WO2002055478A1

WO2002055478A1 - Process for preparation of optically active aminolactone derivatives and intermediates of the derivatives

Info

Publication number: WO2002055478A1
Application number: PCT/JP2001/011627
Authority: WO
Inventors: Masaru Mitsuda; Susumu Amano; Nobuo Nagashima
Original assignee: Kaneka Corporation
Priority date: 2001-01-16
Filing date: 2001-12-28
Publication date: 2002-07-18
Also published as: JPWO2002055478A1

Abstract

Optically active aminobutyric acid derivatives can be efficiently prepared, which are important intermediates of interleukin-1β-converting enzyme inhibitors. An optically active imine (1) is prepared by condensation of an optically active amine (6) with a dialkoxyaldehyde through dehydration, and then converted into an optically active aminobutyric acid derivative (3) through stereoselective addition; and the derivative (3) is further converted into an optically active aminolactone derivative (8) through stereoselective lactonization with an acid. (6) (1) (3) (8)

Description

Specification

Method for producing optically active aminolactone derivatives and intermediates thereof

The present invention relates to a pharmaceutical intermediate, in particular, an important intermediate for producing an interleukin-1-1beta converting enzyme inhibitor (for example, described in WO9903852) and a method for producing the same. . Background art

General formula (3)

(Wherein, RR ² , R ³ , and R ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms, or an aralkyl group having 7 to 18 carbon atoms; R ⁵ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, and * represents an asymmetric carbon atom. As a general method for producing an optically active aminobutyric acid derivative, a carboxyl group and an amino group of L-aspartic acid are sequentially protected, and then the 1-position carboxyl group is selectively reduced to a hydroxyl group, followed by dimethylsulfoxide. A method of oxidizing a hydroxyl group has been used (JP-A-11-96972). However, this method is inefficient due to the large number of steps and complicated operations. In addition, there are many problems in large-scale industrial production, such as dimethyl sulfide generated in large amounts by oxidation with dimethyl sulfoxide, which gives off a bad smell.

The general formula (8)

(Wherein, RR ² and R ³ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, As an example of a method for producing an optically active aminolatatatone derivative represented by the following formula: However, this method does not provide any stereoscopic identification during the Michael addition reaction. The resulting aminolatatatone is a 1: 1 mixture of optical isomers, which is inefficient and requires a complicated method for obtaining a compound having a preferred configuration as a pharmaceutical intermediate. Therefore, it can be said that this method is unsuitable for industrially producing optically active aminolactone. On the other hand, as another production method, a method of adding an amine to an optically active 5-alkoxy-2-furanone by Michael is known (Tetrahedron Asymmetry, 1991, Vol. 2, p. 775). In this method, the Michael addition reaction proceeds in a stereoselective manner, but it is extremely difficult to obtain optically active 5-alkoxy-12-furanone used as a raw material at low cost and in large quantities. Summary of the Invention

The present invention has been made in view of the above circumstances, and provides an extremely efficient method for producing an optically active aminolatatatone derivative and an optically active aminobutyric acid derivative as an intermediate thereof, that is, a stereoselective production method with a small number of steps. .

That is, the present invention provides a compound represented by the general formula (2):

X ^ C 0 ₂ R ⁵

(2)

(In the formula, R ⁵ is a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms. An enolate prepared by reacting a low-valent metal or a base with an acetic acid derivative represented by the formula (I) or an aralkyl group having 7 to 18 carbon atoms, and X represents a halogen or a hydrogen atom. Equation (1)

(Wherein, RRRR ⁴ independently represents an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, and * represents an asymmetric carbon atom. Is reacted with an optically active imine represented by the general formula (3)

(Wherein, RRRR ⁴ , R ⁵ , and * are the same as those described above).

Further, the present invention provides a compound represented by the following general formula (4):

(Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms, or an aralkyl group having 7 to 18 carbon atoms) An acid derivative and the general formula (1)

(Wherein, RR ² , R ³ , and R ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms, or an aralkyl group having 7 to 18 carbon atoms; * Represents an asymmetric carbon), and reacted with an optically active imine represented by the general formula (5)

R ³

(Wherein, RRR ³ , RR ⁵ , and * are the same as those described above), and are decarboxylated to obtain a compound represented by the general formula (3)

(Wherein, RRR ³ , RR ⁵ and * are the same as described above).

Further, the present invention provides a compound represented by the general formula (1):

(In the formula, R ¹ represents an alkyl group having 8 carbon atoms, and R ² represents an alkyl group having 5 to 18 carbon atoms. Represents a reel group; R ³ and R ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms; The present invention relates to an optically active imine represented by the formula (I), which is used by the present inventors as a pharmaceutical intermediate, in particular, as an intermediate of an interleukin-11beta converting enzyme inhibitor and its production. It is a new compound for which a method has been found. The general formula (6)

H ₂ N 8 R ² (6)

(Wherein, R ¹ represents an alkyl group having 1 to 18 carbon atoms, R ² represents an aryl group having 5 to 18 carbon atoms, and * represents an asymmetric carbon). And the general formula (7)

R ³

(Wherein, R ³ and R ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms, or an aralkyl group having 7 to 18 carbon atoms) The present invention relates to a method for producing the novel compound by dehydration condensation of a dialkoxyaldehyde. Further, the present invention provides a compound represented by the general formula (3):

(Wherein, RR ² , R ³ and R ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, and * represents an asymmetric carbon. ) The acid is allowed to act on the optically active aminobutyric acid derivative represented by Converted to couton, general formula (8)

(Wherein, RRR ³ and * are the same as described above). Detailed Disclosure of the Invention

The outline of the production method in the present invention is represented by the following formula (I),

(I)

(Where RRR ³ , R ⁴ , R ⁵ and * are the same as above)

That is, in the step [1], the optically active amine (6) and the dialkoxy aldehyde (7) are dehydrated and condensed to prepare the optically active imine (1), and in the step [2], the optically active imine (1) is converted to the optically active imine (1). The optically active aminobutyric acid derivative (3) is derived to the optically active aminobutaic acid derivative (8) in the step [3].

Each group used in the above formulas (1) to (8) will be described below. R \ RRR ⁴ each independently represents an alkyl group, Ariru group or Ararukiru group with carbon number 7-1 8 5-1 8 carbon atoms having 1 to 1 8 carbon atoms, R ⁵ is water atom, carbon Represents an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, X represents a halogen or a hydrogen atom, and * represents an asymmetric carbon.

The alkyl group having 1 to 18 carbon atoms in RRR ³ , R ⁴ and R ⁵ is a linear, branched or cyclic alkyl group having 1 to 18 carbon atoms which may be substituted. Is a linear, branched or cyclic alkyl group which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen and alkoxy. Specific examples include a methyl group, an ethyl group, a methoxyl group, an isopropyl group, a tert-butyl group, a pentyl group, a cyclohexyl group, an n-octyl group, and an n-dodecyl group. It may be an alkyl group having 1 to 10 carbon atoms.

The aryl group having 5 to 18 carbon atoms in I ¹ , RR ³ , R ⁴ , and R ⁵ is an aryl group having 5 to 18 carbon atoms which may be substituted, and more specifically, halogen and alkyl. And an aryl group having 5 to 18 carbon atoms which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkoxy and alkoxy. Specific examples include a phenyl group, a trinole group, a p-chloropheninole group, a p-methoxypheninole group, a naphthyl group, a pyridyl group, and the like. ~ 12 aryl groups.

The aralkyl group having 7 to 18 carbon atoms in R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is an aralkyl group having 7 to 18 carbon atoms which may be substituted. It is an aralkyl group having 7 to 18 carbon atoms which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen, alkyl and alkoxy. Specifically, benzyl group, 1-phenylenoethyl group, 1-phenylenopropyl group, diphenylenomethyl group, ρ-methoxybenzyl group, p-methoxyphenylethyl group, naphthylmethyl group, etc. And preferably an aralkyl group having 7 to 11 carbon atoms which may be substituted.

As the halogen used as a substituent in each of the above groups, for example, Alkyl, for example, methyl, ethyl, propyl, etc .; and alkoxy, for example, methoxy, ethoxy, propoxy and the like.

Examples of the halogen in X include fluorine, chlorine, bromine, iodine and the like, and preferably bromine and iodine.

Hereinafter, the present invention will be described in detail for each step.

Process “1 Ί

In this step, the general formula (6)

H ₂ ", R ² (6)

Optically active amine represented by the general formula (7)

Dehydration condensation of the dialkoxyaldehyde represented by the general formula (1)

To produce an optically active imine represented by

The description of the group of RRRR ⁴ is as described above.

In the optically active amine (6), RR ² is preferably a methyl group, an ethyl group, a phenyl group, a trinole group, or a methoxyphenyl group.

In the optically active amine (6), * represents an asymmetric carbon, so that R ¹ and R ² must be different from each other. The configuration of the asymmetric carbon is R or S, preferably R.

In particular, R ¹ is more preferably an alkyl group such as a methyl group or an ethyl group, and R ² is more preferably an aryl group such as a phenyl group, a tolyl group, or a p-methoxyphenyl group. In a most preferred combination, R ¹ is a methyl group and R ² is a phenyl group.

Accordingly, the most preferred optically active amine is (R) -phenethylamine. In the dialkoxyaldehyde (7), R ³ and R ⁴ are preferably a methyl group, an ethyl group, a benzyl group or the like, more preferably a methyl group or an ethyl group, and further preferably an ethyl group.

The most preferred dialkoxy aldehyde is glyoxal getyl acetal.

As the optically active amine (6) and the dialkoxyaldehyde (7), those commercially available can be used.

The dehydration-condensation reaction in this step proceeds spontaneously only by mixing the above-mentioned optically active amine (6) and dialkoxyaldehyde (7).

The molar ratio of the optically active amine (6) to the dialkoxyaldehyde (7) is preferably 1: 0.5 to 1.5, more preferably 1: 0.8 to 1.2, and still more preferably. Is 1: 1.

In addition, the dehydration-condensation reaction proceeds without a solvent, but a reaction solvent may be used. The reaction solvent is not particularly limited, but is preferably an aprotic solvent. Examples thereof include getyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, ethylene glycolone dimethyl ether, ethylene glycol dimethyl ether, and triethyl ether. Ethanol solvents such as ethyleneglycol / resin-methinole ether; hydrocarbon solvents such as benzene, tonolene, _n- hexane and cyclohexane; methylene chloride, chloroform, 1,1,1-trichloroethane And aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and hexamethyl phosphate triamide. These may be used alone or in combination of two or more. Preferably, a hydrocarbon solvent such as benzene, toluene, n-hexane, cyclohexane, etc., or getyl ether, diisopropyl ether, tert-butyl methyl ether, tetra Ether solvents such as hydrofuran and dioxane, and more preferably toluene or tetrahydrofuran.

The dehydration-condensation reaction in this step efficiently proceeds at room temperature, and thus does not require any operation such as heating or cooling. Therefore, the reaction temperature is not particularly limited, but the reaction proceeds smoothly, for example, in the range of 12 ° C. to 180 ° C., and preferably 110 ° C. to 80 ° C.

In addition, water is generated as the dehydration condensation reaction in this step proceeds. The reaction proceeds smoothly without actively removing the water generated at this time, but the generated water is removed outside the reaction system by azeotropic dehydration with a reaction solvent or by adding a drying agent. Is also good. The time until the completion of the reaction depends on the reaction temperature, but is about 0.5 to 12 hours, preferably 1 to 5 hours.

The degree of progress of the reaction can be monitored by analytical means such as high performance liquid chromatography and gas chromatography.

After the completion of the reaction, the crude reaction product can be used as it is in Step [2] without requiring any special post-treatment in this step. When a reaction solvent is used, the solvent may be distilled off under reduced pressure, or the solvent may be used for the next step while containing the solvent. When it is desired to obtain an optically active imine (1) having extremely high purity, for example, the crude product may be distilled.

In the optically active imine (1) which can be synthesized by the production method of this step, particularly, R ¹ is an alkyl group having 1 to 18 carbon atoms which may be substituted, and R ² is a carbon atom which may be substituted. 5 to 18 aryl groups, wherein R ³ and R ⁴ are each independently an alkyl group having 1 to 18 carbon atoms which may be substituted, and an alkyl group having 5 to 18 carbon atoms which may be substituted. Compounds that are a group or an aralkyl group having 7 to 18 carbon atoms which may be substituted are particularly preferred as important intermediates of the interleukin-11beta converting enzyme inhibitor, which is the object of the present invention, and are used by the present inventors. Is a new compound found.

In the optically active imine (1) of the present invention, R ¹ is particularly preferably a methyl group, R ² is particularly preferably a phenyl group, and R ³ and R ⁴ are each particularly preferably a methyl group or an ethyl group. Specific examples of the optically active imine (1) of the present invention include N 1 — [(1R) 1-1—phenylethyl) —2,2-di (ethoxy) ethane-1-imine and N 1— [(1 R) — 1-phenylethyl] — 2,2-di (methoxy) ethane 1-imine, N 1-[(1 R) 1-1-phenylenethyl]] — 2,2-di (benzyloxy) ethane — 1-imine, N 1— [(1 R) 1-11 naphthylethyl] — 2,2-di (ethoxy) 1-imine, N 1— [(1 R) 1 1— (4-methoxyphenyl) Tyl] — 2,2-di (ethoxy) ethane-1-imine, N 1— [(1S) -1 -phenylenyl) -1,2,2-di (ethoxy) ethane-1-imine, and N 1 -[(1 R) — 1-pheninoleethinole] 1,2,2-di (ethoxy) ethane-1-imine is particularly preferred.

Process [2]

In this step, the general formula (1) prepared in step [1]

The optically active imine represented by the general formula (3)

To an optically active aminobutyric acid derivative represented by

The description of the groups of R ¹ and RRRR ⁵ is as described above.

The present inventors have developed three methods (Method A, Method B, and Method C) as methods for converting an optically active imine (1) into an optically active aminobutyric acid derivative (3). I do.

<Method A> In method A, the general formula (2) X ^ C 0 ₂ R ⁵

An enolate prepared by reacting a low-valent metal with the acetic acid derivative represented by (2) is reacted with an optically active imine (1) to stereoselectively produce an optically active aminobutyric acid derivative (3). .

In the acetic acid derivative (2) of the method A, the description of the group of R ⁵ is as described above, and R ⁵ is preferably a tert-butyl group, a benzyl group or the like.

In the acetic acid derivative (2) of the method A, X represents a halogen, preferably bromine, iodine or the like, and more preferably bromine.

The most preferred compound as the acetic acid derivative (2) of Method A is tert-butyl bromoacetate. ·

The amount of the acetic acid derivative (2) used in Method A is 1 to 5 moles, preferably 1 to 3 moles, per 1 mole of the optically active imine (1).

The low-valent metal in the method A is, for example, a metal of the third to sixth periods on the long-period table and a group of II 属, ΠΒ, IIIA, IIIB, IVA, IVB, VIB and a 0 to 3 valent metal. In

Zero-valent zinc, zero-valent magnesium, zero-valent aluminum, zero- or divalent tin,

Examples include divalent chromium, zero-valent gallium, zero-valent indium, divalent samarium, zero-valent or trivalent cell, and the like. Preferred are zero-valent zinc or zero-valent magnesium, and most preferred is zero-valent zinc.

The amount of low-valent metal used in Method A is 1 to 1 with respect to the optically active imine (1).

It is 5 moles, preferably 1 to 3 moles.

Although not essential, in the reaction of Method A, various activators may be added for the purpose of activating low-valent metals to facilitate enolate formation. As the activator, for example, a well-known activator for preparing a Reformatsky reaction reagent can be used. Preferred are halogen, mono- or di-halogenated alkanes, benzenes, logenated silanes and the like, and specific examples include iodine, methane iodide, dibromoethane, and trimethylsilane chloride. In the reaction of Method A, it is preferable to use a reaction solvent. The reaction solvent is not particularly limited, but is preferably an aprotic solvent.Examples include getyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dithioxane, ethylene glycolone resin methinolate ether, and diethylene glycol. Ether solvents such as dimethinoleate and triethylene glycolone resin, etc .; hydrocarbon solvents such as benzene, toluene, n-hexane and cyclohexane; methylene chloride, chloroform and 1,1 And halogen solvents such as 1,1-trichloroethane; aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and hexamethylphosphoric acid triamide. These may be used alone or in combination of two or more. Preferably, a hydrocarbon solvent such as benzene, toluene, n-hexane, cyclohexane or the like, or an ether such as getyl ether, diisopropinoleatenole, tert-butinolemethinoleatenole, tetrahydrofuran, dioxane or the like It is a system solvent, more preferably toluene or tetrahydrofuran.

The reaction temperature in the reaction of the method A is not particularly limited, but is preferably from 150 to 120 ° C, more preferably from 120 to 80 ° C.

The order of mixing the respective materials in the reaction of the method A is arbitrary and is not particularly limited. For example, the mixing can be performed by the following procedure. First, a low-valent metal and an acetic acid derivative (2) are mixed in a reaction solvent to prepare an enolate solution. Next, the optically active imine (1) may be added to the prepared enolate solution. As another method, an enolate solution prepared by the same method as described above may be added to the optically active imine (1) or a solution thereof.

The enolate prepared by the above procedure can be stored for a long period of time, and the enolate once prepared may be mixed with the optically active imine (1) and reacted at a later date according to the convenience of the worker. The enolate can be stored in solution, or the solid enolate can be obtained and stored after concentration or crystallization of the solution.

The time until the end of the reaction depends on the reaction temperature, but is about 1 to 24 hours, preferably 2 to 12 hours. The progress of the reaction can be monitored by analytical means such as high performance liquid chromatography and gas chromatography.

The post-treatment method for obtaining the optically active aminobutyric acid derivative (3) from the mixture after the reaction is not particularly limited. For example, an optically active aminobutyric acid derivative (3) can be obtained by mixing the reaction mixture with water or a dilute acid, extracting the mixture with a common extraction solvent, and concentrating the organic layer under reduced pressure. .

In method B, the general formula (2)

X,, C 0 ₂ R ⁵

And enolate prepared by the base is reacted in acetic acid derivative represented by (2), by reacting an optically active imines (1), the _c Method B for producing an optically active amino acid derivative (3) stereoselectively In the acetic acid derivative (2), the description of the group of R ⁵ is as described above, and R ⁵ is preferably a hydrogen atom, a tert-butyl group, a benzyl group, or the like.

In the acetic acid derivative (2) of Method B, X represents a hydrogen atom.

The most preferred compound as the acetic acid derivative (2) of Method B is tert-butyl acetate.

The amount of the acetic acid derivative (2) used in the method B is 1 to 5 moles, preferably 1 to 3 moles relative to the optically active imine (1).

Examples of the base used in the method B include lithium disopropylamide, lithium isopropylcyclohexylamide, magnesium diisopropylamide, lithium hexamethyldisilazide, and sodium hexamethyldisilazide. Metal amides such as zide, potassium hexamethyldisilazide, sodium amide; alkyl metals such as butyllithium, tert-butylmagnesium chloride; metal hydrides such as sodium hydride, hydrogen hydride, calcium hydride Metal alkoxides such as sodium methoxide, sodium methoxide, potassium methoxide, potassium tert-butoxide, and magnesium methoxide; and simple metals such as metal sodium and metal potassium. Preferably, lithium diisopropylamide, Examples include metal amides such as lithium hexamethyldisilazide and sodium hexamethyldisilazide.

The amount of the base used in the method B is 1 to 5 moles, preferably 1 to 3 moles relative to the optically active imine (1).

In the reaction of Method B, it is preferable to use a reaction solvent. The reaction solvent is not particularly limited, but is preferably an aprotic solvent.Examples include getyl ether, diisopropylpropyl ether, tert-butyl methyl ether, tetrahydrofuran, furan, dioxane, ethylene glycolone resin methinolate ether, and diethylene glycol. Ether-based solvents such as cornoremethine oleate ethere and triethylene glycolone methine oleate ethere; hydrocarbon-based solvents such as benzene, toluene, n-hexane, and cyclohexane; methylene chloride, chloroform, Halogen solvents such as 1,1-trichloroethane; and aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and hexametinoleic acid triamide. These may be used alone or in combination of two or more. Preferably, a hydrocarbon solvent such as benzene, toluene, n-hexane, cyclohexane or the like, or an ether such as getyl ether, diisopropinoleatenole, tert-butinolemethinoleatenole, tetrahydrofuran, dioxane or the like It is a system solvent, more preferably toluene or tetrahydrofuran.

The reaction temperature in the reaction of the method B is not particularly limited, but is preferably from 100 to 120. C, more preferably 150 to 50 ° C.

The order of mixing the respective materials in the reaction of the method B is arbitrary and is not particularly limited. For example, the mixing can be performed by the following procedure. First, a base and an acetic acid derivative (2) are mixed in a reaction solvent to prepare an enolate solution. Next, the optically active imine (1) may be added to the prepared enolate solution. As another method, an enolate solution prepared by the same method as described above may be added to the optically active imine (1) or a solution thereof.

The time until the completion of the reaction depends on the reaction temperature, but is about 10 minutes to 24 hours, preferably 1 to 5 hours.

The degree of progress of the reaction can be determined by high performance liquid chromatography, gas chromatography, etc. Can be observed by the analysis means.

In method C, the general formula (4)

Reaction of a malonic acid derivative represented by the formula (1) with an optically active imine (1)

Is prepared and decarboxylated to stereoselectively produce an optically active aminobutyric acid derivative (3).

The description of the groups R ¹ , R ² , R ³ , R ⁴ and R ⁵ is as described above.

In the malonic acid derivative (4) of Method C, R ⁵ is preferably a hydrogen atom, a tert-butyl group, a benzyl group or the like.

As the malonic acid derivative (4) of Method C, the most preferred compound is malonic acid or tert-butyl malonate.

The amount of the malonic acid derivative (4) used in Method C is 1 to 5 moles, preferably 1 to 3 moles, per 1 mole of the optically active imine (1).

In the reaction of Method C, a reaction solvent can be used. The reaction solvent is not particularly limited, and a wide variety of protic or aprotic solvents can be selected. For example, getyl ether, diisopropyl ether, tert-butyl methinoole ether, tetrahydrofuran, dioxane, ethylene glycolone resin Ether-based solvents such as phenol, diethylene glycolone resin, dimethyl ether, and triethylene glycolone; hydrocarbon solvents such as benzene, toluene, n-hexane, and cyclohexane; methylene chloride, chloroform, Halogen solvents such as 1,1 trichloroethane; aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and hexamethylphosphoric triamide; alcohol solvents such as methanol, ethanol, 1: ert-butanol; , Acetone, acetonitrile, water and the like. These may be used alone or in combination of two or more. Preferred are toluene, tetrahydrofuran, acetonitrile and the like, and more preferred are toluene and tetrahydrofuran. The reaction temperature in the reaction of the method C is not particularly limited, but is preferably −50 to 120 ° C., and more preferably 120 to 120 ° C.

In the production method of Method C, the carboxaminobutyric acid derivative (5) formed in the course of the reaction undergoes spontaneous decarboxylation under the above-mentioned reaction conditions, leading to the aminobutyric acid derivative (3).

When a carboxylic acid is present in the reaction of the method C, side reactions can be suppressed.

The carboxylic acid that can be used in the reaction of the method C is, for example, a carboxylic acid having 1 to 20 carbon atoms, and specifically, formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, octanoic acid, oxalic acid, and benzoic acid Acids and the like, and preferably acetic acid and the like. The amount of the carboxylic acid used in the reaction of the method C is 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to the optically active imine (1).

The order of mixing the respective materials in the reaction of Method C is arbitrary and is not particularly limited. For example, a malonic acid derivative (4), an optically active imine (1) and, if necessary, carboxylic acid may be mixed in a reaction solvent.

The time until the completion of the reaction depends on the reaction temperature, but is about 1 to 24 hours, preferably 5 to 20 hours.

The progress of the reaction can be monitored by analytical means such as high performance liquid chromatography and gas chromatography.

After obtaining the optically active aminobutyric acid derivative (3) from the mixture after the reaction, The treatment method is not particularly limited, but usually, the reaction solvent may be concentrated from the reaction mixture under reduced pressure.

The configuration at the 3-position of the optically active aminobutyric acid derivative (3) obtained by the production method of the above methods A to C, that is, the configuration of the newly formed asymmetric carbon is R or S, preferably S. is there. That is, it is preferable to stereoselectively produce the (3S) form as an optically active aminobutyric acid derivative.

When the optically active aminobutyric acid derivative (3) obtained by the production methods of the above methods A to C is insufficient in optical purity, for example, crystallization and purification may be carried out by forming a salt with an appropriate acid.

Process [3]

In this step, the optically active aminobutyric acid derivative represented by the general formula (3) or the salt thereof represented by the general formula (3) prepared in the step [2] is reacted with an acid to stereoselectively form a cyclized lactone, thereby obtaining a compound represented by the general formula (8) It is converted to amino ratatotone derivative.

The description of the groups RR ² , RR ⁴ and R ⁵ is as described above.

Preferably, at least one of R ^x R ² is an aryl group. In particular, R ¹ is more preferably an alkyl group such as a methyl group or an ethyl group, and R ² is more preferably an aryl group such as a phenyl group, a tolyl group, or a -methoxyphenyl group. The most preferred combination is where R ¹ is a methyl group and R ² is a phenyl group. Further, it is preferable that R ³ and R ⁴ are each a methyl group or an ethyl group. Further, it is preferable that R ⁵ is a tert-butyl group.

The configuration at the 3-position of the optically active aminobutyric acid derivative is R or S, and preferably S. The configuration of the asymmetric carbon formed by R ¹ and R ² is R or S, and preferably R.

In this step, an optically active aminobutyric acid derivative can be used as a salt. Here, the salt means a salt formed by adding an optional acid to the optically active aminobutyric acid derivative (3). The type of the acid that forms the salt is not particularly limited, and examples thereof include hydrochloric acid, sulfuric acid, acetic acid, trichloroacetic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid. Among them, p-toluenesulfonic acid is an optically active amino acid. It is particularly preferred because it forms a good salt with the butyric acid derivative. The acid used in the cyclization lactonization reaction in this step is a protic acid or a Lewis acid. Examples of the protic acid include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, and caustic acid; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; Carboxylic acids such as trifluoroacetic acid and trichloroacetic acid are exemplified. In order to promote a high yield and high stereoselective reaction, sulfonic acids such as methanesnolefonic acid, benzeneszolefonic acid, p-tonolenesnolefonic acid, and trifluoromethanesulfonic acid are preferable, and methanesulphonic acid is preferred. Particularly preferred. As the Lewis acid, for example, aluminum chloride, boron fluoride, titanium chloride, tin (IV) chloride, iron (II) chloride, zinc chloride, zinc bromide, magnesium chloride, trimethylsilinoletrifluoromethanesulfonate and the like are preferable. . The amount of the acid used in this step is preferably 0.1 to 30 molar equivalents with respect to the optically active aminobutyric acid derivative (3), and 1 to 20 molar equivalents from the viewpoint of yield and economy. More preferred.

In order to produce the pharmaceutical intermediate described in WO9903852, the optically active aminolactone derivative (8) (4S, 5R) produced by the stereoselective cyclized ratatone conversion of the present invention is required. It is preferable to have a tetrahydrofuran-1-one skeleton.

In addition, a reaction solvent can be used in the cyclization ratatonization reaction. The reaction solvent is not particularly limited. Ether solvents such as benzene, tonolene, _n- hexane, cyclohexane, etc .; hydrocarbon solvents such as methanol, ethanol, butanol, isopropyl alcohol, ethylene glycol, methoxyethanol, etc .; acetonitrile, Nitril solvents such as propionitrile; Halogen solvents such as methylene chloride, chlorophonolem and 1,1,1-trichloroethane; dimethylformamide, N-methylpyrrolidone, and hexane It can be exemplified non-pro ton polar solvents such as Chirurin acid Toria Mi de. These may be used alone or in combination of two or more. To promote high yield and high stereoselective reactions For this purpose, hydrocarbon solvents such as benzene, toluene, n-hexane and cyclohexane are preferred, and toluene is particularly preferred. .

The reaction temperature in the cyclized lactonization reaction is preferably from −50 to 100 ° C., and more preferably from 130 to 30 ° C. in order to promote a high yield and high stereoselective reaction.

The reaction time depends on the reaction temperature, but is about 1 to 24 hours, preferably 2 to 12 hours.

After completion of the reaction, a general post-treatment may be performed to obtain a product from the reaction solution. For example, the reaction solution after the completion of the reaction is mixed with water or weakly alkaline water, and extraction is performed using a common extraction solvent such as ethyl acetate, getyl ether, methylene chloride, toluene, hexane, and the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by an operation such as heating under reduced pressure, the desired product is obtained. After the reaction is completed, the same operation may be performed immediately after distilling off the reaction solvent by an operation such as heating under reduced pressure. The target product thus obtained is almost pure, but may be further purified by a general method such as crystallization purification, fractional distillation, or column chromatography to further increase the purity. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1: N 1-[(1 R) — 1-Fenrj チ cinole Ί-2, 2-Di (ethoxy) ethane-1-imine

EtO ^ JL

、, H

OEt

Dissolve 2.0 g (15.1 mm o 1) of 2,2 di (ethoxy) ethanal in 15 ml of toluene and stir under ice-cooling and stirring (R) -phenethylamine 1.53 g (1 2.6 mm o 1) of a 5 ml toluene solution was added dropwise over 5 minutes. Ice bath at the end of dripping Was removed and the mixture was stirred at room temperature (20 ° C). After 2 hours of stirring at room temperature, toluene was distilled off from the reaction mixture under reduced pressure to obtain 3.0 g of the title compound (quantitative).

1H-NM (400 MHz, CDC1 3) δ 7.57 (lH, dJ = 5.1Hz); 7.2-7.4 (5H, m), 4.80 (. LH, d, J = 5 1Hz), 4.37 (lH, q, J = 6.4Hz), 3.4-3.8 (4H, m), 1.50 (3H, d, J = 6.4Hz), 1.24 (3H, t, J = 6.8Hz), 1.16 (3H, t, J = 6.8Hz) ppm

^{13 H-NMR (100 MHz,} CDC1 3) d 159.7, 144.1, 128.4, 127.0, 126.5, 101.9, 69.1, 62.5, 62.3, 24.2, 15.2, 15.1 ppm Example 2: N 1 - [(1 R) -1 —Phenylethyl] —2,2-di (methoxy) ethane-1-imine

N eight Ph

MeO. 丫人 H

OMe

Dissolve 1.6 g (15.4 mm o 1) of 2,2-di (methoxy) ethanol in 15 ml of toluene and stir with ice-cooled (R) -phenethylamine 1.53 g A toluene solution of (12.6 mmo 1) was added dropwise over 5 minutes, and upon completion of the addition, the ice bath was removed, and the mixture was stirred at room temperature (20 ° C). The toluene was distilled off to obtain 2.6 g of the title compound (quantitative).

1H-NMR (400 MHz, CDCI3) δ 7.57 (lH, d, J = 4.6Hz), 7.2-7.3 (5H, m), 4.72 (lH, d, J = 4.6Hz), 4.40 (lH, q, J = 6.8Hz), 3.43 (3H, s), 3.37 (3H, s), 1.53 (3H, d, J = 6.8Hz) ppm ¹³ H-MR (100 MHz, CDCI3) d 159.0, 143.9, 128.5, 127.0 , 126.6, 103.1, 69.3, 54.0, 53.9, 24.2 ppm Example 3: (3S) —4,4-di (ethoxy) -13 — {“(1R) —1-phenyl-2-ethyl] amino} tert-butyric acid —Butyl [Method A] ζΖ radd (zH8'9 = iVH £ ΐ.ί '(ζ

'(ZH6.S'I'SK'PP'HI)

ί¾'Ηΐ) 88 · £ ^c (zH ^ = X ^c P¾l) 83 '(∞¾S) n £' n 9 ( ^ε Όαθ head ₀₀ ρ) ¾Ν [Μ-Η _Τ

. ^ (% s Ζ) § oz s-z ^ m ^ 璩, (s: 8 ^ 翘 S /

^ 4 mu a ma / '(¾ ¾, つ辛 ^ 缀缀 ο ο ο 06 06 ： Τ Τ Τ Τ ：： 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06

:, /

44: 軎馑 o sv / sao / OHA: τό ^) dH. ^ 'Ba) ^. Tsu ςι

^ ^-i Ci i-(-m-^^ ^ M ^ m ^ m ^-^^- ⁿ ,? s

• 8 Ha, e-ma fi

0 ε, ^ ω ΐ ο

τ ^ m ^ m ^ Ψ ^ 9ΜΜ. Tsu tsu '(Ts. O s) ¾ Tsu spicy ^!

^ ^ ¾ 丄 ^ 丄继 ° 丄毁 / 4 ¾ 缀 d / 4 1 ^ 0 Ο) (ΐ o xnin g, ₈ ) S

0 'ζ-τ-^ m (, ^ 4e)' z-[/ ^ / T1 οι (τ)] τ N ^ a. I \, 丄氺: ^ r, politeness: ^ / 4 D 1 ^

08 丄 ^ au ¾ (〖orauis -Q s) § 9 * 9 @ ^ ¾ ΐα ¾ 0-¾

. ¾ ³ s · 91 ^ @ ¾ ^ 4— 4, e ^ ^ w ^^^ mm ^

¾ ^a n. · ^ ¾ '4 η, ^^^^^^ m ^ ^ n ^ mm ^ im ^ m ^^^

$, Tsu fig¾ ¾ ^a ¾ tsu ½, tsu ^ ^ ^ 萆. ^^ and $ '0. 0 S

, Tsutsu 06 I 0 τ Λ (^-^ ^{J Θ} ^ Μ ^-, α ο g ^ ^ o

^ ¾¾ liL¾ B τ ^ ^ H ^-ΐ ^ra T · 0 ぺェ η — Ζ 'I ¾ ¾, っ觀: I ^ra s¾s 6'

zz

LZ9ll / l0dr / ∑Jd LtSSO / ZO OAV Example 4: (3 S) one 4, 4-di (ethoxy) one 3- {[(1 R) Single 1 one phenylene Ruechiru] amino} butyric acid t _er t-butyl [Method B]

Under a nitrogen atmosphere, a solution of 0.65 g (6.4 mmo 1) of diisopropylamine in 10 ml of tetrahydrofuran was stirred at 0 ° C under stirring at 1.6 ° C for 1.6 NZn-butyllithium / n-hexane solution. 4 mm o 1) was added dropwise. After the completion of the dropwise addition, the solution was cooled to −78 ° C., and a solution of 0.74 g (6.4 mmol) of tert-butyl acetate in 10 ml of tetrahydrofuran was added dropwise with stirring. After a further 30 minutes of stirring, the N 1 — [(1R) —1-phenylethyl) —2,2-di (ethoxy) ethane-1-imine obtained in Example 1 0.5 g (2.12) 5 ml of tetrahydrofuran solution of mmo1) was added dropwise. After 2 hours of stirring, the reaction mixture was added to 25 ml of 1N hydrochloric acid in an ice bath, and a 30% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 8.5. After extraction with n-hexane and washing with a saturated saline solution, the mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrate obtained in this way was analyzed by HP LC (column: YMC / ODS / A-303, mobile phase: acetonitrile acetic acid buffer solution-50 Z50, flow rate: 1.0 ml, Temperature: 40 ° C, detection wavelength: 220 nm), the yield of the title compound was 40%, and the stereoselectivity was (3S): (3R) = 70: 30. there were. Example 5: (3S) -14,4-di (ethoxy) -13-{"(1R) -1-phenylethyl] amino} tert-butyl butyrate [Method]

0.5 g (2.12 mmo1) of N l — [(1 R) —1-fuunylethyl) -1,2,2-di (ethoxy) ethane-1-imine obtained in Example 1 and monomalonic acid Dissolve 0.34 g (2.12 mm o 1) of tert-peptinole in 10 ml of toluene, add 0.25 g of acetic acid (4.16 mm o 1), and at 0 ° C. The mixture was stirred for 3 hours and further at 30 ° C for 15 hours.

The reaction solution was concentrated under reduced pressure, and the obtained concentrate was analyzed by HPLC (column: YMC / OD SZA—303, moving layer: acetonitrile / acetate buffer solution = 50/50, flow rate: 1.0 m) The yield of the title compound was 41%, and the stereoselectivity was (3S): (3R) = 60. : 40 I got it. Example 6: Synthesis of (4S, 5R) -5-ethoxy-4-({[(1R) -1-1-phenylenetinole] amino) tetrahydrofuran-1-one 1

(3 S) —4,4-Diethoxy 3-— {[(1 R) — 1-phenylethyl] amino} tert-butynole butyrate 2.0 g (5.69 mm o 1) was dissolved in 20 ml of tonoleene. Under stirring at 0 ° C., 6 ml (14 molar equivalents) of methanesulfonic acid was added dropwise over 10 minutes. After stirring at 0 ° C. for further 6 hours, 14 ml of triethylamine was added dropwise. Next, the mixture was washed with water, and the solvent was distilled off under reduced pressure to obtain 1.58 g of a crude product. At this point, HP LC analysis (column: YMCZOD S / A-303, eluent: acetonitrile water = 50/50, flow rate: 0.8 ml / min, temperature: 40 ° C, detection wavelength: 210 nm) was performed However, the stereoselectivity was (4S, 5R) :( 4S, 5S) = 88: 12. The crude product was further purified by silica gel column chromatography (hexane / ethyl acetate 5: 5) to obtain 1.02 g (yield: 72%) of the pure title compound.

_{1H- MR (400 MHz, CDC1 3} ) δ 7.25-7.36 (5H, m), 4.96 (lH, d, J = 4.9Hz), 3.74-3.81 (2H, m), 3.33-3.47 (2H, m), 2.61 (lH, dd, J = 16.6,7.6Hz), 2.39 (lH, dd, J = 16.6,10.7Hz), 1.87 (lH, bs), 1.40 (3H, d, J = 6.8Hz), 1.23 (3H , t, J = 7.1Hz) ppm Example 7: Synthesis of (4S, 5R) -5-ethoxy-1-({((1R) —1-phenylenyl] amino) tetrahydrofuran-1-one 2

(3S) -1,4—Jetoxy 3 -— {[(1R) -11-phenylethyl] amino} p-toluenesulfonate of tert-butyl butyrate 37.5 g (71.6 mmo 1) in 260 The resulting suspension was suspended in toluene at 0 ° C and 55 g (8 molar equivalents) of methanesulfonic acid was added dropwise over 20 minutes while stirring at 0 ° C. After stirring at 0 ° C for another 4 hours, Was poured into a sodium hydrogencarbonate solution at 10 ° C or lower while cooling and stirring. After stopping the stirring and separating the organic layer and the aqueous layer, the aqueous layer was extracted twice with n-hexane, and all the organic layers were combined and washed with water. The solvent was distilled off under reduced pressure to obtain 38.5 g of a crude product. At this point, HPLC analysis (column: YMC / OD S / A—30

3. Eluent: acetonitrile / water = 50/50, flow rate: 0.8 ml Z min, temperature:

At 40 ° C, detection wavelength: 210 nm), the stereoselectivity was (4 S, 5 R)

: (4 S, 5 S) = 89: 11 The crude product was further purified by silica gel column chromatography (hexane: ethyl acetate 5: 5) to obtain 14.4 g (yield: 81%) of the pure title compound. Example 8: Synthesis of (4S, 5R) -5-ethoxy-1-41 {[(1R) -11-phenylethyl] amino} tetrahydrofuran-2-one 3-

The same operation as in Example 6 was carried out except that methanesulfonic acid was used at 8 molar equivalents, the methanesulfonic acid dropping temperature, the reaction temperature was set at 120 ° C, and the reaction time was set at 8 hours. The stereoselectivity was (4S, 5R) :( 4S, 5S) = 90: 10, and the yield was 89%. Industrial applicability

According to the present invention, an optically active aminolactone derivative useful as a pharmaceutical intermediate and an optically active aminobutyric acid derivative as an intermediate thereof can be stereoselectively produced from commercially available raw materials in a small number of steps.

Claims

The scope of the claims

1. General formula (2)

(2)

(In the formula, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, and X represents halogen or hydrogen. An enolate prepared by reacting a low-valent metal or base with an acetic acid derivative represented by the following formula:

(Wherein, RRRRR ⁵ and * are the same as above). A method for stereoselectively producing an optically active aminobutyric acid derivative represented by the formula:

2. The production method according to claim 1, wherein an enolate prepared by reacting a low-valent metal with an acetic acid derivative in which X is a halogen in the general formula (2) is used.

3. The production method according to claim 2, wherein zero-valent zinc or zero-valent magnesium is used as the low-valent metal.

4. The production method according to claim 2, wherein X is bromine.

5. The method according to claim 1, wherein an enolate prepared by reacting a base with an acetic acid derivative in which X is a hydrogen atom in the general formula (2) is used.

6. The production method according to claim 5, wherein at least one selected from lithium diisopropylamide, lithium hexamethyldisilazide, and sodium hexamethyldisilazide is used as the base.

7. — General formula (4), G 0 ₂ R ⁵

r

C0 ₂ H (4) (wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms, or an aralkyl group having 7 to 18 carbon atoms. ) And a malonic acid derivative represented by the general formula (1)

(Wherein RR ² and RR ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, Reacting an optically active imine represented by the general formula (5)

(Wherein, RRR ³ , R ⁴ , R ⁵ , and * are the same as those described above), and are decarboxylated to obtain a compound of the general formula (3)

(Wherein, RR ² , RRR ⁵ , and * are the same as above) stereoselectively producing an optically active aminobutyric acid derivative represented by the formula:

8. The production method according to claim 7, wherein a carboxylic acid having 1 to 20 carbon atoms coexists during decarboxylation.

9. The process according to claim 8, wherein acetic acid is used as the carboxylic acid.

1 0. General formula (1)

(Wherein, I ¹ and RRR ⁴ independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, and * represents An optically active imine represented by the general formula (6) R ¹

(6)

(Wherein R R * is the same as described above) and the general formula (7) 0

R ³ 0 people

、, H

OR ⁴

(7)

(Wherein R ³ and R ⁴ are the same as described above). The process according to any one of claims 1 to 9, wherein a product obtained by dehydration condensation of a dialkoxyaldehyde represented by the following formula is used.

1 1. The production method according to any one of claims 1 to 10, wherein at least one of toluene and tetrahydrofuran is used as a reaction solvent.

12. The production method according to any one of claims ¹ to 11, wherein R1 is a methyl group.

13. The production method according to any one of claims 1 to 12, wherein R ² is a phenyl group.

Process according to any one of 14. R ³ and R ⁴ are each, range 1-1 3 according methyl or Echiru group.

1 5. Process according to any one of R. ⁵ force S tert-heptyl group range 1-14 claims is.

'

1 6. Process according to any range 1-1 5 according the configuration of the asymmetric carbon is formed by R ¹ and R ² are R.

17. The process according to any one of claims 1 to 16, wherein the (3S) form is stereoselectively produced as an optically active aminobutyric acid derivative.

1 8. General formula (1)

(Wherein, R ¹ represents an alkyl group having 1 to 18 carbon atoms, R ² represents an aryl group having 5 to 18 carbon atoms, and R ³ and R ⁴ each independently represent a C 1 to C 18 Represents an alkyl group, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, and * represents an asymmetric carbon atom.

19. The compound according to claim 18, wherein R ¹ is a methyl group.

20. The compound according to claim 18 or 19, wherein R ² is a phenyl group.

2 1. · R ³ and R ⁴ are each a compound according to any one of claims 1 8 to 20 according to a methyl group or Echiru group.

22. The compound according to any one of claims 18 to 21, wherein the configuration of the asymmetric carbon formed by R ¹ and R ² is R.

2 3. General formula (6)

R ¹

Hi ₂₂ rT, R2

(6) (Wherein, R ¹ represents an alkyl group having 1 to 18 carbon atoms, R ² represents an aryl group having 5 to 18 carbon atoms, and * represents an asymmetric carbon). And the general formula (7)

R ³

(Wherein, R ³ and R ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms) Dealkoxyaldehyde is dehydrated and condensed to give general formula (1)

(Wherein, RRR ³ , R ⁴ , and * are the same as described above).

24. The production method according to claim 23, wherein R ¹ is a methyl group.

25. The production method according to claim 23, wherein R ² is a phenyl group.

2 6. R ³ and R ⁴ are each, production method according to any one of claims 2 3-2 5 according a methyl group or Echiru group.

27. The process according to any one of claims 23 to 26, wherein the configuration of the asymmetric carbon formed by R ¹ and R ² is R.

2 8. General formula (3)

(Wherein, RR ² , R ³ and R ⁴ each independently represent an alkyl group having 1 to 18 carbon atoms, an aryl group having 5 to 18 carbon atoms or an aralkyl group having 7 to 18 carbon atoms, Table by R ⁵ represents a hydrogen atom, an alkyl group having 1 to 1 8 carbon atoms, were or Ariru group having a carbon number of 5 to 8 Ararukiru group having a carbon number of 7 to 8, and * represents an asymmetric carbon) The acid is acted on the optically active aminobutyric acid derivative or a salt thereof to be stereoselectively converted into a cyclized lactone to obtain a compound represented by the general formula (8)

(Wherein, RR ² , R ³ , and * are the same as described above).

29. The process according to claim 28, wherein the 3-position of the optically active aminobutyric acid derivative is S.

30. The process according to claim 28 or 29, wherein the configuration of the asymmetric carbon formed by R ¹ and R ² is R.

3 1. A process according to any one of the R \ R range 2 8-3 0 according at least one of which is Ariru group ^2.

3 2. Process according to any one of claims 2 8 and 3 1 according R ¹ is a methyl group.

33. The method according to any one of claims 28 to 32, wherein R ² is a phenyl group. -

34. The production method according to any one of claims 28 to 33, wherein R ³ and R ⁴ are each a methyl group or an ethyl group.

35. The production method according to any one of claims 28 to 34, wherein R ⁵ is a tert-butyl group.

36. The production method according to any one of claims 28 to 35, wherein the optically active amino ratatotone derivative formed by ratatonization has a (4S, 5R) -tetrahydrofuran-1-one skeleton.

37. The production method according to any one of claims 28 to 36, wherein toluene is used as a reaction solvent for ratatonization.

38. The production method according to any one of claims 28 to 37, wherein a sulfonic acid is used as the acid used in the ratatonization.

39. The production method according to claim 38, wherein methanesulfonic acid is used as the sulfonic acids.

40. The production method according to any one of claims 28 to 39, wherein the optically active aminobutyric acid derivative is used as a salt of p-toluenesulfonic acid.