WO2000026235A1

WO2000026235A1 - Method for preparing crystal of aspartame derivative excellent in stability

Info

Publication number: WO2000026235A1
Application number: PCT/JP1999/006083
Authority: WO
Inventors: Shigeru Kawahara; Akihiro Kishishita; Kazutaka Nagashima; Tadashi Takemoto
Original assignee: Ajinomoto Co., Inc.
Priority date: 1998-10-30
Filing date: 1999-11-01
Publication date: 2000-05-11
Also published as: CN1315958A; BR9914838A; CA2348162A1; KR20010075420A

Abstract

A method for preparing the A type crystal of N-(3,3-dimethylbutyl)-APM being excellent in stability, which comprises holding the B type crystal thereof under a controlled circumstance of an absolute humidity of 0.203 kg/kg or lower and a material temperature of 25 to 80 °C, to thereby cause crystal transition; and a method for preparing the A type crystal of N-(3,3-dimethylbutyl)-APM comprising holding the D type crystal thereof under a controlled circumstance of an absolute humidity of 0.0550 kg/kg or lower and a material temperature of 25 to 80 °C, to thereby cause crystal transition. These crystal transition methods allow the preparation of a crystal excellent in stability with a low cost and with stability.

Description

Description I. Method for producing aspartame derivative crystals with excellent stability

(Technical field)

TECHNICAL FIELD The present invention relates to a method for producing a highly stable crystal of a high-potency sweet substance N- [N- (3,3-dimethylbutyl) -L-hyaspartyl] 1 L-phenylalanine methyl ester. Things. Incidentally, L-hyaspartyl-L-phenylalanine methyl ester, as is well known, is one of the amino acid-based high-potency sweeteners that has already been established for commercialization, 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 Ne 0 tame in some literature.

(Background technology)

N- (3,3-Dimethylbutyl) -APM is very potent because it has at least 50 times the sweetness potency of aspartame by weight and about 10,000 times that of sucrose (table sugar) A sweetener.

Because sweeteners are primarily intended for use in foods and for human consumption, they should be prepared in such a way that they can be of high purity, virtually free of impurities and degradants. Must be manufactured. In the case of sweeteners that are relatively easy to decompose, such as N- (3,3-dimethylbutyl) -APM, some measures must be taken to prevent decomposition after the product is shipped.

The known crystal structure of N- (3,3-dimethylbutyl) -APM is W 〇 It is described as IR spectrum data in 95 / 30689.The present inventors also found that this crystal was a monohydrate as a result of single crystal structure analysis and was measured by powder X-ray diffraction method. If at least 6.0. , 24.8 °, 8.2 °, and 16.5 ° (26, CuKa line) showed characteristic beaks of diffracted X-rays. Then, the present inventors have referred to this crystal as an A-type crystal for convenience.

On the other hand, the production method of N- (3,3-dimethylbutyl) -APM is also described in USP 5,728,862. Here, high purity (97% according to HP LC) N- (3,3-dimethylbutyl) mono-crystal is precipitated by spontaneous crystallization by crystallization using methanol and water as crystallization solvents. Get APM and review.

Therefore, when the present inventor re-executed Example 1 described in US Pat. No. 5,728,862, it was confirmed that the purity was reproducible (98% according to HP LC). No formation of the type crystal could be confirmed.

In other words, N- (3,3-dimethylbutyl) -APM obtained by the additional test should be at least 5.1 °, 21.1 °, 21.3 ° and 8.3 ° in the wet crystal state. A characteristic beak of diffracted X-rays was shown at a bending angle (20, CuK line). Figure 1 shows the powder X-ray diffraction pattern at this time. Hereinafter, this is referred to as a B-type crystal. Further drying the Form B crystals obtained above according to Example 1 of the above USP 5,728,862 gives at least 5.6 °, 8.4. At the diffraction angles of 17.1 ° and 18.8 ° (20, CuKa line), crystals were obtained which exhibited a characteristic beak of diffracted X-rays. 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.

On the other hand, the present inventor has stated that the B-type crystal was dried until the Rollers exhibit a characteristic beak of diffracted X-rays at least at diffraction angles of 5.4 °, 8.4 °, 18.8 ° and 17.6 ° (2 2, CuK line), N— (3, 3-dimethylbutyl) A new crystal of APM was obtained. Hereinafter, this is referred to as a D-type crystal for convenience. Fig. 3 shows the powder X-ray diffraction pattern at this time.

Next, a stability test of N- (3,3-dimethylbutyl) -APM in the obtained G-type, D-type and A-type crystals was performed at 70 ° C. As a result, after 271 hours, the residual rates of N- (3,3-dimethylbutyl) -APM in the G-type and D-type crystals were 18 wt% and 77 wt%, respectively. It was 96 wt% in the type crystal, indicating that N- (3,3-dimethylbutyl) -APM was most stably present in the type A crystal. Table 1 below shows the relationship between the storage time and the residual ratio of N- (3,3-dimethylbutyl) -APM. Table 1: Stability test at 70 ° C

Thus, it was found that Example 1 described in USP 5,728,862 can provide a G-type crystal of N— (3,3-dimethylbutyl) -APM, which is inferior in stability to the A-type crystal. did. (Disclosure of the Invention)-As described above, a method for obtaining an A-type crystal of N- (3,3-dimethylbutyl) -APM with excellent stability at low cost and stably. Has not yet been fully established.

An object of the present invention is to provide an A-type crystal having high stability of N- (3,3-dimethylbutyl) -APM, which is a high-intensity sweetener, by at least 5.1 °, 21.1 °, 21. 3. And 8.3 ° diffraction angle (2S, CuKct line) shows a characteristic X-ray diffraction peak N- (3,3-dimethylbutyl) -manufactured from APM B-type crystal stably and easily It is to provide a way to do it. Another object of the present invention is to provide an A-type crystal excellent in the stability of N- (3,3-dimethylbutyl) -APM which is a high-intensity sweetener, at least at 5.4 ° and 8.4. , 18.8 ° and 17.6 ° diffraction angles

An object of the present invention is to provide a method for stably and easily producing from D-type crystal of N- (3,3-dimethylbutyl) -APM which shows a peculiar beak of X-ray diffraction at (20, CuK ray). The present inventors have conducted intensive studies to achieve the above object, and as a result, it has been found that the B-type crystal of N- (3,3-dimethylbutyl) -APM can control the product temperature under a constant absolute humidity atmosphere. The fact that the crystal transition to the A-type crystal proceeds, and the D-type crystal of N- (3,3-dimethylbutyl) -APM also The inventors have found that the crystal transition to the type crystal proceeds, and based on such fact, have completed the present invention. That is, the present invention firstly exhibits a characteristic beak of diffracted X-rays at diffraction angles of at least 5.1 °, 21.1 °, 21.3 ° and 8.3 ° (2 °, CuK line). N— [N- (3,3-dimethylbutyl) 1 L-1 ctaspartyl] 1 L 1 Transformation of wet crystals of fenilalanine methyl ester (B-type crystals) by maintaining the temperature at 25-8 CTC in an environment with an absolute humidity of 0.203 kg / kg or less Characterized by at least 6.0. , 24.8 °, 8.2 ° and 16.5 ° beaks, characterized by N- [N- (3,3-dimethylbutyl) -l-H-aspartyl] -l-L-phenylalanine methyl ester Method for producing crystals with good stability (type A crystal), and secondly, at least 5.4 °, 8.4 °, 18.8. And a characteristic beak of diffracted X-rays at a diffraction angle of 17.6 ° (2θ, CuK ray) N— [N— (3,3-dimethylbutyl) 1 L-l-aspartyl] 1 L-l The crystal transformation of the crystals of dilulanine methyl ester (D-type crystal) is controlled by maintaining the temperature of the crystals at 25-80 ° C in an environment with an absolute humidity of 0.0550 kg / kg or less. Characterized by at least 6.0 °, 24.8 °, 8.2. N- [N- (3,3-dimethylbutyl) -1-L-hyaspartyl] -1-L-phenylalanine methyl ester characterized by a beak of 16.5 ° and 16.5 ° Crystal). First, the first crystal production method (crystal transition method) will be described.

According to the present crystal transition method, the temperature at which the N- (3,3-dimethylbutyl) -APM wet B-type crystal must be maintained is such that the crystal transition to the A-type crystal does not progress or is slow at low temperatures. If the temperature is too high, the crystals will be decomposed, so the temperature is preferably 25 to 80 ° C. According to the present crystal transition method, the absolute humidity at which a wet B-type crystal is to be maintained is preferably 0.203 kg / kg or less, because the crystal transition time becomes longer at an excessively high humidity.

It goes without saying that the crystal transition according to the present invention does not depend on the method for producing N- (3,3-dimethylbutyl) -APM or the method for producing the B-type crystal.

In this crystal transition method, N- (3,3-dimethylbutyl) -APM It is characteristic that A-type crystals can be obtained. Such a crystal transition method, for example, reproduces the crystal transition conditions of the present invention with a dryer, and the obtained A-type crystals have a water content of 3 to 6 weights. % To dryness, and such an embodiment is a good method. Next, the second crystal transition method according to the present invention will be described.

According to this crystal transition method, the temperature at which the D-type crystal of N- (3,3-dimethylbutyl) -APM should be maintained is such that the crystal transition to the A-type crystal does not progress or is slow at low temperatures, Decomposition of N- (3,3-dimethylbutyl) -APM even when the temperature is too high is the same as that described for the first crystal transition method, and is preferably 25 to 80 ° C. It is. According to the present crystal transition method, the absolute humidity at which the D-type crystal is to be maintained is the same as that described for the first crystal transition method, since the crystal transition time becomes longer at too high humidity. Preferably it is 0.050 kg / kg or less.

It goes without saying that the crystal transition according to the present invention does not depend on the method for producing N- (3,3-dimethylbutyl) -APM or the method for producing a D-type crystal thereof.

This crystal transition method is characterized in that an A-type crystal can be obtained from a D-type crystal of N— (3,3-dimethylbutyl) —APM. The transition condition can be reproduced by a dryer so that the water content of the obtained A-type crystal becomes 3 to 6% by weight, and such an embodiment is a good method. .

(Brief description of drawings)

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

FIG. 2 shows a powder X-ray diffraction diagram of the G-type crystal. FIG. 3 shows a powder X-ray diffraction pattern of the D-type crystal.

FIG. 4 shows a powder X-ray diffraction diagram of the type A crystal.

(Best mode for carrying out the invention)

Hereinafter, the present invention will be described in more detail with reference to Examples. First, Examples according to the first crystal transition method will be described.

Reference Example 1: Synthesis of N— (3,3-dimethylbutyl) -APM

The following were continuously charged with stirring into a reaction vessel equipped with stirring blades to ensure that gaseous hydrogen could be transferred very well to the liquid layer. That is, 550 mL of ion-exchanged water, 100 mL of methanol, 61 g of aspartame, 20 g of 10% palladium on carbon (50% by weight of water), and 19 g of 3,3-dimethylbutyraldehyde.

After completion of the charging, hydrogen gas was introduced at a flow rate of 20 OmL / min while continuously stirring the mixture at room temperature. The progress of the reaction was monitored by sampling the reaction mixture and analyzing the product by high performance liquid chromatography (HP LC). After 6 hours of reaction, the reactor was filled with a stream of nitrogen gas and the catalyst was filtered through a microporous filter — (0.5 Ou). As a result of analyzing the obtained filtrate (1,460 g), the amount of N- (3,3-dimethylbutyl) -APM produced was 64 (yield: 85%).

Next, when the filtrate was concentrated to 497 g, crystals were precipitated. The resulting slurry is 70. After dissolving the crystals by heating at C, the methanol content of the solution was analyzed by gas chromatography and found to be 8.15% by weight.

Then, apply this homogeneous solution of N- (3,3-dimethylbutyl) -APM to 70. C or et gradually cooled and natural crystallization and held 1 hour at 40 ^e C. Next, the obtained slurry liquid was cooled to 5 ° C at a cooling rate of 5 ° C / hour, aged at the same temperature, and the crystals were collected by filtration. Subsequently, the wet crystals were dried under reduced pressure at 50 ° C. until the water content in the crystals became 5.8% by weight, and 58 g of N— (3,3-dimethylbutyl) -APM was obtained. (72% yield, 97% purity by HPLC).

Reference example 2

22 g of N- (3,3-dimethylbutyl) -APM obtained in Reference Example 1 was placed in a three-necked flask. Then, after adding 22 g and 104 g of methanol and water, respectively, the mixture was heated to ° 0 ° C. to completely dissolve the crystals, and the content of methanol in the whole solution was 15% by weight. Such a solution was prepared. This vessel was equipped with stirring blades and a thermometer, and was immersed in a 25 ° C water bath to cool the solution. When the actual liquid temperature was 25 ° C, spontaneous crystallization occurred. The crystals were aged in a water bath at 25 ° C. for 2 hours, and then the crystals were collected by filtration.

The obtained wet crystals were subjected to powder X-ray diffraction using Cu K lines to measure diffraction X-rays. As a result, at least 5.1 °, 21.1 °, 21.3 ° and 8.3 The characteristic beak of the diffracted X-ray was shown at a diffraction angle of °°, indicating that this was a B-type crystal.

Example 1

The B-type crystal obtained in Reference Example 2 was allowed to stand for 1 hour in a thermostatic chamber whose absolute humidity and product temperature were controlled as shown in Table 2 below, and the obtained N- (3,3- Dimethylbutyl) The crystal form of APM was examined by powder X-ray diffraction, and the results shown in the table were given. Table 2

Example 2

The B-type crystal obtained in Reference Example 2 was left in a ventilation dryer using hot air for 20 minutes (hot air flow rate 1 m ³ / sec), and the obtained N— (3,3-dimethylbutyl) -AP Examination of the crystal form of M by powder X-ray diffraction gave the results shown in Table 3 below. That is, at a product temperature of 35-60 ° C and an absolute temperature of 0.00004-0.0320 kg / kg, at least 6.0 °, 24.8 °, 8.2 ° and 16.5 ° times Crystals were obtained which showed a characteristic diffraction X-ray peak at the diffraction angle (20, CuK line). From this, this crystal was identified as type A crystal. Table 3

Next, an example using the second crystal transition method will be described.

Reference example 3 The B-type crystal obtained in Reference Example 2 was dried under reduced pressure in a vacuum dryer at 25 ° C. or lower until the water content became 4.6 wt%. The obtained wet crystals were analyzed by powder X-ray diffraction using CuK rays, and as a result, at least 5.4 °, 8.4 °, 18.88 °, and 17.6 ° were obtained. At the diffraction angle (20, CuKa line), a characteristic X-ray diffraction peak was observed, indicating that this was a D-type crystal (see Fig. 3).

The D-type crystal obtained in Reference Example 3 was allowed to stand for 2 hours in a thermostatic oven whose absolute humidity and product temperature were controlled as shown in Table 4 below, and the obtained N- (3,3 X-ray powder diffraction analysis of the crystal form of APM gave the results shown in the table. That is, at an absolute humidity of 0.0133 to 0.0403 kg / kg and a product temperature of 30 to 50 ° C, at least 6.0 °, 24.8 °, 8.2. At 16.5 ° diffraction angle (20, CuK line), a crystal with a characteristic beak of X-ray diffraction was obtained. From this, it was found that the obtained product was an A-type crystal. The powder X-ray diffraction diagram at this time is shown in Table 4 below. Table 4

(Industrial applicability) N- (3,3-Dimethylbutyl) -APM A type B crystal or D-type crystal is crystal-transferred to stabilize N- (3,3-Dimethylbutyl) -APM, a high-potency sweetener. An A-type crystal having excellent properties can be easily produced at low cost.

Claims

The scope of the claims -

1. at least 5.1 °, 21.1. N- [N- (3,3-dimethylbutyl) -L-hyperaspartyl shows a characteristic beak of diffracted X-rays at diffraction angles of 21.3 ° and 8.3 ° (20, CuK ray) ] The temperature of wet crystals (type B crystals) of L-phenylalanine methyl ester is 25 to 80 in an environment with an absolute humidity of 0.203 kg / kg or less. Characterized by at least 6.0 °, 24.8 °, 8.2 °, and 16.5 ° peaks, characterized by crystal transition by controlling and maintaining C — (3,3-Dimethylbutyl) 1-L-aspartyl] —A method for producing L-phenylalanine methyl ester with excellent stability (A-type crystal).

2. At least 5.4. 8.4. N- [N- (3,3-dimethylbutyl) -L-l-aspartyl] shows characteristic X-ray diffraction peaks at diffraction angles of 18.8 ° and 17.6 ° (20, CuKa line). Transform the crystals of L-phenylalanine methyl ester (D-type crystals) by maintaining the product temperature at 25-80 ° C in an environment with an absolute humidity of 0.055 Okg / kg or less. Characterized by a peak of at least 6.0 °, 24.8 °, 8.2 ° and 16.5 °, N— [N- (3,3-dimethylbutyl) -L [Hispartyl] A method for producing crystals (A-type crystals) of 1-L-phenylalanine methyl ester with excellent stability.