Title of the Invention: Method for preparing trans-{4-[(alkylamino)methyl]-
cyclohexyl}acetic acid ester
Technical Field
[0 0 0 1]
The present invention relates to a method for producing a trans-{4-
[(alkylamino)methyl]cyclohexyl}acetic acid ester, which is useful as a raw material
compound for manufacture of medicaments, agricultural chemicals, and industrial
products, and also relates to an intermediate for preparation thereof.
Background Art
[0 0 0 2]
Trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid esters are useful as
reagents or raw material compounds for manufacture of medicaments, agricultural
chemicals ,and industrial products. For example, in each of the following
publications (Patent documents 1 to 6), trans-{4-[(alkylamino)methyl]cyclohexyl}-
acetic acid esters are described as important raw material compounds for preparation
of:trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-methyl-4-(trifluoromethyl)phenyl](ethyl) amino}-
methyl)cyclohexyl]acetic acid hydrochloride represented by the following formula (A)
(Patent document 1, Example 142), trans-[4-({[2-({(4S,5R)-5-[3,5-
bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-oxazolidin-3-yl}methyl)-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid represented by
the following formula (B) (Patent document 2, Ex. 73), trans-[4-({[2-({[3,5-
bis(trifluoromethyl)benzyl](5-morpholinopyrimidin-2-yl)amino}methyl)-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid represented by
the following formula (C) (Patent document 3, Ex. 57), trans-[4-({[3-({[3,5-
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid represented
by the following formula (D) (Patent document 4, Ex. 14), trans-[4,({[3-({[3,5-
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)quinolin-2-
yl](ethyl)amino}methyl)cyclohexyl] acetic acid represented by the following formula

(E) (Patent document 5, Ex. 4), trans-(4-{[{2-[({l-[3,5-
bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-
yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetic
acid represented by the following formula (F) (Patent document 6, Example 45) and
the like, which are pyrimidine compounds having a dibenzylamine structure having a
cholesterol ester transfer protein (CETP) inhibitory activity and are useful as
prophylactic and/or therapeutic agents for hyperlipidemia, arteriosclerosis, heart
diseases and the like.
[0 0 0 3]

[0 0 0 4]
As a method for preparing a trans-{4-[(ethylamino)methyl]cyclohexyl}acetic
acid ester, the method shown in the following reaction scheme is known. This
method uses 4-oxocyclohexanecarboxylic acid ethyl ester as a starting material, and
comprises the steps of derivatizing the starting material to obtain the
cyclohexylacetic acid compound by a carbon increasing reaction based on the Horner-

Wittig-Emmons reaction, reducing the double bond of the unsaturated ester of the
cyclohexylacetic acid compound to obtain the cyclohexylcarboxylic acid compound as a
mixture of the compounds of cis- and trans-configurations, then converting the
resulting cyclohexylcarboxylic acid into the acid chloride without separating the
isomers, and then converting the acid chloride into the amide compound by a reaction
with ethylamine. The desired amide compound having the trans-configuration can
be separated by repeating recrystallization several times. The resulting amide
compound can be reduced with sodium borohydride in the presence of acetic acid to
obtain a trans-{4-[(ethylamino)methyl]cyclohexyl}acetic acid ester, which is an amine
compound (refer to Patent document 1, Example 169).
[0 0 0 5]
Reaction route 1
[Formula 2]

However, the operations of the aforementioned method are complicated, since
the desired amide intermediate having the trans-configuration is separated and
purified from a mixture of the cis- and trans-isomers by recrystallization, and thus
the total yield is also low (32.2%). Further, it is difficult to carry out the conversion
of the non-desired cis-compound into the trans-compound by an ordinary method, and
therefore, the method also suffers from a problem that the cis-compound cannot be
recycled. Furthermore, the 4-oxocyclohexanecarboxylic acid ethyl ester as the
starting material is not inexpensive at present, and therefore the method cannot be
regarded as an industrially efficient and advantageous preparation method.
[0 0 0 7]

In order to avoid loss in a yield due to the separation by recrystallization, a
method has been proposed in which the cyclohexylacetic acid, obtained by the carbon
increasing reaction based on the Horner-Wittig-Emmons reaction and the successive
reduction, is derived into a benzyl ester intermediate so as to facilitate the separation
of the cis- and trans-isomers. After separation and purification of the mixture of the
isomers is carried out by column chromatography to obtain the cyclohexylacetic acid
derivative of the trans-configuration, the target compound can be obtained by steps
similar to those of the aforementioned method (see, Intermediate 7 and Intermediate
13 of Patent document 2). This reaction route is shown with reaction formulas as
follows.
[0 0 0 8]
Reaction route 2
[Formula 3]

However, this method additionally comprises the steps of converting the
carboxylic acid into the benzyl ester intermediate for the separation by column
chromatography and, after separating the desired objective substance, converting the
benzyl ester into a carboxylic acid by hydrogenolysis. Therefore, an yield may
possibly be reduced significantly due to the separation of the isomers. Further, the
operations of the column chromatography for the separation of the isomers are
complicated, and accordingly, the method is considered not to be efficient preparation
method from an industrial viewpoint.
Prior Art References
Patent documents
[0 0 10]

Patent document l: International Patent Publication WO2004/020393
Patent document 2: International Patent Publication WO2007/081571
Patent document 3: International Patent Publication WO2007/088996
Patent document 4: International Patent Publication WO2007/073934
Patent document 5: International Patent Publication WO2007/128568
Patent document 6: International Patent Publication WO2008/129951
Summary of the Invention
Object to be Achieved by the Invention
[0 0 11]
An object of the present invention is to provide a method for efficiently
preparing a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester, which is useful
as a reagent or a starting material compound for manufacture of medicaments,
agricultural chemicals, industrial products and the like, from an inexpensive raw
material compound in a high yield.
Another object of the present invention is to provide a novel preparation
intermediate useful for efficiently preparing a trans-{4-[(alkylamino)methyl]-
cyclohexyl}acetic acid ester from an inexpensive raw material compound in a high
yield.
Means for Achieving the Object
[0 0 12]
The inventors of the present invention conducted various researches to
achieve the aforementioned objects, and as a result, they found that, as shown in the
following reaction scheme, by using inexpensively available tranexamic acid (2)
having the trans-configuration as a starting material, and converting tranexamic acid
into an amide compound (3) by acylation, then converting the carboxylic acid into a
compound (4) using a halogenating agent or an active esterifying agent, and further
converting the compound (4) into a diazoketone compound (5) through a reaction with
diazomethane or trimethylsilyldiazomethane, and then subjecting the diazoketone
compound (5) to the ArndtEistert reaction in an alcohol solution in the presence of a
silver salt and a tertiary amine, conversion into a novel ester compound (6) was
efficiently achievable, of which carbon number was increased by one with while the
trans-configuration was maintained. Further, they also found that the desired trans-
{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester (l) was successfully obtained in a

excellent yield by reduction of the amide of the ester compound (6) in a conventional
manner. The present invention was accomplished on the basis of the aforementioned
finding,
[0 0 13]
[Formula 4]

[In the formula, R1 represents hydrogen atom or a C1-6 alkyl group, R2 represents a
C1-6 alkyl group, a C3-6 cycloalkyl group, a (C3-6 cycloalkyl)(C1-6 alkyl) group, a C6-10
aryl group, or a C7-12 aralkyl group, and X represents a halogen atom or an active
ester residue.]
[0 0 14]
The present invention thus provides a method for preparing a trans-{4-
[(alkylamino) methyl] cyclohexyl}acetic acid ester represented by the aforementioned
general formula (l) (in the formula, R1 represents hydrogen atom or a C1-6 alkyl group,
and R2 represents a C1-6 alkyl group, a C3-6 cycloalkyl group, a (C3-6 cycloalkyl)(C1-6
alkyl) group, a C1-10 aryl group, or a C7-12 aralkyl group), which comprises the step of
reducing amide group of a compound represented by the aforementioned general
formula (6) (R1 and R2 in the formula have the same meanings as those defined above).
According to preferred embodiments of the present invention, there are provided the
aforementioned method, wherein sodium borohydride is used as a reducing agent, and
the aforementioned method, wherein R1 is methyl group.
[0 0 15]
The compound represented by the aforementioned general formula (6) used in
the aforementioned method of the present invention is a novel compound, and this

compound is useful as a preparation intermediate of a trans-{4-[(alkylamino)-
methyl]cyclohexyl}acetic acid ester represented by the aforementioned general
formula (l).
Therefore, from further aspects, the present invention provides a compound
represented by the aforementioned general formula (6) (R1 and R2 in the formula have
the same meanings as those defined above), and a compound represented by the
aforementioned general formula (6) for use as an intermediate for preparation of a
trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester represented by the
aforementioned general formula (l). In the compound represented by the
aforementioned general formula (6), R1 is preferably methyl group.
[0 0 16]
The present invention further provides a method for preparing a compound
represented by the aforementioned general formula (6) (R1 and R2 in the formula have
the same meanings as those defined above), which comprises the step of reacting a
compound represented by the aforementioned general formula (5) (R1 in the formula
has the same meaning as that defined above) with an alcohol compound represented
as R2-OH (R2 in the formula has the same meanings as that defined above) in the
presence of a silver salt and a tertiary amine.
[0 0 17]
The present invention also provides a method for preparing a compound
represented by the aforementioned general formula (6) (R1 and R2 in the formula have
the same meanings as those defined above), which comprises the step of reacting a
compound represented by the aforementioned general formula (4) (R1 in the formula
has the same meaning as that defined above, and X represents a halogen atom or an
active ester residue) with diazomethane or trimethylsilyldiazomethane to prepare a
compound represented by the aforementioned general formula (5) (R1 in the formula
has the same meaning as that defined above); and the step of reacting the resulting
compound represented by the aforementioned general formula (5) (R1 in the formula
has the same meaning as that defined above) with an alcohol compound represented
as R2-OH (R2 in the formula has the same meaning as that defined above) in the
presence of a silver salt and a tertiary amine, and
a method for preparing a compound represented by the aforementioned general
formula (6) (R1 and R2 in the formula have the same meanings as those defined above),

which comprises the step of reacting a compound represented by the aforementioned
general formula (3) (R1 in the formula has the same meaning as that defined above)
'with a halogenating agent or an active esterifying agent to prepare a compound
represented by the aforementioned general formula (4) (R1 in the formula has the
same meaning as that defined above, and X represents a halogen atom or an active
ester residue); the step of reacting the resulting compound represented by the
aforementioned general formula (4) with diazomethane or trimethylsilyldiazomethane
to prepare a compound represented by the aforementioned general formula (5) (R1 in
the formula has the same meaning as that defined above); and the step of reacting the
resulting compound represented by the aforementioned general formula (5) (R1 in the
formula has the same meaning as that defined above) with an alcohol compound
represented as R2-OH (R2 in the formula has the same meaning as that defined above)
in the presence of a silver salt and a tertiary amine.
[0 0 18]
The present invention further provides a method for preparing a compound
represented by the aforementioned general formula (6) (R1 and R2 in the formula have
the same meanings as those defined above), which comprises the step of acylating
tranexamic acid (2) to prepare a compound represented by the aforementioned
general formula (3) (R1 in the formula has the same meaning as that defined above);
the step of reacting the resulting compound represented by the aforementioned
general formula (3) (R1 in the formula has the same meaning as that defined above)
with a halogenating agent or an active esterifying agent to prepare a compound
represented by the aforementioned general formula (4) (R1 in the formula has the
same meaning as that defined above, and X represents a halogen atom or an active
ester residue); the step of reacting the resulting compound represented by the
aforementioned general formula (4) with diazomethane or trimethylsilyldiazomethane
to prepare a compound represented by the aforementioned general formula (5) (R1 in
the formula has the same meaning as that defined above); and the step of reacting the
resulting compound represented by the aforementioned general formula (5) (R1 in the
formula has the same meaning as that defined above) with an alcohol compound
represented as R2-OH (R2 in the formula has the same meaning as that defined above)
in the presence of a silver salt and a tertiary amine.
[0 0 19]

In addition to these methods, the present invention also provides a method
for preparing a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester represented
by the aforementioned general formula (l) (in the formula, R1 and R2 have the same
meanings as those defined above), which comprises1
(a) the step of acylating tranexamic acid (2) to prepare a compound represented by
the aforementioned general formula (3) (R1 in the formula has the same meaning as
that defined above);
(b) the step of reacting the compound represented by the aforementioned general
formula (3) (R1 in the formula has the same meaning as that defined above) obtained
in the aforementioned step (a) with a halogenating agent or an active esterifying
agent to prepare a compound represented by the aforementioned general formula (4)
(R1 in the formula has the same meaning as that defined above, and X represents a
halogen atom or an active ester residue),'
(c) the step of reacting the compound represented by the aforementioned general
formula (4) obtained in the aforementioned step (b) with diazomethane or
trimethylsilyldiazomethane to prepare a compound represented by the
aforementioned general formula (5) (R1 in the formula has the same meaning as that
defined above);
(d) the step of reacting the compound represented by the aforementioned general
formula (5) (R1 in the formula has the same meaning as that defined above) obtained
in the aforementioned step (c) with an alcohol compound represented as R2-OH (R2 in
the formula has the same meaning as that defined above) in the presence of a silver
salt and a tertiary amine to prepare a compound represented by the aforementioned
general formula (6) (R1 and R2 in the formula have the same meanings as those
defined above); and
(e) the step of reducing amide group of the compound represented by the
aforementioned general formula (6) (R1 and R2 in the formula have the same
meanings as those defined above) obtained in the aforementioned step (d), and a
method for preparing a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester
represented by the aforementioned general formula (l) (in the formula, R1 and R2
have the same meanings as those defined above), which comprises one or more steps
selected from the group consisting of the aforementioned steps (a) to (e).
Effect of the Invention

[0 0 2 0]
According to the method of the present invention, a trans-{4-[(alkylamino)-
I methyl]cyclohexyl}acetic acid ester, which is useful as a reagent or a raw material
compound for manufacture of medicaments, agricultural chemicals, industrial
products and the like, can be efficiently prepared from an inexpensive raw material
compound in a high yield. This method is especially advantageous for reducing
manufacturing cost and improving manufacturing efficiency from an industrial
viewpoint.
The novel compound represented by aforementioned general formula (6)
provided by the present invention is useful as a preparation intermediate for
efficiently preparing the aforementioned trans-{4-[(alkylamino)methyl]-
cyclohexyl}acetic acid ester in a high yield.
Modes for Carrying out the Invention
[0 0 2 1]
In the present invention, the C1-6 alkyl group means to a linear or branched
alkyl group having 1 to 6 carbon atoms, and examples include, for example, methyl
group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl
group, t-butyl group, pentyl group, hexyl group, and the like.
In the present invention, the C3-6 cycloalkyl group means a cyclic alkyl group
having 1 to 6 carbon atoms, and examples include, for example, cyclopropyl group,
cyclobutyl group, cyclopentyl group, cyclohexyl group, and the like.
[0 0 2 2]
In the present invention, the (C3-6 cycloalkylXC1-6 alkyl) group means a linear
or branched C1-6 alkyl group substituted with a cyclic C1-6 alkyl group, and examples
include, for example, cyclopropylmethyl group, cyclopropylethyl group,
cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group,
cyclobutylpropyl group, cyclopentylmethyl group, cyclopentylethyl group,
cyclopentylpropy 1 group, cyclohexylmethyl group, cyclohexylethyl group,
cyclohexylpropyl group, and the like.
In the present invention, the C1-10 aryl group means an aromatic hydrocarbon
group having 6 to 10 carbon atoms, and examples include, for example, phenyl group,
naphthyl group, azulenyl group, and the like.
In the present invention, the C7-12 aralkyl group means a C1-6 alkyl group

substituted with phenyl group, and examples include, for example, benzyl group,
phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group,
phenylhexyl group, and the like.
In the present invention, examples of the active ester residue include, for
example, phenoxy group, p-nitrophenoxy group, 1,3,5-trichlorophenoxy group,
pentafluorophenoxy group, 2,4-dinitrophenoxy group, (pyridin-2-yl)oxy group, an
ester residue derived from N-hydroxysuccinimide, an ester residue derived from N-
hydroxypiperidine, an ester residue derived from N-hydroxy-5-norbornene-2,3-
dicarboxylic acid imide, an ester residue derived from 8-hydroxyquinoline, and the
like.
[0 0 2 3]
It is clearly understood that the trans-{4-[(alkylamino)methyl]cyclohexyl}-
acetic acid esters prepared by the method of the present invention are useful as
reagents or raw material compounds for manufacture of various medicaments,
agricultural chemicals, industrial products and the like in view of the fact, for
example, that they are used as preparation raw material in Example 142 of Patent
document 1, Example 73 of Patent document 2, Example 57 of Patent document 3,
Example 14 of Patent document 4, Example 4 of Patent document 5, Example 45 of
Patent document 6, and the like.
[0 0 2 4]
Specifically, examples of the trans-{4-[(alkylamino)methyl]cyclohexyl}acetic
acid ester include, for example, trans-[4-({[6-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)indan-5-
yl](ethyl)amino}methyl)cyclohexyl] acetic acid hydrochloride (Patent document 1,
Example 111), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl] acetic
acid hydrochloride (Patent document 1, Example 115), trans-[4-({[2-({[3,5"
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 118), trans-[4-({[6-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-2,2-difluoro-l,3-benzodioxol-5-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent document 1,
Example 134), trans-[4-({[7-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-

yl)ammo}methyl)-2,2,3,3-tetrafluoro-2,3-dihydro-l,4-benzodioxin-6-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent document 1,
(Example 137), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 142), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-methyl-5-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 143), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-
bromophenyl](ethyl)amino}methyl)cyclohexyl] acetic acid hydrochloride (Patent
document 1, Example 147), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-4,5-
dimethylphenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent
document 1, Example 151), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-4-
(trifluoromethylthio)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 152),
[0 0 2 5]
trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-4-chloro-5-ethylphenyl](ethyl)amino}methyl)cyclohexyl]acetic acid
hydrochloride (Patent document 1, Example 153), trans-[4-({[2-({[3,5-
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-
(trifluoromethyl)phenyl](propyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 154), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl"2H-tetrazol-5-yl)amino}methyl)-5methoxy-4-
methylphenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent
document 1, Example 155), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](propyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 157), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-
(trifluoromethoxy)phenyl](propyl)amino}methyl)cyclohexyl]acetic acid hydrochloride

(Patent document 1, Example 158), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](p-
tolyl)amino}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetic
acid dihydrochloride (Patent document 1, Example 162), trans-[4-({[2-({[3,5-
bis(trifluoromethyl)benzyl](5-methyl-[l,2,4]oxadiazol-3-yl)amino}methyl)-4-
(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 163), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](5-
methyl-[l,2,4]oxadiazol"3-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 164), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](5-
methyl-[l,2,4]oxadiazol-3-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](propyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 165), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](propyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 1, Example 166),
[0 0 2 6]
trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl) 4- methyl- 5
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 167), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-
5-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid methanesulfonate
(Patent document 1, Example 168), ethyl trans-[4-({[2-({[3,5-
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 1,
Example 169), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 170), trans-[4-({[2-({[3-methyl-5-(trifluoromethyl)benzyl](2-methyl-2H-
tetrazol-5-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 171), trans-[4-({[2-({[3-methyl-5-(trifluoromethyl)benzyl](5-methyl-
[l,2,4]oxadiazol-3-yl)amino}methyl)-5-methyl-4-

(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 172), ethyl trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-
methyl-2-oxo-l,3-oxazolidin-3-yl}methyl)-4-
(trifluoromethyl)benzyl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 2,
Ex. 11), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-
oxazolidin-3-yl}methyl)-4-
(trifluoromethyl)benzyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
2, Ex. 13), ethyl trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-
oxo-l,3-oxazolidin-3-yl}methyl)-4-
(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 2,
Ex. 34), ethyl trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-
oxo-l,3-oxazolidin-3-yl}methyl)-4-
(trifluoromethoxy)phenyl](propyl)amino}methyl)cyclohexyl]acetate (Patent document
2, Ex. 36),
[0 0 2 7]
trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-
oxazolidin-3_yl}methyl)-4-
(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 2, Ex. 64), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-
methyl-2-oxo-l,3-oxazolidin-3-yl}methyl)-4-
(trifluoromethoxy)phenyl](propyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 2, Ex. 65), trans-[4"({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-
methyl-2-oxo-l,3-oxazolidin-3-yl}methyl)pyridin-3-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 2, Ex. 69), trans-[4-
({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-oxazolidin-3-
yl}methyl)-6-isopropenylpyridin-3-yl](ethyl)amino}methyl)cyclohexyl]acetic acid
(Patent document 2, Ex. 70), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-
4methyl-2-oxol,3-oxazolidin-3-yl}methyl)-6isopropylpyridin-3-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 2, Ex. 71), trans-[4-
({[2-({(4S,5R)-5-[3,5-bi6(trifluoromethyl)phenyl]-4-methyl- 2-oxo-l,3-oxazolidin-3-
yl}methyl)-6-cyclopropylpyridin-3-yl](ethyl)amino}methyl)cyclohexyl]acetic acid
(Patent document 2, Ex. 72), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-
4-methy 1-2-oxo-l,3-oxazolidin-3-yl}methyl)-4-

(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
2, Ex. 73), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl][5-(2-
hydroxyethoxy)pyrimidin-2-yl]amino}methyl)-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
3, Ex. 13), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](5-morpholinopyrimidin-2-
yl)amino}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic
acid (Patent document 3, Ex. 57), ethyl trans-[4-({[3-({[3,5-
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-1),
[0 0 2 8]
ethyl trans-[4-({ethyl[3-({(2-methyl-2H-tetrazol-5-yl)[3-nitro-5-
(trifluoromethyl)benzyl]amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl]amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-2), ethyl trans-[4-({[3-
({[3-cyano-5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-3), ethyl trans-[4-({[3-({[3-chloro-2-fluoro-5-
(trifluoromethyl)benzyl] (2 -methyl-2H-tetrazol- 5-yl)amino}methyl) -5 -
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-4), ethyl trans-[4-({[3-({[3,5-
bis(trifluoromethyl)benzyl](phenyl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-5), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](pheny0amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-6), ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](l-methyl-
lH-pyrazol-3-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-7), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyl-lH-pyrazol-3-yl)amino}methyl)-
5-(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-8), ethyl trans-[4-({[3-({[3,5-his(trifluoromethyl)benzyl](l-methyl-
lH-l,2,4-triazol-3-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-9), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyMH-l,2,4-triazol-3-

yl)amino}methyl) - 5- (trifluoromethy Opyridin - 2 -
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-10), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-
5-(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-11), ethyl trans-[4-({[3-({[3,5-
bis(trifluoromethyl)benzyl](methoxycarbonyl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 6-1), ethyl trans-[4-({[3-({N-[3,5-
bis(trifluoromethyl)benzyl]acetamido}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 6-2), ethyl trans-
[4-({[3-({l-[3,5-bis(trifluoromethyl)benzyl]-3,3-dimethylureido}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 6-3),
[0 0 2 9]
ethyl trans-[4-({[3-({N-[3,5-bis(trifluoromethyl)benzyl]methylsulfonamido}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 6-4), ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-5-phenylpyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 7), ethyl trans-[4-
({[5-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-3,3'-
bipyridin-6-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 8"l),
ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-chloropyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 13-1), ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-5-bromopyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 13-2), trans-[4-
({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 14), trans-[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](2-methyl-2H-
tetrazol-5-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-l), trans-[4-
({ethyl[3-({(2-methyl-2H-tetrazol-5-yl)[3-nitro-5-
(trifluoromethyl)benzyl] amino}methyl)-5-(trifluoromethyl)pyridin- 2 -

yl]amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-2), trans-[4-({[3-
({[3-cyano-5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-3), trans-[4-({[3-({[3-chloro-2-fluoro-5-(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-4),
[0 0 3 0]
trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](phenyl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-5), trans-[4-({[3-({[3-chloro-5-
(trifluoromethyl)benzyl](phenyl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-6), trans-[4-
({[3-({[3,5-bis(trifluoromethyl)benzyl](methoxycarbonyl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-7), trans-[4-({[3-({N-[3,5-
bis(trifluoromethyl)benzyl]acetamido}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclonexyl]acetic acid (Patent document 4, Ex. 15"8), trans-[4-
({[3-({l-[3,5-bis(trifluoromethyl)benzyl]-3,3-dimethylureido}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-9), trans-[4-({[3-({N-[3,5-
bis(trifluoromethyl)benzyl]methylsulfonamido}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-10), trans-
[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](l-methyl-lH-pyrazol-3-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-11), trans-[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyl-
lH-pyrazol-3-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-12), trans-
[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](l-methyl-lH-l,2,4-triazol-3-
yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-13), trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyl-lH-l,2,4-triazol-3-
yl)amino}methyl) - 5- (trifluorome thyl)pyridin - 2 -
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-14),

[0 0 3 1]
trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-bromopyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid
(Patent document 4, Ex. 16-1), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-5-phenylpyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 16-2), trans-[4-
({[5-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-3,3'-
bipyridin-6-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 16-
3), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)quinolin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 5, Ex. 4), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-
tetrazol-5-yl)amino}methyl)-6,7-difluoroquinolin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 5, Ex. 5-1), ethyl
trans-(4-{[{2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-
(methylthio)ethoxy]pyrimidin-2 -yl}amino)methyl] -4-
(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetate (Patent document 6,
Example 43), trans-(4-{[{2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-
(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetic acid (Patent document
6, Example 44), trans-(4-{[{2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-
(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetic acid (Patent document
6, Example 45), and the like, but the esters are not limited to these examples.
Compounds represented by the aforementioned general formula (6) for
preparing the specific compounds mentioned above are also preferred.
[0 0 3 2]
Among them, those compounds in which R1 in the general formula (l) is
methyl group are preferred. More specifically, examples include, for example, trans-
[4-({[6-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)indan-5-yl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 111), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-
(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride

(Patent document 1, Example 115), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 118), trans-[4-({[6-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-2,2-difluoro-l,3-benzodioxol-5-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent document 1,
Example 134), trans-[4-({[7-({[3,5-bis(trifluoromethyl)benzyl] (2-methyl-2H-tetrazol-5-
yl)amino}methyl)-2,2,3,3-tetrafluoro-2,3-dihydro-l,4-benzodioxin-6-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent document 1,
Example 137), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl) 5 - methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 142), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-methyl-5-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 143), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-
bromophenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent
document 1, Example 147), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-4,5-
dimethylphenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent
document 1, Example 151), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-4-
(trifluoromethylthio)phenyl] (ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 152),
[0 0 3 3]
trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-4-chloro-5-ethylphenyl](ethyl)amino}methyl)cyclohexyl]acetic acid
hydrochloride (Patent document 1, Example 153), trans-[4-({[2-({[3,5-
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-methoxy-4-
methylphenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride (Patent
document 1, Example 155), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](p-
tolyl)amino}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetic

acid dihydrochloride (Patent document 1, Example 162), trans-[4-({[2-({[3,5-
bis(trifluoromethyl)benzyl](5-methyl-[l,2,4]oxadiazol-3-yl)amino}methyl)-4-
(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 163), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](5-
methyl-[l,2,4]oxadiazol-3-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid hydrochloride
(Patent document 1, Example 164), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-4-methyl-5-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 167), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl"2H-tetrazol-
5-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid methanesulfonate
(Patent document 1, Example 168), ethyl trans-[4-({[2-({[3,5-
bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 1,
Example 169), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 170), trans-[4-({[2-({[3-methyl-5-(trifluoromethyl)benzyl](2-methyl-2H-
tetrazol-5_yl)aniino}methyl)"5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 171), trans-[4-({[2-({[3-methyl"5-(trifluoromethyl)benzyl](5-methyl-
[l,2,4]oxadiazol"3-yl)amino}methyl)-5-methyl-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
1, Example 172),
[0 0 3 4]
ethyltrans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-
oxazolidin-3-yl}methyl)-4-
(trifluoromethyl)benzyl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 2,
Ex. 11), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-
oxazolidin-3-yl}methyl)-4-
(trifluoromethyl)benzyl](ethyl)amino}methyl)cyclohexyl] acetic acid (Patent document
2, Ex. 13), ethyl trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-

oxo-l,3-oxazolidin-3-yl}methyl)_4-
(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 2,
Ex. 34), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-
oxazolidin-3"yl}methyl)-4-
(trifluoromethoxy)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 2, Ex. 64), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-
methyl-2-oxo-l,3-oxazolidin-3-yl}methyl)pyridin-3-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 2, Ex. 69), trans-[4-
({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-oxazolidin-3-
yl}methyl)-6-isopropenylpyridin-3-yl](ethyl)amino}methyl)cyclohexyl]acetic acid
(Patent document 2, Ex. 70), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-
4methyl-2-oxo-l,3-oxazolidin-3-yl}methyl)-6-isopropylpyridin-3-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 2, Ex. 71), trans-[4-
({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-l,3-oxazolidin-3-
yl}methyl)-6-cyclopropylpyridin-3-yl](ethyl)amino}methyl)cyclohexyl]acetic acid
(Patent document 2, Ex. 72), trans-[4-({[2-({(4S,5R)-5-[3,5-bis(trifluorometbyl)phenyl]-
4-methyl-2-oxo-l,3-oxazolidin-3-yl}methyl)-4-
(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
2, Ex. 73), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl][5-(2-
hydroxyethoxy)pyrimidin_2 -yl] amino}methyl) -4-
(trifluoromethyl)phenylKethyl)amino}methyl)cyclohexyl]acetic acid (Patent document
3, Ex. 13), trans-[4-({[2-({[3,5-bis(trifluoromethyl)benzyl](5-morpholinopyrimidin-2-
yl)amino}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino}methyl)cyclohexyl]acetic
acid (Patent document 3, Ex. 57),
[0 0 3 5]
ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5"(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5"l), ethyl trans-
[4-({ethyl[3-({(2-methyl-2H-tetrazol-5-yl)[3-nitro-5-
(trifluoromethyl)benzyl]amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl]amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-2), ethyl trans-[4"({[3-
({[3-cyano'5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent

document 4, Ex. 5-3), ethyl trans-[4-({[3-({[3-chloro-2-fluoro-5-
(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-4), ethyl trans-[4-({[3-({[3,5-
bis(trifluoromethyl)benzyl](phenyl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-5), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](phenyl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-6), ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](l-methyl-
lH-pyrazol-3-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-7), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyl-lH-pyrazol-3-yl)amino}methyl)-
5-(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-8), ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](l-methyl-
lH-l,2,4-triazol-3-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-9), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyl-lH-l,2,4-triazol-3-
yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 5-10), ethyl trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-
5-(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 5-11),
[0 0 3-6]
ethyl trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](methoxycarbonyl)amino}methyl)-
5-(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 6"l), ethyl trans-[4-({[3-({N-[3,5"
bis(trifluoromethyl)benzyl]acetamido}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 6-2), ethyl trans-
[4-({[3-({l-[3,5-bis(trifluoromethyl)benzyl]-3,3-dimethylureido}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 6-3), ethyl trans-[4-({[3-({N-[3,5-
bis(trifluoromethyl)benzyl]methylsulfonamido}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 6-4), ethyl trans-

[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yDamino}methyl)-5-
phenylpyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 7),
ethyl trans-[4-({[5-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-3,3'-bipyridin-6-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent
document 4, Ex. 8"l), ethyl tran8-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-
2H-tetrazol-5-yl)amino}methyl)-5-chloropyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex. 13-1), ethyl trans-
[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
bromopyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetate (Patent document 4, Ex.
13-2), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 14), trans-[4-
({[3-({[3-chloro-5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-1), trans-[4-({ethyl[3-({(2-methyl-2H-tetrazol-5-yl)[3-nitro-5-
(trifluoromethyl)benzyl]amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl]amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-2),
[0 0 3 7]
trans-[4-({[3-({[3-cyano-5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-3), trans-[4-
({[3-({t3-chloro-2-fluoro-5-(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-4), trans-[4-
({[3-({[3,5-bis(trifluoromethyl)benzyl](phenyl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-5), trans-[4-({[3-({[3-chloro-5-
(trifluoromethyl)benzyl](phenyl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-6), trans-[4-
({[3-({[3,5-bis(trifluoromethyl)benzyl](methoxycarbonyl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-7), trans-[4-({[3-({N-[3,5-
bis(trifluoromethyl)benzyl]acetamido}methyl)-5-(trifluoromethyl)pyridin-2-

yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-8), trans-[4-
({[3-({l-[3,5-bis(trifluoromethyl)benzyl]-3,3-dimethylureido}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-9), trans-[4-({[3-({N-[3,5-
bis(trifluoromethyl)benzyl] methylsulfonamido}methyl) - 5- (trifluoromethyl)pyridin-2 ■
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-10), trans-
[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](l-methyl-lH-pyrazol-3-yl)amino}methyl)-5-
(trifluoromethyl)pyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 4, Ex. 15-11), trans-[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyl-
lH-pyrazol-3-yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-12), trans-
[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](l-methyMH-l,2,4-triazol-3-
yl) amino}methyl) - 5 - (trifluoromethyl)pyridin- 2 -
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-13), trans-
[4-({[3-({[3-chloro-5-(trifluoromethyl)benzyl](l-methyl-lH-l,2,4-triazol-3-
yl)amino}methyl)-5-(trifluoromethyl)pyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 15-14),
[0 0 3 8]
trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)-5-bromopyridin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid
(Patent document 4, Ex. 16-1), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-
methyl-2H-tetrazol-5-yl)amino}methyl)-5-phenylpyridin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 16-2), trans-[4-
({[5-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-3,3'-
bipyridin-6-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 4, Ex. 16-
3), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-
yl)amino}methyl)quinolin-2-yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent
document 5, Ex. 4), trans-[4-({[3-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-
tetrazol-5-yl)amino}methyl)-6,7-difluoroquinolin-2-
yl](ethyl)amino}methyl)cyclohexyl]acetic acid (Patent document 5, Ex. 5-1), ethyl
trans-(4-{[{2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-
(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetate (Patent document 6,

Example 43), trans-(4-{[{2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-
(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetic acid (Patent document
6, Example 44), trans-(4-{[{2-[({l-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-
(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-
(trifluoromethyl)phenyl}(ethyl)amino]methyl}cyclohexyl)acetic acid (Patent document
6, Example 45), and the like, but the esters are not limited to these examples.
Compounds represented by the aforementioned general formula (6) for
preparing the specific compounds mentioned above are also preferred.
[0 0 3 9]
In the method of the present invention, trans-{4-[(alkylamino)methyl]-
cyclohexyl}acetic acid esters represented by the aforementioned general formula (1)
(in the formula, R1 and R2 have the same meanings as those defined above) can be
prepared from tranexamic acid by the following steps:
(a) the step of acylating tranexamic acid (2) to prepare a compound represented by
the aforementioned general formula (3) (R1 in the formula has the same meaning as
that defined above).*
(b) the step of reacting the compound represented by the aforementioned general
formula (3) (R1 in the formula has the same meaning as that defined above) obtained
in the aforementioned step (a) with a halogenating agent or an active esterifying
agent to prepare a compound represented by the aforementioned general formula (4)
(R1 in the formula has the same meaning as that defined above, and X represents a
halogen atom or an active ester residue)'
(c) the step of reacting the compound represented by the aforementioned general
formula (4) obtained in the aforementioned step (b) with diazomethane or
trimethylsilyldiazomethane to prepare a compound represented by the
aforementioned general formula (5) (R1 in the formula has the same meaning as that
defined above);
(d) the step of reacting the compound represented by the aforementioned general
formula (5) (R1 in the formula has the same meaning as that defined above) obtained
in the aforementioned step (c) with an alcohol compound represented as R2_OH (R2 in
the formula has the same meaning as that defined above) in the presence of a silver
salt and a tertiary amine to prepare a compound represented by the aforementioned

general formula (6) (R1 and R2 in the formula have the same meanings as those
defined above); and
(e) the step of reducing amide group of the compound represented by the
aforementioned general formula (6) (R1 and R2 in the formula have the same
meanings as those defined above) obtained in the aforementioned step (d).
[0 0 4 0]
The step (a) is for subjecting tranexamic acid (2) to an acylation reaction to
prepare the amide compound (3).
The acylation can be performed, for example, in an acid anhydride in the
presence of a catalytic amount of sulfuric acid. As the acid anhydride, for example,
symmetric acid anhydrides such as acetic anhydride, propionic anhydride, butanoic
anhydride, pentanoic anhydride, and hexanoic anhydride, and mixed acid anhydrides
such as acetic propionic anhydride, and acetic butanoic anhydride can be used.
However, symmetric acid anhydrides are preferred, and acetic anhydride is
particularly preferred. Although amount of the acid anhydride used is not
particularly limited, the amount may be, for example, about 1.5 to 15.0-fold moles,
preferably about 8.0 to 10.0-fold moles based on tranexamic acid (2).
[0 0 4 1]
Although this reaction can be performed in the presence or absence of a
solvent, the reaction is desirably performed without solvent. Reaction temperature
is usually in the range of -20 to 1000C, preferably 0 to 500C. Reaction time is usually
preferably 5 minutes to 24 hours, more preferably 10 minutes to 15 hours.
As for this reaction, the target amide compound (3) can also be prepared by
performing a similar reaction using an acid halide such as acetyl chloride, acetyl
bromide, propionyl chloride, and butyryl chloride instead of the acid anhydride.
[0 0 4 2]
The step (b) is for converting the carboxyl group of the amide compound (3) to
the acyl derivative (4) with a high eliminating ability by using a halogenating agent
or an active esterifying agent.
Examples of the halogenating agent used for this reaction include, for
example, oxalyl chloride, thionyl chloride, thionyl bromide, carbon tetrachloride and
triphenylphosphine, carbon tetrabromide and triphenylphosphine, cyanuric chloride
and triethylamine, and the like, and thionyl chloride can be preferably used. The

active esterifying agent may be, for example, a combination of a phenol such as
pentafluorophenol and p-nitrophenol and a condensing agent such as DCC and WSC,
/as well as a combination of triethylamine and ethyl chlorocarbonate, isobutyl
chlorocarbonate, trifluoroacetyl chloride, trichloroacetyl chloride, or the like.
Although amount of the halogenating agent or the active esterifying agent used is not
particularly limited, the amount may be, for example, about 1.0 to 50.0-fold moles,
preferably about 1.5 to 10.0-fold moles, of the carboxylic acid compound (3).
[0 0 4 3]
Although this reaction can be performed in the presence or absence of a
solvent, the reaction is preferably performed in a solvent. The solvent to be used is
not particularly limited so long as a solvent inert to the reaction is chosen.
Examples include, for example, aromatic hydrocarbon type solvents such as benzene,
toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene and nitrobenzene,
aliphatic hydrocarbon type solvents such as n-hexane, cyclohexane, n-octane and n-
decane, halogenated hydrocarbon type solvents such as methylene chloride, 1,2-
dichloroethane, chloroform and carbon tetrachloride, ether type solvents such as
diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, t-butyl methyl ether,
monoglyme and diglyme, acetonitrile, acetone, and the like. Among them, aromatic
hydrocarbon type solvents such as benzene, toluene, xylene, mesitylene,
chlorobenzene, 1,2-dichlorobenzene and nitrobenzene are preferred, and benzene and
toluene are particularly preferred. These solvents may be used independently, or
arbitrary two or more kinds of these solvents can also be used in combination.
Amount of the solvent used is not particularly limited.
Reaction temperature is usually in the range of -30 to 120°C, preferably 0 to
50°C. Reaction time is usually preferably 1 to 36 hours, more preferably 3 to 15
hours.
[0 0 4 4]
The step (c) is for reacting the compound (4) and diazomethane or
trimethylsilyldiazomethane to prepare the diazoketone compound (5).
Amount of diazomethane or trimethylsilyldiazomethane used in this reaction
is, for example, about 1.0 to 10.0-fold moles, more preferably about 1.5 to 5.0-fold
moles, of the compound (4).
This reaction is preferably performed in a solvent. Examples of the solvent

to be used include, for example, ether type solvents such as diethyl ether,
tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, t-butyl methyl ether, monoglyme and
diglyme, halogenated hydrocarbon type solvents such as methylene chloride, 1,2-
dichloroethane, chloroform and carbon tetrachloride, acetonitrile, and the like.
Among them, ether type solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane,
1,3-dioxane, t-butyl methyl ether, monoglyme and diglyme, and acetonitrile are
preferred, and a combination of tetrahydrofuran and acetonitrile is particularly
preferred.
Reaction temperature is usually in the range of-35 to 300C, preferably -20 to
200C. Reaction time is usually preferably 1 to 12 hours, more preferably 2 to 8 hours.
[0 0 4 5]
The step (d) is for reacting the diazoketone compound (5) with an alcohol
compound in the presence of a silver salt and a tertiary amine to prepare the
compound (6), in which the carbon number is increased by 1, according to the Arndt-
Eistert reaction.
By variously changing the alcohol compound used in this reaction, variety of
trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid esters (l) can be prepared. In
the alcohol compound represented as R2-OH, R2 represents the aforementioned C1-6
alkyl group, C3-6 cycloalkyl group, (C3-6 cycloalkyl)(C1-6 alkyl) group, C6-10 aryl group,
or C7-12 aralkyl group. R2 is preferably a C1-6 alkyl group, and ethanol in which R2 is
ethyl group is more preferred. Although this reaction advances with an alcoholic
solvent alone, an inert solvent such as ether type solvents may be used in
combination. Examples of such a solvent include, for example, diethyl ether,
tetrahydrofuran, 1,4-dioxane, and the like.
[0 0 4 6]
Examples of the silver salt to be used include, for example, silver oxide
(Ag2O), silver acetate (AgOCOCH3), silver trifluoroacetate (AgOCOCF3), silver
trifluoromethanesulfonate (AgOSO2CF3), silver nitrate (AgNO3), silver nitrite
(AgNO2), silver thiosulfate (AgS2O3), silver carbonate (Ag2CO3), silver benzoate
(AgOCOPh), and the like, and silver benzoate is preferred. Although amount of the
silver salt used for this reaction is not particularly limited, the amount may be, for
example, about 0.001 to 1.0-fold mole, preferably about 0.01 to 0.2-fold mole. As the
tertiary amine to be used, for example, 4-methylmorpholine, triethylamine, and the

like can be used, and triethylamine is preferred. Although amount of the tertiary
amine used for this reaction is not particularly limited, the amount may be, for
(example, about 1.0 to 10.0-fold moles, preferably about 1.2 to 3.0-fold moles.
Reaction temperature is usually in the range of -20 to 1200C, preferably 20 to
801. Reaction time is usually preferably 1 minute to 12 hours, more preferably 5
minutes to 6 hours.
[0 0 4 7]
Step (e)
This step is for subjecting the amide compound (6) to reduction in order to
prepare a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester (l).
Examples of reducing agent include, for example, sodium borohydride, sodium
cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, lithium
aluminum hydride, borane complex, and the like, and sodium borohydride is preferred.
Although amount of the reducing agent used is not particularly limited, the amount
may be, for example, about 2 to 10-fold moles of the compound (6).
[0 0 4 8]
Examples of the solvent include, for example, methanol, ethanol, n-propanol,
n-butanol, isopropanol, dichloromethane, chloroform, diethyl ether, tetrahydrofuran,
1,4-dioxane, monoglyme, diglyme, N,N-dimethylformamide, benzene, toluene, xylene,
acetic acid, mixed solvents of these solvents, and the like. Acetic acid and
tetrahydrofuran are preferred, and a combination of acetic acid and tetrahydrofuran
is particularly preferred.
Reaction temperature is usually 0 to 1400C, preferably a temperature of from
room temperature to around the boiling point of the solvent. Reaction time is
usually 1 to 24 hours, preferably 3 to 12 hours.
Examples
[0 0 4 9]
The present invention will be more specifically explained with reference to
examples. However, the scope of the present invention is not limited to the following
example.
[0 0 5 0]
Example l: Preparation of trans-{4-[(acetylamino)methyl]cyclohexyl}carboxylic acid
Tranexamic acid (10 g, 63.6 mmol) was suspended in acetic anhydride (50 mL),

this suspension was added with concentrated sulfuric acid (0.01 mL) at room
temperature, and the mixture was stirred overnight at the same temperature.
Under ice cooling, the reaction mixture was added with water (100 mL), and the
mixture was stirred at room temperature for 1 hour to decompose excess acetic
anhydride. The reaction solution was concentrated under reduced pressure, and the
residue was further azeotroped with toluene. The resulting precipitates were
collected by filtration, washed with ether, and dried under reduced pressure to obtain
trans-{4-[(acetylamino) methyl]cyclohexyl}carboxylic acid as white solid (12.46 g, 98%).
[0 0 5 1]
Example 2- Preparation of ethyl trans-{4-[(acetylamino)methyl]cyclohexyl}acetate
A suspension of trans-{4-[(acetylamino)]cyclohexyl}carboxylic acid (2.0 g, 10.0
mmol) in toluene (10 mL) was added with thionyl chloride (2.38 g, 20.0 mmol), and
the mixture was stirred at room temperature for 12 hours, and evaporated under
reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran and
acetonitrile (1:1, 15 mL), the solution was added with a solution of
trimethylsilyldiazomethane (2 M solution in ether, 10.0 mL, 20.0 mmol) in a mixture
of tetrahydrofuran and acetonitrile (1:1, 15 mL) under cooling at l50C, and the
mixture was stirred at 00C for 4 hours. The reaction solution was diluted with 5%
aqueous citric acid (50 mL), and extracted with chloroform (50 mL). The organic
layer was washed successively with saturated aqueous sodium hydrogencarbonate
and saturated brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure to obtain a diazoketone compound (5) as pale yellow crystals (2.28 g).
[0 0 5 2]
The resulting diazoketone compound was dissolved in ethanol (20 mL), the
solution was added dropwise with a solution of silver benzoate (114.5 mg, 0.50 mmol)
in triethylamine (2.20 g, 20.0 mmol) with stirring at 500C, and the mixture was
stirred for 15 minutes. The reaction solution was left to cool, and then added with
saturated aqueous sodium hydrogencarbonate (50 mL), and the mixture was extracted
with ethyl acetate (80 mL). The organic layer was washed successively with 5%
aqueous citric acid and saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The resulting residue was purified by silica
gel chromatography (acetone/hexane = 6% > 66%) to obtain ethyl trans-{4-
[(acetylamino)methyl]cyclohexyl}acetate as white solid (1.19 g, 49% for three steps).

This was recrystallized from hexane and acetone to obtain colorless needles.
IR (ATR) cm:1 3301, 2912, 2849, 1724, 1644, 1557, 1448, 1418, 1376, 1303, 1282, 1236,
1219, 1199, 1176, 1146, 1134, 1037, 747
1H-NMR (400MHz, CDC13) δ: 0.93-1.04 (4H, m), 1.25 (3H, t, J = 7.2 Hz), 1.41-1.43 (1H,
m), 1.72-1.80 (5H, m), 1.98 (3H, s), 2.18 (2H, d, J = 7.2 Hz), 3.10 (2H, t, J = 6.4 Hz),
4.12 (2H, q, J = 7.2 Hz), 5.49 (1H, br-s)
mp: 74-76°C
Elemental analysis for C13H23NO3:
Calculated: C, 64.70; H, 9.61; N, 5.80
Found: C, 64.69; H, 9.47; N, 5.84
[0 0 5 3]
Example 3: Preparation of ethyl trans-{4-[(ethylamino)methyl]cyclohexyl}acetate
Ethyl trans-{4-[(acetylamino)methyl]cyclohexyl}acetate (1.19 g, 4.93 mmol)
was dissolved in tetrahydrofuran (25 mL), the solution was added with sodium
borohydride (932 mg, 24.66 mmol), the mixture was added dropwise with a solution of
acetic acid (1.48 g, 24.66 mmol) in tetrahydrofuran (25 mL) over 1 hour under reflux
by heating, and the mixture was stirred at the same temperature for 6 hours. The
reaction mixture was added dropwise with water with stirring under ice cooling, and
the reaction was thereby quenched. The reaction mixture was made alkaline with 2
M aqueous sodium hydroxide, and extracted with ethyl acetate, and the organic layer
was successively washed with water and saturated brine, and dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced pressure, the resulting
crude product of ethyl trans-{4-[(ethylamino)methyl]cyclohexyl}acetate was dissolved
in ethanol (20 mL), the solution was added with 4 M hydrochloric acid in ethyl acetate
(6 mL), and the mixture was stirred for 12 hours. The reaction mixture was diluted
with ethyl acetate, and the organic layer was successively washed with 2 M sodium
hydroxide, water, and saturated brine, and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure to obtain the objective ethyl
trans-{4-[(ethylamino)methyl]cyclohexyl}acetate as pale brown oil (1.12 g, 99 %).
[0 0 5 4]
As described above, ethyl trans-{4-[(ethylamino)methyl]cyclohexyl}acetate
could be prepared from tranexamic acid by the preparation method of the present
invention at a total yield of 47.5%. The preparation method of the present invention

gave a higher yield than that of the known method described in the reference (yield
being 32.2% in Patent document 1), and no step for separating isomers was necessary
attributable to the use of the inexpensive tranexamic acid as the starting material.
Therefore, the method is an extremely superior method for efficiently preparing a
trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester.
Industrial Applicability
[0 0 5 5]
According to the method of the present invention, a trans-{4-
[(alkylamino)methyl]cyclohexyl}acetic acid ester, which is useful as a reagent or a raw
material compound for manufacture of medicaments, agricultural chemicals,
industrial products and the like, can be efficiently prepared in a high yield from an
inexpensive raw material compound. This method is especially advantageous for
reducing manufacturing cost and improving manufacturing efficiency from an
industrial viewpoint.

WE CLAIM
[Claim 1]
A method for preparing a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid
ester represented by the following general formula (l):
[Formula l]

(in the formula, R1 represents hydrogen atom or a C1-6 alkyl group, and R2 represents
a C1-6 alkyl group, a C3-6 cycloalkyl group, a (C3-6 cycloalkyl)(C1-6 alkyl) group, a C6-10
aryl group, or a C7-12 aralkyl group), which comprises the step of reducing amide
group of a compound represented by the following general formula (6):
[Formula 2]

(6)
(R1 and R2 in the formula have the same meanings as those defined above).
[Claim 2]
The method according to claim 1, wherein sodium borohydride is used as a
reducing agent.
[Claim 3]
The method according to claim 1 or 2, wherein R1 is methyl group.
[Claim 4]
A compound represented by the general formula (6) according to claim 1 (R1
and R2 in the formula have the same meanings as those defined above).
[Claim 5]
The compound according to claim 4, wherein R1 is methyl group.
[Claim 6]
The compound according to claim 4, which is used as an intermediate for

preparation of a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid ester represented
by the general formula (l) according to claim 1 (in the formula, R1 represents
hydrogen atom or a C1-6 alkyl group, and R2 represents a C1-6 alkyl group, a C3-6
cycloalkyl group, a (C3-6 cycle alkyl) (C1-6 alkyl) group, a C6-10 aryl group, or a C7-12
aralkyl group).
[Claim 7]
A method for preparing the compound represented by the general formula (6)
(R1 and R2 in the formula have the same meanings as those defined above) according
to claim 4 or 5, which comprises the step of reacting a compound represented by the
following general formula (5):
[Formula 3]

(R1 in the formula has the same meaning as that defined above) with an alcohol
compound represented as R2-OH (R2 in the formula has the same meanings as that
defined above) in the presence of a silver salt and a tertiary amine.
[Claim 8]
A method for preparing the compound represented by the general formula (6)
(R1 and R2 in the formula have the same meanings as those defined above) according
to claim 4 or 5, which comprises the step of reacting a compound represented by the
following general formula (4):
[Formula 4]

(R1 in the formula has the same meaning as that defined above, and X represents a
halogen atom or an active ester residue) with diazomethane or

trimethylsilyldiazomethane to prepare a compound represented by the general
formula (5) according to claim 7 (R1 in the formula has the same meaning as that
defined above); and the step of reacting the resulting compound represented by the
general formula (5) (R1 in the formula has the same meaning as that defined above)
with an alcohol compound represented as R2-OH (R2 in the formula has the same
meaning as that defined above) in the presence of a silver salt and a tertiary amine.
[Claim 9]
A method for preparing the compound represented by the general formula (6)
(R1 and R2 in the formula have the same meanings as those defined above) according
to claim 4 or 5, which comprises the step of reacting a compound represented by the
following general formula (3):

(R1 in the formula has the same meaning as that defined above) with a halogenating
agent or an active esterifying agent to prepare a compound represented by the
general formula (4) according to claim 8 (R1 in the formula has the same meaning as
that defined above, and X represents a halogen atom or an active ester residue); the
step of reacting the resulting compound represented by the general formula (4) with
diazomethane or trimethylsilyldiazomethane to prepare a compound represented by
the general formula (5) according to claim 7 (R1 in the formula has the same meaning
as that defined above).' and the step of reacting the resulting compound represented
by the general formula (5) (R1 in the formula has the same meaning as that defined
above) with an alcohol compound represented as R2-OH (R2 in the formula has the
same meaning as that defined above) in the presence of a silver salt and a tertiary
amine.
[Claim 10]
A method for preparing the compound represented by the general formula (6)
(R1 and R2 in the formula have the same meanings as those defined above) according
to claim 4 or 5, which comprises the step of acylating tranexamic acid to prepare a
compound represented by the general formula (3) according to claim 9 (R1 in the

formula has the same meaning as that defined above); the step of reacting the
resulting compound represented by the general formula (3) (R1 in the formula has the
same meaning as that defined above) with a halogenating agent or an active
esterifying agent to prepare a compound represented by the general formula (4)
according to claim 8 (R1 in the formula has the same meaning as that defined above,
and X represents a halogen atom or an active ester residue); the step of reacting the
resulting compound represented by the general formula (4) with diazomethane or
trimethylsilyldiazomethane to prepare a compound represented by the general
formula (5) according to claim 7 (R1 in the formula has the same meaning as that
defined above); and the step of reacting the resulting compound represented by the
general formula (5) (R1 in the formula has the same meaning as that defined above)
with an alcohol compound represented as R2-OH (R2 in the formula has the same
meaning as that defined above) in the presence of a silver salt and a tertiary amine.
[Claim 11]
A method for preparing a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid
ester represented by the general formula (1) according to claim 1 (in the formula, R1
and R2 have the same meanings as those defined above), which comprises'
(a) the step of acylating tranexamic acid to prepare a compound represented by the
general formula (3) according to claim 8 (R1 in the formula has the same meaning as
that defined above);
(b) the step of reacting the compound represented by the general formula (3) (R1 in
the formula has the same meaning as that defined above) obtained in the
aforementioned step (a) with a halogenating agent or an active esterifying agent to
prepare a compound represented by the general formula (4) according to claim 9 (R1
in the formula has the same meaning as that defined above, and X represents a
halogen atom or an active ester residue);
(c) the step of reacting the compound represented by the general formula (4) obtained
in the aforementioned step (b) with diazomethane or trimethylsilyldiazomethane to
prepare a compound represented by the general formula (5) according to claim 7 (R1
in the formula has the same meaning as that defined above);
(d) the step of reacting the compound represented by the general formula (5) (R1 in
the formula has the same meaning as that defined above) obtained in the
aforementioned step (c) with an alcohol compound represented as R2-OH (R2 in the

formula has the same meaning as that defined above) in the presence of a silver salt
and a tertiary amine to prepare a compound represented by the general formula (6)
/according to claim 4 (R1 and R2 in the formula have the same meanings as those
defined above); and
(e) the step of reducing amide group of the compound represented by the general
formula (6) (R1 and R2 in the formula have the same meanings as those defined above)
obtained in the aforementioned step (d).
[Claim 12]
A method for preparing a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid
ester represented by the general formula (l) according to claim 1 (in the formula, R1
and R2 have the same meanings as those defined above), which comprises one or more
steps selected from the group consisting of the steps (a) to (e) according to claim 10.
[Claim 13]
The method according to claim 11 or 12, wherein R1 is methyl group.

A method for preparing a trans-{4-[(alkylamino)methyl]cyclohexyl}acetic acid,
which is useful as a raw material compound for manufacture of medicaments and the
like, comprising the step of reducing amide group of a compound represented by the
following general formula (6) (R1 represents hydrogen atom or a C1-6 alkyl group, and
R2 represents a C1-6 alkyl group, a C3-6 cycloalkyl group, a (C3-6 cycloalkyl)(C1-6 alkyl)
group, a C6-10 aryl group, or a C7-12 aralkyl group).