FI59786C - 5-CYCLOHEXYL-1-INDANOL ANVAENDBAR SOM UTGAONGSAEMNE VID FRAMSTAELLNING AV 5-CYKLOHEXYL-6-HALOGEN-INDAN-1-CARBOXYLSYROR OCH DERAS DERIVATER - Google Patents

Description

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Patent and rakifari controlled ...., .. ._. . ., „_,. , (44) NlhUvtksIpenon Js kuLjulksIsun pvm. - _n n, FMant · och raflrtarttyraltan Amekan uttegd och uti ^ kriftwi pubikarad 30.Ob. öl (32) (33) (31) Privilege claimed - «^« rt prtorttat 19-06-72 21.11.72 Japan-JapanJP) 6llUo / 72 II7O21 / 72 Proven-Styrkt (71) Takeda Chemical Industries, Ltd., 27 »Doshomachi 2-chome, Higashi-ku,

Osaka, Japan-Japan (JP) (72) Yoichi Sava, Osaka, Toshinori Hattori, Osaka, Susumu Katsube, Osaka,

Akitoshi Goto, Osaka, Japan-Japan (JP) (7I +) Oy Borenius & C: o Ab (5 ^) 5-cyclohexyl-1-indnol, which is used as a starting material in the preparation of 5-cyclohexyl-6-haloindan-1-carboxylic acids and their derivatives - 5-cyclohexyl-1-indanol, further selected from the group consisting of 5-cyclohexyl-6-halo-indan-1-carboxylsyr and other derivatives (62) Separated from application 1959/73 (patent 56670) - Avdelad fr & n ansökan 1959/73 (patent 56670)

The invention relates to a novel compound, 5-cyclohexyl-1-indanol of formula

OH

II

and used as a starting material in the preparation of 5-cyclohexylindan derivatives of the general formula

? Y

wherein X represents a halogen atom, and Y represents a hydroxyl group, an amino group or an alkoxy group having 1 to 6 carbon atoms. These indan derivatives are suitable for use as anti-inflammatory, analgesic, antipyretic and rheumatic and other drugs.

_ 2 59786

Some processes for the preparation of indan derivatives of the mufcaife of general formula (I) are known, in which cyclohexylbenzene is used as starting material. These processes comprise several different manufacturing steps CUS Patent No. 3,565,943, Japanese Patent Application No. 70,287 / 1971, filed May 11, 1972, and German Patent Application No. P 20.23,800.6, filed August 5, 1972. : 1971). According to Japanese Patent Application No. 70.287 / 1971, an expensive compound, e.g., 1,3-dithian, is used as a starting material in the processes, which requires the use of completely anhydrous conditions, in addition to which toxic mercaptan gas is forced as a by-product in the reaction step of 5-cyclohexylindan-1-carboxylic acid cyclohexyl-1- / 2- (1,3-ditiaanilidee-ni) _7-indan. This process can therefore in no way be considered suitable on an industrial scale.

On the other hand, in the processes of U.S. Patent No. 3,565,943 and German Patent Application No. P 20 23 800.6, the total yield of the desired product, compared to the amount of cyclohexylbenzene used, is very small, i.e. about 9%, so these processes are also disadvantageous on an industrial scale and practical.

Because of the above facts, the inventors of this application have conducted extensive research and have finally come up with the invention disclosed herein.

The essential main object of the invention is therefore to provide a novel compound for use in the preparation of indan derivatives of general formula (I), which preparation does not involve the above-mentioned disadvantages.

By using the compound of the invention as a starting material, the desired derivative can be obtained in a relatively high yield without the use of any expensive compound or reagent, and no toxic gas is evolved, and the reaction can be carried out under normal and mild reaction conditions.

The following formulas illustrate the use of a compound of the invention in the preparation of a compound of formula I.

3,59786

OH

f J (Step C) X / v 11) N.

(Step A) Nvsv

* Z

. Z

- (Gear X

(in) (^ k (iv) (Gear D) (Gear E) I v

CN

. 7 CN

pCp Vp (Step G)

V

COY

° ο ί? wherein X represents a halogen atom, Z represents a halogen atom or an arylsulfonyloxy group, and Y represents a hydroxyl group, an amino group or a lower alkoxy group having 1 to 6 carbon atoms.

The halogen represented by the symbols X and Z may be bromine, chlorine, iodine or fluorine. The aryl-1+ 59786 group of the arylsulfonyloxy group represented by the symbol Z may be, for example, phenyl, tolyl, etc. Among the lower alkoxy groups represented by the symbol Y, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy and n-hexyloxy may be mentioned. Of these, a lower alkoxy group having 1 to 4 carbon atoms is preferred.

In Step A, a halogenation reaction or a sulfonylation reaction of Compound (II) is carried out.

The halogenation reaction which replaces the hydroxyl group in the 1-position of the compound (II) with a halogen atom can be conveniently carried out using a suitable halogenating agent which can replace the hydroxyl group with a halogen, the reaction usually being carried out in the presence of a solvent. Examples of halogenating agents are hydrogen halides (e.g. hydrogen chloride, hydrogen bromide, hydrochloric acid, hydrobromic acid, etc.), thionyl halides (e.g. thionyl chloride), halogenated phosphorus compounds (e.g. phosphorus oxychloride, The amount of the release agent to be used is usually in the range of about 1 to 5 moles, suitably about 1 to 2 moles per mole of the compound (II).

The solvent used in this reaction may be any organic solvent commonly used in conventional halogenation reactions, such as halogenated hydrocarbons, (e.g., carbon tetrachloride, chloroform, ethylene dichloride, methylene chloride, etc.), nitrobenzene, hydrocarbon sulfide. benzene, toluene, etc.), alkyl cyanides (e.g. acetonitrile, etc.), etc. In some cases, a halogenating agent may be used in an excess such that it also acts as a solvent. This halogenation reaction is sometimes more preferably carried out if it is carried out in the presence of an acid-receiving compound, such as tertiary amines, e.g. pyridine, dimethylaniline, triethylamine, etc.).

The sulfonylation reaction can generally be carried out preferably by reacting the compound (II) with an aromatic sulfonylating agent in a suitable solvent. Examples of aromatic sulfonylating agents include benzenesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl bromide, p-toluenesulfonyl bromide, etc. The amount of aromatic sulfonylating agent to be used is generally 1 to 2 moles, suitably 1 to 1.2 moles per compound (II). .

5,59786

As the solvent, for example, pyridine or picoline can be used in this reaction. In some cases, the reaction proceeds successfully in the presence of an acid acceptor. Such acid-receiving agents include, e.g., tertiary amines (e.g., pyridine, dimethylaniline, triethylamine), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.). sodium hydroxide, potassium hydroxide, etc.), alkali metals (e.g. sodium metal), alkali metal alcoholates (e.g. sodium methylate, sodium ethylate, etc.), etc. Of these acid-receiving substances, tertiary amines can also act as a solvent.

In Step B, a halogenation reaction of the compound (III) is carried out, suitably by reacting this compound (III) with a halogenating agent in the presence of a catalyst. Examples of halogenating agents include free halogen (e.g., chlorine, bromine, iodine, etc.), sulfonyl halides (e.g., sulfonyl chloride), N-bromosuccinimide, N-chlorosuccinimide, etc. The amount of the halogenating agent used is generally about 1. ..2 moles, suitably about 1 to 1.2 moles per mole of the compound (III), although the halogenating agent may also be used in excess so that it acts as both a reaction component and a reaction solvent. The catalysts used in this reaction may be gaseous metal or non-metal halogen compounds which can promote ionic reactions of halogens. Examples which may be mentioned are metal halides such as alvunine chloride, iron chloride, antimony trichloride, antimony pentachloride, tin chloride, etc., and non-metallic balloids, e.g. boron trifluoride. The amount of catalyst is widely optional, but is suitably about 0.1 molar equivalent or more, especially about 1 molar equivalent or slightly more per mole of compound (III). Although this reaction can be successfully carried out without a solvent, the reaction is usually carried out in the presence of a solvent, the solvent may be of the same type as in the halogenation reaction of Step A. To avoid a side reaction, the reaction temperature is generally at most about 100 ° C. The reaction can also be performed by cooling with ice.

In step C, the halogenation reaction of compound (II) is carried out, generally in substantially the same manner as the halogenation reaction of step B.

6,59786

The reaction of Step D is carried out by substituting the nitrile group of the 1-azerane of the compound (III) (this reaction is hereinafter referred to as the nitrilation reaction). The nitrilation reaction may conveniently be carried out by reacting the compound (III) with a substance capable of favoring the substituent at the 1-position of the compound (III) with a nitrile group (hereinafter referred to as a nitrilating agent), the reaction generally being carried out in a solvent. As the nitrilating agent, any substance capable of replacing the halogen atom or the arylsulfonyloxy group denoted by the symbol Z at the 1-position of the compound (III) can be used. Examples are alkali metal cyanides (e.g. sodium cyanide, potassium cyanide, etc.). The amount of nitrilating agent is not critical as long as it is present in at least an equimolar amount relative to compound (III). However, for practical reasons, about 1 to about 5 moles per mole of compound (lii) are generally used. As the solvent, any reaction-inert solvent can be used, for example, hydrocarbons (e.g., benzene, xylene, toluene, etc.), dialkylformamides (e.g., dimethylformainide, diethylformaride, etc.), dialkyl sulfoxides (e.g., dimethyl sulfoxide, etc.). (e.g. acetonitrile, phenylacetonitrile, etc.), alcohols (e.g. t-butanol, ethanol, etc.), ketones (e.g. acetone, etc.), cyclic amines (e.g. N-methylpyrrolidone, etc.), water and mixtures thereof suitable for solvents. Although the reaction proceeds at room temperature, it can be accelerated by heating the reaction system to a temperature in the range of about 30 ° C ... close to the boiling point of the solvent used. The nitrilation reaction of this step sometimes proceeds better in the presence of a catalytic amount of an alkali metal halide such as potassium iodide or sodium iodide.

In step S, a nitrilation reaction of compound (IV) is carried out, which can be carried out in almost the same manner as in the nitration reaction of step I).

In step i ', a nalogenation reaction of compound (V) is carried out, which can be carried out almost in a sauna in the same way as the halogenation reaction of step B.

In Step G, the compound (VI) is hydrolyzed or an alcohol addition reaction is performed, followed by hydrolysis. The hydrolysis and alcohol addition reactions of this step are carried out by applying the conventional 7,59786 hydrolysis and alcohol addition reactions, i.e., in the presence of the catalysts and solvents conventionally used in such reactions. Examples of catalysts are mineral acids (e.g. sulfuric acid, hydrochloric acid, hydrobromic acid, boron trifluoride, polyphosphoric acid, etc.), organic acids (e.g. toluenesulfonic acid, benzenesulfonic acid), strongly acidic ion exchange resins, e.g. , alkali hydroxides (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, etc.) The amount of the catalyst is generally in the range of 1 mole ... suitably about 2 to 20 moles per mole of the compound (VI). Examples of suitable solvents include water, alcohols (e.g. methanol, ethanol, propanol, iso-propanol, butanol, isobutanol, sec-butanol, ethylene glycol, etc.), ketones (e.g. acetone, methyl ethyl ketone, organic carbonic acid (e.g. ethyl acetate, etc.), and mixtures of the above compounds are generally hydrolyzed at this stage. optional, the reaction may conveniently be carried out either at room temperature or under heating or cooling. In the latter cases, the temperature may be in the range 0 ... 200 ° C, suitably 50 ... 150 ° C. When an alcohol or a solvent-containing solvent (other than aqueous mixtures) is used as the reaction solvent, an alcohol addition reaction can take place which results in imidoethers which, on hydrolysis, give compounds in which the symbol Y represents an alkoxy group. To carry out the alcohol addition reactions, an excess of alcohol is used, suitably 5 to 20 moles per mole of compound (VI). This alcohol addition reaction can be carried out at a wide range of optional temperatures, so that it is conveniently carried out either at room temperature or under heating or cooling. In the latter cases, the temperature is selected in the range 0 ... 200 ° C, suitably 50 ... 150 ° C. The alcohol addition reaction and the hydrolysis reaction can be carried out separately or in the same step. When the reaction takes place under relatively mild conditions, e.g. using an organic acid or an alkali hydroxide as a catalyst, and at a relatively low temperature, e.g. about 40 to about 80 ° C, compound (I) in which Y represents an amino group is obtained. In the case where, on the other hand, the reaction is carried out under harsher conditions, i.e. using an inorganic acid as a catalyst and a temperature as high as about 80 ° C to about 150 ° C, compound (I) in which Y is a hydroxyl group is obtained.

8 59786 The final product (I) thus obtained can be isolated from the reaction mixture and purified by methods known per se, e.g. extraction, distillation, recrystallization, chromatography, etc.

The following is a list of some of the compounds (I) that can be typically prepared according to the present invention.

5-cyclohexyl-6-chromoindane-1-carboxylic acid, m.p. 160-164 ° C

Ethyl 5-cyclohexyl-6-chloro-indan-1-carboxylic acid, b.p. 167 ...

175 ° C / 0.1 mm Hg 5-cyclohexyl-6-chloro-indane-1-carboxylic acid propyl ester, b.p.

182 ° C / 0.2 mm Hg 5-cyclohexyl-6-chloro-indane-1-carboxylic acid butyl ester, b.p.

193 ° C / 0.1 mm Hg 5-cyclohexyl-6-bromo-indane-1-carboxylic acid methyl ester, b.p.

181 ° C / 0.1 mm Hg 5-cyclohexyl-6-bromo-indane-1-carboxylic acid ethyl ester, b.p.

198 ° C / 0.2 mm Hg 5-cyclohexyl-6-bromo-indane-1-carboxylic acid propyl ester, b.p.

197 ° C / 0.2 mm Hg 5-cyclohexyl-6-bromo-indane-1-carboxylic acid butyl ether, b.p.

200 ... 208 ° C / 0.05 mm Hg The final products (I) thus prepared have antipyretic, analgesic and anti-inflammatory effects and are of low toxicity. To this end, these compounds can be used as medicaments for the above-mentioned purposes as well as as antirheumatic drugs and other drugs.

The 5-cyclohexyl-1-indanol (II) to be used as a starting compound according to the invention is a novel compound which can be prepared, for example, as follows:

0 B

ring formation (/ yy reduction (Step ""! ') *' (Step K) * .compound (II) KJ (XI) 59786 9b I.

in which R represents a -CH-CH2 group A, (in the latter formula A represents a halogen atom and B represents a hydrogen atom or a halogen atom), X "represents a halogen atom, a hydroxyl group or an R1-CO-O group in which R 'in the latter formula means alkyl, aryl, aralkyl or alkoxy.

In the above formulas, the halogen atoms denoted by the symbols A, B and X "may be chlorine, bromine, iodine or fluorine atoms. The alkoxy group denoted by the symbol A may be a lower alkoxy group having 1 to 3 carbon atoms, e.g. methoxy, ethoxy , n-propoxy or isopropoxy In the context of the symbol R ', alkyl is alkyl having 1 to 4 carbon atoms (e.g. methylethyl, n-propyl, isopropyl, n-butyl or isobutyl), aryl is phenyl or naphthyl, aralkyl is benzyl or phenethyl, and alkoxy is alkoxy having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, propoxy, butoxy) The arylsulfonyloxy group represented by Symbol A may be, for example, a phenylsulfonyloxy group or a p-tosyloxy group.

In preparing the starting compound of general formula (II), the reaction of step (I) can be conveniently carried out by reacting cyclohexylbenzene with a compound of general formula (XII), usually using a catalyst. The reaction solvent of this step may be a similar solvent used in the halogenation reaction of Step B. As the catalysts, for example, compounds commonly referred to as mineral acids can be used, and especially metal halides such as aluminum chloride, aluminum bromide, tin chloride, ferric chloride, zinc chloride, arsenic trifluoride, boron trifluoride, titanium chloride are generally used, etc. Catalyst. (XII) per mole.

The reaction of Step J is generally carried out by carrying out the intramolecular cyclization reaction with the compound (X) obtained in Step I in the presence of a catalyst and with or without a solvent. When the solvent used in the reaction, any of the solvents of Step I as well as organic solvents, e.g., formic acid, acetic acid, etc., can be used. The catalysts used are the same metal halides as in Step I, inorganic acids, e.g. , polyphosphoric acid, polyphosphoric acid esters, etc., phosphorus halides, e.g. phosphorus pentafluoride, and mixtures of these catalysts. The cyclization reaction is generally carried out at a temperature between room temperature and the boiling point of the solvent used, or at about 100 ° C, but can sometimes also be carried out at higher or earlier temperatures. The cyclization reaction of step J can be carried out immediately after the reaction of step I without isolating the intermediate, i.e. the compound of formula (X).

In step K, the carbonyl group of the compound of general formula (XI) obtained as a result of the reaction of step J is reduced. This reduction can be performed in any suitable manner that converts the carbonyl group to a hydroxyl group but does not add hydrogen to the benzene ring. The reduction reaction may be, for example, catalytic reduction in the presence of a conventional catalyst such as nickel, palladium, copper, chromium or the like. The reduction can also be carried out in the presence of hydrogen evolved in the reaction, which can be developed using a metal such as sodium amalgam, alunine amalgam, zinc, iron or tin and an acid, e.g. hydrochloric acid, water, alcohol, e.g. ethanol, alkali, e.g. sodium, etc.

The reduction can also be carried out by means of a hydrogenated metal compound, e.g. lithium aluminum hydride, diethylaluminum hydride or sodium borohydride, or by electrolytic reduction. In the case where a compound of general formula (XI) in which B 'represents a halogen atom is reduced using a suitable combination of said hydrogenated metal compound and Raney nickel, the halogen atom X "· is reduced from the reductant while the 1-position carbonyl group is reduced. so as to give a compound of general formula (II).

If, due to the type of reducing agent used, the reduction of the compound of formula (XI) in which B 'represents a halogen atom is limited to the reduction of the carbonyl group in the 1-position, it is further necessary to remove the 2-halogen atom by reduction. In this case, said combination of a metal hydride compound and Raney nickel is used. The amount of catalyst, the type of solvent, the pressure, the reaction temperature and other conditions depend on the type of starting material used.

11 59786

The following examples and comparative examples further illustrate the invention. The ratio of parts by weight to parts by volume used in these examples corresponds to the ratio of grams to milliliters.

(Step A)

Example 1 1 part by weight of 5-cyclobecyl-1-indenol is dissolved in 1.5 parts by weight of pyridine, and the solution is cooled thoroughly. 0.9 parts by weight of tosyl chloride are then added and the reaction mixture is allowed to stand at room temperature for 1 to 12 hours. The reaction mixture is then poured into ice water, where it is allowed to stand for some time, whereupon colorless needles crystallize. These needles are collected by filtration, washed a few times with 1 K hydrochloric acid, and then with cold water and ether in that order. 1.7 parts by weight of 5-cyclohexyl-1-indanol tosylate are thus obtained in the form of colorless needles.

Output: 100 56.

Elemental analysis; Calculated for C22H26 ^ 3S

C, 71.32; H, 7.07 Found C, 71.48; H, 6.98

Example 2 2.2 parts by weight of 5-cyclohexyl-1-indanol are dissolved in 10 parts by volume of dichloromethane and the solution is cooled with ice. A solution of 1.3 parts by weight of thionyl chloride in dichloromethane is then added at low temperature, and the mixture is allowed to react at room temperature for one hour, after which the solvent is removed by distillation. Obtained in almost quantitative yields 1-chloro-5-cyclohexylindan with oil.

NMH (CDCl 3) δ 7.00-7.40 (aromatic protons), 5.37 (1-methyl protons), 2.30-3.35 (methylene protons), 1.00-2.30 (cyclohexyl protons).

(Step B)

Example 3 4.4 parts by weight of 1-chloro-5-cyclohexylindan are dissolved in 40 volumes of acetonitrile. The solution is cooled to 5 ° C, after which chlorine is bubbled through the solution while stirring. After completion of the reaction, the solvent is removed by distillation, and the crystalline residue is recrystallized from acetonitrile. 4.5 parts by weight of 1,6-dichloro-5-cyclobexylindan are thus obtained in the form of colorless prisms.

Melting point: 65 ·· * 66 ° C.

Output: 90 jC.

Elemental analysis: Calculated for C 18 H 19 Cl 2 Cl 2, 66.92; H, 6.74 Found C, 66.4; H, 6.88 (Step C)

Example 4 4 parts by weight of 5-cyclohexyl-1-indenol are dissolved in 40 parts by volume of acetonitrile, after which chlorine gas is bubbled through the solution. After completion of the reaction, the acetonitrile is removed by distillation, and the crystalline residue is recrystallized from acetonitrile. 4 parts by weight of 5 * -cyclohexyl-1,6-dichloroindane are thus obtained in the form of colorless crystals melting at 65 DEG-66 DEG C.

Output 60 Jt.

(Step Ρ)

Example 5 2.4 parts by weight of sodium cyanide are dissolved in 8 parts by volume of water, and a solution of 2.3 parts by weight of 1-clone-5-cyclohexylindan in 20 parts by volume of dimethylformamide is added dropwise. At the end of the dropwise addition, the reaction is allowed to proceed at 60 ° C for 30 minutes, after which the reaction mixture is poured into water and extracted with benzene. The extract is washed with water, dried and distilled to remove the solvent to give a tan solid. This oil is chromatographed on a column of silica gel and eluted with benzene. 1.35 parts by weight of 5-cyclohexylindan-1-carbonitrile are thus obtained in the form of a colorless oil boiling at 160 DEG-5 DEG C./ ImmHg. The oil crystallizes easily. Melting point 61 ° c.

13 59786

Output: £ 60.

Elemental Analysis: Calculated for C 16 H 19 C, 85.28; H, 8.50; N, 6.22 Found C, 85.36; H, 8.62; N, 5.90.

Example 6 0.7 parts by weight of sodium cyanide are suspended in a mixture of 40 parts by volume of N-methylpyrrolidone and 2 parts by volume of t-butenol.

Then 1 part by weight of 5-cyclohexyl-1-indanol olitosylate is added to the suspension. The mixture is heated at 80 ° C for 7 hours while stirring. The reaction mixture is then cooled, poured into ice water and extracted with benzene. The extract is washed with water, dried and distilled to remove the solvent. Finally, the residue is chromatographed on a column of silica gel and eluted with benzene to give 0.35 parts by weight of 5-cyclohexylindan-1-carbonitrile as a colorless oil. The IR and NMR spectra of this product correspond to those of the product of Example 5. Yield 56 £.

(Step E)

Example 7 _ * 4 parts by weight of sodium cyanide are dissolved in 50 parts by volume of dimethylformamide, and a solution of 5.4 parts by weight of 1,6-dichloro-5-cyclobexylindan in diethylformamide is added dropwise with stirring, while stirring. After the addition is complete, the mixture is allowed to react at 60-70 ° C for 3 hours. The solvent is then removed by distillation, the residue is diluted with water and washed with benzene. The extract is washed with water, dried and distilled to remove the solvent. The residue is poured through a chromatography column containing silica gel using a mixture of n-hexane and benzene (10: 1) to give 4-chloro-o-6-chloro-5-cyclohexyl-1-ylanocarbonitrile. Output: 77 j £.

Elemental Analysis: Calculated for C 16 H 18 Cl 2 C, 73.98; H, 6.98; N, 5.39 Found C, 73.76; H, o84; K, 5.22.

B

59786

Example 8 4.5 parts by weight of 5-cyclohexylindan-1-carbonitrile are dissolved in 50 parts by volume of acetonitrile, and chlorine gas is bubbled through the solution, cooling with ice and stirring vigorously. Gas chromatography shows that chlorine is attached to the 6-position in about 5 minutes. The reaction mixture is then evaporated to dryness to give 5 parts by weight of yellowish-brown crystals. Recrystallization from a mixture of ethyl ether and n-hexane gives 4.5 parts by weight of 5-cyclohexyl-6-chloroindane-1-carbonitrile as colorless prisms, melting at 96 ...

At 98 ° C. Yield: 86,496.

Elemental analysis: Calculated for c16Hi8cin C 73.98? H 6.98; N 5.39 Found C 73.88; H 7.04; N 5.46 (Step G)

Example 9 1 part by weight of cyclohexyl-6-chloroindane-1-carbonitrile is suspended in dilute sulfuric acid, and the suspension is boiled with vigorous stirring in an oil bath at about 120 ° C for about 5 hours. After cooling, the reaction mixture is poured into ice water and extracted with ether. The extract is washed thoroughly with water and dried, after which the solvent is removed by distillation to give 1 part by weight of yellowish-brown crystals. Recrystallization from a mixture of ether and hexane gives 0.9 parts by weight of 5-cyclohexyl-6-chloroindan-1-carboxylic acid as colorless crystals.

Melting point: 150-152 ° C. Yield: 83.9%

Elemental analysis: Calculated for C 16 H 19 ClO 2 C 68.94; H 6.87; Cl 12.72 found C 68.88; H 6.74; Cl 12.62

Example 10 1 part by weight of 5-cyclohexyl-6-chloroindane-1-carbonitrile is added to 5 parts by volume of a 30% aqueous solution of sodium hydroxide, and the mixture is boiled with vigorous stirring using a vertical condenser in an oil bath overnight. After cooling, the reaction mixture is poured into ice water and washed with ether. Further cool and make an aqueous layer with acidic hydrochloric acid, then extract with benzene.

15

The organic layer is washed with water and dried, after which the solvent is removed by distillation. The crystalline residue is then recrystallized from a mixture of ether and n-hexane to give 0.9 parts by weight of 5-cyclohexyl-6-chloroindane-1-carboxylic acid as colorless crystals. Yield: 83.7%.

The melting point, IR absorption spectrum and other properties of this product correspond exactly to the corresponding properties of the compound of Example 9.

Example 11 1 part by weight of 5-cyclohexyl-6-chloroindan-1-carbonitrile is added to 1 part by weight of an ethylene glycol solution of potassium hydroxide and the mixture is boiled at 180 ° C with stirring. After cooling, the reaction mixture is poured into ice water and extracted with ether. The aqueous layer is acidified with hydrochloric acid, extracted with ether and washed thoroughly with water and dried, after which the solvent is distilled off and the resulting crystals are recrystallized from n-hexane. 0.8 part by weight of 5-cyclohexyl-6-chloroindane-1-carboxylic acid is thus obtained in the form of colorless crystals. Yield: 74-, 4%.

Elemental analysis: Calculated for C 28 H 28 O 3 C 78.65; H 8.25 found C 78.36; H 8.14.

Example 12 2.6 parts by weight of 5-cyclohexyl-6-chloroindan-1-carbonitrile are suspended in hydrochloric acid, and the suspension is boiled at 80-100 ° C with vigorous stirring for about 10 hours. The reaction mixture is then poured into ice water and extracted with ether. The extract is washed thoroughly with 10% aqueous sodium carbonate solution and then with water, then dried and the ether is removed by distillation. The remaining starting material is separated by chromatography on a column of silica gel. 2.1 parts by weight of 5-cyclohexyl-6-chloroindane-1-carboxamide are obtained.

Melting point: 184-185 ° C. Yield: 73%.

Elemental analysis: Calculated for C

C 69.18; H 7.26; N 5.04 found C 69.02; H 7.34; W 5.12.

Example 15 16 59786 2.6 parts by weight of 5-cyclohexyl-6-chloroindane-1-carbonitrile are heated with stirring for 2 hours in a mixture of 20 parts by volume of methanol and 2 parts by weight of concentrated sulfuric acid. After cooling, the reaction mixture is poured into ice water and extracted with ether. The extract is washed thoroughly with water, 5% aqueous sodium bicarbonate solution and again with water in this order. The extract is dried, the solvent is removed by distillation, and the residue is distilled under reduced pressure. There is thus obtained 2,4-parts by weight of 5-cyclohexyl-6-chloroindane-1-carboxylic acid methyl ester as an oily product. Boiling point: 170-171 ° C / 1 mm Hg. Yield: QZ%.

Elemental analysis: Calculated for C 18 H 19 ClO 2 C 69.73; H 7.23 found C 69.52; H 7.01.

Example 14

In the same manner as in Example 13, 2.5 parts by weight of 5-cyclohexylindan-1-carboxylic acid ethyl ester are prepared from 2.6 parts by volume of 5-cyclohexylindan-1-carbonitrile, using ethanol as a solvent. This product boils at 165-175 ° C / 1 nm Hg. Output: 81? Ί.

Example 15 To 2 parts by weight of 5-cyclohexyl-6-chloroindane-1-carbonitrile are added 50 parts by volume of a 38% acetic acid solution of boron trifluoride and 5 parts by volume of water. The mixture is heated to dissolve 5-cyclohexyl-6-chloroindane-1-carbonitrile, then allowed to stand overnight at room temperature. 1000 volumes of water are added to the reaction mixture, and the precipitate formed is collected by filtration, washed with water and dried. The precipitate is recrystallized from methanol to give 5-cyclohexyl-6-chloroindane-1-carboxamide. Melting point: 184-186.5 ° C. Yield: 77.31 / ». Elemental analysis: calculated for c16H20ClNO

Cl 12.77; c 69.17; H 7.26; H 5.04 found Cl 12.70; C 69.04; H 7.08; K 4.95.

Example 16 17 59786 2.0 parts by weight of 5-cyclohexyl-6-chloroindane-1-carbonitrile are dissolved in 100 volumes of methanol, and 10 parts by volume of 5% aqueous sodium hydroxide solution and 3 parts by volume of 30% aqueous hydrogen peroxide solution are added to the solution. . The mixture is then heated at 60 ° C for 2 hours, after which it is acidified with dilute hydrochloric acid. 1500 volumes of water are added to the solution, and the mixed solution thus obtained is allowed to stand overnight at room temperature. · The precipitate formed is collected by filtration, washed with water and dried. The precipitate is recrystallized from methanol to give 5-cyclohexyl-6-chloroindane-1-carboxamide ·

Melting point: 184.5-186.5 ° C. Yield: 82%.

Elemental analysis: Calculated for C

C 69.17; H 7.26; H 5.04; Cl 12.77 found C 68.98; H 7.21; N 4.98; Cl 12.53.

Example 17 2 parts by weight of 5-cyclohexyl-6-chloroindane-1-carbonitrile are added to 100 parts by weight of polyphosphoric acid and the mixture is stirred at 60 [deg.] C. while stirring. The mixture is allowed to stand overnight at room temperature, after which it is poured into 1000 volumes of water. The precipitate formed is collected by filtration, washed with water and dried. The precipitate is recrystallized from methanol to give 5-cyclohexyl 6-chloroindane-1-carboxamide. Melting point: 184.5-186.5 ° C. Yield: 82%.

Elemental analysis: Calculated for C 16 H 20 ClNO C 69.17; H 7.26; N 5.04; Cl 12.77 found C 69.11; H 7.30; N 5.03; Cl 12.68.

ie 59786 Preparation of 5-cyclohexyl-1-indanol (Step I)

Example 18

The celiac flask is charged with 405 parts by weight of cyclohexylbenzene, 390 parts by weight of anhydrous aluminum chloride and 2000 parts by volume of carbon disulfide. Stir and cool with ice and add dropwise over a period of about 1 hour a solution of 315 parts by weight of 3-chloro: propiooyl chloride in 250 parts by volume of carbon sulphide. The mixture is stirred at room temperature for one hour, after which it is poured into ice water. The organic layer is separated, washed with water and dried. The organic solvent is distilled off and the residue is crystallized from n-hexane. Thus, 580 parts by weight of μl-chloro-4-cyclohexylpropion-phenone are obtained in the form of white needles.

Melting point: 58-59 ° C. Output: 91 »5 $.

Elemental analysis: Calculated for C 15 H 19 Cl 1, 71.84? H, 7.64 Found C, 71.oh; H, 7.58.

(Step J)

Example 19

The four-necked flask is charged with 5 parts by weight of uj-chloro-4-cyclohexylpropiophenone, and 50 parts by volume of concentrated sulfuric acid are added dropwise while cooling. At the end of the dropwise addition, the mixture is gradually heated in water bath water to 90 ° C, at which temperature it is further maintained for one hour. The mixture is then poured into ice water and extracted with benzene. The extract is washed with water, dried and distilled to remove the solvent to give a dark brown oil. Crystallization from n-hexane gives 3 to 9 parts by weight of 5-cyclobexyl-1-indanone as white crystals. Melting point: 77-78 ° C. Output: $ 88 S.

Elemental analysis: Calculated for C 18 H 18 N 2 O 3

C, 84.06; H, Ö.47 Found C, 83.9Ö h, 3.54.

(Steps I and J)

Example 20 59786 12.7 parts by weight of β-chloropropionyl chloride are added dropwise to a mixture of 16 parts by weight of cyclohexylbenzene, 13 parts by weight of aluminum chloride and 50 parts by volume of carbon disulphide, while stirring and cooling with ice. The mixture is then stirred at room temperature for 1 hour, after which the carbon disulphide is removed by distillation at 20-30 ° C. Gradually add 100 volumes of concentrated sulfuric acid to the residue while stirring, and the mixture is slowly heated to 90 ° C, at which temperature it is stirred for one hour, after which the mixture is poured into ice water and extracted with benzene. The extract is washed with water, dried and distilled to remove benzene. Finally, the residue is crystallized from n-hexene to give 17 to 5 parts by weight of 5-cyclohexyl-1-indanone as needles with a melting point of 75 to 77 ° C. Output £ 82.

(Step K)

Example 21 30 parts by weight of cyclohexyl-1-indanone are dissolved in 130 parts by volume of methanol, after which 10 parts by weight of sodium borohydride are gradually added with stirring and ice-cooling. The mixture is refluxed for 30 minutes, after which the solvent is removed by distillation. The residue is diluted with water and extracted with benzene. The extract is washed with water, dried and distilled to remove the solvent to give a light brown crystalline residue. This residue is recrystallized from n-hexane. 28 parts by weight of 5-cyclohexyl-1-indanol are thus obtained in the form of colorless crystals. Melting point 88, 90 ° C. Output: 93? &.

Elemental Analysis: Calculated for? 25 DEG-20 DEG C., 83.28; H, 9.32 Found C, 83.06; H, 9.44

Claims (1)

59786 Claim 5-Cyclohexyl-1-indanol of the formula OH 0 ° 4 and used as a starting material for the preparation of a 5-cyclohexylindan compound of the general formula wherein X represents a halogen atom and Y represents a hydroxyl group, an amino group or 1 to 6 carbon atoms. alkoxy. 5-cyclohexyl-1-indanol with OH form. C / Cii ooh som avvänds som utgängsämne vid framställning av en 5-cyclohexyl-indanförening med denmänna formeln COeln o06 där X betecknar en halogenatom ooh Y en hydroxylgrupp, en aminogroup eller alko alkoxygroup med 1 ... 6 kolatomer.