NO753530L - - Google Patents

Description

The present invention relates to a method for the production of new organic compounds with formula I

wherein means hydrogen or alkyl of 1-2 carbon atoms,

1*2 means hydrogen or halogen with an atomic weight below 80,

R^ and R^ each stand for hydrogen or together stand for oxygen and

Rg means hydrogen or alkyl with 1-4 carbon atoms

or, if R^ and R^ are attached to the same carbon atom, R^ and R^ together form an alkylene chain of 3-6 carbon atoms,

or, if A stands for a (Cf^)2~9ruPPe'also

R^ and R(- together form a bond and R^ means hydrogen,

Rg stands for hydrogen or alkyl with 1-4 carbon atoms and A stands for a (CI^) n-group, in which

n if R^ and R^ together mean oxygen, stands for 0 or

n if at least one of the substituents R^, Rg and R^ means

alkyl with 1-4 carbon atoms or R^ and R^ together

means an alkylene chain with 3-6 carbon atoms or if R^, Rg and R7 mean hydrogen, R3 and R^ together oxygen

and R 2 halogen, with atomic weight below 80, stands for 1, or

n, if R^ and R^ together mean oxygen or R^ and R,. together form a bond or if R2 means halogen with an atomic weight below 80 or, if at least one of the substituents R^, R^, Rg and R^ means alkyl with 1-4 carbon atoms or . R,- and R^ together mean an alkylene chain with 3 - 6 carbon atoms, stand for 2 or, if R^ and R^ mean hydrogen, also Rg and A together with the carbon atom to which they are attached, form a

1,2-cycloalkylene group of formula

means 3 or,

in which m

if R^ and R^ together stand for oxygen, m also means 4,

R^ stands for hydrogen or, when Rg means hydrogen, also for alkyl with 1-4 carbon atoms

.3and their, salts.

The distinctive feature of the method according to the invention for the production of the new organic compounds of formula I and their salts is that

a) for the preparation of compounds of formula Ia,

in which

R1 and R2 have the above meaning,

RJ? stands for hydrogen, alkyl with 1-4 carbon atoms or,

II etc

if R^ and R_ are bound to the same carbon atom, R^ stands

together with R^ for an alkylene chain of 3-6 carbon atoms,

R^ stands for hydrogen or alkyl with 1-4 carbon atoms and A<1> stands for a (CI^)nI group, in which n I stands for 0 or 2 or

n<1>, if at least one of the substituents R^, Rg and R<*> means alkyl with 1-4 carbon atoms or Rj? and R* together means an alkylene chain with 3-6 carbon atoms or if R2 means halogen with an atomic weight below 80, also stands for 1 or,

if Rj? and R<*>means hydrogen, also ,

r

R, and A-^together with the carbon atom to which-LL they are bound, form

1,2-cycloalkylene group of formula

3 or 4,

where m<1>means

R<*>stands for hydrogen or, if Rg means hydrogen, also for alkyl with 1-4 carbon atoms

ring-closed compounds of formula II

in which R^, R^, R*, Rg, R<*>and A1 have the above meaning, or

their reactive acid derivatives, or

• b) for the preparation of compounds of formula Ib

in which

and R 2 has the above meaning,

R^ and R^ are each hydrogen,

Rg<1> means hydrogen or alkyl with 1-4 carbon atoms

or, if R^ and R^ are attached' to the same carbon atom,

together R^1 and R<*1> form an alkylene chain with 3-6 carbon atoms,

Rg1 stands for hydrogen or alkyl with 1-4 carbon atoms and

A<11> stands for a (CH2) ^H group, in which

n11, if at least one of the substituents R?, R?1 and rE1 stands for II5 J 6II 7 alkyl with 1-4 carbon atoms or R^ and R^ together mean an alkylene chain with 3-6 carbon atoms, stands for -1, or n11 , if R 2 means halogen with an atomic weight below 80 or if at least one

of subst in tuehteneR, , Rp, R?1 and rI1 means alkyl with 1-4

II II

carbon atoms or R,, and R^ together form an alkylene chain with 3-6 carbon atoms, stands for 2

or if, R^<1>and R<*1>are hydrogen, also

RIDE. In oa A 'II together with that carbon atom. to which they are bound.

forms a 1,2-cyclopentylene group of formula

TT TT

R^ stands for hydrogen or, if R& means hydrogen, also for alkyl with 1-4 carbon atoms

compounds of formula III are reduced

wherein R1, R2, Rg1, R*1 and A11 have the above meaning,

II "cII

R^ and* R3 together stand for oxygen and

Rg<11>represents hydrogen or alkyl with 1-4 carbon atoms or, if R?11 and R*1 are bonded to the same carbon atom, form R^^and

II

R^ an alkylene chain with 3-6 carbon atoms or

Rf and R<*11> together form a bond and

R^<1> stands for hydrogen and

Rg means hydrogen or, if R^<1>and R<*1>together stand for oxygen, means a hydrolytically cleavable residue, and-Jivris-RQ means a hydrolytically cleavable residue, this is cleaved at the same time, or

c) for the preparation of compounds of formula Ic,

in which

R^, R^ and R* have the above meaning and R*11 means hydrogen or alkyl with 1-4 carbon atoms,

water is split off from compounds of formula IV

in which R^, R^, R3 0<3 R<*11> has the above meaning and Rg means • hydrogen or an acidolytically cleavable residue, and if Rg stands for an acidolytically cleavable residue, this is also cleaved at the same time and

the obtained compounds of formula I are optionally transferred in their salts.

In the compounds of formula I, the substituent R., preferably means hydrogen or methyl. The substituent R2 preferably stands for hydrogen. If R2 means . • ' ett.in the preceding defined halogen, this constitutes preferably chlorine. Preferably, the substituents R 4 and R 4 together stand for oxygen or each for hydrogen. If the substituents R^, Rg or R^ denote a lower alkyl group, these preferably contain 1-3 carbon atoms and constitute, if A stands for an eH2 group. or a-CH2-CH2 group, especially ethyl or methyl and, where A represents a bond, especially n-propyl, isopropyl or ethyl. If Rg and R^ together form an alkylene chain, this preferably contains 5 carbon atoms. In the compounds of formula I, ring B is preferably monoalkylated. Preferably, an alkyl substituent is arranged in the 6-position or, if A stands for a (CH 2 ) group or a (CH 2 ) 2 group, also in the 7-position. Preferably, A stands for a (CH2)2~ group or together forms, at Rg and the carbon atom to which it is attached, a cycloalkylene ring defined above, which is preferably cis-linked to ring B.

The cyclization of the compounds of formula II using method a) can be carried out by methods known per se. The reaction preferably takes place in the presence of a strongly acidic condensing agent, possibly with the addition of an organic solvent inert under the reaction conditions, e.g.

an aromatic compound or a chlorinated hydrocarbon. As acidic condensation agents, e.g. strong /acids such as preferably polyphosphoric acid, sulfuric acid or methanesulfonic acid/ phosphorus pentoxide. The reaction temperature can be between approx. 60

and 160°C. Instead of an acid of formula II, its reactive derivatives can also be used for the ring closure. As reactive derivatives of the acids with formula II, e.g. their acid halides or mixed anhydrides of acids of formula II and lower organic carboxylic acids or also lower alkyl esters of acids of formula II. In a method variant, e.g. the acids of formula II first by means of an inorganic

acid chloride such as thionyl chloride is transferred into its acid chlorides and these then under the reaction conditions of a Friedel-Crafts reaction, e.g. in the presence of aluminum trichloride, in et

under the reaction conditions, inert organic solvent is ring-closed. The reaction conditions for the hydrolysis of the organometallic complex intermediately formed by the Friedel-Crafts reaction are chosen so that possible acid derivatives with acetic acid grouping are simultaneously hydrolysed to free acid groups.

The reduction of the compounds of formula III can take place after

i1 -and provide for the selective reduction of a double bond with a carbonyl group to a methylene group by common methods. Suitable reduction methods are e.g. if R3 means hydrogen, the catalytic hydrogenation or, if R3 and R3 share oxygen, also reduction with maserating hydrogen, e.g. reduction according to Clemmensen or the reduction method according to Wolff-Kishner and their modifications. Under the reaction conditions for the reduction methods according to Clemmensen or. Wolff-Kishner cleaves possible hydrolytically cleavable residues Rg, e.g. alkyl, especially lower alkyl or aryl groups, simultaneously from the compounds of formula III. The catalytic hydrogenation can e.g. carried out in presence

of a catalyst in a solvent inert under the reaction conditions at a hydrogen pressure of between approx. 1 and 5 aiitjo?,spheres and temperatures between approx. 10 and 100°C. Suitable as catalysts

e.g. platinum or palladium catalyst or also Raney nickel. As a loosening agent, e.g. lower alcohols or alcohol/water mixtures or preferably acetic acid. The hydrogenation is preferably carried out with the addition of a strong mineral acid such as e.g. sulfuric acid or perchloric acid or, hydrogen chloride. The reduction of the compounds with formula III with nascent hydrogen can e.g. carried out according to Clemmensen with amalgamated zinc/hydrochloric acid, possibly with the addition of an organic solvent inert under the reaction conditions, e.g. an aromatic hydrocarbon or a water-miscible solvent such as a lower alcohol. The reduction is preferably carried out at temperatures between 20 and approx. 120°C. According to the method of Wolff-Kishner, the compounds of formula III can first be transferred into their hydrate zones and these are then treated with strong bases such as e.g. alkali metal hydroxides or alcoholates;

The Wolff-Kishner reduction is carried out preferably according to the method variant of Huang-Minlon, as e.g. the compounds of formula II-1 are brought into reaction with hydrazine hydrate in the presence of an alkali metal hydroxide and an under the reaction conditions inert high-sided polar water-miscible organic solvent at temperatures between approximately 20 and 220°C.

The water separation from the compounds of formula IV according to process variant c) can be carried out in a manner known per se, e.g. by the action of suitable water-splitting agents on the compounds of formula IV, optionally with the addition of a solvent inert under the reaction conditions. As a water-releasing agent, e.g. strong cyphers or also acid anhydrides or acid halides are used. If Rg in the compounds of formula III stands for an acidolytically cleavable residue, e.g.

an alkyl, especially lower alkyl or aryl group, the water cleavage is suitably carried out for simultaneous cleavage of the residue Rg by means of strong acids.

The compounds of formula I which can be prepared by the method according to the invention can be in the form of the free acids or their salts. The free acids can be transferred in a manner known per se into their salts and vice versa. If in the compounds of formula I A pg-Rg, together with the carbon atom to which they are attached, form a cycloalkylene ring as defined above, the mixtures of cis- and trans-isomers obtained by the method according to the invention can be separated, in and of themselves known way, e.g. by fractional crystallization.

The output connections can be made in the following way:

a') Compounds of formula II can e.g. is produced by compounds with the form V

wherein R^, R<*>, r*, r^ and A1 have the above meaning and

<R>100<=* R11*lver means lower alkyl, is hydrolyzed and, if desired, a halogen atom R^ is introduced in a manner known per se into the dicarboxylic acids obtained. If desired, the acids of formula II can be converted into derivatives in a manner known per se, e.g. halides.

b'.) The compounds with formula V can e.g. forwarded by

that compounds of formula VI

in which R^, Rg, R*, Rg, A1 and R^q have the above meaning, are converted under oxidizing conditions. The oxidizing conversion can be carried out according to methods known per se, e.g. in that compounds of formula VI are oxidized with thallium-III trinitrate in the presence of a strong acid and an alcohol R-^OH. c') If R^ stands for methyl or ethyl, the compounds of formula VI are preferably transferred in a manner known per se first by reaction with phosphorus pentachloride in an inert aprotic solvent to compounds of formula VII,

I I I I

in which R^, Rg, Rg, R^, A and have the above-mentioned meaning, from these are cleaved with the aid of sodium methylate in a bipolar aprotic solvent, e.g. dimethylsulfoxide, hydrochloric acid and the obtained compounds of formula VIII,

wherein R^, Rg, Rg, R*, A1 and R^q have the above-mentioned meaning, is transferred by treatment with thallium-III trinitrate in the presence of an alcohol R1QOH in compounds of formula V. d<1>) The compounds of formula WE can e.g. is prepared by compounds of IX in which Rg, Rg, R*, A* and R^q have the above meaning are acylated by compounds of formula X in which R^ has the above meaning, under the conditions of a Friedel-Crafts reaction. e<1>) The compounds of formula IX can, for example, are prepared by compounds of formula XI, I I IV in which Rg, R^q and A have the above meaning, Rg means hydrogen or alkyl with 1-4 carbon atoms and rIV stands for IV I o hydrogen or, if Rg and Rg mean hydrogen, also stands for alkyl, is reduced by catalytic hydrogenation. and the obtained compounds of formula IXa in which R^/Rg>R^/A1 and R1Q have the above-mentioned meaning, if desired alkylated to disubstituted compounds of formula IX in the a-position of the ester group. For alkylation in the a-position of the ester group, the compounds of formula IXa can be reacted in a manner known per se with alkyl halides or, if Rg stands for hydrogen, if desired also for the introduction of an Rg-R^-alkylene chain, reacted with LU-alkyldi -halides in the presence of strongly basic condensation agents, e.g. alkali metal amides or hydrides. f) The compounds of formula XI can e.g. is produced by compounds of formula XII,

in which Rg,R^<V>and A<1>have the above meaning, are reacted with compounds of formula XIII

IV

wherein Rg and R^Q have the above meaning.

The reaction leads to isomeric mixtures of compounds

with formula XI and thus isomeric compounds, in which the ester group is arranged (the 3-position of the double bond, and which by catalytic hydrogenation is transferred in connection with formula IXa.

g<1>) Compounds of formula .III, in which Rg means a hydrolytic

cleavable residue, can be prepared from the corresponding acids.

h') Compounds of formula III, in which R^<1> and Rg11 together form a bond, can e.g. is produced by the keto group in corresponding compounds of formula III, in which R^1 and R*1 together mean oxygen, is reduced to the hydroxy group and water is then split off from the hydroxy compounds obtained.

i') Compounds of formula ..IV can be prepared from corresponding compounds of formula Ia in that in these the keto group, optionally after introduction of an acidolytically cleavable residue Rg, is reduced to the hydroxy group.

To the extent that the preparation of the starting compounds is not described, these are known or can be prepared according to i and for. known methods respectively analogous to those described here or analogously to methods known in and of themselves.

The compounds of formula I and their physiologically tolerable salts are distinguished by interesting pharmacological properties and can consequently be used as medicine.

Thus, in animal experiments, the compounds show particularly antiphlogistic properties and inhibit e.g. in rats the edema formation in the carrageenan poteoedema test.

The compounds of formula I show in animal experiments analgesic properties and inhibit e.g. the phenylbenzoquinone syndrome in mice.

Due to their antiphlogistic properties, the compounds can be used as antiphlogistics or to inhibit the exudation in bone inflammations or in oedemas.

Due to their analgesic effect, the compounds can be used for the treatment of pain of various origins.

As medicine, the compounds of formula I and their salts can be contained together with common pharmaceutical excipients in galenic preparations, such as e.g. tablets, capsules or solutions. These galenic preparations can be prepared according to known methods per se.

In the following examples which illustrate the invention in more detail, all temperature indications are in °C.

EXAMPLE 1 6i2l§l5zt?t£5hYÉ£2l7lEl?^Xi~9I0^sol5?Z^B55l

cycloheptene-2-acetic acid

To 200 g polyphosphoric acid is added while stirring at 100°C

17.8 g of 5-(4-carboxymethylphenyl)-3-methylvaleric acid. The reaction mixture is stirred for 1 hour at 100°C, cooled to approx. 60°C and add 100 ml of water drop by drop. The reaction mixture is then poured onto ice, extracted with methylene chloride, the methyl chloride extract is washed with water and dried over sodium sulfate. The 6,7,8,9-tetrahydro-7-methyl-9-oxo-5H-benzo-cycloheptene-2-acetic acid obtained after evaporation of the solvent is purified by chromatography on silica gel. Melting point of the compound mentioned in the title 105 - 107°C (from acetonitrile). Melting point of the cyclohexylammonium salt of the compound mentioned in the title 135 137°C

(from acetonitrile).

The starting material can be produced in the following way:

a) To a solution of sodium methylate (prepared from 67 g of sodium) in 1000 ml of methanol, a solution of 292 g of (diethylphosphono) acetic acid methyl ester in 200 ml of methanol is added dropwise at 0 - 5°C with stirring. It is stirred at 0 - 5°C for 15 min., a solution of 215 g of benzylacetone in 200 ml of ethanol is added dropwise and stirred for 18 hours at room temperature. 55 ml of acetic acid are then added dropwise, the solution is evaporated, diluted with water and extracted with ether. The ether extract is washed with 3% sodium bicarbonate solution, dried over sodium sulphate and evaporated. The remaining 3-methyl-5-phenylpent-2-renoic acid methyl ester is purified by distillation. Boiling point ^ 132 - 135°C. The 3-methyl-5-phenylpent-2-enoic acid-i.. methyl ester obtained above is dissolved in 1.5 1 of ethanol and hydrogenated with the addition of 10 g of palladium charcoal (10%) at 1 atmosphere of hydrogen pressure and 25°C. After absorbing the theoretical amount of hydrogen, it is filtered and the solution is evaporated. The remaining 5-phenyl-3-methylvaleric acid methyl ester is purified by distillation. Boiling point Q Q3 = 98 - 101°C.

b) In a suspension of 46.5 g of aluminum chloride in 250 ml of methyl-. chlorine is added dropwise at 0 - 5 oC while stirring a solution of

20.6 g of 5-phenyl-3-methylvaleric acid methyl ester and 14.7 g of acetyl chloride in 50 ml of methylene chloride in the course of 10 min. The solution is stirred for 3 hours at room temperature and then poured into ice-cold water. The mixture is extracted with methylene chloride

the extract is washed with water, dried over sodium sulfate and evaporated; The remaining crude 5-(4-acetylphenyl)-3-methylvaleric acid methyl ester is further processed directly.

c) A solution of 32.2 g of thallium-III trinitrate and 10 ml of _70 aqueous perchloric acid in 200 ml of methanol is added under

stirring a solution of 17.2 g of 5-(4-acetylphenyl)-3-methyl-. valeric acid methyl ester in 100 ml of methanol. The reaction mixture is stirred at room temperature for 16 hours, filtered, the filtrate

then diluted with water and extracted with chloroform. After evaporation of the water-washed, sodium sulfate-dried chloroform phase, the crude 5-(4-carboxymethoxymethylphene) becomes;

3-methylvaleric acid methyl ester back, which is purified by distillation. Boiling point QQ5= 174 - 178°C.

d) To dissolve 19.3 g of 5-(4-carboxymethoxymethylphenyl)-3-methylvaleric acid methyl ester in 200 ml of methanol, add a

solution of 20 g of potassium hydroxide in 40 ml of water and heated for 2 hours under reflux. The solution is then evaporated,

diluted with water, acidified with 2 N hydrochloric acid and extracted with ether. The crude 5-(4-carboxymethylfehyl-3-methylvaleric acid obtained after evaporation of the ether extract) is recrystallized from ether/hexane. Melting point 100 - 102°C.

EXAMPLE 2: 5^6^7^8-tetrahydro-e-a-d^

acetic acid.

4-£4-(1-carboxyethyl)phenyl]|-2-methylbutyric acid is ring-closed with polyphosphoric acid analogously to example 1. Melting point of the cyclohexylammonium salt of the compound mentioned in the title is 196 - 199°C (from methanol/ether). '

The starting material can be produced in the following way:

a) 2-methyl-4-(4-propionylphenyl)butyric acid methyl ester, prepared analogously to example 1b from 4-phenyl-2-methylbutyric acid methyl ester

and propionyl chloride, Boiling point Q Q5 = 150 154°C

b). To a solution of 76.8 g of 2-methyl-4-(4-propionylphenyl)butyric acid methyl ester in 1 liter of anhydrous ether, add 193 g

phosphorus pentachloride and the mixture is stirred for 16 hours at

room temperature and. then heated for 1 hour under reflux.

The mixture is slowly poured onto ice, stirred for 1 hour and extracted with ether. The 4-[4-(1-chloro-1-propenyl)-phenyl}-2-methylsuccinic acid methyl ester obtained after evaporation of the ether extracts is distilled under vacuum (coiler) Boiling point Q6 = 160 - 170°C.

c) To a solution of 78 g of 4-[^4-(1-chloro-1~propenyl)-phenyl^}-2-methylbutyric acid methyl ester in 500 ml of dimethylsulfoxide is added

78 g of sodium methylate and the solution is stirred for 2 hours at

room temperature, and neutralized with 180 ml of 50% sulfuric acid. The mixture is diluted with water and extracted with ether. , The ether extract is washed with water, dried over sodium sulphate and evaporated. The remaining oily 2-methyl-4jjl-(1-propenyl)phenyl-Q butyric acid methyl ester is further processed directly.

d) To a solution of 124 g of thallium trinitrate trihydrate

in 400 ml of methanol is added under ice-cooling in a solution

of 64 g of 2-methyl-4^4-(1-propenyl)phenyl]butyric acid methyl ester.

The mixture is stirred for 1 hour at room temperature, filtered,

the filtrate is diluted with 1 1 of water and extracted with methylene chloride. The methylene chloride extract is washed with water, dried over sodium sulphate, evaporated and the remaining 4£.4-(1-carbomethoxyethyl)phenyl]-.2-methylbutyric acid methyl ester is distilled in a still, Boiling points .. = 160 - 170°C.

e) 4-[4-(1-carboxyethyl)phenyl]-2-methylbutyric acid is prepared analogously to example ld. Melting point 107 - 109°C

(from hexane/ether).

EXAMPLE 3: 1-isobutyl-3-oxo-S-indaneacetic acid^

4-carboxymethyl-P-isobutyldihydrocinnamic acid is cyclized analogously to example 1. Melting point of the cyclohexylamine salt of the compound mentioned in the title 140 - 142°C (from methanol/ether).

The starting material can e.g. produced in the following way:

a) in a suspension of 100 g of zinc dust and some crystalline iodine in 100 ml of benzene is added dropwise over the course of 30 min. in a solution

of 16.2 g of 3'-methylbutyrophenone and 18 g of bromoacetic acid methyl ester in 100 ml of benzene. The solution is heated for 2 hours below

reflux, cooled to room temperature, filtered, diluted with 2% hydrochloric acid and extracted with ether. The extract is washed with water, dried over sodium sulphate and evaporated. The crude |3-hydroxy-|3-isobutyldihydrocinnamic acid methyl ester is further processed directly.

In a solution of 18.9 g of p-hydroxy-(3-isobutyldihydrocinnamic acid methyl ester and -2.5 g of p-toluenesulfonic acid in 400 ml. benzene is heated for 2 hours under reflux (water separator). The cooled solution is washed with 1% sodium bicarbonate solution, dried over sodium sulfate and evaporated. The crude mixture of unsaturated (3-isobutyldihydrocinnamic acid methyl ester. further processed directly.

15.8 g of the above-obtained mixture of unsaturated esters are dissolved in 400 ml of ethanol and hydrogenated with the addition of 0.3 g of platinum (IV) oxide catalyst at 1 atmosphere of hydrogen pressure and 25°C. After absorbing the theoretical amount of hydrogen, it is filtered and the solution is evaporated. The remaining (3-isobutyldihydrocinnamic acid methyl ester - distills at 91 - 100°C/0.02 mm. b) From the above product is prepared analogously, with example lb to ld 4-carboxymethyl-P-isobutyldihydrocinnamic acid,

melting point 143 - 147°C.

Analogous to examples 1-3, the following compounds of formula Ia mentioned in Table 1 are also prepared by cyclization of corresponding compounds of formula II.

EXAMPLE 4: 6z®tyl-516^718-tetrahydronaphthalene-2-acetic acid^

5.4 g of 6-ethyl-5,6,7,8-tetrahydro-8-oxonaphthalene-2-acetic acid are dissolved in 150 ml of acetic acid and hydrogenated while adding 1 g of palladium/charcoal (10%) and 2 ml of 70% aqueous perchloric acid at 4 atmospheres of hydrogen pressure and 45°C. After absorbing the theoretical amount of hydrogen, it is filtered, 2 g of sodium acetate are added and the solution is evaporated. The residue is extracted between ether and water, the ether extract is filtered over sodium sulphate and evaporated. The remaining 6-methyl-5-6,7,8-tetrahydro-naphthalene-2-acetic acid is recrystallized from hexane and melts at 64--66°C.

Analogous to example 4, the following are also produced in a table

2 listed compounds of formula Ib. by reduction of the corresponding keto compounds:

EXAMPLE 5: 6i.Zldi^y^5lZzm®tYil^Ib?n52cY^i2^eBtenZ2z5dÉi^YE®l

5.9 g of 6,7,8,9-tetrahydro-9-hydroxy-7-methyl-5H-benzo-cycloheptene-2-acetic acid are dissolved in 50 ml of benzene, 1 g of p-toluenesulfonic acid is added and the solution is boiled for 3 hours under j return. The solution is diluted with water, extracted with benzene,

. the benzene extract - washed with water, dried over sodium sulphate

and evaporated. The crude 6/7-dihydro-7-methyl-5H-benzocycloheptene-2-acetic acid is purified by chromatography on silica gel. - Melting point of the compound mentioned in the title 80 - 82 C (from hexane) .

The starting material can be produced in the following way:

a) 6,7,8,9-tetrahydro-7-methyl-9-oxo-5H-benzocycloheptene-2-acetic acid (6.3 g) is dissolved in 90 ml of methanol and added

.4.1 g sodium borohydride in small portions, .i. the course of 10 min.

'•• -r under stirring at room temperature.-The solution is then stirred in

30 min., dilute with water, make acidic with IN hydrochloric acid

and the crude 6,7,8,9-tetrahydro-9-hydroxy-7-methyl-5H-benzocycloheptene-2-acetic acid is filtered off. Melting point of the raw product 161 - 163°C.

Claims (1)

Process for the preparation of new organic compounds of formula I in which R., means hydrogen or alkyl with 1-2 carbon atoms, R2 means hydrogen or halogen with an atomic weight below 80, R^ and R^ each stand for hydrogen or together stand for oxygen and, Rg means hydrogen or alkyl of 1-4 carbon atoms, or, if Rg and R^ are attached to the same carbon atom, Rg and R^ together form an alkylene chain of 3-6 carbon atoms or, if A stands for a (CH2) 2- group, too - R^ and Rg together form a bond and R^ means hydrogen, Rg stands for hydrogen or alkyl with 1-4 carbon atoms and A stands for a (CH2 )n group, in which n, if R^ and R^ jointly mean oxygen, stands for 0 or n, if at least one of the susbstituents Rg, Rg and R^ means alkyl with 1-4 carbon atoms or Rg and R^ together mean . an alkylene chain with 3-6 carbon atoms or if R5/Rg °<3 R^ means hydrogen, R^ bg R^ together means oxygen and R2 means halogen with an atomic weight below 80, stands for 1:: or m, if R^ and R ^ means oxygen or. R^ and Rg together form a bond or if R2 means halogen with an atomic weight below 80 or, if at least one of the substituents R^, Rg, Rg and R^ means alkyl with 1-4 carbon atoms or Rg and R^ together means an alkylene chain with 3 - 6 carbon atoms, stands for 2 or if Rg and R7 mean hydrogen, also R, and A together with the carbon atom to which they are_bonded, forms a 1,2-cycloalkylene group of formula wherein m means 3 or , if R^ and R^ together stand for oxygen,, also means 4, R^ stands for hydrogen or if Rg means hydrogen, too for alkyl with 1-4 carbon atoms and their salts / • • characterized by ata) for the preparation of compounds of formula Ia in which R., and R2 has the above meaning, Rc stands for hydrogen, alkyl with 1-4 carbon atoms or, II I if Rg and R^ are bound to the same carbon atom, Rg together with R™ represents an alkylene chain with 3-6 carbon atoms, R^ I stands for hydrogen or alkyl with 1-4 carbon atoms and A stands for a (CH9) i group, in which Io n stands for 0 or 2 or n if at least one of the substituents R ? if R<*> and R~ mean hydrogen, also I I R, - and A together with the carbon atom to which they are attached, forms a 1,2-cycloalkylene group of formula wherein m1 means 3 or 4, R* stands for hydrogen or, if Rg means hydrogen, also for alkyl with 1-4 carbon atoms, ring-closed compounds of formula II fr R <g> COOH CH-COOH R7 r RI ^A-A 1/^^ 2 <1> I I I I in which R.^ , R.sub.2 , Rg/ Rg/ R^ and A have the above-mentioned meaning, or their reactive acid derivatives, or for the preparation of compounds of formula Ib, I I Rl TTRI R3 IR ,t 2 in which R1 and R9 have the above meaning, I I R^ and R^ each represent hydrogen, R <*1> means hydrogen or alkyl with 1-4 carbon atoms II II or, if R- and R_ are attached to the same carbon atom, II II Rg and R^ together form an alkylene chain with 3-6 carbon atoms, R^1 stands for hydrogen or alkyl with 1-4 carbon atoms and A stands for a (CH2 )n II group, in which n if at least one of the substituents R,. R, -and R7 mean Il II alkyl with 1-4 carbon atoms or Rg and R7 together means an alkylene chain with 3-6 carbon atoms, stands for 1, or n11, if R„ means halogen with an atomic weight below 80, or if II II II at least one of the substituents R,, RR, R, and R- means alkyl with 1-4 carbon atoms or RIg I and R7 II together means an alkylene chain with 3-6 carbon atoms, stands for 2, or, if R <g1> and R <*1> are hydrogen, also R^1 and A <11> together with the carbon atom to which they are attached form a 1,2-cyclopentylene group with the formula (C*^)3 - compounds of formula III are reduced wherein R1 , R», R <*1> , R <*1> and A <11> have the above meaning, II II RA and R., together stand for oxygen and RI- II stands for hydrogen or alkyl with 1-4 carbon atoms or, III II II if Rj- and R7 are bound to the same carbon atom, R_ and II R7 form an alkylene chain with 3-6 carbon atoms or R^* and Rg"^ together form a bond and R** stands for hydrogen and Rg means hydrogen or, if R^1 and R <*1> together stand for oxygen, means a hydrolytically cleavable residue, and if Rg means a hydrolytically cleavable residue, this is cleaved at the same time, or c) for the preparation of compounds of formula Ic , in which Rl' R2°^ R3 'where ^a above-mentioned meaning and R^ <11> means hydrogen or alkyl with 1-4 carbon atoms, water is split off from compounds of formula IV, in which R^ , R2 , R* and R*11 have the above meaning and Rg means hydrogen or an acidolytically cleavable residue, and if R^ stands for an acidolytically cleavable residue, this is also cleaved at the same time and the obtained compounds of formula I are optionally transferred in their salts.