TW200400165A - Process for preparing trans-4-aminocylcohexanecarboxylic acids - Google Patents

Abstract

The present invention provides a process for preparing a trans-4-aminocylcohexanecarboxylic acid or a salt thereof, or an amino-protected derivative of trans-4-aminocylcohexanecarboxylic acid or a salt thereof, which comprises treating a 4-aminocyclohexanecarboxylic acid or a reactive derivative thereof, which is in the cis form or in the form of a cis/trans mixture, with a base selected from the group consisting of a sodium hydroxide and a potassium alkoxide, and protecting the amino group of the product, when necessary.

Description

200400165 V. Description of the invention (1) [Technical field to which the invention belongs] The present invention relates to a novel method for producing trans-4-aminocyclohexanecarboxylic acids which is useful as a raw material compound for pharmaceuticals and the like. Specifically, it relates to a novel method for producing a high-purity trans isomer from a cis isomer of 4-aminocyclohexanecarboxylic acid or a mixture of cis and trans isomer. [Prior art] Trans-4 -aminocyclohexanecarboxylic acid and its amine-protected derivatives are raw materials of medicines and pesticides. Intermediate compounds and other useful compounds, such as raw material compounds of dipeptidyl dipeptidase IV (DPP IV) inhibitors that can be used in the treatment of diabetes, etc. (refer to International Patent No. 2002-3 0 8 9 1) . Production of trans-4 -aminocyclohexanecarboxylic acid, for example, a large amount of inexpensive 4-aminocyclohexanecarboxylic acid (trans and cis-iso A mixture of structures) A method for obtaining trans isomers by recrystallization separation method [Ref. J. Medicinal Chemistry, Vol. 36, 1 1 0 to 1 10 3, (1933 years)]. However, this method has the disadvantage that the yield of the trans isomers obtained is extremely low. In addition, the method of preparing isomers of 4-substituent-cyclohexanecarboxylic acid isomers or mixtures of cis and trans isomers may be used, for example, 4 -Isopropyl-cyclohexanecarboxylic acid is esterified with ethyl acetate and then heated in the coexistence of sodium nitride (refer to European Patent No. 0 1 9 6 2 2), and 4-isopropyl -A method of heating cyclohexanecarboxylic acid in the coexistence of sodium hydroxide [Ref. J. Chemical Society, 1245 to 1247, (1939)], and a 4-substituent-cyclohexanecarboxylic acid base A method for heating a metal salt or an alkaline earth metal salt (refer to JP 6 0-2 5 8 1 41), or

314510.ptd Page 5 200400165 V. Explanation of the invention (2) 4-Substituent method for heating cyclohexanylweiric acid (refer to JP 5 6-1 2 0 6 3 6 and JP 5 6- 1 2 5 3 4 2) and other well-known methods. These methods are all isomerization using a solvent (such as water, alcohols, etc.) that can dissolve the matrix or the product, or & without using a solvent, and the matrix or the product itself serves as a solvent in a homogeneous state (that is, a solution state). Method of reaction. Since the ratio of trans isomers obtained by these methods is relatively low, complicated purification operations must be performed again to obtain high purity trans isomers. In addition, Japanese Patent Application Laid-Open No. 10-2 3 7 0 1 5 describes the coexistence of a cyclohexanecarboxylic acid or an active derivative thereof having an alkyl group, a fluorinated alkyl group, or a carboxyl group at a 4-position in the presence of potassium hydroxide Method of isomerization under heating. However, when this method was applied to 4-aminocyclohexanecarboxylic acid, it was found that the disadvantage was that it required a long reaction time. In other words, when the above-mentioned conventional method is used as a method for preparing a high-purity trans-4-aminocyclohexanecarboxylic acid without cis isomer, the efficiency is not good, and it is highly desirable to research and develop a better method. SUMMARY OF THE INVENTION An object of the present invention is to provide a highly efficient and excellent manufacturing method of trans-4 -aminocyclohexanecarboxylic acids. Specifically, the present invention provides the efficient production of high-purity trans isomers from cis isomers of 4-aminocyclohexanecarboxylic acids or their reactive derivatives, or mixtures of cis and trans isomers IP. Method. • In order to solve the above problems, the researcher of the present invention has researched actively and found that using cheap sodium hydroxide or potassium alkoxide can convert the cis isomer or cis and trans of 4-aminocyclohexanecarboxylic acid. Mixtures of formula isomers are isomerized very efficiently to form trans isomers. That is, it was found that with this base, it is possible to

314510.ptd Page 6 200400165 V. Description of the invention (3) A method for preparing high-purity trans-4 -aminocyclohexanecarboxylic acid by reaction in a short time. If necessary, a protective group is added to the amine group of the product after the isomerization reaction, and it is found that a trans isomer having a higher purity can be obtained, and the present invention has been completed. The present invention is characterized in that the cis isomer or a mixture of cis and trans isomers of 4-aminocyclohexanecarboxylic acid or its active derivative is selected from the group consisting of sodium hydroxide and alcohol In the test process, if necessary, a protective group is formed on the amine group of the resulting product to make trans-4 -aminocyclohexanecarboxylic acid or a salt thereof, or trans-4 -aminocyclohexanecarboxylic acid. A method for preparing an amino-protected derivative or a salt thereof. [Embodiment] An active derivative of 4-aminocyclohexanecarboxylic acid refers to a carboxylic acid that can be converted into a carboxylic acid by removing the protective group in the coexistence of sodium hydroxide or potassium alkoxide used in the isomerization reaction of the present invention. Protect derivatives. Specific examples of the active derivative of 4-aminocyclohexanecarboxylic acid are 4-aminocyclohexanecarboxylic acid esters (e.g., lower alkyl esters or phenylacetates of p-esters, ethyl esters, etc., p-nitrobenzene). An aryl lower alkyl ester which may have a substituent, such as a fluorenyl ester, a benzyl ester, a triphenyl fluorenyl ester, an anthryl fluorenyl ester, etc.). In the isomerization reaction of the present invention, sodium hydroxide or potassium alkoxide is used as the base. Examples of potassium alkoxides include potassium tert-butoxide, potassium ethoxide, potassium alkoxide, and the like. The base used in the isomerization reaction of the present invention is preferably sodium hydroxide and potassium tert-butoxide, and most preferably sodium hydroxide. The amount of sodium hydroxide or potassium alkoxide used in the isomerization reaction of the present invention is usually based on 4-aminocyclohexanecarboxylic acid or its active derivative.

Page 7 314510.ptd 200400165 V. Description of the invention (4) The range of 2 to 10 equivalents, of which 2 to 3 equivalents is better, and the best is 2 equivalents. In the isomerization reaction of the present invention, when sodium hydroxide is used as a base, sodium trans-4 -aminocyclohexanecarboxylate is produced, and when potassium alkoxide is used as a base, trans-4 is produced. -Potassium aminocyclohexanoate. ^ The sodium or potassium salt of trans-4 -aminocyclohexanecarboxylic acid obtained by the isomerization reaction of the present invention can be converted into free trans-4 -aminocyclohexane-carboxylic acid or Other salts (such as lithium, magnesium, calcium, barium, zinc, aluminum, etc.). The above conversion can be implemented by a well-known and commonly used method. In other words, according to the present invention, trans-4 -aminocyclohexanecarboxylic acid® salts (such as sodium salt, bell salt, bell salt, ballast salt, mother salt, barium salt, zinc salt, aluminum salt, etc. ). The isomerization reaction is usually carried out in the range of 100 to 250 ° C, and it is more preferable to implement it in the range of 150 to 240 ° C. When alkali treatment is performed using sodium hydroxide, it is preferably performed in a range of 170 to 240 ° C, and when treated with potassium alkoxide, it is preferably performed in a range of 150 to 220 ° C. In the present isomerization reaction, the trans form is particularly suitable under the condition that the reaction proceeds to a heterogeneous solid-liquid system. In other words, although the amount of the salt of trans-4 -aminocyclohexanecarboxylic acid is small, at least a part of it is present as a solid, and the salt of cis-4 -aminocyclohexanecarboxylic acid is not solid The reaction is preferably performed in the presence of a dissolved or molten state. When the isomerization reaction is carried out under the conditions described above, at least a part of the trans isomers produced becomes solid and precipitates out of the reaction system. On the other hand, the cis isomers remain in a dissolved or molten state. In the reaction system, the thermodynamic equilibrium state is biased towards one of the trans isomers. Therefore, the trans isomers

3145]. Ptd page 8 200400165 V. Description of the invention (5) The isomerization proceeded smoothly, thus increasing the production rate of trans isomers. The present isomerization reaction can be carried out in a solvent. The solvent is used at a temperature at which the isomerization reaction is performed, and at least a part of the salt of the trans-4 -aminocyclohexanecarboxylic acid can be solid. The kind of solvent which is present and the cis-4-aminocyclohexanecarboxylic acid salt produced does not form a solid but exists in a dissolved or molten state. The above solvents may be exemplified by di-xylene (o-xylene, m-xylene, p-xylene, mixtures thereof, etc.), mesitylene, fluorenyl isopropylbenzene (o-xylene) Propylbenzene, m-fluorenylisopropylbenzene, p-methylisopropylbenzene and mixtures thereof), decalin (trans-naphthalene, cis-naphthalene and mixtures thereof, etc.), naphthalene, decyl Burning, thorium--carbane, dodecane burning, dodecene, biphenyl, and other hydrocarbons having 8 or more carbon atoms, diethylene glycol dimethyl ether, phenyl ether, diethylene glycol diethyl ether, Ethers having 6 or more carbon atoms, such as triethylene glycol dimethyl ether and diphenyl ether; amines having 8 or more carbon atoms, such as tributylamine and triphenylamine; and mixtures thereof. Among them, hydrocarbons having 8 or more carbon atoms, ethers having 6 or more carbon atoms, and mixtures thereof are preferred, and xylene (o-xylene, m-xylene, p-xylene, and Mixtures thereof), mesitylene, fluorenyl-isopropylbenzene (o-fluorenyl cumene, m-fluorenyl-cumene, p-fluorenyl cumene, and mixtures thereof) Etc.), decalin (trans-naphthyl, cis-naphthyl, and mixtures thereof, etc.), naphthalene, decane, fluorene-carbon, dodecyl, diphenyl, diethylene glycol difluorene ether , Diethylene glycol diethyl ether, diphenyl ether and mixtures thereof are more preferred. In particular, mesitylene, cumene isopropylbenzene (o-fluorenyl cumene, m-fluorenyl cumene, p-fluorenyl cumene

314510.ptd Page 9 200400165 V. Description of the invention (6) and its mixtures such as table-fired (trans-table-fired, cis-table-fired and mixtures thereof), dodecane, diethylene glycol diethyl ether, and Its mixture is optimal. • When using sodium hydroxide as a base, the solvent used is stable under the reaction conditions, and the sodium salt of trans-4 -aminocyclohexanecarboxylic acid can exist as a solid, while cis-4 -aminocyclohexanecarboxylic acid The sodium salt of the acid does not form a solid and can be dissolved or exists in a molten state. Such a solvent may be exemplified by dibenzobenzene (o-diphenylbenzene, m-diphenylbenzene, p-diphenylbenzene, and others). Mixture, etc.), mesitylene, isopropyl isopropylbenzene (o-fluorenyl isopropylbenzene, m-fluorenyl isopropyl, p-fluorenyl isopropylbenzene, and mixtures thereof), naphthalene (Trans-naphthene, cis-naphthalene, and mixtures thereof), naphthalene, decane, fluorene-carbon, dodecyl, dodecene, biphenyl, and other carbon atoms having a carbon number of 8 or more Hydrogen compounds, diethylene glycol dimethyl ether, phenyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, diphenyl ether, ethers having 6 or more carbon atoms, tributylamine, triphenyl Amines having 8 or more carbon atoms, such as amines, and mixtures thereof. Among them, a boiling point above 180 ° C is more preferable. Examples of such solvents include decalin (trans-decalin, cis-naphthalene, and mixtures thereof), naphthalene, fluorene-carbon, and Dioxane, dodecene, bibenzyl, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, diphenyl ether, tributylamine, triphenylamine, and mixtures thereof, and the like. Among them are Firing (trans-Cai Weiwan, cis-Cai burning and mixtures thereof), Tsai, undecane, dodecane, biphenyl, diethylene glycol diethyl ether, triethylene glycol di曱 scales, diphenyl scales, and mixtures thereof are more preferred, especially table-fired (trans-table-fired, cis-naphthalene-fired and mixtures thereof), twelve-carbon fired, diethylene glycol diethyl scale, and others Mixtures are optimal.

314510.ptd Page 10 200400165 V. Description of the invention (7) When potassium alkoxide is used as the base, the solvent used is stable under the reaction conditions and the potassium salt of trans-4 -aminocyclohexanecarboxylic acid can exist as a solid. At the same time, the potassium salt of cis-4-aminocyclohexanecarboxylic acid does not form a solid and can be dissolved or exists in a molten state. This solvent can be exemplified by xylene (o-xylene, m-xylene Benzene, p-diphenylbenzene and mixtures thereof, etc.), mesitylene, cumene isopropylbenzene (o-fluorenyl cumene, m-fluorenyl cumene, p-fluorenyl isopropyl Propylbenzene and mixtures thereof, etc.), decalin (trans-naphthane, cis-naphthane and mixtures thereof, etc.), naphthalene, decane, undecane, dodecane, dodecene, biphenyl Hydrocarbons having 8 or more carbon atoms, such as benzene, diethylene glycol dimethyl ether, benzene diazepam, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, diphenyl ether, etc. Amines having 8 or more carbon atoms, such as ethers, tributylamine, and triphenylamine, and mixtures thereof. Among them, those with a boiling point above 160 ° C are more preferred. Examples of such a solvent include mesitylene, fluorenyl isopropylbenzene (o-fluorenyl isopropylbenzene, m-methyl cumene, p-fluorenyl cumene, and mixtures thereof). ), Decalin (trans-naphthyl, cis-table, and mixtures thereof), Tsai, decane, undecyl, dodecane, dodecene, biphenyl, diethylene glycol Dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, dibenzyl ether, tributylamine, triphenylamine, and mixtures thereof. Among them, mesitylene, isopropyl isopropylbenzene (o-isopropyl isopropylbenzene, m-methylisopropylbenzene, p-isopropylisopropylbenzene, and mixtures thereof), decalin ( Trans-naphthane, cis-naphthane and mixtures thereof, etc.), Tsai, decane, hydrazone—carbane, dodecane, biphenyl, diethylene glycol dimethyl ether, diethylene glycol diethyl ether , Diphenyl ether and mixtures thereof are more preferred. In particular, mesitylene, isopropyl isopropylbenzene (o-methyl cumene, m-methyl

314510.ptd Page 11 200400165 V. Description of the invention (8) Isopropylbenzene, p-fluorenylisopropylbenzene and mixtures thereof), decalin (trans-naphthyl, cis-naphthyl and its Mixtures, etc.), dodecane, diethylene glycol diethyl ether, and mixtures thereof are most preferred. ^ The isomerization reaction can be carried out smoothly under normal pressure or pressure. Among them, it is better to carry out under normal pressure to 3 atm, especially to carry out under normal pressure. In addition, the isomerization reaction can be monitored by common methods such as high-efficiency liquid layer analysis (HPLC), thin-layer chromatography (TLC) and other analytical methods. The reaction usually ends in 6 to 30 hours. It is more preferable to terminate the reaction in 6 to 24 hours. # In the present invention, after the isomerization reaction with sodium hydroxide or potassium alkoxide, if necessary, a protective group addition reaction (hereinafter, referred to as an amine protection reaction) can be prepared on the amine group of the product. Into reactive isomers (ie, amine-protected derivatives of trans-4 -aminocyclohexanecarboxylic acid). The amino protected derivative of trans-4 -aminocyclohexanoic acid is more crystalline than the cis isomer. With this feature, trans isomers with higher purity can be efficiently separated. In other words, separating and washing the obtained amine-protected derivative after crystallization according to a general method can improve the purity of the trans isomer more than separating and washing after recrystallization according to a general method. When carrying out the amine-protection reaction, the sodium or potassium salt of the dependent formula-4 -aminocyclohexanecarboxylic acid prepared by the isomerization reaction can be used, or the above can be converted into the free trans-form according to the general method -4-After aminocyclohexanecarboxylic acid or other salts (such as lithium salt, magnesium salt, calcium salt, barium salt, zinc salt, aluminum salt, etc.),-to provide the use of amine protection reaction. Also, the sodium of trans-4 -aminocyclohexanecarboxylic acid prepared by the isomerization reaction

314510.ptd Page 12 200400165 V. Description of the invention (9) Salt or potassium salt, or the free trans-4 -aminocyclohexane carboxylate or other salt obtained after conversion, can provide amine group after separation For protection reaction, the solution containing the compound can also be used for protection reaction of amine group without isolation. The protective group for the amine group may be, for example, a lower alkoxycarbonyl group, a lower alkylfluorenyl group, an arylfluorenyl group, etc. which may have a substituent, and specifically, for example, a phenylfluorenyl carbonyl group, a 4-fluorenylphenoxy group , 9-fluorenylfluorenyloxycarbonyl, third butoxycarbonyl, 2, 2, 2-trichloroethyloxycarbonyl, fluorenyl, ethylfluorenyl, propylfluorenyl, butylfluorenyl, phenylfluorenyl, etc. . Among them, a lower alkoxycarbonyl group which may have a substituent is more preferable, and a phenylfluorenyloxycarbonyl group and a third butoxyweil group are more preferable. When the protective group of amine group is added with benzyloxycarbonyl group, the amine protected derivative of trans-4 -aminocyclohexanecarboxylic acid can be used to prepare trans-4-(phenylfluorenyloxycarbonylamino group). ) Cyclohexanecarboxylic acid. The amine group protection reaction in the present invention can be carried out according to a general method. For example, the addition of a phenylfluorenyloxycarbonyl group to an amino group can be carried out by reacting with a phenylfluorenyloxycarbonyl halide in the presence of a base in a solvent. The solvent can be used as long as it does not affect the reaction. For example, water, methanol, and ethanol can be used. Examples of the alkali include sodium hydroxide, potassium hydroxide, and potassium carbonate. As the phenylfluorenyloxycarbonyl iide, phenylfluorenyloxycarbonyl chloride is more suitable. The reaction is carried out at a temperature range of -40 ° C to 100 ° C, and it can proceed smoothly from 0 ° C to room temperature. In addition, for example, the reaction of addition of a third butoxycarbonyl group to an amine group can be carried out in a solvent in the presence of a base in the presence of a base.

314510.ptd Page 13 200400165 V. Description of the invention (10) Solvents can be used as long as they do not affect the reaction, such as water, methanol, ethanol, etc. Sodium hydroxide, potassium hydroxide, etc. can be used for testing. This reaction can be carried out in the range of -20 ° C to 40 ° C, and it is more preferably carried out at 0 ° C to room temperature. The amine-protected derivative of trans-4-aminocyclohexanecarboxylic acid obtained in the present invention can be crystallized > isolated, washed, recrystallized if necessary, separated, washed and isolated separately. For the net crystallization, diisopropyl ether, > hexane, ethyl acetate and other solvents can be used. Among them, diisopropylamidine is the best. The separation and purification of crystallization and recrystallization can be performed according to general methods. In particular, it is best to use a milling operation. The amine-protected derivative of trans-4 -aminocyclohexanecarboxylic acid obtained in the present invention can be converted into its salt (such as sodium salt, 4methyl salt, lithium, etc.) if necessary. Salt, magnesium salt, barium salt Λ zinc salt Λ aluminum salt, etc.) < This conversion can be carried out according to a general method. In other words, according to the present invention, an amine-protected derivative of trans-4-aminocyclohexanecarboxylic acid or a salt thereof (e.g., sodium salt, lithium salt, lithium salt, magnesium Salt calcium salt Λ barium salt zinc salt aluminum salt etc.). In addition, as the raw material compound of the present invention, a commercially available cis-isomer of 4-aminocyclohexanecarboxylic acid or an active derivative thereof or a mixture of cis- and trans-isomers can be used. The mixture of cis and trans isomers of cyclohexyl carboxylic acid can be referred to in the literature [iH ^ Or gar 1 ic: Syntheses Coll ective Vo 1 um (3 Vo: 1. 5. 6 7 0 to 672 (1 9 7 3 years:), J. Cherr li ca 1 S oc: ie 'ty ρ (3 r 1 (in r Γ ransactil ons I? 1199 to 1 20 1 (19 76), etc.); It is made by known methods such as catalytic reduction of 4-aminophenylarsinic acid.

314510.ptd Page 14 200400165 V. Description of the invention (11) In addition, trans-4 -aminocyclohexanecarboxylic acid or a salt thereof, or trans-4 -amino ring obtained by the method of the present invention When an amine-protected derivative of hexanecarboxylic acid or a salt thereof is used as a raw material compound, a DPP IV inhibitory drug represented by the general formula [1] can be prepared according to the following method (refer to International Publication 2 0 0 2-3 0 8 9 Number 1

NC (wherein A represents -CH2- or -S-, and R represents formula (N—— ,, (a) (1) may have a monocyclic, bicyclic or tricyclic nitrogen-containing heterocyclic group which may have a substituent, Or (2) an amine group which may have a substituent) For example, trans-4 -aminocyclohexanecarboxylic acid or a salt thereof, or trans-4 -aminocyclohexanecarboxylic acid prepared according to the method of the present invention The amine-protected derivative of an acid or a salt thereof is reacted with a compound represented by the general formula [2] or a salt thereof (for example, in the presence of a condensing agent), R-Η [2] (where R represents the same meaning as above), if necessary The compound of the general formula [3] or a salt thereof can be removed by removing the protecting group of the amine group, and R'mII ,,,,, {Z ^ NH2 [3].

314510.ptd Page 15 200400165 V. Description of the invention (12) ^ ~ __ (where 'R shows the same meaning as above) Then the compound shown by the general formula [3] is reacted (for example, in the coexistence of a deacidifier) Salt and the general formula [4] to transform the product into pharmacologically acceptable, non-existent or non-existent), and show the compound or its pharmacologically acceptable salt (夂 i to make general formula [1] as required)硖 A Shao,. Η | $ 考 国际 发布 2 0 0 2-3 0 8 9 1 ZO-(¾ One C — Ν ΧΑ

NC [4] (In the formula, 'A represents the same meaning as above, and ζ, ^, and ^ are inactive residues.) The following examples are used to explain this in more detail. This example is clear, but the present invention is not limited to Example 1. 5 g of 4-aminocyclohexane carboxyl cis.g "curtain (product of Dongya Chemical Industry Co., Ltd., trans / cis isomer = 15 / 85) and 97% sodium hydroxide 2.92 g-suspended in 50 ml of trans-1 at 90 ° C for 24 hours for isomerization reaction. The reaction solution was cooled to room temperature, 100 ml of water was added, and washed twice with 100 ml of ether. Then, 7.4 ml of concentrated hydrochloric acid was added to the ice-cold g for neutralization, and water was distilled off under reduced pressure. 45 ml of methanol was added to the zero residue, insoluble matter was filtered off, and methanol was distilled off under reduced pressure. The crude product was washed with chloroform and -methanol mixed solution to obtain 3 24 g of

BB 4-Amino yellow hexanecarboxylic acid (trans / cis isomer = 8 6 / 丨 4) light yellow knot ΰ Melting point: 2 1 4 to 2 1 7 ° C (decomposition). And the ratio of the trans and cis isomers of the 4-aminoamine

Page 16

Eli 314510.ptd 200400165 V. Description of the invention (13) The conversion rate is based on the conversion to 4-(phenylphenoxycarbonylamino) cyclohexanecarboxylic acid and then quantified by HPLC analysis according to the following conditions. Separation tube: CAPCELL PAK C18 UG120 (4.6x 150mm) Eluent: Acetonitrile / 0 · 1% trifluoroacetic acid (3 0/70) Flow rate: 1.0 m 1 / min Temperature: 2 5 ° C Wavelength: 2 10 nm sample: 1 mg / m 1 (eluent) Retention time of trans isomers: 12.6 minutes. Retention time of cis isomer: 13.8 minutes. Example 2 (1) A mixture of cis and trans isomers of 1 g of 4-aminocyclohexanecarboxylic acid (product of Tokyo Chemical Industry Co., Ltd., trans / cis isomer = 1 5/8) 5) and 97% sodium hydroxide 0.58 g-suspended in 10 m 1 of trans-naphthalene, and stirred at an external temperature of 19 (TC for 24 hours for isomerization). After cooling to room temperature, 20 m 1 of water was added to the reaction solution, and washed twice with 20 m 1 of diethyl ether. (2) In the water layer obtained in the above item (1), under ice-cooling for 1 hour 1.43 g of benzamyloxyhexyl chloride was added dropwise, followed by 5 m 1 of 2 N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour, and the reaction solution was washed with 20 ml of ether. Water The layer was adjusted to be acidic (pH = 4) with 10% hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium acetate, and distilled to remove the solvent to obtain 1.7 g of 4- (Benzyloxycarbonylamino) colorless crystals of cyclohexanecarboxylic acid (trans / cis isomer = 9 6/4).

314510.ptd Page 17 200400165 V. Description of the invention (14) (3) The crystal obtained in the above item (2) was washed with diisopropyl ether to obtain 1. 4 g of 4- (phenylfluorenyloxycarbonylamino) ) Colorless crystals of cyclohexanecarboxylic acid (trans / cis isomer di 99.6 / 0.4). Melting point: 2 2 0 to 2 2 1 ° C. In addition, the ratio of the trans and .cis isomers of the obtained 4- (phenylfluorenyloxycarbonylamino) cyclohexanecarboxylic acid was quantified by HPLC analysis under the same conditions as described in Example 1 above. Example 3 (1) A mixture of 2 g of cis and trans isomers of 4-aminocyclohexanecarboxylic acid (product of Tokyo Chemical Industry Co., Ltd., trans / cis isomer = 1 5 / • 5), and 97% sodium hydroxide 1. 15 g—suspended in 20 m 1 of trans-naphthalene, and stirred at an external temperature of 19 ° C. for 2 4 hours for isomerization. reaction. The reaction solution was cooled to room temperature, 40 m 1 of water was added, and washed with 50 m 1 of ether twice. (2) To the water layer obtained in the above item (1), 6.17 g of bis-tert-butyl dicarbonate was added under ice cooling, followed by 10 m 1 of 2 N sodium hydroxide aqueous solution. Stir at room temperature; stir overnight, and wash the reaction solution with 50 ml of diethyl ether. The water layer was adjusted to be acidic (pH = 4) with a 10% aqueous solution of citric acid, and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium acetate, and the solvent was removed by distillation to obtain 3. 2 g of 4- (third-butoxycarbonylamino) cyclohexanecarboxylic acid (trans / Colorless crystals of the cis isomer di 8 8/1 2). ® (3) The crystal obtained in (2) above was washed with diisopropyl ether to obtain 2. 17 g of 4- (third butoxycarbonylamino) cyclohexanecarboxylic acid (trans / cis Colorless crystals of the formula isomer 2 3 3/7). Melting point: 176 to 17 ° C. The ratio of the trans and cis isomers of the obtained 4- (third-butoxycarbonylamino) cyclohexanecarboxylic acid was determined by HPLC analysis under the following conditions.

314510.ptd Page 18 200400165 V. Description of the invention (15) Quantity. Separation tube: CAPCELL PAK C18 UG 1 2 0 (4.6x 1 50 mm) Eluent: Acetonitrile / pH2 · 0 phosphoric acid aqueous solution (2 5/7 5) Flow rate: 1 · 0 m 1 / Decomposition temperature: 2 5 ° C Wavelength: 2 1 0 nm Sample ·· 1 ιώ g / 1 m 1 (eluent) Retention time of trans isomers: 1 4 · 4 minutes Retention time of cis isomers · 1 5. 4 minutes Example 4 (1) A mixture of 1 g of 4-aminocyclohexanoic acid in cis and trans isomers (product of Tokyo Chemical Industry Corporation, trans / cis isomer = 5/8) 5) Suspend it together with 1.57 g of potassium tert-butoxide in 50 m of p-fluorenylisopropylbenzyl 'and stir at an external temperature of i 6 or 0 h for an isomerization reaction. After the reaction liquid-cooled part was brought to room temperature, 50 ml of water was added to remove the organic layer. The water layer was washed twice with 5 ml of toluene. (2) To the aqueous solution obtained in the above item (1), 1.79 g of benzylmethoxycarbonyl chloride and 5.3] 111 2N aqueous sodium hydroxide solution were added dropwise under ice-cooling over 2 hours. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, and the reaction solution was washed with 5 ml of ethyl acetate. Furthermore, methanol 'was added dropwise under concentrated cooling for 1.5 minutes at a concentration of 1.5 ml of hydrochloric acid. After searching directly for 1 hour, the precipitate was collected by filtration, washed with water-methanol mixture ^ water: methanol = 3: 1), washed and dried in air to obtain 1.22 g of 4- (benzyloxyalkylamino) ) Colorless crystals of cyclohexanecarbonyl acid (trans / cis isomer = 9 5/5).

Page 19, 200400165 V. Description of the invention (16) In addition, the ratio of the trans and cis isomers of the obtained 4- (phenylfluorenyloxycarbonylamino) cyclohexanecarboxylic acid is as described in Example 1 above. Quantitative analysis by HPLC under the same conditions. Example 5 (1) According to the same method as described in Example 4 (1) above, but the reaction time was changed to 16 hours, an isomerization reaction of 4-aminocyclohexanecarboxylic acid was performed. (2) The amine group protection reaction is performed according to the same method as shown in the above Example 4 (2) to obtain 4- (phenylphenyloxycarbonylamino) cyclohexanecarboxylic acid (trans / cis isomer = 8 6/1 4) colorless crystals. # (3) Suspend the crystal obtained in the above item (2) in 100 m 1 of bisisopropyl ether, and stir at an external temperature of 60 ° C for 30 minutes. After cooling to room temperature with stirring, the precipitate was collected by filtration and washed with diisopropyl ether to obtain 13.7 g of 4- (phenylfluorenyloxycarbonylamino) cyclohexanecarboxylic acid (trans / cis Color isomers of the formula isomer = 9 9 · 9 / 0.1). Melting point: 2 2 2 to 2 2 4 ° C. The ratio of the trans- and cis-isomers of the 4- (phenylfluorenyloxycarbonylamino) cyclohexanecarboxylic acid obtained was quantified by HPLC analysis under the conditions described in Example 1 above. Industrial feasibility According to the method of the present invention, #purity of trans-4 -aminocyclohexanecarboxylic acids can be easily and efficiently produced in a short time. Furthermore, in the present invention, the isomerization reaction is carried out in a solid or liquid form, so that trans-isomers with high purity can be obtained more. Further, in the present invention, a protective group is added to the amine group of the resulting product after the isomerization reaction, and a trans isomer having a higher purity can be obtained.

314510.ptd Page 20 200400165 Schematic description

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Claims (1)

200400165 6. Scope of patent application 1. A method for preparing trans-4 -aminocyclohexanecarboxylic acid or a salt thereof, or an amino-protected derivative of trans-4 -aminocyclohexanecarboxylic acid or a salt thereof, It is characterized by cis isomer of 4-aminocyclohexanecarboxylic acid or its active derivative, or a mixture of cis and trans isomers, and is composed of sodium hydroxide and potassium alkoxide. The base in the group is treated, and the amine group of the resulting product may be protected as necessary. '2. —A method for preparing trans-4-aminocyclohexanecarboxylic acid or its salt, characterized in that it is a cis isomer of 4-aminocyclohexanecarboxylic acid or its active derivative, or cis A mixture of formula and trans isomers is treated with a base selected from the group consisting of sodium hydroxide and potassium alkoxide. 3. A method for preparing trans-4-aminocyclohexanecarboxylic acid or a salt thereof, which is characterized in that the cis isomer of 4-aminocyclohexanecarboxylic acid or its active derivative, or cis And trans isomers, treated with a base selected from the group consisting of sodium hydroxide and potassium alkoxide, and then protecting the amine group of the product. 4. The method according to any one of claims 1 to 3 in the scope of patent application, wherein the alkali treatment is performed under the conditions of heterogeneity of solid-liquid as the reaction proceeds. 5 · If any one of the claims 1 to 3 of the scope of the patent application method, in which the alkali treatment is in the trans-4 -amino cyclohexane produced by the treatment Some of them are in a solid state, and the generated cis-4-aminocyclohexanecarboxylic acid salt is not in a solid state and is carried out under the conditions of being dissolved or molten. .6. If the system of any one of items 1 to 3 of the scope of patent application, 314510.ptd Page 22 200400165 6. In the scope of the patent application, the alkali treatment is that at least a part of the salt of trans-4 -aminocyclohexanecarboxylic acid produced by the treatment is in a solid state at the temperature at which the treatment is performed. Exist, and the generated cis-4-aminocyclohexanecarboxylic acid salt is not in a solid state and is carried out in a solvent in a dissolved or molten state. 7. The manufacturing method of any one of items 1 to 3 of the scope of patent application, wherein (i) the alkali is sodium hydroxide, and the treatment temperature is in the range of 1 70 to 240 ° C, or ( ii) The alkali system uses potassium alkoxide, and the treatment temperature is performed in the range of 150 to 220 ° C. 8. The method according to any one of claims 1 to 3 in the scope of patent application, wherein the alkali treatment is selected from the group consisting of dibenzobenzene, mesitylene, cumene isopropylbenzene, decalin, naphthalene, Decane, undecane, dodecane, undecene, biphenyl, diethylene glycol dimethyl ether, phenyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, diphenyl Ether, tributylamine, triphenylamine and mixtures thereof in a solvent. 9. For the method for preparing any one of items 1 to 3 of the scope of patent application, wherein (i), the alkali is sodium hydroxide, and the treatment is performed in a solvent having a boiling point of 180 ° C or more, or (Ii) The alkali system uses potassium alkoxide, and its treatment is carried out in a solvent with a boiling point of 16 (TC or more. 1). As in the method of any one of claims 1 to 3, ( i), the base system uses sodium hydride, and its treatment is selected from the group consisting of decalin, naphthalene, fluorene--carbane, dodecane, dodecene, biphenyl, diethylene glycol diethyl ether, triethyl Glycol dimethyl ether, tributylamine, triphenylamine, and mixtures thereof in a solvent, or (ii) the test system uses potassium alkoxide, and the treatment is selected from the group consisting of fluorenyl isopropylbenzyl, melamine Benzene, decalin, 314510.ptd Page 23 200400165 VI. Application scope of patents naphthalene, decane, eleven carbon, dodecyl, dodecene, biphenyl, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, Triethylene glycol dimethyl ether, diphenyl ether, tributylamine, triphenylamine, and mixtures thereof. .1 1. The production method according to any one of claims 1 to 3 in the scope of patent application, wherein the alkali is sodium hydroxide. 1 2. If the method of applying any one of items 1 to 3 of the scope of the patent application, the experience is to use a burner. 13. The manufacturing method according to item 12 of the scope of patent application, wherein the potassium alkoxide is a third potassium butoxide. 14. If the method for applying item 1 or item 3 of the scope of patent application, wherein the protective group added to the amine group of the product is a benzyloxy group. 1 5. If the method for applying item 1 or item 3 of the scope of patent application, wherein the protective group added to the amine group of the product is the third butoxycarbonyl group. 314510.ptd Page 24