WO2007055180A1 - Method for producing optically active trans-2-aminocyclohexanol and derivative thereof - Google Patents

Abstract

Disclosed is a method for producing an optically active trans-2-aminocyclohexanol represented by the general formula (2) below or a protonic acid salt thereof. The method is characterized in that an optically active trans-2-benzylaminocyclohexanol derivative represented by the general formula (1) below or a protonic acid salt thereof is subjected to hydrogenolysis. This method enables to produce an optically active trans-2-aminocyclohexanol and protonic acid salts thereof from a commercially advantageous inexpensive raw material through a simple process with high yield. [Chemical formula 1] (1) (In the formula, R1 represents one group selected from a hydrogen atom, a halogen atom, an alkyl group having 1-6 carbon atoms, an alkoxyl group and a nitro group; and symbol * shows that the carbon atom marked by it is the asymmetric center.) [Chemical formula 2] (2) (In the formula, symbol * shows that the carbon atom marked by it is the asymmetric center.)

Description

 Process for producing optically active trans-2-aminocyclohexanol and its derivatives

 Technical field

 The present invention relates to a method for producing optically active trans-2-benzylaminocyclohexanol derivatives and optically active trans-2-aminocyclohexanol derivatives and derivatives thereof.

 Background art

 Optically active trans-2-aminocyclohexanol derivatives are useful compounds as raw materials for pharmaceuticals and agricultural chemicals. This optically active trans 2-aminocyclohexanol derivative can be produced using optically active trans-2-aminocyclohexanol as a raw material.

 [0003] For example, a method for producing optically active trans-2-benzyloxycyclohexylamine, which is a compound useful as a raw material for pharmaceuticals, is obtained by amidating optically active trans-2-aminocyclohexanol with acetic anhydride, followed by chlorination. A method of producing benzyl ether using benzyl and sodium hydride and hydrolyzing it under basic conditions is known (Non-patent Document 1).

[0004] [Chemical 1]

[0005] Thus, optically active trans 2 aminocyclohexanol is a useful compound that is used as a raw material for various optically active trans-2-aminocyclohexanol derivatives.

[0006] As a method for producing optically active trans-2-aminocyclohexanol, for example, an enzymatic kinetic resolution method for racemic trans 2-aminocyclohexanol derivatives has been reported (Patent Document 1). [0007] [Chemical 2]

[0008] In this method, the above-mentioned acetate is treated with acylase or lipase, and each photoactive substance is separated by column chromatography, followed by hydrolysis with hydrochloric acid, thereby producing photoactive trans-2-aminocyclohexane. It leads to xanol. Although this reaction can be optically resolved with high optical purity, the reaction solution for kinetic resolution is a very dilute solution, and the productivity is low, so that it is a difficult method for industrial production.

 As a diastereomeric salt resolution method, a method of optical resolution of racemic trans 2 aminocyclohexanol using optically active di-O-benzoyltartaric acid is known (Patent Document 2). However, in this method, the optical purity of the optically active trans-2-aminocyclohexanol is about 80% ee even after the third crystallization, and the optically active trans-1-aminocyclohexanol has satisfactory optical purity. Is difficult to get. In addition, since optically active trans 2-aminocyclohexanol is a readily soluble compound in water, it is necessary to use a large amount of dichloromethane when extracting free amine with aqueous solution. hard.

[0010] Furthermore, racemic trans 2-aminocyclohexanol, which is a raw material for the above-mentioned production method, usually requires cyclohexeneoxide and ammonia hydropower. In some cases, the reaction requires a pressurized container. Also, in this reaction, 2- (2-hydroxycyclohexyl) aminocyclohexanol was produced as a by-product of the reaction of 1 molecule of ammonia and 2 molecules of cyclohexenoxide, so that racemitrans 2-aminocyclohexanol was converted to In order to produce in high yield, it is necessary to use an excessive amount of ammonia water, and removal of the excess amount of ammonia after the reaction is a problem. Furthermore, it is difficult to remove the by-product from the reaction solution, which is industrially advantageous. Not a manufacturing method

[0011] [Chemical 3]

 By-product Non-patent document 1: Chemical 'and' Pharmaceutical 'bulletin (33, 3, 1140, 19 85)

 Patent Document 1: Japanese Patent No. 2846770 (Example 3)

 Patent Document 2: JP-A-9 59252 (Example 1)

 Disclosure of the invention

 Problems to be solved by the invention

 [0012] As described above, it is the present situation that the optically active trans 2-aminocyclohexanol and derivatives thereof cannot be produced easily and with high yield by the conventional technology, and the creation of an efficient industrial production method is present. Has been strongly desired.

 [0013] An object of the present invention is to provide a method for producing an optically active trans-2-aminocyclohexanol and derivatives thereof from an industrially advantageous and inexpensive raw material in a simple and high yield. I will.

 Means for solving the problem

 [0014] As a result of intensive studies on the method for solving the above-mentioned problems, the present inventors have carried out hydrogenolysis of an optically active trans-2-benzylaminocyclohexanol derivative to obtain an optically active trans-2- The inventors have found that aminocyclohexanol can be produced, and have reached the present invention.

 That is, the present invention relates to the general formula (1)

[0016] [Chemical 4]

(In the formula, R ¹ represents a group selected from a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group, and a -tro group, and * represents this symbol. The optically active trans 2-benzylaminocyclohexanol derivative represented by) or its protonic acid salt is hydrogenolyzed and is represented by the general formula (2)

[0018] [Chemical 5]

[0019] (* means that the carbon atom with this symbol is an asymmetric center.) This is a method for producing an optically active trans 2-aminocyclohexanol or a protonic acid salt thereof. . By this method, an optically active trans 2-aminocyclohexanol derivative or its protonic acid can be obtained from an industrially advantageous and inexpensive raw material that does not impair the optical purity of the optically active trans 2-benzylaminocyclohexanol derivative. The salt can be produced simply and with high yield.

 [0020] The present invention also provides a general formula (3)

[0021] [Chemical 6]

[Wherein R ¹ represents a group selected from a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group, and a -tro group] An optically active trans 2-benzylaminocyclohexanol derivative represented by the general formula (1) or a protonic acid salt thereof is produced by optically dividing a benzylaminocyclohexanol derivative using an optically active carboxylic acid derivative. A process for producing the above-mentioned optically active trans-2-aminocyclohexanol or a protonic acid salt thereof. By this method, a highly pure racemic trans 2-benzylaminocyclohexanol derivative can be easily produced in high yield and used in the next step. Optically active trans 2-aminocyclohexanol or a protonic acid salt thereof can be produced more industrially advantageously and in a higher yield.

The present invention also provides an optically active trans-2-aminocyclohexanol or a protonic acid salt thereof by the above-described method, and the optically active trans-2-aminocyclohexanol is represented by the general formula (4)

R ² COX (4)

(Wherein R ² represents a group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group, and X represents a chlorine atom, And a group selected from a bromine atom)) or an acid halide represented by the general formula (5)

(R ² CO) O (5)

 2

(Wherein R ² represents a group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group.) Is the general formula (6)

R ² CO R ³ (6)

 2

(Wherein R ² represents a group selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group, and R ³ represents A group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group, and a general formula (7)

[0024] [Chemical 7]

(Wherein R ² represents a group selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group. This is a method for producing an optically active trans-2-substituted aminocyclohexanol derivative represented by the following formula: [0026] The present invention also provides an optically active trans-2-substituted aminocyclohexanol derivative prepared by the above method, and then the optically active trans-2-substituted aminocyclohexanol derivative is alkali-free in a non-aqueous solvent. In the presence of a metal hydride, or in an aqueous or non-aqueous solvent, in the presence of an alkali metal hydroxide, the general formula (8)

[0027] [Chemical 8]

(Where R ⁴ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, and a halogen nuclear group. Wherein m represents an integer of 1 to 5, and X represents a group selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.) General formula (9) characterized by reacting

 [0029] [Chemical 9]

(Wherein represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group, or a hydrogen atom. Represents a group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, and a halogen atom, and * represents a carbon atom to which this symbol is attached. Is an asymmetric center.) The optically active trans-2-benzyloxycyclohexylamide derivative represented by

 [0031] The present invention also provides an optically active trans-2-benzyloxycyclohexylamide derivative by the above method, and the optically active trans-2-benzyloxycyclohexylamide derivative is mixed with water or a water-containing organic solvent. In general formula (10), characterized in that a basic compound is added and treated.

[0032] [Chemical 10]

(Where R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, and a halogen nuclear group. * Means that the carbon atom with this symbol is an asymmetric center.) The optically active trans-2-benzyloxycyclohexylamine derivative represented by It is a manufacturing method.

 [0034] By using the method of the present invention, an optically active 2-aminocyclohexanol derivative with high yield and high purity can be produced while maintaining high optical purity. The invention's effect

 [0035] According to the present invention, optically active trans 2-aminocyclohexanol and derivatives thereof can be produced simply and in high yield from industrially advantageous and inexpensive raw materials. BEST MODE FOR CARRYING OUT THE INVENTION

 [0036] The present invention will be specifically described. In the process for producing the optically active trans 2-aminocyclohexanol or its protonic acid salt of the present invention, the raw material, racemic trans-2-benzylaminocyclohexanol, may be produced by any method. For example, it can be produced according to the following reaction formula.

 [0037]

That is, cyclohexene oxide and a benzylamine derivative (wherein R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group, or a group selected from -tro group forces). ) Can be produced in the presence or absence of a catalyst to produce a racemic trans 2-benzylaminocyclohexanol derivative (Yoguchi Bian 'Journal' Ob 'Organic' Chemistry 3597 , 2004). this By using this method, it is possible to produce a racemic trans 2-benzylaminocyclohexanol derivative with high yield and high purity by using only about one equivalent of benzylamine derivative relative to cyclohexene oxide. .

[0039] The optically active trans-2-benzylaminocyclohexanol derivative can be produced by a method of optically resolving a racemic trans-2-benzylaminocyclohexanol derivative using an optically active carboxylic acid derivative.

[0040] Examples of the optically active carboxylic acid derivative that is an optical resolution agent used in the present invention include an optically active amino acid derivative, an optically active tartaric acid derivative (for example, an optically active diacyl tartaric acid derivative, an optically active tartaric acid amide derivative, etc.), An optically active mandelic acid derivative may be mentioned, and any one of them is preferably an optically active substance having an excess of 95% or more, that is, an optical purity of 95% ee or more.

Here, the optically active amino acid derivative of the optical resolution agent can be produced, for example, according to the following reaction formula.

[0042] [Chemical 12]

[0043] That is, optically active aspartic acid is reacted with benzenesulfuryl chloride in an aqueous solvent. At that time, it is preferable to add a sodium hydroxide aqueous solution to the reaction solution and maintain the pH at about 10 because the reaction proceeds suitably. After completion of the reaction, the reaction solution is dropped into hydrochloric acid water, and the precipitated crystals are separated by filtration and then dried to produce optically active N-benzenesulfo-norrasinic acid.

 Such optically active amino acid derivatives include those represented by the general formula (11)

[0045] [Chemical 13]

[0046] (wherein R ⁵ represents a hydrogen atom and a group whose methyl group power is also selected, j is 1 or 2, and k is 0. Or 1 Also, * means that the carbon atom with this symbol is an asymmetric center. ) Acidic amino acid derivatives represented by the general formula (12)

[0047] [Chemical 14]

(Wherein R ⁶ represents an alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted phenyl group, benzyl group, or phenyl group, and R ⁷ represents a carbon number of 1 to 5 is an acyl group, or an aromatic ring is substituted or unsubstituted benzoyl group, benzylcarbol group, benzenesulfonyl group, p-toluenesulfol group, or benzylsulfol group. The neutral amino acid derivative represented by the above formula is used.

 [0049] Acidic amino acid derivatives include, for example, optically active N-benzenesulfonyldalamic acid, optically active Np-toluenesulfol glutamic acid, optically active N benzylsulfurglutamic acid, optically active N-benzenesulfone. -Luaspartic acid, optically active N-p-toluenesulfo-luraspartic acid, optically active N-benzylsulfo-lurasnoramic acid, and the like.

[0050] Examples of the neutral amino acid derivatives include optically active N-formylalanin, optically active N-acetylylalanine, optically active N benzoylalanin, optically active N benzenesulfolalanine, optically active N-p-toluenesulfo-lulananin, optical Active N-benzylsulfuralanine, optically active N-formylfur-glycine, optically active N-acetylphenylglycine, optically active N-benzoylphenylglycine, optically active N-benzenesulfurferulglycine, optically active N-p-toluenesulfuryl Ferruglycine, optically active N benzylsulfurferrglycin, optically active N formylferranalanin, optically active N acetylsulfuralanine, optically active N benzoylferranalanin, optically active N benzenesulfurferallanine, Optically active Np Toluenesulfur Examples include holferulanin and optically active N-benzylsulfurferulanine. Particularly preferably, optically active N-benzenesulfo-luraspartic acid, optically active N-p-toluenesulfo-luraspartic acid, optically active N-base N-sulfuryl glutamic acid, optically active N-benzylsulfolalanine, and optically active N-toluenesulfurulalanin are used.

[0051] The optically active diacyl tartaric acid derivative of the optical resolving agent may be represented by the general formula (13)

[0052] [Chemical 15]

[In the formula, R ⁸ represents a group selected from a hydrogen atom, a methyl group, and a methoxy group. * Means that the carbon atom with this symbol is an asymmetric center.) For example, optically active dibenzoyltartaric acid, optically active di-toluoyl tartaric acid, optically active di-p-toluoyl tartaric acid, optically active di-o-soyltartaric acid, optically active di-p-isobutyltartaric acid and the like can be mentioned. Particularly preferably, optically active di-toluoyl tartaric acid and optically active di-toluoyl tartaric acid are used. As optically active di-toluoyl tartaric acid and optically active di-P toluoyl tartaric acid, products of Toray Fine Chemical Co., Ltd. can be used.

 [0054] The optically active tartaric acid amide derivative of the optical resolution agent may be represented by the general formula (14)

[0055] [Chemical 16]

(Wherein R ⁹ represents a group in which the aromatic ring is substituted or unsubstituted phenylamino group, benzylamino group, and phenylethylamino group, and a carbon atom with *. For example, optically active tartranilic acid, optically active o-methyltaltoranilic acid, optically active m-methyltaltoranilic acid, optically active p-methyltartoralic acid , Optical activity o crotal tartranilic acid, optical activity m-crotal tartaric acid, optical activity p crotal tartaric acid, optical activity o-trotal tralic acid, optical activity m--trotal tolanic acid, optical activity p -Trothal toluic acid, optical activity Specific examples include o-methoxytaltoranilic acid, optically active m-methoxytaltralic acid, and optically active p-methoxytallanic acid. Particularly preferably, optically active p-crotal tartaric acid is used.

 As the optically active mandelic acid derivative of the optical resolution agent, the general formula (15)

[0058] [Chemical 17]

[In the formula, R ¹ ″ represents a group selected from a hydrogen atom, a methyl group, and a methoxy group. * Means that the carbon atom with this symbol is an asymmetric center. For example, optically active mandelic acid, optically active o-methylmandelic acid, optically active m-methylmandelic acid, optically active P-methylmandelic acid, optically active o-methoxymandelic acid, optically active m- Examples thereof include methoxymandelic acid and optically active p-methoxymandelic acid, particularly preferably optically active mandelic acid.

 Of the above optical resolution agents, N-benzenesulfo-luraspartic acid, di-p-toluoyltartaric acid, mandelic acid and the like can be used particularly preferably.

 [0061] Optically active carboxylic acids such as optically active tartaric acid derivatives, optically active amino acid derivatives, and optically active mandelic acid derivatives used for optical resolution are 0.4 to 4 with respect to racemic trans-2-benzylaminocyclohexanol derivatives. 1. 2 times mole is preferred, and more preferably 0.5 to 1.0 times mole.

 [0062] In addition to optically active carboxylic acid derivatives such as optically active tartaric acid derivatives, optically active amino acid derivatives, and optically active mandelic acid derivatives, an optically inactive acidic compound may be used in combination. Examples of such acidic compounds include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, carboxylic acids such as acetic acid and propionic acid, and sulfonic acids such as methanesulfonic acid and benzenesulfonic acid. In that case, the amount of optically active carboxylic acid derivatives such as optically active tartaric acid derivatives, optically active amino acid derivatives and optically active mandelic acid derivatives can be reduced.

[0063] The solvent used in the optical resolution must not react with the substrate. For example, water, alcohols such as methanol and ethanol, -tolyl such as acetonitrile, tetrahydrofluoro, etc. Ether such as orchid can be preferably used. These can be used alone or as a mixed solvent, and particularly preferably water, methanol, ethanol, propanol, or a mixture thereof.

 [0064] The temperature of optical resolution varies depending on the raw racemic trans 2-benzylaminocyclohexanol derivative, the optical resolution agent, and the type of solvent, but is usually a temperature from 0 ° C to the boiling point of the solvent.

 [0065] As the optical resolution method, a raw racemic trans 2-benzylaminocyclohexanol derivative, an optical resolution agent, and a solvent are charged, and the precipitated salt is filtered. In this case, the batch preparation method, the raw racemic trans 2-benzylaminocyclohexanol derivative and the solvent are added, and then the optical resolving agent is added while stirring. Conversely, the solvent and the optical resolving agent are added. After that, there is no particular limitation on the power, for example, a method of charging the raw material racemic trans-2-benzylaminocyclohexanol derivative with stirring. After these are charged, the solution is heated to be dissolved, or the slurry is sufficiently equilibrated. The temperature raising temperature is not particularly limited, but 40 ° C to 100 ° C is preferable. After temperature increase and aging, the temperature is gradually decreased, and the precipitated crystals are isolated by filtration. The temperature at which the crystallization is performed after the temperature is lowered is not particularly limited, but the 10 ° C force is preferably 40 ° C. When the influence of the mother liquor is significant, or when producing products with a particularly high optical purity, it is necessary to add a solvent again to dissolve or wash the slurry, and after cooling, filter the precipitated crystals. The optical purity can be easily increased.

 [0066] The method for isolating the optically active trans 2 benzylaminocyclohexanol derivative is not limited.

 [0067] For example, by adding water to a salt of an optically active trans-2-benzylaminocyclohexanol derivative and an optical resolving agent, adding an aqueous sodium hydroxide solution, and filtering the precipitated crystals, the optically active trans- A 2-benzylaminocyclohexanol derivative can be obtained.

[0068] Further, an optically active trans 2 benzylaminocyclohexanol derivative and an optical resolution agent salt are added to a mixed solution of water and hydrochloric acid, and the precipitated crystal is filtered to remove the optical resolution agent, and the filtrate By making it alkaline and then extracting it with an organic solvent. Thus, an optically active trans-2-benzylaminocyclohexanol derivative can be obtained. Examples of the organic solvent used for extraction include alcohols such as methanol, ethanol and propanol, ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate and butylacetate, jetyl ether, tetrahydrofuran and diglyme. Hydrocarbons such as ethers, hexane, toluene, xylene and the like, and halogen-containing solvents such as dichloromethane and chloroform are preferably used. These solvents can be used alone or as a mixed solvent.

 [0069] The optically active trans-2-benzylaminocyclohexanol derivative can also be isolated as its protonic acid salt according to a conventional method. For example, an optically active trans 2-benzylaminocyclohexanol derivative and an optical resolution agent salt are added to a mixed solution of water and hydrochloric acid, and the precipitated optical resolution agent is filtered, and then the filtrate is concentrated and precipitated. The protic acid salt can be isolated by filtering the obtained crystals. Examples of the protonic acid include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, carboxylic acids such as formic acid, acetic acid, and propionic acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.

 [0070] By optically decomposing the optically active trans-2-benzylaminocyclohexanol derivative represented by the general formula (1) or its protonic acid salt obtained by force, the general formula (2) The optically active trans 2-aminocyclohexanol or protonic acid salt thereof represented can be produced. In addition, the optically active trans-2-benzylaminocyclohexanol derivative or its protonic acid salt to be subjected to hydrogenolysis may be isolated by the method described above, or it may remain in the solution (extract solution, etc.) before isolation. Alternatively, it may be used as a concentrated solution thereof.

 [0071] The hydrocracking reaction is preferably performed in the presence of a transition metal catalyst. Transition metal catalysts include Raney metal, palladium on carbon (PdZc), palladium on alumina (PdZAl 2 O 3), rhodium on carbon (RhZC), and carbon.

 twenty three

Platinum (PtZC) and ruthenium (RuZC) supported on carbon can be preferably used. The amount of the transition metal catalyst used is 0.001 to 0.5 times the weight of the optically active trans 2-benzylaminocyclohexanol derivative, and considering the simplicity of the catalyst removal operation, 0 005 force, etc. 0.1 weight booster [0072] The hydrocracking reaction is usually carried out while supplying hydrogen into the reaction system. The hydrogen supply method is not particularly limited, but there are a method of supplying hydrogen at atmospheric pressure using a gas introduction tube with a hydrogen balloon and a method of supplying pressurized hydrogen using an autoclave. preferable. The hydrogen pressure of the supplied hydrogen is preferably 0.1 to 5 MPa, more preferably 0.1 to LMPa.

 [0073] The hydrogenolysis is preferably performed in a solvent. As the solvent, for example, water, alcohols such as methanol, ethanol and propanol, carboxylic acids such as acetic acid and propionic acid, ethers such as tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene are preferably used. More preferably, water, methanol, ethanol or toluene is used.

[0074] The reaction temperature is preferably 0 to 100 ° C, more preferably 20 to 70 ° C. The reaction time varies depending on the conditions. Usually, it is 3 to 20 hours.

[0075] After the hydrogenolysis reaction, the produced optically active trans 2 aminocyclohexanol or its protonic acid salt can be isolated by a usual method. For example, optically active trans-2-aminocyclohexanol or its protonic acid salt can be obtained by filtering the reaction solution to remove the transition metal catalyst and concentrating the solvent, followed by distillation or recrystallization. .

 [0076] The optically active trans-2-aminocyclohexanol represented by the general formula (2) obtained by force or its protonic acid salt is converted to an acid halide compound represented by the general formula (4). Or an acid anhydride represented by the general formula (5) or an ester represented by the general formula (6) to react with the optically active trans 2-substituted aminocyclo represented by the general formula (7). Xanol derivatives can be produced.

 [0077] Examples of the acid halide represented by the general formula (4) include alkyl carboxylic acid chlorides such as acetyl chloride and chloropropyloyl, alkyl carboxylic acid bromides such as acetyl bromide and butyroyl bromide, Aromatic carboxylic acid chlorides such as benzoyl chloride and toluoyl chloride

Aromatic carboxylic acid promids such as benzoyl bromide and toluoyl bromide, alkyl carbonates such as black carbonate, ethyl butyl carbonate, black carbonate carbonate, and black carbonate carbonate Chloroalkyl carbonates such as chloroalkyl carbonate, phenylacetyl chloride, phenylpropionyl chloride, aralkyl carboxylic acid chlorides such as benzyl bromocarbonate, bromocarbon carbonate Preference is given to salts such as bromoalkyl carbonates such as salt, preferably salt acetyl chloride, salt benzene, toluoyl chloride, butyl carbonate, chloro carbonate, ferro acetyl chloride, and phenyl chloride. Benzyl chlorocarbonate and ferroethyl chlorocarbonate. The amount used is usually 0.8 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, with respect to the optically active trans 2-aminocyclohexanol represented by the general formula (2).

 [0078] Acid anhydrides represented by the general formula (5) include alkyl carboxylic acid anhydrides such as acetic anhydride and butyric anhydride, and dialkyls such as dimethyl dicarbonate, jetyl dicarbonate, and di-t-butyl dicarbonate. Dicarbonates, aromatic carboxylic anhydrides such as benzoic anhydride and toluic anhydride, aralkyl carboxylic anhydrides such as phenylacetic anhydride and furpropionic anhydride, and diaralkyls such as dibenzyldicarbonate Forces including dicarbonate, etc. Preferred are acetic anhydride, jetyl dicarbonate, di-t-butyl dicarbonate, and dibenzyl dicarbonate. The amount to be used is usually 0.8 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, with respect to the optically active trans 1-2 aminocyclohexanol represented by the general formula (2).

 [0079] Examples of the ester represented by the general formula (6) include alkyl esters such as methyl formate, ethyl formate, propylene formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, and ethyl propionate. And the like, aromatic esters such as methyl benzoate and ethyl benzoate, and the like. Preferred are methyl formate, ethyl formate, methyl acetate, and ethyl acetate. The amount used is usually 0.8 to 1.5 equivalents, preferably 1.0 to 1.3 equivalents, with respect to the optically active trans 2-aminocyclohexanol represented by the general formula (2). .

 [0080] This reaction is preferably performed in a solvent. As the solvent, for example, water, alcohols such as methanol, ethanol and propanol, carboxylic acids such as acetic acid and propionic acid, ethers such as tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene are preferably used. More preferably, water, methanol, ethanol or toluene is used.

 [0081] The reaction temperature is preferably 20 to 100 ° C, more preferably 0 to 50 ° C. The reaction time varies depending on the conditions. Usually, it is 3 to 20 hours.

[0082] In this reaction, a basic compound may be added for the purpose of trapping the acid generated in the reaction system so that the reaction proceeds smoothly. Basic compounds include sodium hydroxide Examples include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, and alkylamines such as trimethylamine and triethylamine. Preferred are sodium hydroxide, potassium hydroxide, sodium carbonate and triethylamine. The amount used is generally 0.8 to 1.5 equivalents, preferably 1.0 to L 2 equivalents, with respect to the optically active trans 2 aminocyclohexanol represented by the general formula (2).

 [0083] After completion of the reaction, the produced optically active trans-2-substituted aminocyclohexanol derivative can be isolated by a usual method. For example, an optically active trans 2-substituted aminocyclohexanol derivative can be obtained by concentrating and removing the reaction solution solvent and then performing distillation or recrystallization.

 [0084] The optically active trans-2-substituted aminocyclohexanol derivative represented by the general formula (7) obtained by force is an optically active trans 2 benzyloxy cyclohexylamide represented by the general formula (9). Derivatives can be derived. That is, it reacts with the halogenated benzyl derivative represented by the general formula (8) in the presence of an alkali metal hydride in a non-aqueous solvent, or in the presence or absence of an alkali metal hydroxide in a hydrous or non-aqueous solvent. By doing so, an optically active trans 2 benzyloxycyclohexylamide derivative represented by the general formula (9) can be produced.

 [0085] Examples of the alkali metal hydride used in the reaction include lithium hydride, sodium hydride, potassium hydride and the like. Preferred are sodium hydride and potassium hydride. The amount used is usually 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents with respect to the optically active trans-2-substituted aminocyclohexanol represented by the general formula (7). is there. The solvent used for the reaction is preferably a non-hydrous solvent, and specific examples thereof include dimethylformamide, dimethylacetamide, and dimethyl sulfoxide.

[0086] The optically active trans 2-substituted aminocyclohexanol derivative represented by the general formula (7) is used as a raw material in a water-containing or non-water-containing solvent in the presence of an alkali metal hydroxide. The optically active trans 2 benzyloxycyclohexylamide derivative represented by the general formula (9) can also be produced by reacting with a halogenated benzyl derivative represented by the following formula (9). [0087] Examples of the alkali metal hydroxide used in the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide, It is potassium hydroxide. The amount used is usually 1.0 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents, with respect to the optically active trans-2-substituted aminocyclohexanol represented by the general formula (7).

 [0088] The reaction can be carried out in a hydrous or non-hydrous solvent. Specific examples include aliphatic ethers such as tetrahydrofuran, tetrahydropyran, isopropyl ether and cyclopentylmethyl ether, aromatic ethers such as azole and ethoxybenzene, aliphatic hydrocarbons such as hexane, heptane and octane, benzene, toluene, Aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as black form, dichloromethane and carbon tetrachloride, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like are particularly preferable. Tetrahydrofuran, toluene Dimethyl sulfoxide and the like.

 [0089] Examples of the halogen benzyl derivatives represented by the general formula (8) include benzyl fluoride, benzyl chloride, benzyl bromide, benzyl iodide. Forces such as monochloromethyltoluene, p-chloromethyltolenene, m-bromomethylenoretenolene, p-chloromethylenoretinobenzene, m-bromomethylcumene, p-chloromethyl-t-butylbenzene, etc. Preferably, benzyl chloride Benzyl bromide. The amount of the halogenated benzyl derivative is usually 1.0 to 5.0 equivalents, preferably 1.0 to 3 with respect to the optically active trans 2-substituted aminocyclohexanol represented by the general formula (7). 0 equivalents.

 [0090] The reaction temperature is preferably 0 to 100 ° C, more preferably 10 to 70 ° C. The reaction time varies depending on the conditions. Usually, it is 3 to 20 hours.

 [0091] After completion of the reaction, the produced optically active trans 2 benzyloxycyclohexylamide derivative can be isolated by a usual method. For example, an optically active trans 2-benzyloxycyclohexylamide derivative can be obtained by concentrating and removing the reaction solution solvent and then performing distillation or recrystallization.

[0092] The optically active trans 2-benzyloxy mouth hexylamide derivative represented by the general formula (9) obtained by force is treated by adding a basic compound in water or a water-containing organic solvent. The optically active trans-2-benzyloxy represented by the general formula (10) A cyclohexylamine derivative or a protonic acid salt thereof can be produced.

 [0093] Examples of the basic compound used in the reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide, sodium carbonate, potassium carbonate, and lithium carbonate. Alkali metal carbonates, alkaline earth metal hydroxides such as calcium hydroxide, magnesium hydroxide, etc. are preferable, but sodium hydroxide, sodium hydroxide, potassium hydroxide,ア ル カ リ Alkali metal hydroxides such as lithium, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate. Preferred are sodium hydroxide and potassium hydroxide. The amount used is usually 2.0 to 15.0 equivalents, preferably 5.0 to 8.0 equivalents, with respect to the optically active trans 2 benzyloxycyclohexylamide derivative represented by the general formula (9). .

 [0094] The reaction can be carried out in water or a water-containing organic solvent. Specific examples of the solvent include alcohols such as methanol, ethanol and propanol, aliphatic ethers such as tetrahydrofuran, tetrahydropyran, isopropyl ether, cyclopentylmethyl ether, methoxymethanol and diglyme, aromatic ethers such as azole and ethoxybenzene, Aliphatic hydrocarbons such as hexane, heptane, and octane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as black form, dichloromethane, tetrasalt and carbon, dimethylformamide, dimethylacetate Powers such as amide and dimethyl sulfoxide are preferable, and water, methoxymethanol, diglyme and the like are preferable.

 [0095] The reaction temperature is preferably 50 to 150 ° C, more preferably 80 to 130 ° C. The reaction time varies depending on the conditions. Usually it is 5-30 hours.

 [0096] After completion of the reaction, the produced optically active trans 2 benzyloxycyclohexylamine derivative can be isolated by a usual method. For example, the reaction solution is mixed with an organic solvent and water, separated to remove the basic compound, concentrated, and then distilled or recrystallized to obtain optically active trans-2-benzyloxy. A cyclohexylamine derivative can be obtained.

[0097] The optically active trans 2 benzyloxycyclohexylamine derivative can be isolated as its protonic acid salt according to a conventional method. For example, optically active transformer 2-benzil The protonate can be isolated by adding the oxycyclohexylamine derivative to a mixed solution of water and hydrochloric acid and then concentrating the water to filter the precipitated crystals. Examples of peptonic acid include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, carboxylic acids such as formic acid, acetic acid, and propionic acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.

 [0098] By using the method of the present invention, a high yield and high purity optically active 2-aminocyclohexanol can be produced without impairing the optical purity of the optically active trans-2-benzylaminocyclohexanol derivative. be able to. Further, by using the obtained optically active 2-aminocyclohexanol raw material and using the method of the present invention, a high yield and high purity optically active 2-aminocyclohexanol derivative is maintained while maintaining high optical purity. Can be manufactured.

 [0099] Optically active trans 2 aminocyclohexanol and its derivatives obtained by the production method of the present invention are useful compounds as raw materials for pharmaceuticals and agricultural chemicals.

 Example

 [0100] Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

 [0101] In the examples, the chemical purity of trans 2-benzylaminocyclohexanol derivative is high performance liquid chromatography (HPLC), and the chemical purity of trans 2-aminocyclohexanol is gas chromatography ( GC).

 [0102] <Chemical purity analysis of trans 2-benzylaminocyclohexanol derivative (HPLC)>

 Column: CAPCELL PAK C18 SG—120 (Shiseido)

 150mm— 4.6 mm φ (5 μm)

 Mobile phase: Liquid A; 5 mM sodium lauryl sulfate aqueous solution (pH 2. 20)

 Liquid B: Acetonitrile

 AZB = 60Z40 (15 minutes)-(10 minutes) → 50Z50 (10 minutes)

 Flow rate: 1. Om mm

Detector: UV 210nm Temperature: 40 ° C.

 [0103] Ku-trans 1-aminocyclohexanol chemical purity analysis (GC)>

 Column: TC—17 (GL Sciences)

 60m— 0. 32mm I. D. 0. 25 ^ m

 Temperature: 70 (10 minutes) → 20 7 minutes → 270 (10 minutes)

 Inlet: 200 ° C

 Detector: 200 ° C

 [0104] In addition, the optical purity of trans-1-benzylaminocyclohexanol derivative and trans-2-aminocyclohexanol is 2, 3, 4, 6-Tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate. After labeling with GITC (manufactured by Wako Pure Chemical Industries, Ltd.), analysis was performed with HPLC.

[0105] <Optical purity analysis (HPLC)>

 Column: CAPCELL PAK C18 SG—120 (Shiseido)

 150mm— 4.6 mm φ (5 μm)

 Mobile phase: Liquid A; 5 mM sodium lauryl sulfate aqueous solution (pH 2. 20)

 Liquid B: Acetonitrile

 A / B = 60/40 (trans-2-benzylaminocyclohexanol)

 A / B = 80/20 (trans-2-aminocyclohexanol)

 Flow rate: 1. Om mm

 Detector: UV 243nm

 Temperature: 40 ° C.

 [0106] Reference Example 1 (Synthesis of racemic trans-1-benzylaminocyclohexanol)

A 500 ml 4-neck flask equipped with a stirrer, condenser and thermometer is charged with 49. lg (0.5 mol) of cyclohexene, 64.3 g (0.6 mol) of benzylamine, and 50 g of water. The mixture was stirred at 100 ° C for 4 hours. The reaction solution was extracted with 118.9 g of toluene, and then the toluene layer was concentrated. N-hexane was added to the concentrate, and the precipitated crystals were filtered and dried under reduced pressure at 50 ° C. to obtain 58. lg of racemic trans-2-benzylaminocyclohexanol as a white solid. Example 1 (Optical resolution of racemic trans-2-benzylaminocyclohexanol with di-p-toluoy roux D tartaric acid)

In a sample bottle with a capacity of 20 ml, racemic trans-2 benzylaminocyclohexanol obtained in Reference Example 0.31 g (l. 5 mmol), di-p-toluoyl-D-tartaric acid monohydrate 0.58 g (l (5 mm monole) and methanol 3. After adding Oml, the solution was heated to 60 ^° C and dissolved. The solution was cooled to 20-23 ° C, and the precipitated crystals were filtered and dried to obtain 0.32 g of salt. (IS, 2S) —optical purity of trans-2-benzylaminocyclohexanol 96% ee.

 Example 2 (Optical resolution of racemic trans 2 benzylaminocyclohexanol with N benzylsulfol-L-alanine)

In a sample bottle with a capacity of 20 ml, racemic trans-2 benzylaminocyclohexanol 0.31 g (l. 5 mmol) obtained in Reference Example 1, N-benzylsulfo-luo L-alanine 0.37 g (l. 5 millimonole) And methanoly 5. After charging Oml, it was dissolved by heating to 60 ^° C. The solution was cooled to 20-23 ° C, and the precipitated crystals were filtered and dried to obtain 0.23 g of salt. (IS, 2S) —optical purity of trans-2-benzylaminocyclohexanol 66% ee.

 [0109] Example 3 (Optical resolution of racemic trans-2-benzylaminocyclohexanol with p-chlorodiethyl L-tartranilic acid)

 In a sample bottle with a capacity of 20 ml, racemic trans-2 benzylaminocyclohexanol obtained in Reference Example 0.31 g (l. 5 mmol), p-clo-l-l Taltra-uric acid 0.39 g (1.5 mmol) ), And methanol 3. After adding Oml, the mixture was heated to 40 ° C and dissolved. The solution was cooled to 20-23 ° C., and the precipitated crystals were filtered and dried to obtain 0.38 g of salt. (1R, 2R) —optical purity of trans-2-benzylaminocyclohexanol 49% ee.

 [0110] Example 4 (Optical resolution of racemic trans 2 benzylaminocyclohexanol with R-mandelic acid)

In a sample bottle with a capacity of 20 ml, racemic trans-2 benzylaminocyclohexanol obtained in Reference Example 0.31 g (l. 5 mmol), R-mandelic acid 0.23 g (l. 5 mmol), And after adding 2 ml of water, it was dissolved by heating to 60 ° C. The solution was cooled to 20-23 ° C, and the precipitated crystals were filtered and dried to obtain 0.21 g of salt. (IS, 2S) —optical purity of trans 2 benzylaminocyclohexanol 86% ee.

 [0111] Reference Example 2 (Synthesis of racemic trans-2-benzylaminocyclohexanol)

A 500 ml four-necked flask equipped with a stirrer, dropping funnel, condenser and thermometer was charged with 107.2 g (l. 0 mol) of benzilamine and 100 g of methanol, 65-70. While stirring at C, 98.14 g (l. 0 mol) of cyclohexenoxide was added over 3 hours. The reaction solution was stirred for 14 hours while maintaining the temperature at 65 to 70 ° C. to obtain 293.9 g of a methanol solution of racemic trans-2-benzylaminocyclohexanol (62.5% by weight as racemic trans-2-benzylaminocyclohexanol). _{^{0/0, 183. 7g, 90}} % yield).

 [0112] Example 5 (Optical Resolution of Racemic Trans-2-Benzylaminocyclohexanol with Di-p-Toluoi-Lu Tartaric Acid)

 In a 200 ml 4-necked flask equipped with a stirrer, thermometer and condenser, 20.0 g (61 mmol) of racemic trans 2-benzylaminocyclohexanol methanol solution obtained in Reference Example 2, di-p- Toluoyl-L-tartaric acid monohydrate 24.7 g (61 mmol) and methanol 48.9 g were charged and heated to 70 ° C. After aging at 70 ° C for 1 hour, the mixture was cooled to 10-15 ° C over 3 hours, and then stirred at the same temperature for 1 hour. The precipitated crystals were filtered and dried to obtain 17.5 g of salt. The content of trans-2-benzylaminocycline hexanol in the salt was 31.9%. Optical purity of (1R, 2R) -trans-2-benzylaminocyclohexanol 95% ee.

 [0113] Example 6 (Optical resolution of racemic trans-2-benzylaminocyclohexanol with S-mandelic acid)

In a 100 ml flask equipped with a stir bar, 20.0 g (61 mmol) of the methanolic solution of racemic trans-2 benzylaminocyclohexanol obtained in Reference Example 2, 9.3 g (61 millimonoles) of S mandelic acid, 32.7 g of water and 2. lg of methanol were charged and dissolved by heating to 40 ^° C. After cooling to 20-25 ° C over 3 hours, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were filtered and dried to obtain 5.9 g of salt. The content of trans-2-benzylaminocyclohexanol in the salt was 55.9%. (1R, 2R) —Trans 2 Optical purity of benzylaminocyclohexanol 95% ee.

 [0114] Example 7 (Optical resolution of racemic trans 2 benzylaminocyclohexanol with N-benzenesulfonyl-L-aspartic acid)

 In a 200-ml flask equipped with a stir bar, the methanolic solution of racemic trans 2 benzylaminocyclohexanol obtained in Reference Example 2 20. Og (61 mmol), N-benzenesulfol-l L-aspartic acid 16. 7 g (61 mmol) and 80.65 g of methanol were charged and heated to 70 ° C. After aging at 70 ° C for 1 hour, the mixture was cooled to 20-25 ° C over 3 hours and then stirred at the same temperature for 1 hour. The precipitated crystals were filtered and dried to obtain 13.7 g of salt. The content of trans-1-benzylaminocyclohexanol in the salt was 43.3%. (1R, 2R) —optical purity of trans-2-benzylaminocyclohexanol 99.7% ee.

 Example 8 (Optical Resolution of Racemic Trans-2-Benzylaminocyclohexanol with Di-p-Toluoi-Lu Tartaric Acid)

A 1000 ml 4-neck flask equipped with a stirrer, thermometer and condenser was charged with 26.8 g (645 mmol) of di-p-toluoyl-: L-tartaric acid monohydrate and 500. lg of methanol. The methanolic solution of racemic trans-2-benzylaminocyclohexanol obtained in Reference Example 2 was added to 212.Og (645 millimonoles) and heated to 70 ^° C. After aging for 1 hour at 70 ^o C, after cooling to 10 to 15 ° C over 5 hours, and 1 hour stirred at the same temperature. The precipitated crystals were filtered and dried to obtain 170. Og salt. The content of trans-2 benzylaminocyclohexanol in the salt was 34.2%. The optical purity of (1R, 2R) -trans-2-benzylaminocyclohexanol was 99.3% ee, and the yield of the (1R, 2R) isomer was 87.4%.

 [0116] Example 9 ((1R, 2R) —trans-l-benzylaminocyclohexanol'di-p-tolyoyl-L-tartrate salt)

(1R, 2R) -trans-2-benzylaminocyclohexanol 'di-p-toluoyl-L-tartrate obtained in Example 8 was added to a 2000 ml 4-neck flask equipped with a stirrer, thermometer and condenser. 162. 5 g ((lR, 2R) —trans-2-benzylaminocyclohexanol content 34.2%, 55.5 g, 270 mmol), water 480 g, toluene 480 g While stirring, 48% aqueous sodium hydroxide solution 42. Og (504 mmol) was added to adjust the pH to 11.0. The separated toluene layer (536. 7 g) contained (1R, 2R) trans-1, 2-benzylamino p p-hexananol force S 10.2% (55.0 g, 268 midimonore)! The solution was concentrated to obtain 192.2 g of a partially solidified concentrate.

[0117] Example 10 ((1R, 2R) —hydrogenolysis of trans-2-benzylaminocyclohexanol)

 In a 1000 ml four-necked flask equipped with a stirrer, thermometer, condenser, gas inlet tube with 5 liters of hydrogen lane at the tip, 192.2 g (2 68 mmol) of the concentrate obtained in Example 9 5% PdZC 6.5 g (PE type 55.9% water content) and methanol 259.8 g were charged and stirred at 50 to 55 ° C for 4 hours. During the reaction, hydrogen gas was added as needed according to the absorption of hydrogen. Next, the mixture was cooled to room temperature with stirring, and the catalyst was filtered. The filtrate was concentrated to about 100 g with an evaporator and then concentrated with a vacuum concentrator to precipitate crystals. The crystals precipitated at room temperature were filtered and dried to obtain 25.9 g (yield 83.9%) of (1R, 2R) trans-2-aminocyclohexanol as a white solid. (1R, 2R) —Trans 2 aminocyclohexanol chemical purity 99.8%, optical purity 99.5% ee or higher.

 The obtained (1R, 2R) -trans 2 aminocyclohexanol was measured for optical rotation with a polarimeter, and the following results were obtained.

 [α] = —40.2 ° (c = 0.41, water, 23.C)

 D

[0119] Identification was also performed using ipi-NMI ^ ^13C- NMR. As a result, a peak appeared as shown below, which was confirmed to be (1R, 2R) -trans 2-aminocyclohexanol.

 [0120] 'H-NMR (400MHz, CDC1) δ: 3. 10— 3. 15 (m, 1Η), 2. 40— 2. 46 (m,

 Three

 1H), 2.23 (br, 3H), 1.67— 1.97 (m, 4H), 1.23— 1.27 (m, 3H), 1.10-1.16 (m, 1H)

¹³ C—NMR (400 MHz, CDC1) δ: 75. 8, 57. 0, 34. 8, 33. 7, 25. 1, 24. 8

 Three

Example 11 ((1R, 2R) —Hydrogenation of trans-1,2-benzylaminocyclohexanol Disassembly)

 In a 100 ml four-necked flask equipped with a stirrer, thermometer, condenser, and gas inlet tube with 5 liters of hydrogen lane at the tip, 7.0 g of concentrate obtained in the same manner as in Example 9 ( 10 mmol), 5% PdZAl O 0.2 g (Aldrich), methanol 5. Og

 twenty three

 The mixture was stirred at 55-60 ° C for 4 hours. When the reaction solution was analyzed, (1 R, 2R) -trans-2-aminocyclohexanol contained in the reaction solution was 1.15 g (yield 100%).

 [0122] Example 12 ((1R, 2R) -trans-I-aminocyclohexanol acetylation) Obtained in Example 10 in a 300 ml four-necked flask equipped with a stirrer, thermometer and condenser. (1R, 2R) -trans-2-aminocyclohexanol 20.2 g (176 mmol), methanol 50 g, toluene 25 g were charged, and 18.9 g (185 mmol) of acetic anhydride was maintained while maintaining the internal temperature at 5-10 ° C. And then stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness with an evaporator and then dried under reduced pressure to obtain 28. Og (yield 100%) of (1R, 2R) -trans- (2-hydroxymonocyclohexyl) -acetamide as a white solid. .

[0123] The obtained (1R, 2R) -trans mono (2-hydroxymonocyclohexyl) monoacetamide was identified using 'H-NMR and ¹³ C-NMR. As a result, a peak appeared as shown below, and it was confirmed that it was (1R, 2R) -trans- (2-hydroxymonocyclohexyl) monoacetamide.

 [0124] 'H-NMR (400 MHz, CDCl) δ: 6. 68 (br, IH), 4. 31 (br, IH), 3. 44— 3

 Three

 51 (m, 2H), 3.21— 3.27 (m, 2H), 1. 85— 1.96 (m, 2H), 1. 91 (s, 3H), 1. 57- 1. 63 (m, 2H), 1.03— 1.27 (m, 4H)

1 ³ C—NMR (400 MHz, CDCl) δ: 171.7, 74. 0, 55. 6, 34. 3, 31. 3, 24.

 Three

 5, 24. 1, 23. 1.

Example 13 (Formylation of (1R, 2R) -trans-1-aminocyclohexanol) A method similar to Example 10 was applied to a 500-ml four-necked flask equipped with a stirrer, thermometer and condenser. (1R, 2R) -trans-2-aminocyclohexanol 5.8 g (50 mmol) obtained in 1), 5 g of methanol, and 40 g of toluene were charged, and 4.5 g (75 mmol) of methyl formate was added at room temperature. Thereafter, the mixture was stirred at room temperature for 6 hours, and the precipitated crystals were filtered. The filtrate was concentrated, and the precipitated crystals were filtered. Combine the crystals and dry under vacuum (1R, 2R ) -Trans- (2-hydroxymonocyclohexyl) monoformamide (6.6 g, yield 91.2%) was obtained as a white solid.

Example 14 ((1R, 2R) —t-butoxycarbonylation of trans-2-aminocyclohexanol)

(1R, 2R) -trans-2-aminocyclohexanol (11.5 g, 100 mmol) obtained in the same manner as in Example 10 in a 300-ml four-necked flask equipped with a stirrer, thermometer and condenser. Methanol (40 g) and toluene (70 g) were charged, di-t-butyl dicarbonate (22.9 g, 105 mmol) was added at room temperature, and the mixture was stirred at room temperature for 4.5 hours. After concentrating the reaction solution with an evaporator, _n- hexane is precipitated, and the precipitated crystals are filtered and then dried (1R, 2R) -trans- (2-hydroxymonocyclohexyl) t-butylcarbamate 19 Obtained 2 g (89.2% yield) as a white solid.

Example 15 ((1R, 2R) —o-benzenolation of trans- (2hydroxymonocyclohexyl) monoacetamide;)

 In a 200 ml 4-neck flask equipped with a stirrer, thermometer and condenser, 60% sodium hydrogen carbonate 0.72 g (18 millimonoles), dimethinoles norexoxide 30.0 g, the same method as in practice column 12 (1R, 2R) -trans- (2-hydroxymonocyclohexyl) monoacetamide obtained in 1.36 g (15 mmol) was charged, and the internal temperature was 25-30. In C, 1.9 g (15 mmol) of salted benzyl was added and stirred for 3 hours. As a result of analysis, 2.58 g (yield: 69.6%) of (1R, 2R) -trans- (2-benzyloxymonocyclohexyl) monoacetamide in the reaction solution was obtained.

Example 16 ((1R, 2R) —o-benzenolation of trans- (2hydroxymonocyclohexyl) monoacetamide;)

(1R, 2R) -trans- (2-hydroxymonocyclohexyl) monoacetamide obtained in Example 12 (27.9 g, 177 midimonore) in a 300 ml four-necked flask equipped with a stirrer, thermometer and condenser , 139.3 g of dimethinoles norefoxy and 29.2 g (231 mimoles) of salt 匕 benzinole, and 7. lg (177 mmol) of sodium hydroxide powder at an internal temperature of 25-30 ° C The mixture was added and stirred for 3 hours. 7. 7 lg (177 mmol) of powdered sodium hydroxide was added again and the mixture was stirred at 25-30 ° C. for 3 hours. As a result of analysis, (1R, 2R) -trans- (2— The amount of benzyloxy (cyclohexyl)) acetamide was 35.54 g (yield 81.0%). Water lOOg was added to the reaction solution, and the precipitated solid was filtered. Toluene and water are added to the obtained solid to dissolve the solid, the aqueous layer is removed, n-hexane is added, and the precipitated crystals are filtered and dried under reduced pressure at 50 ° C (1R, 2R) 30.7 g (yield: 70.1%) of —trans- (2 benzyloxy-cyclohexyl) acetamide was obtained as a white solid.

[0129] The obtained (1R, 2R) -trans- (2 benzyloxy-cyclohexyl) monoacetamide was identified using 1 H-NMR and ¹³ C-NMR. As a result, the following peaks appeared, confirming that it was (1R, 2R) -trans- (2-benzyloxy-cyclohexyl) monoacetamide.

 [0130] 'H-NMR (400MHz, CDC1) δ: 7. 28— 7. 37 (m, 5Η), 5. 45 (br, 1H), 4

 Three

 66 (d, 1H), 4.42 (d, 1H), 3.77 (dd, 1H), 3.14—3.20 (m, 1H), 2.08—2.06 (m, 2H ), 1.91 (s, 3H), 1.74— 1.78 (m, 1H), 1.59— 1.62 (m, 1H), 1.09-1.42 (m, 4H)

1 ³ C-NMR (400MHz, CDC1) δ: 169. 6, 138. 7, 128. 3, 127. 6, 127. 5

 Three

 , 79. 0, 69. 8, 52. 6, 31. 2, 30. 0, 24. 0, 23. 8, 23. 6.

Example 17 (hydrolysis of (1R, 2R) -trans- (2 benzyloxy-cyclohexyl) monoacetamide)

 (1R, 2R) -trans- (2-benzyloxy-cyclohexyl) -acetamide obtained in the same manner as in Example 16 in an autoclave with a capacity of 500 ml equipped with a stirrer and a thermometer 37.2 g (150 mmol), 85% potassium hydroxide (Peretz 卜) 69.3 g (1050 mmol), 2-methoxyethanol 206.6 g, water 45.0 g, and internal temperature 125-130. Stir at C for 18 hours. After concentrating the reaction solution with an evaporator, 282.5 g of toluene and 116.5 g of water were added, and the aqueous layer was separated and removed. Toluene and water were added to the obtained solid to dissolve the solid, the aqueous layer was removed, and the mixture was concentrated with an evaporator. The concentrated solution was distilled under reduced pressure to obtain 25.9 g of (1R, 2R) trans-2-benzyloxyhexoxylamide as a fraction of 129-133 ° C / 0.53 kPa (yield 84.1%).

[0132] The obtained (1R, 2R) -trans-2-benzyloxy-cyclohexylamide was identified using NMR and ¹³ C-NMR. As a result, the peak is as follows And (1R, 2R) -trans-2-benzyloxy-cyclohexylamide was confirmed.

 [0133] 'H-NMR (400MHz, CDCl) δ: 7.25— 7.36 (m, 5Η), 4.67 (dd, 1H), 4

 Three

 .46 (d, 1H), 2.99-3.03 (m, 1H), 2.64— 2.70 (m, 1H), 2.12— 2.15 (m, 1H), 1.85-1.88 (m, 1H), 1.64—1.77 (m, 2H), 1.46 (br, 2H), 1.1 1-1.26 (m, 4H)

¹³ C-NMR (400 MHz, CDCl) δ: 138.7, 128.2, 127.6, 127.4, 84.6,

 Three

 70.7, 55.1, 33.6, 29.8, 24.6, 24.5.

 [0134] Comparative Example 1 (Synthesis of racemic trans 1-aminocyclohexanol)

 A 60 ml autoclave equipped with a stirrer was charged with 49. lg (0.5 mol) of cyclohexoxide and 152. lg (2.5 mol) of a 28% aqueous ammonia solution. The mixture was stirred at C for 4 hours. After cooling to room temperature, the precipitated crystals (2- (2-hydroxycyclohexyl) aminocyclohexanol) were removed by filtration, and ammonia was concentrated at normal pressure. The reaction solution was concentrated to about 50 g with an evaporator and distilled under reduced pressure to obtain 34.2 g of racemic trans-2-aminocyclohexanol as a fraction of 106-112 ° C / 2. OkPa (yield 59.4% ).

 [0135] Comparative Example 2 (Racemic trans—Optical resolution of 2-aminocyclohexanol with dibenzoyl-L-tartaric acid)

 In a 1000 ml four-necked flask equipped with a stirrer, thermometer and condenser, 25.4 g (221 mmol) of racemic trans-2-aminocyclohexanol obtained in Comparative Example 1, dibenzoyl-L-tartaric acid monohydrate After charging 41.4 g (110 mmol) of product, 60 g of methanol and 60 g of ethanol 3, the mixture was heated to 90 ° C. After cooling to 70 ° C and aging for 1 hour, the mixture was cooled to 20-25 ° C over 5 hours and then stirred at the same temperature for 1 hour. The precipitated crystals were filtered and dried under reduced pressure to obtain 36.7 g of first crystals. This operation was repeated once more to obtain 23. lg of second crystal. The content of trans-2-aminocyclohexanol in the salt was 24.3%. The optical purity of (1R, 2R) -trans-2-aminocyclohexanol was 69.2% ee, and the yield of (1R, 2R) isomer was 37.5%.

[0136] According to the method of the present invention, it is difficult to concentrate and remove ammonia, which is difficult to implement industrially. Optically active trans 2-aminocyclohexanol can be easily and efficiently produced without the difficult production of 2- (2-hydroxycyclohexyl) aminocyclohexanol and the like. Furthermore, various optically active trans-2-aminocyclohexanol derivatives can be produced in high yield and efficiency without impairing high optical purity.

Claims

Claim [1] General formula (1)

 [Chemical 1] (1)

(In the formula, R ¹ represents a group selected from a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group, and a -tro group, and * represents a carbon atom to which this symbol is attached. The optically active trans 2-benzylaminocyclohexanol derivative represented by) or a protonic acid salt thereof is hydrogenolyzed and is represented by the general formula (2)

[Chemical 2]

(* Means that the carbon atom with this symbol is an asymmetric center.) A method for producing optically active trans 2-aminocyclohexanol or its protonic acid salt represented by

 [2] The process for producing optically active trans 2-aminocyclohexanol or a protonic acid salt thereof according to claim 1, wherein the hydrogenolysis is carried out in the presence of a transition metal catalyst.

 [3] Transition metal catalyst is Raney metal, palladium supported on carbon (PdZC), palladium supported on alumina (PdZAl 2 O 3), rhodium supported on carbon (RhZC), and carbon.

 twenty three

 3. The optically active trans 2-aminocyclohexanol or a protonic acid salt thereof according to claim 2, wherein the optically active trans 2-aminocyclohexanol or a protonic acid salt thereof is selected from platinum supported (PtZC) and ruthenium supported on carbon (RuZC). Manufacturing method.

 [4] General formula (3)

[Chemical 3]

(Wherein R ¹ represents a group selected from a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group, and a -tro group), and racemic trans 2-benzylaminocyclo The optically active trans 2-benzylaminocyclohexanol derivative represented by the general formula (1) or a protonic acid salt thereof is produced by optically dividing a hexanol derivative using an optically active carboxylic acid derivative. The process for producing optically active trans 2-aminocyclohexanol or a protonic acid salt thereof according to any one of claims 1 to 3.

 5. The optically active trans 2-aminocyclohexane according to claim 4, wherein the optically active carboxylic acid derivative is selected from an optically active tartaric acid derivative, an optically active amino acid derivative, and an optically active mandelic acid derivative. A method for producing xanol or its protonic acid salt.

 [6] An optical compound represented by the general formula (1), wherein the racemic trans 2 benzylaminocyclohexanol derivative represented by the general formula (3) is optically resolved using an optically active carboxylic acid derivative. Process for producing active trans 2-benzylaminocyclohexanol derivative.

 [Chemical 4]

(In the formula, R ¹ represents a group selected from a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group, and a -tro group, and * represents a carbon atom to which this symbol is attached. Is an asymmetric center.)

An optically active trans 2 aminocyclo by the method according to any one of claims 1 to 5. Hexanol or a protonate thereof is produced, and the optically active trans-2-aminocyclohexanol or a protonate thereof is represented by the general formula (4)

R ² COX (4)

(Wherein R ² represents a group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group. X represents a chlorine atom, an odor An acid halide represented by the general formula (5)

(R ² CO) O (5)

 2

(Wherein, R ² is R ² is an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, Ariru group, Araru kill group, and represents a group selected from § Lal Kill O hexyl group.) Acid represented by Anhydride or general formula (6)

R ² CO R ³ (6)

 2

(Wherein R ² represents a group selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group, and R ³ represents A group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group, and a general formula characterized by reacting with an ester represented by (7)

[Chemical 5]

(Where R represents a group selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group. This means that the carbon atom with the symbol is an asymmetric center.) A method for producing an optically active trans 2-substituted aminocyclohexanol derivative represented by:

After producing an optically active trans-2-substituted aminocyclohexanol derivative by the method according to claim 7, the optically active trans-2-substituted aminocyclohexanol derivative is converted to an alkali metal hydrogen in a non-aqueous solvent. In the presence of a chemical compound (8)

[Chemical 6]

(Where R ⁴ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, and a halogen atomic energy group, M represents an integer of 1 to 5. X represents a group selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.) The general formula (9)

[Chemical 7]

(Wherein R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, and an aralkyloxyl group. R ⁴ represents a hydrogen atom. Represents a group selected from an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, and a halogen atom, and * represents a carbon atom to which this symbol is attached. Is an asymmetric center.) A method for producing a photoactive trans-2-benzyloxycyclohexylamide derivative represented by:

An optically active trans-2-substituted aminocyclohexanol derivative is produced by the method according to claim 7, and the optically active trans-2-substituted aminocyclohexanol derivative is converted to an alkali metal in a hydrous or non-hydrous solvent. In the presence of hydroxides of general formula (8)

[Chemical 8]

(Where R ⁴ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, and a halogen atomic energy group, M represents an integer of 1 to 5. X represents a group selected from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. General formula characterized by reacting with conductor (9)

 [Chemical 9]

(Wherein R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, or an aralkyloxyl group, or a hydrogen atom, carbon A group selected from the group consisting of an alkyl group, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, and a halogen atom, having a number of 1 to 4. A method for producing a photoactive trans-2-benzyloxycyclohexylamide derivative represented by the formula:

An optically active trans-2-benzyloxycyclohexylamide derivative is produced by the method according to claim 8 or 9, and the optically active trans-2-benzyloxycyclohexylamide derivative is prepared in water or a water-containing organic solvent. General formula (10) characterized in that it is treated by adding a basic compound.

[Chemical 10]

(Where IT represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, an aryl group, an aralkyl group, an aralkyloxyl group, a nitro group, or a halogen atom, and * represents this symbol. Which means that the attached carbon atom is an asymmetric center.) The process for producing an optically active trans 2-benzyloxycyclohexylamine derivative represented by the following formula: