JP2003055358A - METHOD FOR PRODUCING beta-HYDROXYAMINO ACID DERIVATIVE - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for producing (2R,3R)-2-(t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid useful as an important synthetic intermediate of a medicine. SOLUTION: This method for producing (2R,3R)-2-(t-butoxycarbonyl)amino-3- hydroxy-3-cyclohexylpropanoic acid of the formula (I) is provided by asymmetrically epoxidizing 3-cyclohexyl-2-propenol expressed by the formula (V) to obtain (2R,3R)-2,3-epoxy-3-cyclohexylpropanol expressed by the formula (IV), oxidizing the obtained compound to obtain (2S,3R)-2,3-epoxy-3-cyclohexylpropanoic acid expressed by the formula (III), performing a reaction of the compound with benzylamine to obtain (2R,3R)-2-benzylamino-3-hydroxy-3-cyclohexylpropanoic acid expressed by the formula (II), subjecting the compound with a hydrogenolysis reaction and then subjecting with a blocking reaction.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a novel β-hydroxyamino acid derivative. More specifically, formula (1) (V)

[0002]

[Chemical 8]

Formula (I) using 3-cyclohexyl-2-propenol represented by

[0004]

[Chemical 9]

A method for producing (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid represented by: and (2) formula (V)

[0006]

[Chemical 10]

3-Cyclohexyl-2-propenol represented by the formula (IV) was subjected to asymmetric epoxidation in the absence of molecular sieves.

[0008]

[Chemical 11]

A method for producing (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by

[0010]

[Prior Art and Problems to be Solved by the Invention] β
-Hydroxyamino acid derivatives are generally important compounds as intermediates for pharmaceuticals, and many synthetic methods have been developed. For example, in Synthesis, 34-36, (1990),
The method represented by Reaction Scheme 1 is described.

[0011]

[Chemical 12]

In the conventional method represented by the reaction process formula 1, β-
As a hydroxyamino acid, a method for synthesizing (2S, 3S) -2-amino-3-hydroxy-4-methylheptanoic acid is known. However, (2R, 3R) -2-
Nothing was known about amino-3-hydroxy-3-cyclohexylpropanoic acid.

Therefore, (2R, 3R) -2-amino-3
A method for producing (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid, which is a protected compound of -hydroxy-3-cyclohexylpropanoic acid, has been desired.

In addition, the asymmetric epoxidation reaction of allyl alcohols is carried out in the presence of optically active diethyl tartrate, tetraisopropyl titanate and peracid to obtain an epoxide having a high chemical yield and a high optical purity. It is known that In addition, if water is mixed in the reaction system, the oxidation rate and the optical purity of the epoxide will decrease, so that molecular sieves 4Å are used as a dehydrating agent in the reaction system.
When coexisting with tetraisopropyl titanate a catalytic amount of 5
It is known that an epoxide having a high chemical yield and a high optical purity can be obtained even at 10 mol%.

The present inventors have conducted intensive studies to achieve the above object, and as a result, found a method represented by the following reaction process formula 2.

[0016]

[Chemical 13]

The compound (2R, 3R) -2-amino-3-hydroxy-3-cyclohexylpropanoic acid is protected for the first time (2R, 3R) by the production method represented by the reaction process formula 2 found by the present inventors. , 3R) -2- (t-
Butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid was prepared.

Further, the present inventors have found that the formula (V)

[0019]

[Chemical 14]

In the asymmetric epoxidation reaction of 3-cyclohexyl-2-propenol represented by the formula (4), tetraisopropyl titanate is used in a catalytic amount, in a high chemical yield, even in the absence of molecular sieves 4Å in the reaction system. Formula (IV) having high optical purity

[0021]

[Chemical 15]

It has been found that (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by the following formula can be obtained.

[0023]

DISCLOSURE OF THE INVENTION 1) Formula (V)

[0024]

[Chemical 16]

3-cyclohexyl-2-propenol represented by the formula (IV) was subjected to an asymmetric epoxidation reaction.

[0026]

[Chemical 17]

(2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by the formula (3) is obtained, and the compound is subjected to an oxidation reaction to obtain the compound of formula (III)

[0028]

[Chemical 18]

(2S, 3R) -2,3-epoxy-3-cyclohexylpropanoic acid represented by the formula (II) is obtained by reacting the compound with benzylamine.

[0030]

[Chemical 19]

(2R, 3R) -2-benzylamino-3
-Hydroxy-3-cyclohexylpropanoic acid is obtained, and the compound is subjected to a hydrogenolysis reaction, and further subjected to a protection reaction.

[0032]

[Chemical 20]

Method for producing (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid, 2) Formula (V)

[0034]

[Chemical 21]

3-Cyclohexyl-2-propenol represented by the formula (I) is subjected to an asymmetric epoxidation reaction in the presence or absence of molecular sieves.
V)

[0036]

[Chemical formula 22]

Method for producing (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by: 3) Formula (V)

[0038]

[Chemical formula 23]

3-cyclohexyl-2-propenol represented by the formula (IV) is characterized by reacting in an organic solvent in the presence of optically active diethyl tartrate, a catalytic amount of tetraisopropyl titanate and peracid.

[0040]

[Chemical formula 24]

Method for producing (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by: 4) Formula (V)

[0042]

[Chemical 25]

3-cyclohexyl-2-propenol represented by the formula (IV) is reacted in an organic solvent in the presence of optically active diethyl tartrate, a catalytic amount of tetraisopropyl titanate and peracid.

[0044]

[Chemical formula 26]

(2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by the formula (III) is obtained by subjecting the compound to an oxidation reaction.

[0046]

[Chemical 27]

(2S, 3R) -2,3-epoxy-3-cyclohexylpropanoic acid of formula (II) is obtained by reacting the compound with benzylamine.

[0048]

[Chemical 28]

(2R, 3R) -2-benzylamino-3
-Hydroxy-3-cyclohexylpropanoic acid is obtained, and the compound is subjected to a hydrogenolysis reaction, and further subjected to a protection reaction.

[0050]

[Chemical 29]

It relates to a method for producing (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid.

In the present invention, unless otherwise specified,
Symbols as will be apparent to those skilled in the art

[0053]

[Chemical 30]

Indicates that it is connected to the other side of the paper (that is, α-arrangement),

[0055]

[Chemical 31]

Indicates that it is connected to the front side of the paper (that is, β-arrangement),

[0057]

[Chemical 32]

Represents α-, β- or a mixture thereof, or E-form, Z-form or a mixture thereof,

[0059]

[Chemical 33]

Indicates that it is a mixture of α-configuration and β-configuration.

In the present invention, all isomers are included unless otherwise specified. For example, the alkyl group, the alkoxy group and the alkylene group include straight chain and branched chain groups. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings and condensed rings, isomers due to the presence of asymmetric carbon (R, S isomers, α, β isomers, enantiomers, diastereomers) , Optically active substances having optical activity (D, L, d, l isomers), polar substances (high polar substances, low polar substances) by chromatographic separation, equilibrium compounds, mixtures of these at arbitrary ratios, racemic mixtures, All are included in the present invention.

[0062]

PRODUCTION METHOD OF THE INVENTION (2R, 3)
R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid has the formula (V)
Can be produced from 3-cyclohexyl-2-propenol represented by the following method or the method described in Examples.

Formula (I)

[0064]

[Chemical 34]

(2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid has the formula (II)

[0066]

[Chemical 35]

It can be produced by subjecting (2R, 3R) -2-benzylamino-3-hydroxy-3-cyclohexylpropanoic acid represented by to a hydrogenolysis reaction and then a protection reaction.

This hydrogenolysis reaction is known, and the deprotection reaction by hydrogenolysis can be carried out, for example, with an inert solvent [ether system (eg tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether etc.), alcohol system (eg methanol). , Ethanol, isopropyl alcohol, etc.), benzene series (eg, benzene, toluene etc.), amide series (eg, dimethylformamide etc.),
Water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof, etc.] in a hydrogenation catalyst (eg, palladium-carbon, palladium black, palladium, palladium hydroxide, platinum-carbon, platinum dioxide, nickel, ruthenium chloride, etc.) In the presence of an inorganic acid (for example, hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, etc.) or an organic acid (for example,
Acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.) in the presence or absence of hydrogen atmosphere under normal pressure or pressure or in the presence of ammonium formate,
It is carried out at a temperature of 0 to 200 ° C. When an acid is used, its salt may be used.

This protection reaction is known, and a base (sodium hydroxide, potassium hydroxide, triethylamine, dimethylaminopyridine, etc.) and diamine are mixed with each other in a mixture of water-miscible organic solvent (dioxane, acetone, etc.) and water. -T
-In the presence of butyl dicarbonate, at a temperature of 0-40 ° C.

Formula (II)

[0071]

[Chemical 36]

(2R, 3R) -2-benzylamino-3-hydroxy-3-cyclohexylpropanoic acid represented by the formula (III)

[0073]

[Chemical 37]

It can be produced by reacting (2S, 3R) -2,3-epoxy-3-cyclohexylpropanoic acid represented by: with benzylamine.

This reaction is known, and in a solvent (such as water),
It is carried out in the presence of a base (sodium hydroxide, potassium hydroxide, etc.) and benzylamine at a temperature of 50 to 150 ° C.

Formula (III)

[0077]

[Chemical 38]

(2S, 3R) -2,3-epoxy-3-cyclohexylpropanoic acid represented by the following formula (IV)

[0079]

[Chemical Formula 39]

It can be produced by subjecting (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by: to an oxidation reaction.

This oxidation reaction is known, and there are a method of forming an aldehyde from an alcohol and further oxidizing it to a carboxylic acid, and a method of oxidizing an alcohol to a carboxylic acid.

Methods for oxidizing alcohols to aldehydes are known and include (1) Swern oxidization
ation), (2) a method using sulfur trioxide / pyridine complex, and the like.

These methods will be described in detail. (1) The method using swan oxidation is, for example, the reaction of oxalyl chloride with dimethyl sulfoxide in an inert organic solvent (chloroform, methylene chloride, etc.) at -78 ° C. Then, the obtained solution is reacted with an alcohol compound and further with a tertiary amine (triethylamine or the like) at -78 to 20 ° C.
It is carried out by reacting with. (2) The method using a sulfur trioxide / pyridine complex is carried out by using a sulfur trioxide / pyridine complex in the presence of a tertiary amine (triethylamine, diisopropylethylamine, etc.) in an inert organic solvent (dimethyl sulfoxide, etc.).
It is carried out at a temperature of ~ 50 ° C.

It is desirable to carry out the reactions (1) and (2) under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

The reaction of oxidizing an aldehyde to a carboxylic acid is known, and for example, an organic solvent (acetonitrile etc.)
Among them, alkali metal salts of 2-methyl-2-butene and phosphoric acid (sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.)
By reacting with sodium chlorite at 0 to 50 ° C in the presence of.

The method of oxidizing an alcohol to a carboxylic acid is known, and is carried out, for example, in an organic solvent (acetone or the like) in the presence of Jones reagent at a temperature of 0 to 50 ° C.

Other than the above, the oxidation reaction is not particularly limited as long as it is a method of easily and selectively forming an aldehyde from an alcohol and further oxidizing it to a carboxylic acid and a method of oxidizing an alcohol to a carboxylic acid. . For example, "Comprehensive Organic Transformation
s '' (Richard C. Larock, VCH Publishers, Inc., (198
9) The ones described on pages 604-614) are used.

Formula (IV)

[0089]

[Chemical 40]

The (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by the formula has the formula (V):

[0091]

[Chemical 41]

It can be produced by subjecting 3-cyclohexyl-2-propenol represented by ## STR10 ## to an asymmetric epoxidation reaction.

This asymmetric epoxidation reaction is known,
In the presence of molecular sieves 4Å, optically active diethyl tartrate, catalytic amount of tetraisopropyl titanate, peracid (cumene hydroperoxide, t-butyl hydroperoxide, hydrogen peroxide, etc.) in an organic solvent (dichloromethane, chloroform, etc.) , -30 to 50 ° C.

The asymmetric epoxidation reaction can also be carried out by the following method. For example, in an organic solvent (dichloromethane, chloroform, etc.), in the absence of molecular sieves 4Å, optically active diethyl tartrate, catalytic amount of tetraisopropyl titanate, peracid (cumene hydroperoxide, t-butyl hydroperoxide, peroxide) Hydrogen or the like) at a temperature of -30 to 50 ° C.

It is desirable to carry out these asymmetric epoxidation reactions under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

3-Cyclohexyl-2-propenol represented by the formula (V) used as a starting material is a known compound, and the CAS registration number is 114096-03-6.

The product of each reaction may be subjected to isolation, washing, drying, and purification in each step before being subjected to the next reaction, or the operations may not be performed at all or may be stopped at an appropriate stage. , May proceed to the next step. The reaction product in each reaction is purified by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography, washing, recrystallization and the like. can do.

[0098]

The present invention will be described in detail below with reference to reference examples and examples, but the present invention is not limited thereto. Chromatographic separation points and TLC
The solvent in parentheses shown in () indicates the elution solvent or developing solvent used, and the ratio represents the volume ratio. The solvent in parentheses shown in the NMR part indicates the solvent used for the measurement.

Example 1 (1) (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol

[0100]

[Chemical 42]

Tetraisopropyl titanate (41 ml) was added at −30 ° C. to a suspension of molecular sieves 4Å (powder, 74 g) in dichloromethane (2500 ml) which had been dried by heating at 100 ° C. overnight under reduced pressure. D-(-)-
Diethyl tartrate (34.6g) in dichloromethane (100m
l) The solution was added dropwise. The mixture was stirred at the same temperature for 30 minutes. A solution of 3-cyclohexyl-2-propenol (98 g, CAS Registry No. 114096-03-6) in dichloromethane (200 ml) was added dropwise to the reaction mixture. A solution of cumene hydroperoxide (194 ml) in dichloromethane (100 ml) was added dropwise to the reaction mixture. The reaction mixture at -30 ° C
Stir for 2.5 hours. Dimethyl sulfide (1
57 ml) was added. The mixture was warmed to room temperature. The reaction mixture was added to a solution of tartaric acid (290 g) in water (3000 ml),
Stir for 30 minutes at room temperature. The mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate. All organic layers were concentrated. To a solution of the obtained residue in t-butyl methyl ether was added 1N aqueous sodium hydroxide solution (750 m) under ice cooling.
l) was added. The mixture was stirred under ice cooling for 1 hour. The mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate. All organic layers were dried over anhydrous magnesium sulfate and concentrated. The above operation was performed 4 times in total. All the residues were combined and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 1: 1), and the compound of the present invention (372.
3 g) was obtained. TLC: Rf 0.43 (hexane: ethyl acetate = 2:
1); NMR (CDCl ₃ ): δ3.91 (m, 1H), 3.62 (m, 1H), 2.9
8 (m, 1H), 2.76 (dd, J = 6.9, 2.4Hz, 1H), 1.90-1.50
(m, 6H), 1.36-1.01 (m, 5H); Specific rotation: [α] _D ²² + 33.0 ° (c 2.145, CHCl ₃ ).

Example 1 (2) (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol

[0103]

[Chemical 43]

Tetraisopropyl titanate (0.6 ml)
Was added dropwise to a dichloromethane (20 ml) solution of D-(−)-diethyl tartrate (0.495 g) in an argon atmosphere at −10 ° C. Mix -10
The mixture was stirred at 0 ° C for 30 minutes. 3-Cyclohexyl-2-propenol (1.40 g, CAS Registry No. 114 was added to the reaction mixture.
A solution of 096-03-6) in dichloromethane (1 ml) was added dropwise. The mixture was stirred at -10 ° C for 30 minutes. Cumene hydroperoxide (2.2 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at -10 ° C for 2 hours. Dimethyl sulfide (2.2 ml) was added to the reaction mixture. The mixture was warmed to room temperature. Tartaric acid (4.2g) in water (30m)
l) The solution was added and stirred at room temperature for 10 minutes. The mixture was separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate (50 ml). All organic layers were washed with water and concentrated. The obtained residue was dissolved in t-butyl methyl ether (25 ml) and, under ice cooling, 1N aqueous sodium hydroxide solution (15 ml).
Was added. The mixture was stirred under ice cooling for 1.5 hours. The mixture was diluted with water (30 ml) and then separated into an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate (30 ml). All organic layers were washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 1: 1) to obtain the compound of the present invention (1.32 g) having the following physical properties. TLC: Rf 0.43 (hexane: ethyl acetate = 2:
1); NMR (CDCl ₃ ): δ3.91 (m, 1H), 3.62 (m, 1H), 2.9
8 (m, 1H), 2.76 (dd, J = 6.9, 2.4Hz, 1H), 1.90-1.50
(m, 6H), 1.36-1.01 (m, 5H); Specific rotation: [α] _D ³² + 32.9 ° (c 1.088, CHCl ₃ ).

Example 2 (2S, 3R) -2,3-epoxy-3-cyclohexylbutanal

[0106]

[Chemical 44]

Triethylamine (322 ml) was added to a solution of the compound (92 g) prepared in Example 1 in dimethyl sulfoxide (414 ml). Sulfur trioxide / pyridine complex (184 g) was added to the mixture under ice cooling. The reaction mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with 0.5N hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the compound of the present invention (91 g) having the following physical properties. TLC: Rf 0.65 (hexane: ethyl acetate = 2:
1); NMR (CDCl ₃ ): δ 9.01 (d, J = 6.2 Hz, 1H), 3.19
(dd, J = 6.2, 2.0 Hz, 1H), 3.04 (dd, J = 6.2, 2.0 H
z, 1H), 1.96-1.58 (m, 5H), 1.49-0.98 (m, 6H).

Example 3 (2S, 3R) -2,3-epoxy-3-cyclohexylpropanoic acid

[0109]

[Chemical formula 45]

To a solution of the compound (91 g) prepared in Example 2 in acetonitrile (1800 ml) was added water (900 ml), 2
-Methyl-2-butene (270 ml) and sodium dihydrogen phosphate (92 g) were added. Sodium chlorite (80%, 220 g) was slowly added to the mixture under ice cooling. The reaction mixture was stirred at room temperature for 30 minutes. T-Butyl methyl ether (870 ml) and 1N aqueous sodium hydroxide solution (870 ml) were added to the reaction mixture, and the mixture was stirred. The deposited solid matter was filtered, and the filtrate was separated into an organic layer and an aqueous layer. 1 in the organic layer
An aqueous solution of N sodium hydroxide (435 ml) was added for extraction. Under ice cooling, 6N hydrochloric acid (200 ml) was added to the aqueous layer, and t
-Extracted with butyl methyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The above-mentioned operations were repeated 4 times to obtain the compound of the present invention (275 g) having the following physical properties. TLC: Rf 0.09 (chloroform: methanol = 1)
0: 1); NMR (CDCl ₃ ): δ3.31 (d, J = 1.8 Hz, 1H), 3.02
(dd, J = 6.4, 1.8 Hz, 1H), 1.95-1.58 (m, 5H), 1.44-
1.00 (m, 6H).

Example 4 (2R, 3R) -2-Benzylamino-3-hydroxy-3-cyclohexylpropanoic acid

[0112]

[Chemical formula 46]

A suspension of the compound (140 g) prepared in Example 3 in water (198 ml) was cooled under ice-cooling with benzylamine (269).
ml) and a 5N sodium hydroxide aqueous solution (148 ml) were added. The reaction mixture was stirred at 95 ° C for 3 hours. The reaction mixture was allowed to stand at room temperature and 5N aqueous sodium hydroxide solution (37
ml) was added. The mixture was washed with ethyl acetate. 2N hydrochloric acid was added to the aqueous layer until the pH reached 5. The precipitated solid was filtered, washed with cold water, cold acetone and t-butyl methyl ether, and dried. The above-mentioned operation was carried out twice in total to obtain the compound of the present invention (227 g) having the following physical properties. TLC: Rf 0.71 (n-butanol: acetic acid: water = 4:
2: 1); NMR (DMSO-d ₆ ): δ7.48-7.22 (m, 5H), 3.87 (d, J
= 13.2 Hz, 1H), 3.69 (d, J = 13.2 Hz, 1H), 3.05
(d, J = 6.0 Hz, 1H), 1.72-1.50 (m, 5H), 1.24-0.80
(m, 6H).

Example 5 (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid

[0115]

[Chemical 47]

Palladium hydroxide on carbon (20% wt, wet, 15
The compound (75 g) prepared in Example 4 was added to a suspension of g) in methanol (1500 ml). Under ice cooling to the mixture,
A 1N aqueous sodium hydroxide solution (270 ml) was added. The reaction mixture was stirred under a hydrogen gas atmosphere at room temperature for 8 hours. The mixture was replaced with hydrogen gas for argon gas. The mixture was mixed with 1N aqueous sodium hydroxide solution (40 ml) and di-t.
-Butyl dicarbonate (80 ml) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated. The obtained aqueous solution was washed with t-butyl methyl ether. 5 in the water layer
% Aqueous potassium hydrogen sulfate solution was added until pH3 was reached.
The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated. The above-mentioned operation was carried out twice in total to obtain the compound of the present invention (151.2 g) having the following physical properties. TLC: Rf 0.31 (chloroform: methanol = 5:
1); NMR (CD ₃ OD): δ 4.27 (d, J = 6.0 Hz, 1H), 3.46
(t, J = 6.0 Hz, 1H), 1.92 (m, 1H), 1.82-1.48 (m, 5
H), 1.43 (s, 9H), 1.40-0.94 (m, 5H). HPLC conditions: Column used: daicel chiralcel OD-H (4.6mmi.d.x2
50 mm), Flow rate used: 1 mL / min Solvent used: Hexane / 2-purupyl alcohol / trifluoroacetic acid = 95/5 / 0.1, temperature: 25 ° C., pressure: 47 bar, detection: UV210 nm, HPLC retention time: 8.4 Minutes.

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Claims (6)

[Claims] 1. A formula (V): 3-cyclohexyl-2-propenol represented by the formula (IV): To obtain (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol, which is subjected to an oxidation reaction to give a compound of the formula (III) To obtain (2S, 3R) -2,3-epoxy-3-cyclohexylpropanoic acid, which compound is reacted with benzylamine to give a compound of formula (II) (2R, 3R) -2-benzylamino-3-hydroxy-3-cyclohexylpropanoic acid is obtained, and the compound is subjected to a hydrogenolysis reaction and further subjected to a protection reaction. 5] A method for producing (2R, 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid. 2. Formula (V): 3-cyclohexyl-2-propenol represented by the formula (IV) embedded image which is subjected to asymmetric epoxidation in the presence or absence of molecular sieves. A method for producing (2R, 3R) -2,3-epoxy-3-cyclohexylpropanol represented by: 3. The asymmetric epoxidation reaction is carried out in an organic solvent in the presence of optically active diethyl tartrate, a catalytic amount of tetraisopropyl titanate, and peracid, (2R, 3R) -2,3-epoxy-3-
Method for producing cyclohexyl propanol. 4. An asymmetric epoxidation reaction in an organic solvent in the presence of optically active diethyl tartrate and molecular sieves,
3. The reaction according to claim 2, wherein the reaction is carried out in the presence of a catalytic amount of tetraisopropyl titanate and peracid.
R) -2,3-Epoxy-3-cyclohexylpropanol production method. 5. The asymmetric epoxidation reaction is carried out in an organic solvent in the presence of optically active diethyl tartrate, a catalytic amount of tetraisopropyl titanate, and peracid, (2R, A method for producing 3R) -2- (t-butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid. 6. An asymmetric epoxidation reaction in an organic solvent in the presence of optically active diethyl tartrate and molecular sieves,
The reaction (2R, 3) according to claim 1, wherein the reaction is carried out in the presence of a catalytic amount of tetraisopropyl titanate and peracid.
R) -2- (t-Butoxycarbonyl) amino-3-hydroxy-3-cyclohexylpropanoic acid.