Intermediate for sweetener with high sweetness and process...

Details Intermediate for sweetener with high sweetness and process... Intermediate for sweetener with high sweetness and process...

2002-05-20

2004-02-17

Richter, Johann (Department: 1621)

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

Organic compounds

Carboxylic acids and salts thereof

C568S425000, C568S715000

Reexamination Certificate

active

06693214

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a 3-substituted-phenyl-3-merthylbutyric acid and 3-substituted-phenyl-3-methylaldehyde derivatives, which are useful in the production of N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, which is a sweetener with high sweetening potency.
BACKGROUND OF THE INVENTION
In recent years, as eating habits have changed dramatically, excessive weight gain caused by the increasing amounts of sugar found in foods have resulted in health related problems. Accordingly, the development of a low-calorie sweetener (sweetening agent) that replaces sugar has been strongly in demand. An example of such a low-calorie sweetener that is commonly used is aspartame, which is safe and effective for providing a high level of sweetness. However, aspartame is somewhat unstable.
To solve these problems, an —[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester shown below has been found, which is not only highly stable but is also far better with respect to the sweetening potency it imparts.
To make the N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester a process of reductively alkylating a &bgr;-O-benzyl-&agr;-L-aspartyl-L-phenylalanine methyl ester with a 3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde followed by removing the benzyl group of a protecting group therefrom has been provided previously by the present inventors. However, in this process, the aldehyde, which is used as an intermediate in the process, requires 7 reaction steps to be synthesized from the 3-hydroxy-4-methoxy acetophenone, which is used as the starting material. This 7-step reaction scheme is shown in the Reaction Process 1 below. Therefore, from the point of industrial profitability, such a reaction is not desirable.
In view of this problem, there is a need in the art for a process for producing industrially and easily the aspartyl dipeptide ester derivative described above.
Therefore, to solve this problem, the present inventors set out to provide processes for industrially and efficiently producing the N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester; and novel intermediate compounds useful in such production processes.
SUMMARY OF THE INVENTION
The present inventors have studied earnestly to solve the above problem, and as a result succeeded in newly synthesizing a 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde and found that the compound is extremely useful as an intermediate for the production of the N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester. Further, the inventors have discovered an efficient process for producing the compound, which is shown in the following reaction process 2.
Therefore, an object of the present invention is to provide a process for producing compounds of formula (2):
Another object of the present invention is produce 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid using the above compound of formula (2).
Another object of the present invention is to provide a process for producing 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde with the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid.
Another object of the present invention is to provide a process for producing N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester with the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde.
Another object of the present invention is a compound representated by formula (3):
DETAILED DESCRIPTION OF THE INVENTION
In the process for producing 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid, as depicted in the “Reaction Process 2” shown below the following disclosure is provided:
To protect the hydroxyl group in a 2-methoxy phenol, the 2-methoxy phenol can be converted to a hydroxyl-protective derivative of 2-methoxy phenol represented by formula (1) (where R is a sulfonyl-type protecting group and Me is a methyl group) by forming a sufonic acid ester from the 2-methoxy phenol, which process may be conducted as described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991, JOHN WILEY & SONS. INC. NEW YORK), p.168-170, which is incorporated herein by reference.
The reaction of 2-methoxy phenol with the corresponding sulfonic acid anhydride or sulfonic acid chloride can be performed in the presence of a base. An example of a hydroxyl protecting group can be represented by the formula: —SO
2
—R′ as the sulfonyl type-protecting group. R′ can be a branched chain or a straight chain (linear) alkyl group having 1 to 10 carbon atoms, which may have one or more substituent groups; an aryl group having 6 to 15 carbon atoms, which may have one or more substituent groups; and an aralkyl group having 7 to 20 carbon atoms, which may have one or more substituent groups. Preferably, the alkyl group(s) have from 1 to 3 carbon atoms. The alkyl group and/or the aralkyl group may be have a fluorine atom wherein one or more of the hydrogen atoms is replaced by fluorine atom(s). For example, a part or a whole of the alkyl group may be a fluoroalkyl group.
Examples of substituents on the alkyl and/or aralkyl include nitro group(s), halogen atom(s) (e.g, Cl, Br, F), and trialkyl ammonium group(s).
The R group, which is a sulfonyl type protecting group, may be, but not limited to, the following: a benzene sulfonyl group (—SO
2
—C
6
H
5
), a p-toluene sulfonyl group (—SO
2
—C
6
H
4
—CH
3
), a p-bromobenzene sulfonyl group (—SO
2
—C
6
H
4
—Br), a p-nitrobenzene sulfonyl group (—SO
2
—C
6
H
4
—NO
2
), a methane sulfonyl group (—SO
2
—CH
3
), an ammonioalkane sulfonyl group (—SO
2
—(CH
2
)
n
N(CH
3
)
3
+
) (n=0 to 6), a trifluoromethane sulfonyl group (—SO
2
—CF
3
), a nonafluorobuthane sulfonyl group (—SO
2
—C
4
F
9
), a 2,2,2-trifluoroethane sulfonyl group (—SO
2
—CH
2
—CF
3
). Preferably, R is a methane sulfonyl group, a trifluoromethane sulfonyl group, or a p-toluene sulfonyl group.
The reaction of a hydroxyl-protective derivative of 2-methoxy phenol represented by formula (1) with a 3-methylcrotonic acid can be conducted without a solvent, or conducted in an organic solvent with an acid coexistent. The organic solvent can be any solvent which is inactive with the substrate, with an acid and with a reaction product in the reaction. Examples of such solvents include, methylene chloride, chloroform, and nitrobenzene.
When an acid is used, the acid to be used can be a proton acid (H
+
), such as sulfuric acid, para (p-)toluenesulfonic acid and hydrogen chloride, a Lewis acid (L.A.), such as aluminum chloride, and titanium tetrachloride. Plural acids can also be employed, respectively in the proton acid or Lewis acid. A proton acid can also be used in combination with a Lewis acid, such as combination of hydrogen chloride with aluminum chloride. In a preferred embodiment, the acid is fixed firmly onto the surface of a solid phase thereby simplifying the process. Preferred acids include, aluminum chloride, titanium tetrachloride and sulfuric acid.
The amount of acid to be employed is not limited particularly, however, an excess of acid relative to the 3-methylcrotonic acid, will allow the reaction to be completed in a shorter time. However, preferably the amount of acid relative to the 3-methylcrotonic acid is in an amount of not more than 5 molar equivalents, more preferably not more than 3 molar equivalents, and further more preferably from 0.1 to 3 molar equivalents.
The amount of the hydroxyl-protective derivative of 2-methoxy phenol represented by formula (1) relative to the 3-methylcrotonic acid is not limited, however, preferably at least 0.5 molar equivalents or more, more preferably 1 molar equivalents or more, and further more preferably 1 to 10 molar equivalents or so, is used relative to the 3-methylcrotonic acid.

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