RU2305677C2 - Methods for preparing glutamic acid derivatives, methods for preparing intermediates, and a novel intermediate for given methods - Google Patents

Abstract

FIELD: organic synthesis.

SUBSTANCE: invention claims a method for preparing glutamic acid derivatives having general formula (7):

in particular such as monatin:

(radicals in the formulas are specified in description), for use as sweeteners or intermediates for production of drugs and the like. A method for preparing intermediates used in above method, including preparation of novel intermediates, is also claimed. Method of preparing optically active monatin and relevant intermediates also includes preparation of novel intermediates. More specifically, a method for preparing glutamic acid derivatives or salts thereof comprises preparation of a ketoglutaric acid derivative as precursor of desired glutamic acid derivative via aldol cross-condensation of a pyruvic acid derivative with oxaloacetic acid or pyruvic acid and, if necessary, decarboxylation of condensation product and replacement of carbonyl group of ketoglutaric acid derivative by amino group.

EFFECT: expanded synthetic possibilities in amino acid derivatives class.

24 cl, 26 ex

Description

Technical field

This invention relates to methods for producing glutamic acid derivatives, typically comprising monatin, which are useful as intermediates for the manufacture of sweeteners or pharmaceutical products, as well as for the manufacture of intermediates for these methods, including an important new intermediate. More specifically, the invention relates to an effective method for producing glutamic acid derivatives in the industry, a method for preparing intermediates for this, including a new intermediate, a method for producing optically active monatin, a method for preparing intermediates for this method, including a new intermediate, and the like .

State of the art

Glutamic acid derivatives, typically including monatin, are compounds that are promising for use as sweeteners or for the manufacture of intermediates for pharmaceutical products and the like. For example, it is known that 4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid (3- (1-amino-1,3-dicarboxy-3-hydroxybutan-4-yl) indole, sometimes called "monatin" further in this description), represented by formula (7 '), in the (2S, 4S) form is contained in the roots of the plant Schlerochiton ilicifolius and has a sweetness that is several hundred times higher than the sweetness of sucrose (see JP-A-64-25757 (US patent No. 4975298))

In this description, the term "monatin" is not limited only to the natural (2S, 4S) form, but is also used as the generic name 4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid (3- (1-amino-1 , 3-dicarboxy-3-hydroxybutan-4-yl) indole), including individual isomers in the forms (2S, 4S), (2S, 4R), (2R, 4S) and (2R, 4R).

There are the following reports on methods for producing monatin (the following examples (2) to (5)) and protected monatin (the following example (1)).

(1) The method described in Tetrahedron Letters, 2001, Vol. 42, No. 39, pp. 6793-6796

(2) The method described in Organic Letters, 2000, Vol. 2, No. 19, pp. 2967-2970

(3) The method described in US patent 5994559

(4) The method described in Synthetic Communications, 1994, Vol. 24, No. 22, pp. 3197-3211

and

(5) The method described in Synthetic Communications, 1993, Vol. 23, No. 18, pp. 2511-2526 and US patent No. 4975298 and No. 5128164

Since any of these methods consists of several stages, their introduction into the industry is really associated with many difficulties. Some of the works cited above or other references (see T. Kitahara, et al., Japanese Agrochemical Association, the 2000th Conference, Abstracts of Proceedings, 3B128β (p.221)) describe an analysis of methods for producing optically active monatin . It is disadvantageous, however, that the methods consist of many stages and include stages that are very difficult to carry out practically in industry. Thus, there is a need to develop an effective industrial process for the preparation of glutamic acid derivatives, typically comprising monatin, in particular, an efficient industrial process for the preparation of optically active monatin.

Disclosure of invention

Object of the invention

This invention should solve the following problems: to propose methods for the efficient production in the industry of glutamic acid derivatives, usually including monatin, and to obtain intermediates (including salts) for these methods, and to provide important intermediates for these methods. More specifically, the present invention provides an effective method for the production of glutamic acid derivatives in the industry, a method for preparing intermediates for this, including a new important intermediate, a method for producing optically active monatin and a method for preparing intermediates for this, and a new important intermediate for this method.

Means for solving problems

To solve these problems, the inventors conducted a number of studies. The authors found that glutamic acid derivatives, usually including monatin (including salts), can be efficiently prepared by cross-aldol condensation of a particular pyruvic acid derivative with oxalic acetic acid or pyruvic acid, which gives ketoglutaric acid derivatives as precursors of the target derivatives glutamic acid, and the subsequent conversion of the carbonyl group of the obtained ketoglutaric acid derivatives to an amino group.

In the case of aldol condensation with carbonyl compounds of various types, as in the present invention, usually four types of products are formed in the mixture due to the actual aldol condensation of compounds of the same type and the cross aldol condensation of compounds of different types. Although aldol condensation of oxalic acetic acid (Journal of Organic Chemistry, 1973, Vol. 38, No. 20, pp. 3582-3585) or pyruvic acid (Journal of American Chemical Society, 1964, Vol. 86, pp. 2805-2810 ; Analytical Chemistry, 1986, Vol. 58, No. 12, pp. 2504-2510) is already known as cross-aldol condensation in a system containing a carbonyl compound that does not condense by itself, such as, for example, glyoxylic acid or oxalic acetic acid, so that it is relatively easy to obtain a single product (Tetrahedron Letters, 1987, Vol. 28, pp. 1277-1280), there are no reports of any example the objective of obtaining the only cross-aldol condensation product of oxalic acetic acid or pyruvic acid with pyruvic acid derivatives.

In addition, the inventors of the present invention found that optically active monatin can be obtained by reacting a glutaric acid derivative of formula (9) with a specific optically active amine, which leads to the formation of a diastereoisomeric salt, followed by crystallization and isolation of the resulting diastereoisomeric salt, further dissociation of this diastereoisomeric salt by exchanging the diastereoisomeric salt with another salt to obtain an optically active glutaric acid derivative, followed by alkoxyim conversion the other group (or hydroxyimino group) of the diastereoisomeric salt or the optically active glutaric acid derivative into an amino group, by crystallization of the obtained monatin represented by the formula (13) below (racemate at the 2-position), in a mixed solvent consisting of water and an organic solvent.

Based on the numerous data described above, the objectives of the present invention have ultimately been successfully solved.

In other words, the present invention includes inventions related to the following preparation methods from [1] to [23] and to a new compound [24] in their separate various variants.

[1] A method for producing glutamic acid derivatives represented by formula (7) or salts thereof, comprising the step of cross-aldolically condensing a pyruvic acid derivative represented by formula (1) and oxalic-acetic acid represented by formula (2) and decarboxylation, or cross-aldol condensation of a pyruvic acid derivative (except pyruvic acid) and pyruvic acid represented by the formula (2 ') to obtain a ketoglutaric acid derivative represented by the formula (4) or a salt thereof, and a step of converting the carbonyl group of the ketoglutaric acid or a salt thereof to an amino group, wherein the derivative of pyruvic acid, oxaloacetic acid, pyruvic acid, can individually be in the form of their salts

where in the above formulas, R ¹ represents a group selected from alkyl groups, aryl groups, aralkyl groups and hydrocarbon groups containing a heterocycle; and R ¹ may have at least one substituent selected from halogen atoms, a hydroxyl group, alkyl groups with 1-3 carbon atoms, alkoxy groups with 1-3 carbon atoms and an amino group.

[2] The method as described above in [1], wherein the step of converting the carbonyl group of the ketoglutaric acid derivative represented by formula (4) or a salt thereof to an amino group comprises the step of reacting an amino compound represented by formula (5) or a salt thereof with a ketoglutaric acid derivative or a salt thereof to produce a glutaric acid derivative represented by the formula (6), or a salt thereof, and a step for reducing the resulting glutaric acid derivative or a salt thereof :

where in the above formulas, R ¹ represents a group selected from alkyl groups, aryl groups, aralkyl groups and hydrocarbon groups containing a heterocycle; R ² represents a hydrogen atom or a group selected from alkyl groups, aryl groups, aralkyl groups; and R ¹ may have at least one substituent selected from halogen atoms, a hydroxyl group, alkyl groups containing from 1 to 3 carbon atoms, alkoxy groups containing from 1 to 3 carbon atoms, and an amino group.

[3] The method as described above in [1], wherein the step of converting the carbonyl group of the ketoglutaric acid derivative represented by formula (4) or a salt thereof into an amino group includes the step of reductively aminating the ketoglutaric acid derivative or its salt.

[4] The method as described in [1] to [3], wherein the cross-aldol condensation is carried out in a pH range of 10 to 14.

[5] A method for producing a ketoglutaric acid derivative represented by the formula (4) or a salt thereof, comprising the step of cross-aldolically condensing a pyruvic acid derivative of the formula (1) shown below and oxalic-acetic acid represented by the formula (2) and decarboxylation, or cross-aldol condensation of a pyruvic acid derivative of the formula (1), (except pyruvic acid) with pyruvic acid represented by the formula (2 '), wherein the pyruvic acid derivative is oxalic-acetic acid I acid and pyruvic acid can individually be in the form of corresponding salts

where in the above formulas, R ¹ represents a group selected from alkyl groups, aryl groups, aralkyl groups and hydrocarbon groups containing a heterocycle; and R ¹ may have at least one substituent selected from halogen atoms, a hydroxyl group, alkyl groups with 1 to 3 carbon atoms, alkoxy groups with 1 to 3 carbon atoms, and an amino group.

[6] The method as described above in [5], wherein the cross-aldol condensation is carried out in a pH range of 10 to 14.

[7] A method for producing a glutamic acid derivative represented by the formula (7) below, or a salt thereof, comprising the step of reacting a ketoglutaric acid derivative represented by the formulas below (4) or a salt thereof with an amino compound represented by the formula (5) below or a salt thereof , to obtain a glutaric acid derivative represented by the formula (6) below, or a salt thereof, and a step for reducing a glutaric acid derivative or a salt thereof obtained

where in the above formulas, R ¹ represents a group selected from alkyl groups, aryl groups, aralkyl groups and hydrocarbon groups containing a heterocycle ; R ² represents a hydrogen atom or a group selected from alkyl groups, aryl groups and aralkyl groups; and R ¹ may contain at least one substituent selected from halogen atoms, a hydroxyl group, alkyl groups containing 1-3 carbon atoms, alkoxy groups containing 1-3 carbon atoms, and an amino group.

[8] A method for producing a glutamic acid derivative represented by the formula (7) or a salt thereof, comprising the step of reductively aminating a ketoglutaric acid derivative represented by the formula (4) or a salt thereof:

where in the above formulas, R ¹ represents a group selected from alkyl groups, aryl groups, aralkyl groups and hydrocarbon groups containing a heterocycle; and R ¹ may contain at least one substituent selected from halogen atoms, a hydroxyl group, alkyl groups containing 1-3 carbon atoms, alkoxy groups containing 1-3 carbon atoms, and an amino group.

[9] A method for producing monatin, represented by the formula (7 ') below, or a salt thereof, comprising the step of aldol condensing indole-3-pyruvic acid of formula (1') and oxalic-acetic acid of formula (2) and decarboxylation, or cross-aldol condensation indole-3-pyruvic acid of formula (1 ') and pyruvic acid of formula (2') to produce 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by formula (4 '), or a salt thereof, and the stage of conversion of the carbonyl group of ketoglutaric acid or its salt into an amino group where indole-3-pyruvic acid, oxalic-acetic acid and pyruvic acid may individually be in the form of their salts:

[10] The method as described above in [9], wherein the step of converting the carbonyl group of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by the formula (4 '), or a salt thereof into an amino group includes a reaction step an amino compound of formula (5) or a salt thereof with ketoglutaric acid or a salt thereof to produce a glutaric acid derivative represented by the formula (6 ') or a salt thereof and a step for reducing a glutaric acid derivative or a salt thereof:

where in the formula R ² represents a hydrogen atom or a substituent selected from alkyl groups, aryl groups and aralkyl groups.

[11] The method as described above in [9], wherein the step of converting the carbonyl group of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by formula (4 ') or a salt thereof into an amino group includes the step reductive amination of a ketoglutaric acid derivative or a salt thereof.

[12] The method as described above in [9] - [11], where the cross-aldol condensation is carried out in the pH range from 10 to 14.

[13] A method for producing 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by the formula (4 '), or a salt thereof, comprising the step of cross-aldol condensation of indole-3-pyruvic acid of the formula (1') and oxalic acetic acid of formula (2) and decarboxylation, or aldol condensation of indole-3-pyruvic acid of formula (1 ') and pyruvic acid of formula (2'), where indole-3-pyruvic acid, oxalic acetic acid and pyruvic acid separately be in the form of the corresponding salt

[14] The method as described in [13], wherein cross-aldol condensation is carried out in a pH range of 10 to 14.

[15] A method for producing monatin represented by formula (7 ') or a salt thereof, comprising the step of reacting 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by formula (4'), or a salt thereof with an amino compound represented by formula (5), or a salt thereof to produce a glutaric acid derivative represented by formula (6 '), or a salt thereof, and a step for subsequent reduction of the glutaric acid derivative or its salt

where in the formula R ² represents a hydrogen atom and a substituent selected from alkyl groups, aryl groups and aralkyl groups.

[16] A method for producing monatin represented by formula (7 ') or a salt thereof, comprising the step of reductive amination of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by formula (4'), or a salt thereof:

[17] A method for producing an optically active monatin represented by the formula (8), or a salt thereof, comprising steps a to c:

[in the formula, the designation * indicates an asymmetric center and independently represents the R- or S-configuration]:

step a: a step for producing a salt of an optically active glutaric acid derivative represented by the formula (11)

[in the formula R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same substituents as described below; the designation * indicates an asymmetric center and independently represents the R- or S-configuration] by the interaction of the glutaric acid derivative represented by the formula (9)

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and the bond marked with a wavy line indicates that both the R configuration and the S configuration are included] with an optically active amine represented by the following formula (10)

[in the formula R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group containing 1-3 carbon atoms; the designation * indicates an asymmetric center and represents the R-configuration or S-configuration], which leads to the formation of a diastereoisomeric salt, and the stage of separation of the diastereoisomeric salt by crystallization;

step b: a step for generating monatin represented by the formula (13) or a salt thereof

[in the formula, the designation * indicates an asymmetric center and independently represents the R- or S-configuration; and the bond indicated by a wavy line indicates that both the R configuration and the S configuration are included], by dissociation of a salt of an optically active glutaric acid derivative represented by formula (11), or by exchange of a salt of an optically active glutaric acid derivative with another salt, which it is necessary to obtain an optically active derivative of glutaric acid represented by the formula (12) or a salt thereof (except for the salt of the optically active derivative of glutaric acid represented by the formula (11))

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; in the formula, the designation * indicates an asymmetric center and independently represents the R- or S-configuration] and the stage of conversion of the alkoxyimino group or hydroxyimino group to an amino group;

step c: a step for producing an optically active monatin represented by formula (8) or a salt thereof by crystallization of monatin represented by formula (13) or a salt thereof using a mixed solvent of water and an organic solvent.

[18] A method for producing an optically active monatin represented by the formula (8), or a salt thereof, comprising steps b and c:

[in the formula, the designation * indicates an asymmetric center and independently represents the R- or S-configuration]

step b: a step for generating monatin represented by the formula (13) or a salt thereof

[in the formula, * indicates an asymmetric center and independently represents the R- or S-configuration, and the bond indicated by a wavy line indicates that both the R-configuration and the S-configuration are included], by dissociation of the salt of the optically active glutaric acid derivative represented by formula (11)

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group containing 1-3 carbon atoms; and the designation * indicates an asymmetric center and independently represents the R- or S-configuration] or by exchange of a salt of an optically active glutaric acid derivative with another salt necessary to obtain an optically active glutaric acid derivative represented by the formula (12) or a salt thereof (except salts of an optically active glutaric acid derivative represented by the formula (11))

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and the designation * indicates the asymmetric center and represents the R-configuration or S-configuration],

and effecting the conversion of an alkoxyimino group or hydroxyimino group of an optically active glutaric acid derivative to an amino group

and

step c : a step for producing an optically active monatin represented by formula (8) or a salt thereof by crystallization of monatin represented by formula (13) or a salt thereof using a mixed solvent of water and alcohol.

[19] A method for producing an optically active monatin represented by the formula (8), or a salt thereof

[in the formula, the designation * indicates an asymmetric center and independently represents the R- or S-configuration], comprising the stage of crystallization of the monatin salt represented by the formula (13) using a mixed solvent of water and alcohol:

[in the formula, * indicates an asymmetric center and represents the R- or S-configuration; and the bond marked with a wavy line indicates that both the R configuration and the S configuration are included].

[20] A method for producing a salt of an optically active glutaric acid derivative represented by the formula (11),

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group with 1-3 carbon atoms; and the designation * indicates an asymmetric center and independently represents the R- or S-configuration], including the stage of interaction of the glutaric acid derivative represented by the formula (9)

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; and the bond marked with a wavy line means that both the R configuration and the S configuration are included] with an optically active amine represented by the following formula (10)

[in the formula R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group with 1-3 carbon atoms; the designation * indicates the asymmetric center and represents the R- or S-configuration], with the formation of a diastereoisomeric salt, and the stage of separation of the diastereoisomeric salt by crystallization.

[21] A method for producing an optically active glutaric acid derivative represented by the formula (12) or a salt thereof (except for a salt of the optically active glutaric acid derivative represented by the formula (11))

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; the designation * indicates an asymmetric center and represents the R- or S-configuration], including the stage of dissociation of the salt of the optically active glutaric acid derivative represented by the formula (11)

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group containing 1-3 carbon atoms; and the designation * indicates an asymmetric center and independently represents the R- or S-configuration] or the exchange of a salt of an optically active glutaric acid derivative with another salt.

[22] A method for producing monatin represented by formula (13), or a salt thereof:

[in the formula, * indicates an asymmetric center and represents the R- or S-configuration; and the bond marked with a wavy line indicates that both the R-configuration and the S-configuration are included], including the stage of dissociation of the salt of the optically active glutaric acid derivative represented by the formula (11)

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group with 1-3 carbon atoms; and the designation * indicates an asymmetric center and independently represents the R- or S-configuration] or the exchange of a salt of an optically active glutaric acid derivative with another salt necessary to obtain an optically active glutaric acid derivative represented by the formula (12) or a salt thereof (except salts of an optically active glutaric acid derivative of the formula (11))

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; the designation * indicates the asymmetric center and represents the R- or S-configuration] and the stage of conversion of the alkoxyimino group or hydroxyimino group of the obtained optically active glutaric acid derivative into an amino group.

[23] The method for producing monatin, represented by structural formula (7 '), (including monatin in the form of salts), carried out according to the method according to any one of paragraphs 1-22:

[24] A compound represented by any of the following formulas: (4 '), (6'), (7 "), (11), (12), (14), (15), (16) or (17) ( including these compounds in the form of salts), where in the formulas R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group, containing 1-3 carbon atoms; and the designation * indicates the asymmetric center and represents the R- or S-configuration:

In the case where the derivative is used or obtained in the form of the corresponding salt according to this invention, there are no particular restrictions on the type of salt. Such salts include, for example, sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt, ammonium salt and dicyclohexylammonium salt. The target salt can be obtained by the method of salt formation, the method of desalination, the method of salt exchange and the like, as are already known for widespread use.

Embodiment of the Invention

An embodiment of the present invention is described in detail below.

(Preparation of the ketoglutaric acid derivative by cross-aldol condensation of the pyruvic acid derivative and oxalic-acetic acid followed by decarboxylation to obtain the glutamic acid derivative)

The pyruvic acid derivative represented by the formula (1) and oxalic acetic acid represented by the formula (2) are subjected to cross-aldol condensation and decarboxylation reactions, or the pyruvic acid derivative (except pyruvic acid) and pyruvic acid represented by the formula (2 '), subjected to aldol condensation to obtain a ketoglutaric acid derivative of the formula (4) or a salt thereof, and then the carbonyl group of a ketoglutaric acid derivative or its salt is converted to an amino group and oluchayut glutamic acid derivative represented by the formula (7) or a salt thereof. In this case, the pyruvic acid derivative, oxalic acetic acid, and pyruvic acid may separately be in the form of a corresponding salt

In the formulas, R ¹ represents a group selected from alkyl groups, aryl groups, aralkyl groups, and hydrocarbon groups containing a heterocycle. These groups may contain at least one substituent selected from halogen atoms (iodine atom, bromine atom, chlorine atom, fluorine atom, etc.), hydroxyl group, alkyl groups containing 1-3 carbon atoms, alkoxy groups containing 1 -3 carbon atoms, and amino groups.

As R ¹ , alkyl groups, aryl groups, aralkyl groups and hydrocarbon groups containing a heterocycle with the number of carbon atoms from 1 to 11 are preferred (this number never includes the number of carbon atoms in the substituents if these groups contain substituents). For example, R ¹ includes alkyl groups such as isopropyl group, isobutyl group and 1-methylpropyl group, aryl groups such as phenyl group and 3-indolyl group, aralkyl groups such as benzyl group, 2-phenylethyl group and 2-naphthylmethyl a heterocycle-containing group and hydrocarbon groups, such as a 3-indolylmethyl group and a 3- (6-methylindolyl) methyl group.

For the aldol condensation of the pyruvic acid derivative represented by the formula (1) and the pyruvic acid represented by the formula (2 '), it is never in this invention that the pyruvic acid derivative represented by the formula (1) is pyruvic acid, i.e. . the case where R ¹ is a methyl group (an alkyl group with one carbon atom) does not occur.

Examples of R ¹ include substituents R ^1, comprising an aromatic ring or heterocyclic ring provided that the aromatic ring or the heterocyclic ring contains at least one substituent selected from alkyl groups containing 1-3 carbon atoms, alkoxy containing 1-3 heteroatoms carbon, and amino groups. For example, when a benzyl group or 3-indolylmethyl group is selected as R ¹ in the formula, specifically, the benzene ring or indole ring contained in the group may contain at least one substituent selected from halogen atoms (iodine atom, bromine atom, atom chlorine, fluorine atom, etc.), a hydroxyl group, alkyl groups containing 1-3 carbon atoms, alkoxy groups containing 1-3 carbon atoms, and an amino group.

In the case where R ¹ represents a 3-indolylmethyl group, in other words, where indole-3-pyruvic acid (formula 1 ') is used as the pyruvic acid derivative, 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid (formula 4 ') or its salt can be obtained, and it is an intermediate compound essential for the production of monatin. Then, by converting the carbonyl group of ketoglutaric acid or its salt into an amino group, monatin (formula 7 ') or a salt thereof can be obtained.

Cross Aldol Condensation

Cross aldol condensation is preferably carried out under alkaline conditions. A pyruvic acid derivative and oxalic acetic acid or a pyruvic acid derivative (except pyruvic acid) and pyruvic acid may be present in an appropriate reaction solvent.

As the solvent for the reaction, polar solvents are preferred, such as water, methanol, ethanol, propanol, acetonitrile and dimethylformamide, or mixed solvents composed therefrom. Specifically, water and a mixed solvent (aqueous organic solvent) consisting of water and polar solvents are preferred.

The pH of the solvent is preferably from 10 to 14, more preferably from 10.5 to 14, even more preferably from 11 to 13.

When the pH is too high, the yield is likely to decrease. When the pH is too low, it appears that secondary reactions take place during cross-aldol condensation.

Bases can be satisfactorily used to adjust the pH to these values under alkaline conditions, and these bases include, for example, inorganic bases such as alkali metal salts, alkaline earth metal salts, including alkali metal hydroxides and carbonates, for example lithium hydroxide, hydroxide sodium, potassium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate and organic bases, for example triethylamine.

Although the amount of oxalic acetic acid or pyruvic acid to be used is not particularly limited with respect to the amount of pyruvic acid derivative, the reaction yield is likely to increase with an excess of pyruvic acid, usually from 1 to 10 equivalents and preferably from 3 to 6 equivalents per equivalent pyruvic acid derivative.

The reaction can be carried out at a temperature of preferably from -10 to 70 ° C, more preferably from 10 to 50 ° C. When the reaction temperature is too low, the desired reaction occurs so slowly that secondary reactions are likely to occur. When the reaction temperature is high, the desired ketoglutaric acid derivative (or its salt) obviously decomposes.

The reaction time is not specifically limited and is usually from 1 to 72 hours, preferably from 3 to 24 hours.

Decarboxylation reaction

The reaction in which oxalic acetic acid is used leads to decarboxylation of the obtained product, which then gives the target derivative of ketoglutaric acid (or its salt). The decarboxylation of the aldol condensation product between oxalic acetic acid and a pyruvic acid derivative can be carried out as spontaneous decarboxylation. However, decarboxylation can be effectively carried out by adding to the reaction solution an acid or metal ion, or both. An acid for this use includes, for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, p-toluenesulfonic acid, solid acids such as ion exchange resins, while a metal ion includes, for example, transition metal ions such as nickel ion, ion copper and iron ion. The reaction temperature can be preferably selected from -10 to 100 ° C, more preferably from about 0 to 60 ° C.

The reaction solution after cross-aldol condensation or after cross-aldol condensation and decarboxylation can satisfactorily be used for the next step as such. A ketoglutaric acid derivative (or its salt) represented by the formula (4) is isolated from the reaction solution and purified for use in the next step. When the next amination step is carried out without interruption, there is usually no need to isolate the ketoglutaric acid derivative (or its salt). After completion of the reaction, the reaction solution is concentrated or distilled off, if necessary for the amination step. If the same solvent is used for the amination step as in the cross-aldol condensation reaction, the next step can be carried out without distilling off or replacing the solvent for the reaction or a similar procedure. In the case where the ketoglutaric acid derivative represented by the formula (4) is obtained in the form of a salt, the salt is obtained in free form by a method known to those skilled in the art for use in the amination step. However, this is usually not necessary. Salt can be used in the form of its salt.

In cross-aldol condensation (and decarboxylation, if necessary) according to this invention, where R ¹ is a 3-indolylmethyl group, i.e. where indole-3-pyruvic acid (formula 1 ') is used as a derivative of pyruvic acid, 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid (formula 4'), an important intermediate for the production of monatin, can be obtained or its salt.

Conversion of a carbonyl group to an amino group

After cross-aldol condensation (and then decarboxylation, if necessary), the carbonyl group of the ketoglutaric acid derivative represented by the formula (4), or its salts are converted to the amino group, and the glutamic acid derivative represented by the formula (7) is obtained. The reaction for converting a carbonyl group to an amino group is not particularly limited, and it is carried out, for example, by the following methods.

Example 1 conversion of a carbonyl group to an amino group

After cross-aldol condensation (and then decarboxylation, if necessary), the amino compound (which may be in the form of a salt) represented by formula (5) is reacted with a ketoglutaric acid derivative represented by formula (4) or a salt thereof to produce a glutaric derivative acid represented by formula (6), or its salt, which is then subjected to recovery and get the derivative of glutamic acid represented by formula (7)

In the formula, R ¹ is as described above.

In the case where R ¹ represents a 3-indolylmethyl group, i.e. in the case where 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid (formula 4 ') is used as ketoglutaric acid represented by formula (4) or a salt thereof, a glutaric acid derivative represented by formula (6 '), or its salt, which is then subjected to reduction and get monatin represented by the formula (7'), or its salt.

In the formula, R ² represents a hydrogen atom or a group selected from alkyl groups, aryl groups, aralkyl groups and the like. R ^{2 is} preferably selected from a hydrogen atom, alkyl groups and aralkyl groups containing 7 or less carbon atoms.

More specifically, R ² preferably represents a hydrogen atom, a methyl group or a benzyl group, particularly preferably a hydrogen atom. In other words, specific examples of the amino compound represented by formula (5) preferably include hydroxylamine, methoxyamine and benzyloxyamine, particularly preferably include hydroxylamine.

The salt of the amino compound represented by the formula (5) includes salts of the amino compound with organic acids or inorganic acids and specifically includes, for example, the following salts: hydroxylamine hydrochloride, hydroxylamine sulfate and methoxyamine hydrochloride.

When hydroxylamine hydrochloride is reacted with 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by the formula (4 '), for example, the corresponding 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid is obtained (derivative of formula (6 '), where R ² represents a hydrogen atom) in good yield.

For the reaction of a ketoglutaric acid derivative represented by the formula (4), or a salt thereof with an amino compound represented by the formula (5), or a salt thereof, the reaction temperature can be set preferably from about −10 to 100 ° C., more preferably from about 0 to 60 ° C. Further, the reaction time may preferably be from about 1 to 100 hours, more preferably from about 1 to 24 hours.

For the reaction of the amino compound or its salt, the pH of the reaction solution is preferably 2 or more, since the reaction is slow when the pH is too low. The reaction can occur more preferably in the pH range from about 2 to 13, even more preferably in the pH range from about 4 to 12.

The ratio of the amount of the amino derivative or its salt to be used is not particularly limited. However, preferably from about 1 to 7 moles are used, more preferably from about 1 to 2 moles of the amino compound (or its salt) per 1 mol of the ketoglutaric acid derivative (or its salt) represented by the formula (4).

As the solvent for the reaction, polar solvents such as water, methanol, ethanol, propanol, acetonitrile and dimethylformamide or mixtures of these solvents are preferred. Specifically, water and a mixed solvent (aqueous organic solvent) consisting of water and polar solvents are preferred.

Since a glutaric acid derivative (or salt thereof) represented by the formula (6) is thus obtained, the reaction solution can be used as such for the next step. Or, before use for the next step, the glutaric acid derivative can be isolated and purified from the reaction solution.

When performing isolation and purification, methods known to those skilled in the art, such as extraction and crystallization, can be suitably used. For example, in the case of a glutaric acid derivative represented by the formula (6 '), acidifying the reaction solution and adjusting its pH with acids, for example hydrochloric acid, extracting the glutaric acid derivative with organic solvents such as ethyl acetate, concentrating the obtained organic layer and crystallizing the residue in a mixed solvent, consisting of aqueous ammonia and an alcohol, a glutaric acid derivative represented by the formula (6 ') can be obtained in the form of a crystalline diammonium salt. Using ion exchange resins or adsorption resins or the like, the free derivative of this derivative can be isolated from the reaction solution. The glutaric acid derivative represented by the formula (6 ') or a salt thereof obtained in this way is a racemate from which optically active forms can be obtained using the method described below.

Then the glutaric acid derivative represented by the formula (6) (or a salt thereof) is subjected to reduction, which gives the glutamic acid derivative represented by the formula (7). Using this reaction, the alkoxyimino group (or hydroxyimino group) at position 2 of the glutaric acid derivative represented by the formula (6) can be converted into an amino group

In the formulas, R ¹ and R ² are as described above.

The reduction of an alkoxyimino group (or hydroxyimino group) to an amino group can preferably be carried out by a hydrogenation reaction using a hydrogenation catalyst.

As a hydrogenation catalyst, palladium catalysts (palladium on carbon, etc.), platinum catalysts (platinum on coal, etc.), rhodium catalysts (rhodium on coal, etc.), ruthenium catalysts (ruthenium can be used) coal), nickel catalysts (Raney nickel, etc.) and the like.

These catalysts are preferably used in an amount of from 1 to 20% (mol), more preferably from 0.5 to 5% (mol) of the amount of substrate.

As the solvent for the reaction, polar solvents such as water, methanol, ethanol, propanol, acetonitrile and dimethylformamide or mixtures of these solvents are preferred. Water and a mixed solvent of water and polar solvents are particularly preferred.

This step is preferably carried out under alkaline conditions, usually in the pH range from 7 to 14, preferably from 8 to 12. Specifically, in the case of using rhodium catalysts (rhodium on carbon, etc.), the reaction is usually carried out in the pH range from 7 5 to 11, preferably in the pH range from 8 to 10. When using nickel catalysts (Raney nickel, etc.), however, the reaction preferably occurs under neutral conditions, usually in the pH range from 5 to 9, preferably in the pH range from 6.5 to 7.5. If the pH is too high, the formation of reaction by-products is likely to increase. If the pH is too low, the reaction appears to be slow. When this reaction is carried out under alkaline conditions, the type of alkali used to adjust the pH is not specifically limited. Aqueous ammonia is used for the reduction reaction with rhodium catalysts and palladium catalysts, which is particularly preferred due to the increased yield and low content of by-products.

The hydrogenation reaction is usually carried out in a hydrogen atmosphere. Preferably, the hydrogen pressure is preferably from 0.5 to 100 atmospheres, more preferably from 3 to 70 atmospheres.

The reaction temperature is preferably from −20 to 100 ° C., more preferably from 0 to 70 ° C. The reaction time can be from 6 to 24 hours

Example 2 conversion of a carbonyl group to an amino group

By converting the carbonyl group in the 2-position of the ketoglutaric acid derivative represented by the formula (4) (or its salt) by reductive amination with amines such as ammonia, benzylamine and 1-phenylethylamine, the glutamic acid derivative represented by the formula (7 )

In the formulas, R ¹ is as described above.

When R ¹ represents a 3-indolylmethyl group, i.e. in the case where 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid (formula 4 ') is used as the ketoglutaric acid derivative represented by the formula (4), or a salt thereof, in this invention, it is possible to obtain monatin represented by formula (7 '), or its salt.

The amine can be used in an amount of preferably 1 to 10 equivalents per 1 equivalent of the ketoglutaric acid derivative (or its salt). When ammonia is used as an amine, a large excess of ammonia is preferably used.

In addition to the hydrogenation catalysts described above, hydride catalysts, for example NaBH ₄ , can be used as reduction catalysts. The hydride catalyst can usually be used in an amount of from 0.5 to 2 equivalents. In the case of a hydrogenation catalyst, the catalyst can be used in an amount close to the amount used for contact hydrogenation of a glutaric acid derivative of the formula (6). The reaction can preferably take place at a temperature of from 0 to 50 ° C, more preferably from 20 to 35 ° C. The reaction time is preferably from 1 to 72 hours. When a hydrogenation catalyst is used, the reaction is carried out at a hydrogen pressure of from 1 to 15 atmospheres.

As the solvent for this reaction, polar solvents such as water, methanol, ethanol, propanol, acetonitrile and dimethylformamide or mixtures of these solvents are preferred. Specifically, water and a mixed solvent (aqueous organic solvent) consisting of water and polar solvents are preferred.

The glutaric acid derivative (or its salt) represented by the formula (7), as obtained by these methods in two examples, can be isolated and purified using methods known to one skilled in the art, for example, extraction and crystallization. In the case where R ¹ represents a 3-indolylmethyl group, i.e. in the case where 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid (formula 4 ′) is used as the ketoglutaric acid derivative represented by the formula (4) or a salt thereof, it is possible to obtain a monatin represented by the formula (7 '), or its salt. The monatin represented by the formula (7 '), or a salt thereof, can be isolated and purified by a method for producing optically active monatin, as described below, and to obtain an optically active form.

Obtaining optically active monatin

Monatin contains asymmetric carbon atoms at positions 2 and 4, so the following four types of optical isomers exist.

When 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid (formula 4 ') is used as the ketoglutaric acid derivative represented by the formula (4) or a salt thereof as described above, the reaction with the amino compound represented by the formula ( 5), or with a reagent generating this compound, or with a reagent capable of generating this compound, can give a glutaric acid derivative of the formula (6 ') (or a salt thereof), which is usually a racemate.

The racemate or glutaric acid derivative containing the R-form or S-form in the appropriate ratio (they are included in the glutaric acid derivative represented by formula (9)) is used in the following steps a to c to obtain optically active forms of monatin or its salt.

Stage a: the stage of obtaining the salt of the optically active derivative of glutaric acid represented by the formula (11)

[in the formula R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings as described below; and the designation * indicates an asymmetric center and independently represents the R- or S-configuration], by the interaction of a glutaric acid derivative represented by the formula (9)

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, and a bond marked with a wavy line means that both the R configuration and the S configuration are included] with an optically active amine represented by the formula (10 )

[in the formula R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom or an alkyl group containing 1-3 carbon atoms; and the designation * indicates an asymmetric center and represents the R configuration or S configuration], which leads to the formation of a diastereoisomeric salt, followed by isolation of the diastereoisomeric salt by crystallization;

Stage b: the stage of generation (formation) of monatin represented by formula (13), or its salt

[in the formula, * indicates an asymmetric center and represents the R- or S-configuration, and the bond marked with a wavy line means that both the R-configuration and the S-configuration are included], by dissociation of the salt of the optically active glutaric acid derivative represented by by formula (11), or by exchanging a salt of an optically active glutaric acid derivative with another salt, which is necessary to obtain an optically active glutaric acid derivative represented by formula (12), or a salt thereof (except for a salt of an optically active gl glutaric acid derivatives represented by the formula (11)

[in the formula, R ² represents a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, and the designation * indicates the asymmetric center and represents the R-configuration or S-configuration], and then the conversion of the alkoxyimino group or hydroxyimino group to an amino group;

Stage c: the stage of obtaining the optically active monatin represented by the formula (8) or its salt by crystallization of the monatin represented by the formula (13) or its salt with a mixed solvent consisting of water and an organic solvent.

Stage a is now described.

In order to enable the formation of the diastereoisomeric salt of the glutaric acid derivative represented by the formula (9) and the optically active amine represented by the formula (10), for example, such compounds or their salts are dissolved in a reaction solvent. If the glutaric acid derivative is in the form of its salt, the salt is converted into the free form by neutralizing the salt with an acid, if necessary , then the free form is extracted with an organic solvent, and then the free form is reacted with an optically active amine to form a salt. In addition, the acid may well be added to a solvent containing a salt of the glutaric acid derivative dissolved therein to neutralize the salt, and then an optically active amine may be added for the reaction to form a diastereoisomeric salt. When the salt of the glutaric acid derivative represented by the formula (11) is formed as a result of a salt exchange reaction with the optically active amine represented by the formula (10) in a solvent, even the starting derivative can even be used to react with the optically active amine represented by the formula (10). in the form of salt unchanged. In this case, the optically active amine represented by the formula (10) is preferably used in the form of a salt, such as hydrochloride or sulfate.

Particularly preferred examples of the optically active amine represented by formula (10) include (R) - (+) - 1-phenylethylamine and (S) - (-) - 1-phenylethylamine,

where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ in the formula are hydrogen atoms.

The optically active amine is used in an amount of preferably from about 0.1 to 1-fold (in moles), more preferably from 0.3 to 0.6-fold (in moles) relative to the amount (in moles) of the glutaric acid derivative.

The reaction temperature is preferably set in the range from about -20 to 100 ° C, more preferably from about 0 to 60 ° C. The reaction time is not particularly limited, but it is rather short for the rapid formation of salt.

The solvent for the reaction includes one solvent selected from water, methanol, ethanol, acetonitrile, toluene and ethyl acetate, and a corresponding mixed solvent consisting of two or more of these solvents. Specifically, water or a mixed solvent consisting of water and an organic solvent miscible with water (for example, polar solvents such as methanol, ethanol and acetonitrile) are preferably used. Of these, a single solvent, water, is more preferred.

After completion of the reaction, for example, the reaction solution is concentrated, if necessary, and water is added to crystallize the diastereoisomeric salt. The reaction solution can be cooled if required. Since the resulting diastereoisomeric salt is poorly soluble in water, water or a mixed solvent consisting of water and an organic solvent miscible with water is used as a solvent for the formation of the diastereoisomeric salt so that crystals can precipitate and crystallize simultaneously with the reaction (salt formation ) The crystals obtained by crystallization are separated from the reaction solution by filtration and similar procedures to obtain a diastereoisomeric salt represented by the formula (11). The diastereoisomeric salt obtained in the form of crystals, in the case of using water as a poor solvent for it, varies depending on the steric configuration of the optically active amine used. When using (R) - (+) - 1-phenylethylamine as the optically active amine represented by formula (10) for 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid (derivative of formula (9), where R ² represents a hydrogen atom), for example, a diastereoisomeric salt represented by the formula (14) can be obtained. When using (S) - (-) - 1-phenylethylamine, a diastereoisomeric salt represented by the formula (15) can be obtained

In the case of using (R) - (+) - 1-phenylethylamine, in other words, a crystal of a diastereoisomeric salt can be obtained where the glutaric acid derivative in the S-configuration at the 4-position forms a salt with (R) - (+) - 1-phenylethylamine .

If (S) - (-) - 1-phenylethylamine is used, a crystal of diastereoisomeric salt can be obtained where the glutaric acid derivative in the R-configuration at the 4-position forms a salt with (S) - (-) - 1-phenylethylamine. One of skill in the art can select an optically active amine suitable for the intended compound so that a diastereoisomeric salt is formed and crystallizes in the desired steric configuration.

In addition, the mother liquor, after separation of these diastereoisomeric salts in the form of crystals, contains as its main component a glutaric acid derivative in a steric configuration opposite to that of a glutaric acid derivative separated in the form of crystals. Thus, by adding an optically active amine with a steric configuration opposite the configuration of the optically active amine used to form the salt in the mother liquor, in order to form and crystallize the diastereoisomeric salt in the same manner as described above, one additional crystal of the diastereoisomeric salt can be separated from the mother solution. In other words, step a of this invention can be applied to the mother liquor to obtain another diastereoisomeric salt by crystallization, as described above.

Stage b is now described.

The optically active salt of the glutaric acid derivative represented by the formula (11) as obtained in step a dissociates to form the optically active glutaric acid derivative represented by the formula (12), if required. Alternatively, the salt may be replaced with another salt (salt exchange), if necessary.

Methods known to those skilled in the art can be used to influence dissociation and substitution with another salt (salt exchange). The dissociation method is, for example, a method comprising the step of dissolving or suspending the salt in water, alcohol or a mixed solvent consisting of them, the step of neutralizing the resulting solution or suspension with acids, such as hydrochloric acid or sulfuric acid, and the extraction step with an organic solvent, the method comprising the step of dissolving the salt in water and separating the free form represented by the formula (12), ion-exchange resins or adsorbing resins. To isolate the free form, the intended isolation can be easily carried out in a known manner, for example by distillation of the eluent solution from the resin or the extract solution containing the free form under reduced pressure. In case of substitution with another salt, for example, the salt of the optically active glutaric acid derivative represented by the formula (11) can be dissolved in aqueous solutions of alkali metal hydroxides: sodium hydroxide, potassium hydroxide and aqueous ammonia, from which the free optically active amine is extracted with an organic solvent such so that the salt can be exchanged. Using a known technique, such as distilling under reduced pressure an aqueous solution after extraction or crystallization, it is possible to further isolate the salt of the optically active glutaric acid derivative represented by formula (12) (except for the salt of the optically active glutaric acid derivative represented by formula (11)).

Monatin represented by formula (13) can be obtained from an optically active glutaric acid derivative represented by formula (12), thus obtained from its salt by converting an alkoxyimino group (or hydroxyimino group) to an amino group. In addition, the monatin represented by the formula (13) can be prepared by converting an alkoxyimino group (or hydroxyimino group) of a salt of the optically active glutaric acid derivative represented by formula (11) into an amino group as described above.

As described above, the conversion of an alkoxyimino group (or hydroxyimino group) to an amino group can be accomplished by a hydrogenation reaction using a hydrogenation catalyst under the reaction conditions as described above.

After completion of the reaction, the catalyst is removed by filtration or the like, and the filtrate is concentrated, if necessary, and monatin, represented by formula (13), can be obtained from it using isolation techniques known to a person skilled in the art (for example, crystallization, HPLC, etc.) . In addition, if the next stage c is carried out without interruption, there is no need at all to isolate the monatin represented by the formula (13). After completion of the reaction, the catalyst is removed from the reaction solution by filtration or the like. The reaction solution is then concentrated or distilled off, if necessary, in order to crystallize according to step c . Using the same solvent that is used as the crystallization solvent for the hydrogenation reaction, the next step c can be carried out without distilling off the reaction solvent or an exchange solvent, and the like. When the base is used for the hydrogenation reaction, monatin exists in the reaction solution as a salt. By treating the reaction solution after removing the catalyst with an ion exchange resin or the like, for example, monatin can be obtained in free form or converted to another salt (salt exchange, including, for example, the conversion of the ammonium salt to the sodium salt, potassium salt and the like). Then, the resulting product can be crystallized. For the next step c, it is preferable to use the resulting monatin in the form of its salt as such.

Stage c is now described.

Although the monatin represented by formula (13) or its salt obtained in step b can retain optical activity at position 4, the resulting monatin can be isolated as a mixture of S-form and R-form at position 2. Monatin and its salt can be optically separated by crystallization in accordance with step c described below, so that optically active monatin or a salt thereof optically active in both position 2 and position 4 can be obtained.

The monatin represented by formula (13) or a salt thereof is subjected to a crystallization step using a mixed solvent of water and an organic solvent to obtain an optically active monatin (crystalline) represented by formula (8).

When a base is used for the hydrogenation reaction in step b , it is usually possible to obtain monatin in the form of a salt, which is preferably subjected to the crystallization step in this form. In this case, water is a good solvent for the monatin salt. The crystallization method is not particularly limited and includes, for example, approaches known to those skilled in the art, such as crystallization upon cooling and concentration of the solution before crystallization. To crystallize a monatin salt, for example, it is possible to obtain a monatin crystal in free form by adding an acid to an aqueous solution containing the monatin salt dissolved in it to neutralize the solution, and adding an organic solvent to the resulting solution. Since monatin is probably decomposed by acid, however, the invention can preferably be used specifically for the case where monatin is to be obtained in the form of a salt.

As an organic solvent, an organic solvent that is mixed with water can be used. Particularly preferred are alcohols, such as, for example, methanol, ethanol, propanol and isopropanol. A mixed solvent of two or more types of different organic solvents can satisfactorily be used as an organic solvent. The ratio of water to organic solvent in a mixed solvent containing water can be set preferably in the range of organic solvent: water = from about 1: 0.1 to 1: 1 (volume ratio), more preferably in the range of organic solvent: water = from about 1 : 0.3 to 1: 0.9 (volume ratio). It is sufficient to set the crystallization temperature in the range of preferably from about -20 to 100 ° C, more preferably from about 0 to 60 ° C.

As shown below, in the following diagrams, the steric configuration of the monatin crystal obtained in step c is as follows. In the case of using monatin, represented by formula (13), in the R form in the 4th position and the S form in the 4th position, monatin crystals (2R, 4R) and (2S, 4S) are obtained, respectively. In addition, the mother liquor after separation of the crystals separately contains (2S, 4R) monatin and (2R, 4S) monatin, as the main components. By treating the mother liquors with absorbent resins and the like, it is possible to isolate (2S, 4R) monatin or (2R, 4S) monatin

If desired, the optically active monatin obtained in free form can be obtained in the form of a salt. By methods known to those skilled in the art (salt formation), monatin can be obtained in the form of a salt, for example, in the form of a sodium salt or a potassium salt. In addition, even the optically active monatin obtained in the form of its salt can be obtained in a similar manner in free form, if required, or can be converted into another salt. Using methods known to one skilled in the art, for example, a given salt can be converted into its free form by a method for converting salts to free forms by dissociation or the like. Alternatively, the salt can be converted to another salt by exchange (exchange reaction) of the obtained salt with another salt (salt exchange).

Preferred Embodiments of the Invention

The invention is now described in detail in the following examples. However, the present invention is not limited to these examples.

In the examples, in addition, the optical purity was determined by HPLC under the following conditions

<Column for the separation of optical isomers>

SUMICHIRAL OA-7100 manufactured by Sumika Chemical Analysis Service

<Eluent>

20 mM phosphate buffer (pH 2.8): acetonitrile = 7: 3

<Column temperature>

10 ° C; and

<Flow rate>

0.6 ml / min.

Example 1

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid; Number 1

Potassium hydroxide (8.28 g) (with a purity of 85% wt.) Is dissolved in 27 ml of water, 3.0 g (14.76 mmol) of indole-3-pyruvic acid and 5.85 g (44, 29 mmol) oxalic acetic acid for the reaction at ambient temperature for 72 hours (pH about 13 at the beginning of the reaction). The pH of the solution was adjusted to 3.0 by adding an ion exchange resin (Amberlite IR 120B H AG) to the reaction solution, for extraction with ethyl acetate (200 ml) at 0 ° C. To the resulting ethyl acetate layer was added 100 ml of a saturated aqueous sodium bicarbonate solution, ethyl acetate was distilled off from the extract, and the pH of the solution was adjusted to 7.9 with an ion exchange resin (IRA400 OH AG, manufactured by Organo Corporation). The resulting solution was subjected to freeze drying. 4-Hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid sodium salt is obtained as a crude product. Then, 40 ml of water and 200 ml of ethanol are added to the obtained residue, and the solid is filtered off. The resulting mother liquor was evaporated to dryness to give 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid sodium salt (1.5 g) as a crude product.

Example 2

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid; No. 2

After dissolving 18.91 g (286.5 mmol) of potassium hydroxide (85% by weight) in 64.45 ml of water, 7.50 g (35.8 mmol) of indole-3-pyruvic acid are added to the resulting solution (97, 0% wt. Purity) and 14.18 g (107.4 mmol) of oxalic acetic acid and dissolved in it (at a pH of about 13 at the beginning of the reaction). The resulting mixture was stirred at 35 ° C for 24 hours. Then, 40.0 ml of 3N was added. hydrochloric acid to neutralize (pH 7.0) and get 153.5 g of a neutralized reaction solution. The neutralized reaction solution contains 5.55 g of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid, the yield of which is 53.5% (based on indole-3-pyruvic acid). Water was added to the neutralized reaction solution, bringing the solution to 168 ml, and the solution was passed through a resin column (4.8 cm in diameter) filled with a synthetic adsorbent (840 ml) (DIAION-SP207 manufactured by Mitsubishi Chemical Corporation). Then pure water is passed through the column at a rate of 23.5 ml per minute. From 1.73 to 2.55 L / LR is collected and an aqueous solution is obtained containing 3.04 g of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid — 54.7% yield (relative to the amount loaded on resin).

NMR data

¹ H-NMR (400 MHz, D ₂ O): δ 3.03 (d, 1H, J = 14.6 Hz), 3.11 (d, 1H, J = 14.6 Hz), 3.21 ( d, 1H, J = 18.1 Hz), 3.40 (d, 1H, J = 18.1 Hz), 7.06-7.15 (m, 3H), 7.39 (d, 1H, J = 7.8 Hz), 7.66 (d, 1H, J = 7.8 Hz).

¹³ C-NMR (400 MHz, D ₂ O): δ 35.43, 47.91, 77.28, 109.49, 112.05, 119.44, 119.67, 121.91, 125.42, 128.41, 136.21, 169.78, 181.43, 203.58.

Molecular weight determination

Calculated value (MS-ESI) C ₁₄ H ₁₃ NO ₆ = 291.07

Found Value = 290.02 (MH ^- )

Example 3

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid; No. 3

Potassium hydroxide 3.70 g (56.0 mmol) (with a basic substance content of 85% by weight) is dissolved in 72.1 ml of water, then 0.81 g (4.0 mmol) of indole-3-pyruvic acid and 3 are added. , 17 g (24.0 mmol) of oxalic acetic acid and dissolved in the resulting solution (pH about 13 at the beginning of the reaction). The dissolved mixture was stirred at 35 ° C. for 24 hours. A portion of the reaction solution was treated with hydroxylamine to give 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid, which was analyzed by HPLC. As a result, it was found that 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid was formed in 76.6% yield (calculated as indole-3-pyruvic acid).

Example 4

Synthesis of 4-benzyl-4-hydroxy-2-ketoglutaric acid

After dissolving 16.23 g of potassium hydroxide (with a purity of 85% by weight) in 48 ml of water, 5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxalic-acetic acid are added to the resulting solution. acids for interaction at ambient temperature for 72 hours (pH is about 13 at the beginning of the reaction). Using concentrated hydrochloric acid, the pH of the solution was adjusted to 2.2 and the solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, concentrated and a residue was obtained. The residue was recrystallized from ethyl acetate and toluene to give crystals of 4-benzyl-4-hydroxy-2-ketoglutaric acid (2.8 g, 11.3 mmol).

NMR data

¹ H-NMR (D ₂ O) δ: 2.48 (d, J = 14.4 Hz, 0.18H), 2.60 (d, J = 14.4 Hz, 0.18H), 2.85 -3.30 (m, 3.64H); 7.17-7.36 (m, 5H).

Molecular weight determination

Calculated value (MS-ESI) C ₁₂ H ₁₂ O ₆ = 252.23

The resulting value is 251.22 (MH ^- )

Example 5

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid; No. one

After dissolving 13.8 g of potassium hydroxide (with a purity of 85% by weight) in 50 ml of water, 5.0 g (24.6 mmol) of indole-3-pyruvic acid and 9.8 g (73.8 mmol) are added to the resulting solution. ) oxalic-acetic acid for interaction at ambient temperature for 72 hours (pH is about 13 at the beginning of the reaction). 6.8 g (98.4 mmol) of hydroxylamine hydrochloride are added to the reaction solution. Then the pH of the reaction solution was adjusted to 7.5 with aqueous 4n. sodium hydroxide solution. The reaction solution was stirred for 24 hours at ambient temperature, then the pH of the solution was adjusted to 2.6 6N. hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting residue was dissolved in 10 ml of aqueous 14% ammonia, then 70 ml of ethanol was gradually added dropwise and stirred at ambient temperature for 3 hours. The resulting suspension was filtered. The resulting crystals were dried to give 2.7 g (7.9 mmol) of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid as an ammonium salt.

NMR data

¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 2H), 2.89 (d, J = 14.4 Hz, 1H), 3.04 (d, J = 14.4 Hz, 1H), 6.89-6.94 (m, 1H), 6.97-7.03 (m, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.27 (d , J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 10.71 (br s, 1H).

Molecular weight determination

Calculated value (MS-ESI) (MS-ESI) C ₁₄ H ₁₄ N ₂ O ₆ = 306.28

Found Value = 305.17 (MH ^- )

Example 6

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-methoxyiminoglutaric acid

After dissolving 9.12 g (138.1 mmol) of potassium hydroxide (with a basic substance content of 85% by weight) in 23 ml of water, 2.55 g (12.2 mmol with a purity of 97.0% by weight) are added to the resulting solution. indole-3-pyruvic acid and 7.46 g (56.5 mmol) of oxalic-acetic acid and dissolved in it (pH about 13 at the beginning of the reaction). The solution was stirred at 35 ° C for 24 hours. 5.76 g (69 mmol) of salt, methoxyamine hydrochloride was gradually added to the reaction solution, while the pH of the reaction solution was adjusted to about 10 with an aqueous 25% sodium hydroxide solution. After continuing the reaction at ambient temperature for 14 hours, the pH of the reaction solution was adjusted to 2.23 with 6N. hydrochloric acid and then the solution is extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Magnesium sulfate is filtered off, then the resulting solution is evaporated, and 4.66 g of residue are obtained. The resulting residue was purified by silica gel column chromatography and then purified by preparative thin layer chromatography (PTLC; ethyl acetate / hexane / acetic acid = 5/5/1) to obtain 0.93 g (2.92 mmol) of the title compound 4-hydroxy 4- (3-indolylmethyl) -2-methoxyiminoglutaric acid. Yield 24% (indole-3-pyruvic acid).

NMR data

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 2.89 (d, J = 14.9 Hz, 1H), 3.04 (s, 2H), 3.15 (d, J = 14, 9 Hz, 1H), 3.90 (s, 3H), 6.91-6.96 (m, 1H), 6.98-7.04 (m, 1H), 7.09-7.12 (m , 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 10.80 (br s, 1H).

Example 7

Synthesis of 4-benzyl-4-hydroxy-2-hydroxyiminoglutaric acid

After dissolving 16.23 g of potassium hydroxide (85% by weight) in 45 ml of water, 5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxalic-acetic acid are added to the resulting solution. for interaction at ambient temperature for 24 hours (pH about 13 at the beginning of the reaction). To the reaction solution was added 8.5 g (121.8 mmol) of hydroxylamine hydrochloride salt to interact at ambient temperature for 72 hours. The pH of the reaction solution was adjusted to 2.6 6N. hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting residue was recrystallized from 20 ml of ethyl acetate and 80 ml of toluene to obtain 4.0 g (15.1 mmol) of 4-benzyl-4-hydroxy-2-hydroxyiminoglutaric acid.

NMR data

¹ H-NMR (DMSO-d ₆ ) δ: 2.80 (d, J = 13.9 Hz, 1H), 2.99 (d, J = 12.7 Hz, 1H), 3.01 (d, J = 13.9 Hz, 1H), 3.03 (d, J = 12.7 Hz, 1H), 7.13-7.25 (m, 5H).

Molecular weight determination

Calculated value (MS-ESI) C ₁₂ H ₁₃ NO ₆ = 267.24

Found Value = 266.12 (MH ^- )

Example 8

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid (monatin); No. one

The ammonium salt of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid (0.13 g, 0.38 mmol) is dissolved in 5 ml of aqueous 28% ammonia, 0.09 g of 5% rhodium per coal for interaction at ambient temperature and a hydrogen pressure of 7.5 atm. After 14 hours, the catalyst was filtered off, the resulting solution was evaporated to dryness to give a mixture of 0.075 g (0.23 mmol) of (2S, 4S) / (2R, 4R) -4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric ammonium salt acids (monatin) and 0.036 g (0.11 mmol) of the (2S, 4R) / (2R, 4S) -4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid ammonium salt (monatin).

NMR data

¹ H-NMR (D ₂ O) δ: 2.05 (dd, J = 12.2, 15.1 Hz, 0.67H), 2.21 (dd, J = 9.9, 15.6 Hz, 0.33H), 2.48 (dd, J = 3.2, 15.6 Hz, 0.33H), 2.68 (dd, J = 2.2, 15.1 Hz, 0.67H), 3 08 (d, J = 14.4 Hz, 0.67H), 3.17-3.25 (m, 0.66H), 3.28 (d, J = 14.4 Hz, 0.67H), 3.63 (dd, J = 2.2, 12.2 Hz, 0.67H), 3.98 (dd, J = 3.2, 9.9 Hz, 0.33H), 7.12-7, 18 (m, 1H), 7.19-7.26 (m, 2H), 7.45-7.51 (m, 1H), 7.70-7.76 (m, 1H).

Molecular weight determination

Calculated value (MS-ESI) C ₁₄ H ₁₆ N ₂ O ₅ = 292.29

Found Value = 291.28 (MH ^- )

Example 9

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid (monatin); No. 2

4-Hydroxy-4- (3-indolylmethyl) -2-methoxyiminoglutaric acid (0.264 g, 0.824 mmol) was dissolved in 10 ml of aqueous 28% ammonia. 0.18 g of 5% rhodium on charcoal (dry product) is added and the mixture is stirred for 18 hours at a hydrogen pressure of 7.5 atm. The catalyst is filtered off, the solvent is distilled off under reduced pressure, and a residue is obtained. The resulting residue was investigated (analyzed) by NMR and it was found that a mixture was formed of 0.115 g (0.395 mmol; 48% yield) (2S, 4S) / (2R, 4R) -4-hydroxy-4- (3-indolylmethyl) -2- aminoglutaric acid (monatin) and 0.065 g (0.223 mmol; 27% yield) (2S, 4R) / (2R, 4S) -4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid.

Example 10

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid (monatin); No. 3

Ammonium 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutarate (1.0 g; 2.94 mmol) is dissolved in 10 ml of water, 1 ml of a Raney nickel catalyst (manufactured by Kawaken) is added via syringe to the resulting solution Fine Chemicals Co., Ltd .; active nickel catalyst NDHT-90) and the mixture is stirred for 10 hours at a hydrogen pressure of 20 atm. The catalyst was filtered off and the resulting solution was evaporated to give a residue. The resulting residue was analyzed by NMR. 0.29 g (0.89 mmol; yield 30%) of (2S, 4S) / (2R, 4R) -4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid (monatin) and 0.29 g (0.89 mmol; 30% yield) (2S, 4R) / (2R, 4S) -4-hydroxy-4- (3-indolylmethyl) -2-aminoglutaric acid.

Example 11

Synthesis of 2-amino-4-benzyl-4-hydroxyglutaric acid; No. 1

4-Benzyl-4-hydroxy-2-hydroxyiminoglutaric acid (0.25 g; 0.94 mmol) is dissolved in 10 ml of an aqueous 50% methanol solution, to which 0.5 ml of an aqueous 28% ammonia solution is added. Add 1.0 g of 5% palladium-carbon (50% aqueous product) for the reaction at ambient temperature and a hydrogen pressure of 7.7 atmospheres. After 72 hours, the catalyst was filtered off, the reaction solution was evaporated to dryness to give a mixture of 0.10 g (0.35 mmol) of (2S, 4S) / (2R, 4R) -2-amino-4-benzyl-4-hydroxyglutaric acid ammonium salt and 0.10 g (0.35 mmol) of the (2R, 4S) / (2S, 4R) -2-amino-4-benzyl-4-hydroxyglutaric acid ammonium salt.

NMR data

¹ H-NMR (D ₂ O) δ: 1.94 (dd, J = 11.9, 15.3 Hz, 0.5H), 2.10 (dd, J = 10.2, 15.3 Hz, 0.5H), 2.36 (dd, J = 3.1, 15.3 Hz, 0.5H), 2.56 (dd, J = 2.4, 15.3 Hz, 0.5H), 2 81 (d, J = 13.6 Hz, 0.5H), 2.94 (d, J = 13.5 Hz, 0.5H), 3.01 (d, J = 13.5 Hz, 0, 5H), 3.06 (d, J = 13.6 Hz, 0.5H), 3.55 (dd, J = 2.4, 11.9 Hz, 0.5H), 3.88 (dd, J = 3.1, 10.2 Hz, 0.5H), 7.17-7.31 (m, 5H).

Molecular weight determination

Calculated value (MS-ESI) C ₁₂ H ₁₅ NO ₅ = 253.26

Found Value = 252.23 (MH ^- )

Example 12

Synthesis of 2-amino-4-benzyl-4-hydroxyglutaric acid; No. 2

4-Benzyl-4-hydroxy-2-ketoglutaric acid (0.13 g, 0.52 mmol) and 0.11 ml (1.0 mmol) of benzylamine are dissolved in 5 ml of methanol, to which 0.1 g of 5% is added palladium on carbon (50% aqueous product) for interaction in a hydrogen atmosphere at ambient temperature and atmospheric pressure. After two days, the catalyst is filtered off, the reaction solution is evaporated to dryness and a mixture of 0.03 g (0.12 mmol) of (2S, 4S) / (2R, 4R) -2-amino-4-benzyl-4-hydroxyglutaric acid and 0, 06 g (0.24 mmol) (2R, 4S) / (2S, 4R) -2-amino-4-benzyl-4-hydroxyglutaric acid.

Example 13

Synthesis of 4-hydroxy-4- (4-hydroxyphenylmethyl) -2-hydroxyiminoglutaric acid

To 10 ml of water in which 3.18 g of potassium hydroxide was dissolved, 1.0 g (5.55 mmol) of 4-hydroxyphenylpyruvic acid and 2.2 g (16.7 mmol) of oxalic-acetic acid were added to react at ambient temperature medium for 72 hours (pH is about 13 at the beginning of the reaction). Hydroxylamine hydrochloride (1.54 g, 22.2 mmol) is added to the reaction solution for interaction at ambient temperature for 10 hours. Then, the pH of the reaction solution is adjusted to 2.6 6N. hydrochloric acid solution for extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.7 g (2.47 mmol) of 4-hydroxy-4- (4-hydroxyphenylmethyl) -2-hydroxyiminoglutaric acid as a crude product. The crude product is then recrystallized from methanol and toluene to give 0.22 g (0.78 mmol) of 4-hydroxy-4- (4-hydroxyphenylmethyl) -2-hydroxyiminoglutaric acid in the form of crystals.

NMR data

¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (d, J = 13.7 Hz, 1H), 2.89 (d, J = 13.7 Hz, 1H), 2.95 (d, J = 12.5 Hz, 1H), 2.99 (d, J = 12.5 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H); 9.11 (br s, 1H).

Molecular weight determination

Calculated value (MS-ESI) C ₁₂ H ₁₃ NO ₆ = 283.24

Found Value = 281.93 (MH ^- )

Example 14

Synthesis of 4-hydroxy-4- (4-hydroxyphenylmethyl) -2-hydroxyiminoglutaric acid

0.06 g (0.21 mmol) of 4-hydroxy-4- (4-hydroxyphenylmethyl) -2-hydroxyiminoglutaric acid was dissolved in 2.5 ml of aqueous 28% ammonia; 0.04 g of 5% rhodium on carbon was added to the resulting solution for the reaction at ambient temperature and a hydrogen pressure of 7.5 atmospheres. After 14 hours, the catalyst was filtered off and the resulting solution was evaporated to dryness to give a mixture of 0.044 g (0.145 mmol) (2S, 4S) / (2R, 4R) -4-hydroxy-4- (4-hydroxyphenylmethyl) -2-aminoglutaric acid and 0.021 g (0.069 mmol) (2S, 4R) / (2R, 4S) -4-hydroxy-4- (4-hydroxyphenylmethyl) -2-aminoglutaric acid.

¹ H-NMR (D ₂ O) δ: 1.89 (dd, J = 11.9, 15.7 Hz, 0.68H), 2.06 (dd, J = 10.2, 15.0 Hz, 0.32H), 2.30 (dd, J = 3.3, 15.0 Hz, 0.32H), 2.51 (dd, J = 2.4, 15.7 Hz, 0.68H), 2 70 (d, J = 13.4 Hz, 0.68H), 2.83 (d, J = 13.4 Hz, 0.32H), 2.90 (d, J = 13.4 Hz, 0, 32H), 2.96 (d, J = 13.4 Hz, 0.68 H), 3.52 (dd, J = 2.4, 11.9 Hz, 0.68H), 3.84 (dd, J = 3.3, 10.2 Hz, 0.32H), 6.71-6.77 (m, 2H), 7.02-7.08 (m, 2H).

Molecular weight determination

Calculated value (MS-ESI) C ₁₂ H ₁₅ NO ₆ = 269.26

Found Value = 268.11 (MH ^- )

Example 15

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid; No. four

Indolepyruvic acid (12.30 g, 58.7 mmol) (97.0% by weight) was added to 209 ml of water containing 2.45 g of dissolved sodium hydroxide and dissolved. To the resulting solution was added over 2 hours 47.61 g of aqueous 25% wt. sodium hydroxide solution and a mixture of 25.85 g (293.5 mmol) of pyruvic acid and 25.85 g of water in a nitrogen atmosphere at 35 ° C, maintaining a pH of 11.0 in the reaction mixture. Then the reaction system is stirred for 14 hours. In this way, a reaction solution is obtained which contains 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid (yield 44.1%, based on indolopyruvic acid). 3.60 g of 1N are added to the solution. hydrochloric acid to neutralize (pH 6.91) and get 275 ml of a neutralized reaction solution.

A portion (168 ml) of the thus obtained neutralized reaction solution was passed through a column of resin (4.8 cm in diameter) filled with 840 ml of synthetic adsorbent (DIAION-SP207 manufactured by Mitsubishi Chemical Corporation). Pure water is then passed through the column at a rate of 23.5 ml per minute, collecting from 1.7 to 2.9 L / LR, and 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid of high purity is obtained in a yield 66.3%.

NMR spectrum

¹ H-NMR (400 MHz, D ₂ O): δ 3.03 (d, 1H, J = 14.6 Hz), 3.11 (d, 1H, J = 14.6 Hz), 3.21 ( d, 1H, J = 18.1 Hz), 3.40 (d, 1H, J = 18.1 Hz), 7.06-7.15 (m, 3H), 7.39 (d, 1H, J = 7.8 Hz), 7.66 (d, 1H, J = 7.8 Hz).

¹³ C-NMR (400 MHz, D ₂ O): δ 35.43, 47.91, 77.28, 109.49, 112.05, 119.44, 119.67, 121.91, 125.42, 128.41, 136.21, 169.78, 181.43, 203.58.

Mass spectrometric analysis

Calculated value (MS-ESI) C ₁₄ H ₁₃ NO ₆ = 291.07

Found Value = 290.02 (MH ^- )

Example 16

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid; No. 2

After adding 1.0 g (4.92 mmol) of indole-3-pyruvic acid in 10 ml of a saturated aqueous solution of sodium carbonate and its dissolution, the pH of the resulting solution was adjusted to 12.55 using an aqueous 25% sodium hydroxide solution. Then add 1.3 g (14.8 mmol) of pyruvic acid and adjust the pH of the resulting solution to 12.6 with an aqueous 25% sodium hydroxide solution to react at ambient temperature for 2 hours to obtain a reaction solution containing 4-hydroxy -4- (3-indolylmethyl) -2-ketoglutaric acid. Hydroxylamine hydrochloride (1.37 g, 19.7 mmol) is added to the reaction solution, while the pH of the reaction solution is brought to a value close to neutral with an aqueous 25% sodium hydroxide solution and then stirred at ambient temperature for 4 hours. Concentrated hydrochloric acid adjust the pH of the reaction solution to an acidic value for extraction of organic matter with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated to give a residue. The resulting residue was recrystallized in aqueous 28% ammonia and ethanol to give 0.52 g (1.5 mmol) of crystalline 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid (31% yield of indole-3-pyruvic acid )

NMR spectrum

¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 2H), 2.89 (d, J = 14.4 Hz, 1H), 3.04 (d, J = 14.4 Hz, 1H), 6.89-6.94 (m, 1H), 6.97-7.03 (m, 1H), 7.11 (d, J = 2.8 Hz, 1H), 7.27 (d , J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 10.71 (br s, 1H).

MS analysis

Calculated value (MS-ESI) C ₁₄ H ₁₄ N ₂ O ₆ = 306.28

Found Value = 305.17 (MH ^- )

Example 17

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid; No. 3

After adding 10.0 g (49.2 mmol) of indole-3-pyruvic acid in 98 ml of a saturated aqueous solution of sodium carbonate and its dissolution, the pH of the resulting solution was adjusted to 12.4 using an aqueous 25% sodium hydroxide solution. Then, 16.3 g (147.6 mmol) of sodium pyruvate was added to react at ambient temperature for 2 hours to give a reaction solution containing 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid. Hydroxylamine hydrochloride (13.7 g (197 mmol)) is added to the reaction solution, while the pH of the reaction solution is adjusted to near neutral with an aqueous 25% sodium hydroxide solution and then stirred at ambient temperature for 4 including concentrated hydrochloric acid, the pH of the reaction solution was adjusted to an acidic value for the extraction of organic matter with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated to give a residue. The resulting residue was recrystallized from aqueous 28% ammonia and ethanol to give 5.51 g (16.2 mmol) of crystalline 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid (32% in yield on indole-3-pyruvic acid )

Example 18

After adding 1.0 g (4.92 mmol) of indole-3-pyruvic acid in 10 ml of a saturated aqueous solution of sodium carbonate and dissolving it in the same manner as in example 16, the pH of the resulting solution was adjusted to 12.7 with aqueous 25 % sodium hydroxide solution. Then add 1.3 g (14.8 mmol) of pyruvic acid and adjust the pH of the resulting solution to 10.0 with an aqueous 25% sodium hydroxide solution to react at ambient temperature for 6 hours. Hydroxylamine hydrochloride (1.37 g, 19.7 mmol) is added to the reaction solution, while the pH of the reaction solution is brought to a value close to neutral with an aqueous 25% sodium hydroxide solution and then stirred at ambient temperature for 13 hours. The pH is adjusted with concentrated hydrochloric acid reaction solution to acidic value for the extraction of organic matter with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then evaporated to give a residue. The resulting residue was analyzed by HPLC, which showed that 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid was formed in a yield of about 14%.

Example 19

Synthesis of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid; No. four

Indole-3-pyruvic acid (73.8 g, 352 mmol) is added to 917 g of an aqueous 1.6% (mass) sodium hydroxide solution and dissolved in it. The temperature of the resulting solution was adjusted to 35 ° C. and 310.2 g (1761 mmol) of an aqueous 50% solution of pyruvic acid were added dropwise over 2 hours, while the pH of the reaction solution was kept at 11.1 with an aqueous 30% hydroxide solution sodium. After reacting for another 4.5 hours, a reaction solution containing 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid is obtained. An aqueous 40% solution of hydroxylamine hydrochloride (367.2 g, 2114 mmol) was added to the reaction solution, while the pH of the reaction solution was maintained at 7 using an aqueous 30% sodium hydroxide solution, and stirred at 5 ° C. for 17.5 including concentrated hydrochloric acid, the pH of the reaction solution was adjusted to 2 in order to extract the organic substance with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, then evaporated to give a residue. The resulting residue was recrystallized in 60 ml of aqueous 28% ammonia and 1350 ml of 2-propanol to obtain 43.4 g (142 mmol) of crystals of the di-ammonium salt of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid (40% yield indole-3-pyruvic acid).

Example 20

Preparation of (R) - (+) - 1-phenylethylamine and (4S) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid salt

After dissolving 44.7 g (0.131 mol) of the ammonium salt of 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid in 500 ml of water at 25 ° C, the resulting solution was adjusted to 2 with 36% hydrochloric acid ( 25.5 g). The acidic solution was extracted with 1300 ml of ethyl acetate, and the resulting ethyl acetate solution was washed with 200 ml of a saturated aqueous solution of sodium chloride. To the resulting ethyl acetate solution was added 500 ml of an aqueous solution of sodium carbonate (13.9 g, 0.131 mol of sodium carbonate) to mix to separate the aqueous alkaline solution from ethyl acetate. 23.1 g of 36% hydrochloric acid was added to the resulting aqueous alkaline solution to adjust the pH to 2. 6.99 g (57.6 mmol) of (R) - (+) - 1- was added dropwise to the resulting aqueous acid solution. phenylethylamine and the solution was stirred at 25 ° C for 1 h. The resulting crystals were filtered off, dried under reduced pressure to obtain 21.8 g (47.8 mmol) of the salt of (R) - (+) - 1-phenylethylamine and (4S) - 4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid. (Yield 72.7%; optical purity 87.4%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.48 (d, 3H, J = 6.8 Hz), 2.63 (d, 1H, J = 14.0 Hz), 2.70 (d, 1H, J = 14.0 Hz), 2.90 (d, 1H, J = 14.1 Hz), 3.06 (d, 1H, J = 14.1 Hz), 4.40 (q , 1H, J = 6.8 Hz), 6.91-7.54 (m, 10H).

Example 21

Preparation of (S) - (-) - 1-phenylethylamine and (4R) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid salt

(S) (-) - 1-Phenylethylamine (7.12 g, 58.7 mmol) was added dropwise to the solution of Example 20 (remaining after the crystals were filtered off), and the mixture was stirred at 25 ° C. for 1 h. The resulting crystals are filtered off, dried under reduced pressure to obtain 23.8 g (53.3 mol) of the salt of (S) (-) - 1-phenylethylamine with (4R) -4-hydroxy-4- (3-indolylmethyl) -2 -hydroxyiminoglutaric acid. (Yield 81.1%; optical purity 92.1%.)

Example 22

Preparation of (4S) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid ammonium salt

Water (200 ml) and aqueous 28% ammonia (18.5 g) are added to 21.8 g (51.0 mmol) of the salt of (R) - (+) - 1-phenylethylamine and (4S) -4-hydroxy-4 - (3-indolylmethyl) -2-hydroxyiminoglutaric acid at 25 ° C to dissolve the salt, then 200 ml of toluene are added and stirred. The aqueous layer obtained by separating the resulting layers is heated to 60 ° C. To the resulting aqueous solution, 900 ml of 2-propanol was added dropwise in 2 hours. After the aqueous 2-propanol solution was cooled to 10 ° C. in 5 hours, the solution was stirred at 10 ° C. for 10 hours. The resulting crystals were filtered off, dried under reduced pressure, and 14.75 g of the ammonium salt of (4S) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid are obtained. (Yield 85.1%; optical purity 99.0%.)

Melting point 205 ° C (decomposed)

Specific rotation [α] ²⁰ _D + 13.4 (c = 1.00, H ₂ O)

Example 23

Preparation of (4R) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid ammonium salt

In the same manner as in the example described above, 16.2 g of the (4R) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid ammonium salt was isolated from 23.8 g (53.3 mmol) of the salt (S) - (-) - 1-phenylethylamine and (4R) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid. (Yield 89.3%; optical purity 99.9%.)

Specific rotation [α] ²⁰ _D - 13.6 (c = 1.00, H ₂ O)

Example 24

Obtaining (2S, 4S) Monatin

The ammonium salt of (4S) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid (4.5 g, 13.1 mmol) is dissolved in 100 ml of aqueous 28% ammonia, then 3.4 g of 5% are added rhodium on carbon (50% aqueous product) for interaction at ambient temperature and a hydrogen pressure of 10 atmospheres (1 MPa). After 24 hours, the catalyst was filtered off. The filtrate was concentrated. 40 ml of aqueous 90% ethanol was added to the concentrate and stirred at 25 ° C. for 1.5 hours. The crude crystals precipitated were filtered off. 40 ml of aqueous 90% ethanol was added to the crude crystals and stirred at 25 ° C for 1.5 hours. The purified crystals precipitated were filtered off, dried under reduced pressure to obtain 0.57 g (1.84 mmol) of ammonium salt (2S 4S) monatina. (Yield 14.1%; optical purity 99.5%).

¹ H-NMR (400 MHz, D ₂ O) δ: 2.06 (dd, J = 11.8, 15.3 Hz, 1H), 2.67 (dd, J = 2.0, 15.2 Hz , 1H), 3.08 (d, J = 14.4 Hz, 1H), 3.28 (d, J = 14.4 Hz, 1H), 3.63 (dd, J = 2.2, 12, 2 Hz, 1H), 7.12-7.16 (m, 1H), 7.20-7.24 (m, 2H), 7.48-7.49 (m, 1H), 7.71-7 73 (m, 1H).

Calculated value (MS-ESI) C ₁₄ H ₁₆ N ₂ O ₅ = 292.29

Found Value = 291.28 (MH ^- )

Example 25

Obtaining ammonium salt (2S, 4S) monatin

The (4S) -4-hydroxy-4- (3-indolylmethyl) -2-hydroxyiminoglutaric acid ammonium salt (14.0 g, 41.1 mmol) was dissolved in 120 ml of aqueous 28% ammonia, then 7.38 g of 5% was added rhodium on carbon (50% aqueous product) for interaction at ambient temperature and a hydrogen pressure of 1 MPa. After 24 hours, the catalyst was filtered off. The filtrate was concentrated. To 17.68 g of concentrate was added 110 ml of aqueous 88% ethanol and stirred at 25 ° C for 19 hours. The resulting crude crystals were filtered off and dissolved in 15 ml of water, then 100 ml of ethanol was added. After stirring at 25 ° C for 1.5 hours, the precipitated purified crystals are filtered off, dried under reduced pressure to obtain 4.94 g (16.0 mmol) of ammonium salt of (2S, 4S) monatin. (Yield 39.2%; optical purity 99.9%.)

Example 26

Preparation of (2S, 4S) Monatin in Free Form

The ammonium salt of (2S, 4S) monatin (2.22 g, 7.18 mmol) obtained in the above example was dissolved in a mixed solvent (4.5 ml of water and 4.2 ml (71.8 mmol) of acetic acid) then, 50 ml of ethanol is added dropwise to the resulting solution at 25 ° C. over about 3 hours. After further stirring for 0.5 hours, the crystals formed are filtered off, dried under reduced pressure to obtain 1.93 g (6.62 mmol) ( 2S, 4S) monatin. (Yield 92.2%; ammonium content 0.19% by weight).

Comparative example one

Using cinchonidine instead of the optically active amine used in Example 20, the same procedures are carried out. The optical purity of the obtained crystals is 0%.

Reference Example 2

Instead of the optically active amine used in Example 20, L-lysine is used. However, no crystals are obtained.

Reference Example 3

Instead of the optically active amine used in Example 20, L-arginine is used. However, no crystals are obtained.

Industrial applicability

According to the invention, glutamic acid derivatives, typically comprising monatin, are useful as a sweetener or an intermediate for the manufacture of pharmaceutical products and can be efficiently prepared in industry. In accordance with this invention, optically active monatin, in addition, can be obtained in industry.

Claims (24)

1. A method of obtaining derivatives of glutamic acid represented by the following formula (7), or their salts, comprising (a) a step of cross-aldol condensation of a pyruvic acid derivative represented by formula (1) and oxalic-acetic acid represented by the following formula (2), and a decarboxylation reaction or (b) cross-aldol condensation of this pyruvic acid derivative (except pyruvic acid) with pyruvic acid represented by the formula (2 ') to obtain a ket derivative oglutaric acid represented by the formula (4), or a salt thereof, and a step for converting the carbonyl group of the ketoglutaric acid derivative or its salt into an amino group in which the pyruvic acid derivative, oxalic acetic acid and pyruvic acid can be separately in the form of salts

where R ¹ represents a group selected from a lower (C _1-3 ) alkyl group, a 3-indolyl group, a phenyl group, a phenyl (C _1-3 ) alkyl group or a 3-indolyl (C _1-3 ) alkyl group; R ¹ may have at least one substituent selected from a hydroxyl group, an alkyl group containing 1-3 carbon atoms or an amino group. 2. The method according to claim 1, wherein the step of converting the carbonyl group of the ketoglutaric acid derivative represented by the formula (4) or a salt thereof into an amino group includes the step of reacting an amino compound represented by the following formula (5) or a salt thereof with ketoglutaric acid or a salt thereof for for the preparation of a glutaric acid derivative represented by the formula (6), or a salt thereof, and a step for reducing a glutaric acid derivative or a salt thereof

where R ¹ represents a group selected from a lower (C _1-3 ) alkyl group, a 3-indolyl group, a phenyl group, a phenyl (C _1-3 ) alkyl group or a 3-indolyl (C _1-3 ) alkyl group; R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; R ¹ may have at least one substituent selected from a hydroxyl group, an alkyl group containing from 1 to 3 carbon atoms, or an amino group. 3. The method according to claim 1, where the stage of conversion of the carbonyl group of the ketoglutaric acid derivative represented by the formula (4), or its salt into an amino group, includes the step of reductive amination of the ketoglutaric acid or its salt. 4. The method according to any one of claims 1 to 3, where the cross aldol condensation is carried out in the pH range from 10 to 14. 5. The method according to claim 1, where the glutamic acid derivative of the formula (7) is monatin, represented by the formula (7 ') below, or a salt thereof, indole-3-pyruvic acid of the following formula is used as the pyruvic acid derivative of the formula (1): 1 '), and as a ketoglutaric acid derivative of the formula (4) or its salt, 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by the formula (4') or its salt, where indole-3 is obtained -pyruvic acid, oxalic-acetic acid and pyruvic acid can be individually used b in the form of its salts

6. The method according to claim 5, where the stage of conversion of the carbonyl group of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by the formula (4 '), or its salt into an amino group includes the step of reacting an amino compound of the formula (5) or a salt thereof with ketoglutaric acid or a salt thereof to obtain a glutaric acid derivative represented by the formula (6 '), or a salt thereof and a step for reducing a glutaric acid derivative or a salt thereof

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group. 7. The method according to claim 5, where the stage of conversion of the carbonyl group of 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by formula (4 '), or its salt into an amino group includes the step of reductive amination of the ketoglutaric acid derivative or its salt. 8. The method according to any one of claims 5 to 7, where the cross aldol condensation is carried out in the pH range from 10 to 14. 9. A method of producing a ketoglutaric acid derivative represented by the formula (4) or a salt thereof, comprising a step of cross-aldol condensing the pyruvic acid derivative represented by the formula (1) and oxalic-acetic acid represented by the formula (2), and decarboxylation, or a step cross-aldol condensation of a pyruvic acid derivative (excluding pyruvic acid) and pyruvic acid represented by the formula (2 '), wherein the pyruvic acid derivative is oxalic vinegar Separated acid and pyruvic acid can individually be in the form of their salts

where R ¹ represents a group selected from a lower (C _1-3 ) alkyl group, a 3-indolyl group, a phenyl group, a phenyl (C _1-3 ) alkyl group or a 3-indolyl (C _1-3 ) alkyl group; and R ¹ may have at least one substituent selected from a hydroxyl group, an alkyl group containing 1-3 carbon atoms, or an amino group. 10. The method according to claim 9, where the cross aldol condensation is carried out in the pH range from 10 to 14. 11. A method of producing a glutamic acid derivative represented by the formula (7) below, or a salt thereof, comprising the step of reacting a ketoglutaric acid derivative represented by the formula (4) or a salt thereof with an amino compound represented by the formula (5) or a salt thereof to produce a derivative glutaric acid represented by the formula (6) below, or a salt thereof, and a step for recovering the resulting glutaric acid derivative or salt thereof

where R ¹ represents a group selected from a lower (C _1-3 ) alkyl group, a 3-indolyl group, a phenyl group, a phenyl (C _1-3 ) alkyl group or a 3-indolyl (C _1-3 ) alkyl group; R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; and R ¹ may contain at least one substituent selected from a hydroxyl group, an alkyl group containing from 1 to 3 carbon atoms, or an amino group. 12. The method according to claim 11, where the glutamic acid derivative of formula (7) is monatin, represented by formula (7 ') below, or a salt thereof, 4-hydroxy-4- is used as a ketoglutaric acid derivative of formula (4) or its salt (3-Indolylmethyl) -2-ketoglutaric acid represented by the formula (4 ′) below, or a salt thereof, and, as a glutaric acid derivative of the formula (6) or a salt thereof, the glutaric acid derivative represented by the formula below (6 ′), or its salt

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group. 13. A method of obtaining a glutamic acid derivative represented by the formula (7) or a salt thereof, comprising the step of reductive amination of a ketoglutaric acid derivative represented by the formula (4) or a salt thereof

where R ¹ represents a group selected from a lower (C _1-3 ) alkyl group, a 3-indolyl group, a phenyl group, a phenyl (C _1-3 ) alkyl group or a 3-indolyl (C _1-3 ) alkyl group; and R ¹ may contain at least one substituent selected from a hydroxyl group, an alkyl group containing 1-3 carbon atoms, or an amino group. 14. The method according to item 13, where the glutamic acid derivative of formula (7) is monatin, represented by formula (7 ') below, or a salt thereof, 4-hydroxy-4- is used as a ketoglutaric acid derivative of formula (4) or its salt (3-Indolylmethyl) -2-ketoglutaric acid represented by the formula (4 ') below, or a salt thereof

15. The method of obtaining 4-hydroxy-4- (3-indolylmethyl) -2-ketoglutaric acid represented by the formula (4 '), or its salt, comprising the step of cross-aldol condensation of indole-3-pyruvic acid represented by the formula (1') and oxalic acetic acid represented by the formula (2), and decarboxylation, or aldol condensation of indole-3-pyruvic acid of the formula (1 ') and pyruvic acid of the formula (2'), where indole-3-pyruvic acid, oxalic-acetic acid acid and pyruvic acid may be individually located in de corresponding salts

16. The method according to clause 15, where the cross aldol condensation is carried out in the pH range from 10 to 14. 17. A method of obtaining an optically active monatin represented by the formula (8) below, or a salt thereof

where the designation * indicates an asymmetric center and independently represents the R- or S-configuration, comprising the crystallization step of monatin represented by formula (13), or a salt thereof, using a mixed solvent of water and alcohol

where the designation * indicates the asymmetric center and independently represents the R- or S-configuration, and the bond marked with a wavy line indicates that both the R-configuration and the S-configuration are included. 18. The method according to 17, where the monatin represented by the formula (13), or its salt

where the designation * indicates the asymmetric center and independently represents the R- or S-configuration, and the bond marked with a wavy line indicates that both the R-configuration and the S-configuration are included, obtained by a method comprising stages a-b: step a: a step for producing a salt of an optically active glutaric acid derivative represented by the formula (11)

where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ denote such substituents as described below; the designation * indicates the asymmetric center and independently represents the R- or S-configuration, the interaction of the glutaric acid derivative represented by the formula (9)

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group, and a bond indicated by a wavy line indicates that both the R configuration and S are included -configuration, with an optically active amine represented by the following formula (10)

where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom, the designation * indicates the asymmetric center and represents the R configuration or S configuration, which leads to the formation of a diastereoisomeric salt, and the step of isolating the diastereoisomeric salt by crystallization; step b: the step of generating a monatin of formula (13) or a salt thereof by dissociating a salt of an optically active glutaric acid derivative represented by formula (11) or by exchanging a salt of an optically active glutaric acid derivative with another salt, which is necessary to obtain an optically active glutaric acid derivative, represented by formula (12), or a salt thereof (except for the salt of the optically active glutaric acid derivative represented by formula (11))

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group, the designation * indicates an asymmetric center and independently represents the R or S configuration, and the step of converting an alkoxyimino group or hydroxyimino group to an amino group. 19. The method according to 17, where the monatin represented by the formula (13), or its salt

where the designation * indicates the asymmetric center and independently represents the R- or S-configuration, and the bond marked with a wavy line indicates that both the R-configuration and the S-configuration are included, obtained by a method comprising the step of generating monatin represented by formula (13), or a salt thereof, by dissociating a salt of an optically active glutaric acid derivative represented by formula (11) below

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom; * indicates the asymmetric center and independently represents the R-configuration or S-configuration, or by exchanging a salt of an optically active glutaric acid derivative with another salt necessary to obtain an optically active glutaric acid derivative represented by formula (12) or a salt thereof (except for a salt of an optically active glutaric acid derivative represented by formula (11))

where R represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; and the designation * indicates the asymmetric center and independently represents the R-configuration or S-configuration, and converting an alkoxyimino group or hydroxyimino group of an optically active glutaric acid derivative to an amino group. 20. A method of obtaining a salt of an optically active derivative of glutaric acid represented by the following formula (11)

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom, and the designation * indicates an asymmetric center and independently represents an R or S configuration, comprising the step of reacting a glutaric acid derivative represented by the formula below (9)

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or phenyl (C _1-3 ) alkyl group, and a bond indicated by a wavy line means that both the R configuration and S are included -configuration, with an optically active amine represented by the following formula (10)

where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom, the designation * indicates an asymmetric center and represents the R- or S-configuration, which leads to the formation of a diastereoisomeric salt, and a step for isolating the diastereoisomeric salt by crystallization. 21. A method of obtaining an optically active glutaric acid derivative represented by the formula (12) or a salt thereof (except for the salt of the optically active glutaric acid derivative represented by the formula (11))

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group, the designation * indicates an asymmetric center and represents the R or S configuration, comprising the step of dissociating a salt of an optically active glutaric acid derivative represented by the formula (11)

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom, and the designation * indicates an asymmetric center and independently represents an R or S configuration, or exchanging a salt of an optically active glutaric acid derivative with another salt. 22. A method of producing monatin, represented by the formula (13) below, or a salt thereof

where the designation * indicates the asymmetric center and represents the R- or S-configuration, and the bond marked with a wavy line indicates that both the R-configuration and the S-configuration are included, comprising the step of dissociating a salt of an optically active glutaric acid derivative represented by the formula (11)

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom, and the designation * indicates an asymmetric center and independently represents an R or S configuration, or by exchanging a salt of an optically active glutaric acid derivative with another salt necessary to obtain an optically active glutaric acid derivative represented by formula (12) or a salt thereof (except for a salt of an optically active glutaric acid derivative of formula (11))

where R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group, the designation * indicates an asymmetric center and represents the R or S configuration, and a step for converting the alkoxyimino group or hydroxyimino group of the obtained optically active glutaric acid derivative into an amino group. 23. The method according to any one of claims 1 to 3, 11 or 13, where the glutamic acid derivative of the formula (7) is monatin, represented by structural formula (7 '), (including monatin in the form of salts)

24. A compound represented by any of the following formulas: (4 '), (6'), (7 "), (11), (12), (14), (15), (16) or (17) (including these compounds in the form of salts), where in the formulas R ² represents a hydrogen atom, a lower (C _1-3 ) alkyl group, a phenyl group or a phenyl (C _1-3 ) alkyl group; R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently represent a hydrogen atom; and the designation * indicates an asymmetric center and represents the R- or S-configuration