Process for production of aspartyl dipeptide ester derivatives

Details Process for production of aspartyl dipeptide ester derivatives Process for production of aspartyl dipeptide ester derivatives

2002-11-04

2004-11-23

Zucker, Paul A. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

Reexamination Certificate

active

06822111

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel processes for producing aspartyl dipeptide ester derivatives, which are useful as sweeteners.
2. Discussion of the Background
In recent years, as eating habits have been improved to a high level, obesity caused by excessive sugar intake and the diseases accompanied by obesity have become a serious health issue. Accordingly, the development of low-calorie sweeteners (sweetening agent) that replace sugar has been strongly in demand. As a sweetener that is widely used at present, there is aspartame which is excellent in safety and quality of sweetness, but however, is somewhat problematic in stability.
Against this background, certain N-[N-(phenylpropyl having various and specified substituent group(s) on the benzene ring)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl esters (aspartame derivatives) have been found to be sweeteners which are excellent in stability and, moreover, are better by far in degree of sweetness, i.e., have an advantage in cost per degree of sweet taste, (see, International Patent Publication WO99/52937). However, no method for the efficient process for production of these sweeteners is, as yet, known.
N-[N-(3-phenylpropyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester and N-[N-(3-methoxy-4-hydroxyphenylpropyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, which are poor in a degree (potency) of sweetness as compared to these compounds, are described in the International Patent Publication WO94/11391. However, in this publication, no examples which would show a suitable operation for the synthesis thereof including the starting material employed is provided, and there is no mention of any process for the production of these compounds.
Meanwhile, a process which comprises reductively alkylating aspartame with a 3-(phenyl having various substituent group(s) on the benzene ring)-2-propenyl aldehyde and hydrogen in the presence of a catalyst has been proposed by some of the present inventors and the like for production of the above-mentioned aspartame derivatives which are useful as sweeteners (see, Japanese Patent Application No. 11-287398 and International No. PCT/JP00/06626 description). However, there remains a need for a process which affords these compounds with a further improvement in yield.
SUMMARY OF THE INVENTION
Accordingly, it is one object of the present invention to provide novel processes for the production of N-[N-(phenylpropyl having various and specified substituent group(s) on the benzene ring)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl esters (aspartame derivatives) which are useful as sweeteners and which yields these compounds in an improved yield.
In particular, it is another object of the present invention to provide novel processes which afford improved yields of the compounds of formula (2):
wherein in formula (2) R
1
, R
2
, R
3
, R
4
and R
5
are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R
1
and R
2
, or two symbols of R
2
and R
3
may be combined together to denote a methylenedioxy group.
It is another object of the present invention to provide an efficient and industrial process for producing such compounds.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that N-[N-(phenylpropyl having various and specified substituent group(s) on the benzene ring)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl esters (aspartame derivatives), more specifically aspartyl dipeptide ester derivatives represented by the general formula (2):
wherein in formula (2) R
1
, R
2
, R
3
, R
4
and R
5
are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R
1
and R
2
, or two symbols of R
2
and R
3
may be combined together to denote a methylenedioxy group,
can be easily produced by reductively alkylating aspartame in the presence of a base and a catalyst, with an aldehyde represented by the following general formula (1) and hydrogen:
wherein in formula (1), R
1
, R
2
, R
3
, R
4
and R
5
are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, a benzyloxy group and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R
1
and R
2
, or two symbols of R
2
and R
3
may be combined together to denote a methylenedioxy group, and the hydroxyl group (—OH) may denote a substituent group (—OM; M=metal atom) in its derivative form where the hydrogen atom in said hydroxyl group has been replaced by a metal atom,
and where necessary neutralizing the product with an acid.
That is, the present invention provides the following embodiments and aspects:
(1) A process for producing an aspartyl dipeptide ester derivative represented by the following general formula (2):
wherein in formula (2) R
1
, R
2
, R
3
, R
4
and R
5
are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R
1
and R
2
, or two symbols of R
2
and R
3
may be combined together to denote a methylenedioxy group,
which comprises:
reductively alkylating aspartame with an aldehyde represented by the following general formula (1), and hydrogen in the presence of a catalyst and a base:
wherein in formula (1), R
1
, R
2
, R
3
, R
4
and R
5
are each independently of each other a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms, a benzyloxy group and a hydroxyalkyloxy group having 2 or 3 carbon atoms, wherein two symbols of R
1
and R
2
, or two symbols of R
2
and R
3
may be combined together to denote a methylenedioxy group, and the hydroxyl group (—OH) may denote a substituent group (—OM; M=metal atom) in its derivative form where the hydrogen atom in said hydroxyl group has been replaced by a metal atom.
Said derivative of formula (2) may be in any form of the free form and the salt form.
Accordingly, the object compound can be produced and obtained in the salt form through the reductive alkylation reaction. Where necessary or desired, the salt form may be further converted into the free form, whereby the object compound can be produced and obtained. Any such form of the object compound and any such process therefor are contained in the present invention. To the present invention, in addition to the reductive alkylation reaction process, any usual and conventional process, such as a salt-formation process, a desalination process, and/or a purification process may be added so long as the object thereof is not inhibited or impaired.
Incidentally, in the case when the aldehyde of formula (1) used as the starting material contains a benzyloxy group, the benzyloxy group is converted into a hydroxyl group by the removal of the benzyl group in the benzyloxy moiety, and thereby the object compound of formula (2) obtained after the reaction does not contain a benzyloxy group, and instead contains a hydroxyl group.
(2) The process (1) as defined above, wherein said derivative of formula (2) obtained as the object compound is in the free form.
In this case, the process includes a process for converting said derivative existing in the salt form obtained in the red

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