JPS5946218B2 - Alicyclic derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel ring derivatives represented by the general formula and salts thereof.

In the above formula, R1, R2, R3, and R4 are the same or different and are hydrogen, halogen (fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine), trifluoromethyl, or lower alkyl (methyl, ethyl, propyl,
butyl, pentyl, etc., preferably methyl).

n represents 1 or 2; m represents 1; The dotted line in ring A indicates that when n is 2, this moiety may form a double bond. The compound of the above general formula [I] has a central nervous system depressing effect,
It has an analgesic effect, is useful as a medicine, and is also an important intermediate for producing the compound of the general formula
R6 is the same or different and represents hydrogen, halogen, trifluoromethyl or lower alkyl, and the other symbols are as defined above.

] The compound of the general formula [ ] has a sustained central nervous system depressant effect, and the representative compound among them, 4,4-bis(4
-fluorophenyl)-1-[4(5-chloro-2-oxobenzimidazolin-1-yl)piperidino]cyclohexane is particularly useful as a potent and long-lasting central nervous system depressant.

The compound of general formula [I] is produced by the following method.

[In the above formula, X represents a reactive active ester group, chlorine,
Examples include halogen atoms such as bromine and iodine, and organic sulfonyloxy such as methylsulfonyloxy and p-tolylsulfonyloxy, preferably chlorine, bromine, methylsulfonyloxy and p-tolylsulfonyloxy.

R7 is hydrogen, and is also used as a protecting group for amino groups such as -COR8, -SO2R8, etc., where R8 is hydrogen, lower alkyl (methyl, ethyl, propyl, etc.), phenyl, substituted phenyl ( Substituents include halogen, alkyl, alkoxy, amino, nitro, etc.), pyridyl, furyl, thienyl, etc. Other symbols have the same meanings as above. ] Step 1 may be carried out in the presence or absence of a suitable inert diluent;
Preferably, a diluent is used. As a diluent,
Alcohol solvents such as methanol and ethanol, ketone solvents such as acetone and methyl ethylget, ether solvents such as tetrahydrofuran and dioxane, halogenated hydrocarbon solvents such as methylene chloride and chloroform, and aromatic solvents such as benzene, toluene and xylene. Hydrocarbon solvent, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide (HMPA), N
- Aprotic polar solvents such as methylpyrrolidone can be used. Furthermore, in order to facilitate the reaction, it is preferable to use a suitable deoxidizing agent to remove by-produced acid. As the deoxidizer, either an inorganic base or an organic base can be used. Sodium hydrogen carbonate as an inorganic base,
Potassium bicarbonate, lithium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., as organic bases, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tertiary ptoxide, sodium acetate, potassium acetate, etc. Triethylamine, pyridine, etc. are used respectively. The reaction temperature is 10 to 200°C, and generally reaches a high temperature of 100 to 200°C if no diluent is used. The reaction time varies depending on the dilution temperature used and is approximately 30 minutes to 72 hours. Step 2 is applied when R7 is other than hydrogen. When hydrolysis is carried out under acidic conditions, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc. are used, and under basic conditions, water such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc. Alkali oxides are used, preferably sulfuric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, etc. Diluents used include water, alcoholic solvents such as methanol, ethanol, propanol, and ethylene glycol, acetic acid, dichloroacetic acid, trichloroacetic acid,
Examples include aliphatic carboxylic acid solvents such as triple oroacetic acid, ethereal or aprotic polar solvents as described above, or mixtures thereof. The reaction temperature and reaction time vary depending on the individual reaction, but are generally 1 to 150°C.
It is about 0 minutes to 24 hours. Method 2 This method is a manufacturing method preferably applied when m is O in general formula [1].

[In the above formula, t represents 0, 1, R9 represents an amino protecting group such as -COR8, -SO2R8 as described in Method 1,
Other symbols have the same meanings as above.

] The reaction may be carried out in the presence or absence of a suitable inert diluent, but preferably a diluent as described in Method 1, Step 1 is used. The reaction conditions for Step 1 vary depending on the individual reaction, and are carried out in the presence of a diluent at a temperature ranging from room temperature to 200°C. , organic acids (
Baratorue. Acids such as sulfonic acid (sulfonic acid, etc.) are used as catalysts. When the intermediate (enamine) represented by the general formula 0 is isolated, the diluent and acids are removed in the usual manner:
It can be purified by operations such as distillation, recrystallization, and chromatography. If the intermediate (ena-mine) is not isolated, it can be subjected to the subsequent contact or optical reduction in the presence of the diluent used in the condensation, or with an appropriate exchange of the diluent. As a catalyst for the catalytic reduction in step 2, metals such as palladium, platinum, rhodium, nickel, ruthenium, and cobalt are used, as are activated carbon, alumina, barium sulfate, and calcium carbonate, to which inert agents such as strontium carbonate are attached. Ru. The reaction time depends on hydrogen pressure, reaction temperature, etc., and generally takes a long time at atmospheric pressure and room temperature. When the reduction is carried out chemically, an organic acid such as formic acid (or a derivative thereof) or a metal hydride compound is used.
The former reductive amination reaction using formic acid is generally the Leucart reaction (MOore, M.L.: 0rganic reaction).
(See Reacti-0ns5, 301 (1949))
The purpose can be achieved by adding formic acid to the compound of the general formula and keeping it at an appropriate temperature (generally high temperature). For reduction with metal hydride compounds, lithium aluminum hydride, lithium borohydride, sodium borohydride, borohydride (borane, diborane, etc.), sodium dihydro-bis(2-methoxyethoxy)aluminate, etc. Lithium aluminum hydride
Aluminum chloride, sodium borohydride combinations are also used.

Method 3 - The hydrolysis reaction of aluminum chloride, etc. in step 3 is the same as that described above.

As described in Method 1 Step 2 [In the above formula, RlO represents hydrogen, lower alkyl (methyl, ethyl, propyl, butyl, etc.), phenyl.

] The oxime formation in step 1 is carried out in the presence of various suitable diluents in a conventional manner.

The reduction reaction in Step 2 can be carried out either by catalytic reduction as described in Step 2 of Method 2 or by chemical reduction using a metal hydride compound.

Generally, when a double bond is present in ring A in general formula [X], chemical reduction is preferable to catalytic reduction. [Each symbol in the above formula has the same meaning as above.

] The reductive amination reaction in step 1 is a method of what is generally called the Leukartower-Ratzha reaction, and involves dissolving the ketone derivative of general formula (sub) in formamide, adding formic acid, and keeping it at an appropriate temperature (generally high temperature). By doing so, you can achieve your goals. The resulting compound of general formula] is led to the target product [1] through the following hydrolysis reaction, usually without isolation. The hydrolysis reaction in step 2 is similar to that described in method 1 step 2. In the compound of general formula [1], when ring A is a citalohexene ring or a cyclopentane ring, an asymmetric carbon is generated and an optically inactive racemate is usually obtained.

This racemate can usually be resolved into optically active forms by well-known methods. The base of general formula [1] produced by the above method can be converted into pharmaceutically acceptable acid addition salts and quaternary salts. The acid for forming the salt may be appropriately selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as maleic acid, fumaric acid, succinic acid, citric acid, and tartaric acid. I can do it. Quaternary chlorinating agents include dimethyl sulfate, diethyl sulfate,
Examples include methyl iodide and ethyl bromide. EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 (a) Production method according to method 3 1-[4,4-bis(4-fluorophenyl)cyclohexyl]-4-piperidone 22.2f1 Hydroxylamine hydrochloride 14t1 Pyridine 60ml 1, Ethanol 60m
Reflux the mixed solution of 1 for 2 hours.

The reaction solution was concentrated under reduced pressure, water was added to the residue, the insoluble matter was filtered out, and dissolved in hot chloroform. Dry hot over sodium sulfate and evaporate the solvent. Add ether to the solidified residue, cool it thoroughly, and filter out the precipitated crystals. Thus, 1-[4,4-bis(4-
Fluorophenyl)cyclohexyl]-4-piperidone oxime is obtained. The above oxime 22r is suspended in 100 d of anhydrous benzene, and 115 t of a benzene solution of 700 t) sodium dihydro-bis(2-methoxyethoxy) aluminate is added dropwise little by little at room temperature.

After the dropwise addition, the mixture was stirred at room temperature for 2.5 hours, and then heated, stirred, and refluxed for an additional 2 hours. After cooling the reaction solution, pour it into ice water, add ethyl acetate, and stir for a while. Insoluble materials are removed, and the aqueous solution is dried over sodium sulfate and concentrated. Dissolve the remaining oil in ethanol, add ethanolic hydrochloric acid, and cool thoroughly with ice water. The precipitate was collected and recrystallized from aqueous ethanol to yield 1-[4,4-bis(4-fluorophenyl)cyclohexyl]-4-aminopiperidine dihydrochloride monohydrate with a melting point of 275-279°C. You can get things. (b
) Preparation method according to method 4 1-[4,4-bis(4-fluorophenyl)cyclohexyl]-4-piperidone 1865r was dissolved in formamide 5
0d and 98-100% formic acid at 120°C.
7. Add 4.5 t of formamide mixture all at once.

Heat at 150°C for 12 hours and then at 170°C for 20 hours.

The reaction solution was poured onto ice chips and made alkaline with potassium carbonate, resulting in a precipitation of 3,3-bis(4-fluorophenyl)cyclopentanol tonerate 12.6
A mixture of 7,4-acetamidopiperidine 4.1f1 potassium carbonate 4.1f1 potassium iodide 5r1 dimethylformamide 90d is heated and stirred at 65 to 70°C.

Pour the reaction solution into ice water and extract with ethyl acetate. The extract is thoroughly washed with water, dried over sodium sulfate, and concentrated. The remaining viscous oil is purified as the maleate salt in a conventional manner. Thus, 1-[ with melting point 215-218°C (decomposition)
3,3-bis(4-fluorophenyl)cyclopentyl]-4-acetamidopiperidine maleate is obtained. 1.8V of the above maleate salt in methanol 20ml
Add 40 d of concentrated hydrochloric acid and reflux for 4 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, the mixture was made alkaline with potassium carbonate, and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated. As a result of various analyses, the remaining oily substance contained a considerable amount of unhydrolyzed decomposition, so it was directly converted to 90% ethanol 207n! Add 27% of caustic soda, heat again for 8 hours, stir,
Reflux. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract is washed with water, dried over sodium sulfate, and concentrated. The remaining oil is purified by silica gel chromatography (flowing with chloroformrimethanol=9:1 and methanol in that order). The separated target portion is converted to maleate in a conventional manner. Thus, melting point 168-17
1[3,3-bis(4-fluorophenino(ha)cyclopentyl]-4-aminopiperidine 2) at 0°C (decomposition)
Maleate monohydrate is obtained. The alicyclic derivatives of general formula [1] provided by the present invention further include, for example, the following compounds.

Claims (1)

[Claims] 1. A ring derivative or a salt thereof represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼. [In the formula, R^1, R^2, R^3, and R^4 are the same or different and represent hydrogen, halogen, trifluoromethyl, or lower alkyl, n represents 1, 2, and m represents 0, 1. , the dotted line of ring A indicates that when n is 2, this moiety may form a double bond. ]