CN1315958A - Method for preparing crystal of aspartame derivative excellent in stability - Google Patents
Method for preparing crystal of aspartame derivative excellent in stability Download PDFInfo
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- CN1315958A CN1315958A CN99810417A CN99810417A CN1315958A CN 1315958 A CN1315958 A CN 1315958A CN 99810417 A CN99810417 A CN 99810417A CN 99810417 A CN99810417 A CN 99810417A CN 1315958 A CN1315958 A CN 1315958A
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- 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
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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 DEG 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 DEG 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
Technical field
The present invention relates to the crystalline preparation method of the excellent in stability of the high sweet taste substance N-of sugariness (N-(3, the 3-dimethylbutyl)-L-α-aspartyl)-L-phenyl methyl lactamine.It is in addition, well-known that L-α-aspartyl-the L-phenyl methyl lactamine is a kind of business-like amino acids high-intensity sweetener of having established, and abbreviates APM or aspartame as.Therefore, the above-mentioned sweet taste substance that the present invention relates to can be thought the derivative of APM or aspartame.Here, below its brief note is N-(3, the 3-dimethylbutyl)-APM.In addition, this sweet taste substance also abbreviates Neotame as sometimes according to document.
Background technology
It is at least 50 times of aspartame that the sweet taste of N-(3, the 3-dimethylbutyl)-APM is tired in weight ratio, is about 10000 times of sucrose (edible granulated sugar), can constitute very potent sweeting agent.
Sweeting agent is purpose to be used for food by human consumption mainly, and the method that must employing can access the high purity substance of in fact free from foreign meter or degradation production is prepared.In addition, the occasion of N-(3, the 3-dimethylbutyl)-sweeting agent that this ratio of APM is easier to decompose in order to prevent the decomposition behind the launch, must be taken some time.
Known N-(3, the 3-dimethylbutyl)-APM crystalline structure is documented among the WO95/30689 as the IR spectroscopic data.In addition, the result that this crystal of affirmations such as the inventor carries out the single crystal structure parsing is 1 hydrate, the occasion of measuring with powder X-ray diffractometry shows the distinctive peak of diffraction X ray at least when the diffraction angle (2 θ, CuK α line) of 6.0 °, 24.8 °, 8.2 ° and 16.5 °.In addition, the inventor waits and for convenience this crystal is called the A N-type waferN.
On the other hand, the preparation method of N-(3, the 3-dimethylbutyl)-APM is also recorded among the USP5728862.Here, carry out crystallization as recrystallisation solvent, make it to separate out crystal, obtained N-(3, the 3-the dimethylbutyl)-APM of high purity (adopting HPLC is 97%) by spontaneous nucleation by using the first alcohol and water.
, the inventor has carried out supplementary test to the embodiment 1 of above-mentioned USP5728862 record, has reproducibility (adopting HPLC is 98%) though confirm the purity aspect, can not confirm to have generated the A N-type waferN.
That is to say that the N-that supplementary test obtains (3, the 3-dimethylbutyl)-APM shows the distinctive peak of diffraction X ray at least under wet crystalline state when the diffraction angle (2 θ, CuK α line) of 5.1 °, 21.1 °, 21.3 ° and 8.3 °.At this moment x-ray diffractogram of powder as shown in Figure 1.Below this crystal is called the Type B crystal.
And, if the Type B crystal drying that will obtain according to the embodiment 1 of above-mentioned USP5728862 record obtains at least showing the crystal at the distinctive peak of diffraction X ray when the diffraction angle (2 θ, CuK α line) of 5.6 °, 8.4 °, 17.1 ° and 18.8 °.At this moment x-ray diffractogram of powder as shown in Figure 2.Adopting Karl Fischer method to measure this crystalline amount of moisture is 0.6 weight %.Below this crystal is called the G N-type waferN.
On the other hand, if the inventor finds the Type B crystal is dried to amount of moisture 3-6 weight %, can obtain at least when the diffraction angle (2 θ, CuK α line) of 5.4 °, 8.4 °, 18.8 ° and 17.6 °, showing N-(3, the 3-the dimethylbutyl)-APM novel crystal at the peculiar peak of diffraction X ray.Below, for convenience this material is called the D N-type waferN.At this moment powder X-ray ray diffraction diagram as shown in Figure 3.
Secondly, under 70 ℃, carry out stability test for N-(3, the 3-the dimethylbutyl)-APM of the G type that obtains, D type and A N-type waferN.As a result, after 271 hours, N-(3 in G type and the D N-type waferN, the 3-dimethylbutyl)-residual rate of APM is respectively 18wt% and 77wt%, in this relative A N-type waferN is 96wt%, therefore points out N-in the A N-type waferN (3, the 3-dimethylbutyl)-APM the most stably to exist.At this moment the relation of the residual rate of shelf time and N-(3, the 3-dimethylbutyl)-APM is shown in following table 1.Stability test under showing 1:70 ℃
Thereby, can judge in the embodiment 1 of USP5728862 record, obtained the G N-type waferN of N-(3, the 3-the dimethylbutyl)-APM than A N-type waferN poor stability.
Disclosure of the Invention
As mentioned above, present present situation is that do not establish as yet can be low-cost and stably obtain the method for A N-type waferN of N-(3, the 3-the dimethylbutyl)-APM of excellent in stability.
The object of the present invention is to provide from least at diffraction angle (2 θ of 5.1 °, 21.1 °, 21.3 ° and 8.3 °, CuK α line) N-(3 that shows the peculiar peak of diffraction X ray the time, the 3-dimethylbutyl)-the Type B crystalchecked of APM and prepare the method for A N-type waferN of the excellent in stability of high-intensity sweetener N-(3, the 3-dimethylbutyl)-APM easily.In addition, another object of the present invention is to provide from least at diffraction angle (2 θ of 5.4 °, 8.4 °, 18.8 ° and 17.6 °, CuK α line) N-(3 that shows the peculiar peak of diffraction X ray the time, the 3-dimethylbutyl)-the D N-type waferN of APM is stable and prepare the method for A N-type waferN of the excellent in stability of high-intensity sweetener N-(3, the 3-dimethylbutyl)-APM easily.
The inventor etc. have carried out studying in order to achieve the above object concentratedly, found that N-(3, the 3-dimethylbutyl)-the Type B crystal of APM can carry out crystal to the A N-type waferN by control material temperature (product temperature, material temperature) under certain absolute humidity environment to be shifted; And the D N-type waferN of N-(3, the 3-dimethylbutyl)-APM also can pass through control material temperature under suitable absolute humidity environment, and (the product temperature materialtemperature) is carried out crystal to the A N-type waferN and is shifted, and has finished the present invention based on these facts.
That is to say, first aspect present invention relates at least with 6.0 °, 24.8 °, 8.2 ° and 16.5 ° peak be that (N-(3 for the N-of feature, the 3-dimethylbutyl)-L-α-aspartyl)-preparation method of the crystal (A N-type waferN) of the excellent in stability of L-phenyl methyl lactamine, it is characterized in that at absolute humidity be with its material temperature (product temperature under the environment below the 0.203kg/kg, material temperature) control maintains 25-80 ℃, make at least at 5.1 °, 21.1 °, 21.3 ° and 8.3 ° diffraction angle (2 θ, CuK α line) the wet crystal (Type B crystal) that shows N-(N-(3, the 3-dimethylbutyl)-L-α-aspartyl)-L-phenyl methyl lactamine at the peculiar peak of diffraction X ray the time carries out the crystal transfer; Second aspect relates at least with 6.0 °; 24.8 °; 8.2 ° and 16.5 ° peak be that (N-(3 for the N-of feature; the 3-dimethylbutyl)-L-α-aspartyl)-preparation method of the crystal (A N-type waferN) of the excellent in stability of L-phenyl methyl lactamine; it is characterized in that at absolute humidity be with its material temperature (product temperature under the environment below the 0.0550kg/kg; materialtemperature) control maintains 25-80 ℃; make at least at 5.4 °; 8.4 °; 18.8 ° and 17.6 ° diffraction angle (2 θ; CuK α line) crystal (D N-type waferN) that shows N-(N-(3, the 3-dimethylbutyl)-L-α-aspartyl)-L-phenyl methyl lactamine at the peculiar peak of diffraction X ray the time carries out the crystal transfer.
At first, the first crystal preparation method (crystal transfer method) is described.
According to this crystal transfer method, be suitable for keeping N-(3, the 3-dimethylbutyl)-wet Type B crystalline material temperature (the product temperature of APM, material temperature) preferred 25-80 ℃, this is that crystal does not shift or the crystal transfer is carried out slowly because do not carry out to the A N-type waferN at low temperatures, and the too high crystal that also can cause of temperature decomposes in addition.In addition, according to this crystal transfer method, be suitable for keeping below the wet preferred 0.203kg/kg of Type B crystalline absolute humidity, this is because the too high meeting of humidity makes crystal elongated transfer time.
Crystal of the present invention shifts and does not rely on N-(3, the 3-the dimethylbutyl)-preparation method of APM and the Type B crystalline preparation method of this material certainly.
In this crystal transfer method, be characterised in that from N-(3, the 3-dimethylbutyl)-the Type B crystal of APM can obtain the A N-type waferN, this crystal transfer method for example also can be by reproducing crystal jump condition of the present invention with drying machine, it is that 3-6 weight % implements that the A N-type waferN that obtains is dried to amount of moisture, and this embodiment is good method.
Secondly the above-mentioned second crystal transfer method of the present invention is described.
According to this crystal transfer method, be suitable for keeping N-(3, the 3-dimethylbutyl)-material temperature (the product temperature of the D N-type waferN of APM, material temperature) preferred 25-80 ℃, this is that crystal does not shift or the crystal transfer is carried out slowly because do not carry out to the A N-type waferN at low temperatures, too high N-(3, the 3-the dimethylbutyl)-APM that also can cause of temperature decomposes in addition, and this is identical with the explanation in the above-mentioned first crystal transfer method.In addition, according to this crystal transfer method, be suitable for keeping below the preferred 0.0550kg/kg of absolute humidity of D N-type waferN, this is that this is identical with the explanation in the above-mentioned first crystal transfer method because the too high meeting of humidity makes crystal elongated transfer time.
Crystal of the present invention shifts the preparation method who does not rely on N-(3, the 3-the dimethylbutyl)-preparation method of APM and the D N-type waferN of this material certainly.
In this crystal transfer method, be characterised in that from N-(3, the 3-dimethylbutyl)-the D N-type waferN of APM can obtain the A N-type waferN, this crystal transfer method for example also can be by reproducing crystal jump condition of the present invention with drying machine, the amount of moisture that is dried to gained A N-type waferN is that 3～6 weight % implement, and this embodiment is good method.
The simple declaration of drawing
Fig. 1 represents Type B crystalline x-ray diffractogram of powder.
Fig. 2 represents the x-ray diffractogram of powder of G N-type waferN.
Fig. 3 represents the x-ray diffractogram of powder of D N-type waferN.
Fig. 4 represents the x-ray diffractogram of powder of A N-type waferN.
The preferred forms of invention
Illustrate in greater detail the present invention below in conjunction with embodiment.
At first, enumerate the embodiment that adopts the first crystal transfer method.Reference example 1:N-(3, the 3-dimethylbutyl)-APM's is synthetic
Being equipped with really and can being transferred to gasiform hydrogen very well in the reaction vessel of the agitating vane in the liquid level, drop into following substances while stirring continuously.That is, ion exchanged water 550ml, methyl alcohol 1100mL, aspartame 61g, 10% palladium carbon (moisture is 50 weight %) 20g and 3,3-dimethyl butyraldehyde 19g.
Drop into the end back and continue at room temperature to stir said mixture, simultaneously the flow velocity importing hydrogen that divides with 200mL/.By reaction mixture sampling, with the carrying out of high performance liquid chromatography (HPLC) assay products monitoring reaction.React after 6 hours, be full of reaction vessel, with millipore filter (0.50 μ m) filtering catalyst with nitrogen gas stream.The filtrate that analysis obtains (1460g), the result, the output of N-(3, the 3-dimethylbutyl)-APM is 64g (yield 85%).
Secondly, this filtrate is concentrated into 497g, separates out crystal.After 70 ℃ down the slurries that generate of heating make dissolution of crystals, be 8.15 weight % with the content of methyl alcohol in the gc analysis solution.
Then, the uniform solution of this N-(3, the 3-dimethylbutyl)-APM is slowly cooled off by 70 ℃, kept 1 hour, make it spontaneous nucleation at 40 ℃.
Secondly, the slurries that obtain are cooled to 5 ℃, after 1 night of slaking under this temperature, filter and collect crystal with 5 ℃/hour speed of cooling.Then, under reduced pressure, the amount of moisture that 50 ℃ of crystal that will wet down are dried in the crystal reaches 5.8 weight %, obtains N-(3, the 3-dimethylbutyl)-APM (yield 72%, employing HPLC mensuration purity is 97%) of 58g.Reference example 2:
N-(3, the 3-dimethylbutyl)-APM 22g that reference example 1 is obtained packs in the three-necked bottle.After then adding first alcohol and water 22g and 104g respectively, be heated to 70 ℃ crystal is dissolved fully, the content of compounding methanol in complete soln is the solution of 15 weight %.Agitating vane and thermometer are installed in this container, it are immersed in 25 ℃ the water-bath cooling solution, spontaneous nucleation when the real solution temperature reaches 25 ℃.Directly in 25 ℃ water-bath, make the crystal slaking after 2 hours, filter and collect crystal.
The wet crystal that obtains uses CuK α line to measure the diffraction X ray with powder X-ray diffractometry, and the result shows when the diffraction angle of 5.1 °, 21.1 °, 21.3 ° and 8.3 ° at least and therefore learns that this material is the Type B crystal in the distinctive peak of diffraction X ray.Embodiment 1:
The Type B crystal that reference example 2 obtains was placed 1 hour in the thermostatic bath shown in following table 2 respectively at control absolute humidity and material temperature, and the crystal formation with powder X-ray diffractometry investigation gained N-(3, the 3-dimethylbutyl)-APM the results are shown in the same table.
Table 2
Embodiment 2
| The crystal jump condition | Absolute humidity (kg/kg) | Material temperature (℃) | Crystal formation |
| ????(1) ????(2) | ????0.00726 ????0.0250 | ????20 ????40 | ????B ????A |
The Type B crystal that reference example 2 obtains is placed 20 minutes (hot air flow 1m in the throughcirculation dryer that uses hot blast
3/ sec), investigating the crystal formation of gained N-(3, the 3-dimethylbutyl)-APM with powder X-ray diffractometry, the result is as described in the following table 3.Just, under the condition of 35～60 ℃ of material temperature, absolute humidity 0.00417～0.08320kg/kg, diffraction angle (2 θ that obtain at least 6.0 °, 24.8 °, 8.2 ° and 16.5 °, CuK α line) crystal that shows the peculiar peak of diffraction X ray the time. therefore, identify that this crystal is the A N-type waferN.
Table 3
| The crystal jump condition | Absolute humidity (kg/kg) | Material temperature (℃) | Crystal formation |
| ????(3) ????(4) ????(5) ????(6) | ????0.00579 ????0.00417 ????0.02890 ????0.08320 | ????20 ????35 ????35 ????60 | ???B ???A ???A ???A |
Secondly, enumerate the embodiment that adopts the second crystal transfer method.Reference example 3
In Vacuumdrier, below 25 ℃, Type B crystal drying under reduced pressure to the amount of moisture that above-mentioned reference example 2 is obtained reaches 4.6wt%.The wet crystal that obtains uses CuK α line to measure the diffraction X ray with powder X-ray diffractometry, the result is at least at diffraction angle (2 θ of 5.4 °, 8.4 °, 18.8 ° and 17.6 °, CuK α line) show the distinctive peak of diffraction X ray the time, so this material is D N-type waferN (with reference to Fig. 3).
The D N-type waferN that reference example 3 obtains was placed 2 hours in the thermostatic bath shown in following table 4 respectively at control absolute humidity and material temperature, and the crystal formation with powder X-ray diffractometry investigation gained N-(3, the 3-dimethylbutyl)-APM the results are shown in the same table.Just, under the condition of 30～50 ℃ of absolute humidity 0.0133～0.0403kg/kg, material temperature, obtain at least when the diffraction angle (2 θ, CuK α line) of 6.0 °, 24.8 °, 8.2 ° and 16.5 °, showing the crystal at the peculiar peak of diffraction X ray.Therefore, identify that the material that obtains is the A N-type waferN.At this moment x-ray diffractogram of powder is shown in following table 4.
Table 4
| The crystal jump condition | Absolute humidity (kg/kg) | Material temperature (℃) | Crystal formation |
| ????(7) ????(8) ????(9) ????(10) | ???0.0043 ???0.0133 ???0.0220 ???0.0403 | ????20 ????30 ????40 ????50 | ???D ???A ???A ???A |
Industrial applicibility
Type B crystal by making N-(3,3-dimethylbutyl)-APM or D type crystal carry out crystal to be shifted, can be low-cost and prepare easily the A type crystal of the excellent in stability of high-intensity sweeteners N-(3,3-dimethylbutyl)-APM.
Claims (2)
1; at least with 6.0 °; 24.8 °; 8.2 ° and 16.5 ° peak be that (N-(3 for the N-of feature; the 3-dimethylbutyl)-L-α-aspartyl)-preparation method of the crystal (A N-type waferN) of the excellent in stability of L-phenyl methyl lactamine; it is characterized in that at absolute humidity being under the environment below the 0.203kg/kg its material temperature control to be maintained 25-80 ℃; make at least at 5.1 °; 21.1 °; 21.3 ° and 8.3 ° diffraction angle (2 θ; CuK α line) the wet crystal (Type B crystal) that shows N-(N-(3, the 3-dimethylbutyl)-L-α-aspartyl)-L-phenyl methyl lactamine at the peculiar peak of diffraction X ray the time carries out the crystal transfer.
2; at least with 6.0 °; 24.8 °; 8.2 ° and 16.5 ° peak be that (N-(3 for the N-of feature; the 3-dimethylbutyl)-L-α-aspartyl)-preparation method of the crystal (A N-type waferN) of the excellent in stability of L-phenyl methyl lactamine; it is characterized in that at absolute humidity being under the environment below the 0.0550kg/kg its material temperature control to be maintained 25-80 ℃; make at least at 5.4 °; 8.4 °; 18.8 ° and 17.6 ° diffraction angle (2 θ; CuK α line) crystal (D N-type waferN) that shows N-(N-(3, the 3-dimethylbutyl)-L-α-aspartyl)-L-phenyl methyl lactamine at the peculiar peak of diffraction X ray the time carries out the crystal transfer.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10310228A JP2000136198A (en) | 1998-10-30 | 1998-10-30 | Production of crystal of aspartame derivative excellent in stability |
| JP31022798 | 1998-10-30 | ||
| JP310228/1998 | 1998-10-30 | ||
| JP310227/1998 | 1998-10-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1315958A true CN1315958A (en) | 2001-10-03 |
Family
ID=26566235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99810417A Pending CN1315958A (en) | 1998-10-30 | 1999-11-01 | Method for preparing crystal of aspartame derivative excellent in stability |
Country Status (5)
| Country | Link |
|---|---|
| KR (1) | KR20010075420A (en) |
| CN (1) | CN1315958A (en) |
| BR (1) | BR9914838A (en) |
| CA (1) | CA2348162A1 (en) |
| WO (1) | WO2000026235A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0362706B1 (en) * | 1988-10-03 | 1996-01-17 | Ajinomoto Co., Inc. | Process for preparing dry IB type crystals of alpha-L-aspartyl-L-phenylalanine methyl ester having improved solubility |
| FR2719590B1 (en) * | 1994-05-09 | 1996-07-26 | Claude Nofre | Improved process for the preparation of a compound derived from aspartame useful as a sweetening agent. |
| FR2719591B1 (en) * | 1994-05-09 | 1996-07-26 | Claude Nofre | New compound useful as a sweetening agent, its preparation process. |
-
1999
- 1999-11-01 CN CN99810417A patent/CN1315958A/en active Pending
- 1999-11-01 WO PCT/JP1999/006083 patent/WO2000026235A1/en not_active Application Discontinuation
- 1999-11-01 KR KR1020017003946A patent/KR20010075420A/en not_active Application Discontinuation
- 1999-11-01 BR BR9914838-2A patent/BR9914838A/en not_active Application Discontinuation
- 1999-11-01 CA CA002348162A patent/CA2348162A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000026235A1 (en) | 2000-05-11 |
| KR20010075420A (en) | 2001-08-09 |
| CA2348162A1 (en) | 2000-05-11 |
| BR9914838A (en) | 2001-08-14 |
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