U.S. patent application number 11/105428 was filed with the patent office on 2005-08-11 for process for production of aspartyl dipeptide ester derivative, novel production intermediate therefor, and process for production thereof.
This patent application is currently assigned to Ajinomoto Co., Inc.. Invention is credited to Aoki, Yuuichi, Funakoshi, Nao, Nagashima, Kazutaka, Ono, Eriko, Takemoto, Tadashi.
Application Number | 20050175755 11/105428 |
Document ID | / |
Family ID | 26556716 |
Filed Date | 2005-08-11 |
United States Patent
Application |
20050175755 |
Kind Code |
A1 |
Nagashima, Kazutaka ; et
al. |
August 11, 2005 |
Process for production of aspartyl dipeptide ester derivative,
novel production intermediate therefor, and process for production
thereof
Abstract
The present invention relates to a method of manufacturing
aspartyl dipeptide ester compounds, which can be used as
sweeteners, and aldehydes that can be used in the manufacturing
processes.
Inventors: |
Nagashima, Kazutaka;
(Kawasaki-shi, JP) ; Aoki, Yuuichi; (Kawasaki-shi,
JP) ; Takemoto, Tadashi; (Kawasaki-shi, JP) ;
Funakoshi, Nao; (Kawasaki-shi, JP) ; Ono, Eriko;
(Kawasaki-shi, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Ajinomoto Co., Inc.
Tokyo
JP
104-8315
|
Family ID: |
26556716 |
Appl. No.: |
11/105428 |
Filed: |
April 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11105428 |
Apr 14, 2005 |
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10796093 |
Mar 10, 2004 |
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10796093 |
Mar 10, 2004 |
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10117196 |
Apr 8, 2002 |
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6794531 |
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10117196 |
Apr 8, 2002 |
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PCT/JP00/06626 |
Sep 26, 2000 |
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Current U.S.
Class: |
426/548 |
Current CPC
Class: |
A23L 27/32 20160801;
C07K 5/06113 20130101 |
Class at
Publication: |
426/548 |
International
Class: |
A23L 001/236 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 7, 1999 |
JP |
11-287398 |
Dec 27, 1999 |
JP |
11-371284 |
Claims
1.-48. (canceled)
49. 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde.
Description
CROSS-REFERENCE TO A RELATED APPLICATION
[0001] The present application is a continuation application of
PCT/JP00/06626 filed Sep. 26, 2000, the entire contents of which is
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] 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-.alpha.-aspartyl]-L-phenylal-
anine 1-methyl ester.
[0004] 2. Discussion of the Background
[0005] 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.
[0006] 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. 1
[0007] In formula (3), R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.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.sub.1 and R.sub.2, or two symbols of R.sub.2 and
R.sub.3 may be combined together to denote a methylenedioxy
group.
[0008] N-[N-(3-phenylpropyl)-L-.alpha.-aspartyl]-L-phenylalanine
1-methyl ester and
N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl)-L-.alpha.-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.
[0009] For example, to produce 3-hydroxy-4-methoxyphenyl derivative
a .beta.-O-benzyl-.alpha.-L-aspartyl-L-phenylalanine methyl ester
is reductively alkylated with 3-benzyloxy-4-methoxycinnamaldehyde
and NaB(OAc).sub.3H, followed by the removal of the benzyl group of
a protecting group was employed. However,
3-benzyloxy-4-methoxycinnamaldehy- de 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-.alpha.-aspartyl]-L-phenylal-
anine 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. 2
[0010] 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-.alpha.-aspartyl]-L-phenylal-
anine 1-methyl ester is needed.
SUMMARY OF THE INVENTION
[0011] 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.
[0012] 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. 3
[0013] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.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.sub.1 and
R.sub.2, or two symbols of R.sub.2 and R.sub.3 may be combined
together to denote a methylenedioxy group.
[0014] Another object of the present invention is to provide novel
intermediate 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde.
DETAILED DESCRIPTION OF THE INVENTION
[0015] 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).
[0016] 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.
[0017] 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.
[0018] 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).
[0019] For example,
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-a-
spartyl]-L-phenylalanine 1-methyl ester, which provides high
sweetening potency, may be prepared from
3-(3-hydroxy-4-methoxyphenyl)propionaldehyd- e thereby providing an
industrially efficient process as depicted in the following
reaction process 2. 4
[0020] Processes for Producing Aspartyl Dipeptide Ester
Derivative
[0021] 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: 5
[0022] In the these formula, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.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.sub.1 and R.sub.2, or R.sub.2 and
R.sub.3 may be combined together to denote a methylenedioxy group.
6
[0023] In the formula (3), R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.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.sub.1 and R.sub.2, or R.sub.2 and
R.sub.3 may be combined together to denote a methylenedioxy
group.
[0024] In the reductive alkylation reaction of the present
invention, where R.sub.1 to R.sub.5 is a hydroxyl group, the
hydroxyl group may be protected with a benzyl group, for example,
R.sub.1 to R.sub.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.
[0025] Processes for Producing Cinnamaldehyde Derivative and the
Hydrocinnamaldehyde
[0026] The carboxyl group in the cinnamic acid derivative
represented by formula (4) is partially reduced into a formyl
group, preferably in the presence of a catalyst, to obtain the
cinnamaldehyde derivative represented by formula (2). Subsequently,
the carbon-carbon double bond therein is selectively reduced,
preferably in the presence of a hydrogenation catalyst whereby the
hydrocinnamaldehyde derivative represented by formula (1) is
obtained.
[0027] Further, in the cinnamic acid derivative represented by
formula (4), the carbon-carbon double bond therein is selectively
reduced, preferably in the presence of a hydrogenation catalyst to
obtain the hydrocinnamic acid derivative represented by formula
(5). Subsequently, the carboxyl group therein is partially reduced,
preferably in the presence of a catalyst, into a formyl group,
whereby the hydrocinnamaldehyde derivative represented by formula
(1) is obtained. 7
[0028] In the above formulas, R.sub.1, R.sub.2, R.sub.3, R.sub.4
and R.sub.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.sub.1 and R.sub.2, or R.sub.2 and
R.sub.3 may be combined together to form a methylenedioxy
group.
[0029] Hydrocinnamaldehyde Derivatives (Arylpropionaldehyde),
Process for Production Thereof, and Uses Thereof
[0030] To prepare a 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde, a
3-hydoroxy-4-methoxycinnamaldehyde may be subjected to reaction
conditions to selectively reduce a carbon-carbon double bond; or a
3-(3-hydoroxy-4-methoxyphenyl)propionic acid may be subjected to
reaction conditions to convert a carboxyl group into a formyl
group. In a preferred embodiment the
3-hydoroxy-4-methoxycinnamaldehyde is obtained through a process by
converting a carboxy group in a 3-hydoroxy-4-methoxycinnamic acid
into a formyl group. The conversion of a carboxy group into a
formyl group is preferably accomplished by partially reducing the
carboxyl group. In a preferred embodiment the
3-(3-hydoroxy-4-methoxyphenyl)propionic acid is obtained by a
process where a carbon-carbon double bond in
3-hydoroxy-4-methoxycinnamic acid is selectively reduced, more
preferably the carbon-carbon double bond is selectively reduced in
the presence of hydrogenation a catalyst, and most preferably the
hydrogenation catalyst is at least one of palladium, platinum
and/or rhodium based catalysts.
[0031] To produce a
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-a-
spartyl]-L-phenylalanine 1-methyl ester the above processes can be
extended to include a step of reductive alkylation of the
arylpropionaldehyde with an aspartame.
[0032] In the process for producing an aspartyl dipeptide ester, to
a solution which has dissolved or suspended aspartame, the aldehyde
is dissolved, a catalyst is added, and is stirred under a hydrogen
gas atmosphere. After completion of the reaction, the catalyst may
be removed by filtration, and the filtrate is concentrated to
obtain the aspartyl dipeptide ester derivative. This derivative may
be subjected to purification uising chromatography or the like.
[0033] There is no particular limitation to the solvent to be
employed in the reaction provided it is an inactive material to the
starting material for the reaction, the catalyst and the product.
The solvent to dissolve aspartame and the aldehyde may be a
homogenous solvent consisting of one kind of organic solvent only;
a mixed solvent consisted of two or more organic solvents, or a
mixture of one ore more organic solvents with water may be
employed. Preferred solvents include, for example, methanol,
ethanol, tetrahydrofuran, acetonitrile and dimethylformamide. Most
preferred a methanol or a water-containing methanol solvents.
[0034] Suitable hydrogenation catalyst include, but are not limited
to as palladium based catalyst (palladium carbon and the like),
platinum based catalyst (platinum carbon and the like), and rhodium
based catalyst. Preferred catalysts are palladium carbon and
platinum carbon.
[0035] The reductive alkylation reaction can be conducted by
hydrogenation (hydrogen addition), preferably under hydrogen
pressure, which is preferably from about 0.1 to about 1.0 MPa.
[0036] The temperature for the reactions is not limited provided it
is selected to be suitable for the reductive alkylation reaction.
In order to suppress a secondary reaction and to promote the
reaction desired, preferred temperature ranges are from about 15 to
about 50.degree. C., for reaction time of from about 2 to about 72
hours.
[0037] The molar ratio of aspartame to the aldehyde can be employed
preferably from about 0.5 to about 1.5 moles of aspartame per 1
mole of the aldehyde.
[0038] To produce the aspartyl dipeptide ester derivative by way of
the reductive alkylation reaction, in one embodiment R.sub.2 is a
hydroxyl group, R.sub.3 is a methoxy group, and R.sub.1, R.sub.4
and R.sub.5 are a hydrogen atom in the above formulas (1)-(3), and
in the formulae (1) and (2), R.sub.2 may be a benzyloxy group. In
another embodiment R.sub.2 is a methyl group, R.sub.3 is a hydroxyl
group, and R.sub.1, R.sub.4 and R.sub.5 are hydrogen atoms in
formulas (1)-(3), and in the formulas (1) and (2), R.sub.3 may be a
benzyloxy group. In another embodiment R.sub.2 and R.sub.3 are
combined together to denote a methylenedioxy group, and R.sub.1,
R.sub.4 and R.sub.5 are hydrogen atoms in formulas (1)-(3). In
another embodiment R.sub.1 is a hydroxyl group, R.sub.3 is a
methoxy group, and R.sub.2, R.sub.4 and R.sub.5 are hydrogen atoms
in the formulas (1)-(3), and in the formulas (1) and (2), R.sub.1
may be a benzyloxy group. In another embodiment R.sub.3 is a
hydroxyl group, and R.sub.1, R.sub.2, R.sub.4 and R.sub.5 are
hydrogen atoms in formulas (1)-(3), and in the formulas (1) and
(2), R.sub.3 may be a benzyloxy group. In another embodiment
R.sub.2 is a hydroxyl group, R.sub.3 is a methyl group, and
R.sub.1, R.sub.4 and R.sub.5 are hydrogen atoms in formulas
(1)-(3), and in the formulas (1) and (2), R.sub.2 may be a
benzyloxy group. In another embodiment R.sub.1 and R.sub.3 are a
hydroxyl group, and R.sub.2, R.sub.4 and R.sub.5 are hydrogen atoms
in formulas (1)-(3), and in the formulas (1) and (2), R.sub.1
and/or R.sub.3 may be a benzyloxy group.
[0039] Processes for Producing Cinnamaldehyde Derivatives and
Hydrocinnamaldehyde Derivatives
[0040] To produce the cinnamaldehyde derivative and the
hydrocinnamaldehyde derivative a manufacturing method 1 depicted
below may be employed. In this method the carboxyl group of the
cinnamic acid derivative of formula (4) is partially reduced,
preferably in the presence of a catalyst. Subsequently, the
carboxyl group is converted into a formyl group to yield the
cinnamaldehyde derivative of formula (2). The carbon-carbon double
bond then is selectively reduced, preferably in the presence of a
hydrogenation catalyst, yielding the hydrocinnamaldehyde derivative
of formula (1).
[0041] In another embodiment, as shown in the following
manufacturing method 2 a carbon-carbon double bond of the cinnamic
acid derivative of formula (4) is selectively reduced, preferably
in the presence of a hydrogenation catalyst yielding a
hydrocinnamic acid derivative of formula (5). Subsequently, the
carboxyl group is partially reduced, preferably in the presence of
a catalyst, into a formyl group, yielding the hydrocinnamaldehyde
derivative of formula (1). 8
[0042] In the manufacturing method 2, preferably
3-hydroxy-4-methoxycinnam- ic acid is the cinnamic acid derivative
of formula (4).
[0043] In the manufacturing method 1, for example, to produce
3-hydroxy-4-methoxycinnamaldehyde from 3-hydroxy-4-methoxycinnamic
acid, the 3-hydroxy-4-methoxycinnamic acid may be partially
reduced, using methods known in the art, for example, as described
in Chem. Lett., 1998, 11, 1143. This process includes the step of
reducing the 3-hydroxy-4-methoxycinnamic acid with hydrogen in an
organic solvent and in the presence of pivalic acid anhydride,
palladium based compounds (such as palladium acetate), and
triphenylphosphine derivatives (triarylphosphine and the like).
There is no particular limitation to the solvent to be employed in
the reaction provided it is an inactive material to the starting
material for the reaction, the catalyst and the product.
Preferably, acetone, tetrahydrofuran, and the like are employed.
The amount of pivalic acid anhydride used in the reaction is
preferably an equimolar amount or more of pivalic acid anhydride
relative to the 3-hydroxy-4-methoxycinnamic acid. For example, from
about 1 to about 5 times moles of pivalic acid anhydride to the
3-hydroxy-4-methoxycinnamic acid may be used.
[0044] Triphenylphosphine derivative useful include, but are not
limited to triphenylphosphine, and tritolylphosphine. The
catalyst(s), for example, palladium acetate and triphenylphosphine
derivative are employed in varying molar percentages.
[0045] The temperature for reaction may be conducted at any
temperature, but at higher reaction temperature, the reaction may
proceed faster and therefore completed in a shorter time.
[0046] To produce the 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde
from the 3-hydroxy-4-methoxycinnamaldehyde obtained in the above
reaction, the carbon-carbon double bond in the
3-hydroxy-4-methoxycinnamaldehyde may be selectively reduced,
preferably in the presence of the hydrogenation catalyst. More
preferably, the carbon-carbon double bond is selectively reduced
using methods known in the art, for example, as described in
Engelhard. Ind. Tech. Bull., 1963, 4, 49. This process comprises
the step of selectively reducing the
3-hydroxy-4-methoxycinnamaldehyde, in particular the carbon-carbon
double bond therein with hydrogen in an organic solvent, for
example, in the presence of the catalyst, which includes, for
example, palladium based catalysts (such as palladium-alumina,
palladium-calcium carbonate and the like), platinum based catalysts
(such as platinum carbon and the like), rhodium based catalysts
(such as rhodium-alumina and the like), or nickel based catalysts
(such as nickel-formic acid and the like).
[0047] There is no particular limitation to the solvent to be
employed in the reaction provided it is an inactive material to the
starting material for the reaction
(3-hydroxy-4-methoxycinnamaldehyde), the catalyst and the product
(3-(3-hydroxy-4-methoxyphenyl)propionaldehyde). Preferably, the
solvent is a lower alcohol such as methanol, ethanol and the like,
tetrahydrofuran, and the like; more preferably, a lower alcohol may
be employed, and most preferably methanol may be employed.
[0048] The catalyst may be a generic and conventional hydrogenation
catalyst, such as palladium based catalysts (palladium-alumina,
palladium-calcium carbonate and the like), platinum based catalysts
(platinum carbon and the like), and rhodium based catalyst
s(rhodium-alumina and the like), or nickel based catalysts
(nickel-formic acid and the like). The catalyst may be used in any
amount. For example, in case of 5% palladium-alumina, it may be
preferably employed within a range of weight ratio of about one
hundredth ({fraction (1/100)}) to about one third (1/3) relative to
the 3-hydroxy-4-methoxycinnamaldehyde. The reaction can be
conducted by hydrogenation (hydrogen addition), preferably at a
pressure of 0.1 MPa, and more preferable under hydrogen pressure of
from about 0.1 to about 5.0 MPa.
[0049] The temperature for the reaction temperature is preferably
from about 10 to about 30.degree. C. However, to improve the
solubility of the starting material or the object product, and also
to improve the speed of the reaction, preferably the reaction
solution may be heated up to about 60.degree. C., more preferably
from about 20 to about 50.degree. C. The reaction may also be
conducted at this temperature. The reaction may proceed for any
amount of time, but preferably the reaction proceeds for about 2 to
about 48 hours.
[0050] In the manufacturing method 2, for example, to produce
3-(3-hydroxy-4-methoxyphenyl)propionic acid from
3-hydroxy-4-methoxycinna- mic acid, the carbon-carbon double bond
may be selectively reduced in 3-hydroxy-4-methoxycinnamic acid.
Preferably, the selective reduction is conducted using known
process, for example, as described in J. Org. Chem., 1994, 59,
2304. This process comprises the step of selectively reducing the
3-hydroxy-4-methoxycinnamic acid, in particular the carbon-carbon
double bond therein with hydrogen in an organic solvent.
Preferably, the reaction is conducted in the presence of a
catalyst. Preferred catalysts, include palladium based catalysts
(such as palladium carbon, palladium-alumina and the like),
platinum based catalysts (such as platinum carbon and the like),
rhodium based catalysts (such as rhodium-alumina and the like), or
nickel based catalysts (such as Raney Nickel and the like).
[0051] There is no particular limitation to the solvent to be
employed in the reaction provided it is an inactive material to the
starting material for the reaction (3-hydroxy-4-methoxycinnamic
acid), the catalyst and the product
(3-(3-hydroxy-4-methoxyphenyl)propionic acid). Preferably, a lower
alcohol such as methanol, ethanol and the like, tetrahydrofuran,
and a mixed solvent of such organic solvent(s) with water, and the
like can be used. More preferably, a lower alcohol may be employed,
for example, methanol and most preferred is a mixed solvent of
methanol and water.
[0052] If a catalyst is used in the reaction, a generic and
conventional hydrogenation catalyst may be used. For example,
palladium based catalysts (palladium carbon, palladium-alumina and
the like), platinum based catalysts (platinum carbon and the like),
and rhodium based catalysts (rhodium-alumina and the like), or
nickel based catalysts (Raney Nickel and the like), can be
used.
[0053] The catalyst can be used in any amount but, for example, in
case of 10% palladium carbon in the water content of 50%, the
catalyst may be preferably employed within a range of weight ratio
of about one hundredth ({fraction (1/100)}) to about one third
(1/3) relative to the 3-hydroxy-4-methoxycinnamic acid. The
hydrogenation (hydrogen addition) is preferably carried out at a
pressure of about 0.1 Mpa, and more preferably under hydrogen
pressure of about 0.1 to about 1.0 MPa. The reaction temperature is
preferably from about 10 to about 30. However, to improve the
solubility of the starting material or the object product, and
further to improve a reaction speed, the reaction solution may be
heated up to about 60.degree. C., preferably from about 30 to about
50.degree. C. The can also be conducted at the preferred
temperature. The reaction may proceed for any length of time, but
preferred is a reaction time of about 2 to about 48 hours.
[0054] To produce a 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde
from the 3-(3-hydroxy-4-methoxyphenyl)propionic acid obtained in
the above reaction, the 3-(3-hydroxy-4-methoxyphenyl)propionic acid
may be directly partially reduced.
[0055] To produce an aspartyl dipeptide ester derivative,
preferably a
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-aspartyl]-L-phenylal-
anine 1-methyl ester, from the cinnamaldehyde derivative or the
hydrocinnamaldehyde derivative, preferably form the
3-(3-hydroxy-4-methoxyphenyl)propionaldehyde, the process may be
conducted as explained in the process for production of the
aspartyl dipeptide ester derivative, described above. Particularly,
the aldehyde derivative obtained is reductively alkylated with an
.alpha.-L-aspartyl-L-phenylalanine methyl ester (aspartame) under a
condition for hydrogenation (hydrogen addition). The solvent that
can be used should dissolve the starting materials, for example,
alcohol, water-containing alcohol or the like may be used. The
catalyst for hydrogenation is as described above, under the
pressure, temperature and time conditions described herein.
[0056] The catalyst can be removed from the reaction after the
aspartyl dipeptide ester derivative is prepared and the aspartyl
didpeptide ester can be further purified yielding a sweetener
having a high sweetening potency. For example, in case of
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propy-
l]-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester, after the
catalyst is removed, the solvent is removed by distillation,
yielding a residue that may be subjected to a purification with a
silica gel chromatography (for example, eluting solvent: ethyl
acetate/methanol/chloroform=3/3/2). The eluted fractions containing
the object compound, are concentrated under reduced pressure to
yield N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl-
]-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester in the solid
form.
[0057] The following Examples provide an illustration of
embodiments of the invention and should not be construed to limit
the scope of the invention, which is set forth in the appended
claims. In the following Examples, all methods described are
conventional unless otherwise specified.
EXAMPLES
Example 1
Production of
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl Ester
[0058] Aspartame (5.89 g, 20.0 mmol) and
3-(3-hydroxy-4-methoxyphenyl)prop- ionaldehyde (3.42 g, 19.0 mmol)
were added to 80% methanol aqueous solution (200 ml), and the
mixture was stirred at 40.degree. C. in a short time. To this
solution, 10% palladium carbon in the water content of 50% (1.78 g)
was added, and thus obtained mixture was stirred under hydrogen
atmosphere of normal pressure (0.1 MPa) at 40.degree. C. for 40
hours. The reaction solution was filtrated to remove the catalyst,
and the filtrate was subjected to the high performance liquid
chromatography (HPLC) for determination to produce the title
compound (6.89 g, 15.0 mmol, 78.9%).
Example 2
Production of
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl Ester
[0059] Aspartame (5.89 g, 20.0 mmol) and
3-(3-hydroxy-4-methoxyphenyl)prop- ionaldehyde (3.42 g, 19.0 mmol)
were added to methanol (150 ml), and the mixture was stirred in a
short time. To thus obtained slurry, 10% palladium carbon in the
water content of 50% (1.78 g) was added, and thus obtained mixture
was stirred under hydrogen atmosphere of normal pressure (0.1 MPa)
at room temperature for 24 hours. The reaction solution was
filtrated to remove the catalyst, and the filtrate was subjected to
the HPLC for determination to produce the title compound (5.92 g,
12.9 mmol, 67.9%).
Example 3
Production of
N-[N-[3-(2-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl Ester
[0060] Aspartame (5.89 g, 20.0 mmol) and
3-(2-hydroxy-4-methoxyphenyl)prop- ionaldehyde (3.42 g, 19.0 mmol)
were added to 80% methanol aqueous solution (200 ml), and the
mixture was stirred at 40.degree. C. in a short time. To this
solution, 10% palladium carbon in the water content of 50% (1.78 g)
was added, and thus obtained mixture was stirred under hydrogen
atmosphere of normal pressure (0.1 MPa) at 40.degree. C. for 48
hours. The reaction solution was filtrated to remove the catalyst,
and the filtrate was subjected to the HPLC for determination to
generate the title compound (6.26 g, 13.7 mmol, 72.1%).
Example 4
Production of
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl Ester
[0061] Aspartame (0.40 g, 1.47 mmol) and
3-hydroxy-4-methoxycinnamaldehyde (0.25 g, 1.40 mmol) were added to
methanol (13 ml), and the mixture was stirred in a short time. To
thus obtained slurry, 10% palladium carbon in the water content of
50% (0.12 g) was added, and thus obtained mixture was stirred under
hydrogen atmosphere of normal pressure (0.1 MPa) at room
temperature for 24 hours. The reaction solution was filtrated to
remove the catalyst, and the filtrate was subjected to the HPLC for
determination to generate the title compound (0.21 g, 0.46 mmol,
32.8%).
Example 5
Production of
N-[N-[3-(3-methyl-4-hydroxyphenyl)propyl]-L-.alpha.-aspartyl-
]-L-phenylalanine 1-methyl Ester
[0062] Aspartame (5.89 g, 20.0 mmol) and
3-(3-methyl-4-hydroxyphenyl)propi- onaldehyde (3.12 g, 19.0 mmol)
were added to 60% methanol aqueous solution (150 ml), and the
mixture was stirred in a short time. To thus obtained slurry, 10%
palladium carbon in the water content of 50% (2.00 g) was added,
and thus obtained mixture was stirred under hydrogen atmosphere of
normal pressure (0.1 MPa) at room temperature for 48 hours. The
reaction solution was filtrated to remove the catalyst, and the
filtrate was subjected to the HPLC for determination to generate
the title compound (6.92 g, 15.7 mmol, 82.6%).
Example 6
Production of
N-[N-[3-(3,4-methylenedioxyphenyl)propyl]-L-.alpha.-aspartyl-
]-L-phenylalanine 1-methyl Ester
[0063] Aspartame (5.89 g, 20.0 mmol) and
3-(3,4-methylenedioxyphenyl)propi- onaldehyde (3.12 g, 19.0 mmol)
were added to 80% methanol aqueous solution, and the mixture was
stirred in a short time. To thus obtained slurry, 10% palladium
carbon in the water content of 50% (1.78 g) was added, and thus
obtained mixture was stirred under hydrogen atmosphere of normal
pressure (0.1 MPa) at room temperature for 48 hours. The reaction
solution was filtrated to remove the catalyst, and the filtrate was
subjected to the HPLC (high performance liquid chromatography) for
determination to generate the title compound (6.21 g, 14.0 mmol,
73.7%).
Example 7
Production of
N-[N-[3-(4-hydroxyphenyl)propyl]-L-.alpha.-aspartyl]-L-pheny-
lalanine 1-methyl Ester
[0064] Aspartame (5.89 g, 20.0 mmol) and
3-(4-hydroxyphenyl)propionaldehyd- e (2.85 g, 19.0 mmol) were added
to 60% methanol aqueous solution (200 ml), and the mixture was
stirred at 40.degree. C. in a short time. To this solution, 10%
palladium carbon in the water content of 50% (1.78 g) was added,
and thus obtained mixture was stirred under hydrogen atmosphere of
normal pressure (0.1 MPa) at 40.degree. C. for 48 hours. The
reaction solution was filtrated to remove the catalyst, and the
filtrate was subjected to the HPLC for determination to produce the
title compound (6.18 g, 14.4 mmol, 75.8%).
Example 8
Production of
N-[N-[3-(3-hydroxy-4-methylphenyl)propyl]-L-.alpha.-aspartyl-
]-L-phenylalanine 1-methyl Ester
[0065] Aspartame (5.89 g, 20.0 mmol) and
3-(3-hydroxy-4-methylphenyl)propi- onaldehyde (3.12 g, 19.0 mmol)
were added to 80% methanol aqueous solution (150 ml), and the
mixture was stirred in a short time. To thus obtained slurry, 10%
palladium carbon in the water content of 50% (1.78 g) was added,
and thus obtained mixture was stirred under hydrogen atmosphere of
normal pressure (0.1 MPa) at room temperature for 48 hours. The
reaction solution was filtrated to remove the catalyst, and the
filtrate was subjected to the HPLC for determination to produce the
title compound (6.97 g, 15.8 mmol, 83.2%).
Example 9
Production of
N-[N-[3-(2-hydroxy-3-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl Ester
[0066] Aspartame (5.89 g, 20.0 mmol) and
2-hydroxy-3-methoxycinnamaldehyde
[3-(2-hydroxy-3-methoxyphenyl)-2-propenyl aldehyde] (3.38 g, 18.0
mmol) were added to 80% methanol aqueous solution (200 ml), and the
mixture was stirred in a short time. To thus obtained slurry, 10%
palladium carbon in the water content of 50% (1.78 g) was added,
and thus obtained mixture was stirred under hydrogen atmosphere of
normal pressure (0.1 MPa) at room temperature for 48 hours. The
reaction solution was filtrated to remove the catalyst, and the
filtrate was subjected to the HPLC for determination to produce the
title compound (4.26 g, 9.3 mmol, 48.9%).
Example 10
Production of
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl Ester
[0067] Aspartame (5.89 g, 20.0 mmol) and
3-(3-benzyloxy-4-methoxyphenyl)pr- opionaldehyde (5.15 g, 19.0
mmol) were added to 80% methanol aqueous solution (200 ml), and the
mixture was stirred in a short time. To thus obtained slurry, 10%
palladium carbon in the water content of 50% was added, and thus
obtained mixture was stirred under hydrogen atmosphere of normal
pressure (0.1 MPa) at room temperature for 40 hours. The reaction
solution was filtrated to remove the catalyst, and the filtrate was
subjected to the HPLC for determination to produce the title
compound (7.01 g, 15.3 mmol, 80.5%).
Example 11
Production of
N-[N-[3-(3-hydroxy-4-methoxy]phenyl)propyl]-L-.alpha.-aspart-
yl]-L-phenylalanine 1-methyl Ester
[0068] Aspartame (5.89 g, 20.0 mmol) and
3-(3-hydroxy-4-methoxyphenyl)prop- ionaldehyde (3.42 g, 19.0 mmol)
were added to 80% methanol aqueous solution (180 ml), and further
acetic acid (10 ml) was added thereto, and the mixture was stirred
in a short time. To thus obtained slurry, 10% palladium carbon in
the water content of 50% (1.78 g) was added, and thus obtained
mixture was stirred under hydrogen atmosphere of normal pressure
(0.1 MPa) at room temperature for 24 hours. The reaction solution
was filtrated to remove the catalyst, and the filtrate was
subjected to the HPLC for determination to produce the title
compound (6.72 g, 14.7 mmol, 77.4%).
Example 12
Production of
N-[N-[3-(2,4-dihydroxyphenyl)propyl]-L-.alpha.-aspartyl]-L-p-
henyalanine 1-methyl Ester
[0069] Aspartame (5.89 g, 20.0 mmol) and
3-(2,4-dihydroxyphenyl)propionald- ehyde (3.15 g, 19.0 mmol) were
added to 80% methanol aqueous solution (200 ml), and the mixture
was stirred in a short time. To thus obtained slurry, 10% palladium
carbon in the water content of 50% was added, and thus obtained
mixture was stirred under hydrogen atmosphere of normal pressure
(0.1 MPa) at room temperature for 40 hours. The reaction solution
was filtrated to remove the catalyst, and the filtrate was
subjected to the HPLC for determination to produce the title
compound (5.94 g, 13.4 mmol, 70.5%).
Example 13
Production of 3-hydroxy-4-methoxycinnamaldehyde
[0070] In a chemical reactor for hydrogen addition (hydrogenation)
under elevated pressure, previously tetrahydrofuran (64 ml) was
bubbled with nitrogen gas for 10 minutes.
[0071] Palladium acetate (58 mg, 0.257 mmol), tri(p-tolyl)
phosphine (157 mg, 0.515 mmol), 3-hydroxy-4-methoxycinnamic acid
(5.00 g, 25.7 mmol) and pivalic acid anhydride (14.4 g, 77.2 mmol)
were added thereto, and thereafter the mixture was bubbled with
nitrogen gas for 30 minutes to substitute nitrogen gas completely
for the gas in the system of reaction, whereby the system was
filled with nitrogen gas. Next, hydrogen gas was added thereinto to
substitute hydrogen gas for the gas in the system, and then the
mixture was stirred under hydrogen pressure of 3.4 MPa at
80.degree. C. for 24 hours for reaction. Thus obtained reaction
solution was concentrated under reduced pressure to remove
tetrahydrofuran by vaporization. The remaining residue was
subjected to a purification process with a silica gel column
chromatography (eluting solvent: toluene/ethyl acetate=4/1) to
obtain 3-hydroxy-4-methoxycinnamaldehyde (2.26 g, 12.7 mmol, yield:
49%).
Example 14
Production of 3-(3-hydroxy-4-methoxyphenyl)propionic Acid
[0072] 3-Hydroxy-4-methoxycinnamic acid (15.0 g, 77.2 mmo) and 10%
palladium carbon in the water content of 50% (2.26 g) were added to
a mixed solvent (330 ml) of methanol and water (mixing ratio of
10:1 v/v), and the mixture was stirred under hydrogen atmosphere of
normal pressure (0.1 MPa) at 50.degree. C. for 5 hours for
reaction. The reaction solution was filtrated to remove the
catalyst, and the filtrate was concentrated under reduced pressure
to solidification to obtain 3-(3-hydroxy-4-methoxyphenyl)propionic
acid (15.1 g, 76.7 mmol, yield: 99%).
Example 15
Production of 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde
[0073] 3-Hydroxy-4-methoxycinnamaldehyde (8.66 g, 48.6 mmol) and 5%
palladium-alumina (aluminum oxide) (0.540 g) were added to methanol
(144 ml), and the mixture was stirred under hydrogen atmosphere of
normal pressure (0.1 MPa) at 35.degree. C. for 7 hours for
reaction. The reaction solution was filtrated to remove the
catalyst, and further the catalyst was washed with methanol (40
ml). The filtrate and the wash solution were combined together, and
then concentrated. Thus concentrated solution was subjected to a
purification process with a silica gel column chromatography
(eluting solvent: toluene/ethyl acetate=4/1). The thus eluted
fractions containing the object compound were concentrated under
reduced pressure to obtain crude
3-(3-hydroxy-4-methoxyphenyl)propionalde- hyde (6.86 g, 38.1 mmol,
yield: 78%) in the slightly yellow coloured solid.
[0074] Thus obtained crude
3-(3-hydroxy-4-methoxyphenyl)propionaldehyde was recrystallized
from toluene to obtain purified
3-(3-hydroxy-4-methoxyphenyl)propionaldehyde (5.83 g, 32.3 mmol,
crystallization yield: 85%) in the white crystalline form.
Example 16
Production of 3-(3-hydroxy-4-methoxyphenyl)propionaldehyde
[0075] Into a chemical reactor for hydrogen addition
(hydrogenation) under elevated pressure,
3-(3-hydroxy-4-methoxyphenyl)propionic acid (5.09 g, 25.9 mmol),
pivalic acid anhydride (14.3 g, 76.6 mmol), and tetrahydrofuran (64
ml) were added, and thereafter the mixture was bubbled with
nitrogen gas for 10 minutes. Palladium acetate (57 mg, 0.254 mmol)
and triphenylphosphine (349 mg, 1.33 mmol) were added thereto, and
thereafter the mixture was bubbled with nitrogen gas for 20 minutes
to substitute nitrogen gas completely for the gas in the system of
reaction, whereby the system was filled with nitrogen gas. Next,
hydrogen gas was added thereinto to substitute hydrogen gas for the
gas in the system, and then the mixture was stirred under hydrogen
pressure of 5.4 MPa at 80.degree. C. for 24 hours for reaction.
Thus obtained reaction solution was concentrated under reduced
pressure to remove tetrahydrofuran by vaporization. The remaining
residue was subjected to a purification process with a silica gel
column chromatography (eluting solvent: hexane/ethyl acetate=2/1).
The thus eluted fractions containing the object compound were
concentrated under reduced pressure to obtain crude
3-(3-hydroxy-4-methoxyphenyl)propionaldehyde (2.26 g, 12.5 mmol,
yield: 48%) in the slightly yellow coloured solid.
[0076] Thus obtained crude
3-(3-hydroxy-4-methoxyphenyl)propionaldehyde was recrystallized
from toluene to obtain purified
3-(3-hydroxy-4-methoxyphenyl)propionaldehyde (1.94 g, 10.8 mmol,
crystallization yield: 86%) in the white crystalline form.
Example 17
Physical Properties on
3-(3-hydroxy-4-methoxyphenyl)propionaldehyde
[0077] The physical properties on the title compound obtained in
the present invention were in the followings.
[0078] White Crystals
[0079] (Differential Thermal Analysis)
[0080] Temperature range for the determination: 50-300.degree. C.;
Heating-up speed: 10.degree. C./minute; Melting point: 71.degree.
C.
[0081] .sup.1H-NMR (CDCl.sub.3):
[0082] .delta.: 2.70-2.75 (m, 2H), 2.84-2.89 (m, 2H), 3.86 (s, 3H),
5.64 (s, 1H), 6.64-6.68 (m, 1H), 6.75-6.78 (m, 2H), 9.80 (t, J=1.5
Hz, 1H).
[0083] ESI-MS:
[0084] Calculation: C.sub.10H.sub.12O.sub.3=180.2, Analysis:
179.2(MH.sup.-).
Example 18
Production of
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl Ester
[0085] 3-(3-Hydroxy-4-methoxyphenyl)propionaldehyde (1.50 g, 8.32
mmol) and aspartame (2.57 g, 8.74 mmol) were added to a mixed
solvent (86 ml) of methanol and water (Mixing ratio of 4:1 v/v),
and 10% palladium carbon in the water content of 50% (0.77 g) was
added thereto. The mixture was stirred under hydrogen atmosphere of
normal pressure (0.1 MPa) at 35.degree. C. for 48 hours for
reaction. After completion of the reaction, the catalyst was
removed by filtration and further washed with methanol (20 ml). The
filtrate and the wash solution were combined together, and
subjected to the high performance liquid chromatography (HPLC) for
determination to generate N-[N-[3-(3-hydroxy-4-methoxyphenyl)p-
ropyl]-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester (2.69 g,
5.87 mmol, yield: 71%).
[0086] Data on the NMR spectrum and mass spectrum of
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-aspartyl]-L-phenylal-
anine 1-methyl ester are shown in the followings.
[0087] .sup.1H-NMR (DMSO-d.sub.6):
[0088] .delta.: 1.50-1.60 (m, 2H), 2.15-2.40 (m, 6H), 2.87-2.97
(dd, 1H), 3.05-3.13 (dd, 1H), 3.37-3.43 (m, 1H), 3.62 (s, 3H), 3.71
(s, 3H), 4.50-4.60 (m, 1H), 6.52 (d, 1H), 6.60 (s, 1H), 6.79 (d,
1H), 7.18-7.30 (m, 5H), 8.52 (d, 1H), 8.80 (brs, 1H).
[0089] ESI-MS:
[0090] Calculation: C.sub.24H.sub.30N.sub.2O.sub.7=458.5, Analysis:
459.2 (MH.sup.+).
[0091] Effect of Invention
[0092] According to the present invention, a N-[N-[3-(phenyl with
substituent group(s)) propyl]-L-.alpha.-aspartyl]-L-phenylalanine
1-methyl ester expected to serve as a sweetener, can be produced
industrially and efficiently.
[0093] Further, according to the present invention, a
cinnamaldehyde derivative derivative and a hydrocinnamaldehyde
derivative useful as intermediates for the production of the above
N-[N-[3-(phenyl with substituent group(s))
propyl]-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester, can be
produced industrially and efficiently.
[0094] In addition, by using a
3-(3-hydroxy-4-methoxyphenyl)propionaldehyd- e which is a novel
arylpropionaldehyde used desirably as an intermediate for the
production in the present invention, a N-[N-[3-(3-hydroxy-4-metho-
xyphenyl)propyl]-L-.alpha.-aspartyl]-L-phenylalanine 1-methyl ester
particularly useful as a sweetener having a high sweetening potency
can be produced industrially and efficiently.
[0095] The above arylpropionaldehyde is a novel compound, and it
can be produced easily and efficiently based on the process for
using a 3-hydroxy-4-methoxycinnamic acid as the starting
material,
[0096] converting the carboxyl group in the compound into a formyl
group, and then reducing the carbon-carbon double bond therein
selectively, or
[0097] reducing the carbon-carbon double bond in the compound
selectively, and then converting the carboxyl group therein into a
formyl group.
[0098] As explained above, according to the process in the present
invention, a
N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-.alpha.-asparty-
l]-L-phenylalanine 1-methyl ester which is a particularly useful
sweetener having a high sweetening potency, can be produced
industrially and advantageously.
[0099] The present application claims priority to JP 1'-287398,
which was filed on Oct. 7, 1999 and JP11-37128, which was filed on
Dec. 27, 1999, and are incorporated herein by reference.
* * * * *