JP2010193746A - Method for producing optically active trans-2-aminocyclohexanol derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an optically active trans-2-aminocyclohexanol derivative simply and in a high yield. <P>SOLUTION: The method for producing a trans-2-aminocyclohexanol derivative includes a step (a) of obtaining a racemic isomer by t-Boc reaction and acetylation of 2-aminocyclohexanol, a step (b) of obtaining a mixture of a compound represented by formula (3) and its acetylated optical isomer by asymmetrically hydrolyzing the racemic isomer by treatment with lipase and a step (c) of dissolving, filtrating and cleaning the mixture of the optical activator. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing an optically active trans-2-aminocyclohexanol derivative.

  Conventionally, as a method for producing an optically active trans-2-aminocyclohexanol derivative, a method that undergoes asymmetric hydrolysis using an enzyme such as lipase as reported in Patent Document 1 is known. In this document, an optically active trans-2-aminocyclohexanol derivative is produced according to the scheme represented by the following formula (7).

  However, in the examples of the document, the compound (3) which is an optically active hydroxy compound and the compound (4) which is an optically active acetate are separated using a silica gel column, which is an inefficient production method. .

Japanese Patent No. 2846770

  In view of the above circumstances, the problem to be solved by the present invention is to provide a method for producing an optically active trans-2-aminocyclohexanol derivative in a simple and high yield.

  As a result of intensive studies on the above problems, the present inventor produced a racemate of the compound represented by the formula (2) from the compound represented by the formula (1). The mixture of the optically active compounds represented by formula (3) and formula (4) is obtained by treating the racemic form of the compound represented by formula (3) with lipase and carrying out asymmetric hydrolysis. The present invention has been completed by finding that an optically active trans-2-aminocyclohexanol derivative can be produced easily and in a high yield by washing with the use of.

で表される化合物から下記式（２）

で表される化合物のラセミ体を得る工程と、
工程（ｂ）：前記式（２）で表される化合物のラセミ体をリパーゼで処理して不斉加水分解することにより下記式（３）

及び、下記式（４）

で表される光学活性体の混合物を得る工程と、
工程（ｃ）：前記式（４）で表される化合物を溶解し、かつ、前記式（３）で表される化合物を溶解しない溶媒（Ａ）を用いて、前記光学活性体の混合物から前記式（４）で表される化合物を溶解、ろ過して、洗浄する工程と、
を含む、光学活性なトランス−２−アミノシクロヘキサノール誘導体の製造方法。
［２］
前記工程（ｂ）における前記式（２）で表される化合物のラセミ体は、水に湿潤した状態である、上記［１］項記載の製造方法。
［３］
前記溶媒（Ａ）はＳＰ値が８以下の有機溶媒である、上記［１］又は［２］記載の製造方法。
［４］
工程（ｄ）：前記工程（ｂ）の後、前記光学活性体の混合物を抽出溶媒を用いて抽出し、次いで前記式（４）で表される化合物を溶解し、前記式（３）で表される化合物を溶解せず、かつ、前記抽出溶媒より沸点の高い溶媒（Ｂ）を加えた後、前記抽出溶媒を留去する工程、をさらに含む、上記［１］〜［３］のいずれか記載の製造方法。
［５］
前記工程（ｄ）における抽出溶媒は、脂肪族エステル系溶媒又はハロゲン系溶媒である、上記［４］記載の製造方法。
［６］
前記溶媒（Ｂ）はＳＰ値が８以下の有機溶媒である、上記［４］又は［５］記載の製造方法。
［７］
工程（ｅ）：前記工程（ｃ）の洗浄後の母液を濃縮し、残渣に水と混合する溶媒（Ｃ）と、水を加えて、前記式（４）で表される化合物を析出させて単離する工程、をさらに含む、上記［４］〜［６］のいずれか記載の製造方法。
［８］
前記溶媒（Ｃ）はＳＰ値が１０以上の有機溶媒である、上記［７］記載の製造方法。 That is, the present invention is as follows.
[1]
Step (a): Formula (1) below

From the compound represented by the following formula (2)

Obtaining a racemate of the compound represented by:
Step (b): A racemic isomer of the compound represented by the formula (2) is treated with lipase and subjected to asymmetric hydrolysis, whereby the following formula (3)

And the following formula (4)

A step of obtaining a mixture of optically active substances represented by:
Step (c): using a solvent (A) that dissolves the compound represented by the formula (4) and does not dissolve the compound represented by the formula (3), Dissolving, filtering and washing the compound represented by formula (4);
A process for producing an optically active trans-2-aminocyclohexanol derivative.
[2]
The production method according to item [1], wherein the racemic isomer of the compound represented by formula (2) in the step (b) is wet with water.
[3]
The method according to [1] or [2] above, wherein the solvent (A) is an organic solvent having an SP value of 8 or less.
[4]
Step (d): After the step (b), the mixture of the optically active substances is extracted using an extraction solvent, and then the compound represented by the formula (4) is dissolved, and is represented by the formula (3). Any one of the above [1] to [3], further comprising a step of adding the solvent (B) having a boiling point higher than that of the extraction solvent without dissolving the compound to be extracted and then distilling the extraction solvent off The manufacturing method as described.
[5]
The production method according to [4] above, wherein the extraction solvent in the step (d) is an aliphatic ester solvent or a halogen solvent.
[6]
The method according to [4] or [5] above, wherein the solvent (B) is an organic solvent having an SP value of 8 or less.
[7]
Step (e): The mother liquor after washing in the step (c) is concentrated, and the solvent (C) mixed with water and water are added to the residue to precipitate the compound represented by the formula (4). The production method according to any one of [4] to [6], further comprising an isolation step.
[8]
The method according to [7], wherein the solvent (C) is an organic solvent having an SP value of 10 or more.

  ADVANTAGE OF THE INVENTION According to this invention, the method of manufacturing an optically active trans-2-aminocyclohexanol derivative simply and with a sufficient yield can be provided.

  Hereinafter, a mode for carrying out the present invention (hereinafter referred to as the present embodiment) will be described in detail. In addition, this invention is not limited to the following embodiment, It can implement by changing variously within the range of the summary.

で表される化合物から下記式（２）

で表される化合物のラセミ体を得る工程と、
工程（ｂ）：前記式（２）で表される化合物のラセミ体をリパーゼで処理して不斉加水分解することにより下記式（３）

及び、下記式（４）

で表される光学活性体の混合物を得る工程と、
工程（ｃ）：前記式（４）で表される化合物を溶解し、かつ、前記式（３）で表される化合物を溶解しない溶媒（Ａ）を用いて、前記光学活性体の混合物から前記式（４）で表される化合物を溶解、ろ過して、洗浄する工程と、
を含む。 The production method of the optically active trans-2-aminocyclohexanol derivative of the present embodiment is as follows:
Step (a): Formula (1) below

From the compound represented by the following formula (2)

Obtaining a racemate of the compound represented by:
Step (b): A racemic isomer of the compound represented by the formula (2) is treated with lipase and subjected to asymmetric hydrolysis, whereby the following formula (3)

And the following formula (4)

A step of obtaining a mixture of optically active substances represented by:
Step (c): using a solvent (A) that dissolves the compound represented by the formula (4) and does not dissolve the compound represented by the formula (3), Dissolving, filtering and washing the compound represented by formula (4);
including.

  The manufacturing method of the present embodiment is a method according to the scheme represented by the following formula (8).

Hereinafter, each step will be described.
[Step (a)]
Step (a) is a racemate of a compound represented by formula (1) (hereinafter also referred to as compound (1)) to a compound represented by formula (2) (hereinafter also referred to as compound (2)). It is the process of obtaining.

  In the step (a), for example, a compound represented by the formula (1) as a raw material (hereinafter also referred to as a compound (1)) is reacted with di-tert-butyl-di-carbonate and acetic anhydride. Thus, a racemate of the compound represented by the formula (2) (hereinafter also referred to as the compound (2)) can be obtained. Hereinafter, one aspect in this step will be described.

  First, after compound (1) ((±) trans-2-aminocyclohexanol) is dissolved in a solvent, di-tert-butyl-di-carbonate is added to perform Boc reaction.

  The amount of di-tert-butyl-dicarbonate used is preferably 1.0 to 1.3 equivalents, more preferably 1.0 to 1.1 equivalents, relative to compound (1).

  Although it does not specifically limit as a solvent used for Boc-ized, From a viewpoint of reducing the load to an environment, Preferably, it is a cyclic ether solvent and an aliphatic ketone solvent.

  As the cyclic ether solvent, for example, tetrahydrofuran, 4-methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolane, morpholine and the like can be used, preferably tetrahydrofuran, 1, 4-dioxane, more preferably tetrahydrofuran.

  Examples of the aliphatic ketone solvent include acetone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone, methyl-n-butyl ketone, methyl-sec-butyl ketone, diisobutyl ketone, diethyl ketone, diisopropyl ketone, ethyl propyl ketone, butyl ethyl ketone. Etc., preferably acetone or methyl ethyl ketone.

  The usage-amount of a solvent is 2-20 times volume normally with respect to a compound (1), Preferably it is 3-5 times volume, More preferably, it is about 4 times volume.

  The reaction temperature in the Boc-forming reaction with di-tert-butyl-dicarbonate is usually 15 to 50 ° C, preferably 25 to 45 ° C, more preferably 30 to 40 ° C. Moreover, reaction time is 0.5 to 3 hours normally, More preferably, it is 1.5 to 2.5 hours.

  After completion of the Boc reaction, acetic anhydride and a base are added to carry out an acetylation reaction to produce a racemic compound (2). Here, when a solvent that dissolves both the compound (1) and the compound (2) is used as a reaction solvent in the Boc-formation, the Boc-formation with di-tert-butyl-di-carbonate and the acetyl with acetic anhydride are used. Is preferable because it can be carried out continuously in the same container (one-pot reaction).

  The reaction temperature in the acetylation reaction with acetic anhydride is usually 20 to 60 ° C, preferably 30 to 55 ° C, more preferably 40 to 50 ° C. Moreover, reaction time is 6 to 24 hours normally, Preferably it is 8 to 16 hours, More preferably, it is 8 to 12 hours.

  The base used for acetylation is not particularly limited, and for example, triethylamine, pyridine, sodium hydrogen carbonate, sodium carbonate and the like can be used. As a usage-amount of a base, Preferably it is 1-2 equivalent with respect to acetic anhydride, More preferably, it is 1.0-1.1 equivalent.

  Isolation and purification of the racemate of compound (2) can be carried out by conventional methods. For example, the racemate of compound (2) can be isolated and purified by a method known in the art such as extraction with a solvent, chromatography using a silica gel column, high performance liquid chromatography, vacuum distillation, recrystallization and the like. .

[Step (b)]
In the step (b), the racemic isomer of the compound represented by the formula (2) is treated with lipase and subjected to asymmetric hydrolysis, whereby the optically active form represented by the formulas (3) and (4) , Also referred to as compound (3) and compound (4), respectively).

  For asymmetric hydrolysis, a commonly used lipase may be used. Specific examples include lipase PS “Amano” SD originating from Pseudomonas cepacia lipase and lipase A6 originating from Aspergillus niger.

  The amount of lipase to be used is preferably 0.1 to 0.5 times mass, more preferably about 0.125 times mass with respect to compound (2).

  This enzyme reaction can be performed in an appropriate medium that does not inhibit the reaction, and can be performed, for example, in a 0.1 M sodium phosphate buffer (pH 6.0 to 7.0). The amount of the medium to be used is preferably 10 to 100 times the volume, more preferably 20 to 25 volumes with respect to the compound (2). The reaction temperature is usually 30 to 50 ° C, preferably about 45 ° C. The reaction time is usually 6 to 24 hours, preferably about 20 hours.

  The stirring speed in the enzyme reaction is preferably 30 to 300 rpm, more preferably 50 to 150 rpm. When the stirring speed is in the above range, the inactivation of the enzyme is reduced, and the asymmetric hydrolysis reaction tends to proceed better.

  In step (b), the racemate of the compound represented by formula (2) is preferably in a state wetted with water. When the compound (2) is in a dry state, the compound (2), which is a substrate, has a strong hydrophobic property, which makes it difficult to mix with a phosphate buffer used as a reaction medium, and the asymmetric hydrolysis reaction is excellent. May not progress.

  In the manufacturing method of the present embodiment, the following formula (3) is obtained by performing the steps (a) and (b).

And the following formula (4)

It is possible to obtain a mixture of optically active trans-2-aminocyclohexanol derivatives represented by:

[Step (c)]
In the production method of the present embodiment, a solvent (A) that dissolves the compound represented by the formula (4) and does not dissolve the compound represented by the formula (3) after the step (b). ) Is used to dissolve, filter and wash the compound represented by the formula (4) from the mixture of optically active substances.

  In this step, the compound (3) is more easily and efficiently obtained by washing the mixture of optically active substances using a specific organic solvent, compared with the conventional method using a silica gel column. It became possible to isolate.

The solvent (A) that dissolves the compound represented by the formula (4) and does not dissolve the compound represented by the formula (3) is preferably an organic solvent having an SP value of 8 or less. Preferred are aliphatic hydrocarbon solvents having 5 to 10 carbon atoms, more preferred are pentane, hexane, heptane, octane, nonane and decane, and particularly preferred is hexane. In the present embodiment, the SP value (solubility parameter) is also referred to as a Hildebrand solubility parameter. For typical solvents, see Chemical Reviews, 1975, Vol. 75 has been described as δ (cal ^1/2 cm ^-3/2) to TABLEV of No6,731-753.

  The washing operation can be carried out by adding the solvent (A) to the optically active substance mixture, stirring and then filtering. The washing operation may be repeated a plurality of times. The amount of the solvent (A) used in the washing operation is preferably 1 to 10 times, more preferably about 4 times the volume of the mixture of optically active substances.

  Compound (3) which is an optically active hydroxy form is obtained by washing operation, and further, by recrystallizing with solvent (A) as necessary, compound (3) is isolated with high optical purity and yield. Can do. The volume of the solvent (A) used in the recrystallization is preferably 10 to 40 times, more preferably about 25 times the volume of the compound (3).

[Step (d)]
In the production method of the present embodiment, after the step (b), the mixture of optically active substances is extracted using an extraction solvent, and then the compound represented by the formula (4) is dissolved. The method may further include a step of distilling off the extraction solvent after adding the solvent (B) having a boiling point higher than that of the extraction solvent without dissolving the compound represented by (3).

  In this step, a mixture of compound (3) which is an optically active hydroxy compound and compound (4) which is an optically active acetate is extracted using an extraction solvent, and if necessary, the extraction solvent is distilled off to a certain amount. The solvent is replaced by adding the solvent (B) and completely distilling off the extraction solvent. By adding the solvent (B) having a boiling point higher than that of the extraction solvent, the extraction solvent can be distilled off more rapidly and completely. Conversely, when a solvent having a boiling point lower than that of the extraction solvent is added, the extraction solvent is not completely distilled off, so that a part of the compound (3) remains dissolved in the extraction solvent, and the above-described step (c) ) Tends to deteriorate the yield of compound (3).

  Moreover, when the extraction solvent is distilled off without adding the solvent (B), the compound (3) and the compound (4) are solidified, and subsequent isolation and purification become difficult. When the solvent (B) is added and the extraction solvent is completely distilled off, the solvent (B) remains after the extraction solvent is distilled off. Therefore, the compound (3) which is an optically active hydroxy compound and the optically active acetate The mixture of the compound (4) is precipitated in a liquid with good fluidity, and the subsequent isolation and purification tend to be easy.

  As an extraction solvent for extracting a mixture of the compound of the following formula (3) which is an optically active hydroxy compound and the compound of the following formula (4) which is an optically active acetate, a compound (3) and a compound (4) are dissolved. Although it will not specifically limit if it exists, Preferably it is an aliphatic ester solvent or a halogen-type solvent.

  As the aliphatic ester solvent, for example, methyl acetate, ethyl acetate, butyl acetate, methyl propionate, ethyl propionate and the like can be used, and ethyl acetate is preferable.

  As the halogen solvent, methylene chloride, chloroform, carbon tetrachloride, dichloromethane, dichloroethane, trichloroethylene, monochlorobenzene, dichlorobenzene, trichlorobenzene and the like can be used, and methylene chloride and chloroform are preferable.

  The amount of the extraction solvent used is usually 10 to 30 times, preferably about 15 times the volume of the mixture of compound (3) and compound (4). After extraction, if necessary, the extraction solvent is distilled off under reduced pressure until crystals are precipitated. The extraction solvent is preferably distilled off to 1/10 to 3/10 times the volume, more preferably about 1.5 / 10 times the volume.

  The solvent (B) is preferably an organic solvent having an SP value of 8 or less, more preferably an aliphatic hydrocarbon solvent having 6 to 10 carbon atoms, and still more preferably hexane, heptane, octane, nonane or decane. Yes, particularly preferably heptane.

  The volume of the solvent (B) to be added is preferably 1 to 10 times, more preferably about 3 times the volume of the extraction solvent (after partial distillation). Thereafter, the extraction solvent is completely distilled off to replace the solvent.

[Step (e)]
In the step (e), the mother liquor after the washing in the step (c) is concentrated, and a solvent (C) mixed with water and water are added to the residue to precipitate the compound represented by the formula (4). It is the process of isolating.

  In this step, the mother liquor after washing in step (c) is concentrated, the solvent (C) is added to the concentrated residue, the residue is dissolved, water is added, and the precipitated crystals are collected by filtration. Compound (4) which is acetate can be isolated.

  The solvent (C) is not particularly limited as long as it is mixed with water, but is preferably an organic solvent having an SP value of 10 or more, more preferably a lower alcohol having 3 or less carbon atoms, and further preferably methanol. , Ethanol, n-propyl alcohol and isopropyl alcohol, particularly preferably methanol.

  The volume of the solvent (C) used is usually 3 to 10 times the volume of the concentrated residue, preferably about 5 times the volume. The volume of water used is usually 3 to 10 times the volume of the concentrated residue, preferably about 7.5 times the volume.

  The compounds (3) and (4) remaining in the mother liquor of water and solvent (C) used in step (e) can be further obtained by repeating the above steps (c), (d) and (e). And can be purified.

  After the step (c), the obtained optically active hydroxy compound represented by the formula (3) is treated with an acid such as hydrochloric acid as shown in the following formula (9), thereby obtaining the following formula (5). It can be converted into an appropriate salt such as (1R, 2R) trans-2-aminocyclohexanol hydrochloride represented.

  The (1R, 2R) trans-2-aminocyclohexanol hydrochloride represented by the formula (5) obtained by using the production method of the present embodiment is 2,4 as shown by the following formula (10). -Treated with dinitrofluorobenzene to obtain a compound represented by the following formula (11), and its optical purity was measured by high performance liquid chromatography. e. It turned out to be. The absolute configuration of compound (11) was referred to Japanese Patent No. 2846770.

  Further, after the step (e), the obtained optically active acetate represented by the formula (4) is converted to 1.0 to 3.0 equivalents of sodium methylate in a methanol solvent as shown by the following formula (12). To obtain an optically active hydroxy compound represented by the following formula (13), and then tert-butyloxycarbonyl is removed using an appropriate acid such as 1.0 to 3.0 equivalents of hydrochloric acid, It can be converted into an appropriate salt such as (1S, 2S) trans-2-aminocyclohexanol hydrochloride represented by the following formula (6).

  Examples that specifically describe the present embodiment will be described below, but the present embodiment is not limited to the following examples unless it exceeds the gist.

Example 1
[Step (a)]
Preparation of (±) trans-2-tert-butoxycarboamidocyclohexyl acetate 18.9 g (86.8 mmol) of di-tert-butyl-dicarbonate was added to 42 mL of tetrahydrofuran, and (±) 2-aminocyclohexanol 10. After adding 0 g (86.8 mmol) over 30 minutes and reacting at 35 ° C. for 2 hours, 17.6 g (174 mmol) of triethylamine and 17.7 g (174 mmol) of acetic anhydride were added and reacted at 45 ° C. for 10 hours. It was. After completion of the reaction, the reaction solution was added to 245 mL of water and stirred for 30 minutes. The precipitated crystals were collected by filtration, and 20.7 g (80.34 mmol, yield 92) of (±) trans-2-tert-butoxycarboamidocyclohexyl acetate. .6%).
The NMR spectrum of the obtained compound was consistent with the data of Example 2 of Japanese Patent No. 2846770.

[Step (b)]
Preparation of (1R, 2R) trans-2-tert-butoxycarboxamide cyclohexanol and (1S, 2S) trans-2-tert-butoxycarboxamide cyclohexyl acetate mixture (±) trans-2-tert-butoxycarboxamide cyclohexyl acetate 20 g (77.7 mmol) of 50% wet product (hydrated product) was suspended in 400 mL of 0.1 M sodium phosphate buffer (pH 7.0), and lipase PS (Amano) SD (manufactured by Amano Enzyme Co., Ltd.) was added. 5 g was added, and asymmetric hydrolysis was carried out at 48 ° C. for 20 hours with slow stirring using a stirring motor.

[Step (c)] and [Step (d)]
Production of (1R, 2R) trans-2-tert-butoxycarboamidocyclohexanol After completion of the above reaction, 5.0 g of diatomaceous earth, 180 mL of ethyl acetate and 128.5 g of sodium chloride were added and stirred for 30 minutes, followed by filtration, The aqueous layer was extracted again with 90 mL of ethyl acetate, and the ethyl acetate layers were combined, washed with 30 mL of 1% aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After 230 mL of ethyl acetate in the organic layer was distilled off, 85 mL of heptane was added, and 34 mL of the ethyl acetate / heptane mixture was distilled off. Further, 34 mL of heptane was added, and the operation of distilling 34 mL of the ethyl acetate and heptane mixture was repeated 2-3 times. After all ethyl acetate was distilled off, 68 mL of hexane was added, and the precipitated crystals were collected by filtration. Crystals on the filter paper were washed with stirring at 200 mL of hexane at 25 ° C. for 30 minutes and filtered. Furthermore, 5.46 g (24.9 mmol, yield 32.6%) of (1R, 2R) trans-2-tert-butoxycarboxamide cyclohexanol was obtained by recrystallizing the crystals on the filter paper with 233 mL of hexane. Obtained.
The washed and recrystallized heptane and hexane mother liquors were concentrated, the residue was dissolved in 56 mL of methanol, and 84 mL of water was added and the precipitated crystals were collected by filtration. Concentrate the mother liquor to 70 mL, add sodium chloride, extract twice with 30 mL of ethyl acetate, dry over magnesium sulfate, concentrate the organic layer, and wash and recrystallize using heptane and hexane in the same manner as above. (Purification) was performed to obtain 1.51 g (7.1 mmol) of (1R, 2R) trans-2-tert-butoxycarboxamide cyclohexanol.
The total amount of (1R, 2R) trans-2-tert-butoxycarboamidocyclohexanol obtained by the above method was 7.02 g (32.2 mmol, yield 41.4%).
Further, the NMR spectrum of the obtained compound coincided with the data of Example 1 of Japanese Patent No. 2846770.
These optically active (1R, 2R) trans-2-tert-butoxycarboxamide cyclohexanol (100 mg) was treated with dioxane (1.5 mL), concentrated hydrochloric acid (120 uL) at 10 ° C. for 1 hour, concentrated, then chloroform (10 mL, 2, 4). -Dinitrofluorobenzene (1.86 g) and triethylamine (200 uL) were added and treated at 60 ° C for 1 hour. After distilling off the solvent, the solution was diluted with 100 mL of ethanol and analyzed by high performance liquid chromatography (HPLC). The peak of (1R, 2R) trans-2-tert-butoxycarboxamide cyclohexanol was detected. In addition, the enantiomer of this compound was not detected and the optical purity was 100% e.e. e. Met.
HPLC analysis conditions were as follows: Column: Daicel Chemical Industries CHIRALPAK IB, column temperature 25 ° C., mobile phase: hexane / tert-butyl methyl ether / ethanol = 50/50/2, flow rate: 1.0 mL / min, detection wavelength: 350 nm I went there.

[Step (e)]
Preparation of (1S, 2S) trans-2-tert-butoxycarboxamide cyclohexanol The heptane and hexane mother liquors after washing and recrystallization in the above step (c) are concentrated, the residue is dissolved in 56 mL of methanol, and 84 mL of water is added. In addition, the precipitated crystals were collected by filtration to obtain 7.30 g (28.4 mmol, yield 36.6%) of (1S, 2S) trans-2-tert-butoxycarboxamide cyclohexyl acetate. 1.0 g of this crystal was treated in the same manner as in Example 7 of Japanese Patent No. 2846770 to give (1S, 2S) trans-2-tert-butoxycarboxamidocyclohexanol. After the addition of 4-dinitrofluorobenzene, the optical purity was measured by high performance liquid chromatography. As a result, a peak of (1S, 2S) trans-2-tert-butoxycarboxamide cyclohexanol was detected at a retention time of about 14 minutes. did. In addition, the enantiomer of this compound was not detected and the optical purity was 100% e.e. e. Met. The optical purity was measured by the same method as described above.
Further, the NMR spectrum of the obtained compound coincided with the data of Example 1 of Japanese Patent No. 2846770.

(Example 2)
Production of (1R, 2R) trans-2-tert-butoxycarboxamide cyclohexanol and (1S, 2S) trans-2-tert-butoxycarboxamide cyclohexyl acetate (±) trans-2-tert-butoxycarboxamide cyclohexyl acetate 3 0.0 g (11.66 mmol) is dissolved in 6 mL of methanol, added to 60 mL of 0.1 M sodium phosphate buffer (pH 7.0), 0.375 g of lipase PS (Amano) SD is added, and the mixture is inactivated at 48 ° C. for 16 hours. Simultaneous hydrolysis was performed. After completion of the reaction, 1.03 g (4.72 mmol, 41.0% yield) and (1S, 2S) of (1R, 2R) trans-2-tert-butoxycarboxamide cyclohexanol were obtained in the same manner as in Example 1. 1.10 g (4.27 mmol, yield 35.0%) of trans-2-tert-butoxycarboxamide cyclohexyl acetate was obtained. Each optical purity was 100% e.e. e. Met. The optical purity was measured by the same method as in Example 1.

Claims (8)

Step (a): Formula (1) below

From the compound represented by the following formula (2)

Obtaining a racemate of the compound represented by:
Step (b): A racemic isomer of the compound represented by the formula (2) is treated with lipase and subjected to asymmetric hydrolysis, whereby the following formula (3)

And the following formula (4)

A step of obtaining a mixture of optically active substances represented by:
Step (c): using a solvent (A) that dissolves the compound represented by the formula (4) and does not dissolve the compound represented by the formula (3), Dissolving, filtering and washing the compound represented by formula (4);
A process for producing an optically active trans-2-aminocyclohexanol derivative.   The production method according to claim 1, wherein the racemate of the compound represented by the formula (2) in the step (b) is in a wet state in water.   The manufacturing method according to claim 1 or 2, wherein the solvent (A) is an organic solvent having an SP value of 8 or less.   Step (d): After the step (b), the mixture of the optically active substances is extracted using an extraction solvent, and then the compound represented by the formula (4) is dissolved, and is represented by the formula (3). The method further includes the step of distilling off the extraction solvent after adding the solvent (B) having a higher boiling point than the extraction solvent without dissolving the compound to be produced. Manufacturing method.   The production method according to claim 4, wherein the extraction solvent in the step (d) is an aliphatic ester solvent or a halogen solvent.   The said solvent (B) is a manufacturing method of Claim 4 or 5 which is an organic solvent whose SP value is 8 or less.   Step (e): The mother liquor after washing in the step (c) is concentrated, and the solvent (C) mixed with water and water are added to the residue to precipitate the compound represented by the formula (4). The production method according to claim 4, further comprising an isolation step.   The manufacturing method according to claim 7, wherein the solvent (C) is an organic solvent having an SP value of 10 or more.