Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-04-08
2004-09-21
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S037000, C560S041000
Reexamination Certificate
active
06794531
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel process for production of an aspartyl dipeptide ester derivative that be used as a sweetener. Furthermore, the present invention relates to a process for production of a arylpropionaldehyde, which can be used to produce a N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
2. Discussion of the Background
In recent years, as eating habits have increased, excessive weight gain and obesity caused by excessive sugar intake has been more frequently observed. Additionally, diseases accompanied by such weight gain and obesity are becoming more prevalent. Accordingly, the development of a low-calorie sweetener (sweetening agent) that replaces sugar has been strongly in demand. Aspartame is widely used as a sugar substitute or sweetener; and is excellent in safety and sweetening quality. However, a drawback of aspartame is that is somewhat unstable.
The present inventors have found the compound of formula (3) can be used as a sweetener and is excellent in stability. Moreover, this compound of formula (3) has a greater sweetening potency and therefore, has an advantage in cost per a sweet taste. However, an efficient method for manufacturing this process has not been previously described.
In formula (3), R
1
, R
2
, R
3
, R
4
and R
5
are independently 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.
N-[N-(3-phenylpropyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester and N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, which are described in WO94/11391, are poor sweeteners compared to the compounds of formula (3) described herein. However, WO94/11391 does not provide an example that shows a suitable operation for the synthesis and certain starting material employed as well.
For example, to produce 3-hydroxy-4-methoxyphenyl derivative a &bgr;-O-benzyl-&agr;-L-aspartyl-L-phenylalanine methyl ester is reductively alkylated with 3-benzyloxy-4-methoxycinnamaldehyde and NaB(OAc)
3
H, followed by the removal of the benzyl group of a protecting group was employed. However, 3-benzyloxy-4-methoxycinnamaldehyde used for the process is synthesized in a reaction that requires four reaction steps from the starting material 3-hydroxy-4-methoxycinnamic acid, as shown in the following reaction process 1. Therefore, this reaction process does not provide an industrial profitable means to produce the compounds. Likewise, a production process for N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester that uses the aldehyde described above as the starting material is to not an industrially profitable process, because in addition to the reductive alkylation, a deprotection reaction is required.
Therefore, development of an efficient and industrial process for producing an aspartyl dipeptide ester derivative represented by the general formula (3) described above, in particular, N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is needed.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an efficient and industrial process for producing an aspartyl dipeptide ester derivative represented by the general formula (3), which can be used as a sweetener.
Another object of the present invention is to provide an efficient and industrial process for producing an aldehyde represented by the following general formula (1) or (2), which can serve is intermediates for producing the aspartyl dipeptide ester derivative described above.
wherein R
1
, R
2
, R
3
, R
4
and R
5
are independently selected from 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.
Another object of the present invention is to provide novel intermediate 3-(3-hydroxy-4-methoxyphenyl) propionaldehyde.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have discovered an efficient process for producing the compounds represented by the above general formula (3), and as a result, have found that an aspartyl dipeptide ester derivative can be produced easily through reductive alkylation of an aspartame, in the presence of a catalyst and hydrogen, with an aldehyde of formulas (1) or (2).
In addition, the present inventors have found that the aldehyde represented by formulas (1) or (2) is an excellent intermediate for producing the aspartyl dipeptide ester derivative and have also found industrial efficient processes to produce these aldehydes.
The hydrocinnamaldehyde derivative can be obtained in a process where a cinnamic acid derivative is subjected to reaction conditions suitable for selectively reducing a carbon—carbon double bond therein, which reaction is conducted preferably in the presence of the hydrogenation catalyst (hydrogen addition) to obtain a hydrocinnamic acid derivative. Subsequently, a carboxyl group is reduced to a formyl group, preferably the reduction is performed in the presence of a catalyst.
A hydrocinnamaldehyde derivative can be obtained by a process where a carboxyl group in the cinnamic acid derivative is reduced to a formyl group, preferably in the presence of a catalyst, which yields a cinnamaldehyde derivative. Subsequently a carbon—carbon double bond is selectively reduced in the cinnamaldehyde derivative, preferably in the presence of a hydrogenation catalyst (hydrogen addition).
For example, N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, which provides high sweetening potency, may be prepared from 3-(3-hydroxy-4-methoxyphenyl) propionaldehyde thereby providing an industrially efficient process as depicted in the following reaction process 2.
Processes for Producing Aspartyl Dipeptide Ester Derivative
To produce an aspartyl dipeptide ester derivative represented by the following general formula (3) an aspartame can be reductively alkylated with an aldehyde represented by the following general formula (1) or formula (2), in the presence of hydrogen and a catalyst:
In the these formula, R
1
, R
2
, R
3
, R
4
and R
5
are independently 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. In one embodiment, R
1
and R
2
, or R
2
and R
3
may be combined together to denote a methylenedioxy group.
In the formula (3), R
1
, R
2
, R
3
, R
4
and R
5
are independently 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. In one embodiment R
1
and R
2
, or R
2
and R
3
may be combined together to denote a methylenedioxy group.
In the reductive alkylation reaction of the present invention, where R
1
to R
5
is a hydroxyl group, the hydroxyl group may be protected with a benzyl group, for example, R
1
to R
5
may be independently a benzyloxy group. In this case, the benzyl group may be removed (benzyl group-removing reaction) in the benzyloxy moiety, where the protected hydroxyl group may be converted into a hydroxyl group, and the compound of formula (3) obtained.
Processes for Producing Cinnamaldehyde Derivative and the Hydrocinnamaldehyde
The carboxyl group in the cinnamic acid derivative represented by formula (4) is partially reduced into a formyl group, preferably in the presenc
Amino Yusuke
Aoki Yuuichi
Funakoshi Nao
Nagashima Kazutaka
Ono Eriko
Ajinomoto Co. Inc.
Richter Johann
Zucker Paul A.
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