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WO2000026235A1 - Procede de preparation de cristaux de derive d'aspartame possedant une excellente stabilite - Google Patents

Procede de preparation de cristaux de derive d'aspartame possedant une excellente stabilite Download PDF

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Publication number
WO2000026235A1
WO2000026235A1 PCT/JP1999/006083 JP9906083W WO0026235A1 WO 2000026235 A1 WO2000026235 A1 WO 2000026235A1 JP 9906083 W JP9906083 W JP 9906083W WO 0026235 A1 WO0026235 A1 WO 0026235A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal
dimethylbutyl
crystals
apm
type
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1999/006083
Other languages
English (en)
Japanese (ja)
Inventor
Shigeru Kawahara
Akihiro Kishishita
Kazutaka Nagashima
Tadashi Takemoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP10310228A external-priority patent/JP2000136198A/ja
Application filed by Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Priority to CA002348162A priority Critical patent/CA2348162A1/fr
Priority to BR9914838-2A priority patent/BR9914838A/pt
Priority to KR1020017003946A priority patent/KR20010075420A/ko
Publication of WO2000026235A1 publication Critical patent/WO2000026235A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C07K5/06121—Asp- or Asn-amino acid the second amino acid being aromatic or cycloaliphatic
    • C07K5/0613—Aspartame

Definitions

  • 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.
  • L-hyaspartyl-L-phenylalanine methyl ester 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.
  • 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.
  • 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.
  • N- (3,3-dimethylbutyl) -APM The known crystal structure of N- (3,3-dimethylbutyl) -APM is W ⁇ 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.
  • N- (3,3-dimethylbutyl) -APM is also described in USP 5,728,862.
  • 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.
  • 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.
  • 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.
  • this is referred to as a D-type crystal for convenience.
  • Fig. 3 shows the powder X-ray diffraction pattern at this time.
  • 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.
  • (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 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).
  • 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.
  • 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.
  • 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.
  • N- (3,3-dimethylbutyl) -APM N- (3,3-dimethylbutyl) -APM It is characteristic that A-type crystals can be obtained.
  • Such a crystal transition method 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.
  • the second crystal transition method according to the present invention will be described.
  • 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.
  • 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.
  • 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. .
  • 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.
  • 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.
  • 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.
  • 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.
  • Table 4 The powder X-ray diffraction diagram at this time is shown in Table 4 below. Table 4
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Seasonings (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)

Abstract

Procédé de préparation du cristal de type A de N-(3,3-diméthylbutyl)-APM qui possède une excellente stabilité. Ledit procédé consiste à maintenir le cristal de type B de ladite substance dans des conditions régulées d'humidité absolue de 0,203 kg/kg ou moins et de température de la matière entre 25 et 80 °C, ce qui provoque la transition du cristal. La présente invention concerne également un procédé de préparation du cristal de type A de N-(3,3-diméthylbutyl)-APM qui consiste à maintenir le cristal de type D de ladite substance dans des conditions régulées d'humidité absolue de 0,0550 kg/kg ou moins et de température de la matière entre 25 et 80 °C, ce qui provoque la transition du cristal. Ces procédés de transition du cristal permettent la préparation d'un cristal d'une excellente stabilité à un coût peu élevé.
PCT/JP1999/006083 1998-10-30 1999-11-01 Procede de preparation de cristaux de derive d'aspartame possedant une excellente stabilite Ceased WO2000026235A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002348162A CA2348162A1 (fr) 1998-10-30 1999-11-01 Procede de preparation de cristaux de derive d'aspartame possedant une excellente stabilite
BR9914838-2A BR9914838A (pt) 1998-10-30 1999-11-01 Processo para preparar cristais altamente estáveis (cristais do tipo a) de éster metìlico de n-[n-(3,3-dimetilbutil)-l-alfa-aspartil]-l-fenilalanina
KR1020017003946A KR20010075420A (ko) 1998-10-30 1999-11-01 안정성이 우수한 아스파르탐 유도체 결정의 제조방법

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP31022798 1998-10-30
JP10310228A JP2000136198A (ja) 1998-10-30 1998-10-30 安定性に優れたアスパルテーム誘導体結晶の製造方法
JP10/310227 1998-10-30
JP10/310228 1998-10-30

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US09830158 A-371-Of-International 2001-06-27
US10/160,000 Continuation US6844465B2 (en) 1998-10-30 2002-06-04 Method for preparing highly stable crystals of aspartame derivative

Publications (1)

Publication Number Publication Date
WO2000026235A1 true WO2000026235A1 (fr) 2000-05-11

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PCT/JP1999/006083 Ceased WO2000026235A1 (fr) 1998-10-30 1999-11-01 Procede de preparation de cristaux de derive d'aspartame possedant une excellente stabilite

Country Status (5)

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KR (1) KR20010075420A (fr)
CN (1) CN1315958A (fr)
BR (1) BR9914838A (fr)
CA (1) CA2348162A1 (fr)
WO (1) WO2000026235A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362706A2 (fr) * 1988-10-03 1990-04-11 Ajinomoto Co., Inc. Procédé pour la préparation de cristaux IB secs de l'ester méthylique de l'alpha-L-aspartyl-L-phénylalanine ayant une solution modifiée
WO1995030689A1 (fr) * 1994-05-09 1995-11-16 Claude Nofre Procede perfectionne de preparation d'un compose derive de l'aspartame utile comme agent edulcorant
WO1995030688A1 (fr) * 1994-05-09 1995-11-16 Claude Nofre N-[N-(3,3-DIMETHYLBUTYL)-L-α-ASPARTYL]-L-HEXAHYDROPHENYLALANINE 1-METHYL ESTER UTILE COMME AGENT EDULCORANT, SON PROCEDE DE PREPARATION

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362706A2 (fr) * 1988-10-03 1990-04-11 Ajinomoto Co., Inc. Procédé pour la préparation de cristaux IB secs de l'ester méthylique de l'alpha-L-aspartyl-L-phénylalanine ayant une solution modifiée
WO1995030689A1 (fr) * 1994-05-09 1995-11-16 Claude Nofre Procede perfectionne de preparation d'un compose derive de l'aspartame utile comme agent edulcorant
WO1995030688A1 (fr) * 1994-05-09 1995-11-16 Claude Nofre N-[N-(3,3-DIMETHYLBUTYL)-L-α-ASPARTYL]-L-HEXAHYDROPHENYLALANINE 1-METHYL ESTER UTILE COMME AGENT EDULCORANT, SON PROCEDE DE PREPARATION

Also Published As

Publication number Publication date
KR20010075420A (ko) 2001-08-09
BR9914838A (pt) 2001-08-14
CN1315958A (zh) 2001-10-03
CA2348162A1 (fr) 2000-05-11

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