JP2003327568A - METHOD FOR PRODUCING OPTICALLY ACTIVE beta-AMINO ACID DERIVATIVE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently, simply and profitably producing a β-amino acid derivative having a high optical purity. <P>SOLUTION: This method for producing the optically active β-amino acid derivative is characterized by preferentially crystallizing either one of the optical isomer salts of a β-amino acid derivative secondary amine salt represented by the general formula (1) from the solution of the optical isomers mixture, thereby obtaining the crystals excessively containing the optical isomer salt. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an optically active intermediate for pharmaceuticals, especially an interleukin-1β converting enzyme inhibitor (for example, Nature, 1992, 356, 76).
(Described on page 8) and a method for producing an optically active β-amino acid derivative useful as an intermediate. More specifically, the β-
The present invention relates to a method of preferentially crystallizing an optical isomer having a desired configuration from an optical isomer mixture of amino acid derivatives to obtain a crystal containing the optical isomer in excess.

[0002]

Conventionally, as a method for obtaining an optical isomer having any one configuration from an optical isomer mixture in an optically active β-amino acid derivative which is an important intermediate of an interleukin-1β converting enzyme inhibitor. Is obtained by Michael-adding optically active (R) -1-phenylethylamine to 5-ethoxy-2-furanone, and obtained in a ratio of 1: 1 (4S, 5S) -5-ethoxy-4-.
{[(1R) -1-Phenylethyl] amino} tetrahydrofuran-2-one, and (4R, 5R) -5-
A mixture of both optical isomers of ethoxy-4-{[(1R) -1-phenylethyl] amino} tetrahydrofuran-2-one is treated with trichloroacetic acid to form both optical isomers as trichloroacetate, and tert-butylmethyl From an ether solution from (4S, 5S) -5-ethoxy-4-{[(1
R) -1-Phenylethyl] amino} tetrahydrofuran-2-one trichloroacetate as crystallized and separated, and (4S, 5R) -5-ethoxy-4 present in a 90:10 ratio. -{[(1R) -1
-Phenylethyl] amino} tetrahydrofuran-2-
ON, and (4S, 5S) -5-ethoxy-4-
A mixture of both optical isomers of {[(1R) -1-phenylethyl] amino} tetrahydrofuran-2-one is caused to react with dichloroacetic acid to form both optical isomers as a dichloroacetic acid salt, and the mixture is obtained from a tert-butyl methyl ether solution ( 4S,
A method is known in which 5R) -5-ethoxy-4-{[(1R) -1-phenylethyl] amino} tetrahydrofuran-2-one dichloroacetate is crystallized and separated as crystals (WO9903852).

[0003]

However, the general formula (2), which is also an important optically active intermediate of interleukin-1β converting enzyme inhibitor and is described in Japanese Patent Application No. 2000-027908:

[0004]

[Chemical 3] (In the formula, R ¹ and R ² are independently an optionally substituted alkyl group having 1 to 18 carbon atoms, an optionally substituted aryl group having 6 to 18 carbon atoms, or an optionally substituted one. It represents an aralkyl group having 7 to 18 carbon atoms, R ³ and R ⁴ are independently, or R ³ and R ⁴ may be bonded to each other to form a ring, which may be substituted 1 to 1 carbon atoms. An alkyl group having 18 carbon atoms, an aryl group having 6 to 18 carbon atoms which may be substituted, or an aralkyl group having 7 to 18 carbon atoms which may be substituted, wherein R ⁵ is a hydrogen atom or may be substituted. Indicates an alkyl group having 1 to 18 carbon atoms, an optionally substituted aryl group having 6 to 18 carbon atoms, or an optionally substituted aralkyl group having 7 to 18 carbon atoms, * 1, * 2
In the compound represented by (1) and (2) each represent an asymmetric carbon atom, a method of obtaining a desired optical isomer from an optical isomer mixture containing two or more optical isomers is not known.

In view of the above situation, the present invention provides a method for producing a β-amino acid derivative which is efficient and economical and which can be industrially suitably carried out.

[0006]

Means for Solving the Problems The present inventors have completed the present invention as a result of earnest studies for solving the above problems. That is, the present invention has the general formula (2):

[0007]

[Chemical 4] (Wherein R ¹ , R 2, R 3, R ⁴ , R ⁵ * 1, and * 2 are the same as described above), which is formed from a β-amino acid derivative and an acid, the general formula (1):

[0008]

[Chemical 5] (In the formula, R ¹ , R 2, R 3, R ⁴ , R ⁵ * 1, and * 2 are the same as above, and A represents an anion component of the acid.) Β-amino acid derivative No. 2 A method of preferentially crystallizing a desired optical isomer salt from a solution of an optical isomer mixture containing two or more optical isomers of an amine salt to obtain crystals containing the optical isomer salt in excess. Is a method for producing a β-amino acid derivative. The β-amino acid derivative having an improved optical isomer ratio can be obtained by the method of the present invention.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

The β-amino acid derivative which is the starting material of the present invention has the general formula (2):

[0011]

[Chemical 6] Which is a compound represented by the Japanese Patent Application No. 2000-027908.
It can be produced by the method described in.

Where R¹, R²Are independently replaced
Optionally substituted alkyl group having 1 to 18 carbon atoms, substituted
Optionally substituted aryl group having 6 to 18 carbon atoms, or substituted
Is an aralkyl group having 7 to 18 carbon atoms
And is not particularly limited, for example, R¹age
Of these, an alkyl group is preferable, and a methyl group, an ethyl group,
Examples include propyl, isopropyl, butyl, etc.
You can Also, R ²For, an aryl group is preferred
Yes, phenyl group, paramethoxyphenyl group, naphthyl
A group etc. can be illustrated. In particular, R¹Is a methyl group
Yes, and R²Is most preferably a phenyl group.

R ³ and R ⁴ are independently, or may be an optionally substituted alkyl group having 1 to 18 carbon atoms, which R ³ and R ⁴ may bond to form a ring. C6-18 aryl group which may be present, or C7-18 aralkyl group which may be substituted is shown, and it is not particularly limited, and examples thereof include a methyl group, an ethyl group and a propyl group. Group, an alkyl group such as an isopropyl group, a phenyl group, a paramethoxyphenyl group, an aryl group such as a naphthyl group, and an aralkyl group such as a benzyl group. Further, R ³ and R ⁴ are bonded to form a ring. In the case where it is formed, for example, an ethylenedioxy group, a propylenedioxy group or the like can be exemplified as the partial structure containing two oxygen atoms. Of these, an alkyl group is preferable, and an ethyl group is particularly preferably used.

R ⁵ is a hydrogen atom, an optionally substituted alkyl group having 1 to 18 carbon atoms, an optionally substituted aryl group having 6 to 18 carbon atoms, or an optionally substituted carbon atom having 7 to 7 carbon atoms. 18 aralkyl groups are shown, but not particularly limited to, for example, a hydrogen atom, a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, t
Examples thereof include an alkyl group such as an ert-butyl group, a phenyl group, a paramethoxyphenyl group, an aryl group such as a naphthyl group, and an aralkyl group such as a benzyl group. Of these, a tert-butyl group is particularly preferably used.

In the general formula (2), * 1 and * 2 represent asymmetric carbon atoms. It is considered that four kinds of optical isomers are produced due to the presence of two asymmetric carbon atoms, but regarding the configuration of the asymmetric carbon atom of * 1, Compound (2) is described in Japanese Patent Application No. 2000-027908. By using an optically active amine (for example, (R) -phenethylamine) as a raw material during the production by the method of
It can also be fixed in one of the three-dimensional configurations. In this case, from the viewpoint of usefulness as an interleukin-1β converting enzyme inhibitor intermediate, the configuration of the asymmetric carbon atom of * 1 is R
The arrangement is preferred. When * 1 is fixed to R configuration, * 2
Two optical isomers, that is, (* 1, * 2) = (R, R) optical isomers, and (* 1, * 2) = (R, S) depending on the configuration of the asymmetric carbon atom of Gives an optical isomer of. In the present invention, from a mixture of these optical isomers,
The desired optical isomer can be preferentially obtained by the method described below.

Examples of the compound (2) which can be preferably used in the present invention include (3S) and (3R) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyric acid tert. -Butyl and the like can be mentioned.

In the present invention, in order to obtain a desired optical isomer from the above-mentioned optical isomer mixture of β-amino acid derivative, first, an acid is caused to act to form a β-amino acid derivative secondary amine salt, and the β By preferentially crystallizing any one of the optical isomer salts from a solution of the amino acid derivative secondary amine salt optical isomer mixture.

The acid to act is not particularly limited, but an organic acid is preferable, and an organic sulfonic acid, a benzoic acid derivative or an acetic acid derivative is particularly preferable. As the organic sulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, (+)-10-camphorsulfonic acid, paraethylbenzenesulfonic acid, 2,4,6-
Examples thereof include trimethylbenzenesulfonic acid, and examples of the benzoic acid derivative include 2,4-dinitrobenzoic acid, 3,4-dinitrobenzoic acid, and 3,5-dinitrobenzoic acid. , As acetic acid derivatives, trichloroacetic acid, dichloroacetic acid, monochloroacetic acid,
Examples thereof include trifluoroacetic acid, difluoroacetic acid, monofluoroacetic acid and the like. Particularly, benzenesulfonic acid, paratoluenesulfonic acid, (+)-10-camphorsulfonic acid, 3,5-dinitrobenzoic acid and trichloroacetic acid are preferably used.

In the present invention, since the β-amino acid derivative is a mixture of optical isomers, an optically inactive acid such as the above-mentioned benzenesulfonic acid, paratoluenesulfonic acid and 3,5-dinitrobenzoic acid is used. It is possible to separate the desired optical isomer salt as a crystal containing an excess of the isomer salt after forming a salt using, but it is possible to isolate the desired optical isomer salt as a crystal such as mandelic acid, tartaric acid or camphorsulfonic acid. Of the acids having isomers, it is of course possible to form a salt using an optically pure isomer and then separate the desired optical isomer salt as a crystal containing the isomer salt in excess. .

Of the acids used at this time, those acids which normally have water of crystallization in the molecule, such as benzene sulfonic acid and paratoluene sulfonic acid, may be allowed to form a salt with the β-amino acid derivative while containing water of crystallization. Good, after suspending these acids in a hydrocarbon solvent that is usually used for removing water by azeotropic distillation, such as toluene and benzene, and removing the water of crystallization by heating to make it an anhydrous state. Alternatively, a salt may be formed with the β-amino acid derivative.

The amount of the acid used to form these salts is not particularly limited, but it is usually sufficient if it is 0.7 to 1.2 equivalents relative to the β-amino acid derivative used.

As described above, a solvent is usually used when the acid is allowed to act to form the β-amino acid derivative secondary amine salt. The type of solvent is not particularly limited, but acetic acid esters such as methyl acetate, ethyl acetate, butyl acetate, and tert-butyl acetate, diethyl ether, diisopropyl ether, and tert-butyl ester.
Ethers such as butyl methyl ether, ketones such as acetone, methyl ethyl ketone and methyl vinyl ketone, nitriles such as acetonitrile and propionitrile, alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol and tert-butanol. , Aliphatic hydrocarbons such as pentane, hexane and heptane, alicyclic hydrocarbons such as cyclopentane and cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene and styrene, N, N-dimethylformamide Examples thereof include amides such as N, N-N-dimethylacetamide, and halogen-based solvents such as chloroform, dichloromethane, and 1,2-dichloroethane.

Of these solvents, hexane, toluene, heptane, or tert-butyl methyl ether can also serve as a solvent during the subsequent crystallization, and at least one of these can be used as a solvent. From the β-amino acid derivative secondary amine salt optical isomer mixture solution formed, β having the desired configuration
-Preferentially crystallizing the amino acid derivative secondary amine salt,
It can be obtained by solid-liquid separation. Among them, hexane, toluene, a mixed solvent of toluene and hexane, a mixed solvent of toluene and heptane, or a mixed solvent of tert-butyl methyl ether, toluene, and hexane is preferably used.

At this time, the concentration of the β-amino acid derivative secondary amine salt optical isomer mixture solution is not particularly limited, but is usually in the range of 0.5 to 50% by weight, and particularly preferably 0. A range of 5 to 30% by weight / volume is preferable.

In the present invention, the optical isomer salt having a desired configuration is preferentially crystallized from the β-amino acid derivative secondary amine salt optical isomer mixture solution prepared as described above. Preferential crystallization involves special handling if the desired optical isomer salt is present in excess over the other optical isomer salts in the β-amino acid derivative secondary amine salt optical isomer mixture solution. It can be preferably carried out without any addition, or can be carried out by adding a desired optical isomer salt as a seed crystal.

The method of the present invention comprises a second β-amino acid derivative
Although it is applicable to any optical isomer salt of an amine salt, from the viewpoint of its usefulness as an interleukin-1β converting enzyme inhibitor intermediate, as an optical isomer salt to be crystallized, (* 1, * 2) It is preferable that the configuration is (R, S).

When the β-amino acid derivative secondary amine salt optical isomer mixture solution is formed using the above-mentioned preferred organic acid and solvent, crystals are usually formed without any special operation. It is also possible to promote the precipitation and growth of crystals by adding a salt having the same configuration as the desired configuration as a seed crystal as described above or by cooling.

The crystals precipitated from the solution can be easily obtained by a commonly used solid-liquid separation method such as filtration. The obtained crystal can be used as it is in the next reaction, or can be further recrystallized by the method of the present invention to further increase the purity of the optical isomer of the β-amino acid derivative.

[0029]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

(Example 1) (3S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino having a de (diastereomeric excess) at the 3-position of 44% de } After adding 633 mg of 3,5-dinitrobenzoic acid to a mixed solution of 4 g of tert-butyl methyl ether and 4 ml of toluene of 1.0 g of tert-butyl butyrate, it was diluted with 12.5 ml of hexane and prepared in Reference Example 4. The seed crystal was added and stirred at room temperature for 10 minutes. After cooling to 0 ° C. and aging for 30 minutes with stirring, the crystals formed were filtered off and found to be 92% de, (3S) -4,4.
A white crystal of 844 mg (73% recovery) of tert-butyl 3,5-dinitrobenzoate of -diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate was obtained. de is an HPLC analysis (column: Deverosi
l ODS-HG-3, eluent: acetonitrile / 0.
01M acetate buffer = 50/50, temperature 40 ° C., detection wavelength: 220 nm, (3S) isomer = about 32 minutes, (3R)
Isomer = about 40 minutes) and the recovery rate is (3S)-
4,4-Diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate tert-butyl 3,5-dinitrobenzoate as a high-purity product, the content of (3S) form Was determined as a standard. In addition, ¹ H-N of the obtained salt
The main peak of MR is ¹ H-of the high-purity product shown in Reference Example 4.
Consistent with that of NMR.

(Example 2) (3S) -4,4-diethoxy-3-{[(1R)-, in which de at the 3-position is 44% de
To a mixed solution of 1.0 g of tert-butyl 1-phenylethyl] amino} butyrate and 6 ml of tert-butyl methyl ether and 10 ml of toluene was added 433 mg of paratoluenesulfonic acid monohydrate, and then 25 m of hexane was added.
After diluting with 1, the seed crystal prepared in Reference Example 2 was added, and the mixture was stirred at room temperature for 10 minutes. After cooling to 10 ° C. and aging for 30 minutes with stirring, the crystals formed were filtered off.
% De, (3S) -4,4-diethoxy-3-
{[(1R) -1-phenylethyl] amino} butyric acid te
rt-Butyl paratoluenesulfonic acid monohydrate salt 68
5 mg (59% recovery) of white crystals were obtained. de is obtained in the same manner as in Example 1, and the recovery rate is (3S) -4,4-
Diethoxy-3-{[(1R) -1-phenylethyl]
A high-purity product of tert-butyl aminobutyrate / paratoluenesulfonic acid monohydrate salt was used as a standard product, and the content of the (3S) form was determined as a standard. In addition, ¹ H-NM of the obtained salt
The main peak of R is ¹ H-N of the high-purity product shown in Reference Example 2.
It coincided with that of MR.

Example 3 Paratoluenesulfonic acid 43
A suspension of 8 mg of toluene in 4 ml of de at the 3rd position is 44%.
(3S) -4,4-diethoxy-3-, which is de
{[(1R) -1-phenylethyl] amino} butyric acid te
A solution of 1.0 g of rt-butyl in 5 ml of tert-butyl methyl ether was added, diluted with 20 ml of hexane, the seed crystal prepared in Reference Example 2 was added, and the mixture was stirred at room temperature for 10 minutes. After cooling to 0 ° C. and aging for 30 minutes with stirring, the crystals formed were filtered off and found to be 96% de: (3S) -4,4-diethoxy-3-{[(1R)
866 mg (81% recovery) of white crystals of tert-butyl para-1-toluenesulfonate -1-phenylethyl] amino} butyrate were obtained. de was obtained in the same manner as in Example 1, and the recovery rate was (3S) -4,4-diethoxy-3-.
{[(1R) -1-phenylethyl] amino} butyric acid te
A high-purity rt-butyl paratoluenesulfonic acid monohydrate salt was used as a standard, and the content of the (3S) isomer was determined as a standard. The main peak of ¹ H-NMR of the obtained salt is
This was in agreement with that of the ¹ H-NMR of the high purity product shown in Reference Example 2.

Example 4 Benzenesulfonic acid 405 m
g in toluene 5 ml suspension, the 3rd de is 44% de
(3S) -4,4-diethoxy-3-{[(1
R) -1-Phenylethyl] amino} butyric acid tert-butyl 1.0 g, tert-butyl methyl ether 5 m
After adding 1 l solution, the mixture was diluted with 15 ml of hexane, the seed crystal prepared in Reference Example 3 was added, and the mixture was stirred at room temperature for 10 minutes.
After cooling to 0 ° C. and aging for 30 minutes with stirring, the crystals formed were filtered off and found to be 90% de (3
698 mg (64% recovery) of white crystals of tert-butyl benzenesulfonate of S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate were obtained. de was obtained in the same manner as in Example 1, and the recovery rate was (3S) -4,4-diethoxy-3-{[(1R) -1.
-Phenylethyl] amino} butyric acid tert-butyl benzenesulfonic acid monohydrate high-purity product as a standard,
The content of the (3S) form was determined as a standard. Further, the main peak of ¹ H-NMR of the obtained salt coincided with that of ¹ H-NMR of the highly purified product prepared in Reference Example 3.

(Example 5) (3S) -4,4-diethoxy-3-{[(1R)-, in which de at the 3-position is 44% de
To a mixed solution of 1.0 g of tert-butyl 1-phenylethyl] amino} butyrate and 1 ml of toluene and 10 ml of hexane, (+)-10-camphorsulfonic acid 59 was added.
After adding 4 mg, toluene 4 ml and hexane 10
Crystals formed when diluted with ml. After stirring at room temperature for 10 minutes, the mixture was cooled to 0 ° C. and aged while stirring for 20 minutes. When the crystals were separated by filtration, it was 94% de, (3
S) -4,4-Diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate tert-butyl. (+)
1050 mg of -10-camphor sulfonate (88%
(Yield) white needle crystals were obtained. de was obtained in the same manner as in Example 1, and the recovery rate was (3S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate tert-butyl. (+)-10. -A high-purity camphorsulfonate salt was used as a standard, and the content of the (3S) form was used as a standard. The main peak of ¹ H-NMR of the obtained salt, ¹ H-NMR of high purity was prepared in Reference Example 6
It coincided with that.

(Example 6) (3S) -4,4-diethoxy-3-{[(1R)-in which de at the 3-position is 44% de
After adding 418 mg of trichloroacetic acid to a solution of 1.0 g of tert-butyl 1-phenylethyl] amino} butyrate in hexane, 418 mg of trichloroacetic acid was added, and the mixture was diluted with 5 ml of hexane, and the seed crystal prepared in Reference Example 5 was added. Crystals formed when cooled to. Further dilute with 10 ml of hexane,
After cooling to 10 ° C, the mixture was aged with stirring for 10 minutes.
The crystals were separated by filtration and found to be 98% de, (3S)-
White crystals of tert-butyl trichloroacetate 4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyric acid 514 mg (49% recovery) were obtained. d
e was obtained in the same manner as in Example 1, and the recovery rate was (3S)-
4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyric acid tert-butyl trichloroacetate as a high-purity product was used as a standard, and the content of the (3S) form was used as a standard. . Further, the main peak of ¹ H-NMR of the obtained salt coincided with that of ¹ H-NMR of the highly purified product prepared in Reference Example 5.

Example 7 Paratoluenesulfonic acid 3.
88 g of toluene 32.5 ml and hexane 10 ml
In the mixed suspension of, the 3rd de is 48% de (3
S) -4,4-Diethoxy-3-{[(1R) -1-phenylethyl] amino} tert-butyl butyrate 7.56
A solution of 20 g of hexane in 20 g was added, and the seed crystal prepared in Reference Example 2 was added, whereby crystals were formed. 67.5 ml of hexane was added dropwise over 1 hour with stirring at room temperature, cooled to 0 ° C., and aged with stirring for 30 minutes. The crystals were separated by filtration and found to be 99.2% de, (3S)
-4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate tert-butyl paratoluenesulfonate 6.17 g (77% recovery) of slightly yellowish white crystals were obtained. de was obtained in the same manner as in Example 1, and the recovery rate was (3S) -4,4-diethoxy-3-{[(1R)
A highly pure product of tert-butyl 1-phenylethyl] amino} butyrate / toluenesulfonic acid monohydrate salt was obtained as a standard product. Further, the main peak of ¹ H-NMR of the obtained salt coincided with that of ¹ H-NMR of the highly purified product prepared in Reference Example 2.

(Example 8) (3S) -4,4-diethoxy-3-{[(1R)-, wherein de at the 3-position is 46% de
1-Phenylethyl] amino} butyrate tert-butyl 1
8.34 g of toluene 30 ml and heptane 80 m
To the mixed solution of 1 was added a solution of 8.88 g of para-toluene sulfonic anhydride heated at 50 ° C. in 50 ml of toluene, and the seed crystal prepared in Reference Example 2 was added, whereby crystals were formed. 100 ml of heptane was added dropwise over 1 hour and 20 minutes with stirring at room temperature, then cooled to 0 ° C., and aged with stirring for 1 hour. When the crystals were separated by filtration, 94% de
Is (3S) -4,4-diethoxy-3-{[(1
R) -1-Phenylethyl] amino} butyrate tert-butyl paratoluenesulfonate 15.7 g (79% recovery) of slightly yellowish white crystals were obtained. de was obtained in the same manner as in Example 1, and the recovery rate was (3S) -4,4-diethoxy-.
A highly purified product of tert-butyl toluenesulfonic acid monohydrate salt of 3-{[(1R) -1-phenylethyl] amino} butyrate was determined as a standard. In addition, ¹ H-of the obtained salt
The main peak of NMR is the high-purity product prepared in Reference Example 2.
Consistent with that of ¹ H-NMR.

(Example 9) (3R) -4,4-diethoxy-3-{[(1R)-, in which de at the 3-position is 46% de
1-phenylethyl] amino} butyric acid tert-butyl 1.18 g, tert-butyl methyl ether 5 ml
To a mixed solution of 2.5 ml of toluene and toluene, 690 mg of 3,5-dinitrobenzoic acid was added, and then hexane 16
Diluted with ml. When the seed crystal prepared in Reference Example 7 was added thereto, crystals were formed. After stirring for 10 minutes at room temperature,
The mixture was cooled to 0 ° C. and aged with stirring for 20 minutes. The reaction solution was diluted with a mixed solution of 5 ml of tert-butyl methyl ether, 4 ml of toluene and 40 ml of hexane, and the crystals were separated by filtration to find that it was 96% de, (3R)-.
Tert-Butyl 4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate 3,5-dinitrobenzoate 878 mg (66% recovery) of white crystals were obtained. de was obtained in the same manner as in Example 1, and the recovery rate was (3R) -4,4-diethoxy-3-{[(1R) -1.
-Phenylethyl] amino} butyrate tert-butyl
A high-purity 3,5-dinitrobenzoate is used as a standard,
It was determined based on the content of the (3R) form. Further, the main peak of ¹ H-NMR of the obtained salt coincided with that of ¹ H-NMR of the highly purified product prepared in Reference Example 7.

Reference Example 1 Japanese Patent Application No. 2000-027908
According to the method described in (3S) -4,4-diethoxy-
67 g (86% yield, 46% de) of tert-butyl 3-{[(1R) -1-phenylethyl] amino} butyrate was obtained. The yield was determined using a highly pure product of (3S)-and (3R) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate tert-butyl.
Part of the silica gel column chromatography (Wako
gel C-200, 2000 g, developing solvent; hexane / ethyl acetate = 80/20) and purified (3S)
Tert-butyl -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate 10.8 g,
And (3R) -4,4-diethoxy-3-{[(1
There was obtained 4.3 g of tert-butyl R) -1-phenylethyl] amino} butyrate.

Reference Example 2 (3S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino}
After adding 216 mg of paratoluenesulfonic acid monohydrate to a solution of tert-butyl butyrate (500 mg) in tert-butyl methyl ether (2.5 ml), toluene (10.5) was added.
When diluted with 2 ml of hexane and 22.5 ml of hexane and cooled to -20 ° C, (3S) -4,4-diethoxy-3-
{[(1R) -1-phenylethyl] amino} butyric acid te
rt-butyl paratoluenesulfonic acid monohydrate salt 6
00 mg (98% recovery) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ1.14 (6H, q, J =
6.8 Hz), 1.44 (9 H, s), 1.83 (3
H, d, J = 8.0 Hz), 2.36 (3H, s),
2.70 (1H, dd, J = 6.8, 17.6Hz),
2.91 (1H, dd, J = 4.4, 17.6Hz),
3.34 (1H, brs), 3.50 to 3.66 (4
H, m), 4.53 (1H, brs), 4.76 (1
H, d, J = 5.2 Hz), 7.17 (2H, d, J =
7.6 Hz), 7.35 to 7.52 (5H, m), 7.
78 (2H, d, J = 7.6 Hz).

Reference Example 3 (3S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino}
To a solution of tert-butyl butyrate (200 mg) in tert-butyl methyl ether (1 ml) was added benzenesulfonic acid monohydrate (80 mg), the mixture was diluted with toluene (5 ml) and hexane (2 ml) and cooled to -20 ° C.
S) -4,4-Diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate tert-butyl benzenesulfonic acid monohydrate salt was obtained as 190 mg (64% recovery) as white crystals. Was given. ¹ H-NMR (CDCl ₃ ) δ1.14 (6H, q, J =
6.0 Hz), 1.44 (9 H, s), 1.83 (3
H, d, J = 6.8 Hz, 2.70 (1H, dd, J
= 6.4, 17.6 Hz), 2.91 (1H, dd, J
= 5.2, 17.6 Hz), 3.33 (1H, m),
3.50 to 3.66 (4H, m), 4.53 (1H,
m), 4.76 (1H, d, J = 5.2Hz), 7.3
7 to 7.49 (7H, m), 7.89 to 7.91 (3
H, m).

Reference Example 4 (3S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino}
After adding 200 mg of 3,5-dinitrobenzoic acid to a solution of tert-butyl butyrate 400 mg in tert-butyl methyl ether 2.5 ml, the mixture was diluted with toluene 9 ml and hexane 12 ml and allowed to stand at room temperature.
S) -4,4-Diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate tert-butyl-3,5
-340 mg of dinitrobenzoate (65% recovery),
Obtained as white needle crystals. ¹ H-NMR (CDCl ₃ ) δ1.13 (3H, t, J =
6.8 Hz), 1.16 (3H, t, J = 6.8H)
z), 1.46 (9H, s), 1.71 (3H, d, J
= 6.8 Hz), 2.66 (1H, dd, J = 6.8,
16.8 Hz), 2.82 (1H, dd, J = 5.6H)
z, 16.8 Hz), 3.29 (1H, m), 3.38.
-3.62 (4H, m), 4.39 (1H, q, J =
6.8Hz), 4.57 (1H, d, J = 4.8H
z), 7.35 (1H, m), 7.42 (2H, t, J
= 6.8 Hz), 7.48 (2H, d, J = 6.8H)
z), 9.13 (1H, t, J = 2.4 Hz), 9.2.
2 (2H, d, J = 2.4 Hz).

Reference Example 5 (3S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino}
After adding 74 mg of trichloroacetic acid to a 10 ml solution of tert-butyl butyrate 200 mg in hexane, the temperature is -30 ° C.
When cooled to (3S) -4,4-diethoxy-3
-{[(1R) -1-phenylethyl] amino} butyric acid t
70 mg of ert-butyl trichloroacetate (30%
It was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ1.17 (6H, m),
1.45 (9H, s), 1.79 (3H, d, J = 6.
8 Hz), 2.68 (1H, dd, J = 7.2, 17.
2 Hz), 2.90 (1H, dd, J = 4.4, 17.
2 Hz), 3.33 (1 H, m), 3.47 to 3.66.
(4H, m), 4.51 (1H, q, J = 6.8H
z), 4.69 (1H, d, J = 4.4 Hz), 7.4
0 to 7.48 (5H, m).

Reference Example 6 (3S) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino}
A solution of 200 mg of tert-butyl butyrate in 10 ml of hexane was added with 106 mg of (+)-10-camphorsulfonic acid.
Was added and then cooled to -20 ° C, (3S)-
Tert-Butyl 4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino} butyrate. (+)-10
-153 mg (42% recovery) of camphor sulfonate was obtained as white needle crystals. ¹ H-NMR (CDCl ₃ ) δ 0.82 (3H, s),
1.08 (3H, s), 1.18 (6H, q, J = 7.
0Hz), 1.33 (1H, m), 1.46 (9H,
s), 1.69 (1H, septet, J = 4.8H)
z), 1.83 (3H, d, J = 6.8Hz), 1.9.
4 to 2.07 (3H, m), 2.28 (1H, brd,
J = 18.0 Hz), 2.64 (1H, m), 2.76
(1H, dd, J = 6.0, 17.6Hz), 2.85
(1H, d, J = 14.6Hz), 2.92 (1H, d
d, J = 5.2, 17.6 Hz), 3.25 (1H,
d, J = 14.6 Hz), 3.37 (1H, brs),
3.58 to 3.72 (4H, m), 4.58 (1H, b
rs), 4.88 (1H, d, J = 5.8Hz), 7.
39 to 7.46 (3H, m), 7.50 to 7.52 (2
H, m).

Reference Example 7 (3R) -4,4-diethoxy-3-{[(1R) -1-phenylethyl] amino}
After adding 100 mg of 3,5-dinitrobenzoic acid to a solution of tert-butyl butyrate 200 mg in tert-butyl methyl ether 1.5 ml, the mixture was diluted with toluene 1 ml and hexane 7 ml and cooled to -20 ° C.
(3R) -4,4-diethoxy-3-{[(1R) -1
-Phenylethyl] amino} butyrate tert-butyl
200 mg (56% recovery) of 3,5-dinitrobenzoate was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ1.21 (3H, t, J =
6.8 Hz), 1.29 (3H, t, J = 6.8H
z), 1.40 (9H, s), 1.69 (3H, d, J
= 6.8 Hz), 2.55 (1H, dd, J = 6.4,
16.4 Hz), 2.76 (1H, dd, J = 6.8,
16.4 Hz), 3.30 (1H, m), 3.52
3.82 (4H, m), 4.63 (1H, q, J = 6.
8 Hz), 4.75 (1 H, d, J = 4.4 Hz),
7.37 (1H, m), 7.42 (2H, t, J = 7.
2Hz), 7.51 (2H, d, J = 7.2Hz),
9.11 (1H, t, J = 2.4Hz), 9.23 (2
H, d, J = 2.4 Hz).

[0046]

Industrial Applicability According to the method of the present invention, an acid is allowed to act on a solution of a β-amino acid derivative optical isomer mixture,
-By solid-liquid separation of any one of the optical isomer salts from the solution of the amino acid derivative secondary amine salt optical isomer mixture as crystals containing the optical isomer salt in excess, from the optical isomer salt mixture solution. , For producing intermediates such as medicines, especially interleukin-1β converting enzyme inhibitors,
A β-amino acid derivative having a high optical purity can be produced efficiently, conveniently, and industrially advantageously.

Claims (13)

[Claims] 1. The following general formula (1): (In the formula, R ¹ and R ² are independently an optionally substituted alkyl group having 1 to 18 carbon atoms, an optionally substituted aryl group having 6 to 18 carbon atoms, or an optionally substituted one. It represents an aralkyl group having 7 to 18 carbon atoms, R ³ and R ⁴ are independently, or R ³ and R ⁴ may be bonded to each other to form a ring, which may be substituted 1 to 1 carbon atoms. An alkyl group having 18 carbon atoms, an aryl group having 6 to 18 carbon atoms which may be substituted, or an aralkyl group having 7 to 18 carbon atoms which may be substituted, wherein R ⁵ is a hydrogen atom or may be substituted. Represents an alkyl group having 1 to 18 carbon atoms, an optionally substituted aryl group having 6 to 18 carbon atoms, or an optionally substituted aralkyl group having 7 to 18 carbon atoms, and A represents an anion component of an acid. , * 1 and * 2 each represent an asymmetric carbon atom) -A crystal containing any one optical isomer salt preferentially crystallized from a solution of an optical isomer mixture containing two or more optical isomers of the amino acid derivative secondary amine salt, and containing the optical isomer in excess. And a method for producing an optically active β-amino acid derivative. 2. A solution of an optical isomer of a β-amino acid derivative secondary amine salt represented by the general formula (1) is represented by the following general formula (2): An optical isomer mixture containing two or more optical isomers of the β-amino acid derivative represented by the formula (wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , * 1, and * 2 are the same as above). The method according to claim 1, wherein the solution is formed by reacting an acid with the solution. 3. The production method according to claim 1, wherein the acid forming the β-amino acid derivative secondary amine salt is an organic acid. 4. The method according to claim 3, wherein the organic acid is an organic sulfonic acid, a benzoic acid derivative or an acetic acid derivative. 5. The organic acid is benzenesulfonic acid, paratoluenesulfonic acid, (+)-10-camphorsulfonic acid,
The production method according to claim 9, which is 3,5-dinitrobenzoic acid or trichloroacetic acid. 6. The production method according to claim 1, wherein at least one of hexane, toluene, heptane, and tert-butyl methyl ether is used as a crystallization solvent. 7. In the crystallization, a solution of a β-amino acid derivative secondary amine salt containing two or more optical isomers is added as a seed crystal with an optical isomer salt having any one configuration, The production method according to claim 1, wherein the optical isomer salt having the same configuration as the added seed crystal is preferentially crystallized. 8. An optical isomer which is present in excess of other optical isomers in a mixture of optical isomers of a β-amino acid derivative secondary amine salt is preferentially crystallized. 7. The manufacturing method according to any one of to 7. 9. The production method according to claim 1, wherein R ¹ is a methyl group and R ² is a phenyl group. 10. R ¹ and R ⁴ are ethyl groups.
9. The manufacturing method according to any one of 9. 11. The production method according to claim 1, wherein R ⁵ is a tert-butyl group. 12. The production method according to claim 1, wherein the configuration of the asymmetric carbon atom of * 1 is R. 13. The production method according to claim 1, wherein the configuration of the asymmetric carbon atom of * 2 is S.