Description
Title of Invention:
METHOD FOR MANUFACTURING SPILANTHOL AND INTERMEDIATE
MANUFACTURING PRODUCT THEREFOR
Technical Field
The present invention relates to a manufacturing method
enabling manufacturing of spilanthol which is useful as flavors
and fragrances in an aromatically favorable state, and a novel
intermediate used in the method.
Background Art
Spilanthol (N-isobutyl-2,6,8-decatrienamide) is known
to cause a smarting or numbing stimulus and/or a piercing
stimulative feeling, and used as spices and/or herb spices in
foods and beverages. Particularly, a (2E, 6Z, 8E) isomer is
known to be a main component of Spilanthes oleracea, and as an
effective component having strong numbing and astringent
actions. The (2E, 6Z, 8E) isomer is useful as a sense stimulus
component in a wide range of products such as foods, beverages,
fragrances and cosmetic. Meanwhile, as a method of obtaining
spilanthol there is known a method, for example, in which
spilanthol is derived from naturally-occurring products such
as by extraction from Spilanthes oleracea. In addition, Non
Patent Literatures 1, 2 and 3, and so forth disclose methods
of synthesizing spilanthol. However, such methods are not
considered as industrially-applicable production methods.
Incidentally, Patent Literature 1 discloses several
industrially-applicable production methods.
1
Citation List
Patent Literature
Patent Literature 1: WO2009/091040 Al
Non Patent Literatures
Non Patent Literature 1: J. Am. Chem. Soc, 2461-2463, (1955)
Non Patent Literature 2: Naturally Occurring Insecticides,
149-156 (1971)
Non Patent Literature 3: Tetrahedron, 731-741 (1987)
Summary of Invention
Technical Problem
An object of the present invention is to provide a method
for manufacturing aromatically favorable spilanthol in high
yield, and a novel intermediate used in the method.
Solution to Problem
The present inventors have earnestly studied to achieve
the above-described object. As a result, the inventors have
found out that by using a novel amide ester as an intermediate,
high-purity, aromatically favorable spilanthol is obtained in
high yield.
In other words, the present invention includes the
following contents.
[1] An amide ester represented by the following general
formula (1):
O
U
Ri^^O O
jp-^^^^N-^' (1)
where R'"' represents an alkyl group having 1 to 6 carbon atoms;
2
and a phenyl group may have a substituent selected from the group
consisting of alkyl groups having 1 to 4 carbon atoms, alkoxy
groups having 1 to 4 carbon atoms and a halogen atom, R^
represents a hydrocarbon group having 1 to 8 carbon atoms, and
each wavy line represents a cis configuration, a trans
configuration, or a mixture of the two configurations.
[2] The amide ester according to [1] , in which R-^ is an alkyl
group having 1 to 4 carbon atoms.
[3] The amide ester according to [2] , in which R''' is a methyl
group.
[4] The amide ester according to any one of [1] to [3], in
which R^ is an isobutyl group or a s-butyl group.
[5] A method for producing 2, 6, 8-decatrienamide, including
reacting the amide ester according to any one of [1] to
[4] with a basic compound.
[6] A food, beverage, fragrance, cosmetic, or pharmaceutical,
including 2,6,8-decatrienamide synthesized by the method
according to [5] and having a chemical purity of 80% or more
and a content of a 2E,6Z,8E-isomer of 65% or more.
Advantageous Effects of Invention
The present invention provides a novel intermediate
useful in manufacturing N-isobutyl-2,6,8-decatrienamide
(spilanthol) useful as flavors and fragrances. The use of the
intermediate enables manufacturing of high-purity,
aromatically favorable spilanthol in high yield.
Description of Embodiments
Hereinafter, the present invention will be described in
more details.
A compound of the present invention represented by a
3
general formula (1) is an amide ester which can be obtained by
the following method.
acyjating o
(h) " „) "
Examples of an alkyl group having 1 to 6 carbon atoms
represented by R'"' include a methyl group, an ethyl group, a
n-propyl group, an isopropyl group, a n-butyl group, an isobutyl
group, a s-butyl group, a t-butyl group, a n-pentyl group, a
n-hexyl group, and the like.
Moreover, R^ represents a phenyl group which may be
substituted with an alkyl group having 1 to 4 carbon atoms, an
alkoxy group having 1 to 4 carbon atoms, or a halogen atom.
Examples of the alkyl group include a methyl group, an ethyl
group, a n-propyl group, an isopropyl group, a n-butyl group,
an isobutyl group, a s-butyl group, and a t-butyl group.
Examples of the alkoxy group having 1 to 4 carbon atoms include
a methoxy group, an ethoxy group, a n-propoxy group, an
isopropoxy group, a n-butoxy group, an isobutoxy group, a
s-butoxy group, and a t-butoxy group. Examples of the halogen
atom include a fluorine atom, a chlorine atom, and a bromine
atom. R''' is preferably an alkyl group having 1 to 4 carbon atoms.
Above all, a methyl group is more preferable.
Examples of a hydrocarbon group having 1 to 8 carbon atoms
represented by R^ include: linear or branched alkyl groups such
as a methyl group, an ethyl group, a n-propyl group, an isopropyl
group, a n-butyl group, an isobutyl group, a s-butyl group, a
t-butyl group, a pentyl group, a 2-methylbutyl group, and a
hexyl group; a phenyl group and alkyl-substituted phenyl groups
4
such as a tolyl group and a xylyl group; and aralkyl groups such
as a benzyl group and a phenethyl group. R^ is preferably an
isobutyl group or a s-butyl group.
Examples of an acylating agent used herein include acid
anhydrides (R^COOCORM, acid chlorides (R-^COCl), and the like.
Examples of R'"' include those described above. Specific
examples of the acid anhydride include acetic anhydride,
propanoic anhydride, butyric anhydride, and the like.
Examples of the acid chloride include acetyl chloride,
propionyl chloride, pivaloyl chloride, benzoyl chloride, and
the like.
Meanwhile, when the compound (h) is subjected to an
acylation reaction, it is preferable that a basic compound
coexist. Examples of the basic compound used include
triethylamine, tributylamine, pyridine, sodium carbonate,
sodium hydroxide, potassium hydroxide, and the like. Among
these, triethylamine is preferable.
The acylation reaction for the compound (h) can be
performed at a temperature of approximately -5°C to 100°C,
preferably 10°C to 30°C. The reaction period of around
approximately 1 hour to 6 hours is sufficient. Examples of a
solvent which can be used in the reaction include toluene,
hexane, heptane, diethyl ether, and tetrahydrofuran. Among
these, toluene is preferable. The amount of the acylating agent
used is 1 time to 2 times, preferably 1.05 times to 1.2 times,
as large as the compound (h) in terms of mole.
After the reaction is completed, the product can be
purified by extraction, distillation, various
chromatographies, or the like.
Note that the compound (h) which is the raw material of
5
the amide ester of the compound of the present invention can
be produced, for example, by the following method.
" ^ T " aPh3P-^^°'* i^^^
(a) (b) '^ base ^^^ 8
>L/CI 0 0
IL OH . i t ^ o ^ ^ ^^=WO
'^N^>r^
(g) "
*9^ (h)
Methyl 3-hydroxy-6,8-decadienoate (g) (86.1 g, 0.43 mol)
and isobutylamine (95. 3 g, 1.3 mol) were put into a 500-ml flask,
followed by stirring at 90°C for 24 hours. After isobutylamine
was recovered under a reduced pressure, heptane (700 ml) was
added thereto, followed by cooling to 0°C. A white solid thus
precipitated was filtered and dried under a reduced pressure.
Thus, N-isobutyl-3-hydroxy-6,8-decadienamide (h) was obtained
(85.2 g, 0.35 mol, yield 82%).
(Example 1) Production of
N-isobutyl-3-acetoxy-6,8-decatrienamide
13
o
•9 OH 0 AC2O ^
(h) " '
In a stream of nitrogen, H-'iSofeiu^l"
3-hydr'oxy-6,8-ciecadien/simi OH O NEt3 MeO^S^Q ^
(h) " ,i, f<
NaOMe .^^ O
In a stream of nitrogen,
N-isobutyl-3-hydroxy-6, 8-decadienamide (h) (85.2 g, 0.35mol),
ethyl acetate (680 ml), and triethylamine (72.1 g, 0.70 mol)
were put into a 1-L flask equipped with a stirrer, a thermometer,
and a dropping funnel, followed by cooling to 5°C. Then,
methanesulfonyl chloride (44.7 g, 0.392 mol) was added dropwise
thereto for 1 hour. After completion of the dropwise addition,
water (170 ml) was added thereto, followed by separation of
liquid. Further washing with water (170 mL) was carried out
three times, and the solvent was removed under a reduced
pressure. Thus, N-isobutyl-3-sulfonyloxy-6,8-decadienamide
(i) was obtained (108.9 g, yield 98%).
N-isobutyl-3-sulfonyloxy-6,8-decadienamide (i)
GC/MS (m/e); 317 (M+, 3%), 301 (18), 288 (2), 260 (3), 243 (1),
222 (48), 206 (12), 192 (7), 178 (5), 155 (4), 141 (18), 128
(40), 115 (50), 107 (53), 93 (63), 79 (80), 57 (100), 41 (68)
16
For 1 hour, a 28% sodium methoxide-methanol solution
(75.5 g, 0.39 mol) was added dropwise to a solution prepared
by dissolving N-isobutyl-3-sulfonyloxy-6,8-decadienamide (i)
(108.9 g) in THF (425 ml) and cooling to 0°C. After completion
of the dropwise addition, stirring was further carried out for
2 hours. Water (170 g) was added thereto, followed by
separation of liquid. Washing with water (170 mL) was carried
out twice, and the solvent was removed under a reduced pressure
to obtain a crude product. This crude product was distilled
under a reduced pressure (140°C/0.3 torr), and
N-isobutyl-2,6,8-decatrienamide (spilanthol) (58.8 g) was
obtained with a 76% yield (from
N-isobutyl-3-hydroxy-6,8-decadienamide (h)).
In this connection, the purity of
N-isobutyl-2,6,8-decatrienamide was 97.2%, and the isomer
ratios of the alkene moiety were: 78.2% for (2E,6Z,8E), 18.0%
for (2E,6E,8E), and 3.8% for (2E,6Z,8Z).
(Stability evaluation)
The crude product of N-isobutyl-2,6,8-decatrienamide
obtained in Example 2 before the distillation and the crude
product obtained in Comparative Example 1 were compared as
follows in terms of thermal stability at 180°C assuming
distillation at high temperature.
In a stream of nitrogen, 1 g of each of the crude products
was put into a flask together with 0.1 g of hexadecane as an
internal standard substance, followed by stirring at 180°C for
6 hours. By gas chromatography, the area ratio of
N-isobutyl-2,6,8-decatrienamide was compared with the area
ratio of the internal standard substance to measure the
remaining percentage of N-isobutyl-2,6,8-decatrienamide.
17
The remaining percentage after 3 hours was 98% in Example
2, and 89% in Comparative Example 1. This confirmed that
N-isobutyl-2,6,8-decatrienamide produced by the production
method of the present invention apparently had improved thermal
stability.
(Sensory evaluation)
The sensory evaluation was performed using aqueous
solutions respectively containing 10 ppm of
N-isobutyl-2,6,8-decatrienamide obtained in Example 2 and
Comparative Example 1. Table 1 shows the result.
[Table 1]
Odor Sensory evaluation
(numbing and
astringent actions)
Example 2 little odor clear and strong
Comparative unpleasant fishy strong, but
Example 1 odor and/or slightly foreign
amine-lilce odor were taste
smelled
It was confirmed that, in comparison with
N-isobutyl-2,6,8-decatrienamide obtained in Comparative
Example 1, N-isobutyl-2,6,8-decatrienamide obtained in
Example 2 hardly had an unusual odor and exhibited excellent
numbing and astringent actions.
Industrial Applicability
The present invention provides a novel intermediate
useful in manufacturing N-isobutyl-2,6,8-decatrienamide
(spilanthol) useful as flavors and fragrances. The use of the
intermediate enables manufacturing of high-purity spilanthol
18
in high yield, the spilanthol being also favorable in terms of
thermal stability, odor, and effectiveness.
Claims
Claim 1
An amide ester represented by the following general
formula (1):
O
y
R1"^0 O
wherein R'^ represents an alkyl group having 1 to 6 carbon atoms;
and a phenyl group which may have a substituent selected from
the group consisting of alkyl groups having 1 to 4 carbon atoms,
alkoxy groups having 1 to 4 carbon atoms and a halogen atom,
R^ represents a hydrocarbon group having 1 to 8 carbon atoms,
and each wavy line represents a cis configuration, a trans
configuration, or a mixture of the two configurations.
Claim 2
The amide ester according to claim 1, wherein R""" is an
alkyl group having 1 to 4 carbon atoms.
Claim 3
The amide ester according to claim 2, wherein R'^ is a
methyl group.
Claim 4
The amide ester according to any one of claims 1 to 3,
wherein R^ is an isobutyl group or a s-butyl group.
Claim 5
20
A method for producing 2,6,8-decatrienaraide, comprising
reacting the amide ester according to any one of claims
1 to 4 with a basic compound.
Claim 6
A food, beverage, fragrance, cosmetic, or pharmaceutical
comprising 2,6,8-decatrienamide synthesized by the method
according to claim 5 and having a chemical purity of 80% or more
and a content of a 2E,6Z,8E-isomer of 65% or more.