WO2001079264A1 - PROCESS FOR PRODUCING α-L-ASPARTYL-L-PHENYLALANINE METHYLESTER HYDROCHLORIDE - Google Patents
PROCESS FOR PRODUCING α-L-ASPARTYL-L-PHENYLALANINE METHYLESTER HYDROCHLORIDE Download PDFInfo
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- WO2001079264A1 WO2001079264A1 PCT/KR2001/000604 KR0100604W WO0179264A1 WO 2001079264 A1 WO2001079264 A1 WO 2001079264A1 KR 0100604 W KR0100604 W KR 0100604W WO 0179264 A1 WO0179264 A1 WO 0179264A1
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- toluene
- aspartyl
- acetic acid
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- phenylalanine methylester
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D3/00—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping
- B01D3/34—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping with one or more auxiliary substances
- B01D3/36—Azeotropic distillation
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/145—Extraction; Separation; Purification by extraction or solubilisation
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
- A23L27/31—Artificial sweetening agents containing amino acids, nucleotides, peptides or derivatives
- A23L27/32—Artificial sweetening agents containing amino acids, nucleotides, peptides or derivatives containing dipeptides or derivatives
Definitions
- the present invention relates to a process for producing ⁇ -L-aspartyl-L- phenylalanine methylester hydrochloride from N-protected ⁇ -L-aspartyl-L- phenylalanine methylester. It is used for food and beverages as an artificial sweetener, because ⁇ -L-aspartyl-L-phenylalanine methylester is sweeter than sugar by 200 times and has low calories, ⁇ -L-aspartyl-L-phenylalanine methylester is a dipeptide synthesized by coupling reaction of the activated carboxylic acid of an amino acid and amine of another amino acid.
- N-protected ⁇ -L-aspartyl-L-phenylalanine methylester is a intermediate for the synthesis of the ct -L-aspartyl-L-phenylalanine methylester hydrochloride.
- This compound can be synthesized by the coupling reaction of the N-protected L- aspartic anhydride and L-phenylalanine methylester, and is obtained as a mixture of ⁇ and ⁇ isomers of N-protected L-aspartyl-L-phenylalanine methylester.
- the mixture of ⁇ and ⁇ isomers can be separated after N-deprotecti ⁇ n.
- USP 5,292,923 discloses a method for obtaining ⁇ -L-aspartyl-L-phenylalanine methylester hydrochloride which comprises distilling the solvent under reduced pressure after a coupling reaction, extracting N-protected ⁇ -L-aspartyl-L-phenylalanine methylester with about 60 °C water from the reaction mixture by layer separation to remove organic layer, then proceeding to a deprotection reaction by treating the resulting syrup or oil state of N- protected ⁇ -L-aspartyl-L-phenylalanine methylester with methanol and aqueous hydrochloric acid.
- USP 5,292,923 suggests a method for removing acetic acid from the acetic acid and toluene medium used as a coupling reaction solvent, which comprises removing acetic acid by vacuum distillation while continuously adding toluene into the reaction system, then proceeding to layer separation by adding water.
- the inventors searched for a method of producing ⁇ -L-aspartyl-L- phenylalanine methylester hydrochloride with simple process and low cost on a industrial scale, then invented the present invention.
- the object of the present invention is to provide a method for producing -L- aspartyl-L-phenylalanine methylester hydrochloride from acetic acid/toluene reaction mixture containing N-protected ⁇ -L-aspartyl-L-phenylalanine methylester with simple process and low cost.
- the present invention provides a method for producing ⁇ -L-aspartyl-L-phenylalanine methylester hydrochloride comprising the steps of :
- Acetic acid/toluene reaction mixture containing N-protected ⁇ -L-aspartyl-L- phenylalanine methylester (“N-protected APM") used in the presen , invention is prepared by condensing N-protected L-aspartic anhydride and L-phenylalanine methylester ("PAM”) in the acetic acid/toluene solvent, which reaction is common in the art.
- BOC t-butoxycarbonyl
- CBZ(benzyloxycarbonyl) or formyl groups can be used as the amine protective group.
- the reaction proceeds by adding N-formyl L-aspartic anhydride to the acetic acid/toluene (about 1:1 — :1 v/v) mixture solvent, dropping PAM solved in the acetic acid/toluene (about 1:1 —2:1 v/v) t ⁇ the mixture, then stirring at 0 ⁇ 30 °C .
- N-protected ⁇ / ⁇ -APM can be synthesized by the above reaction, and with regard to the quality of the ⁇ -APM as the final product, the removing of the solvent used in the coupling reaction is essential.
- extraction and layer separation using about 60 ° C water is applied to remove the reaction solvent, but the present invention is characterized in that syrup or oil type N-protected APM is obtained by reduced-pressure distillation Using toluene/water, without layer separation, and then high purity ⁇ -APM hydrochloride is obtained by directly adding hydrochloric acid and methanol to above obtained syrup or oil type
- distilling step can be practiced any one of the following: i) after repeatedly distilling the reaction mixture with adding toluene/water mixture then finally distilling with adding water, ii) repeatedly distilling with adding only water, or iii) repeatedly using toluene/water mixture.
- This distilling step can be practiced by reduced-pressure distillation after adding above said solvent while stirring. Because toluene/water mixture or water is added in the continuous stirring state, layer separation does not occur but forms three phase azeotropic point. Syrup or oil type N-protected ⁇ / ⁇ -APM is obtained after removing remaining acetic acid and toluene by distilling the azeotropic mixture under the reduced pressure.
- the ratio of toluene/water is about 1 —5:1, preferably about 1.5 — 3:1, or more preferably about 2:1.
- the method of the present invention is able to produce ⁇ -APM hydrochloride directly without layer separation, the present invention leads to a simple process and low cost on the industrial scale.
- Acetic acid/toluene mixture containing N-protected APM used as the starting material in the present invention was prepared by adding N-formyl L-aspartic anhydride (22.7g, 158.7mmol) to 141ml of acetic acid/toluene (1:1) solvent, and dropping phenylalanine methylester (27.3g, 152.3mmol) dissolved in the 283ml of acetic acid/toluene (1:1) to the mixture over 1.5 hour at 10 — 15 °C, then stirring 1.5 hour.
- N-formyl L-aspartic anhydride 22.7g, 158.7mmol
- phenylalanine methylester 27.3g, 152.3mmol
- Reference Example 1 was distilled under reduced pressure (680mmHg), toluene/water (2:1) (120mlx 5) and water (33mlx 1) were added thereto stirring not to cause layer separation, and the remaining acetic acid and toluene were removed by the reduced pressure (680mmHg, 62 - 65 °C) distillation, then 47.6g (53 - 62% in water) of the resulting syrup or oil type N-formyl APM was prepared. Then, concentrated hydrochloric acid (34ml, 2.6eq), 20% hydrochloric acid (61.8ml,
- Acetic acid/toluene reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under reduced pressure (680mmHg), toluene/water (2:1) (120mlx 5) and water (33mlx 1) were added thereto stirring not to cause layer separation, and the remaining acetic acid and toluene were removed by the reduced pressure (680mmHg, 62 — 65 °C) distillation, then 47.6g (53 —62% in water) of the resulting syrup or oil type N-formyl APM was prepared.
- Example 3 Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under the reduced pressure (680mmHg), distilled again under the reduced pressure (680mmHg, 62 — 65 ° C) with adding toluene/water (1:1) (120mlx 5; no layer separation, added while stirring) and water (33 mix 1) to remove remaining acetic acid and toluene, then 47.6g (53 —62% in water) of resulting syrup or oil type N-formyl APM was prepared.
- Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under reduced pressure (680mmHg), distilled again under reduced pressure (680mmHg, 62 — 65 °C) with adding water (33mlx 4; no layer separation, added while stirring) and water (33mlx 1) to remove remaining acetic acid and toluene, then 47.6g (53 —62% in water) of the resulting syrup or oil type N-formyl APM was prepared. Then, concentrated hydrochloric acid (11.6ml, 1.5eq), filtrate (36.4ml, 1.5eq) of APM hydrochloride obtained in Example
- Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under the reduced pressure (680mmHg), distilled again under the reduced pressure (680mmHg, 62 — 65 ° C) with adding toluene/water (2:1) (120mlx 5; no layer separation, added while stirring) and water
- Example 6 Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under the reduced pressure (680mmHg), distilled again under the reduced pressure (680mmHg, 62 — 65 °C) with adding toluene/ water (2:1) (120mlx 5; no layer separation, added while stirring) and water (33 mix 1) to remove the remaining acetic acid and toluene, then 47.6g (53 —62% in water) of the resulting syrup or oil type N-formyl APM was prepared.
- APM hydrochloride was obtained by filtering the above obtained mixture under the reduced pressure (680mmHg). Yield : 73.5%
- ⁇ -L-aspartyl-L-phenylalanine methylester hydrochloride can be produced more simply and with lower cost on an industrial scale.
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Abstract
The present invention relates to a process for producing α - L-aspartyl-L-phenylalanine methylester hydrochloride from N-protected α -L-aspartyl-L-phenylalanine methylester, and the process comprises the steps of; adding toluene, water or toluene/water to the N-protected α -L-aspartyl-L-phenylalanine methylester reaction mixture containing acetic acid/toluene, while controlling not to cause layer separation; removing acetic acid and toluene in the reaction mixture by reduced-pressure distillation; then producing α -L-aspartyl-L-phenylalanine methylester hydrochloride by adding aqueous hydrochloride and methanol to above obtained syrup or oil state of N-protected α -L-aspartyl-L-phenylalanine methylester.
Description
PROCESS FOR PRODUCING α -L-ASPARTYL-L-PHENY ALAJNINE
METHYLESTER HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to a process for producing α -L-aspartyl-L- phenylalanine methylester hydrochloride from N-protected α -L-aspartyl-L- phenylalanine methylester. It is used for food and beverages as an artificial sweetener, because α -L-aspartyl-L-phenylalanine methylester is sweeter than sugar by 200 times and has low calories, α -L-aspartyl-L-phenylalanine methylester is a dipeptide synthesized by coupling reaction of the activated carboxylic acid of an amino acid and amine of another amino acid.
BACKGROUND OF THE INVENTION
N-protected α -L-aspartyl-L-phenylalanine methylester is a intermediate for the synthesis of the ct -L-aspartyl-L-phenylalanine methylester hydrochloride. This compound can be synthesized by the coupling reaction of the N-protected L- aspartic anhydride and L-phenylalanine methylester, and is obtained as a mixture of α and β isomers of N-protected L-aspartyl-L-phenylalanine methylester. The mixture of α and β isomers can be separated after N-deprotectiόn. There have been many attempts to increase the ratio of the α compound by controlling reaction temperature and adapting appropriate solvents, because the ratio of the α compound in the coupling reaction greatly affects the final yield. For example, the ratio of the α compound is increased by controlling the ratio of toluene/acetic acid used as solvent. On the other hand, it is essential and important to remove the solvent after coupling reaction, because solvent remaining after coupling reaction negatively affects the quality of the products. USP 5,292,923 discloses a method for obtaining α -L-aspartyl-L-phenylalanine methylester hydrochloride which comprises distilling the solvent under reduced pressure after a coupling reaction, extracting N-protected α -L-aspartyl-L-phenylalanine methylester with about 60 °C water from the reaction mixture by layer separation to remove organic layer, then
proceeding to a deprotection reaction by treating the resulting syrup or oil state of N- protected α -L-aspartyl-L-phenylalanine methylester with methanol and aqueous hydrochloric acid. In addition, USP 5,292,923 suggests a method for removing acetic acid from the acetic acid and toluene medium used as a coupling reaction solvent, which comprises removing acetic acid by vacuum distillation while continuously adding toluene into the reaction system, then proceeding to layer separation by adding water.
SUMMARY OF THE INVENTION
The inventors searched for a method of producing α -L-aspartyl-L- phenylalanine methylester hydrochloride with simple process and low cost on a industrial scale, then invented the present invention.
The object of the present invention is to provide a method for producing -L- aspartyl-L-phenylalanine methylester hydrochloride from acetic acid/toluene reaction mixture containing N-protected α -L-aspartyl-L-phenylalanine methylester with simple process and low cost.
The object described above and other objects would be well described to one skilled in the art by a detailed description.
DETAILED DESCRIPTION OF THE INVENTION
To accomplish above said objects, the present invention provides a method for producing α -L-aspartyl-L-phenylalanine methylester hydrochloride comprising the steps of :
(1) removing acetic acid from the acetic acid/toluene reaction mixture containing N-protected α -L-aspartyl-L-phenylalanine methylester by distilling the reaction mixture under reduced pressure ;
(2) removing remaining acetic acid and toluene by distilling the mixture under the reduced-pressure, after adding toluene/water mixture or water repeatedly, otherwise them(toluene/water mixture and water) alternately to the reaction mixture prepared from the step (1), while stirring,
(3) preparing α -L-aspartyl-L-phenylalanine methylester hydrochloride by adding hydrochloric acid and methanol to above obtained syrup or oil type N- protected α -L-aspartyl-L-phenylalanine methylester.
Above said object, other objects and advantages would be well described to one skilled in the art by the detailed description below.
The constitution and the effects of the present invention will be described in detail in the following pages.
Acetic acid/toluene reaction mixture containing N-protected α -L-aspartyl-L- phenylalanine methylester ("N-protected APM") used in the presen , invention is prepared by condensing N-protected L-aspartic anhydride and L-phenylalanine methylester ("PAM") in the acetic acid/toluene solvent, which reaction is common in the art. BOC (t-butoxycarbonyl), CBZ(benzyloxycarbonyl) or formyl groups can be used as the amine protective group. Therefore, for example, the reaction proceeds by adding N-formyl L-aspartic anhydride to the acetic acid/toluene (about 1:1 — :1 v/v) mixture solvent, dropping PAM solved in the acetic acid/toluene (about 1:1 —2:1 v/v) tυ the mixture, then stirring at 0 ~ 30 °C .
N-protected α /β -APM can be synthesized by the above reaction, and with regard to the quality of the α -APM as the final product, the removing of the solvent used in the coupling reaction is essential. In the conventional method, extraction and layer separation using about 60 °C water is applied to remove the reaction solvent, but the present invention is characterized in that syrup or oil type N-protected APM is obtained by reduced-pressure distillation Using toluene/water, without layer separation, and then high purity α -APM hydrochloride is obtained by directly adding hydrochloric acid and methanol to above obtained syrup or oil type
N-protected APM.
Specifically, acetic acid/toluene reaction mixture containing N-protected α /β -APM is distilled under the reduced pressure to remove acetic acid. Considerable amount of acetic acid is removed in this distillation process, but a little acetic acid remains in the reaction mixture. To remove remaining acetic acid and toluene, one of toluene/water mixture or water is repeatedly used, otherwise both of them are alternately used in the reaction mixture. In other words, distilling step can
be practiced any one of the following: i) after repeatedly distilling the reaction mixture with adding toluene/water mixture then finally distilling with adding water, ii) repeatedly distilling with adding only water, or iii) repeatedly using toluene/water mixture. This distilling step can be practiced by reduced-pressure distillation after adding above said solvent while stirring. Because toluene/water mixture or water is added in the continuous stirring state, layer separation does not occur but forms three phase azeotropic point. Syrup or oil type N-protected α /β -APM is obtained after removing remaining acetic acid and toluene by distilling the azeotropic mixture under the reduced pressure. The ratio of toluene/water is about 1 —5:1, preferably about 1.5 — 3:1, or more preferably about 2:1.
Then to practice deprotection reaction, if hydrochloric acid and methanol is added to above syrup or oil phase at room temperature and stirred, solid state of α - APM hydrochloride is obtained with good yield. In this case, a mixture of concentrated hydrochloric acid and dilute hydrochloric acid is used as hydrochloric acid, and each of the total amount of hydrochloric acid and methanol added is about 3 — 8 equivalent and about 1 or more equivalent respectively, preferably about 4 — 6 equivalent and about 1.3 equivalent respectively, α -APM hydrochloride thus obtained is white solid state, and the filtrate after separating α -APM hydrochloride by filtering can be recycled.
Because the method of the present invention is able to produce α -APM hydrochloride directly without layer separation, the present invention leads to a simple process and low cost on the industrial scale.
The present invention is described with reference to preferred examples below, but the present invention is not restricted to those embodiments.
EXAMPLE
Reference Example 1 Acetic acid/toluene mixture containing N-protected APM used as the starting material in the present invention was prepared by adding N-formyl L-aspartic anhydride (22.7g, 158.7mmol) to 141ml of acetic acid/toluene (1:1) solvent, and
dropping phenylalanine methylester (27.3g, 152.3mmol) dissolved in the 283ml of acetic acid/toluene (1:1) to the mixture over 1.5 hour at 10 — 15 °C, then stirring 1.5 hour.
Example 1
Acetic acid/toluene reaction mixture containing N-formyl APM obtained in the
Reference Example 1 was distilled under reduced pressure (680mmHg), toluene/water (2:1) (120mlx 5) and water (33mlx 1) were added thereto stirring not to cause layer separation, and the remaining acetic acid and toluene were removed by the reduced pressure (680mmHg, 62 - 65 °C) distillation, then 47.6g (53 - 62% in water) of the resulting syrup or oil type N-formyl APM was prepared. Then, concentrated hydrochloric acid (34ml, 2.6eq), 20% hydrochloric acid (61.8ml,
2.6eq) and methanol (9.1ml, 1.5eq) were added at room temperature. When white solid was formed after stirring 5 — 11 days, the resulting product was filtered under reduced pressure (680mmHg), to obtain α -APM hydrochloride as white solid
Yield : 73.5%
Example 2
Acetic acid/toluene reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under reduced pressure (680mmHg), toluene/water (2:1) (120mlx 5) and water (33mlx 1) were added thereto stirring not to cause layer separation, and the remaining acetic acid and toluene were removed by the reduced pressure (680mmHg, 62 — 65 °C) distillation, then 47.6g (53 —62% in water) of the resulting syrup or oil type N-formyl APM was prepared. Then, concentrated hydrochloric acid (34ml, 2.6eq), filtrate (61.8ml, 2.6eq) of APM hydrochloride obtained in Example 1 and methanol (9.1ml, 1.5eq) were added at room temperature. When white solid was formed after stirring 5 — 11 days, the resulting product was filtered under the reduced pressure (680mmHg) to obtain α - APM hydrochloride as white solid. Yield : 75.5%
Example 3
Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under the reduced pressure (680mmHg), distilled again under the reduced pressure (680mmHg, 62 — 65 °C) with adding toluene/water (1:1) (120mlx 5; no layer separation, added while stirring) and water (33 mix 1) to remove remaining acetic acid and toluene, then 47.6g (53 —62% in water) of resulting syrup or oil type N-formyl APM was prepared. Then, concentrated hydrochloric acid (11.6ml, 1.5eq), 20% hydrochloric acid (36.4ml, 1.5eq) and methanol (9.1ml, 1.5eq) were added at room temperature. When white solid was formed after stirring 5 — 11 days, the resulting product was filtered under the reduced pressure (680mmHg) to obtain α -APM hydrochloride as white solid.
Yield : 80.5%
Example 4
Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under reduced pressure (680mmHg), distilled again under reduced pressure (680mmHg, 62 — 65 °C) with adding water (33mlx 4; no layer separation, added while stirring) and water (33mlx 1) to remove remaining acetic acid and toluene, then 47.6g (53 —62% in water) of the resulting syrup or oil type N-formyl APM was prepared. Then, concentrated hydrochloric acid (11.6ml, 1.5eq), filtrate (36.4ml, 1.5eq) of APM hydrochloride obtained in Example
3 and methanol (9.1ml, 1.5eq) were added at room temperature. When white solid was formed after stirring 5 — 11 days, the resulting product was filtered under the reduced pressure (680mmHg) to obtain α -APM hydrochloride as white solid. Yield : 82.5%
Example 5
Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under the reduced pressure (680mmHg), distilled again under the reduced pressure (680mmHg, 62 — 65 °C) with adding toluene/water (2:1) (120mlx 5; no layer separation, added while stirring) and water
(33 mix 1) to remove the remaining acetic acid and toluene, then 47.6g (53 —62% in water) of the resulting syrup or oil type N-formyl APM was prepared. Then,
methanol (9.1ml, 1.5eq) and 35% hydrochloric acid (7ml, 0.5eq) were added, and the mixture was heated for 15 minutes at 60 °C then cooled rapidly to 20 °C . 20% hydrochloric acid (61.8ml, 1.5eq) and 35% hydrochloric acid (27ml, 2.1eq) were dropped to the mixture at room temperature, and after stirring 5 — 11 days, white solid was obtained. White solid type of α -APM hydrochloride was obtained by filtering the above obtained mixture under the reduced pressure (680mmHg). Yield : 72.6%
Example 6 Acetic acid/toluene (1:1) reaction mixture containing N-formyl APM obtained in the Reference Example 1 was distilled under the reduced pressure (680mmHg), distilled again under the reduced pressure (680mmHg, 62 — 65 °C) with adding toluene/ water (2:1) (120mlx 5; no layer separation, added while stirring) and water (33 mix 1) to remove the remaining acetic acid and toluene, then 47.6g (53 —62% in water) of the resulting syrup or oil type N-formyl APM was prepared. Then, methanol (9.1ml, 1.5eq) and 35% hydrochloric acid (7ml, 0.5eq) were added, and the mixture was heated for 15 minutes at 60 °C then cooled rapidly to 20 °C. The filtrate (61.8ml, 1.5eq) of APM hydrochloride obtained in Example 5 and 35% hydrochloric acid (27ml, 2.1eq) were dropped to the mixture at room temperature, and after stirring 5 — 11 days, white solid was obtained. White solid type of α -
APM hydrochloride was obtained by filtering the above obtained mixture under the reduced pressure (680mmHg). Yield : 73.5%
As seen above, because the present invention does not comprise the layer separation step, α -L-aspartyl-L-phenylalanine methylester hydrochloride can be produced more simply and with lower cost on an industrial scale.
Claims
1. A process for producing α -L-aspartyl-L-phenylalanine methylester hydrochloride from N-protected α -L-aspartyl-L-phenylalanine methylester comprising the steps of
(1) removing acetic acid from the acetic acid/toluene reaction mixture containing N-protected α -L-aspartyl-L-phenylalanine methylester by distillation under reduced pressure ;
(2) removing remaining acetic acid and toluene by distilling the mixture under the reduced-pressure with adding toluene/water mixture or water repeatedly otherwise them (toluene/water mixture and water) alternately to the reaction mixture prepared from the step (1), while stirring not to cause layer separation;
(3) preparing α -L-aspartyl-L-phenylalanine methylester hydrochloride by adding hydrochloric acid and methanol to the syrup or oil type N-protected α -L- aspartyl-L-phenylalanine methylester obtained from the step (2).
2. A process according to Claim 1, the volume ratio of acetic acid/toluene in the step 1 is about 1:1 —2:1.
3. A process according to Claim 1, the volume ratio of toluene/water mixture in the step 2 is about 1:1 — 5:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU50650/01A AU5065001A (en) | 2000-04-19 | 2001-04-12 | Process for producing alpha-l-aspartyl-l-phenylalanine methylester hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR2000-0020639 | 2000-04-19 | ||
| KR1020000020639A KR20010096940A (en) | 2000-04-19 | 2000-04-19 | A process for producing alpha-L-aspartyl-L-phenylalanine methylester hydrochloride |
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|---|---|
| WO2001079264A1 true WO2001079264A1 (en) | 2001-10-25 |
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| PCT/KR2001/000604 Ceased WO2001079264A1 (en) | 2000-04-19 | 2001-04-12 | PROCESS FOR PRODUCING α-L-ASPARTYL-L-PHENYLALANINE METHYLESTER HYDROCHLORIDE |
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| KR (1) | KR20010096940A (en) |
| AU (1) | AU5065001A (en) |
| WO (1) | WO2001079264A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110638027A (en) * | 2019-10-10 | 2020-01-03 | 南京益唯森生物科技有限公司 | Method for extracting plant salt from nitraria tangutorum leaves |
| CN110638026A (en) * | 2019-10-10 | 2020-01-03 | 南京益唯森生物科技有限公司 | Method for extracting plant salt from fresh nitraria tangutorum leaves |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4680403A (en) * | 1985-01-17 | 1987-07-14 | Ajinomoto Co., Inc. | Process for producing N-protected-α-L-aspartyl-L-phenylalanine methyl ester |
| US5053532A (en) * | 1988-02-12 | 1991-10-01 | The Nutra Sweet Company | One-pot process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester hydrochloride |
| EP0582303A1 (en) * | 1992-08-05 | 1994-02-09 | Ajinomoto Co., Inc. | Method for the production of alpha-L-aspartyl-L-phenylalanine methyl ester hydrochloride |
| EP0600521A1 (en) * | 1992-12-07 | 1994-06-08 | Ajinomoto Co., Inc. | Method for preparing alpha-L-aspartyl-L-phenylalanine |
| US5334746A (en) * | 1992-08-27 | 1994-08-02 | Miwon Co., Ltd. | Process for producing α-L-aspartyl-L-phenylalanine methyl ester |
| EP0673921A1 (en) * | 1994-03-24 | 1995-09-27 | Ajinomoto Co., Inc. | Process for recovering L-phenylalanine |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4618695A (en) * | 1983-06-02 | 1986-10-21 | Ajinomoto Co., Inc. | Method of preparing methyl ester and its hydrochloride |
| JP2880744B2 (en) * | 1990-03-01 | 1999-04-12 | 三井化学株式会社 | Method for producing α-L-aspartyl-L-phenylalanine ester |
| JP3239431B2 (en) * | 1991-05-31 | 2001-12-17 | 味の素株式会社 | Method for producing α-L-aspartyl-L-phenylalanine methyl ester or hydrochloride thereof |
| JP2970109B2 (en) * | 1991-06-06 | 1999-11-02 | 味の素株式会社 | Concentration method of α-L-aspartyl-L-phenylalanine methyl ester solution |
| JP3144430B2 (en) * | 1991-08-27 | 2001-03-12 | 味の素株式会社 | Organic solvent separation method |
| KR101997043B1 (en) * | 2017-12-26 | 2019-07-08 | 린나이코리아 주식회사 | Apparatus and method for heating temperature control of each control system using boiler return temperature |
-
2000
- 2000-04-19 KR KR1020000020639A patent/KR20010096940A/en not_active Ceased
-
2001
- 2001-04-12 WO PCT/KR2001/000604 patent/WO2001079264A1/en not_active Ceased
- 2001-04-12 AU AU50650/01A patent/AU5065001A/en not_active Abandoned
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4680403A (en) * | 1985-01-17 | 1987-07-14 | Ajinomoto Co., Inc. | Process for producing N-protected-α-L-aspartyl-L-phenylalanine methyl ester |
| US5053532A (en) * | 1988-02-12 | 1991-10-01 | The Nutra Sweet Company | One-pot process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester hydrochloride |
| EP0582303A1 (en) * | 1992-08-05 | 1994-02-09 | Ajinomoto Co., Inc. | Method for the production of alpha-L-aspartyl-L-phenylalanine methyl ester hydrochloride |
| US5334746A (en) * | 1992-08-27 | 1994-08-02 | Miwon Co., Ltd. | Process for producing α-L-aspartyl-L-phenylalanine methyl ester |
| EP0600521A1 (en) * | 1992-12-07 | 1994-06-08 | Ajinomoto Co., Inc. | Method for preparing alpha-L-aspartyl-L-phenylalanine |
| EP0673921A1 (en) * | 1994-03-24 | 1995-09-27 | Ajinomoto Co., Inc. | Process for recovering L-phenylalanine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110638027A (en) * | 2019-10-10 | 2020-01-03 | 南京益唯森生物科技有限公司 | Method for extracting plant salt from nitraria tangutorum leaves |
| CN110638026A (en) * | 2019-10-10 | 2020-01-03 | 南京益唯森生物科技有限公司 | Method for extracting plant salt from fresh nitraria tangutorum leaves |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010096940A (en) | 2001-11-08 |
| AU5065001A (en) | 2001-10-30 |
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