried over 30 sodium sulfate and evaporate. Obtained as residue The oily title compound is purified by distillation lation. The boiling point is 138-140 ° / 0.3 mm Hg.

By analogy with example XXII you can also get [alpha] -alkyl-35 acid alkyl ester derivatives as follows Of the -5-indanoacetic acid by catalytic hydrogenation of the dehydration the corresponding derivatives of alkyl esters of the α-alkyl lo-α-hydroxy-5-indane acetic acid: 2-ethyl-2, α-dimethyl-3-indanoic acid ethyl ester new, 40 16 2,2,6, α-tetramethyl-5-indanoac- acid methyl ester this, 2-isopropyl acid methyl esterTa-methyl-5-indanoac- this, 2-isopropyl-α-methyl-5-indanooc- acid ethyl ester this, 2-ethyl-6, α-dimethyl-5-indano-acid methyl ester vinegar, 2-ethyl-α-methyl-5-indano-acetic acid methyl ester wego, 2, α-dimethyl-5-indanoacetic acid methyl ester, 2-ethyl-6-chloro-α-methyl-5-inda acid methyl ester noacetic, 2,2, α-trimethyl-5-indaoacetic acid methyl ester, 2-ethyl-4,7-dichloro-α-methyl- acid methyl ester -5-indane acetic acid, 2-ethyl-2, α-dimethyl-5-indano-acid n-butyl ester vinegar, ^ / CH-C00R3 MODEL 1 % / C-C00R3 WZdR2a P £ V7 and " / CH-COOH WZtfR 1a R. and W / CH-COORj and 5 WZCfR 2b C-COOR, PATTERN 2 C-COOR, WZtfR 2c93 421 R. & c COCL COOR! WZdR 4 Rj-Mg-Xr MODEL 5 PATTERN3 COOH WZdR 6 and and i V WZdR 3a R.

R CH-CH 2 \ / \ COOH Y and R « WZdR 6a93 421 K K J1 / CH2-C-COOH WZdR 6b R, -MgBr WZdR 9 WZdR fQ CHO 0 R, this | 1 (C2H50) 2 P-CH-COOAik WZdR 12 R; R1 " : ch-coqr.

WZdR 13 r6AAch_xi WZdR 14

Claims (1)

Claim 1. A process for the preparation of the new indanoacetic acid derivatives of formula I, wherein R ± is a lower alkyl radical, R2 is a hydrogen atom or a lower alkyl radical, R3 is a hydrogen atom or a lower alkyl radical, R4 is a hydrogen atom or lower alkyl, R5 is hydrogen, chlorine or lower alkyl and R6 and R7 are hydrogen, or when R5 is hydrogen, R6 is also chlorine or lower alkyl and R7 is chlorine or a lower alkyl radical, and salts of acids of formula 1, characterized in that the compounds of formula 2 are reduced in which Rla, R 2, R 3, R5, R6 and R7 are as defined above, and R8 and R9 together represent an oxygen atom or a lower alkylidene group or R 8 is a hydrogen atom or a lower alkyl radical and R 1 is a hydroxyl group, and the optionally obtained acids of formula Ia, in which Ru, R 2, R 4, R 5, R 6 and R 7 are as defined above, ¬ not salted.! 93 421? 7? *