Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-07-19
2004-02-10
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C560S040000, C560S041000, C560S042000
Reexamination Certificate
active
06689902
ABSTRACT:
CROSS REFERENCES TO RELATED APPLICATIONS
This application claims priority to Japanese Patent Application No. 2000-11538, filed on Jan. 20, 2000, and International Patent Application No. PCT/JP01/00174, filed on Jan. 12, 2001, both of which are incorporated herein by reference in their entireties.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel arylpropyl aldehyde derivatives which are useful as production intermediates for food products, pharmaceutical products, and the like, and in particular for the production of N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, which is excellent as a sweetener having a high potency of sweetness. The present invention also relates to novel processes for the production of such intermediates. The present invention further relates to novel processes for the production of N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
2. Discussion of the Background
In recent years, as eating habits and diet have improved to a high level, obesity caused by excessive sugar intake and diseases accompanied by obesity have become a serious health issue. Accordingly, the development of low-calorie sweeteners (sweetening agents) as sugar replacers 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, N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester has been found to be a sweetener which has excellent stability and moreover is better by far in regard to the degree of sweetness, i.e., affords an advantage in regard to cost per sweet taste, by some of the present inventors and the like.
N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester may be prepared by reductively alkylating &bgr;-O-benzyl-&agr;-L-aspartyl-L-phenylalanine methyl ester with 3-(3-methyl-4-benzyloxyphenyl)-3-methylbutyl aldehyde and NaB(OAc)
3
H, followed by removing the benzyl group protecting group therefrom. However, 3-(3-methyl-4-benzyloxyphenyl)-3-methylbutyl aldehyde is synthesized from 3-methyl-4-hydroxyacetophenone in a seven-stage process which involves many reaction steps, as shown in the following Reaction Process 1. Accordingly, it is difficult to say that 3-(3-methyl-4-benzyloxyphenyl)-3-methylbutyl aldehyde is an industrially profitable starting material, because of the complicated reaction process for its synthesis.
Wherein BzlBr represents benzyl bromide, Bzl represents a benzyl group, LAH represent lithium aluminum hydride, and DMSO represents dimethyl sulfoxide.
Thus, there remains a need for a process for producing industrially and efficiently N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, which is excellent as a sweetener and has a high potency of sweetness. There also remains a need for production intermediates which are useful for producing N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester. There also remains a need for methods for producing such production intermediates.
SUMMARY OF THE INVENTION
Accordingly, it is one object of the present invention to provide novel compounds which are useful as intermediates for the production of N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
It is another object of the present invention to provide novel methods for preparing such intermediates.
There also remains a need for novel methods for producing N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester from such intermediates.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester may be conveniently synthesized from new arylpropyl aldehyde derivatives, in particular 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde. Thus, the present inventors have found certain new arylpropyl aldehyde derivatives, particularly 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde, which are extremely useful for the production of the sweetener having a high potency of sweetness described above.
In addition, the inventors have discovered convenient methods for producing such arylpropyl aldehyde derivatives, particularly 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde. One preferred embodiment of an efficient process for production of 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde is shown in the following Reaction Process 2. According to this embodiment, 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde can be synthesized by a reaction process having a total of only three stages, which comprises: (1) reacting 2-methoxytoluene with 3-methylcrotonic acid, preferably in the presence of an acid (first stage); (2) converting the methoxy group in the butyric acid thus obtained to a hydroxyl group, preferably through an acid hydrolysis (second stage); and (3) finally converting the carboxylic acid thus obtained to an aldehyde (third stage). Accordingly, with respect to the production of the production intermediates, the present process is industrially advantageous (is superior to) in comparison with the process which uses 3-(3-methyl-4-benzyloxyphenyl)-3-methylbutyl aldehyde as an production intermediate, because of the complicated synthesis of 3-(3-methyl-4-benzyloxyphenyl)-3-methylbutyl aldehyde, which requires seven stages of many reaction steps as described above.
In addition, the present inventors have found that the compound also is industrially excellent as an intermediate for the production of N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester. These findings have led to the completion of the present invention.
Where Piv represents a pivaloyl group and (Piv)
2
O represents pivalic acid anhydride.
Thus, in a first embodiment, the present invention provides a process for producing 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde, which comprises:
subjecting 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid to a reaction for converting a carboxyl group into a formyl group.
In a preferred embodiment, the present invention provides a process for producing 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde, which comprises:
subjecting 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid to a reaction for converting a carboxyl group into a formyl group,
wherein said 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid is obtained by subjecting 3-(3-methyl-4-methoxyphenyl)-3-methylbutyric acid to a reaction for converting a methoxy group into a hydroxyl group.
In another preferred embodiment, the present invention provides a process for producing 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde, which comprises:
subjecting 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid to a reaction for converting a carboxyl group into a formyl group,
wherein said 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid is obtained by subjecting 3-(3-methyl-4-methoxyphenyl)-3-methylbutyric acid obtained through the reaction of 2-methoxytoluene with 3-methylcrotonic acid to a reaction for converting a methoxy group into a hydroxyl group.
In another preferred embodiment, the present invention provides a process for producing 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl aldehyde, which comprises:
subjecting 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid to a reaction for converting a carboxyl group into a formyl group,
wherein said 3-(3-methyl-4-hydroxyphenyl)-3-methylbutyric acid is
Kawahara Shigeru
Mori Ken-ichi
Takemoto Tadashi
Ajinomoto Co. Inc.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Reyes Hector M
Rotman Alan L.
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