Claims
- 1. A process for producing an aspartyl dipeptide ester derivative represented by formula (2): wherein said compound is in any form of the free form and the salt form, said process comprising: reductively alkylating aspartame with an aldehyde represented by formula (1), and hydrogen in the presence of a catalyst and a base: wherein said base is at least one member selected from the group consisting of metal hydrides, metal alkoxides, metal hydrozides, diethylamine, triethylamine, sodium carbonate, sodium hydrogen carbonate, and mixtures thereof, and wherein R1, R2, R3, R4, and R5 satisfy one of the following definitions (a), (b), (c), or (d): (a) in said formulae (1) and (2), R1 is a hydrogen atom, a methyl group or a methoxy group, R2 is a hydrogen atom, a methyl group or a methoxy group, R3 is a hydroxyl group, and R4 and R5 are a hydrogen atom; (b) in said formulae (1) and (2), R1, R4 and R5 are a hydrogen atom, R2 is a hydroxyl group, and R3 is a methoxy group; (c) in said formula (2), R1 is a hydrogen atom, a methyl group or a methoxy group, R2 is a hydrogen atom, a methyl group or a methoxy group, R3 is a hydroxyl group, and R4 and R5 are a hydrogen atom, and in said formula (1), R1 is a hydrogen atom, a methyl group or a methoxy group, R2 is a hydrogen atom, a methyl group or a methoxy group, R3 is a benzyloxy group, and R4 and R5 are a hydrogen atom; or (d) in said formula (2), R1, R4 and R5 are a hydrogen atom, R2 is a hydroxyl group, and R3 is a methoxy group, and in said formula (1), R1, R4 and R5 are a hydrogen atom, R2 is a benzyloxy group, and R3 is a methoxy group.
- 2. The process of claim 1, wherein in formulae (1) and (2), R1 is a hydrogen atom, a methyl group or a methoxy group, R2 is a hydrogen atom, a methyl group or a methoxy group, R3 is a hydroxyl group, and R4 and R5 are a hydrogen atom.
- 3. The process of claim 1, wherein in said formulae (1) and (2), R1, R4 and R5 are a hydrogen atom, R2 is a hydroxyl group, and R3 is a methoxy group.
- 4. The process of claim 1, wherein said aspartyl dipeptide ester compound is in the free form, and which comprises a process for converting said compound from the salt form into the free form.
- 5. The process of claim 1, wherein said aldehyde has a hydroxyl group, and wherein at least a portion of hydrogen atoms in said hydroxyl groups of the aldehyde molecules is replaced by a metal atom, and at least a portion of said aldehyde molecules in which the hydroxyl group has been converted into metal alkoxide, is present as said base.
- 6. The process of claim 1, wherein the base is sodium hydroxide or potassium hydroxide.
- 7. The process of claim 1, which further comprises mixing said base with said aldehyde prior to addition of said aspartame.
- 8. The process of claim 1, which further comprises a process for converting said aldehyde into a compound represented by the following general formula (3) or (4); wherein in the above formulae (3) and (4), X denotes any one of lithium atom, sodium atom, and potassium atom.
- 9. The process of claim 1, wherein said base is selected from the group consisting of lithium compounds, sodium compounds, and potassium compounds, and wherein said aldehyde is an aldehyde represented by the formula (3′) or (4′), and which further comprises a process for mixing said aldehyde with said base prior to addition of said aspartame to form a salt represented by the following general formula (3) or (4); wherein in formulae (3′), (4′), (3) and (4), Me denotes a methyl group, and in the above formulae (3) and (4), X denotes any one of lithium atom, sodium atom, and potassium atom.
- 10. The process of claim 1, which further comprises a process for converting said compound of formula (1) from a salt form obtained in said reductive alkylation reaction, into the free form through neutralization with an acid.
- 11. The process of claim 10, wherein said acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, and mixtures thereof.
- 12. The process of claim 10, wherein in said reductive alkylation reaction, said neutralization with an acid is conducted during said hydrogenation reaction.
- 13. The process of claim 1, wherein said reductive alkylation reaction is conducted at a temperature in a range of 0 to 60° C.
- 14. The process of claim 1, which further comprises forming a reaction mixture comprising said aspartame, said aldehyde, and said base, and holding said reaction mixture while stirring for at least 10 minutes at a temperature of 40° C. or lower before hydrogenation.
- 15. The process of claim 1, wherein said catalyst is at least one selected from the group consisting of palladium on carbon, palladium black, Raney Nickel, platinum on carbon, and mixtures thereof.
- 16. The process of claim 1, wherein said reductive alkylation reaction is conducted in a solvent, and said solvent is methanol.
- 17. The process of claim 1, wherein said reductively alkylating comprises a hydrogenation reaction with a hydrogen pressure of 0.1 to 10 MPa.
- 18. The process of claim 1, wherein said compound of formula (2) is in the free form, and which further comprises a process for crystallization of said free form with a mixed solvent of water-alcohol.
- 19. The process of claim 18, wherein said alcohol is methanol.
- 20. The process of claim 1, wherein in said formula (2), R1 is a hydrogen atom, a methyl group or a methoxy group, R2 is a hydrogen atom, a methyl group or a methoxy group, R3 is a hydroxyl group, and R4 and R5 are a hydrogen atom, and in formula (1), R1 is a hydrogen atom, a methyl group or a methoxy group, R2 is a hydrogen atom, a methyl group or a methoxy group, R3 is a benzyloxy group, and R4 and R5 are a hydrogen atom.
- 21. The process of claim 1, wherein in said formula (2), R1, R4 and R5 are a hydrogen atom, R2 is a hydroxyl group, and R3 is a methoxy group, and in formula (1), R1, R4 and R5 are a hydrogen atom, R2 is a benzyloxy group, and R3 is a methoxy group.
- 22. The process of claim 1, wherein said base is selected from the group consisting of LiH, NaH, KH, LiOMe, NaOMe, KOMe, LiOH, NaOH, KOH, Mg(OH)2, sodium carbonate, sodium hydrogen carbonate, triethyl amine, diethyl amine, and mixtures thereof.
- 23. The process of claim 2, wherein said base is at least one member selected from the group consisting of LiH, NaH, KH, LiOMe, NaOMe, KOMe, LiOH, NaOH, KOH, Mg(OH)2, sodium carbonate, sodium hydrogen carbonate, triethyl amine, diethyl amine, and mixtures thereof.
- 24. The process of claim 3, wherein said base is at least one member selected from the group consisting of LiH, NaH, KH, LiOMe, NaOMe, KOMe, LiOH, NaOH, KOH, Mg(OH)2, sodium carbonate, sodium hydrogen carbonate, triethyl amine, diethyl amine, and mixtures thereof.
- 25. The process of claim 20, wherein said base is at least one member selected from the group consisting of LiH, NaH, KH, LiOMe, NaOMe, KOMe, LiOH, NaOH, KOH, Mg(OH)2, sodium carbonate, sodium hydrogen carbonate, triethyl amine, diethyl amine, and mixtures thereof.
- 26. The process of claim 21, wherein said base is at least one member selected from the group consisting of LiH, NaH, KH, LiOMe, NaOMe, KOMe, LiOH, NaOH, KOH, Mg(OH)2, sodium carbonate, sodium hydrogen carbonate, triethyl amine, diethyl amine, and mixtures thereof.
Priority Claims (1)
Number |
Date |
Country |
Kind |
2000-137028 |
May 2000 |
JP |
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CROSS REFERENCES TO RELATED APPLICATIONS
This application is continuation of International Patent Application No. PCT/JP01/03479, filed on Apr. 23, 2001, and claims priority to Japanese Patent Application No. 2000-137028, filed on May 10, 2000, both of which are incorporated herein by reference in their entireties.
US Referenced Citations (12)
Foreign Referenced Citations (6)
Number |
Date |
Country |
1 070 726 |
Jan 2001 |
EP |
02202855 |
Aug 1990 |
JP |
05-178802 |
Jul 1993 |
JP |
WO 9411391 |
May 1994 |
WO |
WO 9952937 |
Oct 1999 |
WO |
WO 0125260 |
Apr 2001 |
WO |
Continuations (1)
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Number |
Date |
Country |
Parent |
PCT/JP01/03479 |
Apr 2001 |
US |
Child |
10/286840 |
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US |