GB2140805A - Isolation of aspartame - Google Patents
Isolation of aspartame Download PDFInfo
- Publication number
- GB2140805A GB2140805A GB08413386A GB8413386A GB2140805A GB 2140805 A GB2140805 A GB 2140805A GB 08413386 A GB08413386 A GB 08413386A GB 8413386 A GB8413386 A GB 8413386A GB 2140805 A GB2140805 A GB 2140805A
- Authority
- GB
- United Kingdom
- Prior art keywords
- process according
- methyl ester
- aspartyl
- aspartame
- phosphoric acid
- 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.)
- Granted
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
Abstract
Aspartame is isolated from a reaction mixture containing N-formyl- alpha , beta -L-aspartyl-L-phenylalanine methyl ester by adding phosphoric acid (preferably 50-99% in water) and an alkanol (preferably methanol) to the reaction mixture, collecting the alpha -L-aspartyl-L-phenylalanine methyl ester phosphate which precipitates and neutralizing it with a base, e.g. Na2CO3, NaOH or NH3.
Description
SPECIFICATION
Aspartame Synthesis
The invention relates to a new synthesis for aspartame, i.e. a-L-aspartyl-L-phenylalanine methyl ester. Aspartame has sweetening properties like cane and beet sugar, and is used as a sweetening agent for foods and beverages.
Aspartame can be prepared by reaction of
N-protected-L-aspartic anhydride with L-phenyl-alanine methyl ester. This gives a mixture of N-protected a-L-aspartyl-L-phenylalanine methyl ester and ss-L-aspartyl-L-phenyl-alanine methyl ester which requires N-deprotection followed by separation of the two isomers.
The N-protecting group used in this reaction may be any of the N-protecting gioups com, monly used in peptide chemistry, such as the benzyloxycarbonyl and formyl groups. It is well known that the removal of these Nprotecting groups is complicated by the need to avoid splitting of the peptide bond with resultant formation of undesired by-products such as diketopiperazine. Commonly used Ndeprotection reactions are performed in the presence of strong acid (United States Patent
Specification No. 4,071,511) or in the presence of hydroxylamine (United States Patent
Specification No. 4,021,418).Although these processes are considered to be suitable from an industrial point of view, they nevertheless have several disadvantages such as low yields, expensive reagents, esterification of the fi-carboxy group and hydrolysis of ester or peptide bonds. Furthermore, the product so obtained is not pure, being mixed with substantial amounts of by-products. It is necessary, therefore, subsequently to purify the praduct with a resulting increase in the manufacturing cost. Furthermore, it is necessary to separate the a- and isomers since the ss- isomer does not have sweetening properties.
This leads to a further increase in the manufacturing cost.
The invention provides a process for the isolation of aspartame from a reaction mixture containing N4ormyl-a, ss-L-aspartyl-L-phenyla- lanine methyl ester, the process comprising adding phosphoric acid and an alkanol having from 1 to 4 carbon atoms to the reaction mixture, collecting the a-L-aspartyl-L-phenylalanine methyl ester phosphate which precipitates, and neutralizing it with a base.
The phosphoric acid employed in the process of the invention is suitably an aqueous solution of from 50 to 99%, preferably 85%, by weight. It is desirably used in an amount of from 1.2 to 5 moles per mole of N-formylaspartame in the reaction mixture. The alkanol is preferably methanol.
The deformylation may be carried out at from room temperature to 60"C for from 4 to 1 2 hours. It may be carried out in a solvent such as ethyl acetate or a dichloroethane: acetic acid mixture. On cooling the reaction mixture, the aspartame phosphate precipitates out, whereas the L-ss-aspartyl-L-phenylalanine methyl ester phosphate remains in solution.
Collection of the aspartame phosphate may be by filtration. The base used to neutralize it, and yield free aspartame, may be an aqueous solution of sodium carbonate, sodium hydroxide or ammonia.
The process according to the invention offers several advantages over the conventional prior art processes. It is not necessary to isolate the N4ormyl-L-a, ssaspartyl-L-phenyla- lanine methyl ester from the reaction mixture in which it is prepared prior to deformylating it. The separation of the isomers is accomplished in the same step as the deformylation, by virtue of the precipitation of the aspartame phosphate alone and not the isomer. The mild acid hydrolysis conditions of the process of the invention avoid the risks of splitting the peptide bond, esterifying the fi-carbonyl group, removing the esterifying methyl group, or forming the undersired by-product diketopiperazine.Better isolation yields are achieved as compared to the conventional prior art processes, and the process is suitable for commercial application.
The invention is illustrated by the following
Examples.
Example 1
360 ml of methanol and 35.2 ml of 85% aqueous phosphoric acid were added at room temperature to a solution of 100 g of N formyl-a, fl-Laspartyl-Lphenylalanine methyl ester (a/ss - isomer ratio 8:2) in 1 60 ml of dichloroethane and 40 ml of acetic acid. The mixture was heated at 40"C for eight hours and then cooled. The a-L-aspartyl-L-phenylalanine methyl ester phosphate which crystallized out was collected by filtration and dried.
Yield, 85% (on the basis of the N-formylaspartame).
Example 2
51 g of a-L-aspartyl-L-phenylalanine methyl ester phosphate were dissolved in 300 ml of water. The resulting solution was adjusted to pH 5.2 with 20% aqueous sodium hydroxide, stirred for one hour at room temperature and cooled. The free aspartame precipitated and was collected by filtration. 27.9 g of pure compound were obtained in 73% yield, m.p.
233-235 C (with decomposition), [aB =
+ 33.2 (e = 1, acetic acid).
Example 3
400 ml of methanol and 70.4 ml of 85% aqueous phosphoric acid were added to solution of 100 g of N-formyl-a, ss-L-aspartyl-L- phenylalanine methyl ester (a/ss - isomer ratio 8:2) in 380 ml of ethyl acetate and 40 ml of acetic acid. Operating as in Example 1, the aspartame phosphate was obtained in 90% yield.
Example 4
Operating as in Example 1, but using 99% aqueous phosphoric acid instead of 85% aqueous phosphoric acid, the aspartame phosphate was obtained in 75% yield.
Example 5
Operating as in Example 1, but using 50% aqueous phosphoric acid instead of 85% aqueous phosphoric acid, the aspartame phosphate was obtained in 65% yield.
Claims (10)
1. A process for the isolation of aspartame from a reaction mixture containing N4ormyl-a, jB-L-aspartyl-L-phenylalanine methyl ester, the process comprising adding phosphoric acid and an alkanol having from 1 to 4 carbon atoms to the reaction mixture, collecting the a-L-aspartyl-L-phenylalanine methyl ester phosphate which precipitates and neutralizing it with a base.
2. A process according to claim 1 in which the phosphoric acid is an aqueous solution of from 50% to 99% by weight.
3. A process according to claim 1 or claim 2 in which the phosphoric acid is an 85% by weight aqueous solution.
4. A process according to any preceding claim in which the amount of phosphoric acid used is from 1.2 to 5 moles per mole of Nformyl-aspartame to be deformylated.
5. A process according to any preceding claim in which the alkanol is methanol.
6. A process according to any preceding claim in which the reaction is carried out at a temperature of from the ambient temperature to 60"C for a period of from 4 to 12 hours.
7. A process according to any preceding claim in which the reaction is carried out in ethyl acetate or in a dichloroethane: acetic acid mixture.
8. A process according to any preceding claim in which the a-L-aspartyl-L-phenylalanine methyl ester phosphate is collected by filtration.
9. A process according to any preceding claim in which the base is an aqueous solution of sodium carbonate, sodium hydroxide or ammonia.
10. A process for the isolation of aspartame from a reaction mixture containing Nformyl-a, ss-L-aspartyl-L-phenylalanine methyl ester, the process being substantially as described herein with reference to any of the
Examples.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08413386A GB2140805B (en) | 1983-05-31 | 1984-05-24 | Isolation of aspartame |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB838314907A GB8314907D0 (en) | 1983-05-31 | 1983-05-31 | Aspartame synthesis |
GB08413386A GB2140805B (en) | 1983-05-31 | 1984-05-24 | Isolation of aspartame |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8413386D0 GB8413386D0 (en) | 1984-06-27 |
GB2140805A true GB2140805A (en) | 1984-12-05 |
GB2140805B GB2140805B (en) | 1986-08-13 |
Family
ID=26286267
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08413386A Expired GB2140805B (en) | 1983-05-31 | 1984-05-24 | Isolation of aspartame |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2140805B (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4677220A (en) * | 1985-10-31 | 1987-06-30 | Monsanto Company | Process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester |
EP0264803A2 (en) * | 1986-10-20 | 1988-04-27 | Hoechst Aktiengesellschaft | Purification process of N-acyl aspartame |
EP0333036A2 (en) * | 1988-03-14 | 1989-09-20 | MITSUI TOATSU CHEMICALS, Inc. | Separation method of alpha-L-aspartyl-L-phenylalanine methyl ester |
EP0402926A2 (en) * | 1989-06-14 | 1990-12-19 | MITSUI TOATSU CHEMICALS, Inc. | Method for preparing alfa-L-aspartyl-L-phenylalanine methyl ester |
EP0526854A2 (en) * | 1991-08-05 | 1993-02-10 | Ajinomoto Co., Inc. | Method for recovery of alpha-L-aspartyl-L-phenylalanine methyl ester, L-phenylalanine and l-aspartic acid |
US5283357A (en) * | 1988-03-14 | 1994-02-01 | Mitsui Toatsu Chemicals, Incorporated | Separation method of α-l-aspartyl-l-phenylalanine methyl ester |
EP0582351A1 (en) * | 1992-08-05 | 1994-02-09 | Holland Sweetener Company V.O.F. | Process for the crystallisation of aspartame |
US5302743A (en) * | 1988-03-22 | 1994-04-12 | Mitsui Toatsu Chemicals, Inc. | Preparation of N-protected α-L-aspartyl-L-phenylalanine methyl ester |
US6245934B1 (en) | 1997-06-06 | 2001-06-12 | Dsm Nv | Method for preparing salts of aspartame from N-protected aspartame |
-
1984
- 1984-05-24 GB GB08413386A patent/GB2140805B/en not_active Expired
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4677220A (en) * | 1985-10-31 | 1987-06-30 | Monsanto Company | Process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester |
US4900863A (en) * | 1986-10-20 | 1990-02-13 | Hoechst Aktiengesellschaft | Process for the purification of N-acylaspartame |
EP0264803A2 (en) * | 1986-10-20 | 1988-04-27 | Hoechst Aktiengesellschaft | Purification process of N-acyl aspartame |
EP0264803A3 (en) * | 1986-10-20 | 1989-04-26 | Hoechst Aktiengesellschaft | Purification process of n-acyl aspartame |
EP0333036A3 (en) * | 1988-03-14 | 1991-05-08 | MITSUI TOATSU CHEMICALS, Inc. | Separation method of alpha-l-aspartyl-l-phenylalanine methyl ester |
EP0333036A2 (en) * | 1988-03-14 | 1989-09-20 | MITSUI TOATSU CHEMICALS, Inc. | Separation method of alpha-L-aspartyl-L-phenylalanine methyl ester |
US5283357A (en) * | 1988-03-14 | 1994-02-01 | Mitsui Toatsu Chemicals, Incorporated | Separation method of α-l-aspartyl-l-phenylalanine methyl ester |
US5302743A (en) * | 1988-03-22 | 1994-04-12 | Mitsui Toatsu Chemicals, Inc. | Preparation of N-protected α-L-aspartyl-L-phenylalanine methyl ester |
EP0402926A2 (en) * | 1989-06-14 | 1990-12-19 | MITSUI TOATSU CHEMICALS, Inc. | Method for preparing alfa-L-aspartyl-L-phenylalanine methyl ester |
EP0402926A3 (en) * | 1989-06-14 | 1991-10-30 | MITSUI TOATSU CHEMICALS, Inc. | Method for preparing alfa-l-aspartyl-l-phenylalanine methyl ester |
EP0526854A2 (en) * | 1991-08-05 | 1993-02-10 | Ajinomoto Co., Inc. | Method for recovery of alpha-L-aspartyl-L-phenylalanine methyl ester, L-phenylalanine and l-aspartic acid |
EP0526854A3 (en) * | 1991-08-05 | 1994-04-06 | Ajinomoto Kk | |
EP0582351A1 (en) * | 1992-08-05 | 1994-02-09 | Holland Sweetener Company V.O.F. | Process for the crystallisation of aspartame |
US6245934B1 (en) | 1997-06-06 | 2001-06-12 | Dsm Nv | Method for preparing salts of aspartame from N-protected aspartame |
Also Published As
Publication number | Publication date |
---|---|
GB8413386D0 (en) | 1984-06-27 |
GB2140805B (en) | 1986-08-13 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19970524 |