DESCRIPTION
METHOD OF MANUFACTURING PHOSPHONOCROTONIC ACID DERIVATIVE
TECHNICAL FIELD
[ 0 0 0 1 ]
The present invention relates to a method of
manufacturing a phosphonocrotonic acid derivative,
particularly, triethyl-3-methyl-4-phosphonocrotonate, which
is useful as raw materials of a medicine, an agricultural
chemical and an industrial product, and a method of
manufacturing a useful compound using the same.
BACKGROUND ART
[0002]
Aphosphonocrotonic acid derivative is usedin synthesis
of various compounds from its high functionality, and
particularly, triethyl-3-methyl-4-phosphonocrotonate [ethyl
(2E,Z)-4-(diethoxyphosphono)-3-methylbuta-2-enoateI
hereinafter, also referred to as "TEMPC"] is useful as a raw
material of a medicine, an agricultural chemical and an
industrial product, and, for example, is useful in synthesis
of a compoundhaving a 3-methylpenta-2,4-dienoate residue (the
parts surrounded by the solid lines) represented by the
following formulae.
[0003]
COOH
COOH
It is known that among them,
(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexene
-1-y1)nona-2,4,6,8-tetraenoic acid (generic name: tretinoin)
is useful as a therapeutic agent for acute promyelocytic
leukemia; and ethyl
(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimet
hylnona-2,4,6,8-tetraenoate (generic name: etretinate) is
useful as atherapeuticagentforafamilyofpsoriasis, a family
of ichthyosis, and the like; and
(2E, 4E, 6E, 10E) -3,7,11,15-tetramethylhexadeca-2, 4, 6, 10, 14-pe
ntaenoic acid (generic name: peretinoin) is useful as an
inhibitor for liver cell cancer recurrence. TEMPC can be an
important raw material for manufacture of these compounds
(Patent Document 1) .
[0005]
It is known that TEMPC can be manufactured by Arbuzov
reaction in which ethyl 4-bromo-3-methylcrotonate is reacted
with triethyl phosphite as illustrated in Scheme 1 described
below.
[0006]
[scheme 11
E~ON~AOE~
OEt
EK3
[0007]
With respect to the reaction, specifically, for example,
a method in which a mixture of a cis form and a trans form of
ethyl 4-bromo-3-methylcrotonate is reacted with triethyl
p h o s p h i t e a t 9 0 ° C f o r 3 h o u r s , andthendistillationis performed
to obtain TEMPC as a mixture of a cis/trans form = 40/60
(Non-Patent Document 1); a method in which the trans form of
ethyl 4-bromo-3-methylcrotonate is reacted with triethyl
phosphite at 120°C for 30 minutes, and then distillation is
performed to remove bromoethane, and the reaction mixture is
f u r t h e r r e a c t e d f o r 2 h o u r s , andthendistillationisperformed,
whereby a trans form of TEMPC (Non-Patent Document 2) can be
obtained; or a method in which a trans form of ethyl
4-bromo-3-methylcrotonate is reacted with triethyl phosphite
at165to175OC for5minutes, andthendistillation is performed
to obtain a trans form of TEMPC (Non-Patent Document 3).
CITATION LIST
PATENT DOCUMENT
[0008]
Patent Document 1: Japanese Patent Application Laid-Open
(JP-A) NO. 2004-331654
NON-PATENT DOCUMENT
[0009]
Non-Patent Document 1: Journal of Labelled Compounds and
Radiopharmaceuticals, 22, 807-17; 1985
Non-Patent Document 2: Tetrahedron, 42, 2635-42; 1986
Non-PatentDocument3: J. Chem. Soc. PerkinTransl, 1995,
785-99
Non-Patent Document 4: J. Econ. Entomol., 44, 405-418;
1951
SUMMARY OF INVENTION
TECHNICAL PROBLEM
[ OOlO]
The present inventors found out for the first time that
when TEMPC is manufactured with the methods described in
Non-Patent Documents 1 to 3, tetraethyl pyrophosphate
(hereinafter, also referred to as "TEPP") represented by the
following formula is by-produced.
[OOll]
0 0
I I II
/p\ /pEtO 1 0 I OEt
EtO OEt
[0012]
A pyrophosphoric acid ester such as TEPP has strong
neurotoxicity such as choline esterase inhibitory action and
the like, and also has insecticidalaction (Non-Patent Document
4), and thus TEPP is conventionally used as an organic
phosphorous agricultural chemical. Consequently, removal or
lowering of TEPP not only improves the quality of TEMPC and a
compound synthesized using this as a raw material, but also is
important in an aspect of securing the safety of a manufacture
worker, and the like. However, Non-Patent Documents 1 to 3 did
not describe or suggest the presence of TEPP, and the present
inventors alsodidnot expectproductionof TEPP. Furthermore,
TEPP was not removable or lowerable with the method described
in Patent Document 1.
[0013]
Consequently, an object of the present invention is to
provide a method of manufacturing a high quality
phosphonocrotonic acid derivative. More specifically, an
object of the present invention is to provide a method of
manufacturing aphosphonocrotonic acidderivative with lowered
content of pyrophosphoric acid ester, preferably to provide a
method of manufacturing TEMPC with lowered content of TEPP.
SOLUTION TO PROBLEM
[0014]
The present inventors performedearnest investigation to
resolve the above-mentionedsubject, as aresult, foundout that
a phosphonocrotonic acid derivative with lowered content of
pyrophosphoric acid ester, which is an impurity, is obtained
by treatment with use of an acid or base in manufacturing of
the phosphonocrotonic acidderivative froma halocrotonic acid
ester and a phosphite ester. The present inventors performed
the investigation further specifically, and found out that it
is possible to manufacture a compound having a
3-methylpenta-2,4-dienoic acid residue that is substantially
free of pyrophosphoric acid ester by reacting the
phosphonocrotonic acid derivative manufacturedby the present
method as a raw material with a carbonyl compound, and thus
completed the present invention.
[0015]
That is to say, the present invention provides those
described below.
[I] A method of manufacturing a compound represented by
Formula (3) described below by reacting a compound represented
by Formula (1) described below with a compound represented by
Formula (2) described below, the method comprising a treatment
process using an acid or base.
[0016]
[0017]
(in the formula, R1 represents a C1-6 linear or branched
alkyl group that may be substituted by a C6-10 aryl group; a C2-6
linear or branched alkenyl group that may be substituted by a
Cs-lo aryl group; a C2-6 linear or branched alkynyl group that
may be substituted by a C6-10 aryl group; or a C6-10 aryl group,
and each R1 may be the same or different).
[0019]
(in the formula, X represents a halogen atom, R2
represents a hydrogen atom, or a C1-6 linear or branched alkyl
group that may be substituted by a C6-lo aryl group, and R3
represents a C1-6 linear or branched alkyl group, a C6-10 aryl
group, or a halogen atom.)
[0020]
[0021]
(in the formula, R1, R2 and R3 are the same as described
above, and each Rl may be the same or different.)
[0022]
[2] A method of manufacturing a compound having a
3-methylpenta-2,4-dienoic acid residue, the method comprising
reacting a compound represented by Formula (3) obtained by the
above-mentionedmanufacturingmethodwith a carbonylcompound.
[3] A method of manufacturing a compound having a
3-methylpenta-2,4-dienoic acid residue by performing a
treatment using an acid or base at the time of the reaction
between a compound represented by Formula (1) with a compound
represented by Formula (2), or after the reaction, whereby a
compound represented by Formula (3) is obtained, and then
reacting the compound with a carbonyl compound.
[dl
(2E, 4E, 6E, 10E) -3,7, 11, 15-tetramethylhexadeca-2, 4, 6, 10, 14-pe
ntaenoic acid that is substantially free of tetraethyl
pyrophosphate.
[5] A pharmaceutical composition comprising
(2E, 4E, 6E, 10E) -3,7, 11, 15-tetramethylhexadeca-2, 4, 6, 10, 14-pe
ntaenoic acid described in the above-mentioned [4].
EFFECT OF THE INVENTION
[0023]
According to the method of the present invention, it is
possible tomanufacture a phosphonocrotonic acidderivative in
higher purity, and for example, it is possible to manufacture
TEMPC with lowered content of TEPP. In addition, according to
the method of the present invention, it is possible to
manufacture a medicine, an agricultural chemical and an
industrial product with high quality by using a
phosphonocrotonic acid derivative with lowered content of
pyrophosphoric acid ester as a raw material, and specifically
for example, it is possible to manufacture
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2, 6, 6-trimethyl-1-cyclohexene
-1-y1)nona-2,4,6,8-tetraenoic acid, ethyl
(2E,4E,6E18E)-9-(4-methoxy-2,3,6-trimethy1pheny1)-3,7-dimet
hylnona-2,4,6,8-tetraenoate, or
(2E, 4E, 6E, 10E) -3,7,11,15-tetramethylhexadeca-2,4,6,10,14-pe
ntaenoic acid that is substantially free ofpyrophosphoric acid
ester such as TEPP.
DESCRIPTION OF EMBODIMENTS
[0024]
Definitions of the terms as used herein are as described
below.
[0025]
The "halogen atom" as used herein means a fluorine atom,
achlorineatom, abromineatom, oraniodineatom. The "halogen
atom" ispreferablya fluorine atom, achlorineatomorabromine
atom, and more preferably a bromine atom.
[0026]
The "linear or branched alkyl group" as used herein is
a monovalent group in which one hydrogen atom is removed from
an aliphatic saturatedhydrocarbon, andencompasses linear and
branched groups. Examples of the C1-6 linear or branched alkyl
group include specifically, for example, a methyl group, an
ethyl group, an n-propyl group, an isopropyl group, an n-butyl
group, an isobutyl group, a s-butyl group, a t-butyl group, a
n-pentyl group, an isopentyl group, a 2-methylbutyl group, a
neopentyl group, a 1-ethylpropyl group, an n-hexyl group, an
isohexylgroup, a 4-methylpentylgroup, a 3-methylpentylgroup,
a 2-methylpentyl group, a 1-methylpentyl group, a
3,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a
1,l-dimethylbutyl group, a 1,2-dimethylbutyl group, a
1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a
1-ethylbutyl group, a 2-ethylbutyl group and the like. Among
these, the C1-6 linear or branched alkyl group is preferably a
methyl group, an ethyl group, an isopropyl group or a neopentyl
group, andmorepreferablyanethylgroupor anisopropylgroup.
[0027]
The "linear or branched alkenyl group" as used herein
means alinear orbranchedalkenylgrouphaving a carbon-carbon
double bond at any one or more sites on the alkyl chain.
Examples of the C2-6 linear or branched alkenyl group include
specifically, for example, an ethenyl group (a vinyl group),
a propa-1-en-1-yl group, a propa-2-en-1-yl group, a
propa-1-en-2-yl group, a buta-1-en-1-yl group, a
buta-2-en-1-ylgroup, abuta-3-en-1-ylgroup, abuta-1-en-2-yl
group, a buta-3-en-2-yl group, a penta-1-en-1-yl group, a
penta-2-en-1-yl group, a penta-3-en-1-yl group, a
penta-4-en-1-yl group, a penta-1-en-2-yl group, a
penta-4-en-2-yl group, a 3-methylbuta-1-en-1-yl group, a
3-methylbuta-2-en-1-ylgroup, a 3-methylbuta-3-en-1-ylgroup,
a hex-1-en-1-yl group, a hex-5-en-1-yl group, a
4-methylpenta-3-en-1-yl group and the like, and preferably an
ethenylgroup, apropa-2-en-1-ylgroup, abuta-2-en-1-ylgroup,
and a 3-methylbuta-3-en-1-yl group.
[0028]
The "linear or branched alkynyl group" as used herein
means alinear orbranchedalkynylgrouphaving a carbon-carbon
triple bond at any one or more sites on the alkyl chain.
Examples of the C2+ linear or branched alkynyl group include
specifically, for example, anethynylgroup, apropa-1-yne-1-yl
group, a propa-2-yne-1-yl group, a buta-1-yne-1-yl group, a
buta-3-yne-1-yl group, a 1-methylpropa-2-yne-1-yl group, a
penta-1-yne-1-yl group, a penta-4-yne-1-yl group, a
hex-1-yne-1-yl group, a hex-5-yne-1-yl group and the like, and
preferably a propa-2-yne-1-yl group.
[0029]
The "aryl group" as used herein means an aromatic
hydrocarbon group. Examples of the C6-10 aryl group include
specifically, for example, a phenyl group, a naphthyl group or
anazulenylgroup, andpreferablya phenylgroup. With respect
to other groups that are not defined herein, the other groups
follow ordinary definitions.
[0030]
The "substantially free ofpyrophosphoric acidester" as
usedhereinrefersthattheresidualratioofthepyrophosphoric
acid ester in the analysis conditions described in Examples
described later is less than 5%, and preferably less than 4%.
This is similar with respect to "TEPP".
[0031]
Hereinafter, the manufacturing method of the present
invention will be described.
The manufacturingmethod of the present invention maybe
illustrated in Scheme 2 described below.
[0032]
[scheme 2)
[0033]
(In Scheme 2, R, and Rb each independently represent a
hydrogen atom or an organic group, R1, R2, R3 and X are the same
as described above, and multipleRls may be the same or
different, with the proviso that R, and Rb are not a hydrogen
atom at the same time.)
[0034]
Examples of the organic group in R, and Rb may include
hydrocarbon groups. Examples ofthe hydrocarbon group include
analiphatichydrocarbongroup, analicyclichydrocarbongroup,
an aryl group and the like, which may have a substituent.
Examples of the substituent include a halogen atom, a hydroxyl
group, a C1-6 alkoxy group, a phenyl group, an alicyclic
hydrocarbon group and the like, and the phenyl group and the
alicyclichydrocarbongroupmaybesubstitutedbyahalogenatom,
a hydroxyl group, a C1-6 alkyl group or a C1-6 alkoxy group.
Meanwhile, the position and the number of the substituent are
Step 2 A,
arbitrary, and in the case where the hydrocarbon group has 2
or more substituents, the substituents may be the same or
different.
Examples of the C1-6 alkoxy group include for example, a
methoxy group, an ethoxy group, a propoxy group, an isopropoxy
group, abutoxygroup andthe like. Among these, the C1-6 alkoxy
group is preferably a methoxy group or an ethoxy group. In
addition, the C1-6 alkyl group may be linear or branched chain,
and specific examples thereof may include those described
above.
[0035]
Examples of the aliphatic hydrocarbon group include an
alkyl group, an alkenyl group and an alkynyl group. The carbon
number of these aliphatic hydrocarbon groups is preferably 1
to 32, more preferably 1 to 30, and further preferably 1 to 20.
In addition, these aliphatic hydrocarbon groups may be linear
or branched.
The alkyl group is preferably a C1-30,m ore preferably a
C1-25, and even more preferably a C1-20 alkyl group, and
specifically examples thereof may include a decyl group, a
undecyl group, a 1-methyldecyl group, a pentadecyl group, an
octadecyl group and the like in addition to the specific
examples as described above.
In addition, the alkenyl group is preferably a C2-32mro re
preferably a C5-30 alkenyl group, and specifically, examples
thereof may include an octa-2-en-1-yl group, a deca-2-en-1-yl
group, a 2-methylbuta-1,3-dienyl group, a
6-methyleneocta-2,7-dien-2-yl group, a
6-methylocta-2,5,7-trien-2-yl group,
6,10,15, 19,23-pentamethyltetracosa-2, 6, 10, 14, 18,22-hexaen-2
-yl, a 2,6,10-trimethylundeca-l,5,9-trienylgroup andthe like
in addition to the specific examples as described above. The
alkenyl group may be substituted with an aryl group, or an
alicyclic hydrocarbon group described later, and for example,
examples of the aryl-substituted alkenyl group may include a
4-(4-methoxy-2,3,6-trimethylphenyl)-2-methylbuta-ll3-dienyl
group and the like, and examples of the alicyclic
hydrocarbon-substituted alkenyl group may include a
4-(2,6,6-trimethyl-1-cyclohexenyl)-2-methylbuta-ll3-dienyl
group and the like, respectively.
Furthermore, the alkynyl group is preferably a C2-30mro re
preferably a C2-25arn d even more preferably a C2-20a lkynyl group,
and specifically, examples of the alkynyl group may include an
octa-2-yne-1-yl group, a deca-2-yne-1-yl group and the like in
addition to the specific examples as described above.
[0036]
Examples of the alicyclic hydrocarbon group may include
a cycloalkyl group, a cycloalkenyl group, a condensed
polycyclic hydrocarbon group, a bridged cyclic hydrocarbon
group, a cyclic terpene hydrocarbon group and the like. The
carbon number of these alicyclic hydrocarbon groups is
preferably 3 to 30, more preferably 3 to 25, and even more
preferably 3 to 20. Specific examples of the cycloalkyl group
include a cyclopropyl group, a cyclobutyl group, a cyclohexyl
group, a t - b u t y l c y c l o h e x y l group, a cyclooctyl group and the
l i k e . I n a d d i t i o n , s p e c i f i c examples o f t h e cycloalkenylgroup
i n c l u d e a l - c y c l o h e x e n y l g r o u p a n d t h e l i k e . Specificexamples
of the condensed p o l y c y c l i c hydrocarbon group include a
t r i c y c l o d e c a n y l group, an adamantyl group and t h e l i k e .
Examples of t h e bridged c y c l i c hydrocarbon group include a
pentacyclopentadecanyl group, an isobornyl group,
t r i c y c l o p e n t e n y l group and t h e l i k e . Examples of the c y c l i c
terpene hydrocarbon group may include a monovalent group and
the l i k e i n which one hydrogen atom is removed from m-menthane,
m-menthene, thujane, carane, pinane, bornane, norcarane,
norpinane, norbornane and the l i k e .
The a r y l group is p r e f e r a b l y a C6-20r and even more
p r e f e r a b l y a C6-10 a r y l group. S p e c i f i c examples of t h e a r y l
group may include those described above.
[ 0 0 3 7 ]
Among them, R, is p r e f e r a b l y a s u b s t i t u t e d or
unsubstitutedaliphatichydrocarbon group, andmore p r e f e r a b l y
a s u b s t i t u t e d or u n s u b s t i t u t e d alkenyl group. In a d d i t i o n , Rb
is preferablyahydrogenatomor a s u b s t i t u t e d o r u n s u b s t i t u t e d
a l i p h a t i c hydrocarbon group, and more p r e f e r a b l y a hydrogen
atom.
[ 0 0 3 8 ]
H e r e i n a f t e r , each s t e p w i l l be described.
InScheme 2, the s t e p l i s a p r o c e s s of r e a c t i n g a compound
represented by Formula (1) ( h e r e i n a f t e r , a l s o r e f e r r e d t o as
"compound (1)") with a compound represented by Formula (2)
(hereinafter, also referred to as "compound (2)"), to obtain
acompoundrepresentedby Formula (3) (aphosphonocrotonicacid
derivative) by SN2 reaction of the compound (1) to the compound
(2).
[0039]
This reaction can be performed according to the
conditions of conventionallywell-knownArbuzov reaction. For
example, theconditionsdescribedinRuss. Phys. Chem. Soc.1906,
38, 687, or Russ. Phys. Chem. Soc. 1910, 42, 395 and the like
may be applied, but the conditions are not limited thereto.
[0040]
The compound (1) used in the step 1 can be obtained, for
example, by reaction between phosphorus trichloride and an
alcohol. In addition, the compound (2) can be obtained, for
example, by halogenating a crotonic acid ester compound with
a halogenating agent such as N-halosuccinic imide. The
compound (1) and the compound (2) may use a commercialized
product. The alcohol is preferably a alcohol, and examples
of the alcohol may include, for example, methanol, ethanol,
propanol, isopropanol and the like. Among these, the alcohol
is preferably methanol or ethanol.
[0041]
The present invention is characterized by including a
treatment process using an acid or base in manufacture of the
phosphonocrotonic acidderivative by reactingthe compound (1)
with the compound (2) .
The treatment process is specifically preferably either
one or both of (A) and (B) described below.
(A) Process ofreactingthe compound (1) with the compound
(2) in the presence of an acid or base.
(B) Processofreactingthe compound (1) with the compound
(2), and then performing a treatment using an acid or base.
By this, it is possible to lower the content of a compound
represented by Formula (4) (pyrophosphoric acid ester) wherein
TEPP is typical of the pyrophosphoric acid ester.
[0042]
A method for the treatment process is not particularly
limitedifatleastcontacttreatmentisperformedusinganacid
or base at the time of the reaction of the compound (1) with
the compound (2), or after the reaction. For example, in the
case of the process (A), the acid or base may be added to the
reaction system, and in the case of the process (B), the acid
or base may be added and contacted, for example, to a reaction
solution after the reaction, to a solution of the organic layer
separated after the reaction, or to a solution in which the
phosphonocrotonic acid derivative isolated with distillation
and the like is dissolved again in an organic solvent, and the
like. The contact treatment may be performed once, twice or
more times. Meanwhile, examples of the organic solvent may
include, for example, hydrocarbons (for example, heptane,
hexane, toluene, benzene, xylene), and halogenation
hydrocarbons (for example, dichloromethane, chloroform,
chlorobenzene) , which may be used in one kind or in combination
of two or more kinds.
[0043]
As the acid used i n the treatment process of the present
invention, any one of organic acid and inorganic acid may be
used, which may be used i n one kind or i n combination of two
or more kinds. Examples of the inorganic acid include, for
example, hydrochloricacid (pKa=-7), s u l f u r i c a c i d (pKa=-3),
n i t r i c acid (pKa = - 1 . 4 ) , phosphoric acid (pKa = 2 . 1 2 ) , nitrous
acid (3.15) andthe l i k e . Examples o f t h e organic acid include,
for example, t r i f luoroacetic acid (pKa = 0.3) , oxalic acid (pKa
= 1 . 2 7 ) , formicacid (pKa=3.54), a c e t y l a c e t i c a c i d (pKa=3.57),
l a c t i c acid (pKa = 3.64) , succinic acid (pKa = 3.99) , benzoic
acid (pKa = 4 . 0 0 ) , a d i p i c a c i d (pKa = 4 . 2 6 ) , a c e t i c acid (pKa
= 4.76), propionic acid (pKa = 4.87) and the l i k e .
The acid used in the treatment process is preferably an
acid having less than 5 of pKa, more preferably an acid having
-5 or more and less than 5 of pKa, and further preferably an
acid having -5 or more and l e s s than 3 of pKa. Among them, the
a c i d u s e d i n t h e treatment process is preferably s u l f u r i c acid,
n i t r i c acid, phosphoric acid, a c e t i c acid o r t r i f l u o r o a c e t i c
acid, oxalic acid, and further preferably s u l f u r i c acid.
Herein, the "pKa" i n t h e s p e c i f i c a t i o n refers to t h e a c i d
dissociation constant a t 25OC, which is t h e dissociation
constant of the f i r s t acid i n the case of a multivalent acid.
Meanwhile, the pKa value of an acid may r e f e r t o the numerical
value described in a document and the l i k e .
As the acid in the present invention, a s o l i d acid may
be used, andexamplesthereof include, for example, anacidtype
ion exchange r e s i n , an a c t i v a t e d clay, a s i l i c a - a l u m i n a and the
l i k e . As t h e a c i d type ion exchange r e s i n , a commercialized
product suchas Dowex (manufacturedbyThe DowChemical Company),
Nafion (manufactured by Du Pont) and DIAION (manufactured by
Mitsubishi Chemical Corporation) may be used.
In a d d i t i o n , t h e a c i d may be used as a s o l u t i o n including
an aqueous s o l u t i o n . The concentration of the s o l u t i o n i n the
case where t h e a c i d is used as a s o l u t i o n is such t h a t t h e upper
l i m i t is p r e f e r a b l y l e s s than 100 mass%, more p r e f e r a b l y l e s s
than 90 mass%, and f u r t h e r p r e f e r a b l y l e s s than 60 mass%,
whereas the lower l i m i t is p r e f e r a b l y 1 mass%, more p r e f e r a b l y
3 mass%, and is f u r t h e r p r e f e r a b l y 5 mass%. The concentration
range of t h e a c i d s o l u t i o n i s p r e f e r a b l y 1 mass% or more and
l e s s than 100 mass%, more p r e f e r a b l y 3 mass% or more and l e s s
than 90 mass%, and f u r t h e r p r e f e r a b l y 5 mass% or more and l e s s
than 60 mass%. The pH (25OC) of t h e aqueous s o l u t i o n of the
acid used i n the t r e a t m e n t p r o c e s s of t h e p r e s e n t invention is
not p a r t i c u l a r l y l i m i t e d , b u t is p r e f e r a b l y pH 1 t o 5, and more
p r e f e r a b l y pH 1 t o 3.
[0044]
As the base used i n the t r e a t m e n t p r o c e s s of the p r e s e n t
invention, anyone of a n i n o r g a n i c b a s e , a n o r g a n i c b a s e , a m e t a l
alkoxide and an a l k y l metal may be used, which may be used i n
one kind or i n combination of two or more kinds.
The i n o r g a n i c base is not p a r t i c u l a r l y l i m i t e d , but f o r
example, ammonia (pKb = 4.64) , and an a l k a l i metal hydroxide,
an a l k a l i m e t a l h y d r i d e , a n a l k a l i m e t a l c a r b o n a t e , an a l k a l i
metal hydrogen carbonate, an alkali metal hydrogen phosphate,
or an alkali metal may be used. The alkali metal hydroxide is
preferably, for example, lithium hydroxide, sodiumhydroxide,
potassium hydroxide and the like. The alkali metal hydride is
preferably, for example, lithium hydride, sodium hydride (pKb
= 0.2), potassium hydride and the like. The alkali metal
carbonateispreferably, for example, lithiumcarbonate, sodium
carbonate (pKb = 3.67) , potassium carbonate, cesium carbonate
andthe like. The alkalimetalhydrogencarbonateispreferably,
for example, sodium hydrogen carbonate (pKb = 3-67), potassium
hydrogen carbonate, cesium hydrogen carbonate and the like.
The alkalimetal hydrogenphosphate is preferably, for example,
disodiumhydrogen phosphate, disodiumhydrogen phosphate (pKb
= 1.60), dipotassium hydrogen phosphate, potassium dihydrogen
phosphate and the like. The alkali metal is preferably, for
example, metal lithium, metal sodium, metal potassium and the
like.
[0045]
Examples ofthe organicbase include is not particularly
limited, but for example, a nitrogen-containing heterocyclic
compound or an organic amine may be used. The
nitrogen-containing heterocyclic compound is preferably, for
example, pyridine (pKb = 8-33), 4-dimethylaminopyridine (DMAP)
(pKb = 4-80), lutidine (pKb = 7-04), collidine and the like,
and the organic amine is preferably, for example,
trimethylamine (pKb = 4-24), dimethylamine (pKb = 2.98),
triethylamine (pKb = 3.32), diethylamine (pKb = 2.98),
N,N-diisopropylethylamine, N,N-diisopropylpentylamine,
morpholine (pKb = 5.64) , piperidine (pKb = 2.76) , pyrrolidine
(pKb = 2.6) , 1,8-diazabicyclo [5.4.0] undeca-7-ene (DBU) (pKb =
2.00) , 1,5-diazabicyclo [4.3.0] nona-5-ene (DBN) ,
1,4-diazabicyclo[2.2.2]octane (DABCO) and the like.
[0046]
The metal alkoxide is not particularly limited, but is
preferably, for example, sodiummethoxide, potassiummethoxide,
sodiumethoxide, potassiumethoxide, t-butoxy sodium, t-butoxy
potassium and the like.
[0047]
The alkyl metal is not particularly limited, but is
preferably, for example, lithium diisopropylamide, sodium
diisopropylamide, potassium diisopropylamide, lithium
hexamethyl disilazide, sodium hexamethyl disilazide,
potassium hexamethyl disilazide, n-butyl lithium, s-butyl
lithium, t-butyl lithium and the like.
[0048]
T h e b a s e u s e d i n t h e t r e a t m e n t p r o c e s s i s p r e f e r a b l y t h o s e
having a pKb of 0 to 6, and more preferably those having a pKb
of 2 to 5. Specifically, the base is preferably sodium
hydroxide, sodium carbonate, sodium hydrogen carbonate,
triethylamine, 4-dimethylaminopyridine or sodium methoxide,
andmore preferably sodiumhydroxide. Herein, the "pKb" in the
specification refers to the dissociation constant of the base
at 25OC, and the dissociation constant of the first acid in the
case of a multivalent base. Meanwhile, the pKb value of a base
may refer to the numerical value described in a document and
the like.
[0049]
In addition, the base may be used as a solution including
an aqueous solution. The concentration of the base solution
in the case where the base is used as a solution is such that
the upper limit is preferably less than 100 mass%, more
preferably less than 80 mass%, even more preferably less than
50 mass%, even more preferably less than 30 mass%, and further
preferably 10 mass%, whereas the lower limit is preferably 1
mass%. The concentration range of the base solution is
preferably 1 mass% or more and less than 50 mass%, more
preferably 1 mass% or more and less than 30 mass% and further
preferably 1 to 10 mass%. The pH (25OC) of the aqueous solution
of the base used in the treatment process of the present
invention is not particularly limited, but is preferably pH 8
to 14, and more preferably pH 11 to 12.
[0050]
The addition amount of the acid or base used in the
treatment process ofthe present invention is not particularly
limited, but for example, is preferably 1 to 50 mass%, and
further preferably 5 to 20 mass% with respect to a reaction
solution after the reaction, a solution of the organic layer
after the reaction, and a solution obtained by re-dissolution
in an organic solvent after the isolation in the case of the
process (B) . The same addition amount as described above may
be also adopted in the case of the process (A).
[0051]
The temperature i n t h e t r e a t m e n t p r o c e s s of t h e p r e s e n t
invention is not p a r t i c u l a r l y l i m i t e d , b u t is p r e f e r a b l y 0 t o
100°C, more p r e f e r a b l y 1 t o 90°C, even more p r e f e r a b l y 20 t o
80°C, and f u r t h e r p r e f e r a b l y 40 t o 70°C. The time i n t h e
t r e a t m e n t p r o c e s s of the p r e s e n t invention is not p a r t i c u l a r l y
l i m i t e d , b u t p r e f e r a b l y is 1 t o 15 hours, more p r e f e r a b l y 3 t o
15 hours, even more p r e f e r a b l y 3 t o 10 hours, and f u r t h e r
p r e f e r a b l y 3 t o 5 hours.
[0052]
The t r e a t m e n t p r o c e s s of the p r e s e n t invention may be
performed f u r t h e r i n the presence of an alcohol. The alcohol
is p r e f e r a b l y added s i n c e t h e organic l a y e r and the aqueous
l a y e r become uniform with the a d d i t i o n . The alcohol t h a t can
beusedisnotparticularlylimited, butispreferablymethanol,
ethanol, 1-propanol, 2-propanol and the l i k e , and f u r t h e r
p r e f e r a b l y methanol or ethanol.
[0053]
The amount o f t h e a l c o h o l u s e d i s n o t p a r t i c u l a r l y l i m i t e d ,
but is p r e f e r a b l y 1 t o 50 mass%, more p r e f e r a b l y 5 t o 20 mass%,
and f u r t h e r p r e f e r a b l y 8 t o 15 mass% with r e s p e c t t o a r e a c t i o n
s o l u t i o n a f t e r t h e r e a c t i o n , a s o l u t i o n of the organic l a y e r
a f t e r t h e r e a c t i o n , or a s o l u t i o n obtained by r e - d i s s o l u t i o n
i n an organic s o l v e n t a f t e r the i s o l a t i o n .
[0054]
By s u b j e c t i n g t o a general p u r i f i c a t i o n means such as
c e n t r i f u g a t i o n , s e p a r a t i o n , washing, c o n c e n t r a t i o n , drying,
distillation and column chromatography as necessary after the
treatment process, it is possible to isolate a
phosphonocrotonic acid derivative with removed or lowered
pyrophosphoric acidesters including TEPPthatare impurities.
[0055]
Hereinafter, the step 2 will be described.
In Scheme 2, the step 2 is a process of reacting the
phosphonocrotonic acid derivative with a compound represented
by Formula (5) (carbonylcompound), wherebytoobtaina compound
represented by Formula (6) (a compound having a
3-methylpenta-2,4-dienoic acid residue) by the Horner-Emmons
reaction of the phosphonocrotonic acid derivative and the
carbonyl compound. Meanwhile, the compound represented by
Formula (5) is not particularly limited if it is a carbonyl
compoundallowing Horner-Emmons reaction, but example sthereof
may include, for example, farnesal, P-ionylidene acetaldehyde,
(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2
,4-dienal and the like.
[0056]
This reaction can be performed according to
conventionally well-known conditions of Horner-Emmons
reaction. For example, the conditions described in Chemical
Reviews 1974, 74, 87-99 and the like may be applied, but the
conditions are not limited thereto. In addition, in the case
where the compound represented by Formula (6) produced by
Horner-Emmons reaction of the phosphonocrotonic acid
derivative and the carbonyl compound is an ester compound,
hydrolysis thereof can give a compound having a
3-methylpenta-2,4-dienoicacidresidueinwhichtheestergroup
is convertedtoacarboxylgroup. Meanwhile, forthehydrolysis,
conventionally well-known method may be applied. Then, the
compound having a 3-methylpenta-2,4-dienoic acid residue may
beisolatedandpurifiedbycentrifugation, separation, washing,
concentration, drying, recrystallization, distillation,
column chromatography, or a combination thereof.
[00571
The phosphonocrotonic acid derivative used in the step
2 is substantially free of pyrophosphoric acid ester, and thus
it is possible in the present invention to obtain a compound
havinga 3-methylpenta-2,4-dienoicacidresidueinhighpurity.
For example, it is possible to obtain
(2E, 4E, 6E, 10E) -3,7, 11, 15-tetramethylhexadeca-2, 4,6, 10, 14-pe
ntaenoic acidinhighpuritybyusing TEMPC obtainedinthe step
1as the phosphonocrotonic acid derivative, and farnesal as the
carbonylcompound, respectively as rawmaterialcompounds. In
addition, it is possible to obtain
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2, 6, 6-trimethyl-1-cyclohexene
-1-y1)nona-2,4,6,8-tetraenoic acid in high purity by using
TEMPC obtained in the step 1 as the phosphonocrotonic acid
derivative and P-ionylidene acetaldehyde as the carbonyl
compound, respectively as the raw material compounds.
Furthermore, it is possible to obtain ethyl
(2E,4E,6E,8E)-9-(4-methoxy2,3,6-trimethylphenyl)-3,7-dimeth
ylnona-2,4,6,8-tetraenoate in high purity by using TEMPC
obtainedinthe step 1as the phosphonocrotonic acidderivative
and
(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2
,4-dienal as the carbonyl compound, respectively as the raw
material compounds.
Thus-obtained compound having a
3-methylpenta-2,4-dienoic acid residue is of high purity that
is substantially free of pyrophosphoric acid ester that is an
impurity, and thus is with excellent quality.
[0058]
Consequently, a compound having a
3-methylpenta-2,4-dienoic acid residue that is substantially
free of pyrophosphoric acid ester, particularly preferably
(2E, 4E, 6E, 1 0E)- 3,7,11,15-tetramethylhexadeca-2,4 ,6 ,1 0,14-pe
ntaenoic acid,
(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexene
-1-y1)nona-2,4,6,8-tetraenoic acid, or ethyl
(2E,4 E, 6E,8 E)- 9- (4-methoxy-2,3,6-trimethylphenyl)- 3,7-dimet
hylnona-2,4,6,8-tetraenoatethatis substantially free of TEPP,
isuseful as rawmaterialsofapharmaceutical composition. The
pharmaceutical composition is substantially free of
pyrophosphoric acid ester that is an impurity, and thus is with
excellent quality.
[0059]
The pharmaceutical composition of the present invention
can be made to various dosage forms by using formulation
additives suitably in accordance with a well-known method
described in GENERAL RULES FOR PREPARATIONS, The Japanese
Pharmacopeia edition and the like. Examples of the
formulation in the present invention include various
formulations such as preparations for oral administration,
preparations for oro-mucosalapplication, andpreparations for
injection. The dosage form is not particularly limited, but
examples thereof include, for example, a tablet (including
orallydisintegratingtablet, a chewable tablet, a dispersible
tablet, soluble tablet; tablets for oro-mucosal applications
such as a lozenge, a sublingual tablet, a buccal tablet,
mucoadhesive tablet and a medicated chewing gum), a capsule,
a pill, a powder, a granule, a subtle granule, a dry syrup, an
oral jelly, an oral solution (an elixir, a suspension, an
emulsion, a lemonade and the like), a syrup and the like.
[0060]
The dosage of the pharmaceutical composition of the
present inventionmaybe suitablyselecteddependingonthe kind
of the disease to be applied, the purpose of the prevention or
treatment, conditions ofthepatient suchas the age, theweight
and the symptom, but the dosage for an adult per a day is, for
example, 10 to 1000 mg or so, as the amount of the active
ingredient in the oral administration. The above-mentioned
dosagemaybe generally administeredinoneto several divisions
per a day, but also may be administered every several days.
For example, in the case where tretinoin obtained by the
present invention is used, 60 to 80 mg per a day is preferably
orally administered in three divisions. In addition, in the
casewhereetretinateisused, l O t o 7 5 m g p e r a d a y i s p r e f e r a b l y
orallyadministeredinonetothreedivisions. I n c a s e o f using
p e r e t i n o i n , 200 t o 1000 mg per a day is p r e f e r a b l y o r a l l y
administered i n one t o t h r e e d i v i s i o n s .
[0061]
In r e l a t i o n t o the embodiments described above, t h e
p r e s e n t invention f u r t h e r d i s c l o s e s the manufacturing method,
the compound, and the pharmaceutical composition described
below.
<1> A method of manufacturing a compound represented by
Formula ( 3 ) describedbelowby r e a c t i n g a compound represented
by the following Formula (1) and a compound represented by the
following Formula ( 2 ) , wherein themethod comprises a t r e a t m e n t
process using an a c i d or base.
[0062]
(R,O) ,P (1)
[0063]
wherein R1 r e p r e s e n t s a C1+ l i n e a r o r branched a l k y l group t h a t
may be s u b s t i t u t e d by a C6-10 a r y l group, a C2-6 l i n e a r or branched
alkenyl group t h a t may be s u b s t i t u t e d by a C6-10 a r y l group, a
C2-6 l i n e a r or branched alkynyl group t h a t may be s u b s t i t u t e d
by a C6-10 a r y l group, or a C6-10 a r y l group, and each R1 may be
the same or d i f f e r e n t .
[0064]
[0065]
wherein X represents a halogen atom, R2 represents a hydrogen
atom, or a C14 linear or branched alkyl group that may be
substituted by a C6-10a ryl group, and R3 represents a C1+ linear
or branched alkyl group, a aryl group, or a halogen atom.
[0066]
[0067]
wherein R1, R2, and R3 are as described above, and each R1 may
be the same or different.
[0068]
<2> The method as described in the above-mentioned
wherein the treatment process comprises either one or both of
(A) and (B) described below.
(A) Process of reacting the compound represented by
Formula (1) with the compound represented by Formula (2) in the
presence of an acid or base.
(B) Process of reacting the compound represented by
Formula (1) with the compound represented by Formula (2), and
then treating with an acid or base.
<3>Themethodasdescribedinabove-mentioned<1>or<2>,
wherein triethyl phosphite as the compound represented by
Formula (I), and ethyl 4-bromo-3-methylcrotonate as the
compound represented by Formula (2) are used, respectively, to
manufacture triethyl-3-methyl-4-phosphonocrotonate as a
compound represented by Formula (3) .
[0069]
<4> A method of manufacturing a compound having a
3-methylpenta-2,4-dienoic acid residue by reacting a compound
represented by Formula (3) obtained by the method as described
in any one of the above-mentioned <1> to <3> with a carbonyl
compound.
<5> The method as described in the above-mentioned <4>,
wherein triethyl-3-methyl-4-phosphonocrotonate as the
compoundrepresentedby Formula (3) andfarnesalasthe carbonyl
compound are used, respectively, to manufacture
(2E, 4E, 6E, 10E) -3,7, 11, 15-tetramethylhexadeca-2, 4, 6, 10, 14-pe
ntaenoic acid as a compound having a 3-methylpenta-2,4-dienoic
acid residue.
<6> The method as described in the above-mentioned <4>,
wherein triethyl-3-methyl-4-phosphonocrotonate as the
compound represented by Formula (3) and P-ionylidene
acetaldehyde as the carbonyl compound are used, respectively,
to manufacture
(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexene
-1-y1)nona-2,4,6,8-tetraenoic acid as the compound having a
3-methylpenta-2,4-dienoic acid residue.
<7> The method as described in the above-mentioned <4>,
wherein triethyl-3-methyl-4-phosphonocrotonate as the
compound represented by Formula (3) and
(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2
,4-dienal as the carbonyl compound are used, respectively, to
manufacture ethyl
(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimet
hylnona-2,4,6,8-tetraenoate as the compound having a
3-methylpenta-2,4-dienoic acid residue.
[0070]
<8> A method of manufacturing a compound having a
3-methylpenta-2,4-dienoic acid residue by performing a
treatment using an acid or base at the time of the reaction of
a compound represented by Formula (1) with a compound
represented by Formula ( 2 ) , or after the reaction, whereby a
compound represented by Formula (3) is obtained, and then
reacting the compound with a carbonyl compound.
[0071]
<9> The method as described in any one of the
above-mentioned to <8>, wherein the acid is an acid having
a pKa of preferably less than 5, more preferably -5 or more and
less than 5, and further preferably -5 or more and less than
3.
The method as described in any one of the
above-mentioned to <9>, wherein the acid is used as a
solution, and the concentration of the acid solution is
preferably less than 100 mass%, more preferably than 90 mass%
less, and further preferably less than 60 mass%, and preferably
1 mass% or more, more preferably 3 mass% or more, and further
preferably 5 mass% or more.
<11> The method as described i n any one of the
above-mentionedto < l o > , wherein an aqueous solution o f t h e
acid has the pH of preferably 1 t o 5, and more preferably 1 t o
3.
<12> The method as described i n any one of the
above-mentioned <1> t o <11>, wherein t h e a c i d is an inorganic
acid.
<13> Themethodas d e s c r i b e d i n t h e above-mentioned<12>,
wherein the inorganic acid is s u l f u r i c acid or phosphoric acid.
<14> The method as described i n any one of the
above-mentioned t o <11>, wherein the acid is an organic
acid.
<15> Themethodas d e s c r i b e d i n t h e above-mentioned<14>,
wherein the organic acid is a c e t i c acid.
[0072]
<16> The method as described in any one of the
above-mentioned <1> t o <8>, wherein the base is a base having
a pKb of preferably 0 t o 6, and more preferably 2 t o 5.
<17> The method as described i n any one of the
above-mentioned <1> t o <8> and <16>, wherein the base is used
as a solution, and the concentration of the base solution i s
preferably l e s s than 100 mass%, more preferably l e s s than 80
mass%, even more preferably l e s s than 50 mass%, even more
preferably l e s s than 30 mass%, and f u r t h e r preferably equal t o
or l e s s than 10 mass%, and preferably 1 mass% or more.
<18> The method as described i n any one of the
above-rnentionedto<8> and<16> and<17>, whereinanaqueous
solution of the base has the pH of preferably 8 t o 1 4 , and more
preferably 11 t o 12.
<19> The method as described in any one of the
above-mentioned <1> t o <8> and <16> t o <18>, wherein the base
i s an inorganic base.
<20> Themethodas d e s c r i b e d i n t h e above-mentioned<19>,
wherein the inorganic base is an a l k a l i metal carbonate.
<21>Themethodas d e s c r i b e d i n t h e above-mentioned<20>,
wherein the a l k a l i metal carbonate is sodium carbonate.
<22> Themethodas d e s c r i b e d i n t h e above-mentioned<19>,
wherein the inorganic base i s an a l k a l i metal hydrogen
carbonate.
<23>Themethodas d e s c r i b e d i n t h e above-mentioned<22>,
wherein the a l k a l i metal hydrogen carbonate is sodiumhydrogen
carbonate.
<24> Themethod as d e s c r i b e d i n t h e above-mentioned<19>,
wherein the inorganic base is an a l k a l i metal hydroxide.
<25>Themethodas d e s c r i b e d i n t h e above-mentioned<24>,
wherein the a l k a l i metal hydroxide is sodium hydroxide.
<26>Themethodas d e s c r i b e d i n t h e above-mentioned<19>,
wherein the inorganic base is an a l k a l i metal hydrogen
phosphate.
<27>Themethodas d e s c r i b e d i n t h e above-mentioned<26>,
wherein the a l k a l i metal hydrogen phosphate is disodium
hydrogen phosphate.
<28> The method as described i n any one of the
above-mentioned <1> t o <8> and <16> t o <18>, wherein the base
is an organic. base.
<29> Themethodas describedinthe above-mentioned<28>,
wherein the organic base is triethylamine or
4-dimethylaminopyridine.
<30> The method as described in any one of the
above-mentioned <1> to <8> and <16> to <18>, wherein the base
is a metal alkoxide.
<31> Themethod as describedinthe above-mentioned<30>,
wherein the metal alkoxide is sodium methoxide or sodium
ethoxide .
<32> The method as described in any one of the
above-mentioned <1> to <8> and <16> to <18>, wherein the base
is an alkyl metal.
[0073]
<33> The method as described in any one of the
above-mentioned <1> to <32>, wherein the treatment process is
performed in the presence of an alcohol.
<34> Themethodas describedinthe above-mentioned<33>,
wherein the alcohol is methanol or ethanol.
<35> The method as described in the above-mentioned <33>
or <34>, wherein the use amount of the alcohol is preferably
1 to 50 mass%, more preferably 5 to 20 mass%, and further
preferably 8 to 15 mass% with respect to a reaction solution
after the reaction, a solution.of the organic layer after the
reaction, orasolutionobtainedbyre-dissolutioninanorganic
solvent after the isolation.
<36> The method as described in any one of the
above-mentioned <1> t o <35>, wherein t h e a d d i t i o n amount o f t h e
a c i d or base used i n the t r e a t m e n t p r o c e s s is p r e f e r a b l y 1 t o
50 mass%, and more p r e f e r a b l y 5 t o 20 mass% with r e s p e c t t o a
r e a c t i o n s o l u t i o n a f t e r t h e r e a c t i o n , a s o l u t i o n o f t h e organic
l a y e r a f t e r the r e a c t i o n , or a s o l u t i o n obtained by
r e - d i s s o l u t i o n i n an organic s o l v e n t a f t e r t h e i s o l a t i o n .
<37> The method as described i n any one of the
above-mentioned <1> t o <36>, wherein the temperature i n the
treatment process is p r e f e r a b l y 0 t o 100°Cf more p r e f e r a b l y 1
t o 90°C, even more p r e f e r a b l y 20 t o 80°Cf and f u r t h e r p r e f e r a b l y
40 t o 70°C.
<38> The method as described i n any one of t h e
above-mentioned <1> t o <37>, wherein the time i n t h e treatment
process is p r e f e r a b l y 1 t o 15 hours, more p r e f e r a b l y 3 t o 15
hours, even more p r e f e r a b l y 3 t o 10 hours, and f u r t h e r
p r e f e r a b l y 3 t o 5 hours.
[0074]
<39> The method as described i n any one of t h e
above-mentioned <4> and <8> t o <38>, wherein t h e carbonyl
compound is a compound r e p r e s e n t e d b y t h e formula (5) described
below.
[0075]
wherein R, and Rb each represent independently, a hydrogen atom
or an organic group, with the proviso that R, and Rb are not
a hydrogen atom at the same time.
[0077]
<40> Themethodas describedinthe above-mentioned<39>,
wherein R, is a substituted or unsubstituted aliphatic
hydrocarbon group, and Rb is a hydrogen atom or a substituted
or unsubstituted aliphatic hydrocarbon group.
<41> The method as described in the above-mentioned <39>
or <40>, wherein R, is a substituted or unsubstituted alkenyl
group, and Rb is a hydrogen atom.
<42>Themethodas describedinthe above-mentioned<41>,
wherein the carbon number of the alkenyl group is preferably
2 to 32, and more preferably 5 to 30.
<43> The method as described in any one of the
above-mentioned <39> to <42>, wherein R, is a
2-methylbuta-1,3-dienyl group, a
6-methyleneocta-2,7-dien-2-yl group, a
6-methylocta-2,5,7-trien-2-yl group, a
6,10,15,19,23-pentamethyltetracosa-2,6,1Oll4,l8,22-hexaen-2
-yl group, a 2,6,10-trimethylundeca-1,5,9-trienyl group, a
4-(4-methoxy-2,3,6-trimethylphenyl)-2-methylbuta-l,3-dienyl
group, or a
4-(2,6,6-trimethyl-1-cyclohexenyl)-2-methylbuta-l,3-dienyl
group.
[0078]
<44>
(2E,4E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,4,6,lO,l4-pe
ntaenoic acid that is substantially free of tetraethyl
pyrophosphate.
<45> A pharmaceutical composition
comprising(2E,4E,6E,10E)-3,7,11,15-tetramethy1hexadeca-2,4,
6,10,14-pentaenoic acid as described in the above-mentioned
<44>.
<46> The pharmaceutical composition as described in the
above-mentioned <45>, wherein the dosage form is a tablet, a
capsule, a pill, a powder, a granule, a subtle granule, a dry
syrup, an oral jelly, an oral solution or a syrup.
EXAMPLES
[0079]
The present invention will be further specifically
described with Examples below, but the scope of the present
invention is not limited to the Examples described below.
Meanwhile, the analysis conditions inExamples are as described
below.
[0080]

CLAIMS
1. A metho'd of manufacturing a compound represented by
Formula (3) :
wherein Rl r e p r e s e n t s a C1-6 l i n e a r o r branched a l k y l group t h a t
may be s u b s t i t u t e d by a C6-10 a r y l group, a C2-6 l i n e a r or branched
alkenyl group t h a t may be s u b s t i t u t e d by a C6-10 a r y l group, a
C2-6 l i n e a r or branched alkynyl group t h a t may be s u b s t i t u t e d
by a C6-10 a r y l group, or a C6-10 a r y l group, and each R1 may be
the same or d i f f e r e n t , R2 r e p r e s e n t s a hydrogen atom, or a ClW6
l i n e a r orbranchedalkylgroupthatmaybe s u b s t i t u t e d b y a C6-10
a r y l group, and R3 r e p r e s e n t s a C1-6 l i n e a r or branched a l k y l
group, a C6-10 a r y l group, or a halogen atom, by r e a c t i n g a
compound represented by Formula (1) :
(R,O) ,P (1)
wherein R1 is as described above, with a compound represented
by Formula (2) :
wherein X r e p r e s e n t s a halogen atom, and R2 and R3 a r e as
described above,
the method comprising a treatment process using an acid
or base.
2. The method according to claim 1, wherein the treatment
process is either one or both of (A) and (B) described below,
(A) Process of reacting the compound represented by
Formula (1) with the compound represented by Formula (2) in the
presence of an acid or base
(B) Process of reacting the compound represented by
Formula (1) with the compound represented by Formula (2),
followed by performing a treatment using an acid or base
3. The method according to claim 1 or 2, wherein triethyl
phosphite as the compoundrepresentedby Formula (1) with ethyl
4-bromo-3-methylcrotonate as the compound represented by
Formula (2) are used, respectively, to manufacture
triethyl-3-methyl-4-phosphonocrotonate as the compound
represented by Formula (3).
4. A method of manufacturing a compound having a
3-methylpenta-2,4-dienoic acid residue by reacting a compound
represented by Formula (3) obtained by the method according to
any one of claims 1 to 3, with a carbonyl compound.
5. The method according to claim 4, wherein
triethyl-3-methyl-4-phosphonocrotonate as the compound
representedbyFormula (3) andfarnesalasthe carbonylcompound
are used, respectively, to manufacture
(2E, 4E, 6E, 10E) -3,7, 11, 15-tetramethylhexadeca-2, 4, 6, 10, 14-pe
ntaenoic acid as the compound having a
3-methylpenta-2,4-dienoic acid residue.
6. The method according to claim 4, wherein
triethyl-3-methyl-4-phosphonocrotonate as the compound
representedby Formula (3) andp-ionylidene acetaldehyde as the
carbonyl compound are used, respectively, to manufacture
(2E,4E,6E,8E)-3,7-dimethy1-9-(2,6,6-trimethy1-1-cyc1ohexene
-1-y1)nona-2,4,6,8-tetraenoic acid as the compound having a
3-methylpenta-2,4-dienoic acid residue.
7. The method according to claim 4, wherein
triethyl-3-methyl-4-phosphonocrotonate as the compound
represented by Formula (3) and
(2E,4E)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2
,4-dienal as the carbonyl compound are used, respectively, to
manufacture ethyl
(2E,4E,6E18E)-9-(4-methoxy-2,3,6-trimethy1pheny1)-3,7-dimet
hylnona-2,4,6,8-tetraenoate as the compound having a
3-methylpenta-2,4-dienoic acid residue.
8. A method of manufacturing a compound having a
3-methylpenta-2,4-dienoic acid residue by performing a
treatmentusinganacidorbaseatthetimeofareactionbetween
a compound represented by Formula (1):
(RIO) , P (1)
wherein R1 represents a C1+ linear or branched alkyl group that
may be substituted by a C6-10a ryl group, a C2-6l inear or branched
alkenyl group that may be substituted by a C6-10 aryl group, a
CZ-6 linear or branched alkynyl group that may be substituted
by a C6-10 aryl group, or a C6-10 aryl group, and each R1 may be
the same or different, and
a compound represented by Formula (2) :
wherein X represents a halogen atom, R2 represents a
hydrogen atom, or a C1-6 linear or branched alkyl group that may
be substituted by a C6-lo aryl group, and R3 represents a C1-6
linear or branched alkyl group, a C6-10 aryl group, or a halogen
atom,
or after the reaction, to obtain a compound represented
by Formula (3) :
wherein R1, R2, and R3 are as described above, followed
by reacting the compound with a carbonyl compound.
9. The method according to any one of claims 1 to 8, wherein
the acid is an inorganic acid.
10. The method according to claim 9, wherein the inorganic
acid is sulfuric acid or phosphoric acid.
11. The method according to any one of claims 1 to 8, wherein
t h e a c i d is an organic a c i d .
12. Themethodaccording t o c l a i m l l , whereinthe o r g a n i c a c i d
is a c e t i c a c i d .
13. The method according t o any one of claims 1 t o 8, wherein
t h e base is an i n o r g a n i c b a s e .
1 4 . The method according t o claim 13, wherein the inorganic
base is an a l k a l i m e t a l c a r b o n a t e .
15. Themethodaccordingto claim14, whereinthe a l k a l i m e t a l
carbonate is sodium carbonate.
16. The method according t o claim 13, wherein t h e inorganic
base is an a l k a l i metal hydrogen carbonate.
17. Themethodaccording t o claim16, wherein the a l k a l i m e t a l
hydrogen carbonate is sodium hydrogen carbonate.
18. The method according t o claim 13, wherein the inorganic
base is an a l k a l i metal hydroxide.
19. Themethodaccordingto claim18, whereinthe a l k a l i m e t a l
hydroxide is sodium hydroxide.
20. The method according t o claim 13, wherein t h e inorganic
base is an a l k a l i metal hydrogen phosphate.
21. Themethodaccordingto claim20, whereinthe a l k a l i m e t a l
hydrogen phosphate is disodium hydrogen phosphate.
22. The method according t o any one o f c l a i m s 1 t o 8, wherein
the base is an organic base.
23. Themethodaccordingtoclaim22, w h e r e i n t h e o r g a n i c b a s e
i s t r i e t h y l a m i n e or 4-dimethylaminopyridine.
24. The method according t o any one of claims 1 t o 8, wherein
the base is a m e t a l a l k o x i d e .
25. The method according to claim 24, wherein the metal
alkoxide is sodium methoxide or sodium ethoxide.
26. The method according to any one of claims 1 to 8, wherein
the base is an alkyl metal.
27. The method according to any one of claims 1 to 8, wherein
the treatment process is performed in the presence of an
alcohol.
28. The method according to claim 27, wherein the alcohol is
methanol or 'ethanol.
29. The method according to any one of claims 4 and 8 to 28,
wherein the carbonyl compound is a compound represented by
Formula (5) :
wherein R, and Rb each independently represent a hydrogen
atom or an organic group, with the proviso that R, and Rb are
not a hydrogen atom at the same time.
30. The method according to claim 29, wherein R, is a
substituted or unsubstituted aliphatic hydrocarbon group, and
Rbis ahydr~genatomorasubstitutedorunsubstitutedaliphatic
hydrocarbon group.
31. (2E, 4E, 6E, 10E) -3,7, 11, 15-tetramethylhexadeca-2, 4, 6,
10,14-pentaenoic acid that is substantially free of tetraethyl
pyrophosphate .
32. A pharmaceutical composition comprising
ntaenoic acid according to claim 31.
33. The pharmaceutical composition according t o claim 32,
whereinthedosage formis a t a b l e t , a capsule, a p i l l , apowder,
a granule, a subtle granule, a dry syrup, an o r a l j e l l y , an oral
s o l u t i o n o r a syrup.