NO750264L - - Google Patents

Description

The present invention relates to a process for the production of new carbocyclic compounds of formula I

in which R~ means hydrogen or an alkyl group with 1-4 carbon atoms and R means an alkyl group with 2-10 carbon atoms, a cycloalkyl group with 3-8 carbon atoms or a phenyl group, and if R ? means an alkyl group with 1-4 carbon atoms, R^ also stands for a methyl group.

The peculiarity of the method according to the invention for producing the compounds of formula I is that either

a) compounds of formula II

in which R^ and R^ have the above meaning, 1 is actonized,

or compounds of formula I'

in which ' stands for an alkyl group with 2-10 carbon atoms, a cycloalkyl group with 3-8 carbon atoms or a phenyl group and R2' stands for hydrogen, is prepared by

b) compounds of formula III

wherein R^' has the above meaning, is treated with Raney nickel, or compounds of formula I"

in which R^ has the above meaning and R2" stands for an alkyl group with 1-4 carbon atoms, is prepared by

c) compounds of formula IV

in which R1 has the above meaning and R2" stands for an alkyl group with 1-4 carbon atoms and Ac stands for the acetyl residue, is hydrogenated catalytically.

For R1, the preferred alkyl groups have 2-4 carbon atoms and are especially the isopropyl and isobutyl group, preferred cycloalkyl groups have 5-7 carbon atoms, especially the cyclopentyl and cycloheptyl group, and especially the cyclohexyl group. For R^, the preferred alkyl groups have one or two carbon atoms, and are especially the methyl group.

The turnover according to the invention according to the method

a) can occur by lactonizing the compounds of formula II in the presence of a catalytic amount of an acid, e.g. concentrated

sulfuric acid or p-toluenesulfonic acid. The water formed during the lactonization can be continuously distilled off with an inert solvent, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene. If water-binding acids such as hydrogen chloride or concentrated sulfuric acid are used, the water formed does not need to be distilled off.

After completion of the reaction, the compounds of formula I can be isolated

and cleaned according to known methods.

The compounds of formula II and their salts used as starting material are prepared by e.g. compounds of formula V

wherein R has the above Meaning, in a solvent inert under the reaction conditions, such as benzene or carbon tetrachloride is reacted at 20 - 80°C with acetyl chloride in the presence of a Friedel-Crafts catalyst, preferably with stannous chloride, the formed compounds of formula VI in which R^ has the above meaning is allowed to react with sulfur and morpholine, the thus obtained compounds of formula* VII in which R^ has the above meaning are saponified with alcoholic alkali hydroxide solution and the thus obtained compounds of formula VIII in which R^ has the above meaning, is treated with a boron trihalide, preferably boron tribromide, or with a hydrogen halide, preferably hydrogen bromide, whereby compounds of formula II'

in which R ■ and R^' have the above-mentioned meaning, is obtained.

Compounds of formula II are new.

Of the compounds of formula II, those in which R^ means an alkyl group with 2-10 carbon atoms and R^ has the above meaning, in which R^ means a cycloalkyl group with 3-8 carbon atoms and R£ means hydrogen or in which R^ means a phenyl group and -R^ means an alkyl group with 1-4 carbon atoms.

The method a) according to the invention can also be used for the preparation of compounds of formula I', in which R^' and R^' have the above meaning, in that a compound of formula VIII, directly without isolation of the resulting compound of formula II', treated with a boron trihalide or with hydrogen halide.

The previously unknown compounds of formula II used as starting material can e.g. also produced by compounds with formula

IX

in which R^ has the above meaning, in the presence of a base is reacted with 2-haloalkyl acid alkyl ester, the formed compounds of formula

X

in which R^ and R^" have the above-mentioned meaning and R^ stands for an alkyl group with 1-4 carbon atoms, saponified with alcoholic alkali hydroxide solution and the formed compounds of formula XI in which and R^" have the above-mentioned meaning, irradiated with ■ultraviolet light , whereby compounds of formula II"

in which R^ and R^" have the above meaning, is obtained.

The compounds of formula II (the compounds of formula II<*>and II") can optionally be transferred in a manner known per se in their salts.

Method b) according to the invention can be carried out in such a way that compounds of formula III are dissolved in a suitable solvent, such as e.g. ethyl acetate, dioxane, etc. and then moist neutral raney^nickel is added, preferably at room temperature for complete desulphurisation.

The reduction is carried out under normal conditions or under elevated pressure and/or temperature.

After completion of the reaction, the compounds of formula I<*> can be isolated and purified using known methods.

The previously unknown compounds of formula III used as starting material are prepared by reacting compounds of formula IX with aluminum chloride and oxalyl chloride and the formed compounds of formula XII

in which R^ has the above meaning, in the presence of an acid is reacted with ethanedithiol.

Method c) according to the invention can be carried out in

the way that compounds of formula IV are dissolved in a solvent inert under the reaction conditions, such as e.g. ethyl acetate, dioxane, etc. and hydrated with the possible addition of a buffer (phosph.at.

pH 7). The reaction takes place preferably at room temperature and normal pressure. Of the usual hydrogenation catalysts, above all palladium catalysts, especially on supports, have proved beneficial. After completion of hydrogen uptake, the catalyst is filtered off and the compounds of formula I" are isolated and purified by means of methods known in the art.

They used previously unknown compounds as starting material

with formula IV is prepared by reacting compounds of formula XII with a compound of formula XIII

wherein R^" has the above-mentioned meaning, to a compound of formula XIV wherein and R^" has the above-mentioned meaning, and the latter compound is then allowed to react with acetic anhydride or acetic anhydride/pyridine at room temperature or under reflux. The compounds of formula I as well as the compounds of formula II used as starting material and their salts have not previously been described in the literature. They stand out in the pharmacological test with varied and strongly pronounced effects and can therefore be used as medicines. Thus, the compounds of formula I and II have an anti-edematous and anti-inflammatory effect, which can be demonstrated by carrageenan edema tests in rats in doses of 60 mg/kg p.o. Furthermore, the compounds of formula I and II have a fever-reducing and analgesic effect, which can be detected in yeast fever in rats in doses of 30 mg/kg s.c., and in the phenylbenzoquinone outline test in mice in doses of 50 mg/kg p.o. The dose used varies, of course, depending on the method of administration and the condition to be treated. Usually, however, with experimental animals, satisfactory results are achieved with a dose of 1 -

100 mg/kg body weight. If necessary, this dose can be given in 2 to 3 partial doses or also as a slow-release form. For larger mammals, the daily dose is 20 - 1000 mg. For oral administration, a suitable administration form contains 20 - 500 mg of the active compound, mixed with liquid or solid carrier substances.

Compounds that have proven particularly suitable are the following: 6-cyclohexyl-2,3-dihydrobenzofuran-2-one

6-cyclohexyl-2,3-dihydro-3-methylbenzofuran-2-one

4'-cyclopentyl-2'-hydroxyphenylacetic acid.

As a medicine, the new compounds can be added to the body or in suitable preparation form together with pharmacologically indifferent excipients.

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

Example 1; 6-cyclohexy1-2,3-dihydro-benzofuran-2-one

5'. 0 g of 4'-cyclohexyl-2'-hydroxy-phenylacetic acid is refluxed in the presence of 50 mg of p-toluenesulfonic acid in 200 ml of toluene for 2 hours with water separation. The solution is evaporated and the residue is chromatographed on 250 g of silica gel. With methylene chloride, 6-cyclohexyl-2,3-dihydrobenzofuran-2-one is uniformly eluted, which after two crystallizations from petroleum ether melts at 80 - 81°C.

The 4'-cyclohexyl-2<1->hydroxy-phenyl-acetic acid used as starting material is prepared in the following way:

a^ ^lz£y]Si2!2f=?S5Yiz2^3methoxy-acetophenone._

20 g of 3-cyclohexylanisole are dissolved in 200 ml of benzene, 8.15 g of acetyl chloride are added and then, with stirring at 5 - 10°C, 27.4 g of stannous chloride are added dropwise. After stirring for 16 hours at 23°C, the mixture is poured onto ice and extracted 3 times with benzene. The organic phase is washed one after the other with 2N hydrochloric acid, 2N caustic soda and water, dried over anhydrous sodium sulfate and evaporated. The residue is recrystallized from acetone-petroleum ether. Temp. of the compound mentioned in the title thus obtained is 99 - 100°C.

b) 4'-cyclohexyl-2'-methoxy-phenylthioacetic acid morphol id.

15.0 g 4'-cyclohexyl-2'-methoxy-acetophenone, 4.05 g sulfur and 11.0 g

morpholine is boiled for 16 hours under reflux. The reaction mixture is poured onto ice and extracted 3 times with methylene chloride. The organic phases are washed twice with water, dried over anhydrous sodium sulfate and evaporated. The residue, which consists predominantly of 4'-cyclohexyl-2'-methoxyphenylthio acetic acid morpholide, is recrystallized from ethanol. Temp. 140 - 141°C.

c) 4^-cyclohexyl-2^-methoxy-phenylacetic acid.

15.0 g 4'-cyclohexyl-2'-methoxy-phenylthioacetic acid morphol id

suspended in 70 ml of ethanolic 3N KOH and boiled for 16 hours under reflux. The reaction solution is evaporated vigorously, acidified with 2N hydrochloric acid and extracted 3 times with methylene chloride. The organic phases are washed twice with water, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from methylene chloride-petroleum ether.

The compound mentioned in the title with a melting point of 132 - 136°C is obtained.

d) 4^_-cyclohexyl-2'-hydroxy-phenylacetic acid.

Dissolve 6.0 g of 4'-cyclohexyl-2'-methoxy-phenylacetic acid in 100 ml

dry methylene chloride and add 12 ml of boron tribromide dropwise at 0°C with stirring. After 30 minutes, the reaction mixture is added to approximately 200 ml of 2N NaOH while stirring due to cooling.

Then acidify with 2N hydrochloric acid until the pH is equal to 1 and extract

three times with methylene chloride. The organic phases are washed twice with water, combined, dried over sodium sulphate and evaporated. The residue is crystallized from methylene chloride-petroleum ether. The thus obtained 4<1->cyclohexyl-2'-hydroxy-phenylacetic acid melts at 108 - 109°C.

Example 2: 6-cyclopentyl-2,3-dihydro-benzofuran-2-one

5.0 g of 4'-cyclopentyl-2'-hydroxy-phenylacetic acid is boiled under reflux in the presence of 50 mg of p-toluenesulfonic acid in 200 ml of toluene for 2 hours with water separation. The solution is evaporated and the residue is chromatographed on

250 g silica gel. With methylene chloride, 6-cyclopentyl-2,3-dihydro-benzofuran-2-one is uniformly eluted, which after two crystallizations from petroleum ether melts at 42 - 43°C.

The 4'-cyclopentyl-2'-hydroxyphenylacetic acid used as starting material is prepared analogously to examples la, b, c and d.

Example 3; 6-cyclohexyl-2,3-dihydro-benzofuran-2-one

Dissolve 4.5 g of 4'-cyclohexyl-2'-methoxy-phenylacetic acid in 100 ml of dry methylene chloride and add 10 ml of boron tribromide dropwise at 0°C with stirring. After 30 minutes, the reaction mixture is added dropwise while cooling and stirring to 500 ml of ice-mixed water and then extracted three times with methylene chloride. The organic phases are washed twice with water, combined, dried over anhydrous sodium sulfate and evaporated. The crude product is boiled with 20 mg of p-toluenesulfonic acid in 150 ml of toluene for 2 hours with a water separator. The solution is evaporated and the residue is chromatographed on 200 g of silica gel. With methylene chloride, 6-cyclohexyl-2,3-dihydro-benzofuran-2-one is uniformly eluted which, after two crystallizations from petroleum ether, melts at 80 - 81°C.

Example 4: 2,3-dihydro-6-isobutyl-benzofuran-2-one

7.2 g of 2'-hydroxy-4'-isobutyl-phenylacetic acid is taken up in 100 ml of toluene, 20 mg of p-toluenesulfonic acid is added and boiled for 2 hours with a water separator:; The solution is evaporated and the residue is chromatographed on 350 g of silica gel. With chloroform, uniform 2,3-dihydro-6-isobutyl-benzofuran-2-one is isolated which, after crystallization from petroleum ether, melts at 24 - 25°C.

The 2•-hydroxy-4'-isobutyl-phenyl-acetic acid used as starting material is prepared in the following way:

a) 4'-isobuty1-2^-methoxy^acetof enone_

46 g of 3-isobutylanisole are mixed with 500 ml of abs. benzene and added

22 g acetyl chloride. Then, while stirring and cooling at 5 - 10°C, 73 g of stannous chloride are added dropwise. After stirring for 16 hours at 23°C, the reaction mixture is poured onto ice, washed once with 2N hydrochloric acid, twice with 2N NaOH and once with water, the aqueous phases are subsequently extracted twice with benzene. -The organic phases are dried over anhydrous sodium sulfate and evaporated. From methanol, the desired product can be extracted pure in amorphous form by careful addition of water.

NMR spectrum (CDClg) i.a. é = 0.9 d (J = 6 Hz), 1.3 - 2.3 m, 2.45 s, 2.55 s, 3.9 s, 6.6 - 6.9 m, 7.65 d (J = 8.6).

b) 4'-isobutyl-2'-methoxy-phenylthioacetic acid morphol id

29.1 g 4'-isobutyl-2'-methoxy-acetophenone, 9.02 g sulfur and 24.6 g

morpholine is boiled for 16 hours under reflux. The reaction mixture is poured onto ice and extracted 3 times with methylene chloride, the organic phases are washed with water until the aqueous phase becomes neutral, dried over anhydrous sodium sulfate and evaporated. The oily residue is chromatographed on silica gel. The desired substance is eluted with chloroform and crystallized from ether/petroleum ether. Temp. 81 - 83°C.

c) 4'-isobutyl-2'-methoxy-phenylacetic acid

22.8 g of 4'-isobutyl-2<1->methoxy-phenylthioacetic acid morpholide is boiled in

200 ml of 3N ethanolic KOH for two hours under reflux, then acidify with 2N hydrochloric acid, dilute with water and extract with methylene chloride. The methylene chloride phase is washed 4 times with water, dried over sodium sulphate and evaporated. The residue can be crystallized from ether/petroleum ether. Temp. 71 - 73°C.

d) 2^-hydroxy-4^-isobutyl-phenylacetic acid

8g of 4'-isobutyl-2'-methoxy-phenylacetic acid is dissolved in 20 ml of dry methylene chloride and 15 ml of boron tribromide is added dropwise while stirring at 0°C. The cooling bath is then removed and it is stirred further for 30 minutes at room temperature. Next, approximately 50 ml of 2N NaOH is added dropwise to the reaction mixture while stirring and cooling. Then acidify with 2N hydrochloric acid to pH 1 and extract 3 times with methylene chloride.

The organic phases are washed twice with water, combined, dried over sodium sulphate and evaporated. The remainder is crystallized from petroleum ether. Temp. 81 - 82°C.

Example 5: 2,3-dihydro-6-phenyl-benzofuran-2-one.

5 g of 25-hydroxy-4<1->phenyl-phenylacetic acid is boiled under reflux in the presence of 50 mg of p-toluenesulfonic acid in 200 ml of toluene for 2 hours with water separation. The solution is evaporated and the residue is chromatographed on

125 g silica gel. With methylene chloride, uniform 2,3-dihydro-6-phenyl-benzofuran-2-one is eluted, which after decolorization with activated charcoal in methylene chloride is crystallized from methylene chloride-petroleum ether. Temp.

109 - 110°C.

NMR spectrum (CDCl 3 ): é> = 3.77 S (2H); 7.2 - 7.7M (8H) .

The 2'-hydroxy-4V-phenyl-phenylacetic acid used as starting material is prepared in the following way:

a) 3-Methoxybif eny 1

102 g of 3-hydroxybiphenyl is dissolved in a solution of 67.8 g of potassium hydroxide

in 650 ml of water. While stirring, 86.6 ml of dimethylsulphate is added dropwise over the course of 30 minutes, whereby the reaction mixture is heated. The mixture is then held for 15 minutes at 75°C. After 1 hour, a further 33.6 g of potassium hydroxide in 45 ml of water are added dropwise and then, over <:>15 minutes, 37.8 g of dimethylsulphate at 65°C. The mixture is kept for 1 hour at 75°C. After a/cooling, the oily layer is separated and taken up in methylene chloride. It is washed once with 2N sodium hydroxide and once with water. It is extracted a further 2 times with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulfate

and evaporated. 3-Methoxybiphenyl is obtained which is used for the next step without purification.

b) 2'-Methoxy-4_|_-phenyl-acetof enone" "

To a solution of 36.8 g of 3-methoxybiphenyl and 15.6 g of acetyl chloride in

700 ml of benzene are added dropwise under vigorous stirring at 5°C to 52 g of SnCl3. It is stirred overnight at 23°C. The reaction mixture is washed twice with 2N sodium hydroxide and twice with water. It is then extracted twice with toluene. The organic phases are combined, dried over anhydrous sodium sulphate and evaporated. 44 g of raw

product which is chromatographed on the twenty-fold amount of silica gel. Solvent for application and elution: Methylene chloride. Crystallization of the pure fractions from ether-petroleum ether gives 4-acetyl-3-methoxy-biphenyl with m.p. 74 - 75°C.

c) 2'-methoxy-4_|_-phenyl-phenyl thioneacetic acid-morphol id_

17.4 g 4-acetyl-3-methoxy-biphenyl, 14 g morpholine and 5.1 g sulfur

boil under reflux for 6 hours. The reaction mixture is taken up in ether, washed once with 2N hydrochloric acid and twice with water. It is further extracted twice with ether. The organic phases are combined, dried over anhydrous sodium sulfate and evaporated. Crystallization of the residue from methylene chloride-ether gives 2'-methoxy-4'-phenyl-phenylthione-acetic acid morphol id . Temp. 132 - 133°C.

d)'2'-methoxy-4'-phenyl-phenylacetic acid

18.8 g of 2'-methoxy-4'-phenyl-phenylthioacetic acid morpholide is boiled over

overnight under reflux in 90 ml of 3N-ethanolic potassium hydroxide. The reaction mixture is evaporated, the residue is dissolved in water, as the solution must be strongly alkaline. It is then extracted three times with methylene chloride. The organic phases are washed once with water. The aqueous phases are combined and acidified. It is then extracted three times with ethyl acetate and washed once with water. The ethyl acetate fractions are combined, dried over anhydrous sodium sulfate and evaporated. Crystallization of the residue from methylene chloride-petroleum ether gives 2'-methoxy-4'-phenyl-phenyl-acetic acid. Temp. 164 - 165°C.

e) 2_|_-hydroxy-4'-phenyl-phenylacetic acid.

Dissolve 2 g of 2•-methoxy-4'-phenyl-phenylacetic acid in 60 ml of dry methylene chloride and add 4 ml of boron tribromide dropwise at 0°C. After 30 minutes at room temperature, 150 ml of 2N sodium hydroxide is poured on. Then acidify with 2N hydrochloric acid to pH 1 and extract 3 times with ethyl acetate. The organic phases are washed twice with water, combined, dried over anhydrous sodium sulfate and evaporated. The residue is crystallized from acetone-hexane.

The 2<1->hydroxy-4'-phenyl-phenylacetic acid thus obtained melts

at 150 - 151°C.

NMR spectrum (dg-dimethylsulfoxide): i.a. 3.49 S (2H);

6.9 - 7.7 (M, -8H).

Example 6: 6-cyclohexyl-2,3-dihydro-3-methyl-benzofuran-2-one

5 g of 2-(4-cyclohexyl-2-hydroxy-phenyl)-propionic acid are boiled under

reflux in the presence of 50 mg of p-toluenesulfonic acid in 200 ml of toluene for 2 hours with a water separator. The solution is evaporated and the residue is chromatographed on 500 g of silica gel. Pure 6-cyclohexyl-2,3-dihydro-3-methyl-bezofuran-2-one is eluted with methylene chloride which, after crystallization from petroleum ether, melts at 87 - 89°C.

The 2-(4-cyclohexyl-2-hydroxy-phenyl)-v"* propionic acid used as starting material is prepared in the following way:

a^ 2-^3-diclohexylphenoxy)-propionic acid

11 g of a 55% oil containing disodium hydride dispersion in oil under

nitrogen with petroleum ether and then add 500 ml of dry tetrahydrofuran. While stirring, 44 g of 3-cyclohexylphenol in 500 ml of dry tetrahydrofuran are added dropwise over approximately 30 minutes. 46 g of 2-bromopropionic acid ethyl ester are then added dropwise while stirring. It is heated for 1 hour at 60°C and the mixture is then set aside for 16 hours at room temperature. The reaction mixture is evaporated and the residue is distributed 3 times between methylene chloride and water. The aqueous phases are subsequently extracted twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate and evaporated. The residue is boiled in a solution of 50 g of potassium hydroxide in 900 ml of methanol and 100 ml of water for 2 hours under

backflow. The reaction mixture is strongly evaporated, acidified with 2N hydrochloric acid to pH = 2 and extracted 3 times with methylene chloride.

The organic phases are washed once with water, combined, dried over

. anhydrous sodium sulfate and evaporate. Recrystallization of the residue from petroleum ether gives 2-(3-cyclohexyl-phenoxy)-propionic acid with m.p. 81 -.82°C.

b) 2-[4-cyclohexyl-2-hy)-propionic acid

2 g of 2-(3-cyclohexy1-phenoxy)-propionic acid is irradiated in 180 ml

95% ethanol under argon and under water cooling for 2 hours with a 150 watt mercury high pressure lamp. The solution is evaporated and the residue is chromatographed on 150 g of silica gel. With ethyl acetate-hexane (1:1), by-products are first eluted <.... With ethyl acetate, pure 2-(4-cyclohexyl-2-hydroxy-phenyl)propionic acid is then obtained.

NMR spectrum (CDC13): i.a. to 1.50 d (J = 7 Hz); about. 2.4m;

3.92 dd (J = 7 Hz); 6.6 - 7.2 m; about. 8.2 m.

Example 7: 6-cyclohexyl-2,3-dihydro-benzofuran-2-one

306 mg 6-cyclohexyl-2,3-dihydro-3(1,3-dithiolane)-2-yl-benzofuran-2-

is dissolved in 20 ml of ethyl acetate, 1 g of moist, neutral Raney nickel is added and stirred for 16 hours at room temperature T

For processing, filter over talc, dry the filtrate with sodium sulphate and evaporate. By recrystallization from chloroform/hexane, 6-cyclohexyl-2,3-dihydro-benzofuran-2-one is obtained* M.p. 80 - 81°C.

The 6-cyclohexyl-2,3-dihydro-3(1,3-dithiolan)-2-yl-benzofuran-2-one used as starting material is prepared in the following way:

a) I :_|_-cyclohexyl-2^-hydroxy-2-oxo-phenylacetic acid

Dissolve 3.4 g of 3-cyclohexylphenol in 100 ml of methylene chloride and cool with

ice. 5.32 g of AlCl^ are added in one portion and stirred for half an hour.

From a dropping funnel, 3.54 g of oxalyl chloride dissolved in 20 ml of methylene chloride are slowly added dropwise while stirring and cooling with ice. After completion of the addition, the mixture is stirred for 2 hours at 0°C and the mixture is then poured onto some ice.

After standing overnight, distribute between methylene chloride and water

(2 times), then 3% NaOH.

The basic extract is given after sewing the crystalline one

4<1->cyclohexyl-2<1->hydroxy-2-oxo-phenylacetic acid with m.p. 91 -.93°C.

<b>) §z2Y.iE:!:0.ne,<sy' 3-dihydro-3-(-1 , 3-dithiolane)-2-yl-benzofuran-2-one

Dissolve 2.5 g of 4'-cyclohexyl-2'-hydroxy-2-oxo-phenylacetic acid in 100 ml

benzene. 2 ml of ethanedithiol and 100 mg of p-toluenesulfonic acid are added and boiled under reflux overnight with a water separator.

For processing, benzene is driven off in a vacuum and the residue is distributed between water and ethyl acetate. The organic phases are dried over sodium sulfate and evaporated. After recrystallization from chloroform/hexane, pure 6-cyclohexyl-2,3-dihydro-3(1,3-dithiolan)-2-yl-benzofuran-2-one is obtained with m.p. 156 to 158°C.

Example 8: 6-cyclohexyl-2,3-dihydro-3-methyl-benzofuran-2-one.

Dissolve 288 mg 3-acetoxy-6-cyclohexyl-2,3-dihydro-3-methylbenzofuran-2-one in 25 ml ethyl acetate or 20 ml dioxane/10 ml phosphate buffer pH 7

and 28 mg of palladium on activated carbon 10% is added. It is hydrogenated until no starting product can be detected by thin-layer chromatography. After completion of hydrogenation, filter over talc and evaporate the filtrate. The product recrystallized from chloroform/hexane gives 6-cyclohexyl-2,3-dihydro-3-methyl-benzofuranon-2-one with m.p. 87 - 89°C.

The 3-acetoxy-6-cyclohexyl-2,3-dihydro-3-methyl-benzofuran-2(3H)-one used as starting material is prepared in the following way: 992 mg of 4'-cyclohexyl-2'-hydroxy-2-oxo -phenylacetic acid is dissolved in 100 ml of tetrahydrofur an.. It is cooled to -70°C and at this temperature 6 ml of methyllithium (2N in diethyl ether) is added under an argon atmosphere. The reaction mixture is slowly allowed to warm to room temperature and

it is then stirred for 3 hours. For processing, the mixture is poured onto buffer pH 7 and extracted with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated. The product thus obtained is now dissolved directly in 5 ml of acetic anhydride and boiled for 20 minutes under reflux. For processing, evaporate in high vacuum. The oily residue is dissolved in a little benzene and filtered over 6 g of silica gel

with benzene as eluent. After recrystallization from chloroform/hexane, pure 3-acetoxy-6-cyclohexyl-2,3-dihydro-3-methyl-benzofuran-2(3H)-one is obtained with m.p. 137 - 139°C.

Claims (1)

1. Procedure for the production of high carbocyclic compounds of formula I wherein Rp means hydrogen or an alkyl group of 1-4 carbon atoms and means an alkyl group of 2-10 carbon atoms, a cycloalkyl group of 3-8 carbon atoms or a phenyl group and, if R 2 means an alkyl group of 1 to 4 carbon atoms, R^ also stands for a methyl group, characterized by ata) compounds of formula II in which R 1 and R 2 have the above-mentioned meaning, are lactonized or for the preparation of compounds of formula I' in which R^ ' stands for an alkyl group with 2-10 carbon atoms, a cycloalkyl group with 3-8 carbon atoms, or is . a phenyl group and Rg<1> stands for hydrogen, are produced by atb) compounds of formula III wherein R^' has the above meaning, is treated with Raney nickel, or compounds of formula I" in which R^ has the above-mentioned meaning and R2" stands for an alkyl group with 1-4 carbon atoms', are prepared by atc) compounds of formula IV in which R^ has the above meaning and R^ " stands for an alkyl group with 1-4 carbon atoms and Ac stands for the acetyl residue, is hydrogenated catalytically.j 2. Process for the preparation of compounds of formula I <1> in which R^' and R2' have the above meaning, characterized in that a compound of formula VIII wherein R^ has the above meaning, directly and without isolation of the formed compound of formula II <1> in which R 1 and R 2' have the above meaning, is treated with a boron trihalide or with hydrogen halide. 3. 6-cyclohexy1-2,3-dihydrobenzofuran-2-one. 4. „ 6-cyclohexyl-2,3-dihydro-3-methylbenzofuran-2-one. 5. New carbocyclic compounds of formula II in which R^ means hydrogen or an alkyl group of 1-4 carbon atoms and R^n means an alkyl group of 2-10 carbon atoms, a cycloalkyl group of 3-8 carbon atoms or a phenyl group and, if R 2 stands for an alkyl group of 1-4 carbon atoms, means R, also a methyl group, and salts thereof. 6. 4'-cyclopentyl-2'-hydroxyphenylacetic acid. 7. Process for the preparation of compounds of formula II in which R_ means hydrogen or an alkyl group of 1-4 carbon atoms and R means an alkyl group of 2-10 carbon atoms, a cycloalkyl group of 3-8 carbon atoms or phen phenyl group and, if R 2 stands for an alkyl group-of 1- 4 carbon atoms,. means R^ also a methyl group, characterized by ata) for the preparation of compounds of formula II <*> in which R^ and R^ ' have the above meaning, compounds are subject with formula VIII in which R^ has the above meaning, an ether cleavage, or b) for the preparation of compounds of formula II" wherein .R^ and R^" have the above meaning, compounds are irradiated with formula 'XI, ~i wherein R^ and R^ " have the above meaning, irradiated with ultraviolet light, and the thus obtained compounds of formula II are optionally transferred in a manner known per se into their salts.