WO2012169661A1

WO2012169661A1 - Monatin polyvalent metal salt crystal

Info

Publication number: WO2012169661A1
Application number: PCT/JP2012/065176
Authority: WO
Inventors: 森　健一
Original assignee: 味の素株式会社
Priority date: 2011-06-08
Filing date: 2012-06-07
Publication date: 2012-12-13
Also published as: JP2014156404A

Abstract

[Problem] To provide a novel monatin crystal capable of forming a sweet composition that resists decomposition even when exposed to heat and humidity together with a reducing salt. [Solution] It was found that a (2R,4R)-monatin polyvalent metal salt crystal solves said problem.

Description

Monatin polyvalent metal salt crystals

The present invention relates to a novel (2R, 4R) monatin polyvalent metal salt crystal. The present invention also relates to a sweetening composition containing the crystals. Furthermore, the present invention relates to a sweetening composition containing a reducing sugar.

Monatin is a naturally occurring amino acid derivative isolated from the root bark of the plant Schlerochiton Ilicifolius, which grows naturally in the northern Transvaal region of South Africa. Vleggaar et al. (2S, 4S) -2-amino-4-carboxylic-4-hydroxy-5- (3-indylyl) -pentanoic acid ((2S, 4S) -4-hydroxy-4- ( 3-indolethyl) -glutamic acid) (Non-patent Document 1). The sweetness intensity of the (2S, 4S) body (natural monatin) derived from this natural plant is reported to be 800 to 1400 times that of sucrose according to the literature. Although several methods have been reported for the synthesis of monatin, many of them relate to the synthesis of stereoisomer mixtures, and four stereoisomers having the same chemical structure as natural monatin. Each was synthesized and isolated as a pure product, their properties were investigated in detail, and there were almost no examples reported. (Patent Documents 1 to 3, Non-Patent Documents 2 to 3)

In recent years, several studies have been made on the production method of monatin (Patent Documents 4 to 5), and some findings have been reported on monatin crystals. Examples of polyvalent metal salt crystals and their effects There was no description about. (Patent Documents 6 to 10)
ZA 87/4288 ZA 88/4220 US 5,994,559 WO2003-056026 WO2003-059865 WO2003-045914 US2005-272939 JP-A-2005-154291 JP 2006-052213 A JP2010-155817A R. Vleggaar et. Al. , J .; Chem. Soc. Perkin Trans. , 3095-3098, (1992) Holzapfel et. al. , Synthetic Communications, 24 (22), 3197-3211 (1994). K. Nakamura et. al. , Organic Letters, 2, 2967-2970 (2000).

An object of the present invention is to provide a novel monatin crystal that can form a sweetening composition that hardly decomposes even when exposed to high temperature and high humidity in the presence of reducing sugar.

As a result of intensive studies, the present inventors have found that (2R.4R) monatin polyvalent metal salt crystals can solve the above problems.

That is, the present invention includes the following aspects.
[1] (2R, 4R) monatin polyvalent metal salt crystal.
[2] The (2R, 4R) monatin polyvalent metal salt crystal according to [1], wherein the polyvalent metal salt is a divalent metal salt.
[3] The (2R, 4R) monatin polyvalent metal salt crystal according to [2], wherein the polyvalent metal salt is an alkaline earth metal salt.
[4] The (2R, 4R) monatin polyvalent metal salt crystal according to [3], wherein the polyvalent metal salt is at least one salt selected from calcium salts and magnesium salts.
[5] Has intrinsic X-ray diffraction peaks at diffraction angles (2θ ± 0.2 °, CuKα) at 4.9 °, 16.8 °, 18.0 ° and 24.6 ° ((2R, 4R) characterized in that it is a monatin) ₂ magnesium salt crystals, [4], wherein the (2R, 4R) monatin polyvalent metal salt crystals.
[6] A diffraction angle (2θ ± 0.2 °, CuKα) having a characteristic X-ray diffraction peak of any of the following (1) to (3) ((2R, 4R) monatin) is a ₂ magnesium salt crystal. The (2R, 4R) monatin polyvalent metal salt crystal according to [4], wherein
(1) 8.7 °, 10.5 °, 15.9 °, 17.4 °, 21.0 °, 25.6 °
(2) 8.9 °, 11.2 °, 15.0 °, 17.8 °, 22.5 °
(3) 4.9 °, 16.8 °, 18.0 °, 24.6 °
[7] As a diffraction angle (2θ ± 0.2 °, CuKα), it has a characteristic X-ray diffraction peak of any one of the following (1) to (4) ((2R, 4R) monatin) ₂ magnesium salt crystal The (2R, 4R) monatin polyvalent metal salt crystal according to [4], wherein
(1) 7.5 °, 10.3 °, 11.2 °, 16.0 ° 18.1 °, 23.0 °
(2) 8.7 °, 10.5 °, 15.9 °, 17.4 °, 21.0 °, 25.6 °
(3) 8.9 °, 11.2 °, 15.0 °, 17.8 °, 22.5 °
(4) 4.9 °, 16.8 °, 18.0 °, 24.6 °
[8] As a diffraction angle (2θ ± 0.2 °, CuKα), it has a characteristic X-ray diffraction peak of either (1) or (2) below ((2R, 4R) monatin) ₂ calcium salt crystal The (2R, 4R) monatin polyvalent metal salt crystal according to [4], wherein
(1) 5.0 °, 12.8 °, 15.3 °, 18.1 °, 23.7 °
(2) 6.0 °, 9.8 °, 16.0 °, 21.5 °, 22.3 °
[9] diffraction angles (2θ ± 0.2 °, CuKα) as is the following (1) having any unique X-ray diffraction peak of ~ (3) ((2R, 4R) _{monatin) 2} calcium salt crystals The (2R, 4R) monatin polyvalent metal salt crystal according to [4], wherein
(1) 5.1 °, 15.9 °, 19.7 °, 22.3 °
(2) 5.0 °, 12.8 °, 15.3 °, 18.1 °, 23.7 °
(3) 6.0 °, 9.8 °, 16.0 °, 21.5 °, 22.3 °
[10] The (2R, 4R) monatin polyvalent metal salt crystal according to any one of [1] to [9], wherein the enantiomeric excess is 10 to 100% ee.
[11] The (2R, 4R) monatin polyvalent metal salt crystal according to any one of [1] to [10], wherein the diastereomeric excess is 10 to 100% de.
[12] The (2R, 4R) monatin polyvalent metal salt crystal according to any one of [1] to [11], wherein the chemical purity is 50 to 100% by mass.
[13] The (2R, 4R) monatin polyvalent metal salt according to any one of [1] to [12], wherein the sweetness multiplication factor is 200 times or more with respect to a 5% sucrose aqueous solution crystal.
[14] A sweetening composition comprising the (2R, 4R) monatin polyvalent metal salt crystal according to any one of [1] to [13].
[15] The sweetening composition according to [14], further comprising a reducing sugar.
[16] The reducing sugar is dihydroxyacetone, glyceraldehyde, erythrulose, erythrose, threose, ribulose, xylulose, ribose, arabinose, xylose, lyxose, deoxyribose, psicose, fructose, sorbose, tagatose, allose, altrose, glucose, mannose [15] The sweetening composition according to [15], characterized in that the composition is gulose, idose, galactose, talose, fucose, fucose, rhamnose, cedoheptulose, lactose, maltose, tulanose, cellobiose, maltotriose, acarbose.
[17] The sweetening composition according to any one of [14] to [16], which is in a powder form.
[18] The sweetening composition according to [14], further comprising a reducing sugar-producing substance.
[19] An oral product comprising the (2R, 4R) monatin polyvalent metal salt crystal according to any one of [1] to [13].
[20] An oral product comprising the sweetening composition according to any one of [14] to [18].

It has been found that (2R.4R) monatin polyvalent metal salt crystals can form a sweetening composition that is difficult to decompose even when exposed to high temperature and high humidity in the presence of reducing sugar.
It has become possible to clarify the utility and various physical properties of these stereoisomers as sweeteners. It has also become possible to provide oral products such as beverages, foods, pharmaceuticals, quasi-drugs, and feeds that contain general-purpose stable and safe monatin polyvalent metal salt crystals. The present invention is naturally applicable to (2S, 4S) monatin.

The present invention relates to a novel (2R, 4R) monatin polyvalent metal salt crystal.

In the present invention, natural monatin exhibits a (2S, 4S) isomer in its three-dimensional structure, but all compounds having the same chemical structural formula are collectively referred to as “monatin”, and therefore, non-natural stereoisomers of monatin. Are referred to as “stereoisomers of natural monatin”, “non-natural monatin”, “(2S, 4R) monatin”, “(2R, 4S) monatin”, “(2R, 4R) monatin” or the like. In addition, monatin ((2S, 4S) form) is added to these stereoisomers, and these are referred to as “four kinds of stereoisomers”, or natural monatin is particularly referred to as “(2S, 4S) monatin”. Alternatively, it is referred to as “(2S, 4S) monatin” or the like.

(2R, 4R) monatin used in the present invention can be prepared by a known method, and its production method is not limited. For example, it can be obtained from tryptophan via indolepyruvic acid by an enzymatic method (Patent Document 4; WO2003-056026), or it can be obtained from tryptophan via indolepyruvic acid via an oxime body (reduction) Patent Document 5; WO2003-059865). In the production stage, in addition to (2R, 4R) monatin, natural monatin (2S, 4S) isomers, non-natural stereoisomers (2S, 4R) isomers, (2R, 4S) isomers are included. It doesn't matter.

The (2R, 4R) monatin thus obtained can be used as a mixture containing the four isomers of monatin, or can be separated and purified using adsorption resins, ion exchange resins and other known methods. You may use what you did. It can also be picked up as a known salt such as a free end, ammonium salt, potassium salt, basic amino acid salt and the like. The method for obtaining the monatin polyvalent metal salt is not particularly limited, but it is possible to obtain a polyvalent metal salt by neutralization or salt exchange with a known free form or monovalent salt of monatin, Those exchanged with an exchange resin can be used.

The polyvalent metal salt used in the present invention is an element having a valence of 2 or more in the periodic table, which can be ingested by the human body, and can form monatin and salt. If it does, it will not be restricted in particular. Specifically, as the divalent metal salt, alkaline earth metal salts such as magnesium salt, calcium salt, strontium salt, barium salt; transition metal salts such as iron salt, nickel salt, copper salt, zinc salt, etc. Examples of the trivalent metal include metal salts such as aluminum salts. These may be used alone or in combination of two or more. Among them, divalent metal salts are preferable, alkaline earth metal salts are more preferable, magnesium salts, calcium salts, strontium salts, and barium salts are more preferable, magnesium salts, calcium salts, and barium salts are still more preferable, magnesium salts, calcium A salt is particularly preferred.

As a simple method for obtaining a polyvalent metal salt used in the present invention, inorganic polyvalent metal compounds such as calcium hydroxide, magnesium hydroxide, calcium carbonate, magnesium carbonate, calcium acetate, magnesium acetate, calcium oxalate It can be introduced by various methods such as neutralization and salt exchange with organic polyvalent metal compounds such as magnesium oxalate, calcium lactate and magnesium lactate.

Among the (2R, 4R) monatin polyvalent metal salt crystals of the present invention, ((2R, 4R) monatin) ₂ divalent metal salt crystals are preferable from the viewpoint of being acceptable for human consumption and easy to prepare. (2R, 4R) monatin) ₂ alkaline earth metal salt crystals are more preferred, ((2R, 4R) monatin) ₂ magnesium salt crystals, ((2R, 4R) monatin) ₂ calcium salt crystals, ((2R, 4R) Monatin ₂ strontium salt crystals, ((2R, 4R) monatin) ₂ barium salt crystals are more preferred, ((2R, 4R) monatin) ₂ magnesium salt crystals, ((2R, 4R) monatin) ₂ calcium salt crystals, (( 2R, 4R) _monatin) is even more preferably ₂ barium salt crystals, ((2R, 4R) _{monatin) 2} magnesium salt crystals, ((2R 4R) _{monatin) 2} calcium salt crystals are particularly preferred.

Of the present invention (2R, 4R) monatin out of the polyvalent metal salt crystals ((2R, 4R) _monatin) will be described in detail ₂ calcium salt crystals.

Crystallization can be obtained by subjecting an aqueous solution containing (2R, 4R) monatin and a calcium source or an organic solvent-containing aqueous solution to standing or stirring crystallization. The (2R, 4R) monatin calcium concentration in the solution is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The temperature at which the crystals are precipitated is not particularly limited as long as the crystals are precipitated, but is preferably 15 to 100 ° C.

Precipitated crystals can be easily obtained wet crystals by subjecting them to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included.

The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, using ((2R, 4R) monatin) temperature range _to the extent _{that 2} calcium salt crystals are not dissolved can be used, vacuum drying or flash drying, hot air drying, etc. it can.

₂ calcium salt ((2R, 4R) monatin) of the present invention include those having a crystal polymorphism, depending on the type and crystallization method of crystallization solvent, because it forms a very different crystal forms, on that point or less Detailed description.

[((2R, 4R) _{monatin) 2} calcium salt 4.6 hydrate 0.67 ethanol solvate crystal]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting an ethanol-containing aqueous solution of (2R, 4R) monatin and a calcium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The proportion of ethanol in the ethanol-containing aqueous solution is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} calcium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and vacuum drying, airflow drying, hot air drying, and the like can be used.

Thus obtained ((2R, 4R) _{monatin) 2} calcium salt 4.6 hydrate 0.67 ethanolate crystals, as shown in FIG. 6, exhibited needles, the diffraction angle (2 [Theta] ± 0 .2 °, CuKα) have intrinsic X-ray diffraction peaks at 5.4 °, 6.0 °, 16.4 °, 22.2 ° and 27.3 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} calcium salt 3.8 hydrate 0.63 isopropanol solvate crystal]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting an isopropanol-containing aqueous solution of (2R, 4R) monatin and calcium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The proportion of isopropanol in the isopropanol-containing aqueous solution is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} calcium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and vacuum drying, airflow drying, hot air drying, and the like can be used. Thus obtained ((2R, 4R) _{monatin) 2} calcium salt 3.8 hydrate 0.63 isopropanol solvate crystal, such as shown in FIG. 12, exhibited needles, the diffraction angle (2 [Theta] ± 0 .2 °, CuKα) have intrinsic X-ray diffraction peaks at 5.4 °, 15.9 °, 19.7 ° and 22.3 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} calcium salt 5.9 hydrate 0.72THF solvate crystal]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting a THF-containing aqueous solution of (2R, 4R) monatin and a calcium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The proportion of THF in the aqueous solution containing THF is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} calcium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and vacuum drying, airflow drying, hot air drying, and the like can be used.

Thus obtained ((2R, 4R) _{monatin) 2} calcium salt 5.9 hydrate 0.72THF hydrate crystals, as shown in FIG. 10, exhibits a needle-like crystals, the diffraction angle (2θ ± 0. 2 °, CuKα) has intrinsic X-ray diffraction peaks at 5.1 °, 15.9 °, 19.7 °, and 22.3 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} calcium salt 5.7 hydrate crystalline]
The method for obtaining the title crystal is shown below.
Crystallization can be obtained by allowing an aqueous solution of (2R, 4R) monatin and a calcium source to stand or stirring crystallization, but an acetonitrile-containing aqueous solution is particularly preferable. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. When an acetonitrile-containing aqueous solution is used, the proportion of acetonitrile is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} calcium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and vacuum drying, airflow drying, hot air drying, and the like can be used.

Thus obtained ((2R, 4R) _{monatin) 2} calcium salt 5.7 hydrate crystal, as shown in FIG. 8, exhibited needles, the diffraction angle (2θ ± 0.2 °, CuKα) As having intrinsic X-ray diffraction peaks at 5.0 °, 12.8 °, 15.3 °, 18.1 ° and 23.7 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} calcium salt pentahydrate crystals]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting an organic solvent-containing aqueous solution of (2R, 4R) monatin and a calcium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The type of the organic solvent in the organic solvent-containing aqueous solution is not particularly limited, but is preferably a water-soluble organic solvent having a boiling point of 100 ° C. or lower, and more preferably a water-soluble organic solvent having a boiling point of 80 ° C. or lower. The proportion of the organic solvent is 50% to 99%, more preferably 75% to 99%. Examples of the organic solvent to be used include water-miscible solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, and THF. A preferred solvent is ethanol. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} calcium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and vacuum drying, airflow drying, hot air drying, and the like can be used. Furthermore, when it is an organic solvate, desired crystals can be obtained by storing it under high temperature and high humidity. The temperature at that time is 25 ° C. to 100 ° C., more preferably 40 ° C. to 80 ° C. The relative humidity is stored in the range of 20% to 100%, more preferably 60% to 100%. The storage time is 24 hours to 168 hours, more preferably 48 hours to 120 hours.

As thus obtained ((2R, 4R) _{monatin) 2} calcium salt pentahydrate crystals exhibit needles as shown in FIG. 2, the diffraction angle (2θ ± 0.2 °, CuKα) , 6 It has intrinsic X-ray diffraction peaks at 0.0 °, 9.8 °, 16.0 °, 21.5 °, and 22.3 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal. Furthermore ((2R, 4R) monatin) even when exposed to high temperature and high humidity in a state of coexistence with reducing sugars than ₂ calcium salt organic solvate crystal also has decomposed hard nature.

((2R, 4R) _monatin) Of ₂ calcium salt crystal, in terms of a stable coexist with a reducing sugar under high temperature and high humidity, ((2R, 4R) _{monatin) 2} calcium salt 4.6 Water hydrate 0.67 ethanol solvate crystal, ((2R, 4R) _{monatin) 2} calcium salt 3.8 hydrate 0.63 isopropanol solvate crystal, ((2R, 4R) _{monatin) 2} calcium salt 5.9 water solvate 0.72THF solvate crystal, ((2R, 4R) _{monatin) 2} calcium salt 5.7 hydrate crystal, ((2R, 4R) _monatin) is preferably ₂ calcium salt pentahydrate crystals, ((2R , 4R) _{monatin) 2} calcium salt 5.9 hydrate 0.72THF hydrate crystals, ((2R, 4R) _{monatin) 2} calcium salt 5.7 hydrate crystal, ((2R, 4R) _{monatin) 2} Cal Umushio pentahydrate crystals are more preferable, ((2R, 4R) _{monatin) 2} calcium salt 5.7 hydrate crystal, ((2R, 4R) _monatin) is more preferably ₂ calcium salt pentahydrate crystals, ((2R, 4R) _{monatin) 2} calcium salt pentahydrate crystals are particularly preferred.

Next, ((2R, 4R) monatin) ₂ magnesium salt crystal among the (2R, 4R) monatin polyvalent metal salt crystals of the present invention will be described in detail.

Crystallization can be obtained by subjecting an aqueous solution containing (2R, 4R) monatin and a magnesium source or an organic solvent-containing aqueous solution to standing or stirring crystallization. The (2R, 4R) monatin magnesium concentration in the solution is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The temperature at which the crystals are precipitated is not particularly limited as long as the crystals are precipitated, but is preferably 15 to 100 ° C.

The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, using ((2R, 4R) monatin) temperature range enough _{to 2} magnesium salt crystals are not dissolved can be used, vacuum drying or flash drying, hot air drying, etc. it can.

₂ magnesium salt ((2R, 4R) monatin) of the present invention include those having a crystal polymorphism, depending on the type and crystallization method of crystallization solvent, because it forms a very different crystal forms, on that point or less Detailed description.

[((2R, 4R) _{monatin) 2} magnesium salt 3.1 hydrate 2.4 ethanol solvate crystal]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting an ethanol-containing aqueous solution of (2R, 4R) monatin and a magnesium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The proportion of ethanol in the ethanol-containing aqueous solution is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} magnesium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and drying under reduced pressure or airflow drying can be used.

The resulting ((2R, 4R) _{monatin) 2} magnesium salt 3.1 hydrate 2.4 ethanol solvate crystal is thus, as shown in FIG. 18, it exhibited a fine crystal, the diffraction angle (2θ ± 0. 2 °, CuKα) has intrinsic X-ray diffraction peaks at 7.2 °, 10.0 °, 10.6 °, 12.3 °, 14.8 °, 17.8 °, and 25.3 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} magnesium salt 7.2 hydrate 0.23 methanolate crystal]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting a methanol-containing aqueous solution of (2R, 4R) monatin and a magnesium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The proportion of methanol in the methanol-containing aqueous solution is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} magnesium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and drying under reduced pressure or airflow drying can be used.

The resulting ((2R, 4R) _{monatin) 2} magnesium salt 7.2 hydrate 0.23 methanolate crystals Thus, as shown in FIG. 20, exhibits fine crystals, the diffraction angle (2θ ± 0. 2 °, CuKα) have intrinsic X-ray diffraction peaks at 8.0 °, 10.0 °, 10.3 °, 11.4 °, 16.1 °, 19.0 °, 23.7 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} magnesium salt 8.5 hydrate 2.5DMF solvate crystal]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting a DMF-containing aqueous solution of (2R, 4R) monatin and a magnesium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The proportion of DMF in the DMF-containing aqueous solution is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} magnesium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., the quality in manufacturing stability From the viewpoint of safety, 10 ° C. to 40 ° C. is more preferable, and drying under reduced pressure or airflow drying can be used.

Thus obtained ((2R, 4R) _{monatin) 2} magnesium salt 8.5 hydrate 2.5DMF hydrate crystals, as shown in FIG. 22, exhibited a fine crystal, the diffraction angle (2 [Theta] ± 0.2 (°, CuKα) has intrinsic X-ray diffraction peaks at 7.5 °, 10.3 °, 11.2 °, 16.0 ° 18.1 °, and 23.0 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} magnesium salt nonahydrate crystals]
The method for obtaining the title crystal is shown below.
Crystal deposition can be obtained by subjecting an aqueous solution containing (2R, 4R) monatin and a magnesium source or an organic solvent-containing aqueous solution to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 10 to 100 ° C. The temperature of the slurry on which the crystals are precipitated is preferably 10 ° C. to 100 ° C., more preferably 10 ° C. to 65 ° C. The holding time of the slurry liquid is within 24 hours if it is 65 ° C. or higher, and is not particularly limited if it is 65 ° C. or lower. Moreover, when acquiring the target crystal | crystallization stably above 65 degreeC, as an inorganic anion density | concentration, 0.028 N / kg or less is preferable and 0.0069 N / kg or less is more preferable. However, the inorganic anion concentration mentioned here is a specified number (N) of the salt concentration relative to the total weight (kg).
The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included.
The wet crystals thus obtained can be led to dry crystals by controlling the drying conditions. ((2R, 4R) monatin) temperature range enough _{to 2} magnesium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., more preferably from 10 ° C. ~ 40 ° C. from the viewpoint of quality stability during manufacture. The drying time can be selected as long as it is not overdried, preferably within 6 hours, and more preferably within 4 hours from the viewpoint of the stability of the water content, and vacuum drying or airflow drying can be used.

The resulting ((2R, 4R) _{monatin) 2} magnesium salt nonahydrate crystals Thus, as shown in FIG. 24, exhibits a columnar crystal, the diffraction angle (2θ ± 0.2 °, CuKα) as, 8 It has intrinsic X-ray diffraction peaks at 0.7 °, 10.5 °, 15.9 °, 17.4 °, 21.0 ° and 25.6 °. And ((2R, 4R) ₂ monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal. Furthermore, ((2R, 4R) monatin) ₂ magnesium salt organic solvate crystals have the property of not easily decomposing even when exposed to high temperature and high humidity in the presence of reducing sugar.

[((2R, 4R) _{monatin) 2} magnesium salt 7.5 hydrate crystalline]
The method for obtaining the title crystal is shown below.
Crystal deposition can be obtained by subjecting an aqueous solution containing (2R, 4R) monatin and a magnesium source or an organic solvent-containing aqueous solution to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 10 to 100 ° C. The temperature of the slurry on which the crystals are precipitated is preferably 10 ° C. to 100 ° C., more preferably 10 ° C. to 65 ° C. The holding time of the slurry liquid is within 24 hours if it is 65 ° C. or higher, and is not particularly limited if it is 65 ° C. or lower. Moreover, when acquiring the target crystal | crystallization stably above 65 degreeC, as an inorganic anion density | concentration, 0.028 N / kg or less is preferable and 0.0069 N / kg or less is more preferable. However, the inorganic anion concentration mentioned here is a specified number (N) of the salt concentration relative to the total weight (kg).
The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included.
The wet crystals thus obtained can be led to dry crystals by controlling the drying conditions at a low temperature. ((2R, 4R) monatin) temperature range enough _{to 2} magnesium salt crystals are not dissolved can be used, preferably 10 ~ 60 ° C., more preferably from 10 ° C. ~ 40 ° C. from the viewpoint of quality stability during manufacture, drying time As long as it is not overdried, any time can be selected, and vacuum drying or airflow drying can be used.

The resulting ((2R, 4R) _{monatin) 2} magnesium salt 7.5 hydrate crystals Thus, as shown in FIG. 14, exhibits a columnar crystal, the diffraction angle (2θ ± 0.2 °, CuKα) as , 8.7 °, 10.5 °, 15.9 °, 17.4 °, 21.0 °, 25.6 °, have intrinsic X-ray diffraction peaks. And ((2R, 4R) ₂ monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal. Furthermore, ((2R, 4R) monatin) ₂ magnesium salt organic solvate crystals have the property of not easily decomposing even when exposed to high temperature and high humidity in the presence of reducing sugar.

[((2R, 4R) _{monatin) 2} magnesium salt tetrahydrate crystals]
The method for obtaining the title crystal is shown below.
Crystal precipitation can be obtained by subjecting an organic solvent-containing aqueous solution of (2R, 4R) monatin and a magnesium source to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 15 to 100 ° C. The type of the organic solvent in the organic solvent-containing aqueous solution is not particularly limited, but is preferably a water-soluble organic solvent having a boiling point of 100 ° C. or lower, and more preferably a water-soluble organic solvent having a boiling point of 80 ° C. or lower. The proportion of the organic solvent is 50% to 99%, more preferably 75% to 99%. The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included. The wet crystals thus obtained can be led to dry crystals by controlling the drying conditions. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) the temperature range _to the extent _{that 2} magnesium salt crystals are not dissolved can be used, preferably 25 ~ 120 ° C., the quality in manufacturing stability From the viewpoint of safety, 40 ° C. to 100 ° C. is more preferable, and vacuum drying, air flow drying, hot air drying, and the like can be used. Furthermore, when it is an organic solvate, desired crystals can be obtained by storing it under high temperature and high humidity. The temperature at that time is 25 ° C. to 100 ° C., more preferably 40 ° C. to 80 ° C. The relative humidity is stored in the range of 20% to 100%, more preferably 60% to 100%. The storage time is 24 hours to 168 hours, more preferably 48 hours to 120 hours.

The resulting ((2R, 4R) _{monatin) 2} magnesium salt tetrahydrate crystals Thus, as shown in FIG. 4, present a fine crystal, the diffraction angle (2θ ± 0.2 °, CuKα) as, 8 It has intrinsic X-ray diffraction peaks at .9 °, 11.2 °, 15.0 °, 17.8 ° and 22.5 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal.

[((2R, 4R) _{monatin) 2} magnesium salt dihydrate crystals]
The method for obtaining the title crystal is shown below.
Crystal deposition can be obtained by subjecting an aqueous solution containing (2R, 4R) monatin and a magnesium source or an organic solvent-containing aqueous solution to standing or stirring crystallization. The (2R, 4R) monatin crystal concentration in the solvent is not particularly limited as long as it is supersaturated and crystals are precipitated, but 1 wt% to 60 wt% is preferable. From the viewpoint of obtaining a viscosity of a solution suitable for production, it is more preferably 2 wt% to 50 wt%, further preferably 5 wt% to 45 wt%. The melting temperature is not particularly limited as long as the crystals continue to dissolve, but is preferably 10 to 100 ° C. The temperature of the slurry on which the crystals are precipitated is preferably 10 ° C. to 100 ° C., more preferably 65 ° C. to 100 ° C. The holding time of the slurry liquid is not particularly limited. The target crystal can be obtained by high-temperature crystallization or a high salting-out effect even at a low temperature. When obtaining the target crystal only by temperature control, the crystallization temperature is preferably 50 ° C. or higher, more preferably 55 ° C. or higher, still more preferably 60 ° C. or higher, and particularly preferably 65 ° C. or higher. In addition, when stably obtaining the target crystal at less than 65 ° C., the inorganic anion concentration is preferably 0.14 N / kg or more, more preferably 0.28 N / kg or more, and 0.55 N / kg. The above is more preferable, and 0.88 N / kg or more is particularly preferable. However, the inorganic anion concentration mentioned here is a specified number (N) of the salt concentration relative to the total weight (kg).
The proportion of the organic solvent in the organic solvent-containing aqueous solution is 0.1% to 75%, more preferably 0.1% to 50%.
The deposited crystal can be easily obtained by subjecting it to a separation step such as a filtration step. The crystal washing is not particularly limited as long as crystal solvent exchange does not occur, but water can be used. In addition, a solvent miscible with water such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, sec-butanol, propylene glycol, acetonitrile, THF, etc. An inorganic salt or the like may also be included.
The wet crystal thus obtained can be converted into a dry crystal by subjecting it to a known drying step. Drying equipment used for drying is not particularly limited, ((2R, 4R) monatin) temperature range enough _{to 2} magnesium salt crystals are not dissolved can be used, preferably 10 ~ 120 ° C., during production Productivity From the viewpoint, 60 ° C. to 120 ° C. is more preferable, and drying under reduced pressure or airflow drying can be used.

The resulting ((2R, 4R) _{monatin) 2} magnesium salt dihydrate crystals Thus, as shown in FIG. 16, exhibited needles, the diffraction angle (2θ ± 0.2 °, CuKα) as, It has intrinsic X-ray diffraction peaks at 4.9 °, 16.8 °, 18.0 ° and 24.6 °. Further, ((2R, 4R) monatin) has a property that it is difficult to decompose even if it is exposed to high temperature and high humidity in the state of coexisting with reducing sugar from a potassium salt crystal. Furthermore, ((2R, 4R) monatin) ₂ magnesium salt organic solvate crystals have the property of not easily decomposing even when exposed to high temperature and high humidity in the presence of reducing sugar. Furthermore, ((2R, 4R) monatin) ₂ magnesium salt tetrahydrate crystal or 7.5 hydrate crystal or 9 hydrate crystal decomposes even when exposed to high temperature and high humidity in the presence of reducing sugar. It also has the most useful properties that are difficult.

((2R, 4R) monatin) Among the _two magnesium salt crystals, ((2R, 4R) monatin) ₂ magnesium salt 3.1 water from the viewpoint of being stable even if it coexists with a reducing sugar under high temperature and high humidity. Japanese hydrate 2.4 ethanol solvate, ((2R, 4R) monatin) ₂ magnesium salt 7.2 hydrate 0.23 methanol solvate crystal, ((2R, 4R) monatin) ₂ magnesium salt 8.5 water solvate 2.5DMF solvate crystal, ((2R, 4R) _{monatin) 2} magnesium salt nonahydrate crystals, ((2R, 4R) _{monatin) 2} magnesium salt 7.5 hydrate crystal, ((2R, 4R ) _{monatin) 2} magnesium salt tetrahydrate crystals, ((2R, 4R) _monatin) dihydrate crystals preferably ₂ magnesium salt, ((2R, 4R) _{monatin) 2} magnesium salt 8.5 hydrate 2.5DMF solvate crystal, ((2R, 4R) _{monatin) 2} magnesium salt nonahydrate crystals, ((2R, 4R) _{monatin) 2} magnesium salt 7.5 hydrate crystal, ((2R, 4R) monatin ) ₂ magnesium salt tetrahydrate crystals, ((2R, 4R) _monatin) is more preferably ₂ magnesium salt dihydrate crystals, ((2R, 4R) _{monatin) 2} magnesium salt nonahydrate crystals, ((2R , 4R) _{monatin) 2} magnesium salt 7.5 hydrate crystal, ((2R, 4R) _{monatin) 2} magnesium salt tetrahydrate crystals, ((2R, 4R) _{monatin) 2} magnesium salt dihydrate crystals more preferably, ((2R, 4R) _{monatin) 2} magnesium salt 7.5 hydrate crystal, ((2R, 4R) _{monatin) 2} magnesium salt tetrahydrate crystals, ((2R, 4R) Even more preferably _{Natin) 2} magnesium salt dihydrate crystals, ((2R, 4R) _{monatin) 2} magnesium salt tetrahydrate crystals, ((2R, 4R) _{monatin) 2} magnesium salt dihydrate crystals especially preferably, ((2R, 4R) _{monatin) 2} magnesium salt dihydrate crystals are particularly preferred.

The (2R, 4R) monatin polyvalent metal salt crystal of the present invention is slightly different in the ratio of monatin to metal, the ratio of monatin to water, or the ratio of monatin to solvent, as long as it has this peak set. Even if there are fluctuations, they should be regarded as the same crystal.

The (2R, 4R) monatin polyvalent metal salt crystal of the present invention can form a monatin crystal together with the (2S, 4S) monatin polyvalent metal salt crystal as another monatin isomer. In this case, the enantiomeric excess is not particularly limited, but the enantiomeric excess is preferably 10% to 100% ee, and preferably 30% to 100% from the viewpoint of maintaining stable crystals and exhibiting an effective sweetness in a small amount. ee is more preferable, 50% to 100% ee is further preferable, 70% to 100% ee is still more preferable, 90% to 100% ee is particularly preferable, and 95% to 100% ee is particularly preferable.

The (2R, 4R) monatin polyvalent metal salt crystal of the present invention further comprises, as other monatin isomers, (2S, 4R) monatin polyvalent metal salt crystals, monatin crystals together with (2R, 4S) monatin polyvalent metal crystals. Can be formed. The diastereomeric excess is not particularly limited, but from the viewpoint of maintaining stable crystals and exhibiting an effective sweetness in a small amount, the diastereomeric excess is preferably 10% to 100% de, and 30% to 100% de Is more preferable, 50% to 100% de is more preferable, 70% to 100% de is still more preferable, 90% to 100% de is particularly preferable, and 95% to 100% de is particularly preferable.

The (2R, 4R) monatin polyvalent metal salt crystal of the present invention can form a monatin crystal together with other inorganic / organic impurities. The lower limit of the chemical purity of the monatin crystal containing the (2R, 4R) monatin polyvalent metal crystal of the present invention is not particularly limited as long as the crystal is formed, but from the viewpoint that a stable crystal can be formed. % By weight is preferred, 60% by weight is more preferred, 70% by weight is more preferred, 80% by weight is even more preferred, 90% by weight is particularly preferred, and 95% by weight is particularly preferred. On the other hand, the upper limit of the chemical purity is preferably 100% by mass from the viewpoint of achieving a sweetness multiplication factor even with a smaller amount. The chemical purity here is the ratio of the “monatin polyvalent metal salt hydrate crystal” mass to the total mass of the monatin crystal. The causes of purity reduction include impurities of monatin itself (including other isomers), inorganic salts, calcium, metal salts other than magnesium, and the like, but are not limited thereto.

The (2R, 4R) monatin polyvalent metal salt crystal of the present invention further comprises (2S, 4S) monatin polyvalent metal salt, (2S, 4R) monatin polyvalent metal, (2R, 4S) monatin as other monatin isomers. Monatin crystals can be formed with polyvalent metal salts and other inorganic and organic impurities. The sweetening power of the monatin crystal containing the (2R, 4R) monatin polyvalent metal salt crystal of the present invention is not particularly limited. However, from the viewpoint of exhibiting an effective sweetness in a small amount while maintaining a stable crystal, It is preferably 200 times or more, more preferably 500 times or more, still more preferably 1000 times or more, still more preferably 1500 times or more, still more preferably 2000 times or more, and particularly preferably 2500 times or more with respect to the aqueous sugar solution.

The (2R, 4R) monatin polyvalent metal salt crystal of the present invention can be widely used as a sweetening composition. The form of the sweetening composition is not particularly limited, and examples thereof include liquids, powders, and solids. In particular, from the viewpoint that the stabilization effect derived from the crystal structure can be sufficiently exerted, a powder form and a solid form are preferable, and a powder form is particularly preferable.

The sweetening composition of the present invention can further contain a reducing sugar. This sweetening composition has the property that monatin is hardly decomposed even when exposed to high temperature and high humidity.

The reducing sugar used in the present invention is not particularly limited as long as it is a sugar capable of causing a Maillard reaction having a reducing ability. Specifically, dihydroxyacetone, glyceraldehyde, erythrulose, erythrose, threose, ribulose, Monosaccharides such as xylulose, ribose, arabinose, xylose, lyxose, deoxyribose, psicose, fructose, sorbose, tagatose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, fucose, fucrose, rhamnose, cedoheptulose; And disaccharides such as lactose, maltose, tulanose, sucrose, trehalose, and robiose. Glucose, fructose, maltose, lactose, galactose, mannose, arabinose, and xylose are preferred, glucose, fructose, maltose, and lactose are more preferred, and glucose and maltose are further preferred in terms of good sweetness characteristics and high market needs preferable.

In addition, the reducing sugar used in the present invention can be replaced with a “substance that can produce reducing sugar on the formulation”, that is, a reducing sugar-producing substance. The reducing sugar-producing substance of the present invention is not particularly limited as long as it can produce reducing sugar depending on each formulation condition, and specific examples include sucrose and trehalose. Sucrose is preferable from the viewpoint of good sweetness characteristics and high market needs.

Conventionally, when a sweetening composition of known monatin crystals ((2R, 4R) monatin monopotassium salt, (2R, 4R) monatin monosodium salt, etc.) and a reducing sugar is prepared, monatin is produced under high temperature and high humidity. However, it is very significant that this phenomenon can be remarkably improved by the (2R, 4R) monatin polyvalent metal salt crystal of the present invention.

It is speculated that the monatin disappearance phenomenon is caused by the Maillard reaction caused by the reducing sugar and the amino group of monatin. By combining a plurality of monatins with a polyvalent metal, it is possible that the amino group of monatin is sterically covered so that the reducing sugar is difficult to access.

The sweetener composition of the present invention can further contain other sweeteners (except for monatin or a salt thereof). Other sweeteners are not particularly limited, and specific examples include oligosaccharides such as fructooligosaccharide, maltooligosaccharide, isomaltoligosaccharide, and galactooligosaccharide; xylitol, lactitol, sorbitol, erythritol, mannitol, maltitol, reduced palatinose -Sugar alcohols such as reduced starch saccharified products; Aspartame, acesulfame K, sucralose, saccharin, stevioside, neotame, cyclamate, stevia, glycyrrhizin, monelin, thaumatin, alitame, dulcin, brazein, neocrine, MHPPAPM (N- [N- [ 3- (3-Hydroxy-4-methoxyphenyl) propyl] -L-α-aspartyl] -L-phenylalanine 1-methyl ester monohydrate (Advantame, (CAS No. 7 4229-20-6)), etc. These may be used alone or in admixture of two or more. From the viewpoint of obtaining an effect, aspartame, acesulfame K, sucralose, saccharin, cyclamate, stevioside, neotame are preferred, aspartame, acesulfame K, sucralose, saccharin, stevioside, neotame are more preferred, aspartame, acesulfame K, sucralose, stevioside, Neotame is more preferred, aspartame, acesulfame K, sucralose and neotame are even more preferred, aspartame, acesulfame K and sucralose are particularly preferred, and aspartame and sucralose are particularly preferred. In particular, aspartame is particularly preferable from the viewpoint of obtaining a sweet synergistic effect.

In addition to various food materials, various additives that can be used as oral products such as beverages, foods, pharmaceuticals, quasi drugs, and feeds can be used to the extent that the effects of the present invention are not impaired. Specifically, dextrins such as dextrin, maltodextrin, starch degradation product, reduced starch degradation product, cyclodextrin, indigestible dextrin, polysaccharides such as crystalline cellulose, polydextrose, etc .; citric acid PH adjusters such as phosphoric acid, lactic acid, malic acid, tartaric acid, gluconic acid and their salts; antioxidants such as L-ascorbic acid, erythorbic acid, tocopherol (vitamin E); sodium acetate, glycine, glycerin Preservatives such as fatty acid esters and lysozyme; preservatives such as sodium benzoate and potassium sorbate; stabilizers such as pectin, gum arabic, carrageenan, soybean polysaccharide, hydroxypropyl cellulose (HPC); xanthan gum, locust bean gum, Guar gum, tamarind gum, Thickening stabilizers such as Raya gum; anti-caking agents such as calcium phosphate, calcium carbonate, magnesium carbonate, silicon dioxide, shell calcium; natural flavors such as cinnamon oil, lemon oil, mint oil, orange oil, vanilla, menthol, citral, Synthetic fragrances such as synthetic alcohol, terpineol, and vanillin, and fragrances such as blended fragrances prepared from them; coloring of gardenia pigments, caramel pigments, cochineal pigments, anato pigments, safflower pigments, β-carotene, and various tar-based synthetic pigments Disintegrants such as sodium bicarbonate, starch, agar powder, gelatin powder and crystalline cellulose, lubricants such as stearic acid, sugar ester, benzoic acid and talc; swelling agents such as sodium bicarbonate and glucono delta lactone; Lecithin, sucrose fatty acid ester, glycerin fatty acid ester Examples include emulsifiers such as stealth and sorbitan fatty acid esters. These can be used together in an arbitrary ratio, and these may be used alone or in combination of two or more.

The monatin polyvalent metal salt crystal or sweetening composition of the present invention can be used for oral products such as beverages, foods, pharmaceuticals, quasi drugs, and feeds. The dosage form is not particularly limited, and examples thereof include powder, granules, cubes, pastes, and liquids. Specifically, liquid drinks such as fruit drinks, vegetable drinks, colas, carbonated drinks, sports drinks, coffee, tea, cocoa, milk drinks; powdered drinks such as powdered juices; plum drinks, medicinal liquors, fruit liquors, sake, etc. Beverages such as liquor; chocolate, cookies, cakes, donuts, chewing gum, jelly, pudding, mousse, Japanese confectionery, etc .; French bread, croissants, etc .; dairy products such as coffee milk, yogurt; ice cream, Ice confectionery such as sherbet; powder mix such as baking mix and dessert mix; tabletop sweetener such as liquid tabletop sweetener and powder tabletop sweetener; seafood dried products and seafood salted products; Processed products; dressing, sauce, soy sauce, miso, mirin, sauce, ketchup, noodle soup Spices such as curry powder; processed cereals such as instant noodles; foods such as cereals; tablet pharmaceuticals; powder pharmaceuticals; syrup pharmaceuticals; drop pharmaceuticals; etc. Quasi-drugs represented by agents, dentifrices, drinks, etc., pet foods, liquid feeds, powdered feeds, etc. In particular, beverages, foods, pharmaceuticals, quasi-drugs, and feeds that retain the crystal form of monatin are preferable from the viewpoint of maintaining the sweetness and sweetness stability of monatin, and powdered beverages, confectionery, powder mixes, and powder tabletops. Sweeteners, tablet pharmaceuticals, powdered pharmaceuticals, and powdered feeds are more preferable, and powdered beverages, powdered tabletop sweeteners, and powder mixes are more preferable.

The monatin polyvalent metal salt crystal or sweetening composition of the present invention is extremely effective as a metabolic syndrome prevention / treatment agent, obesity prevention / treatment agent, diabetes prevention / treatment agent, and caries prevention agent. In addition, it has sweetness synergistic effect, flavor synergistic effect, bitterness masking, and photodegradation stabilizing effect.

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

〔Measuring method〕
First, various measurement methods will be described.

[Powder X-ray diffraction measurement method]
1) 0.5 g of sample crystals were collected and ground in an agate mortar for 60 seconds. The obtained powder was set on a glass plate and flattened by applying pressure from above. The sample was immediately set on a powder X-ray diffractometer and measured under the following conditions.
2) Measurement of powder X-ray diffraction by Cu-Kα rays was performed using an X-ray diffractometer PW3050 manufactured by Spectris Co., Ltd., tube: Cu, tube current: 30 mA, tube voltage: 40 kV, sampling width: 0.020 °, Measurement was performed under the conditions of scanning speed: 3 ° / min, wavelength: 1.54056 mm, measurement diffraction angle range (2θ): 4 to 30 °.
Measurement program: X 'PERT DATA COLLECTION
Analysis program: X'PERT High Score
3) The obtained data was graphed with Excel, and a characteristic acute maximum peak in the range of 4 to 30 ° was read. The error of the diffraction angle of this method is ± 0.2 °.

[Method for measuring monatin content]
The molar ratio of (2R, 4R) monatin to calcium or magnesium was determined by measuring the monatin content in a (2R, 4R) monatin polyvalent metal salt crystal solution at a predetermined concentration under the following conditions by HPLC under the following conditions. Decided.
<Devices used>
Pump: LC-9A manufactured by Shimadzu Corporation Column oven: CTO-10A manufactured by Shimadzu Corporation Detector: SPD-10A manufactured by Shimadzu Corporation Autosampler: SIL-9A manufactured by Shimadzu Corporation Gradient: LPG-1000 manufactured by Tokyo Rika Kikai Co., Ltd. <Column> CAPCELL PAK C18 TYPE MGII 5 μm 4.6 mm × 250 mm manufactured by Shiseido Co., Ltd. <Column temperature> 40 ° C.
<Detection wavelength> 210 nm
<Moving liquid composition> A liquid 20 mM KH2PO4 / acetonitrile = 100/5
Liquid B Acetonitrile only <Gradient pattern>

<Retention time> (2S, 4R) monatin: 11.8 minutes (2R, 4R) monatin: 15.1 minutes <Injection volume> 10 μL
<Analysis cycle> 70 minutes / sample <Monatin content measurement standard>
(2R, 4R) monatin potassium salt monohydrate crystal molecular weight 348.4
Monatin content in (2R, 4R) monatin polyvalent metal salt crystal solution = (292.3 / 348.4) * (Wstd * Qs) / (Ws * Qstd) * 100 (%)
Wstd: standard substance concentration (mg / mL)
Qstd: area value of standard substance Ws: (2R, 4R) monatin polyvalent metal salt concentration (mg / mL)
Qs: area value of (2R, 4R) monatin polyvalent metal salt (2R, 4R) monatin free form molecular weight 292.3
(However, in the case of hydrates and solvates, the mass is also converted.)

[Calcium or magnesium ion measurement method]
The molar ratio of (2R, 4R) monatin to calcium or magnesium is the ion chromatograph of the calcium ion concentration or magnesium ion concentration in the predetermined concentration of (2R, 4R) monatin polyvalent metal salt crystal solution under the following conditions: And determined by the concentration ratio.
<Device Name> Ion Chromatograph IC-2001 manufactured by Tosoh Corporation
<Cation measurement column> TSKgel SuperIC-Cation manufactured by Tosoh Corporation, inner diameter 4.6 mm, length 150 mm
<Guard column> Tosoh Co., Ltd. TSKguardcolumn SuperIC-C, inner diameter 4.6mm, length 10mm
<Eluent> 2.2 mmol / L methanesulfonic acid +1.0 mmol / L 18-crown-6 +0.5 mmol / L histidine <column temperature> 40 ° C.
<Flow rate> 1 ml / min
<Standard solution> Calcium chloride or magnesium chloride (special grade reagent) was dissolved in pure water to obtain a standard solution.

[1H-NMR spectrum measurement method]
<Device name> AVANCE400 1H made by Bruker; 400 MHz
<Solvent> Heavy water <Temperature> Room temperature <Concentration> About 1% by mass

[MS spectrum measurement method]
<Device name> TSQ700 manufactured by Thermo Quest
<Measurement mode> ESI mode

[Moisture measurement method]
The molar ratio of (2R, 4R) monatin to water was determined by measuring the water concentration in a (2R, 4R) monatin polyvalent metal salt crystal solution at a predetermined concentration by the Karl Fischer method under the following conditions. Calculated from
<Device Name> Hiranuma Sangyo Co., Ltd. Automatic Moisture Analyzer AQV-2000

n made)
<Solvent> 150 ml methanol <Temperature> Room temperature <Sample amount> 30 mg

(Solvent content measurement method)
Using the 1H-NMR spectrum described above, the ratio of the proton integral value per 1H derived from the target substituent of each solvent and the proton integral value per 1H derived from the 3rd-position methylene (σ: 2 ppm, 1H) of monatin Calculated as the molar ratio of each solvent to monatin.

[Monatin solution permeability measurement method]
<Device name> Varian UV-Vis spectrophotometer Cary50
<Measurement wavelength> 430 nm
<Temperature> 25 ° C
<Sample> 1 g of the sweetening composition is completely dissolved in 50 ml of water.

(Water vapor adsorption / desorption measurement)
<Apparatus> Automatic vapor adsorption measuring device BELSORP18 manufactured by Nippon Bell Co., Ltd.
<Measurement method> constant volume Ryoshiki gas adsorption method <adsorbed gas> _H 2 O
<Air temperature chamber temperature (K)> 353
<Adsorption temperature (K)> 298
<Saturated vapor pressure (kPa)> 3.169
<Adsorption sectional area (nm ² )> 0.125
<Maximum adsorption pressure (relative pressure P / PO)>Desorption; 0.90 Adsorption; 0.95
<Minimum adsorption pressure (relative pressure P / PO)>Desorption; 0.10 Adsorption; 0.05
<Equilibrium time> 500 sec

[Production Example 1] Preparation of (2R, 4R) monatin potassium salt crystal 10 g of (2R, 4R) monatin monopotassium salt crystal was prepared according to [Example 17] described in WO2003-045914 (Patent Document 6). did.

[Production Example 2] Preparation of (2R, 4R) monatin-free crystals 40 g (109 mmol) of (2R, 4R) monatin potassium salt crystals obtained in Production Example 1 were dissolved in 700 ml of water. While maintaining the temperature, 54.5 ml of 1M sulfuric acid aqueous solution was added dropwise over 2 hours. The precipitated crystals were filtered and dried under reduced pressure at 40 ° C. overnight to prepare 31.5 g of (2R, 4R) monatin free form.

Example 1 ((2R, 4R) _monatin) dissolved ₂ calcium salt 5 hydrate crystal prepared in Production Example 1 of a (2R, 4R)) monatin potassium salt crystals 5 g (13.7 mmol) in water 75ml At 50 ° C., 0.758 g (6.83 mmol) of calcium chloride was added. To the monatin solution, 75 ml of ethanol was added and stirred at 50 ° C. for 3 hours, then cooled to 25 ° C. over 2.5 hours, and further stirred at 25 ° C. for 10 hours. The precipitated crystals were separated by filtration and dried under reduced pressure at 40 ° C. The dried crystals were stored in a constant temperature and humidity chamber at 44 ° C. and 78% for 24 hours to obtain 4.6 g of desired calcium salt crystals.

<1HNMR (D2O) σ> 1.94-2.01 (q1H), 2.57-2.61 (q1H), 2.99-3.03 (d1H), 3.19-3.23 (D 1H), 3.54-3.57 (q 1H), 7.05-7.17 (m 3H), 7.40-7.42 (m 1H), 7.64-7.66 (m 1H).
<ESI-MS> 293.1 (M + H) ⁺ , 291.1 (M−H) ⁻
<Moisture content> 13.5 wt% (equivalent to monatin: water = 2: 5)
<Calcium content> 5.6 wt% (equivalent to monatin: calcium = 2: 1)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 6.0 °, 9.8 °, 16.0 °, 21.5 °, 22.3 ° (FIG. 1)
<Crystal shape> The crystal shape in crystallization ML was a comparatively fine needle shape. (Figure 2)

Example 2 ((2R, 4R) _monatin) dissolved ₂ magnesium salt 4 hydrate crystal prepared in Production Example 1 of a (2R, 4R)) monatin potassium salt crystals 10 g (28.5 mmol) in water 20ml Then, 28.3 mL of a 501 mM magnesium chloride aqueous solution was added at room temperature. After stirring at 25 ° C. for 18 hours, 80 g of methanol was added to the monatin solution, followed by stirring at room temperature for 6 hours. The precipitated crystals were separated by filtration, washed with slurry with 50 g of 80% methanol for 2 hours, filtered and dried under reduced pressure at 40 ° C. The dried crystals were stored for 24 hours in a constant temperature and humidity chamber at 44 ° C. and 78%, and further dried under reduced pressure at 40 ° C. to obtain 8.8 g of desired magnesium salt crystals.

<1HNMR (D2O) σ> 1.94-2.01 (q1H), 2.57-2.61 (q1H), 2.99-3.03 (d1H), 3.19-3.23 (D 1H), 3.54-3.57 (q 1H), 7.05-7.17 (m 3H), 7.40-7.42 (m 1H), 7.64-7.66 (m 1H).
<ESI-MS> 293.1 (M + H) ⁺ , 291.1 (M−H) ⁻
<Moisture content> 10.8 wt% (equivalent to monatin: water = 2: 4)
<Magnesium content> 3.6 wt% (equivalent to monatin: magnesium = 2: 1)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 8.9 °, 11.2 °, 15.0 °, 17.8 °, 22.5 ° (FIG. 3)
<Crystal shape> The crystal shape in crystallization ML was a comparatively fine fragment shape. (Fig. 4)
<Sweetness magnification> 2700 times (comparison with 5% sucrose aqueous solution, average of 7 panelists)

Example 3 ((2R, 4R) _monatin) Preparation of ₂ calcium salt 4.6 hydrate 0.67 ethanol solvate crystal (2R, 4R) monatin potassium salt crystals 15g (41 mmol) in water 225ml After dissolution, 2.274 g (20.5 mmol) of calcium chloride was added. The monatin solution was heated to 50 ° C., added with 75 ml of ethanol, stirred for 1.5 hours, cooled to 25 ° C. over 2.5 hours, and further stirred at 25 ° C. for 12.5 hours. The precipitated crystals were separated by filtration and dried under reduced pressure at 40 ° C. 14.1 g of the desired calcium salt crystals were obtained.
<Moisture content> 12.2 wt% (equivalent to monatin: water = 1.9: 4.6)
<Calcium content> 5.8 wt% (equivalent to monatin: calcium = 1.9: 1)
<EtOH content> 4.5 wt% (monatin: EtOH = 1.9: 0.67 equivalent)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 5.4 °, 6.0 °, 16.4 °, 22.2 °, 27.3 ° (FIG. 5)
<Crystal shape> The crystal shape in the crystallization ML was acicular. (Fig. 6)

Example 4 ((2R, 4R) _monatin) Preparation of ₂ calcium salt 5.7 hydrate crystal ((2R, 4R) _{monatin) 2} calcium salt crystal pentahydrate crystals 0.4 g (1.08 mmol ) Was dissolved in 8.5 ml of water, heated to 65 ° C., and 8.5 ml of CH ₃ CN was added. Stir at 45 ° C. for 12 hours. The precipitated crystals were separated by filtration and dried under reduced pressure at 40 ° C. to obtain 0.288 g of calcium salt crystals.
<Water content> 12.6 wt% (monatin: water = 2.3: 5.7 equivalent)
<Calcium content> 4.9 wt% (monatin: calcium = 2.3: 1 equivalent)
<CH ₃ CN content> 0 wt%
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 5.0 °, 12.8 °, 15.3 °, 18.1 ° 23.7 ° (FIG. 7)
<Crystal shape> The crystal shape in crystallization ML was a fine needle shape. (Fig. 8)

Example 5 ((2R, 4R) _monatin) Preparation of ₂ calcium salt 5.9 hydrate 0.72THF hydrate crystals (2R, 4R) _{monatin) 2} calcium salt crystal pentahydrate crystals 0.4 g ( 1.08 mmol) was dissolved in 8.5 ml of water, heated to 65 ° C., and 8.5 ml of THF was added. Stir at 45 ° C. for 12 hours. The precipitated crystals were separated by filtration and dried under reduced pressure at 40 ° C. to obtain 0.288 g of calcium salt crystals.
<Water content> 11.4 wt% (monatin: water = 2.5: 5.9 equivalent)
<Calcium content> 4.3 wt% (equivalent to monatin: calcium = 2.5: 1)
<THF content> 5.6 wt% (monatin: THF = 2.5: 0.72 equivalent)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 5.1 °, 15.9 °, 19.7 °, 22.3 ° (FIG. 9)
<Crystal shape> The crystal shape in crystallization ML was a fine needle shape. (Fig. 10)

Example 6 ((2R, 4R) _monatin) Preparation of ₂ calcium salt 3.8 hydrate 0.63i-PrOH hydrate crystals ((2R, 4R) _{monatin) 2} calcium salt crystal pentahydrate crystals 0 0.4 g (1.08 mmol) was dissolved in 8.5 ml of water, heated to 65 ° C., and 8.5 ml of i-PrOH was added. Stir at 45 ° C. for 25 hours. The precipitated crystals were separated by filtration and dried under reduced pressure at 40 ° C. to obtain 0.337 g of calcium salt crystals.
<Water content> 10.67 wt% (monatin: water = 1.7: 3.8 equivalent)
<Calcium content> 6.2 wt% (equivalent to monatin: calcium = 1.7: 1)
<I-PrOH content> 5.87 wt% (monatin: i-PrOH = 1.7: 0.63 equivalent)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 5.4 °, 15.9 °, 19.7 °, 22.3 ° (FIG. 11)
<Crystal shape> The crystal shape in the crystallization ML was acicular. (Fig. 12)

Example 7 ((2R, 4R) _monatin) Preparation of ₂ magnesium salt 7.5 hydrate crystals (2R, 4R) Mona tin-free substance crystals 30 g (100 mmol) dispersed in water 300 ml, the 40 ° C. Then 3.36 g (58 mmol) of magnesium hydroxide was added. After stirring at 40 ° C. for 4 hours, the mixture was stirred at 25 ° C. for 16 hours. The precipitated crystals (38.38 g) were collected by filtration and dried under reduced pressure at 40 ° C. to obtain 28.9 g of magnesium salt crystals.
<Water content> 18.34 wt% (monatin: water = 2: 7.5 equivalent)
<Magnesium content> 3.67 wt% (equivalent to monatin: magnesium = 2: 1)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 8.7 °, 10.5 °, 15.9 °, 17.4 ° 21.0 °, 25.6 ° (FIG. 13)
<Crystal shape> The crystal shape in the crystallization ML was columnar. (Fig. 14)

The Example 8 ((2R, 4R) _monatin) Preparation of ₂ magnesium salt dihydrate crystals (2R, 4R) Mona Tin potassium salt crystals 120 g (345 mmol) was dissolved in water 150 ml, sulfate at 60 ° C. 4.15 g (34.5 mmol) of magnesium was added. Further, 16.61 g (138 mmol) of magnesium sulfate (100 ml of water) was added over 6.4 hours. After completion of the addition, the precipitated crystals were separated by filtration and washed with 100 ml of water to obtain wet crystals (204.7 g). The wet crystals were dried under reduced pressure at 40 ° C. to obtain 105 g of magnesium salt crystals. Further, 400 ml of water was added to 105 g of the dried crystals and stirred at 25 ° C. for 1.5 hours in order to remove a small amount of potassium sulfate. The resulting slurry was filtered and washed with 300 ml of water to obtain wet crystals (153.9 g). The wet crystals were dried under reduced pressure at 40 ° C. to obtain 85.7 g of magnesium salt crystals.
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 4.9 °, 16.8 °, 18.0 °, 24.6 ° (FIG. 15)
<Moisture content> 6.0 wt% (equivalent to monatin: water = 1: 1)
<Magnesium content> 3.61 wt% (equivalent to monatin: magnesium = 2: 1)
<Crystal shape> The crystal shape in crystallization ML was a fine crystal. (Fig. 16)

Example 9 ((2R, 4R) _monatin) Preparation of ₂ magnesium salt 3.1 hydrate 2.4 ethanol solvate crystal (2R, 4R) Mona tin-free substance crystals 10 g (33.3 mmol) of water After dispersing in 100 ml, 0.971 g (16.7 mmol) of magnesium hydroxide was added at 25 ° C. and stirred for 3 hours. Further, 506 ml of ethanol was added dropwise in about 3 hours, followed by stirring at 25 ° C. for 25.5 hours. The precipitated crystals (17.73 g) were filtered off and dried under reduced pressure at room temperature. 12.04 g of the desired magnesium salt crystals were obtained.
<Water content> 6.7 wt% (monatin: water = 2.1: 3.1 equivalent)
<Magnesium content> 2.9 wt% (equivalent to monatin: magnesium = 2.1: 1)
<EtOH content> 13.5 wt% (equivalent to monatin: ethanol = 2.1: 2.4)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 7.2 °, 10.0 °, 10.6 °, 12.3 °, 14.8 °, 17.8 °, 25.3 ° (Fig. 17)
<Crystal shape> The crystal shape in the crystallization ML was fine. (Fig. 18)

Example 10 ((2R, 4R) _monatin) Preparation of ₂ magnesium salt 7.2 hydrate 0.23 methanolate crystals (2R, 4R) Mona tin-free substance crystals 10 g (33.3 mmol) of water After dispersing in 100 ml, 0.971 g (16.7 mmol) of magnesium hydroxide was added at 25 ° C. and stirred for 3 hours. Further, 506 ml of methanol was added dropwise in about 3 hours, followed by stirring at 25 ° C. for 20 hours. The precipitated crystals (15.87 g) were filtered off and dried under reduced pressure at room temperature. 11.94 g of the desired magnesium salt crystals were obtained.
<Water content> 18.16 wt% (monatin: water = 1.9: 7.2 equivalent)
<Magnesium content> 3.3 wt% (equivalent to monatin: magnesium = 1.9: 1)
<Methanol content> 1.0 wt% (monatin: methanol = 1.9: 0.23 equivalent)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 8.0 °, 10.0 °, 10.3 °, 11.4 °, 16.1 °, 19.0 °, 23.7 ° (Fig. 19)
<Crystal shape> The crystal shape in the crystallization ML was fine. (Fig. 20)

Example 11 ((2R, 4R) _monatin) Preparation of ₂ magnesium salt 8.5 hydrate 2.5DMF hydrate crystals (2R, 4R) _{monatin) 2} magnesium salt tetrahydrate crystals 0.4 g (0 .56 mmol) was dissolved in 10 ml of water and 10 ml of DMF was added. The mixture was stirred at 45 ° C. for 47 hours. The precipitated crystals were separated by filtration and dried under reduced pressure at 40 ° C. to obtain 0.212 g of magnesium salt crystals.
<Water content> 7.46 wt% (corresponding to monatin: water = 2.5: 8.5)
<Magnesium content> 2.9 wt% (equivalent to monatin: magnesium = 2.5: 1)
<DMF content> 2.7 wt% (monatin: DMF = 2.5: 2.5 equivalent)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 7.5 °, 10.3 °, 11.2 °, 16.0 ° 18.1 °, 23.0 ° (FIG. 21)
<Crystal shape> Crystals in the crystallization ML were fine crystals. (Fig. 22)

Example 12 ((2R, 4R) _monatin) Preparation of ₂ magnesium salt nonahydrate crystals (2R, 4R) Mona tin-free substance crystals 30 g (100 mmol) dispersed in water 300 ml, water at 65 ° C. 3.21 g (55 mmol) of magnesium oxide was added. Stir at 65 ° C. for 1 hour. The precipitated crystals (27.28 g) were filtered off and dried under reduced pressure at 40 ° C. for 4 hours to obtain 22.29 g of magnesium salt crystals.
<Water content> 21.22 wt% (monatin: water = 2: 9 equivalent)
<Magnesium content> 3.45 wt% (equivalent to monatin: magnesium = 2: 1)
<Intrinsic X-ray diffraction peak (2θ ± 0.2 °, CuKα)> 8.7 °, 10.5 °, 15.9 °, 17.4 ° 21.0 °, 25.6 ° (FIG. 23)
<Crystal shape> The crystal shape in the crystallization ML was columnar. (Fig. 24)

Example 13 was obtained by the method of water vapor adsorption desorption curves a second embodiment of the crystal ((2R, 4R) monatin) obtained by the method of ₂ magnesium salt tetrahydrate crystals and Example 8 (2R, 4R ) monatin) was determined water vapor adsorption desorption curves of ₂ magnesium salt dihydrate crystals. The measured values are shown in FIGS.

[Test Example 1] Storage stability evaluation (with glucose)
Obtained in Example 1 ((2R, 4R) _{monatin) 2} calcium salt pentahydrate crystals, obtained in Example 2 ((2R, 4R) _{monatin) 2} magnesium salt tetrahydrate crystals, Example ((2R, 4R) monatin) ₂ calcium salt 4.6 hydrate 0.67 ethanol solvate crystal obtained in Example 3, (2R, 4R) monatin obtained in Example 8 ₂ magnesium salt dihydrate Product crystal, (2R, 4R) monatin) obtained in Example 9, ₂ magnesium salt 1 ethanol solvate crystal, (2R, 4R) monatin obtained in Example 10) ₂ magnesium salt 0.23 methanol solvate crystal The storage stability of the monatin monopotassium salt crystals obtained in Production Example 1 was evaluated by the following method.

[Storage conditions]
1 g of the sweetening composition shown in Formulation Table 1 was filled into a paper wrapping material and sealed with a heat seal. The sample was stored in a constant temperature and humidity chamber at 44 ° C. and 78% for a predetermined time, and the entire amount of the stored sample was dissolved in 50 mL of water, and the residual rate of each monatin salt was calculated from the HPLC analysis value of the dissolved solution.
[Residual rate change with time]
Table 3 shows the results of the monatin survival rate. Calcium salt crystals and magnesium salt crystals were found to have a higher survival rate under high temperature and high humidity than potassium salt crystals. Table 4 shows the results of the transmittance of the stored product solution. In the case of potassium salt crystals, the transmittance decreases and the color is yellow, but in the case of calcium salt crystals and magnesium salt crystals, no color change is observed.

[Test Example 2] Storage stability evaluation (containing sucrose)
Obtained in Example 1 ((2R, 4R) _{monatin) 2} calcium salt pentahydrate crystals, obtained in Example 2 ((2R, 4R) _monatin) and ₂ magnesium salt tetrahydrate crystals Preparation The storage stability of the monatin monopotassium salt crystal obtained in 1 was evaluated by the following method.

[Storage conditions]
1 g of the sweetening composition shown in Formulation Table 2 was filled in a paper wrapping material and sealed with a heat seal. The sample was stored in a constant temperature and humidity chamber at 44 ° C. and 78% for a predetermined time, and the entire amount of the stored sample was dissolved in 50 mL of water.
[Residual rate change with time]
Table 6 shows the results of the monatin survival rate. Calcium salt crystals and magnesium salt crystals were found to have a higher survival rate under high temperature and high humidity than potassium salt crystals. Table 7 shows the results of the transmittance of the stored product solution. In the case of potassium salt crystals, the transmittance decreases and the color is yellow, but in the case of calcium salt crystals and magnesium salt crystals, no color change is observed.

[Prescription Example 1] Powdered tabletop sweetener A formulation example of a powdered tabletop sweetener is shown below.

[Prescription Example 2] Powder Mix An example of a powder mix is shown below.

(2R, 4R) Monatin polyvalent metal crystals have made it possible to provide stable monatin crystals. The utility and various physical properties of these stereoisomers as sweeteners were clarified. It is extremely significant that oral products such as beverages, foods, pharmaceuticals, quasi-drugs, feeds, etc., containing general-purpose stable and safe polyvalent metal crystals of monatin can be provided.

[Figure 1] is a ((2R, 4R) monatin) powder X-ray diffraction diagram after the humidity control ₂ calcium salt pentahydrate crystals. Example 1
[Figure 2] is an illustration of the ((2R, 4R) monatin) optical micrograph of crystallized solution separation shortly before ₂ calcium salt pentahydrate crystals. (Magnification 200 times) (Example 1)
[Figure 3] is a ((2R, 4R) monatin) powder X-ray diffraction diagram after the humidity control ₂ magnesium salt tetrahydrate crystals. (Example 2)
[Figure 4] is an illustration of the ((2R, 4R) monatin) optical micrograph of crystallized solution separation shortly before ₂ magnesium salt tetrahydrate crystals. (Magnification 200 times) (Example 2)
[Figure 5] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ calcium salt 4.6 hydrate 0.67 ethanol solvate crystal. (Example 3)
[6] is an illustration of the (2R, 4R) _monatin) optical micrograph of crystallized solution separation shortly before ₂ calcium salt 4.6 hydrate 0.67 ethanol solvate crystal. (Magnification 200 times) (Example 3)
[Figure 7] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ calcium salt 5.7 hydrate crystals. Example 4
[Figure 8] is an illustration of the ((2R, 4R) monatin) optical micrograph of crystallized solution separation shortly before ₂ calcium salt 5.7 hydrate crystals. (Magnification 200 times) (Example 4)
[Figure 9] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ calcium salt 5.9 hydrate 0.72THF hydrate crystals. (Example 5)
[Figure 10] is an illustration of the ((2R, 4R) _monatin) optical micrograph of crystallized solution separation shortly before ₂ calcium salt 5.9 hydrate 0.72THF hydrate crystals. (Magnification 200 times) (Example 5)
[Figure 11] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ calcium salt 3.8 hydrate 0.63i-PrOH solvate crystal. (Example 6)
[Figure 12] is an illustration of the ((2R, 4R) _monatin) optical micrograph of crystallized solution separation shortly before ₂ calcium salt 3.8 hydrate 0.63i-PrOH solvate crystal. (Magnification 200 times) (Example 6)
[Figure 13] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ magnesium salt 7.5 hydrate crystals. (Example 7)
[Figure 14] is an illustration of the ((2R, 4R) monatin) optical micrograph of crystallized solution separation shortly before ₂ magnesium salt 7.5 hydrate crystals. (Magnification 200 times) (Example 7)
[Figure 15] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ magnesium salt dihydrate crystals. (Example 8)
[Figure 16] is an illustration of the ((2R, 4R) monatin) optical micrograph of crystallized solution separation shortly before ₂ magnesium salt dihydrate crystals. (Magnification 200 times) (Example 8)
[Figure 17] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ magnesium salt 3.1 hydrate 2.4 ethanol solvate crystal. Example 9
[Figure 18] is an illustration of the ((2R, 4R) _monatin) optical micrograph of crystallized solution separation shortly before ₂ magnesium salt 3.1 hydrate 2.4 ethanol solvate crystal. (Magnification 200 times) (Example 9)
[Figure 19] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ magnesium salt 7.2 hydrate 0.23 methanolate crystals. (Example 10)
[Figure 20] is an illustration of the ((2R, 4R) _monatin) optical micrograph of crystallized solution separation shortly before ₂ magnesium salt 7.2 hydrate 0.23 methanolate crystals. (Magnification 200 times) (Example 10)
[Figure 21] is a ((2R, 4R) _monatin) powder X-ray diffraction pattern of ₂ magnesium salt 8.5 hydrate 2.5DMF hydrate crystals. (Example 11)
[Figure 22] is an illustration of the (2R, 4R) _monatin) optical micrograph of crystallized solution separation shortly before ₂ magnesium salt 8.5 hydrate 2.5DMF hydrate crystals. (Magnification 200 times) (Example 11)
[Figure 23] is a ((2R, 4R) _monatin) powder X-ray diffraction chart after drying of ₂ magnesium salt nonahydrate crystals. (Example 12)
[Figure 24] is an illustration of the ((2R, 4R) monatin) optical micrograph of crystallized solution separation shortly before ₂ magnesium salt nonahydrate crystals. (Magnification 200 times) (Example 12)
[Figure 25] is obtained in Example 2 ((2R, 4R) _monatin) steam adsorption and desorption curves of ₂ magnesium salt tetrahydrate crystals.
[Figure 26] was obtained in Example 8 ((2R, 4R) _{monatin) 2} vapor adsorption and desorption curves of the magnesium salt dihydrate crystals.

Claims

(2R, 4R) monatin polyvalent metal salt crystals.
The (2R, 4R) monatin polyvalent metal salt crystal according to claim 1, wherein the polyvalent metal salt is a divalent metal salt.
3. The (2R, 4R) monatin polyvalent metal salt crystal according to claim 2, wherein the polyvalent metal salt is an alkaline earth metal salt.
4. The (2R, 4R) monatin polyvalent metal salt crystal according to claim 3, wherein the polyvalent metal salt is at least one salt selected from calcium salt and magnesium salt.
As diffraction angles (2θ ± 0.2 °, CuKα), there are intrinsic X-ray diffraction peaks at 4.9 °, 16.8 °, 18.0 °, and 24.6 ° ((2R, 4R) monatin) 2 The (2R, 4R) monatin polyvalent metal salt crystal according to claim 4, wherein the crystal is a magnesium salt crystal.
Wherein the diffraction angle (2θ ± 0.2 °, CuKα) as a following (1) having any unique X-ray diffraction peak of ~ (3) ((2R, 4R) monatin) 2 magnesium salt crystals The (2R, 4R) monatin polyvalent metal salt crystal according to claim 4.
(1) 8.7 °, 10.5 °, 15.9 °, 17.4 °, 21.0 °, 25.6 °
(2) 8.9 °, 11.2 °, 15.0 °, 17.8 °, 22.5 °
(3) 4.9 °, 16.8 °, 18.0 °, 24.6 °
Wherein the diffraction angle (2θ ± 0.2 °, CuKα) as a following (1) having any unique X-ray diffraction peak of ~ (4) ((2R, 4R) monatin) 2 magnesium salt crystals The (2R, 4R) monatin polyvalent metal salt crystal according to claim 4.
(1) 7.5 °, 10.3 °, 11.2 °, 16.0 ° 18.1 °, 23.0 °
(2) 8.7 °, 10.5 °, 15.9 °, 17.4 °, 21.0 °, 25.6 °
(3) 8.9 °, 11.2 °, 15.0 °, 17.8 °, 22.5 °
(4) 4.9 °, 16.8 °, 18.0 °, 24.6 °
Wherein the diffraction angle (2θ ± 0.2 °, CuKα) as a have any of the characteristic X-ray diffraction peaks of the following (1) or (2) ((2R, 4R) monatin) 2 calcium salt crystals The (2R, 4R) monatin polyvalent metal salt crystal according to claim 4.
(1) 5.0 °, 12.8 °, 15.3 °, 18.1 °, 23.7 °
(2) 6.0 °, 9.8 °, 16.0 °, 21.5 °, 22.3 °
Wherein the diffraction angle (2θ ± 0.2 °, CuKα) as a following (1) having any unique X-ray diffraction peak of ~ (3) ((2R, 4R) monatin) 2 calcium salt crystals The (2R, 4R) monatin polyvalent metal salt crystal according to claim 4.
(1) 5.1 °, 15.9 °, 19.7 °, 22.3 °
(2) 5.0 °, 12.8 °, 15.3 °, 18.1 °, 23.7 °
(3) 6.0 °, 9.8 °, 16.0 °, 21.5 °, 22.3 °
The (2R, 4R) monatin polyvalent metal salt crystal according to any one of claims 1 to 9, wherein the enantiomeric excess is 10 to 100% ee.
The (2R, 4R) monatin polyvalent metal salt crystal according to any one of claims 1 to 10, wherein the diastereomeric excess is 10 to 100% de.
The (2R, 4R) monatin polyvalent metal salt crystal according to any one of claims 1 to 11, which has a chemical purity of 50 to 100% by mass.
The (2R, 4R) monatin polyvalent metal salt crystal according to any one of claims 1 to 12, which has a sweetening ratio of 200 times or more with respect to a 5% sucrose aqueous solution.
A sweetening composition comprising the (2R, 4R) monatin polyvalent metal salt crystal according to any one of claims 1 to 13.
The sweetening composition according to claim 14, further comprising a reducing sugar.
Reducing sugar is dihydroxyacetone, glyceraldehyde, erythrulose, erythrose, threose, ribulose, xylulose, ribose, arabinose, xylose, lyxose, deoxyribose, psicose, fructose, sorbose, tagatose, allose, altrose, glucose, mannose, gulose, 16. Sweet composition according to claim 15, characterized in that it is idose, galactose, talose, fucose, fucose, rhamnose, cedoheptulose, lactose, maltose, tulanose, cellobiose, maltotriose, acarbose.
The sweetening composition according to any one of claims 14 to 16, wherein the sweetening composition is in a powder form.
The sweetening composition according to claim 14, further comprising a reducing sugar-producing substance.
An oral product comprising the (2R, 4R) monatin polyvalent metal salt crystal according to any one of claims 1 to 13.
An oral product comprising the sweetening composition according to any one of claims 14 to 18.