JP2001275691A - OPTICALLY ACTIVE beta-IMINO ALCOHOL AND beta-AMINO ALCOHOL, PRODUCTION INTERMEDIATE, AND METHOD FOR PRODUCING THEM - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of easily preparing a β-amino alcohol useful as a production intermediate of pharmaceuticals and a β-amino alcohol as a precursor of the β-amino alcohol in high optical purity, and a new production intermediate. SOLUTION: This method for preparing an optically active β-imino alcohol expressed by formula (1) (wherein, R1 is a 1-6C alkyl or a 7-20C aralkyl; R2 is a 1-6C alkyl or a 1-6C haloalkyl; R3 is a 1-6C alkyl or a 7-20C aralkyl; and R4 is hydrogen or trimethylsilyl) comprises a process in which a compound expressed by formula (2) is hydrolyzed using a lipase. The method for preparing β-amino alcohol expressed by formula (3) further comprises a process of reducing the β-imino alcohol. Production intermediate for these compound are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to optically active β-imino alcohols and β-imino alcohols useful as intermediates for producing pharmaceuticals and the like
The present invention relates to amino alcohols, intermediates for producing them, and methods for producing them.

[0002]

2. Description of the Related Art In recent years, an α-hydroxy-β-amino acid derivative (BHP) represented by formula (15) has attracted attention as a chiral synthon of an anti-AIDS drug (HIV protease inhibitor) represented by formula (16). Various production methods have been developed (see the following formula).

[0003]

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Heretofore, the following method has been known as a method for producing the compound represented by the formula (15). (1) EP. No. 72939

[0005]

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(2) The method described in WO98 / 07687

[0007]

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(3) The method described in WO 98/11057

[0009]

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[0010]

However, the above-mentioned method uses a relatively expensive noble metal catalyst, uses a natural product as a starting material, or obtains an optical system of β-amino alcohol obtained. At present, the purity is not always satisfactory and cannot be said to be an established production method.

Therefore, the present invention can easily produce β-amino alcohols represented by the compound represented by the formula (15) and β-imino alcohols which are precursors thereof with high optical purity. It is an object to provide a process, as well as these novel production intermediates.

[0012]

Means for Solving the Problems In order to solve the above problems, the present inventors have studied the kinetic optical resolution of β-imino alcohols represented by the formula (1) using lipase which is a hydrolase. By conducting a study and hydrolyzing the compound represented by the formula (2) using lipase, it is possible to easily obtain the β-imino alcohol represented by the formula (1) with high optical purity. I found it. Equation (1)
That β-amino alcohols represented by the formula (3) represented by the compound represented by the formula (4) can be easily obtained by reducing the β-imino alcohols represented by the formula: Thus, the present invention has been completed.

That is, the present invention firstly provides an equation (2)

[0014]

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(Wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 20 carbon atoms;
² represents an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms, and R ³ represents an alkyl group having 1 to 6 carbon atoms or 7 carbon atoms.
-20 represents an aralkyl group, and R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a trimethylsilyl group. Formula (1) having a step of hydrolyzing the compound represented by the formula (1) using a lipase.

[0016]

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(Wherein, R ¹ , R ² and R ⁴ have the same meanings as described above). The present invention secondly comprises a step of reducing the optically active β-imino alcohol represented by the formula (1),

[0018]

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(Wherein, R ¹ , R ² and R ⁴ have the same meanings as described above).

The present invention thirdly provides a compound represented by the formula (2) and a compound represented by the formula (1).

Further, the present invention fourthly provides a compound (9) which is an intermediate for producing the compound represented by the above (2).

[0022]

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(Wherein R ¹ and R ² have the same meanings as described above). Equation (1),
The compounds represented by (2) and (9) are new substances.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the formulas (9) and (2), R ¹ and R ³ are each independently a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, sec-butyl group, t
-Butyl group, n-pentyl group, linear or branched alkyl group having 1 to 6 carbon atoms such as n-hexyl group, or
Benzyl, α-methylbenzyl, α, α-dimethylbenzyl, phenethyl, 3-phenylpropyl, 4
-Represents a linear or branched aralkyl group having 7 to 20 carbon atoms such as -phenyl-n-butyl group.

The aralkyl group may have a substituent at any position on the benzene ring. Examples of such a substituent include a halogen atom such as nitro group, fluorine, chlorine and bromine; an alkyl group such as methyl group and ethyl group; and an alkoxy group such as methoxy group, ethoxy group, propoxy group and isopropoxy group. Further, the aralkyl group may have a plurality of the same or different substituents.

R ² represents a linear or linear group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl and n-hexyl. Branched alkyl group having 1 to 6 carbon atoms, benzyl, α-methylbenzyl group, α, α-dimethylbenzyl group, phenethyl group, 3-phenylpropyl group, 4-
A linear or branched aralkyl group having 7 to 20 carbon atoms such as a phenyl-n-butyl group, or

Chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, tribromomethyl, 2,2,2-trichloroethyl, Pentachloroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2,2,2
Represents a haloalkyl group having 1 to 6 carbon atoms such as a 2-tribromoethyl group and a pentabromoethyl group.

The aralkyl group for R ² may be, at any position on the benzene ring, one or more identical or different nitro groups, halogen atoms such as fluorine, chlorine and bromine, and alkyl groups such as methyl and ethyl. It may have a substituent such as a group, an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group and an isopropoxy group.

R ⁴ is a hydrogen atom, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t
1 carbon atom such as -butyl, n-pentyl, n-hexyl
To 6 also represent an alkyl group or a trimethylsilyl group.

The compounds represented by the formulas (9) and (2) can be produced, for example, as follows.

[0031]

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(In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, and r represents a lower alkyl group such as methyl, ethyl, propyl and isopropyl.) A compound represented by the formula (7) is obtained by reacting the carboxylic acid ester (5) with a 2-lithium salt of 1,3-dithiane represented by the formula (6).

The 1,3-dithiane 2 represented by the formula (6)
-Lithium salt is, for example, 1,3-dithiane, organic lithium such as n-butyllithium, sec-butyllithium, t-butyllithium, lithium N, N-diisopropylamide (LDA), lithium hexamethyldisilazide It can be prepared by reacting a lithium amide or the like. The amount of the organic lithium or lithium amide used is about 1.0 to 1.5 equivalents per 1 mol of 1,3-dithiane. Equation (6)
Since the lithium salt represented by is generally unstable,
It is preferred to use the solution in the next reaction.

As a solvent used for obtaining the lithium salt represented by the formula (6), an inert solvent such as tetrahydrofuran (THF), diethyl ether, 1,3-
One or a mixture of two or more of ether solvents such as dimethoxyethane, saturated hydrocarbons such as n-pentane and n-hexane, and aromatic hydrocarbons such as benzene, toluene and xylene. The reaction is usually performed in a temperature range of -100C to 0C.

Examples of the solvent used for the reaction of the ester represented by the formula (5) with the lithium salt represented by the formula (6) include inert solvents such as tetrahydrofuran (THF), diethyl ether, One or more of ether solvents such as 3-dimethoxyethane, saturated hydrocarbons such as n-pentane and n-hexane, and aromatic hydrocarbons such as benzene, toluene and xylene;
A mixed solvent of at least one kind is exemplified. In this case, it is preferable to use the same solvent as the solvent of the lithium salt represented by the formula (6). The reaction is usually performed in a temperature range of -100C to 0C. The amount of the compound represented by the formula (6) is
Usually, 1 to 2 relative to 1 mole of the compound represented by the formula (5)
Is equivalent.

Then, an alkoxyamine represented by the formula (8): R ¹ ONH ₂ (where R ¹ has the same meaning as described above) acts on the compound represented by the formula (7). As a result, a compound represented by the formula (9) can be obtained.

In this reaction, a salt of an alkoxyamine represented by the formula (8) is added to the reaction system, and the alkoxyamine is converted into a free form in the reaction system using a base. With the compound to be prepared. Examples of such an alkoxyamine salt include a hydrochloride and a sulfate. Examples of the base used include triethylamine, diisopropylethylamine, pyridine, piperidine, DBU (1,8-diazabicyclo [5.4.0] unde-7-cene), DABCO (1,
Organic bases such as 4-diazabicyclo [2.2.2] octane) and metal alkoxides such as sodium methoxide and sodium ethoxide.

As a solvent used in this reaction, water,
Alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol and isopropyl alcohol; ether solvents such as THF, diethyl ether and 1,3-dimethoxyethane; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride , Aromatic hydrocarbons such as benzene, toluene and xylene, n-
Aliphatic hydrocarbons such as hexane and n-pentane;
One kind of N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like, or a mixed solvent of two or more kinds of these may be used.

The reaction proceeds smoothly in a temperature range from room temperature to the boiling point of the solvent used. In the compound represented by the formula (9) obtained by this reaction, two types of stereoisomers derived from a carbon-nitrogen double bond are usually obtained (hereinafter, compounds derived from this compound are all There are stereoisomers of this kind, all of which are included in the scope of the present invention.) Examples of the compound represented by the formula (9) are shown in Table 1 below.

[0040]

[Table 1]

Next, one of the compounds represented by the formula (9)
By converting the 3-dithian-2-yl group to an aldehyde group, a compound represented by the formula (10) is obtained. This reaction can be performed by reacting a mercury compound in the presence of a base.

The mercury compound used in this reaction includes, for example, mercury perchlorate. Examples of the base include carbonates such as calcium carbonate, potassium carbonate, and sodium carbonate. The amount of the mercury compound to be used is usually 1.5 to 1 mol per mol of the compound represented by the formula (8).
It is about 3.0 equivalents, and the amount of the base used is
It is usually 1.0 to 2.0 equivalents per mol.

Examples of the solvent include a mixed solvent of water with an ether solvent such as THF, diethyl ether, and 1,3-dimethoxyethane. The reaction is usually performed at 0 ° C.
It proceeds smoothly in the temperature range of ~ 80 ° C.

Next, the aldehyde compound represented by the formula (10) is reacted with an alkali metal salt of an alkyne represented by the formula (11) (acetylene which may have a substituent) to obtain a compound represented by the formula (11). The compound represented by (12) can be obtained. The acetylene which may have a substituent includes acetylene, trimethylsilylacetylene,
-Propyne, 1-butyne, 1-pentyne, 1-hexyne and the like.

The compound represented by the formula (11) is, for example,
It can be obtained by reacting acetylene or trimethylsilylacetylene with an alkali metal such as sodium metal or metal lithium, or an organic lithium such as n-butyllithium, sec-butyllithium or t-butyllithium.

The compound represented by the formula (11) is usually subjected to the reaction in a solution state. The amount of the compound represented by the formula (11) is based on 1 mol of the compound represented by the formula (10).
Usually 1.0 to 1.5 molar equivalents.

As a solvent used in this reaction, an inert solvent such as THF, diethyl ether, 1,3-
One or a mixture of two or more of ether solvents such as dimethoxyethane, saturated hydrocarbons such as n-pentane and n-hexane, and aromatic hydrocarbons such as benzene, toluene and xylene. The reaction usually proceeds smoothly in a temperature range of -100 ° C to 0 ° C.

Next, by reacting the compound represented by the formula (12) with an acylating agent in the presence of a base, the compound represented by the formula (2) can be obtained. As the acylating agent, R ³ C (＝ O) X or (R ³ CO)
₂ O (wherein, R ³ has the same meaning as described above, and X represents a halogen atom). The amount of the acylating agent used is
Usually 1.0 mol per 1 mol of the compound represented by the formula (12).
１．５1.5 molar equivalents.

Examples of the base used include organic bases such as triethylamine, diisopropylethylamine, pyridine, piperidine, DBU and DABCO.
The amount of the base used is usually
1.0 to 1.5 molar equivalents.

Among the compounds represented by the formula (12), those in which R ⁴ is a trimethylsilyl group have the formula (12) in which the trimethylsilyl group is converted into a hydrogen atom by the action of a desilylating agent. The compound represented by (R ⁴ = H) can be obtained. Examples of the desilylation agent include fluorine, potassium fluoride, ammonium fluoride salts such as tetrabutylammonium fluoride (TBAF), and the like. The amount of the desilylating agent used is determined by the formula (1)
2) It is usually about 1.0 to 2.0 molar equivalents per 1 mol of the compound represented by (R ⁴ = SiMe ₃ ).

As a solvent used in this reaction, an inert solvent such as THF, diethyl ether, 1,3-
Examples include ether solvents such as dimethoxyethane. The reaction usually proceeds smoothly in a temperature range of 0 ° C to 80 ° C.

Examples of the compound represented by the formula (2) obtained as described above are shown in Table 2 below.

[0053]

[Table 2]

Next, by hydrolyzing the compound represented by the formula (2) using lipase, an alcohol compound represented by the formula (1) can be obtained.

[0055]

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The lipase used in this reaction is an enzyme that catalyzes a hydrolysis reaction of a fat, which is a glycerin ester of a fatty acid, and is an enzyme widely present in animals, plants and microorganisms. Depending on the type of lipase, substrate specificity, optimal pH for action, optimal temperature, and the like differ. In the present invention, selected and used lipase having acyl group (R ³ CO-) partially hydrolyzing ability of the compound represented by formula (2). Such lipases include lipase PS and the like. This product is commercially available as a freeze-dried product, and can be used as it is in the present invention. The amount of lipase required is at least enough to complete the hydrolysis reaction, and the amount used can be appropriately set depending on the reaction system.

As described above, the lipase has an optimum pH (usually pH = 6) at which the catalytic activity of hydrolysis is exhibited.
~ 8). Therefore, it is preferable to use a buffer solution in the reaction system so that the reaction system has an optimum pH. As the buffer solution, potassium dihydrogen phosphate + sodium hydroxide, dipotassium hydrogen phosphate + disodium hydrogen phosphate,
Examples include potassium hydrogen phthalate + sodium hydroxide, boric acid + potassium chloride + sodium hydroxide, borax + sodium hydroxide, disodium phosphate + citric acid, and the like. Of these, the use of a buffer solution containing phosphate is preferred.

Examples of the solvent used in this reaction include a mixed solvent of water and an organic solvent compatible with water such as THF and acetonitrile. Reaction is at room temperature
It proceeds smoothly in a temperature range of 50 ° C. and is completed in several hours to several hundred hours.

This reaction is stereoselective. The compound represented by the formula (2) is an acyloxy group (R ³ COO— group)
There are two types of optical isomers derived from the asymmetric carbon atom bonded to. Lipase selectively proceeds only the hydrolysis reaction of one of the two optical isomers (kinetic optical resolution). The reaction solution contains a hydrolysis product and an unhydrolysed product, and only the hydrolysis product can be isolated and purified by ordinary organic synthetic chemical separation means. The unhydrolyzed product can be racemized and then subjected to the hydrolysis reaction again.

Examples of the compound represented by the formula (1) obtained as described above are shown in Table 3 below.

[0061]

[Table 3]

Next, the obtained compound represented by the formula (1) can be reduced with a reducing agent to obtain a β-amino alcohol compound represented by the formula (3).

[0063]

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As a reducing agent, Na [Al (CH ₃ OC)
_{H 2 CH 2 O) 2 H} 2] (VITRIDE), such as aluminum hydride such as diisobutyl aluminum hydride can be used. Examples of the reaction solvent include inert solvents, for example, ether solvents such as THF, diethyl ether, and 1,3-dimethoxyethane. The reaction usually proceeds smoothly in a temperature range of -100 ° C to 0 ° C.

Further, the compound represented by the formula (3) is prepared by reacting the compound represented by the formula (1) with octacarbonyldicobalt to protect the triple bond and then selectively form the carbon-nitrogen double bond. (See below).

[0066]

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Incidentally, among the compounds represented by the formula (1),
Compounds in which R ⁴ is a trimethylsilyl group (1, R ⁴ = Si
Me ₃ ) can be converted to a compound represented by the formula (1, R ⁴ = H) using a desilylating agent. As the desilylation agent, those similar to those listed above can be used.

Examples of β-amino alcohols obtained as described above are shown in Table 4 below.

[0069]

[Table 4]

Next, among the obtained compounds represented by the formula (3), those in which R ² is a benzyl group (Bn group) are, for example, as follows:
β-amino acid derivative (15) can be derived.

[0071]

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(Wherein, R ¹ has the same meaning as described above;
r ′ represents a lower alkyl group. ) The compound represented by the formula (15) is useful as an intermediate for producing the anti-AIDS drug (protease inhibitor) represented by the formula (16).

[0073]

Next, the present invention will be described in more detail with reference to Production Examples and Examples. (Production Example 1) 1- (1,3) dithiazin-2-yl-2
Synthesis of -phenylethanone (7a)

[0074]

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In an argon atmosphere, 2.0 g of ethyl phenylacetate (0.012 m
ol) in 25 ml of THF was added to 25 ml of THF solution of 2-lithio-1,3-dithiane prepared separately (0.01 ml).
2 mol) was slowly added dropwise at -78 ° C.
Stirred for 0 minutes. The reaction was quenched by adding methanol at −78 ° C. and then 2N hydrochloric acid at room temperature, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was isolated and purified by silica gel chromatography (n-hexane: ethyl acetate = 15: 1) to obtain 1.48 g of the desired product (7a). Yield 51%

¹ H-NMR (CDCl ₃ , δ ppm):
1.97-2.11 (m, 2H), 2.51-2.60
(M, 2H), 3.19-3.29 (m, 2H), 3.
96 (s, 2H), 4.26 (s, 1H), 7.20-
7.34 (m, 5H)

IR (neat, cm ^-1 ): 1718,1
324,1263,1060,702

Example 1 1- (1,3) dithiane-2
-Yl-2-phenylethanone O-benzyloxime
Synthesis of (9a)

[0079]

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In an argon atmosphere, 26.2 g (0.026 m) of the previously obtained (7a) was placed in a 100 ml two-necked flask.
ol) in 90 ml of methanol and then 6.6 g (0.042 mol) of benzyloxyamine hydrochloride
And 4.5 g (0.057 mol) of pyridine were added, and the mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding saturated saline to the reaction solution, and extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (n-hexane: ethyl acetate = 18: 1)
The desired product (isomer 1 and isomer 2)
8.3 g). 84% yield

¹ H-NMR of isomer 1 (CDCl ₃ , δp
pm): 1.78-2.07 (m, 2H), 2.67-
2.99 (m, 4H), 3.67 (s, 2H), 5.1
9 (s, 2H), 5.77 (s, 1H), 7.16-
7.37 (m, 10H)

¹ H-NMR of isomer 2 (CDCl ₃ , δp
pm): 1.78-2.07 (m, 2H), 2.67-
2.99 (m, 4H), 4.07 (s, 2H), 4.5
0 (s, 1H), 5.20 (s, 2H), 7.16-
7.37 (m, 10H)

IR (neat, cm ^-1 ): 3002, ¹
743, 1505, 1463, 1378, 1263, 1
225,1162,1041,701

Example 2 1- (1,3) dithian-2
-Yl-2-phenylethanone O-methyloxime
Synthesis of (9b)

[0085]

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Under an argon atmosphere, 250.1 mg (1.051 mg) of (7a) obtained above was placed in a 50 ml two-necked flask.
mmol) in methanol (12.5 ml) and then add 140.4 mg (1.682 mg) of methoxyamine hydrochloride.
mmol) and 182.9 mg of pyridine (2.312 mm
ol) and stirred at room temperature for 1 hour. After the reaction was stopped by adding saturated saline to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1). 275.3 mg of the desired product (mixture of isomer 1 and isomer 2) (9b) was obtained. 98% yield

¹ H-NMR of isomer 1 (CDCl ₃ , δp
pm): 1.78-2.05 (m, 2H), 2.67-
2.95 (m, 4H), 3.66 (s, 2H), 3.9
2 (s, 3H), 5.71 (s, 1H), 7.18-
7.34 (m, 5H)

¹ H-NMR of isomer 2 (CDCl ₃ , δp
pm): 1.78-2.05 (m, 2H), 2.67-
2.95 (m, 4H), 3.84 (s, 2H), 3.9
4 (s, 3H), 4.55 (s, 1H), 7.18-
7.34 (m, 5H)

IR (neat, cm ^-1 ): 3002,1
749, 1500, 1460, 1270, 1220, 1
161, 1044, 703

(Production Example 2) 2-benzyloxyimino-
Synthesis of 3-phenylpropionaldehyde (10a)

[0091]

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In a 100 ml eggplant-shaped flask, 6.7 g (0.018 mol) of the previously obtained (9a) THF-H _{2 was} added.
60 ml of a mixed solution of O (THF: H ₂ O = 5: 1) was added, and then 4.2 g of calcium carbonate (0.042 mo).
1), 19.6 g of mercury perchlorate hexahydrate
(0.038 mol) of a 5.0 ml aqueous solution was slowly added dropwise, followed by stirring for 10 minutes. Ether was added to the reaction solution, the mixture was filtered through celite, and the filtrate was concentrated to obtain a crude product. It is isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1), and the desired product (mixture of isomer 1 and isomer 2) (10a)
4.16 g were obtained. 82% yield

¹ H-NMR of isomer 1 (CDCl ₃ , δp
pm): 3.80 (s. 2H), 5.34 (s, 2
H), 7.15-7.39 (m, 10H), 9.47
(S, 1H)

¹ H-NMR of isomer 2 (CDCl ₃ , δp
pm): 3.64 (s, 2H), 5.21 (s, 2
H), 7.15-7.39 (m, 10H), 10.28
(S, 1H)

IR (neat, cm ^-1 ): 1710,1
223,1030,756,703

(Production Example 3) 2-methoxyimino-3-f
Synthesis of enylpropionaldehyde (10b)

[0097]

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In a 100 ml eggplant-shaped flask, 3.4 g (0.013 mol) of the previously obtained (9b) THF-H ₂ was added.
After adding 36 ml of an O mixed solution (THF: H ₂ O = 5: 1) and adding 2.8 g (0.028 mol) of calcium carbonate, 13.2 g (0.026 mol) of mercury perchlorate hexahydrate was added.
mol) was slowly added dropwise and stirred at room temperature for 10 minutes. After the reaction was stopped by adding diethyl ether to the reaction solution, the reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. Isolation and purification were performed by silica gel column chromatography (n-hexane: ethyl acetate = 20: 1) to obtain 2.0 g of (10b). 89% yield

¹ H-NMR (CDCl ₃ , δp
pm): 3.65 (s, 2H), 4.14 (s, 3
H), 7.18-7.31 (m, 5H), 10.25
(S, 1H)

¹ H-NMR of isomer 2 (CDCl ₃ , δp
pm): 3.78 (s, 2H), 4.00 (s, 3
H), 7.18-7.31 (m, 5H), 9.47
(S, 1H)

IR (neat, cm ^-1 ): 1713,1
215, 1027, 701

Example 3 3-Hydroxy-1- phenyl
Ru-5-trimethylsilylpent-4-yn-2-one
Synthesis of O-benzyl oxime (12a)

[0103]

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Under an argon atmosphere, trimethylsilylacetylene (640.0 m) was placed in a 50 ml two-necked eggplant type flask.
g (6.516 mmol) in 5.0 ml of THF was added thereto, and 4.5 ml (6.516 mmol) of a 1.44 M solution of n-butyllithium in hexane was added thereto at -78 ° C.
, And the mixture was stirred at the same temperature for 1 hour. There, 1.26g (4.344mmo) of (10a) previously obtained.
l) A THF solution (3.0 ml) was slowly added dropwise at -78 ° C, and the mixture was stirred at the same temperature for 30 minutes. Add -7 to the reaction solution.
The reaction was stopped by adding methanol at 8 ° C and 2N hydrochloric acid at room temperature. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered. The crude product obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (n
Separation and purification with -hexane: ethyl acetate = 10: 1) gave 1.44 g of the desired product (trans-isomer: cis-isomer = 4.5: 1 mixture). 85% yield

¹ H-NMR (CDCl ₃ , δ) of trans form
ppm): 0.00 (s, 9H), 3.02 (d, J =
5.28 Hz, 1 H), 3.52 (d, J = 14.52)
Hz, 1H), 3.90 (d, J = 14.52 Hz, 1
H), 4.76 (d, J = 5.28 Hz, 1H), 5.
01 (s, 1H), 7.05-7.23 (m, 10H)

¹ H-NMR of cis form (CDCl ₃ , δpp
m): 0.00 (s, 9H), 2.81 (d, J = 7.
26Hz, 1H), 3.54 (s, 2H), 5.05
(S, 2H), 5.17 (d, J = 7.26 Hz, 1
H), 7.05-7.23 (m, 10H).

IR (neat, cm ^-1 ): 3400,3
010,1236,866,772

Example 4 3-Hydroxy-1- phenyl
Ru-5-trimethylsilylpent-4-yn-2-one
Synthesis of O-methyl oxime (12b)

[0109]

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Under an argon atmosphere, 1.66 g (0.017 mol) of 50 ml of trimethylsilylacetylene was added, and 12 ml (0.017 mol) of a 1.44 M n-butyllithium hexane solution was slowly added at -78 ° C. The mixture was added dropwise and stirred at the same temperature for 1 hour. In the reaction solution,
2.0 g (0.011 mol) of T obtained previously (10b)
HF (5 ml) was slowly added dropwise at -78 ° C.
Stirred for 0 minutes. The reaction was stopped by adding methanol at −78 ° C. and 2N hydrochloric acid at room temperature, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. This was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain 2.6 g of the desired product (12b). 84% yield

¹ H-NMR (CDCl ₃ , δ) of trans form
ppm): 0.00 (s, 9H), 3.02 (d, J =
5.28 Hz, 1 H), 3.52 (d, J = 14.52)
Hz, 1H), 3.90 (d, J = 14.52 Hz, 1
H), 4.76 (d, J = 5.28 Hz, 1H), 5.
01 (s, 1H), 7.05-7.23 (m, 10H)

¹ H-NMR of cis form (CDCl ₃ , δpp
m): 0.01 (s, 9H), 2.78 (d, J = 7.
26Hz, 1H), 3.55 (s, 2H), 3.80
(S, 3H), 5.18 (d, J = 7.26 Hz),
7.07-7.17 (m, 5H)

IR (neat, cm ^-1 ): 3400,3
000,2950,1227,1060,860

Example 5 3-Hydroxy-1- phenyl
Le-pent-4-yn-2-one O-benzyloxy
Synthesis of the system (12c)

[0115]

Embedded image

Under an argon atmosphere, 262.0 mg (0.7%) of the previously obtained (12a) was placed in a 50 ml two-necked eggplant type flask.
45 mmol) in THF (3.0 ml) was added, and at 0 ° C., 1.0 M TBAF (tetrabutylammonium fluoride) in 0.82 ml (0.82 mmol) of THF was slowly added dropwise, followed by dropwise addition at the same temperature for 10 minutes. 2 in the reaction solution
After adding normal hydrochloric acid to cause a reaction, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) (12c).
193.0 mg (mixture of trans-form: cis-form) was obtained. 93% yield

¹ H-NMR (CDCl ₃ , δ) of trans form
ppm): 2.49 (d, J = 2.31 Hz, 1H),
3.29 (d, J = 5.61 Hz, 1H), 3.63
(D, J = 14.52 Hz, 1H), 4.08 (d, J
= 14.52 Hz, 1H), 4.88 (dd, J = 3.
3 Hz, 2.31 Hz, 1 H), 5.14 (s, 2
H), 7.19-7.35 (m, 10H)

¹ H-NMR of cis form (CDCl ₃ , δpp
m): 2.39 (d, J = 2.31 Hz, 1H);
11 (d, J = 7.92 Hz, 1H), 3.66 (s,
2H), 5.17 (s, 2H), 5.30 (dd, J =
5.61 Hz, 2.31 Hz, 1H), 7.19-7.
35 (m, 10H)

IR (neat, cm ^-1 ): 2993,2
330, 1222, 767

Example 6 3-Hydroxy-1- phenyl
Lupent-4-yn-2-one O-methyloxime
Synthesis of (12d)

[0121]

Embedded image

In an argon atmosphere, 578.0 mg of the previously obtained (12b) was placed in a 50 ml two-necked eggplant type flask.
(2.099 mmol) in 5.0 ml of THF was added, and 5.0 ml of 1.0 M TBAF in THF was added at 0 ° C.
And slowly stirred at the same temperature for 10 minutes. The reaction was stopped by adding 2N hydrochloric acid to the reaction solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the desired product (mixture of trans-form and cis-form) (12d) 362.0
mg was obtained. 91% yield

¹ H-NMR (CDCl ₃ , δ) of trans form
ppm): 2.53 (d, J = 2.31 Hz, 1H),
3.19 (d, J = 5.61 Hz, 1H), 3.60
(D, J = 14.5 Hz, 1H), 3.95 (s, 3
H), 4.09 (d, J = 14.52 Hz, 1H),
4.87 (dd, J = 3.63 Hz, 2.31 Hz, 1
H), 7.22-7.32 (m, 5H)

¹ H-NMR (CDCl ₃ , δpp
m): 2.44 (d, J = 1.98 Hz, 1H);
02 (d, J = 7.92 Hz, 1H), 3.68 (d,
J = 2.97 Hz, 1H), 3.96 (s, 3H),
5.24 (dd, J = 5.93 Hz, 1.98 Hz, 1
H), 7.22-7.32 (m, 5H)

IR (neat, cm ^-1 ): 3000, ¹
230,770

Example 7 1- (1-benzyloxyi)
Mino-2-phenylethyl) propyn-2-ylpro
Synthesis of Pionate (2a)

[0127]

Embedded image

Under an argon atmosphere, 88.0 mg (0.12 mg) of (12c) previously obtained was placed in a 30 ml two-necked eggplant type flask.
315 mmol) of methylene chloride in 2.0 ml was added thereto, and 63.7 mg (0.63 mg) of triethylamine was added thereto.
0 mmol) and a catalytic amount of DMAP were added, and 58.3 mg (0.630 mmol) of propionyl chloride was slowly added dropwise, followed by stirring at 0 ° C. for 10 minutes. After the reaction was stopped by adding a saturated saline solution to the reaction solution, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered. The crude product obtained by concentrating the filtrate under reduced pressure was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give (2a, a mixture of trans and cis isomers). 0.1 mg was obtained. 95% yield

¹ H-NMR (CDCl ₃ , δ) of trans form
ppm): 0.99 (t, J = 7.59 Hz, 3H),
1.96-2.24 (m, 2H), 2.54 (d, J =
2.31 Hz, 1H), 3.71 (d, J = 14.52)
Hz, 1H), 4.00 (d, J = 14.52 Hz, 1
H), 5.17 (s, 2H), 5.99 (d, J = 1.
98Hz, 1H), 7.15-7.37 (m, 5H)

¹ H-NMR of cis form (CDCl ₃ , δpp
m): 0.93 (t, J = 7.26 Hz, 3H);
96-2.24 (m, 2H), 2.41 (d, J = 2.
31 Hz, 1H), 3.67 (s, 2H), 5.21
(S, 2H), 6.72 (d, J = 2.31 Hz, 1
H), 7.15-7.37 (m, 5H)

IR (neat, cm ^-1 ): 3250,3
000,2920,1760,1505,1463,1
370, 1170, 1030, 703

Example 8 1- (1-Methoxyimino-
2-phenylethyl) propyn-2-yl propione
Synthesis of the plate (2b)

[0133]

Embedded image

In an argon atmosphere, 186.3 mg of the previously obtained (12d) was placed in a 30 ml two-necked eggplant type flask.
(0.917 mmol) in 5.0 ml of methylene chloride was added to the bottom, and 185.5 mg of triethylamine (1.
After adding 833 mmol) and a catalytic amount of DMAP, 169.6 mg (1.833 mmol) of propionyl chloride were added.
1) was slowly added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 10 minutes. After the reaction was stopped by adding saturated saline to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Each product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the desired product (mixture of trans isomer and cis isomer) (2
b) 227.0 mg were obtained. 95% yield

¹ H-NMR of trans form (CDCl ₃ , δ
ppm): 0.99 (t, J = 7.59 Hz, 3H),
1.99-2.24 (m, 2H), 2.57 (dd, J
= 1.65Hz, 0.66Hz, 1H), 3.69
(D, J = 14.52 Hz, 1H), 3.96 (s, 3
H), 4.01 (d, J = 14.52 Hz, 1H),
6.01 (d, J = 1.98 Hz, 1H), 7.20−
7.31 (m, 5H)

¹ H-NMR of cis form (CDCl ₃ , δpp
m): 0.93 (t, J = 7.26 Hz, 3H);
99-2.24 (m, 2H), 2.44 (dd, J =
1.65 Hz, 0.66 Hz, 1 H), 3.69 (s,
2H), 3.98 (s, 3H), 6.68 (d, J =
2.31 Hz, 1H), 7.20-7.31 (m, 5
H)

IR (neat, cm ^-1 ): 3250,2
920, 1765, 1503, 1463, 1370, 1
225,1178,1162,900,760,707

Example 9 1- (1-benzyloxyi)
Mino-2-phenylethyl) -3-trimethylsilylp
Synthesis of lopin-2-yl acetate (2c)

[0139]

Embedded image

Under an argon atmosphere, 66.7 mg of the previously obtained (12a) (0.2 g) was placed in a 30 ml two-necked eggplant type flask.
190 mmol) in methylene chloride (2.0 ml) was added, and triethylamine (38.4 mg, 0.380 mmol) was added.
After 1) and a catalytic amount of DMAP were added, 29.8 mg (0.380 mmol) of acetyl chloride was slowly added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 10 minutes. After the reaction was stopped by adding saturated saline to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1), and the desired product (mixture of trans-form and cis-form) was obtained. 0 mg was obtained. 94% yield

¹ H-NMR (CDCl ₃ , δ) of trans form
ppm): 0.00 (s, 9H), 1.75 (s, 3)
H), 3.62 (d, J = 14.52 Hz, 1H),
3.80 (d, J = 14.52 Hz, 1H), 5.02
(S, 2H), 5.87 (s, 1H), 7.07-7.
19 (m, 10H)

¹ H-NMR of cis form (CDCl ₃ , δpp
m): 0.01 (s, 9H), 1.64 (s, 3H),
3.51 (s, 2H), 5.09 (s, 2H), 6.5
9 (s, 1H), 7.07-7.19 (m, 10H)

IR (neat, cm ^-1 ): 3008, 2
950, 1765, 1517, 1471, 1241, 1
038,880,770,705

Example 10 1- (1-Methoxyimino)
-2-phenylethyl) -3-trimethylsilylpropyl
Synthesis of N-2-yl acetate (2d)

[0145]

Embedded image

In an argon atmosphere, 331.6 mg of the previously obtained (12b) was placed in a 30 ml two-necked eggplant type flask.
(1.204 mmol) in 2.0 ml of methylene chloride was added, and 243.7 mg (2.408) of triethylamine was added.
mmol) and a catalytic amount of DMAP, and 189.0 mg (2.408 mmol) of acetyl chloride was added at 0 ° C.
, And the mixture was stirred at the same temperature for 10 minutes. After the reaction was stopped by adding saturated saline to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give the desired product (a mixture of trans and cis forms) (2d ) 355.0m
g was obtained. 93% yield

¹ H-NMR (CDCl ₃ , δ) of trans form
ppm): 0.00 (s, 9H), 1.72 (s, 3
H), 3.61 (d, J = 14.52 Hz, 1H),
3.78 (d, J = 14.52 Hz, 1H), 3.80
(S, 3H), 5.86 (s, 1H), 7.08-7.
16 (m, 10H)

¹ H-NMR (CDCl ₃ , δpp
m): 0.01 (s, 9H), 1.64 (s, 3H),
3.53 (s, 2H), 3.81 (s, 3H), 6.5
4 (s, 1H), 7.08-7.16 (m, 10H)

IR (neat, cm ^-1 ): 2340, ¹
703, 1567, 1518, 1224, 760

Example 11 1- (1-benzyloxy)
Imino-2-phenylethyl) -3-trimethylsilyl
Hydrolysis of propyn-2-yl acetate (2c)

[0151]

Embedded image

In a 20 ml eggplant-shaped flask, (2c, a mixture of trans-form: cis-form = 3.6: 1) 5
1.9 mg (0.132 mmol) was weighed, and THF was added.
0.25 ml and 0.9 ml of a phosphate buffer solution, and 1
After stirring for 0 minutes, lipase PS (316.8 mg) was added, and the mixture was stirred at 40 ° C. for 155.5 hours. After the reaction solution was filtered through celite, the filtrate was concentrated to obtain a constituent organism. This was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1).
13.1 mg of (1a) was obtained. In addition, (2c) is set to 36.
2 g were recovered.

(Yield) 1a: 28% (mixture of trans: cis = 38.4: 1), 2c: 69% (mixture of trans: cis = 1.8: 1). (Optical purity) Trans form of 1a: 99% ee or more, cis form of 5a: 9
9% ee or more 2c trans form: 37% ee, 8a cis form: 11%
ee (optical rotation) 1a: α [D] (23 ° C.) = + 48.5 (c = 0.5
9, CHCl ₃ ) 2c: α [D] (23 ° C.) = + 18.4 (c = 0.7
2. CHCl ₃ )

Example 12 1- (1-Methoxyimino)
-2-phenylethyl) -3-trimethylsilylpropyl
Hydrolysis of N-2-yl acetate (2d)

[0155]

Embedded image

In a 20 ml eggplant-shaped flask, (2d, mixture of trans-form: cis-form = 6.0: 1) 4
4.3 mg (0.132 mmol) was weighed, and THF was added.
Add 0.25 ml and 0.9 ml of phosphate buffer solution and add 10
After stirring for minutes, Lipase PS (39.6 mg) was added, and the mixture was stirred at 40 ° C for 84 hours. The reaction solution was filtered through celite, and the reactor was concentrated to obtain a crude product. This was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1), and (1b) was converted to 1
2.4 mg were obtained. In addition, 26.1 mg of (2d) was recovered.

(Yield) 1b: 34% (trans form: cis form = 9.2: 1) 2d: 57% (trans form: cis form = 1.8: 1) (optical purity) 1b: α [D ] (23 ° C.) = + 56.5 (c = 0.2
5, CHCl ₃ ) 2d: α [D] (23 ° C.) = + 18.2 (c = 0.3
1, CHCl ₃ )

Example 13 1- (1-benzyloxy)
Imino-2-phenylethyl) propyn-2-yl
Hydrolysis of Lopionate (2a)

[0159]

Embedded image

In a 20 ml eggplant-shaped flask, 51.9 m of the previously obtained (2a, trans-form: cis-form = 6.0: 1) was obtained.
g (0.132 mmol) was weighed and THF 0.25m
and 0.9 ml of a phosphate buffer solution, and the mixture was stirred for 10 minutes, and then lipase PS (39.6 mg) was added.
For 84 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. This was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 5:
The target product (1a) was isolated and purified in 1) to obtain 15.4 m
g was obtained. In addition, 26.1 mg of the raw material (2a) was recovered.

(Yield) 1a: 41% (trans form: cis form = 49.4: 1) 2a: 59% (trans form: cis form = 2.1: 1) (optical purity) 1a: α [D ] (23 ° C.) = − 108.1 (c = 0.2
5, CHCl ₃ ) 2a: α [D] (23 ° C.) = − 75.9 (c = 0.4
9, CHCl ₃ )

Example 14 1- (1-methoxyimino)
-2-phenylethyl) propyn-2-yl propio
Hydrolysis of Nate (2b)

[0163]

Embedded image

In a 20 ml eggplant-shaped flask, 220.4 (2b, trans-form: cis-form = 6.4: 1) was obtained.
mg (0.850 mmol) was weighed and the THF 0.8m
and 2.9 ml of a phosphate buffer solution, and after stirring for 10 minutes, lipase PS (255.2 mg) was added.
The mixture was stirred at 4 ° C. for 45.5 hours. The reaction solution was filtered through celite,
The filtrate was concentrated to obtain a crude product. This was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give the desired product (1b) in 6 parts.
5.0 mg were obtained. Also, the starting material (2b) was converted to 125.9.
mg recovered.

(Yield) 1b: 38% (trans form: cis form = 22.2: 1) 2b: 57% (trans form: cis form = 1.8: 1) (optical purity) 1b: α [D ] (23 ° C) = -111.1 (c = 1.
3, CHCl ₃ ) 2b: α [D] (23 ° C.) = − 67.6 (c = 1.7)
2, CHCl ₃ )

Example 15 4-benzyloxyamino
-5-phenylpent-1-yn-3-ol (13
Synthesis of a)

[0167]

Embedded image

In an argon atmosphere, 206.2 mg of a toluene solution of VITRIDE was placed in a 30 ml two-necked eggplant type flask.
(1.260 mmol) was weighed, and 1.5 ml of THF was added, and 44.0 mg (0.158 mm) of (1c) previously obtained.
ol, 96% ee, trans-form: cis-form = 25.4: 1
Of a mixture of the above) in 1.5 ml of THF at -78 ° C.
The solution was slowly dropped over 5 hours. Thereafter, the temperature was naturally raised to −20 ° C. over 2.5 hours. The reaction solution was quenched with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. This was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
3: 1) to purify the desired product (isomer mixture) (1
3a) 33.9 mg were obtained. 77% yield

¹ H-NMR (CDCl ₃ , δ) of anti form
ppm): 2.55 (d, J = 2.31 Hz, 1H),
2.71-3.41 (m, 4H), 4.45-4.53
(Br, 1H), 4.67 (s, 2H), 5.84-
6.00 (br, 1H), 7.18-7.38 (m, 1
0H)

¹ H-NMR (CDCl ₃ , δp
pm): 2.53 (d, J = 1.98 Hz, 1H),
2.71-3.41 (m, 4H), 4.45-4.53
(Br, 1H), 4.70 (s, 2H), 5.84-
6.00 (br.1H), 7.18-7.38 (m, 1
0H)

Α [D] (23 ° C.) = + 10.6 (c =
0.68, CHCl ₃ ) IR (neat, cm ⁻¹ ): 3400, 3250, 30
00, 1505, 1461, 1230

[0172]

As described above, according to the present invention,
Optically active β-imino alcohols and β-amino alcohols useful as pharmaceutical production intermediates and the like can be easily produced with high optical purity.

Claims (6)

[Claims] (1) Formula (2) (In the formula, R ¹ represents an alkyl group or an aralkyl group having 7 to 20 carbon atoms having 1 to 6 carbon atoms, R ² is 1 to the number of carbon atoms
6 represents an alkyl group having 6 to 6 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms; R ³ represents an alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 20 carbon atoms; ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a trimethylsilyl group. ) Having a step of hydrolyzing the compound represented by formula (1) using a lipase. (Wherein, R ¹ , R ² and R ⁴ have the same meanings as described above). 2. A compound of the formula (2) (Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.) The compound represented by the formula (1) is hydrolyzed using a lipase. (Wherein R ¹ , R ² and R ⁴ have the same meanings as described above), and a step of obtaining an optically active β-imino alcohol represented by the formula (1): (3) having a step of reducing (Wherein, R ¹ , R ² and R ⁴ have the same meanings as described above). (3) Formula (2) (Wherein, R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above). 4. A compound of the formula (1) (Wherein, R ¹ , R ² and R ⁴ have the same meanings as described above). 5. A compound of the formula (3) (In the formula, R ¹ , R ² and R ⁴ have the same meanings as described above.) 6. A compound of the formula (9) (Wherein, R ¹ and R ² have the same meanings as described above).