JP2003171365A - Method for producing monatin compound, its production intermediate, and new intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a monatin compound expectable as a sweetening component for sweeteners, foods and drinks on an industrial scale in high efficiency. <P>SOLUTION: An indoleacetic acid derivative having a proper protecting group is reacted with an acid halide of aspartic acid preferably in the presence of a base, the produced condensation product is subjected to decarbonation and deprotection to obtain a new stereoselectively synthesized ketone derivative such as 2-amino-5-(3- indolyl)-4-oxopentanoic acid, the product is cyanohydrinated preferably under a basic condition and the obtained cyanohydrin derivative is hydrolyzed under a basic condition to obtain a crude monatin compound. The objective monatin compound having high purity can be produced by converting the crude monatin compound into a derivative by a means such as the introduction of a protecting group, purifying the compound in the form of the derivative and removing the protecting group by deprotection reaction. The present invention provides an excellent method for the production of a monatin compound (monatin or its steric isomer), a method for the efficient production of an important production intermediate for the former method and the important new intermediate produced by the method. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention includes monatins (stereoisomers, those in the form of salts, those having protected functional groups, etc.) which are excellent as sweeteners or active ingredients thereof. ) And a novel intermediate therefor.

[0002]

2. Description of the Related Art In recent years, with the advancement of eating habits, obesity due to excessive intake of sugar and various diseases associated therewith have become a problem, and development of a low-calorie sweetener to replace sugar is strongly desired. . The required sweetener is required to have various properties and requirements such as low calorie, safety, stability against heat and acid, sweetness quality, cost and the like, in addition to sweetness intensity.

Various sweeteners are currently used or proposed. For example, aspartame, which has been put to practical use as a sweetener having a high sweetness intensity and capable of being mass-produced industrially and widely used, is aspartame which is excellent in safety and sweetness quality. Furthermore, research on derivatives of aspartame is being actively conducted. In addition to these, sweetening substances having various properties have been proposed as sweetening agents, and studies have been made for practical use. In addition, plant-derived thaumatin, glycyrrhizin, stevioside and the like which are naturally present and can be collected in large quantities are currently used as natural sweeteners.

Monatin is a plant that grows naturally in the northern Transvaal region of South Africa. Schlerochito
n. ilicifolius) is a naturally-occurring amino acid derivative isolated from the bark of R. Vleggaar and its structure is (2
S, 4S) -2-amino-4-carboxy-4-hydroxy-5- (3-indolyl) -pe
ntanoic acid ((2S, 4S) -4-hydroxy-4- (3-indolylmethy
l) -glutamic acid; see the structural formula (1) below. ) Is reported (R. Vleggaar et. Al., J. Chem. Soc. Perkin
See Trans., 3095-3098, (1992). ). The sweetness of the (2S, 4S) form derived from this natural plant is reported to be 800 times or 1400 times that of sucrose according to the same literature. Several methods for monatin synthesis have been reported, but none is suitable as an industrial production method (as an example of synthesis, PJ van Wyk et.al., ZA 87/428).
8, Holzapfel et.al., Synthetic Communications, 24
(22), 3197-3211 (1994), E. Abushanab et. Al., US
5,994,559 (1999), K. Nakamura et. Al., Organic Let
ters, 2 , 2967-2970 (2000), etc. ). PJ van Wy
k is methyl 2- (t-butoxycarbony, which is a ketone derivative.
lamino) -5- (Nt-butoxycarbonylindolyl-3 ')-4-oxopent
Anoate is reacted with trimethylsilyl cyanide using 18-crown-6 and potassium cyanide as a catalyst to obtain a cyanohydrin derivative, which is acid-hydrolyzed to obtain monatin. The yield is 22%.
In addition, 2- (t-butoxycarbonylamino) -5- (Nt-butoxycarbo
During the synthesis of nylindolyl-3 ')-4-oxopentanoic acid, a large amount of 3- (t-butoxycarbonylamino) -isomer, which is its positional isomer, is by-produced, and the separation operation is complicated. CW Holzap
fel et al. are similar ketone derivatives such as methyl 2- (benzy
loxycarbonylamino) -5- (p-toluenesulfonylindolyl-3 ')
We have reported a stereoselective method for the synthesis of 4-oxopentanoate, but the removal method of the p-toluenesulfonyl group used as a protecting group for this compound is limited, and this ketone derivative is used as an intermediate for monatin synthesis. Is not suitable (C.
W. Holzapfel et al., Al., Synthetic Communication
s, 23 (18), 2511-2526 (1993). ). That is, a method of adding cyanohydrin to an intermediate ketone derivative and hydrolyzing the product to obtain monatin has not been sufficiently studied.

Under these circumstances, it is required to develop a practical method for synthesizing monatin.

[0006]

The problem to be solved by the present invention is to provide a method for producing monatin which can be expected to be put into practical use as a sweetener. Specifically, we developed a regioselective method for producing a ketone derivative that serves as a substrate for cyanohydrination and has an appropriate protecting group, and based on this, a method for producing monatin in good yield by performing cyanohydrination and hydrolysis. To provide.

[0007] Another object is to provide a method for efficiently purifying monatin from a reaction mixture.

[0008]

Means for Solving the Problems The inventors of the present invention have made extensive studies to solve the above problems. First, 2-amino-5- (lindolyl-3 ')-4-oxopentanoic aci, which is a substrate for cyanohydrination
d hydrochloride (in the general formula (4) described below, R ¹ ,
A stereoselective method for synthesizing a hydrochloride of a compound in which R ³ and R ⁴ are hydrogen atoms was investigated. It was found that the target novel ketone derivative can be obtained by decarboxylation and deprotection of a condensate obtained by reacting an indoleacetic acid derivative having an appropriate protecting group with an acid halide of aspartic acid in the presence of a base. It was It was also found that this method facilitates the purification.

Next, as a result of examining the cyanohydrination reaction conditions for the ketone derivative, it was found that cyanohydrination proceeds smoothly under basic conditions, not under the conventionally known acidic conditions or non-aqueous conditions. I found it.

As a result of various examinations of reaction conditions for hydrolyzing the obtained cyanohydrin derivative to convert it to monatin (α-hydroxy acid derivative), it was found that the base is more commonly used than the hydrolysis under acidic conditions which has been generally performed conventionally. It was found that hydrolysis under sexual conditions proceeded smoothly. It was also found that the reaction proceeds more smoothly when the reaction is carried out in the presence of boric acid or a boric acid salt.

Further, as a result of various studies on methods for purifying monatin from the reaction mixture, high-purity monatin can be easily obtained by introducing a specific protecting group into monatin to derivatize it, and purifying the monatin followed by deprotection. I found that

As described above, according to the present invention, Novel ketone derivative as a production intermediate; b. Novel reaction conditions for cyanohydrination for this intermediate; c. Hydrolysis conditions of the produced cyanohydrin derivative; d. A method for purifying the produced monatin; and e. In addition, new cyanohydrin derivatives, new monatin derivatives, and the like have been newly found, and the present invention has been completed based on these various findings.

That is, the present invention relates to a method for efficiently synthesizing and purifying monatin and related methods.

Particularly, the present invention includes the inventions of the following contents [1]-[10] as various modes of the present invention.

[1] A ketone represented by the following general formula (3) characterized by reacting an indoleacetic acid derivative represented by the following general formula (1) with an aspartic acid derivative represented by the following general formula (2). Method for producing derivative.

The ketone derivative may be in the form of various salts. In particular, a salt form with an acid or a base is adopted,
For example, as the acid, an inorganic acid such as hydrochloric acid and sulfuric acid, and an organic acid such as acetic acid and p-toluenesulfonic acid, and as the base, an inorganic base (hydroxide) containing a metal such as sodium, potassium and magnesium. Etc.), and ammonia,
Organic bases such as dicyclohexylamine may be mentioned. These salts can be easily produced by an ordinary salt-forming step, and the ketone derivative represented by the formula (3) can be removed (deprotected) from various protecting groups by an ordinary deprotecting step. It can also be manufactured in protected form, any of which is included in the method of the invention.

[0017]

[Chemical 30]

[0018]

[Chemical 31]

[0019]

[Chemical 32]

In the above formula, X represents a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, etc.), R ¹ , R ² , R
³ and R ⁴ each independently represent a protecting group. The stereochemistry of the asymmetric carbon is not limited, and any of (R), (S) and (RS) may be used.

As the protecting groups for the amino group, indolyl group and carboxyl group, the protecting groups used therefor in peptide synthesis and the like can be used. For example,
Amino groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, etc., indolyl groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, formyl group, etc., and carboxyl groups have 1 to 4 lower carbon atoms. An alkyl group, a benzyl group and the like can be adopted respectively.

The above reaction can be carried out in the presence of a base, and in this case, the reaction yield is improved, which is preferable.

With respect to the ketone derivative produced in the above reaction, the target substance produced in the purification step can be further purified.

The purification method is not particularly limited, and various chromatography, recrystallization (crystallization) methods and the like can be used.

For the selection of protecting groups throughout the present invention, protecting groups known, used or commonly used for peptide synthesis can be adopted. Therefore, for the carboxyl group, use the protecting group used as the protecting group for the carboxyl group, for the amino group, use the protecting group for the amino group, and for the indolyl group, use the protecting group for the indolyl group. Each of the protecting groups may be employed. The selection of such a protecting group is not limited to the invention of the above-mentioned embodiment, and is commonly applied to the entire invention. As to its specific contents, many publications on peptide synthesis can be referred to (see, for example, Izumiya et al., "Basics and Experiments of Peptide Synthesis", published by Maruzen in 1985. The contents are incorporated herein by reference. Incorporated).

[2] A ketone derivative represented by the following general formula (4) characterized by subjecting the ketone derivative represented by the following general formula (3) to a decarboxylation reaction or a decarboxylation reaction and a deprotection reaction. Production method.

The ketone derivative may be in the form of various salts. In particular, a salt form with an acid or a base is adopted,
For example, as the acid, an inorganic acid such as hydrochloric acid and sulfuric acid, and an organic acid such as acetic acid and p-toluenesulfonic acid, and as the base, an inorganic base (hydroxide) containing a metal such as sodium, potassium and magnesium. Etc.), and ammonia,
Organic bases such as dicyclohexylamine may be mentioned.

The method for producing this ketone derivative is described in [1] above.
From the viewpoint of operability, it is particularly preferable to carry out after the production process of.

[0029]

[Chemical 33]

[0030]

[Chemical 34]

In the above formulas (3) and (4), R ¹ , R ² ,
R ³ and R ⁴ each independently represent a hydrogen atom or a protecting group. The stereochemistry of the asymmetric carbon is not limited, and any of (R), (S) and (RS) may be used.

As the protecting groups for the amino group, the indolyl group and the carboxyl group, the protecting groups used therefor in peptide synthesis and the like can be used. For example,
Amino groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, etc., indolyl groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, formyl group, etc., and carboxyl groups have 1 to 4 lower carbon atoms. An alkyl group, a benzyl group and the like can be adopted respectively.

In this reaction, under catalytic reduction conditions,
Alternatively, it can be carried out in the presence of either acid or base. In this case, the reaction may be carried out in the presence of an acid or a base under catalytic reduction conditions.

Regarding the ketone derivative (4) thus produced,
It can be purified by a purification step. The purification method is not particularly limited, and various chromatography methods, recrystallization (crystallization) methods and the like can be used.

[3] A method for producing a cyanohydrin derivative represented by the following general formula (5) or (6), characterized by subjecting a ketone derivative represented by the following general formula (4) to a reaction for adding hydrogen cyanide .

The cyanohydrin derivative includes those in the form of various salts. In particular, a salt form with an acid or a base or the like is adopted. For example, as the acid, an inorganic acid such as hydrochloric acid or sulfuric acid, and an organic acid such as acetic acid or p-toluenesulfonic acid, and as the base, sodium, Inorganic bases (hydroxides, etc.) containing metals such as potassium and magnesium,
And organic bases such as ammonia and dicyclohexylamine.

The method for producing this cyanohydrin derivative is as follows:
The process can be performed after the manufacturing process [2], or can be continuously performed from the manufacturing process [1] through the manufacturing process [2]. As a result, operability is particularly preferable.

[0038]

[Chemical 35]

[0039]

[Chemical 36]

[0040]

[Chemical 37]

In the above formulas (4) to (6), R ¹ , R ³ and R ⁴ each independently represent a hydrogen atom, a metal atom or a protecting group. M represents a hydrogen atom or a metal atom. There is no restriction on the stereochemistry of the asymmetric carbon.
Any of (R), (S) and (RS) may be used.

Examples of the metal atom include alkali metals such as sodium and potassium, and alkaline earth metals such as magnesium.

As the protecting groups for the amino group, indolyl group and carboxyl group, the protecting groups used therefor in peptide synthesis and the like can be used. For example,
Amino groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, etc., indolyl groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, formyl group, etc., and carboxyl groups have 1 to 4 lower carbon atoms. An alkyl group, a benzyl group and the like can be adopted respectively.

The above reaction can be easily carried out by the reaction of adding hydrogen cyanide to the carbonyl group. For example,
It can be carried out under basic conditions in the presence of cyanide such as sodium cyanide and potassium cyanide.

The cyanohydrin derivative (5) or (6) produced in the above reaction can be purified by a purification step.

The purification method is not particularly limited, and various chromatography, recrystallization (crystallization) methods and the like can be used.

[4] Represented by the following general formula (7) or (8), which is characterized in that the cyanohydrin derivative represented by the following general formula (5) or (6) is subjected to a hydrolysis reaction under basic conditions. Method for producing monatin derivative.

[0048]

[Chemical 38]

[0049]

[Chemical Formula 39]

[0050]

[Chemical 40]

[0051]

[Chemical 41]

In the above formulas (5) to (8), R ¹ , R ³ and R ⁴ each independently represent a hydrogen atom, a metal atom or a protecting group. Multiple M's each independently represent a hydrogen atom or a metal atom.

There is no particular limitation on the stereochemistry of the asymmetric carbon. Any of (R), (S) and (RS) may be used.

Regarding the protecting group, as the protecting group for the amino group, the indolyl group and the carboxyl group, the protecting groups used therefor in peptide synthesis and the like can be used. For example, a t-butyloxycarbonyl group, a benzyloxycarbonyl group or the like is used as an amino group, a t-butyloxycarbonyl group, a benzyloxycarbonyl group, a formyl group or the like is used as an indolyl group, and a carbon group having 1 to 4 carbon atoms is used as a carboxyl group. The lower alkyl group, the benzyl group, etc. of can be adopted respectively.

Examples of the metal of the metal atom include alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium.

As the cyanohydrin derivative represented by the general formula (5) or (6) used as a starting material in the reaction [4], the derivative (5) or (6) produced in the production method [3] is used. Can be used. Therefore, after carrying out the method [3], the method [4] can be continuously carried out to produce the object of the method. Furthermore, from the above method [2] and the previous method [1], method [2]-
[4] or the method [1]-[4] is continuously carried out to carry out the reaction.
The target substance of [4] can also be produced.

The above reaction can be carried out in the presence of a base. There is no limitation on the type of base used. For example, examples of the base include inorganic bases (hydroxides, etc.) containing metals such as sodium, potassium and magnesium, and organic bases such as ammonia and dicyclohexylamine.

The amount of the base used in this case is preferably about 1 to 10 mol, more preferably about 2.2 to 5.5 mol, per mol of the starting material.

Further, the reaction can be carried out in the presence of boric acid (including those in the form of borate) together with a base. For example, per mole of starting material boric acid,
(Boric acid, borate, boric acid + borate, etc.) is preferably about 0.1 to 2 mol, more preferably 0.4 to 0.
About 8 mol can be used.

The produced monatin derivative (7) or (8) can be further purified by a purification step.

The purification method is not particularly limited, and various chromatography, recrystallization (crystallization) method and the like can be used.

The monatin derivative obtained by the above method can be separated into a highly pure target derivative by the above-mentioned purification step. In addition, a reaction [5] in which the following protecting group is introduced and the subsequent deprotection are introduced. Impurities can be removed more simply and efficiently by passing through the protection reaction [6]. Examples of impurities include polymeric substances that are by-products in the above reactions [3] and [4] and are insoluble in water and organic solvents.

[5] The following general formulas (9), (10) and (11) characterized by subjecting the monatin derivative represented by the following general formula (7) or (8) to a reaction for introducing a protecting group. The manufacturing method of the monatin derivative shown by either of 1).

[0064]

[Chemical 42]

[0065]

[Chemical 43]

[0066]

[Chemical 44]

[0067]

[Chemical formula 45]

[0068]

[Chemical formula 46]

In the above formulas (7) and (8), R ¹ and R
⁴ each independently represent a hydrogen atom, a metal atom or a protecting group. Multiple M's each independently represent a hydrogen atom or a metal atom. Among a plurality of existing metal atoms, the same or different kinds of metal atoms can be mutually represented.

In the above formulas (9), (10) and (11),
R ¹ , R ³ , R ⁴ and R ⁵ are each independently of the other,
Each represents a hydrogen atom or a protecting group.

The stereochemistry of the asymmetric carbon is not particularly limited. Any of (R), (S) and (RS) may be used.

As the protecting groups for the amino group, the indolyl group and the carboxyl group, the protecting groups used therefor in peptide synthesis and the like can be used. For example,
Amino groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, etc., indolyl groups include t-butyloxycarbonyl group, benzyloxycarbonyl group, formyl group, etc., and carboxyl groups have 1 to 4 lower carbon atoms. An alkyl group, a benzyl group and the like can be adopted respectively.

Regarding the method of introducing the protecting group itself, the method already known in the peptide synthesis and the like can be used (see the above-mentioned publication).

As the monatin derivative represented by the general formula (7) or (8) used as a starting material in the reaction [5], the derivative (5) produced in the production method [4].
Alternatively, (6) can be used. In particular, it is extremely effective in purifying the product of the reaction [4] containing impurities such as by-products. Furthermore, by continuously performing the following deprotection reaction [6], the target monatin represented by the following general formula (10) can be obtained in high purity.

Regarding the produced monatin derivative (any of the compounds (9), (10) and (11)),
Further purification can be performed by a purification step.

The purification method is not particularly limited, and various chromatographic methods, recrystallization (crystallization) methods and the like can be used.

[6] Deprotecting the monatin derivatives represented by the following general formulas (9), (10) and (11), more preferably containing impurities, the following general formula (9):
The general formula (1) characterized in that the monatin derivative represented by (10) and (11) is purified and then deprotected.
0) (In the formula, R ¹ , R ³ , R ⁴ and R ⁵ are hydrogen atoms.)
A method for producing a compound (monatin) represented by (including those in the form of a salt).

[0078]

[Chemical 47]

[0079]

[Chemical 48]

[0080]

[Chemical 49]

In the above formulas (9), (10) and (11),
R ¹ , R ³ , R ⁴ and R ⁵ are each independently of the other,
Each represents a hydrogen atom or a protecting group.

The stereochemistry of the asymmetric carbon is not particularly limited. Any of (R), (S) and (RS) may be used.

The method of deprotecting (eliminating) the protecting group itself can be carried out by utilizing the method already known in the peptide synthesis and the like (see the above-mentioned publication).

As described above, this method [6] is suitable as a method for purifying the above-mentioned monatin derivative when combined with the above-mentioned method [5], and makes the target monatin represented by the general formula (10) highly pure. Can be obtained.

The product can be purified by a conventional purification means such as various chromatography, recrystallization method, crystallization method (crystallization), extraction operation and the like.

The deprotection method can be carried out by utilizing a reaction carried out under catalytic reduction conditions or in the presence of an acid or a base. An acid or a base may coexist under catalytic reduction conditions.

The monatin derivative represented by any of the general formulas (9), (10) and (11) containing the above-mentioned impurities as the starting material in this method is the compound (9 ), (10) and (11) can be used.

The above general formula (10) (in the formula, R ¹ , R ³ ,
R ⁴ and R ⁵ are hydrogen atoms. The purification method which gives the salt of the compound (monatin) shown by these is preferable.

Examples of the salt in that case include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and p-toluenesulfonic acid,
Examples thereof include salts with metal-containing inorganic bases such as sodium, potassium and magnesium, or organic bases such as ammonia and dicyclohexylamine.

In the present invention, by appropriately selecting the reaction conditions of the reaction step, monatin represented by the general formula (10) is in the form of each stereoisomer and a mixture of two or more thereof. Can be obtained at. It can be used as a sweetener.

On the other hand, the optical isomer can be further separated from a mixture of two or more kinds by a conventional optical resolution means or the like or a part of the optical purification can be performed. The monatin thus separated or partially purified optically corresponds to the monatin obtained by the method of the present invention, and can be used as a sweetener.

The methods of the present invention are listed above.
Inventions of novel substances are listed below. The inventions relating to the following novel substances are naturally included in the present invention. The method for producing these novel substances is omitted because it is as described in the invention of the above method.

[7] A novel compound characterized by being represented by any one of the following general formulas (3) and (4); a ketone derivative. Also included are those in the form of salts.

The stereochemistry of the asymmetric carbon is not limited, and any of (R), (S) and (RS) may be used.

[0095]

[Chemical 50]

[0096]

[Chemical 51]

R ¹ and R ⁴ are each independently a hydrogen atom, a t-butoxycarbonyl group or a benzyloxycarbonyl group, and R ² and R ³ are independently a hydrogen atom, a carbon number of 1 to 1 Either the alkyl group or the benzyl group of 4 is represented.

The ketone derivative of the present invention includes those in the form of various salts, examples of which include salts with acids and salts with bases. Examples of such acids and bases include inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and p-toluenesulfonic acid, inorganic bases containing metals such as sodium, potassium and magnesium, and ammonia and dicyclohexylamine. The organic bases of can be mentioned.

[8] A novel compound characterized by being represented by any one of the following general formulas (5) and (6); a cyanohydrin derivative. Also included are those in the form of salts.

The stereochemistry of the asymmetric carbon is not limited, and any of (R), (S) and (RS) may be used.

[0101]

[Chemical 52]

[0102]

[Chemical 53]

In the above formulas (5) and (6), R ¹ and R ⁴
Are each independently a hydrogen atom, a substituent selected from sodium, potassium, a t-butoxycarbonyl group and a benzyloxycarbonyl group, and R ³ and M are each independently a hydrogen atom, sodium. And a substituent selected from potassium, respectively.

The cyanohydrin derivative of the present invention includes those in the form of various salts, and examples thereof include salts with acids and salts with bases. Such an acid,
Examples of the base include inorganic acids such as hydrochloric acid and sulfuric acid, acetic acid, organic acids such as p-toluenesulfonic acid, sodium, potassium,
Examples thereof include inorganic bases containing metals such as magnesium, and organic bases such as ammonia and dicyclohexylamine.

[9] A novel compound characterized by being represented by any one of the following general formulas (7) and (8); monatin derivatives. Also included are those in the form of salts.

The stereochemistry of the asymmetric carbon is not limited, and any of (R), (S) and (RS) may be used.

[0107]

[Chemical 54]

[0108]

[Chemical 55]

In the above formulas (7) and (8), R ¹ and R ⁴
Are each independently a hydrogen atom, a substituent selected from a sodium atom, a potassium atom, a t-butoxycarbonyl group and a benzyloxycarbonyl group, and a plurality of Ms are each independently a hydrogen atom, a sodium atom and a potassium atom. The substituents selected from are respectively represented.

The monatin derivative of the present invention includes those in the form of various salts, and examples thereof include salts with acids and salts with bases. Examples of such acids and bases include inorganic acids such as hydrochloric acid and sulfuric acid, acetic acid, organic acids such as p-toluenesulfonic acid, inorganic bases containing metals such as sodium, potassium and magnesium, and ammonia,
Organic bases such as dicyclohexylamine may be mentioned.

[10] A monatin derivative characterized by being represented by the following general formulas (9), (10) and (11). Also included are those in the form of salts.

The stereochemistry of the asymmetric carbon is not limited, and any of (R), (S) and (RS) may be used.

[0113]

[Chemical 56]

[0114]

[Chemical 57]

[0115]

[Chemical 58]

In the above formulas (9), (10) and (11),
R ¹ and R ⁴ are each independently of each other a substituent selected from a hydrogen atom, a t-butoxycarbonyl group and a benzyloxycarbonyl group, and R ³ and R ⁵ are independently of each other hydrogen. Atom, carbon number 1
Each of the substituents selected from the alkyl group and the benzyl group of 4 is represented.

The monatin derivative of the present invention includes those in the form of various salts, and examples thereof include salts with acids and salts with bases. Examples of such acids and bases include inorganic acids such as hydrochloric acid and sulfuric acid, acetic acid, organic acids such as p-toluenesulfonic acid, inorganic bases containing metals such as sodium, potassium and magnesium, and ammonia,
Organic bases such as dicyclohexylamine may be mentioned.

[0118]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below.

A method for producing the desired monatin through an optimum reaction route using the indoleacetic acid derivative represented by the general formula (1) and the aspartic acid derivative represented by the general formula (2) as starting materials. I will explain mainly. The present invention includes several inventions in various forms,
Typically, the invention includes a method for producing monatin (s), a method for producing intermediates (plurality of them) and an invention of a novel intermediate among these intermediates. All of the present invention can be easily understood on the basis of the following contents for explaining the production steps from the above-mentioned starting materials to the intended monatin (s). This content shows a preferred embodiment, and thus the present invention naturally includes this content, but is not limited to the content described below.

(Production of Ketone Derivative (3)) The ketone derivative represented by the general formula (3) can be produced according to the following route: “Synthetic route of ketone derivative 3”. As the protecting group and the base, those other than those shown in the following formula may be used.

[0121]

[Chemical 59]

Based on the above “Synthetic route of ketone derivative 3”, the desired ketone derivative (3) (derivative 3 etc.) can be easily produced. The abbreviations are as follows. Bzl: benzyl group; ^t Boc: t-butyloxycarbonyl group; Cbz: benzyloxycarbonyl group; Cl: chlorine atom; LDA: lithium diisopropylamide; THF: tetrahydrofuran.

The reaction temperature is preferably −20 to −.
About 80 ° C, more preferably about -60 to -78 ° C, can be selected. As the reaction solvent, preferably, tetrahydrofuran, ether, pentane, hexane, ethylbenzene, toluene, a mixed solvent of a plurality of these, or the like can be selected. The base used is LD
Examples include bases such as A, n-butyllithium and t-butyllithium. With respect to the amount used, a base can be used, preferably about 1 to 5 mol, more preferably about 2.5 to 3.5 mol, per 1 mol of the aspartic acid derivative.

As described above, for the selection of the protecting group, a protecting group known, used or conventionally used for peptide synthesis can be adopted. Therefore, for the carboxyl group, use the protecting group used as the protecting group for the carboxyl group, for the amino group, use the protecting group for the amino group, and for the indolyl group, use the protecting group for the indolyl group. Each of the protecting groups may be employed. The selection of such a protecting group is not limited to the invention of the above-mentioned embodiment, and is commonly applied to the entire invention. As to its specific content, many publications on peptide synthesis can be referred to (see, for example, Izumiya et al., "Basics and Experiments of Peptide Synthesis", 1985, Maruzen).

(Production of Ketone Derivative (4) by Decarboxylation of Ketone Derivative (3)) Regarding the production of the ketone derivative represented by the general formula (4), the route shown below: "Synthetic route of ketone derivative 4" Can be done according to. As the protecting group and reaction conditions, those other than those shown in the following formula may be used.

[0126]

[Chemical 60]

Based on the above “Synthetic Route of Ketone Derivative 4”, the desired ketone derivative (4) (derivative 4-1,
4-2) can be easily manufactured. The abbreviations are as follows, and the others are as described above. Pd-C: palladium on carbon; MeOH: methanol.

In the decarboxylation reaction, the reaction temperature is preferably about 10 to 40 ° C, more preferably 15 to 30 ° C.
You can choose the degree. As the reaction solvent, alcohols such as methanol, ethanol and isopropanol, water, ethyl acetate, acetonitrile, tetrahydrofuran and a mixed solvent of a plurality of these can be preferably selected. Further, as the reduction catalyst, a commonly used hydrogenation catalyst can be used. For example, palladium carbon, rhodium carbon, platinum carbon and the like can be mentioned as preferable catalysts.

When an acid or base is used, the type of acid or base is not particularly limited. For example, as the acid, an inorganic acid such as hydrochloric acid and sulfuric acid, and an organic acid such as acetic acid and p-toluenesulfonic acid, and as the base, an inorganic base (hydroxide) containing a metal such as sodium, potassium and magnesium. Etc.), and organic bases such as ammonia and dicyclohexylamine.

With respect to the amount used, an acid or a base can be used preferably about 1 to 20 mol, more preferably about 5 to 10 mol per mol of the starting material.

Regarding the deprotection reaction in the latter stage, the target protecting group can be easily eliminated by utilizing the elimination method commonly used in peptide synthesis. For example,
In the presence of hydrogen chloride, the reaction temperature is preferably −20 to 20.
About 25 ° C, more preferably about -5 to 5 ° C can be selected. As the reaction solvent, fatty acids such as formic acid and acetic acid, dioxane, tetrahydrofuran, ethyl acetate, alcohols (methanol, ethanol, isopropanol, etc.), and a mixed solvent of a plurality thereof can be preferably selected.

(Production of Cyanohydrin Derivative (5) by Cyanohydrination of Ketone Derivative (4)) The production of the cyanohydrin derivative represented by the above general formula (5) is carried out by the following route; “Synthetic route of cyanohydrin derivative 5” Can be done. Regarding the protecting group and the reaction conditions, those other than those shown in the following formula may be used as described above.

[0133]

[Chemical formula 61]

Based on the above-mentioned “Synthetic route of cyanohydrin derivative 5”, the desired cyanohydrin derivative (5)
(Derivative 5 and the like) can be easily produced. The abbreviations are as follows. K: potassium atom; KOHaq: potassium hydroxide aqueous solution.

The reaction temperature is preferably -5 to 50.
It is possible to select approximately 0 ° C, more preferably approximately 0 to 30 ° C. As the reaction solvent, water, alcohols such as methanol, ethanol and isopropanol, and a mixed solvent of a plurality of these can be preferably selected.

Regarding the reaction for adding hydrogen cyanide,
It can be carried out by utilizing a method known as a reaction method of adding hydrogen cyanide. Usually, a cyanide (cyan ion donor) such as sodium cyanide or potassium cyanide is used. The amount of cyanide used is preferably about 1 to 5 mol, more preferably about 1 to 2 mol, based on 1 mol of the starting material.

It is preferable to carry out the reaction under basic conditions,
In that case, the pH value can be preferably about 8 to 12, and more preferably about 9 to 11.

In this case, the type of base used is not limited, but potassium hydroxide, sodium hydroxide and the like are preferable.

(Production of Monatin Derivative (7) by Hydrolysis of Cyanohydrin Derivative (5)) Regarding the production of monatin represented by the general formula (7), the route shown below; “Synthetic route of monatin derivative (7)” Can be done according to. Regarding the reaction conditions, those other than those shown in the following formula may be used. In addition, as a result of the test,
Although the optical activity of the asymmetric center at the 2-position of monatin obtained under the following reaction conditions was lost, the monatin derivative having the optical activity can be obtained by using other hydrolysis methods. For example, the optically active monatin can be produced by using an enzymatic hydrolysis reaction.

[0140]

[Chemical formula 62]

Based on the above "synthesis route of monatin derivative (7)", the desired monatin derivative (7) (derivative 7 etc.) can be easily produced. The abbreviations are EtOH: ethanol, and the others are as described above.

The reaction temperature in the previous step (hydrolysis) is preferably about 60 to 100 ° C, more preferably 70 to 9
About 0 ° C can be selected. As the reaction solvent,
Preferably, water, alcohols such as methanol, ethanol and isopropanol, and a mixed solvent of a plurality of these can be selected.

Since the hydrolysis step is carried out under basic conditions,
In this reaction the derivative (7) is obtained in the form of a salt. The reaction temperature in the latter stage can be selected preferably about 80 to 100 ° C, more preferably about 90 to 95 ° C. As the reaction solvent, water, alcohols such as methanol, ethanol and isopropanol, and a mixed solvent of a plurality of these can be preferably selected.

(Production of Monatin Derivatives (9) and (10) by Derivatizing Monatin (7)) The route shown below for the synthesis of monatin derivatives represented by the above general formulas (9) and (10); It can be carried out according to “Synthetic route of monatin derivatives (9) and (10)”. As the protecting group and reaction conditions, those other than those shown in the following formula may be used.

[0145]

[Chemical formula 63]

The above-mentioned "monatin derivatives (9) and (1
Based on the synthetic route of 0), the target monatins can be easily produced. The abbreviations are as follows, and the others are as described above. SOCl ₂ : thionyl chloride; (Boc) ₂ O: di-
t- butyl dicarbonate; NaHCO _3: sodium bicarbonate; CHCl _3: chloroform.

The reaction temperature in the preceding step is preferably-
It is possible to select about 10 to 50 ° C, more preferably about 0 to 25 ° C. As the reaction solvent, alcohols such as methanol and ethanol can be preferably selected.

The reaction temperature in the latter stage is preferably 20 to
About 80 ° C, more preferably about 45-60 ° C, can be selected. The reaction solvent is preferably water,
A mixed solvent such as chloroform or dichloromethane can be selected.

There are no particular restrictions on the purification of the monatin derivatives (9) and (10). In particular, it is effective to carry out by silica gel chromatography, but it can also be purified by other purification methods.

Purified monatin derivatives (9) and (1
0) can be converted to monatin by removing the t-butoxycarbonyl group with hydrochloric acid, hydrolysis of the methyl ester with a base, and desalting purification by ion exchange chromatography. Deprotection and purification by desalting can be performed by other methods. May be.

[0151]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

¹ H-NMR spectrum was obtained by Bruker
MS spectrum was measured by Thermo Quest TSQ700 by AVANCE400 (400 MHz). HPLC-MS is Thermo Que
It was measured by st LCQ. AM for cation exchange resin
BELLITE IR120B AG was used.

Example 1 N-Benzyloxycarbonyl-L-β-aspartyl chloride α-benz
Synthesis of yl ester N-benzyloxycarbonyl-L- in 160 ml of toluene
Aspartic acid 1-benzyl ester (N-benzyloxycar
bonyl-L-aspartic acid 1-benzyl ester) 20.2g
(56.0 mmol) and thionyl chloride 40 ml
Was added and the mixture was heated with stirring at 50 ° C. for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, and N-benzyloxycarbonyl-L-β-aspartyl chloride α-benzyl ester (N-benzylo
xycarbonyl-L-β-aspartyl chloride α-benzyl este
r) 20.4 g (54.2 mmol, 97%) were obtained as a white solid.

(NMR spectrum) ¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm:
4.59-4.66 (1H, m), 5.12 (2H,
s), 5.19 (2H, s), 5.68 (1H, d),
7.30-7.38 (10H, m).

Example 2 Benzyl 2- (Benzyloxycarbonylamino) -5- (Nt-butyloxyc
arbonyl-3-indolyl) -5-benzyloxycarbonyl-4-oxopentan
Synthesis of oate Benzyl 1-t-butyloxycarbonylindole-3- in 20 ml of anhydrous tetrahydrofuran (THF) under nitrogen
Acetate (benzyl 1-t-butyloxycarbonylindole-3-ac
2.19 g (6.00 mmol) of etate) was added, and the reaction solution was cooled to -78 ° C with a dry ice bath. Lithium diisopropylamide (LDA) 9.0 ml (2.0 M
Solution, 18.0 mmol) and N-benzyloxycarbonyl-L-β-aspartyl chloride α-benzyl ester (N-benzyloxycarbonyl-L-β-aspartyl chloride α-
A solution of 2.25 g (6.00 mmol) of benzyl ester) in 15 ml of anhydrous THF was added, and the mixture was added at -78 ° C to 1.
Stir for 5 hours. After heating the reaction solution to 0 ° C., water 10 m
1 was added. The solution was neutralized by adding 100 ml of 10% aqueous citric acid solution, and extracted twice with 100 ml of ether. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give 4.45 g of the reaction mixture as a brown oil. 4.40 g of the crude reaction mixture was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 4) to give benzyl 2- (benzyloxycarbonylamino) -5- (Nt-butyloxycarbonyl-3). -Indolyl) -5-benzyloxycarbonyl-4-oxopentanoate (benzyl 2- (benzyloxycarbonylamino) -5- (Nt-but
yloxycarbonyl-3-indolyl) -5-benzyloxycarbonyl-4-oxo
pentanoate) 2.05 g (2.91 mmol, 49%)
Was obtained as a yellow oil.

(Example 3) 2-Amino-5- (Nt-butyloxycarbonyl-3-indolyl) -4-oxope
Synthesis of ntanoic acid benzyl 2- (benzyloxycarbonylami
no) -5- (Nt-butyloxycarbonyl-3-indolyl) -5-benzyloxy
carbonyl-4-oxopentanoate 138 mg (0.196 mmol) and 10% palladium-carbon (Pd-C) 40 mg
(50% water content) was added and the mixture was reduced under a hydrogen atmosphere at room temperature for 1 hour. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to
Amino-5- (Nt-butyloxycarbonyl-3-indolyl) -4-oxopentanoic acid (2-amino-5- (Nt-butyloxyca
rbonyl-3-indolyl) -4-oxopentanoic acid) 66mg
(0.191 mmol, 98%) was obtained as a white solid.

(NMR spectrum) ¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm:
1.63 (9H, s), 2.74 (1H, dd), 3.
09 (1H, dd), 3.45 (1H, m), 3.95
(2H, dd), 7.22 (1H, t), 7.32 (1
H, t), 7.60-7.58 (2H, m), 8.04.
(1H, d).

(MS spectrum) ESI-MS: 347.24 (M + H) ⁺ , 345.
23 (MH) ^- .

Example 4 2-Amino-5- (3-indolyl) -4-oxopentanoic acid hydrochl
Synthesis of oride 2-amino-5- (Nt-butyloxycarbonyl-3-indo in 2 ml of formic acid
52 mg (0.151 mmol) of lyl) -4-oxopentanoic acid was dissolved and the reaction solution was kept at 0 ° C. 4N-HCl /
0.30 ml of dioxane solution was added dropwise, and the mixture was reacted at 0 ° C for 0.5 hours. The reaction solution was concentrated under reduced pressure, the product was washed twice with 2 ml of ether, and then dried under reduced pressure to give 2-amino-5-
(3-Indolyl) -4-oxopentanoic acid hydrochloride (2-amino
-5- (3-indolyl) -4-oxopentanoic acid hydrochloride)
Obtained 43 mg (0.135 mmol, 89%) as a tan solid.

(NMR spectrum) ¹ H-NMR (CDCl ₃ , 400 MHz) δ ppm:
3.20-3.10 (2H, m), 3.89 (2H,
s), 4.15 (1H, t), 6.98 (1H, t),
7.07 (1H, t), 7.36 (1H, s), 7.3
7 (1H, d), 7.46 (1H, d), 11.04
(1H, s).

(MS spectrum) ESI-MS: 247.20 (M + H) ⁺ , 245.
19 (M-H) ^- .

Example 5 2-Amino-4-cyano-4-hydroxy-5- (3-indolyl) -pentanoic
Synthesis of acid 2-amino-5- (3-indolyl) -4-oxopentanoic acid hydrochl
5.95 g (21.1 mmol) oride of 2N-KOH26.
The suspension was suspended in 3 ml (52.6 mmol) and the solution was kept at 0 ° C. 2.06 g (31.6 mmol) of KCN was added thereto, the temperature was gradually raised, and the mixture was stirred at room temperature overnight. As a result of taking a part of the reaction solution and analyzing it by HPLC-MS, two main products were detected, and their molecular weights (MS spectra) were 2
73 ((M + H) ⁺ = 274), and 2-amino-4-cyano-4-hydroxy-5- (3-indolyl) -pentanoic acid (2
-amino-4-cyano-4-hydroxy-5- (3-indolyl) -pentanoic a
cid) and the molecular weight. Therefore, the two peaks detected by HPLC are 2-amino-4-cyano-4-hydroxy-5- (3-i
ndolyl) -pentanoic acid was identified as the diastereoisomer.

HPLC (High Performance Liquid Chromatography)
The conditions are as follows. Column: Inertsil ODS-80A 5μ 6x150mm; Detection: UV 210nm; Eluent: 10% acetonitrile 0.05% TFA Flow rate: 1.5ml / min; Measurement temperature: 25 ° C; and peak retention time: 12.7 minutes, 20.6
Minutes.

(Example 6) Synthesis of monatin (hydrolysis of cyanohydrin derivative) Borax (sodium tetraborate deachydrate ) was added to the above reaction solution.
Na ₂ B ₄ O ₇ · 10H ₂ O) (5.74 g, 15.1 mmol) was added, and the mixture was heated with stirring at 80 ° C. for 3 hours. 50 ml of ethanol and 2.53 g (63.15 mmol) of sodium hydroxide were added to the reaction solution, and the mixture was heated with stirring at 95 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure and dried. Take a part of the reaction product,
As a result of analysis by PLC, two main products were detected, and these had retention times corresponding to those of the diastereoisomer of authentic monatin (HPLC conditions were the same as above).

Example 7 2- (t-Butyloxycarbonylamino) -4- (3-indolylmethyl) -4-
Methoxycarbonyl-γ-butyrolactone and Metyl 2- (t-but
oxycarbonylamino) -4-methoxycarbonyl-4-hydroxy-5- (3
-Synthesis of indolyl) pentanoate The dried reaction product was suspended in 20 ml of methanol, and the reaction liquid was kept at 0 ° C. To this, thionyl chloride 1
3.5 ml (178.9 mmol) of methanol 50 m
The solution dissolved in 1 was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then di-t-butyl dicarbonate (d
it-butyl dicarbonate) 6.89 g (31.6 mmol), sodium hydrogen carbonate 8.84 g (105.3 mmol), sodium chloride 8.80 g, chloroform 10
0 ml and 100 ml of water were added, and the mixture was stirred at 55 ° C for 2 hours. The chloroform layer was separated and the aqueous layer was extracted with 50 ml of chloroform. Combine the chloroform layers with water 50m
It was washed with 1 and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure. The obtained reaction product was purified by PTLC (preparative thin layer chromatography), and 2- (t-butyloxycarbonylamino) -4- (3-indolylmethyl) -4-methoxycarbonyl was obtained.
-γ-butyrolactone) 2- (t-butyloxycarbonylamino) -4-
(3-indolylmethyl) -4-methoxycarbonyl-γ-butyrolacto
ne) and methyl 2- (t-butoxycarbonylamino) -4
-Methoxycarbonyl-4-hydroxy-5- (3-indolyl) pentanoate (methyl 2- (t-butoxycarbonylamin
o) -4-methoxycarbonyl-4-hydroxy-5- (3-indolyl) pentan
3.07 g of a mixture of oate) was obtained as a viscous oil.
The product was confirmed by MS spectrum.

(MS spectrum) ESI-MS: Lactone: 387.3 (MH) ^- . Diester: 421.3 (M + H) ⁺ , 419.3 (M
-H) ^- .

(Example 8) Synthesis of monatin (deprotection / purification) The above reaction product was dissolved in 35 ml of formic acid and kept at 0 ° C. To this, 19.8 ml of 4N-HCl / dioxane solution (79.1
(Mmol) and stirred at 0 ° C for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was washed with 10 ml of ether, and then dried. 20 ml of ethanol, 20 ml of water and 1.66 g (39.6 mmol) of lithium hydroxide monohydrate were added to the reaction product, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated, the residue was washed with 10 ml of ether and dried. 40 ml of ethanol, 5 ml of water and 5.9 ml of 4N sodium hydroxide were added, and the mixture was heated with stirring at 95 ° C for 3 hours. The reaction solution was concentrated, dissolved again in 20 ml of water, and then adsorbed on a cation exchange resin (H ⁺ type of AMBERLITE IR120B AG).
Elution was performed with aqueous ammonia. The eluate was freeze-dried to obtain 1.66 g of an ammonium salt of monatin.

(MS spectrum) ESI-MS: 291 (MH) ^- .

(NMR spectrum) ¹ H-NMR (400 MHz, D ₂ O) δppm: (2S, 4S) -form and (2R, 4R) -form monatin ammonium salt 1.96 (1H, dd, J = 11.8 Hz, J = 15.
2Hz), 2.57 (1H, dd, J = 1.9Hz, J
= 15.2 Hz), 3.00 (1H, d, J = 14.6)
Hz), 3.20 (1H, d, J = 14.6Hz),
3.54 (1H, d, J = 10.2 Hz), 7.04
(1H, t, J = 7.2 Hz), 7.10 (1H, t,
J = 7.2 Hz), 7.10 (1 H, s), 7.38
(1H, d, J = 8.0 Hz), 7.62 (1H, d,
J = 8.0 Hz).

(2S, 4R) body and (2R, 4S) body monatin ammonium salt 2.11 (1H, dd, J = 10.4 Hz, J = 15.
0Hz), 2.37 (1H, d, J = 15.4Hz),
3.13 (2H, s), 3.88 (1H, d, J = 9.
8Hz), 7.05 (1H, d, J = 7.6Hz),
7.14 (2H, s), 7.38 (1H, d, J = 7.
9 Hz), 7.63 (1H, d, J = 7.9 Hz).

[0171]

INDUSTRIAL APPLICABILITY In the present invention, an excellent method for producing monatins (monatin or stereoisomers thereof), which is a sweet substance and can be expected as a component of a sweetener, and an efficient production method of an important production intermediate therefor And further provides important novel intermediates thus obtained. Monatins can be easily industrially produced by these methods or via the above intermediates.

Therefore, according to the present invention, a sweetening substance having excellent properties as a sweetening ingredient, a sweetening ingredient for food and drink, etc.
Since it can be manufactured and provided industrially efficiently,
The present invention is extremely useful industrially, particularly in the food industry.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Nao Funakoshi             1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa             Amino Science Laboratory, Inc. (72) Inventor Masakazu Sugiyama             1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa             Amino Science Laboratory, Inc. F-term (reference) 4B047 LB04 LB08 LG05 LP16                 4C063 AA01 BB03 CC06 CC73 DD04                       DD06 EE10                 4C204 AB01 BB04 BB10 CB03 DB17                       EB02 FB01 FB27 GB01

Claims (31)

[Claims] 1. A ketone derivative represented by the following general formula (3), which comprises reacting an indoleacetic acid derivative represented by the following general formula (1) with an aspartic acid derivative represented by the following general formula (2). (Including those in the form of salt). [Chemical 1] [Chemical 2] [Chemical 3] In the above formula, X represents a halogen atom, and R ¹ , R ² , R ³ and R ⁴ each independently represent a protective group. Moreover, at least one of the protecting groups of the ketone derivative (3) may be eliminated. 2. The method according to claim 1, wherein the reaction is carried out in the presence of a base. 3. In the formulas (1) to (3), X is a chlorine atom or a bromine atom, R ¹ and R ⁴ are protecting groups selected from t-butoxycarbonyl group and benzyloxycarbonyl group, The method according to claim 1, wherein R ² and R ³ are protecting groups selected from an alkyl group having 1 to 4 carbon atoms and a benzyl group. 4. The method according to claim 1, further comprising a deprotection step and / or a salt formation step. 5. A ketone derivative represented by the following general formula (4), characterized in that the ketone derivative represented by the following general formula (3) is subjected to a decarboxylation reaction, or a decarboxylation reaction and a deprotection reaction. Including those in the form of salt). [Chemical 4] [Chemical 5] In the above formulas (3) and (4), R ¹ , R ² , R ³ and R ⁴
Each independently represent a hydrogen atom or a protecting group. 6. The method according to claim 5, wherein the ketone derivative represented by the general formula (3) is produced by the method according to claim 1. 7. The method according to claim 5, wherein the reaction is carried out under catalytic reduction conditions or in the presence of either an acid or a base.
The reaction may be carried out in the presence of an acid or base under catalytic reduction conditions. 8. In the formulas (3) and (4), R¹And R^Four
Is a hydrogen atom, t-butoxycarbonyl group and benzyl group
A substituent or a protecting group selected from an oxycarbonyl group
R ^TwoAnd R^ThreeIs a hydrogen atom, alkyl having 1 to 4 carbon atoms
A substituent or a protecting group selected from a group and a benzyl group
The method of claim 5. 9. A cyanohydrin derivative represented by the following general formula (5) or (6), characterized in that the ketone derivative represented by the following general formula (4) is subjected to a reaction of adding hydrogen cyanide (form of salt Including those in)). [Chemical 6] [Chemical 7] [Chemical 8] In the above formula (4), R ¹ , R ³ and R ⁴ each independently represent a hydrogen atom or a protecting group. In the above formulas (5) and (6), R ¹ , R ³ and R ⁴ each independently represent a hydrogen atom, a metal atom or a protecting group. M represents a hydrogen atom or a metal atom. 10. The process according to claim 9, wherein the reaction is carried out under basic conditions and in the presence of cyanide. 11. The method according to claim 9, wherein the ketone derivative represented by the general formula (4) is produced by the method according to claim 5. 12. A cyanohydrin derivative represented by the following general formula (5) or (6) is subjected to a hydrolysis reaction under basic conditions, and is represented by the following general formula (7) or (8). A method for producing a monatin derivative (including one in the form of a salt). [Chemical 9] [Chemical 10] [Chemical 11] [Chemical 12] In the above formulas (5) to (8), R ¹ , R ³ and R ⁴ each independently represent a hydrogen atom, a metal atom or a protecting group. In one molecule, a plurality of M's each independently represent a hydrogen atom or a metal atom,
When a plurality of metal atoms are represented, different kinds of metal atoms can be represented. 13. The method according to claim 12, wherein the reaction is carried out in the presence of a base. 14. Boric acid, including those in the form of salts.
14. The method according to claim 13, wherein the reaction is carried out in the presence of 15. The method according to claim 12, wherein the cyanohydrin derivative represented by the general formula (5) or (6) is produced by the method according to claim 9. 16. R ¹ and R ^{4 in the} above formulas (5) to (8).
Is a substituent or a protecting group selected from a hydrogen atom, sodium, potassium, a t-butoxycarbonyl group and a benzyloxycarbonyl group, and R ³ and M are a substituent selected from a hydrogen atom, sodium and potassium.
2. The method described in 2. 17. A monatin derivative represented by the following general formula (7) or (8) is subjected to a reaction for introducing a protecting group, and the following general formulas (9), (10) and (1) are provided.
A method for producing a monatin derivative represented by any of 1). [Chemical 13] [Chemical 14] [Chemical 15] [Chemical 16] [Chemical 17] In the above formulas (7) and (8), R ¹ and R ⁴ each independently represent a hydrogen atom, a metal atom or a protecting group. M represents a hydrogen atom or a metal atom. In one molecule, a plurality of M's each independently represent a hydrogen atom or a metal atom, and when they represent a plurality of metal atoms, they can represent different kinds of metal atoms. In the above formulas (9), (10) and (11), R ¹ , R ³ and R ⁴
And R ⁵ each independently represent a hydrogen atom or a protecting group. 18. The method according to claim 17, wherein the reaction of introducing a protecting group includes any of a reaction of esterifying a carboxyl group, a reaction of t-butoxycarbonylation or a benzyloxycarbonylation of an amino group or an indolyl group. . 19. The method according to claim 17, wherein the monatin derivative represented by the general formula (7) or (8) contains a polymer-like hardly soluble impurity. 20. The method according to claim 17 or 19, wherein the monatin derivative represented by the general formula (7) or (8) is produced by the method according to claim 12. 21. The method according to claim 17, which comprises a purification step after the reaction of introducing the protecting group. 22. The following general formula (9) containing impurities:
The monatin derivative represented by any one of (10) and (11) is subjected to a purification step to remove at least a part of the impurities, and then subjected to a deprotection reaction, the general formula (10) ( In the formula, R ¹ , R ³ , R ⁴ and R ⁵ are hydrogen atoms. A method for producing a monatin derivative (which may be in the form of a salt). [Chemical 18] [Chemical 19] [Chemical 20] In the above formulas (9), (10) and (11), R ¹ , R ³ and
R ⁴ and R ⁵ each independently represent a hydrogen atom or a protecting group. 23. The purification method in the purification step includes any of chromatography, crystallization (crystallization), and extraction operation, and the deprotection reaction is carried out under catalytic reduction conditions and / or acid. Alternatively, it is carried out in the presence of a base.
2. The method described in 2. 24. The above general formula (10) (in the formula, R ¹ ,
R ³ , R ⁴ and R ⁵ are hydrogen atoms. The monatin derivative represented by) is an inorganic acid such as hydrochloric acid or sulfuric acid, an acetic acid, an organic acid such as p-toluenesulfonic acid, sodium, potassium,
The method according to claim 22, which is purified in the form of a salt with an inorganic base containing a metal such as magnesium and an organic base such as ammonia or dicyclohexylamine. 25. The monatin derivative containing the impurities and represented by any one of formulas (9), (10) and (11) is produced by the method according to claim 17. The method described. 26. A ketone derivative represented by the following general formula (3) or (4): Also included are those in the form of salts. [Chemical 21] [Chemical formula 22] In the above formulas (3) and (4), R ¹ and R ⁴ are each independently a substituent selected from a hydrogen atom, a t-butoxycarbonyl group and a benzyloxycarbonyl group, and R ² and R ³ are each a substituent. Each independently represents a substituent selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms and a benzyl group. 27. The ketone derivative according to claim 26, which is in the form of a salt with an acid or a salt with a base. 28. The acid is selected from inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and p-toluenesulfonic acid,
27. The ketone derivative according to claim 26, wherein the base is selected from metal-containing bases such as sodium, potassium and magnesium, and organic bases such as ammonia and dicyclohexylamine. 29. A cyanohydrin derivative represented by any one of the following general formulas (5) and (6). Also included are those in the form of salts. [Chemical formula 23] [Chemical formula 24] In the above formulas (5) and (6), R ¹ and R ⁴ are each independently a substituent selected from a hydrogen atom, sodium, potassium, t-butoxycarbonyl group and benzyloxycarbonyl group. ³ and M each independently represent a hydrogen atom, a substituent selected from sodium and potassium, respectively. 30. A monatin derivative represented by any one of the following general formulas (7) and (8). Also included are those in the form of salts. [Chemical 25] [Chemical formula 26] In the above formulas (7) and (8), R ¹ and R ⁴ each independently represent a plurality of substituents selected from a hydrogen atom, sodium, potassium, t-butoxycarbonyl group and benzyloxycarbonyl group. Present M's each independently represent a hydrogen atom, or a substituent selected from sodium and potassium. 31. A monatin derivative represented by any of the following general formulas (9) to (11). Also included are those in the form of salts. [Chemical 27] [Chemical 28] [Chemical 29] In the formulas (9) to (11), R ¹ and R ⁴ are each independently a substituent selected from a hydrogen atom, a t-butoxycarbonyl group and a benzyloxycarbonyl group, and R ³ and R ⁴ are independent of each other. ^5's each independently represent a substituent selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and a benzyl group.