JP2000136197A - Crystallization of crystal of aspartame derivative excellent in stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To stably obtain N-(3,3-dimethylbutyl)-APM methyl ester of N-[N-(3,3- dimethylbutyl)-L-α-aspartyl]-L-phenylalanine} crystal excellent in stability at a low cost. SOLUTION: This crystallization of N-(3,3-dimethylbutyl)-APM crystal comprises using water or a mixture of the water and a lower alcohol as a crystallization solvent, and adding the N-(3,3-dimethylbutyl)-APM crystal having characteristic peaks at least at the diffraction angle of 6.0 deg., 24.8 deg., 8.2 deg. and 16.5 deg. (2θ, CuKα ray) in the diffraction X-ray analysis, as a seed crystal to precipitate the crystal excellent in stability preferentially.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a highly stable crystal of a high-potency sweet substance N- [N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine methyl ester. And a method for producing the same. Incidentally, as is well known, L-α-aspartyl-L-phenylalanine methyl ester is a kind of amino acid-based high-potency sweetener that has already been commercialized and is abbreviated as APM or aspartame. Therefore, the sweet substance according to the present invention can be considered as a derivative of APM or aspartame. Therefore, hereinafter, this is abbreviated as N- (3,3-dimethylbutyl) -APM. Also, this sweet substance may be abbreviated as NM (Neotame Neoname) depending on the literature.

[0002]

2. Description of the Related Art N- (3,3-dimethylbutyl) -A
PM has a sweet potency at least 50 times that of aspartame by weight and about 1% of sucrose (table sugar).
Since it is 0000 times, it is possible to constitute a very powerful sweetener.

[0003] Since sweeteners are mainly intended for use in foods and for human consumption,
It must be manufactured in such a manner that a high-purity product containing virtually no impurities or decomposition products can be obtained. In addition, in the case of a sweetener that is relatively easily decomposed, such as N- (3,3-dimethylbutyl) -APM, some measure is required in order to prevent decomposition after the product is shipped.

[0004] Therefore, the present inventors considered whether controlling the N- (3,3-dimethylbutyl) -APM to an appropriate crystal form could increase the stability as a product.

[0005] The crystal structure of N- (3,3-dimethylbutyl) -APM, which is already known, is described in WO95 / 3068.
9 is described as IR spectrum data. Further, the present inventors have found that this crystal is a monohydrate as a result of single crystal structure analysis, and when measured by powder X-ray diffraction method, at least 6.0 °, 24.8 °, and 8. 2 ゜, 1
It was confirmed that a characteristic X-ray diffraction peak was exhibited at a diffraction angle of 6.5 ° (2θ, CuKα ray). The present inventors have referred to this crystal as an A-type crystal for convenience.

On the other hand, N- (3,3-dimethylbutyl)-
The production method of APM is also described in US Pat. No. 5,728,862. Here, high purity (97% HPLC) N- (3,3-dimethylbutyl) -APM is obtained by spontaneously generating crystals by crystallization using methanol and water.

Therefore, the present inventor has disclosed US Pat. No. 5,728,86.
When an additional test was conducted on Example 1 described in Example 2, it was confirmed that the purity was reproducible (98% HPLC), but the formation of Form A crystals could not be confirmed.

That is, in the state of wet crystals, at least 5.1
°, 21.1 °, 21.3 ° and 8.3 ° showed characteristic peaks of X-ray diffraction at diffraction angles (2θ, CuKa line). The powder X-ray diffraction pattern at this time is shown in FIG. Hereinafter, this is referred to as a B-type crystal.

Further, when the B-form crystals obtained above according to Example 1 described in US Pat. No. 5,728,862 are dried, at least 5.6 °, 8.4 °, 17.1 °, 1 °
A crystal showing a characteristic peak of diffraction X-ray at a diffraction angle of 8.8 ° (2θ, CuKα ray) was obtained. The powder X-ray diffraction pattern at this time is shown in FIG. The water content of the crystals was measured by the Karl Fischer method and found to be 0.6% by weight. Hereinafter, this is referred to as a G-type crystal.

Next, a stability test of N- (3,3-dimethylbutyl) -APM in the obtained G-type crystal and A-type crystal was carried out at 70 ° C. As a result, 16
After 0 hour, the residual ratio of N- (3,3-dimethylbutyl) -APM was 34 wt% in the G-type crystal, whereas it was 94 wt% in the A-type crystal. It was suggested that N- (3,3-dimethylbutyl) -APM was present more stably. The storage time at this time,
Table 1 shows the relationship with the residual ratio of N- (3,3-dimethylbutyl) -APM.

[0011]

[Table 1]

Thus, Example 1 of US Pat. No. 5,728,862 is inferior in stability to N-type
It was found that a G-form crystal of (3,3-dimethylbutyl) -APM was obtained.

[0013]

As described above, N- (3,3-dimethylbutyl)-which is excellent in stability.
A method for stably and simply producing APM type A crystal from a lower alcohol / water mixed solvent by crystallization has not yet been sufficiently established.

Accordingly, an object of the present invention is to form an A-type crystal excellent in stability of N- (3,3-dimethylbutyl) -APM, which is a high-intensity sweetener, from a low alcohol / water mixed solvent. It is an object of the present invention to provide a method for stably and simply producing the compound by analysis.

[0015]

Means for Solving the Problems The present inventors have made intensive studies to solve the above problems. As a result, when N- (3,3-dimethylbutyl) -APM is crystallized in water or a water / lower alcohol mixed solvent system, the crystal form of the precipitated crystal is obtained by using the A-type crystal as a seed crystal. Was found to be able to be controlled to the desired A-type crystal, and the present invention was completed.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The lower alcohol solvent which can be used in the present invention is methanol, ethanol, isopropanol and the like, and more preferably methanol.

In the present invention, the content of the lower alcohol in the solution is not particularly limited. However, if the alcohol concentration is too high, it is difficult to precipitate crystals, so that the content is preferably 35% by weight or less based on the whole solution.

In the present invention, the temperature at which the type A crystal is added as a seed crystal is not particularly limited as long as the solution is oversaturated at that temperature, but preferably at 20 ° C.
Or more, more preferably 25 ° C. or more.

The amount of the type A crystal as a seed crystal to be added is not particularly limited, but is preferably 0.2 to 30% based on the weight of the solute.

The form of the type A crystal as the seed crystal to be added is not particularly limited, but is preferably added as a solid or a slurry solution. It is also a good method to use the remaining slurry as it is in the continuous crystallization as a seed crystal.

It goes without saying that the present invention can be applied irrespective of crystallization operations such as batch crystallization, continuous crystallization, stirring crystallization, and stationary crystallization.

In the present invention, there is no particular limitation on the cooling temperature of the crystal before filtering the crystals.

N- (3,3-dimethylbutyl) -AP
There is no particular limitation on a device for obtaining a dried A-type crystal having a moisture content of 3 to 6% by weight after obtaining the A-type wet crystal of M and drying it. ,
A vacuum dryer, a spray dryer, a micron dryer and the like can be widely used.

[0024]

The present invention will be described in more detail with reference to the following examples.

[0025]

[Reference Example 1]: N- (3,3-dimethylbutyl) -A
Preparation of PM into a reaction vessel equipped with stirring blades that can ensure the transfer of gaseous hydrogen to the liquid tank very well
The following were continuously charged with stirring. That is, 550 mL of ion-exchanged water, 1100 mL of methanol, 61 g of aspartame, 20 g of 10% palladium carbon, and 19 g of 3,3-dimethylbutyraldehyde.

While stirring the above mixture at room temperature, hydrogen gas was introduced at a flow rate of 200 mL / min. The progress of the reaction
The reaction mixture was sampled and monitored by analyzing the product by high performance liquid chromatography (HPLC). After 6 hours of reaction, the reaction vessel was filled with a stream of nitrogen gas, and the catalyst was filtered through a microporous filter (0.50 μm). As a result of analyzing the obtained filtrate (1460 g), the amount of N- (3,3-dimethylbutyl) -APM produced was 64 g (yield: 85%).

Next, when the filtrate was concentrated to 514 g, crystals precipitated. The obtained slurry solution is
After heating at ゜ C to dissolve the crystals, the methanol content in the solution was analyzed by gas chromatography and found to be 8.15% by weight.

Subsequently, the homogeneous solution of N- (3,3-dimethylbutyl) -APM was gradually cooled from 70 ° C. and kept at 40 ° C. for 1 hour to spontaneously crystallize.

The obtained slurry solution was cooled to 5 ° C. at a cooling rate of 5 ° C./hour. Subsequently, after aging overnight at the same temperature, the crystals were collected by filtration. Next, the above-mentioned wet crystal was subjected to reduced pressure at 50 ° C. to a water content of 5.8 in the crystal.
When dried to a weight percent, 58 g (yield 72
%: N- (3,3-dimethylbutyl) -APM having an HPLC purity of 97%) was obtained.

[0030]

Example 1 The N- (3,3-
(Dimethylbutyl) -APM (22 g) was placed in a three-necked flask. Then, methanol and water each 22g,
After the addition of 104 g, the mixture was heated to 70 ° C. to completely dissolve the crystals, and a solution was prepared such that the content of methanol in the whole solution was 15% by weight. This vessel was equipped with a stirring blade, a thermometer and the like, and was immersed in a water bath at 25 ° C. to cool the solution. When the actual solution temperature was 28 ° C., 0.4 g of A-type crystals were added as seed crystals. The crystals were aged in a water bath at 25 ° C. for 2 hours, and the crystals were collected by filtration.

The obtained wet crystals were subjected to powder X-ray diffractometry using CuKα radiation to measure diffraction X-rays, which revealed that diffraction was at least 6.0 °, 24.8 °, 8.2 ° and 16.5 °. Since it exhibited a characteristic peak of diffraction X-ray at an angle (2θ, CuKα ray), it was an A-type crystal. The powder X-ray diffraction pattern at this time is shown in FIG.

Subsequently, the wet type A crystal was dried under reduced pressure at 50 ° C. until the water content in the crystal became 4.5%, to obtain a dry type A crystal. The powder X-ray diffraction pattern at this time is shown in FIG.

[0033]

Comparative Example 1 The same solution as in Example 1 was immersed in a water bath at 25 ° C., and spontaneous crystallization occurred when the actual solution temperature was 25 ° C. The crystals were aged in a water bath at 25 ° C. for 2 hours, and the crystals were collected by filtration.

The obtained wet crystals were subjected to powder X-ray diffraction using CuKα radiation to measure diffraction X-rays. As a result, at least diffraction angles of 5.2 °, 8.4 °, 10.2 °, and 18.2 ° showed characteristic peaks of diffracted X-rays, indicating that this was a B-type crystal.

[0035]

Example 2 In the same manner as in Example 1, 8.0 g of N- (3,3-dimethylbutyl) -APM, 24.2 g and 129.4 g of methanol and water were added, and the mixture was heated to 70 ° C. The crystals were completely dissolved to prepare a solution having a methanol content of 15% by weight based on the whole solution. Subsequently, this solution was immersed in a water bath at 20 ° C., and when the actual solution temperature reached 22 ° C., 0.16 g of
Type A crystals were added as seeds. The crystals were aged in a water bath at 20 ° C. for 2 hours, and the crystals were collected by filtration.

The obtained wet crystals were subjected to powder X-ray diffraction using CuKα radiation to measure diffraction X-rays. As a result, the obtained wet crystal was an A-type crystal. Thereafter, the obtained wet crystals were dried in the same manner as in Example 1 to obtain dry A-type crystals.

[0037]

Comparative Example 2 When the same solution as in Example 2 was immersed in a water bath at 20 ° C., spontaneous crystallization occurred when the actual liquid temperature reached 21 ° C. After aging for 2 hours in a water bath at 20 ° C., the crystals were collected by filtration.

The obtained wet crystals were subjected to powder X-ray diffraction using CuKα radiation to measure diffraction X-rays. As a result, the obtained wet crystal was a B-type crystal, and an A-type crystal could not be confirmed.

[0039]

EFFECT OF THE INVENTION N- (3,3-dimethylbutyl) -A
By adding an A-type crystal of PM as a seed crystal, N- (3,3-dimethylbutyl) -AP which is a sweetener having a high degree of sweetness is added.
A crystal having excellent stability of M could be produced easily at low cost.

[Brief description of the drawings]

FIG. 1 is a powder X-ray diffraction diagram of a B-type crystal.

FIG. 2 is a powder X-ray diffraction diagram of a G-type crystal.

FIG. 3 is a powder X-ray diffraction diagram of a wet A-type crystal.

FIG. 4 is a powder X-ray diffraction diagram of a dried Form A crystal.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Tadashi Takemoto 1-1, Suzukicho, Kawasaki-ku, Kawasaki-ku, Kanagawa Prefecture Ajinomoto Co., Inc. Amino Science Laboratory F-term (reference) 4B047 LB08 LE10 LG17 LP01 LP02 LP05 LP06 LP07 LP20 4H045 AA20 BA11 EA02 GA40 HA31

Claims (2)

[Claims] 1. Use of water or a mixture of water and a lower alcohol as a crystallization solvent, at least 6.0 ° and 24.8 °
°, 8.2 ° and 16.5 ° diffraction angles (2θ, Cu
K-rays) show a characteristic peak of diffracted X-rays in N-
[N- (3,3-dimethylbutyl) -L-α-aspartyl] -L-phenylalanine methyl ester crystal is added as a seed crystal, and the crystal having excellent stability is preferentially precipitated. N- [N- (3,3
-Dimethylbutyl) -L-α-aspartyl] -L-phenylalanine methyl ester. 2. The method according to claim 1, wherein the lower alcohol is methanol.