GB2133409A - Aspartame synthesis - Google Patents
Aspartame synthesis Download PDFInfo
- Publication number
- GB2133409A GB2133409A GB08400118A GB8400118A GB2133409A GB 2133409 A GB2133409 A GB 2133409A GB 08400118 A GB08400118 A GB 08400118A GB 8400118 A GB8400118 A GB 8400118A GB 2133409 A GB2133409 A GB 2133409A
- Authority
- GB
- United Kingdom
- Prior art keywords
- hydrogenation
- acid
- carried out
- aspartame
- organic solvent
- 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
Links
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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
A method for the preparation of alpha -L-aspartyl-L-phenylalanine methyl ester (aspartame) comprises condensing a fully protected L- aspartic acid derivative with L- phenylalanine methyl ester in the presence of a condensing agent obtained from the reaction between a nitrogen-containing heterocyclic compound and an organic and inorganic acid chloride and removing the protecting groups by hydrogenation with a hydrogen donor other than molecular hydrogen in the presence of an acid.
Description
SPECIFICATION
Aspartame synthesis
The invention relates to a synthesis of 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 is a dipeptide, and as such is formed with an amide bond between an E sated carboxy group of one amino acid and the amino group of another amino acid. Activation is necessary to increase the rate and the yield of the condensation. The desired pure peptide requires the protection of all other functional groups not involved in the peptide bond formation. Finally, the protecting groups are removed.
Aspartame can be prepared by reaction of N-protected-L-aspartic anhydride with L-phenylalanine methyl ester. This gives a mixture of aspartame and p-L-aspartyl-L-phenylalanine methyl ester. The p- isomer does not have sweetening properties, and its separaTion from aspartame leads to a reduction in yield and an increase in cost.
The terminal nitrogen atom of the L-aspartic anhydride may be protected by one of the Nprotecting groups commonly used in peptide chemistry such as benzyloxycarbonyl or t-butoxycarbonyl.
Alternatively, in order to avoid the final removal of an N-protecting group, the terminal nitrogen atom may be protected by simple protonation. Palladium-on-charcoal may be used as a catalyst for removing the protecting groups by catalytic hydrogenation, but carbon dioxide is formed in the reaction and must be removed to avoid stopping the reaction. This is usually done under a hydrogen flow, with a consequent loss of large and dangerous amounts of this explosive gas.
The invention provides a method for the preparation of aspartame, the method comprising condensing a fully protected L-aspartic acid derivative with L-phenylalanine methyl ester in the presence of a condensing agent obtained from the reaction between a nitrogen-containing heretocyclic compound and an organic or inorganic acid chloride, and removing the protecting groups by hydrogenation with a hydrogen donor other than molecular hydrogen in the presence of an acid.
The use of a full protected L-aspartic acid derivative avoids p-isomer formation. Condensing agents of the kind set out above are easily obtainable inexpensive, and effective under mild conditions.
The removal of the protecting groups with a hydrogen donor other than molecular hydrogen can be performed in simple apparatus without dangerous gaseous reagents. The presence of an acid in the last deprotection step avoids the formation of the undesirable by-product diketopiperazine.
The invention can be represented as proceeding according to the following scheme:
wherein:
X represents a terminal nitrogen atom protecting group of the aromatic urethane or aralkyl type;
Y represents a carboxy protecting group;
A represents the condensing agent; and
B represents a hydrogen donor other than molecular hydrogen.
Preferred terminal nitrogen protecting groups X include (of the aromatic urethane type) benzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 4nitrobenzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups; and (of the aralkyl type) benzyl, benzhydryl and trityl groups. Preferred carboxy protecting groups Y include benzyl, 4-methoxybenzyl and 4-nitrobenzyl groups.
Preferred condensing agents A have the general formula R-W-R wherein R represents an imidazolyl, 2-methyl-imidazolyl, benzimidazolyl, pyrazolyl, 3,5-dimethylpyrazolyl, triazolyl or benzotriazolyl group and W represents a group of the formula CO, CS, SO, SO2 or P--OR, wherein R, represents a phenyl, 4-chlorophenyl or benzyl group. The hydrogen donor B is preferably ammonium form ate, cyclohexane or cyclohexadiene.
The condensation of the L-aspartic acid derivative with the L-phenylalanine methyl ester hydrochloride may be effected using equimolecular amounts of reagents in the presence of an excess (up to 50%) of the condensing agent in a solvent, for example dichloromethane, chloroform, tetrahydrofyran, toluene, dimethylformamide, dimethylacetamide, dimethyisulphoxide or Nmethylpyrrolidone. Dichloromethane, chloroform or tetrahydrofuran is preferred. The reaction temperature may be from -300C to ambient temperature. The reaction time is generally less than five hours. The condensing agents may be prepared according to H. A. Staab (Angew. Chem., 1 962, 74, 407). The condensation is preferably carried out in the presence of N-methylmorpholine.
Recovery of the protected dipeptide can be effected by removal of the reaction solvent followed by dissolution of the residue in a solvent such as dimethylformaide, dimethylacetamide, dimethylsulphoxide or N-methylpyrrolidone, dilution with a lower alkanol (preferably methanol or ethanol), and precipitation by addition of water. Recrystallization may be from a mixture of dimethylformamide and a lower alkanol (preferably methanol or ethanol). The protecting groups are quantitatively removed from the protected dipeptide by catalytic transfer hydrogenation using a suitable amount of catalyst. The catalyst may be any of the noble metals known to be suitable (preferably, palladium or platinum), alone or in a complexed or supported form. Ammonium formate is the preferred hydrogen donor.The hydrogenation may be carried out in an organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide or N-methylpyrrolidone containing an organic acid (preferably formic or acetic) or an inorganic acid (preferably hydrochloric acid) and a lower alkanol (preferably methanol or ethanol). The reaction temperature may be from 0 C to 650C.
For the final recovery of the aspartame, any conventional method may be used.
The symbols and abbreviations used herein include:
AcOH=glacial acetic acid; Z=benzyloxycarbonyl; Bzl=benzyl; dec.=decomposition;
DMF=dimethylformamide; Me=methyl; m.p.=melting point; TLC=thin layer chromatography. The Rf values were determined on pre-coated plates of silica gel 60 F254 (Merck-Trade Mark), layer thickness 0.25 mm, length of the plate 20 cm, using the following development systems (all proportions being in parts by volume):
System A: benzene:benzine (60--80):ethyl acetate (25:5:70)
System B: benzene:ethyl acetate:acetic acid:water (10:10:2:1) (upper phase)
System C: n-butanol:acetic acid:water (4:1:1) System D: chloroform methanol :32% ammonium hydroxide (65:45:20).
The TLC analyses were not carried out under standard conditions, so the Rf values may change, particularly at different temperatures. The m.p. were determined in open capillaries and are uncorrected. High voltage paper electrophoresis is carried out with a Pherograph-Original Frankfurt
Type 64 apparatus on Schleicher and Schüll No. 2317 at pH 1.2 (formic acid:acetic acid:water 123:100:777 by volume) at 1600 V (40 V/cm). Electrophoretic mobility (E,2) is given relative to that of glutamic acid.
Example
Step 1. Preparation of Z-Asp (OBzl)-Phe-OMe by condensation
To a solution of 0.2 g of thionyldiimidazole in 300 ml of dichloromethane, 35.7 g of Z-Asp(OBzl) Or, 2'1.6 g of HCl.H-PheOMe and 11.2 ml of N-methylmorpholine were added in sequence at 00 C.
After stirring at this temperature for one hour, and 3 hours at room temperature, the solvent was removed by evaporation in vacuo. The residue was dissolved in 400 ml of dimethylformamide, concentrated to a small volume, and diluted with ethanol. The product was precipitated by dropwise addition of water, and the precipitate was filtered off. The crude compound was recrystallized from a mixture of dimethylformamide and ethanol, to yield 46.1 g of the title compound (89% yield).
m.p. 115--116"C; [a]022=-1 3.1 (C=1 , DMF); RfA 0.86, Rf5 0.89.
Step 2. Preparation of H-Asp-PheOMe by hydrogenation
41.5 g of Z-Asp(OBzl)-PheOMe were dissolved in 300 ml of dimethylformamide and diluted with 1 50 ml of acetic acid and 1 50 ml of methanol. 8 g of 10% by weight palladium-on-charcoal and 24 g of ammonium formate were added with stirring. When the reaction was completed, the catalyst was removed by filtration, and the solvent was evaporated off. The residue was taken up with water, the pH being maintained at 6 with an automatic titrator, and addition of triethylamine caused the precipitation of the product. The mixture was allowed to stand overnight in a refrigerator. After filtration, the product was suspended and stirred in ethanol for 3 hours at room temperature. 20 g of pure compound (II) was obtained in 85% yield.
m.p. 233-2350C (dec.); [c']D22=+33.2 (C=1 , AcOH); E12=0.85; Ref,=0.36; RfD=0.66.
Claims (14)
1. A method for the preparation of aspartame, the method comprising condensing a fully protected L-aspartic acid derivative with L-phenylalanine methyl ester in the presence of a condensing agent obtained from the reaction between a nitrogen-containing heterocyclic compound and an organic or inorganic acid chloride, and removing the protecting groups by hydrogenation with a hydrogen donor other than molecular hydrogen in the presence of an acid.
2. A method according to claim 1 in which the condensing agent has the general formula R
W-R wherein R represents an imidazolyl, 2-methylimidazolyl, benzimidazolyl, pyrazolyl, 3,5- dimethylpyrazolyl, triazolyl or benzotriazolyl group and W represents a group of the formula CO, CS,
SO, SO2 or P-OR1 wherein R1 represents a phenyl, 4-chlorophenyl or benzyl group.
3. A method according to claim 1 or claim 2 in which the L-aspartic acid derivative has the general formula
wherein X represents a terminal nitrogen protecting group selected from benzyloxycarbonyl, 2,4 dichlorobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, benzyl, benzhydryl and trityl groups and Y represents a carboxy protecting group selected from benzyl, 4-methoxybenzyl and 4-nitrobenzyl groups.
4. A method according to any preceding claim in which the condensation is carried out in an organic solvent at from -300C to ambient temperature for a period of up to 5 hours.
5. A mathod according to claim 4 in which the organic solvent is dichloromethane, chloroform, tetra hydrofuran, toluene, dimethylformamide, dimethylacetamide, dimethylsulphoxide or Nmethylpyrrolidone.
6. A method according to any preceding claim in which the condensation is carried out in the presence of N-methylmorpholine.
7. A method according to any preceding claim in which the hydrogen donor is ammonium formate, cyclohexene or cyclohexadiene.
8. A method according to any preceding claim in which the hydrogenation is carried out in the presence of a noble metal catalyst.
9. A method according to claim 8 in which the catalyst is platinum or palladium, alone or in a complexed or supported form.
10. A method according to any preceding claim in which the acid is formic acid, acetic acid or hydrochloric acid.
11. A method according to any preceding claim in which the hydrogenation is carried out in an organic solvent at from Oto 650C.
12. A method according to claim 11 in which the organic solvent for the hydrogenation is dimethylformamide, dimethylacetamide, dimethylsulphoxide or N-methylpyrrolidone.
13. A method according to claim 11 or claim 12 in which the hydrogenation is carried out in the presence of a lower alkanol.
14. A method according to claim 13 in which the lower alkanol is methanol or ethanol.
1 5. A method for the preparation of aspartame, the method being substantially as described herein with reference to the Example.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08400118A GB2133409B (en) | 1983-01-13 | 1984-01-04 | Aspartame synthesis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838300810A GB8300810D0 (en) | 1983-01-13 | 1983-01-13 | Aspartame synthesis |
| GB08400118A GB2133409B (en) | 1983-01-13 | 1984-01-04 | Aspartame synthesis |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8400118D0 GB8400118D0 (en) | 1984-02-08 |
| GB2133409A true GB2133409A (en) | 1984-07-25 |
| GB2133409B GB2133409B (en) | 1986-03-05 |
Family
ID=26284905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08400118A Expired GB2133409B (en) | 1983-01-13 | 1984-01-04 | Aspartame synthesis |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2133409B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4745210A (en) * | 1984-12-17 | 1988-05-17 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of N-formyl-α-aspartyl phenylalanine |
| US4778916A (en) * | 1985-03-26 | 1988-10-18 | Mitsui Toatsu Chemicals, Inc. | Preparation process of α-L-aspartyl-L-phenylalanine methyl ester or hydrochloride thereof |
| US4918216A (en) * | 1986-12-05 | 1990-04-17 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of α-l-aspartyl-l-phenyl-alanine methyl ester or hydrohalide thereof |
| US4962222A (en) * | 1986-12-19 | 1990-10-09 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of α-l-aspartyl-l-phenylalanine methyl ester having low hygroscopicity |
-
1984
- 1984-01-04 GB GB08400118A patent/GB2133409B/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4745210A (en) * | 1984-12-17 | 1988-05-17 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of N-formyl-α-aspartyl phenylalanine |
| US4778916A (en) * | 1985-03-26 | 1988-10-18 | Mitsui Toatsu Chemicals, Inc. | Preparation process of α-L-aspartyl-L-phenylalanine methyl ester or hydrochloride thereof |
| US4918216A (en) * | 1986-12-05 | 1990-04-17 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of α-l-aspartyl-l-phenyl-alanine methyl ester or hydrohalide thereof |
| US4962222A (en) * | 1986-12-19 | 1990-10-09 | Mitsui Toatsu Chemicals, Incorporated | Preparation process of α-l-aspartyl-l-phenylalanine methyl ester having low hygroscopicity |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8400118D0 (en) | 1984-02-08 |
| GB2133409B (en) | 1986-03-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4165311A (en) | Addition compound of dipeptide derivative and amino acid derivative | |
| SE447389B (en) | NEW TRIPEPTIDES AFFECTING THE CENTRAL NERVOUS SYSTEM | |
| US4623639A (en) | Peptide derivatives | |
| Miyoshi | Peptide Synthesis via N-Acylated Aziridinone. II. The Reaction of N-Acylated Aziridinone and Its Use in Peptide Synthesis | |
| CA1151154A (en) | Tripeptide amides and process for preparing same | |
| GB2133409A (en) | Aspartame synthesis | |
| Nichifor et al. | Synthesis of peptide derivatives of 5-fluorouracil | |
| JPS59130846A (en) | Synthesis of aspartame | |
| WO2000039075A1 (en) | N-3, 3-DIMETHYLBUTYL-L-ASPARTIC ACID AND ESTERS THEREOF, THE PROCESS OF PREPARING THE SAME, AND THE PROCESS FOR PREPARING N-[N-(3, 3-DIMENTHYLBUTYL)-L-α-ASPARTYL]-L-PHENYLALANINE 1-METHYL ESTER THEREFROM | |
| Kovacs et al. | Polypeptides with known repeating sequences of amino acids. Comparison of several methods used for the synthesis of poly‐γ‐D‐and L‐glutamylglycine and investigation of its serological reaction with antianthrax immune serum | |
| Kalčić et al. | Synthesis and reactions of some azolecarboxylic acid derivatives | |
| Pellegrini et al. | Pepsin‐catalyzed peptide synthesis | |
| EP0719789A1 (en) | Process of producing alpha-L-aspartyldipeptide amide derivatives | |
| US4257939A (en) | Peptide derivative | |
| US4897507A (en) | Method for producing α-L-aspartyl-L-phenylalanine derivatives | |
| US4730076A (en) | Process for producing α-aspartyl-phenylalanine ester | |
| CA1158237A (en) | Peptide amides and process for their manufacture | |
| US3247178A (en) | Synthesis of peptides containing alpha, omega-diamino acids protected by phthalyl and t-butyloxycarbonyl groups | |
| US3445447A (en) | Tert-amyloxycarbonyl derivatives of amino acids | |
| IL42973A (en) | Polypeptides with acth activity containing an alpha-aminooxy carboxylic acid group on the n-terminal moiety | |
| KAWASAKI et al. | Amino Acids and Peptides. XIII. Synthetic Studies on N-Terminal Tripeptide Amide Analogs of Fibrin α-Chain | |
| CA1326738C (en) | Method for producing .alpha.-l-aspartyl-l-phenylalanine derivatives | |
| Ariyoshi et al. | The reaction of aspartyl dipeptide esters with ketones | |
| US4033997A (en) | Preparation of dopamine derivatives | |
| KR20030033001A (en) | Process for the preparation of 5-phenylpentanoyl-ala-argl-ala-[2-(3-amino-2-oxopyrrolidin-1-yl)propionyl]-ala-arg-ala-4-aminophenylacetamide |
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: 19930104 |