Title of Invention

CARRIER FOR SEPARATION, METHOD FOR SEPARATION OF COMPOUND, AND METHOD FOR SYNTHESIS OF PEPTIDE USING THE CARRIER

Abstract Disclosed are a carrier for use for separation purpose and a method for separation of a compound which enable a chemical reaction to be performed in a liquid phase, enable a compound of interest to be separated from the liquid phase after the completion of the reaction readily, enable the separated compound to be evaluated by structural analysis or the like while the compound being bound to the carrier, and enable the compound to be separated from the carrier readily. A carrier for separation which has a reaction site capable of reacting with other compound on a benzene ring, and a long-chain group having a specified carbon atom(s) at each of the ortho-position and the para-position of the reaction site through an oxygen atom.
Full Text 1
CARRIER FOR SEPARATION, METHOD FOR SEPARATION OF COMPOUND, AND
METHOD FOR SYNTHESIS OF PEPTIDE USING THE CARRIER
TECHNICAL FIELD
The present invention relates to a carrier for separation
and a method for separating a compound, more specifically a
carrier for separation which has both a property to reversibly
change from a liquid phase state to a solid phase state and
crystallize according to changes in the composition and/or
temperature of the solution, and property to be selectively
extracted in a specific phase and/or selectively crystallized
in a specific phase according to changes in the composition
and/or temperature of the solution, and a method for
separating a compound using the carrier for separation.
BACKGROUND ART
Traditionally, in chemical processes, a method of
separating a specific ingredient which has been dissolved in
liquid as a solid has been widely used. This is because the
solidification (crystallization) of only a specific ingredient
enables separation and purification after the reaction..to..be.,
performed readily. This method, for example, in sequential
multi-step syntheses such as compound library synthesis or the
like used in the recent development and research of drugs,
etc. enables the solidified (crystallized) substance to be
easily separated and purified by solidifying (crystallizing) a
necessary or unnecessary compound after the completion of each

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reaction. Therefore, complications in the separation and/or
purification process which have traditionally caused problems
can be resolved.
Furthermore, a method of realizing the separation of a
dissolved specific ingredient from other ingredients is also .
used by selectively dissolving the specific ingredient in a
specific phase (selective partition) according to the phase
separation of liquid. This method enables a specific
ingredient to be separated without solidification
(crystallization), thereby contributing to expediting and
simplification of the process.
Such a solidification (crystallization) of a specific
ingredient dissolved in solution or a selective dissolution of
a specific ingredient in a specific phase of liquid (selective
partition) can be realized by fulfilling certain conditions
with respect to chemical and physical properties of the
compound and the relationship with a solvent.
However, the conditions of solidification
(crystallization) and selective dissolution (selective
partition) must be empirically searched in most cases by trial
and error. Especially, in sequential multi-step syntheses, it
becomes necessary to examine the conditions of each step based
on the specific property of a compound synthesized in each
step, thereby having required tremendous amounts of money and
time for the process development.
Therefore, there has been proposed a carrier molecule
having a linker capable of sensitively perceiving the

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alteration of a solvent composition so as to reversibly change
the soluble state and insoluble (crystallization) state, or
selectively dissolving a specific dissolved ingredient into a
specific phase in high concentration (selective partition)
with the phase separation of the liquid. Such a carrier -■■-..
molecule can bind various compounds via the linker. Therefore,
the bound compound can easily change states with the carrier
molecule from a soluble state to an insoluble
(crystallization) state or vice versa. Alternatively, the
compound bound to the carrier molecule can be selectively
dissolved in high concentration in a specific phase of liquid
separated into multiphase (selective partition).
Furthermore, even when the chemical structure of a
compound bound to such a carrier by the sequential multi-step
reaction alters, the carrier molecule is capable of reversibly
recreating the soluble state and insoluble (crystallized)
state or dissolving in a specific phase of liquid separated
into multiple phases selectively in high concentration
(selective partition) under approximately the same conditions.
Using such a carrier molecule capable of reversibly
changing the soluble state and insoluble (crystallized) state
or inducing the selective partition state, it is possible to
selectively separate an objective compound for separation from
a homogeneous solution state while utilizing general knowledge
of the liquid phase reaction in organic chemistry. That is, it
has become possible to separate a specific compound after the
liquid phase reaction while leaving other soluble ingredients

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in solution.
Concerning a carrier capable of reversibly repeating the
soluble state and insoluble state, for example, a method of
using a polymer soluble in solvents such as poly(ethylene
glycol) is known (see Non-patent Document 1) .
Non-patent Document 1: "Liquid-phase combinatorial
synthesis" Hyunsoo Han, Mary M. Wolfe, Sydney Brenner, and Kim
D. Janda, Proc. Natl. Acad. Sci. USA, Vol. 92, pp. 6419-6423,
July 1995 Chemistry.
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
However, when a polymer such as poly(ethylene glycol)
disclosed in Nonpatent Publication 1 is used as a carrier, it
was difficult to evaluate a compound by structural analysis,
etc. due to heterogeneity of the polymer while the compound is
bound to the carrier. Furthermore, there were problems of
complicated handling associated with difficulty in performing
the anhydrous reaction because of the hydrophilicity of
poly(ethylene glycol).
Besides the use of a carrier molecule capable of
reversibly changing the soluble state and insoluble
(crystallized) state or inducing the selective partition
state, various solid phase extraction methods using solid
carrier particles are known as the different separation method
of compound. In the solid phase extraction method, for
example, by specifically binding a ligand molecule having a '

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high affinity to a probe molecule, which has been previously
chemically bound to the surface of solid phase carriers such
as silica gel, porous polymer, alumina and active carbon, the
ligand molecule is separated differentially from other
molecules. By this method, it is easy to perform a process of
separating a substance captured by solid phase from a
substance remaining dissolved in a liquid phase, and
furthermore, it is possible to handle many samples in a short
time and also to obtain reproducible good data without
requiring expert skill, so that the method can be easily
standardized by automated devices, etc.
However, in the solid phase extraction method using solid
carrier particles, molecules other than the molecule
specifically binding to ligand molecule may nonspecifically
adsorb to the solid surface, causing the reduction of
separation accuracy. Furthermore, in order to release the
compound captured to the solid phase carrier surface again, it
was required to perform specific treatments such as chemical
treatment, biochemical treatment, light irradiation and
application of electric stimuli. Therefore, even though it was
easy to capture the objective compound from the liquid phase,
a complicated process must have been further performed in the
step of separating the objective compound from the solid
phase.
The present invention has been performed in view of the
above-described problems, and an objective of this invention
is to provide a carrier for separation and a method for

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separation of a compound that enable a chemical reaction to be
performed in a liquid phase, the specific compound to be
separated from a liquid phase readily after the completion of
the reaction, the separated compound to be evaluated by
-■-- structural analysis or the like while the compound being bound
to the carrier, and furthermore, the compound to be separated
from the carrier readily.
Means for Solving the Problems
The present inventors have ardently performed research to
solve the aforementioned problems. As a result, they have
discovered that the abovementioned problems can be solved if a
carrier for separation has a reaction site capable of binding
to other compounds on a benzene ring, and a long-chain group
having a specified number or more of carbon atoms at each of
the ortho-position and the para-position of the reaction site
through an oxygen atom, respectively, thereby achieving the
present invention. More specifically, the present invention
provides the following items.
According to a first aspect of the present invention, a
carrier for separation is represented by the following formula
(1) having a reaction site A capable of binding to another
compound through any one of a carbon atom, oxygen atom, sulfur
atom or an nitrogen atom so as to separate the other compound.


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A is a reaction site having one or more atoms selected
from the group consisting of carbon, oxygen, sulfur and
nitrogen atoms; in which
X, Y and Z are each independently selected from any one
of the group consisting of a hydrogen, a halogen, a
hydrocarbon group having a carbon number in the range of 1 to
10 which may have a substituent, an acyl group having a carbon
number in the range of 1 to 10 which may have a substituent,
benzyl group and phenyl group; and
Ri and R2 are groups, which may be identical or different,
containing at least 1 of either a hydrocarbon group having a
carbon number in the range of 14 to 60 which may be
substituted or an acyl group having a carbon number in the
range of 14 to 60 which may be substituted. )
The carrier for separation according to the first aspect
enables a chemical reaction to be performed in a liquid phase,
a specific compound contained in a liquid phase after the
completion of the reaction to be reacted with and bound to the
reaction site A, and other compounds to be selectively
separated from a liquid phase. Thus, the objective compound
can be.efficiently separated in high purity.
Furthermore, since the carrier for separation according
to the first aspect is not a polymer but a simple compound, it
enables the separated compound to be evaluated by structural
analysis or the like, while the compound is bound to the
carrier. Thus, the compound identification or the like can be
performed without performing the separation process, so that

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it is possible to shorten the time required for compound
identification and realize the promotion of research.
Furthermore, the carrier for separation according to the
first aspect enables a compound reacted with and bound to the
reaction -site-A to be separated from the carrier readily.
Thus, the objective compound can be obtained efficiently in a
shorter time compared with the case of performing traditional
complicated processes such as chemical treatment, biochemical
treatment, light irradiation and application of electric
stimuli.
Furthermore, the carrier for separation according to the
first aspect can reversibly recreate the soluble state and
insoluble (crystallized) state or dissolve in a specific phase
of liquid separated into multi-phase selectively in high
concentration under approximately the same conditions, even
when the chemical structure of other compounds bound to the
reaction site A changes by the sequential chemical reactions.
Therefore, it is unnecessary to investigate separation
conditions based on specific characteristics, etc. of
respective compounds.
Furthermore, the carrier for separation according to the
first aspect includes at least of either a hydrocarbon group
having a carbon number in the range of 14 to 60 or an acyl
group having a carbon number in the range of 14 to 60 so as to
contain a long-chain alkyl group. Thus, the carrier for
separation according to the first aspect exhibits
hydrophobicity and can dissolve into many organic solvents in

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high concentration. Therefore, the carrier for separation
according to the first aspect can be widely applied without
selecting the type of liquid into which the objective compound
is dissolved.
The carbon number of the hydrocarbon.group is preferably
in the range of 14 to 50, more preferably in the range of 16
to 40, and most preferably in the range of 18 to 30. The
carbon number of the acyl group is preferably in the range of
14 to 50; more preferably in the range of 16 to 40, and most
preferably in the range of 18 to 30. As long as the carbon
number is within the above-described range, sufficient
hydrophobicity can be exhibited, and the range of choice of
organic solvents is wide.
Furthermore, in the carrier for separation according to
the first aspect, as shown in formula (1), X, Y and Z on the
benzene ring are each independently selected from any one of
the group consisting of a hydrogen, a halogen, a hydrocarbon
group having a carbon number in the range of 1 to 10 which may
have a substituent; an acyl group having a carbon number in
the range of 1 to 10 which may have substituent; a benzyl
group; and a phenyl group. Therefore, the carrier for
separation according to the first aspect will be sufficiently
effective as a carrier for separation even when it remains to
have an unsubstituted hydrogen atom, but can be imparted with
the required characteristics in accordance with the type of
solvents and the type of compounds to be reacted with and
bound thereto, and so on by introducing a halogen, a

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hydrocarbon having a carbon number in the range of 1 to 10
which may have substituent, an acyl group having a carbon
number in the range of 1 to 10 which may have a substituent, a
benzyl group, and phenyl group.
In-the case of a hydrocarbon group which may have a-
substituent, the carbon number is preferably in the range of 1
to 8, and more preferably in the range of 1 to 6. Furthermore,
in the case of an acyl group which may have a substituent, the
carbon number is preferably in the range of 2 to 8, and more
preferably in the range of 2 to 6. If the carbon number is
within the above-described range, the carrier for separation
of the first aspect can exhibit superior solubility toward
many organic solvents.
Since the carrier for separation of the first aspect has
various effects as described above, it not only enables the
process to be developed readily, but also enables, for
example, the research and development of drugs, etc. by the
compound library synthesis or the like to be promoted, so as
to be able to eventually contribute to technical innovation in
the biochemical industry and chemical industry.
-According to a second aspect of the carrier for
separation according to first aspect of the present invention,
the carrier for separation is capable of reversibly changing
from a liquid phase state to a solid phase state, and
crystallizing or solidifying while the carrier being bound
with the other compound according to changes in the
composition and/or temperature of the solution into which the

11
carrier for separation dissolves or the liquid phase into
which the carrier for separation melts.
The carrier for separation according to the second aspect
includes one of a hydrocarbon group having a carbon number in
— the range of 14 to 60 • and- an acyl group having a carbon number.
in the range of 14 to 60, so as to contain a long-chain alkyl
group. Since a long-chain alkyl group shows hydrophobicity, it
enables the carrier for separation to dissolve in many
solvents and at the same time enables the carrier for
separation to crystallize readily by adding a solvent of high
polarity.
Therefore, the carrier for separation according to the
second aspect enables only the objective specific compound to
be crystallized or solidified accompanied with the carrier,
while ingredients other than the objective compound are left
in a liquid phase by changing the composition and/or
temperature of the solution into which the carrier dissolves
or the liquid phase into which the carrier melts. The carrier
for separation accompanied with another compound, either
crystallized or solidified, can be easily separated from the
liquid phase by filtration and so on, etc., so that a complex
excision process can be avoided.
The carrier for separation according to the second aspect
enables the objective compound to be evaluated by structural
analysis or the like without separating the objective compound
from the carrier while the compound is bound to the carrier.
Therefore, evaluation of a compound by structural analysis or

12
the like can be performed without going through the process of
separating the compound from the carrier, so that in the
research and development scene, the time required can be
shortened so as to realize promotion thereof.
According to a. third aspect of the carrier for separation
according to the first aspect, the carrier for separation is
selectively extracted and/or selectively crystallized in a
specific phase according to changes in the composition and/or
temperature of a solution into which the carrier for
separation dissolves, while the carrier is bound to the other
compound,.
The carrier for separation according to the third aspect
is a carrier which enables the carrier to be selectively
extracted (as a liquid) and/or selectively crystallized in a
specific phase of multiple phases after binding the objective
compound to the carrier while the compound is bound thereto.
Thus, only the objective specific compound can be separated
while ingredients soluble in another liquid phase than that of
the objective compound are left in the other liquid phase, so
that the complex excision process can be avoided.
When the carrier for separation according to the third
aspect is one selectively crystallized in a specific phase, it
enables the structural analysis and so on, etc. to be
performed as it is without separating the objective compound
from the carrier so as to have the same effect as that of the
above-described carrier of according to the second aspect.
In a fourth aspect of the carrier for separation

13
according to the first aspect, the carrier for separation is
capable of reversibly changing from a liquid phase state to a
solid phase state according to changes in the composition
and/or temperature of the solution in which the carrier for
separation dissolves or the liquid phase in which the carrier .....
for separation melts, and binding with the other compound in a
solid phase state.
The carrier for separation according to the fourth aspect
is one which reversibly changes from a liquid state to a solid
state according to changes in the composition and/or
temperature of solution before binding another compound,
subsequently capturing the other compound by binding it to the
carrier for separation which has transformed to the solid
phase state so as to perform the so-called solid phase
extraction.
Due to the solid state extraction, the carrier for
separation according to the fourth aspect enables the process
of separating the solid phase carrier which has captured a
compound by binding thereto from the liquid phase to be
readily performed, and subsequently enables the process for
... separating the compound from the..carrier, to. be. also..simply
carried out.
In a fifth aspect of the present invention, a method for
separation of a compound includes a dissolution process of
dissolving the carrier for separation according to the first
aspect in a soluble solvent to prepare a carrier solution; a
first binding process of binding another compound to the

14
reaction site A of the carrier for separation; a
crystallization process of crystallizing the carrier for
separation while the other compound is bound to the carrier;
or a selection process of selectively extracting and/or
selectively crystallizing the carrier for separation into a
specific phase while the other compound is bound to the
carrier.
The method of separating a compound according to the
fifth aspect is a separation method of performing
crystallization or extraction after binding the objective
compound to a carrier using the carrier for separation of the
present invention. The method of separating a compound
according to the fifth aspect includes both a case of
solidifying (crystallizing) the carrier in a single liquid
phase, while the compound is bound to the carrier, and a case
of selectively extracting (as a liquid) and/or selectively
crystallizing the carrier into a specific phase among multiple
liquid phases while the compound is bound thereto.
The method of separating a compound according to the
fifth aspect enables the specific compound to be selectively
..crystallized .or..extracted. Therefore, only the specific
objective compound can be separated while ingredient(s)
soluble in the liquid phase other than the objective compound
is/are left in the liquid phase, thereby avoiding complex
separation processes.
Furthermore, when the carrier is separated by
crystallization by way of the separation method according to

15
the fifth aspect while the carrier is accompanied with the
objective compound, structural analysis, etc. can be performed
as it is without separating the objective compound from the
carrier. Therefore, confirmation, etc. of the obtained
compound can be performed without passing through the process
of separating the compound after crystallization, so that in
the research and development scene, the time required can be
shortened so as to realize the promotion of research.
Therefore, the method of separating compound according to
the fifth aspect is able to become an innovative technique in
the separation and purification of biochemical substances, the
search for drug candidate substances, and the constitution of
novel chemical synthetic reaction methods and peptide
continuous synthesis method, etc.
In a sixth aspect of the present invention, a method of
separating a compound including a melting process of
liquidizing the carrier for separation according to the first
aspect by heating above the melting point thereof; a reaction
process of binding another compound to the reaction site A of
the liquidized carrier for separation by reacting therewith;
and a solidification process of solidifying the carrier for
separation while the other compound is bound thereto.
The method of separating a compound according to the
sixth aspect is a separation method of liquidizing the carrier
for separation itself of the present invention without using
any solvent, and solidifying the carrier after binding the
objective compound to the liquidized carrier for separation.

16
The method of separating a compound according to the
sixth aspect enables the specific compound to be selectively
bound thereto and separated therefrom. Since, in the method of
separating a compound according to the sixth aspect, the
carrier for separation is in a solid phase (solidified), only
the specific objective compound can be easily separated,
thereby avoiding a complex separation process can be avoided.
Furthermore, the method of separating a compound according to
the sixth aspect enables the objective compound to be
evaluated by structural analysis, etc. while the compound is
bound to the carrier.
According to a seventh aspect, the method of separating a
compound according to the sixth aspect further includes, after
the solidification process, a washing process of washing the
carrier for separation with a poor solvent in which the
solubility of the solidified carrier for separation is low,
while the other compound is bound thereto and/or an extraction
process of selectively extracting the carrier for separation
into a specific solvent while the other compound is bound
thereto.
The method of separating a compound according to the
seventh aspect is a method including a process of washing a
complex compound in which the solidified carrier for
separation of the present invention is bound to the objective
specific compound with a poor solvent and/or a process of
selectively extracting the complex compound into a specific
solvent. By this method, the purity of the complex compound of

17
the carrier for separation and the specific compound obtained
in the subsequent process can be increased.
According to an eighth aspect, the method of separating a
compound according to any one of the fifth to seventh aspects
includes, after the first binding.process or the reaction--
process, a second binding process of further binding another
compound to the other compound which has been bound to the
reaction site A of the carrier for separation.
The method of separating a compound according to the
eighth aspect is one including a process of binding another
compound to the other compound bound to the reaction site A of
the carrier for separation. The carrier for separation of the
present invention is capable of reversibly recreating the
soluble state and insoluble (crystallized) state or dissolving
in a specific phase of a liquid separated into multiple phases
selectively in high concentration (selective partition) under
substantially the same conditions, even when the chemical
structure of the other bound compound changes by the
sequential chemical reactions. Therefore, a plurality of other
compounds can be chemically bound in sequence to the reaction
site A of the carrier for separation of the present invention
as a point of origin.
According to a ninth aspect, a method for separation of a
compound includes a dissolution process of dissolving the
carrier for separation according to the first aspect in a
soluble solvent to prepare a carrier solution; a
crystallization process of crystallizing the carrier for

18
separation; and a capturing process of capturing the other
compound by binding thereof to the reaction site A of the
crystallized carrier for separation.
The method of separating a compound according to the
ninth aspect is a separation method of capturing the objective.,-- . ...
compound by binding it to the carrier using the carrier for
separation of the present invention first after crystallizing
(solidifying) the carrier for separation. Therefore, the
method for separating a compound according to the ninth aspect
is mainly used in the case of solidifying (crystallizing) the
carrier in a single liquid phase.
The method of separating a compound according to the
ninth aspect enables the objective specific compound to be
captured selectively in the solid phase. Therefore, only the
objective specific compound can be separated while ingredients
other than the objective compound soluble in the liquid phase
is left in the liquid phase, thereby avoiding a complex
excision process.
Furthermore, the method of separating a compound
according to the ninth aspect enables structural analysis,
etc. .to.be.performed as it is without separating the objective
compound from the carrier. Therefore, confirmation, etc. of
the obtained compound can be performed without passing through
the process of separating the compound, so that in the
research and development scene, the time required can be
shortened so as to realize promotion of research.
Therefore, the method of separating compound according to

19
the ninth aspect is able to become an innovative technique in
the separation and purification of biochemical substances, the
search for drug candidate substances, and the constitution of
novel chemical synthetic reaction methods and peptide
continuous synthesis methods, etc.
According to a tenth aspect, the method of separating a
compound according to any one from the fifth to ninth aspects
further includes an excision process of separating other
compound from the carrier for separation bound with the other
compound after the crystallization process, the selection
process, the solidification process the extraction process, or
the capturing process.
The method of separating a compound according to the
tenth aspect includes a process of separating the compound
accompanied with the carrier for separation from the carrier.
By separating the compound from the carrier, the objective
compound prepared by synthesis, etc. can be obtained as a
single compound. Furthermore, the carrier for separation can
also be subsequently reutilized after separating the compound.
According to an eleventh aspect, the method of separating
a compound according to any one from the fifth to ninth
aspects further includes a process of eliminating impurities
from a solution in which the carrier for separation dissolves
or from a liquid phase into which the carrier for separation
melts before the crystallization process, the selection
process, the solidification process, the extraction process,
or the capturing process. ■■■ •

20
The method of separating a compound according to the
eleventh aspect is one including a process of eliminating
impurities from a solution in which the objective specific
compound dissolves before the carrier for separation of the
■•■--• present invention binds with the objective specific compound..
Thereby, the purity of the complex compound of the carrier for
separation and specific compound obtained in the subsequent
process can be raised.
According to a twelfth aspect, in the method of
separating a compound according to the fifth or any one from
the eighth to eleventh, the crystallization process, the
selection process or the crystallization process is performed
by a means of changing the composition of a solution in which
the carrier for separation dissolves and/or a means of
changing the temperature of a solution in which the carrier
for separation dissolves.
The method of separating a compound according to the
twelfth aspect is a method of crystallizing the carrier bound
with the specific compound, extracting the carrier bound with
the specific compound, or crystallizing (solidifying) the
carrier itself by changing the composition and/or the
temperature of a solution in which the carrier for separation
dissolves.
The carrier for separation of the present invention
sharply responds to changes in the composition and/or
temperature of a solution in which the carrier for separation
dissolves. Therefore, the carrier for separation accompanied

21
with a compound can be crystallized or extracted, or the
carrier itself can be crystallized (solidified) using a means
of changing the composition and/or temperature of the
solution. Furthermore, in this case, other soluble substances
not bound.to.the carrier for separation can maintain the state .
left in solution.
According to a thirteenth aspect, in the method for
separation of a compound according to the twelfth aspect, the
means of changing the solution composition is a means of
adding a solvent having a high affinity toward the soluble
solvent.
The method of separating a compound according to the
thirteenth aspect is a method of adding, to a solution in
which the carrier for separation itself or the carrier for
separation bound to the compound dissolves, a solvent having a
high affinity toward the solution. The solution composition
can be altered by adding a high affinity solvent, so that the
carrier itself or the carrier for separation bound to the
compound can be crystallized or extracted.
According to a fourteenth aspect, in the method for
separation of a compound according to twelfth aspect, the
means of changing the composition is a means of dividing the
solution into multiple phases by adding a solvent having low
affinity toward the soluble solvent.
The method of separating a compound according to the
fourteenth aspect is a method of dividing a solution in which
the carrier for separation itself or the carrier for

22
separation bound to the compound dissolves into multiple
phases by adding a solvent having a low affinity toward the
solution. Thus, by adding a low affinity solvent, it is
possible to change the solution composition and divide it into
multiple phases, and at the.same time transfer the carrier for
separation itself or the carrier for separation bound to the
compound selectively to a specific phase.
According to a fifteenth aspect, in the method for
separation of a compound according to the twelfth aspect, the
means of changing the composition is a means of concentrating
the soluble solvent.
The method of separating a compound according to the
fifteenth aspect is a method of concentrating a solution in
which the complex compound of the carrier for separation and
specific compound dissolves. By concentrating the solution,
the concentration of the complex compound of the carrier for
separation and specific compound is elevated. Thus, it becomes
possible to change the solution composition and crystallize
the carrier for separation accompanied with the compound.
According to a sixteenth aspect, in the method of
separating a compound according to the twelfth aspect, the
means for changing temperature is a means of cooling the
solution.
The method of separating a compound according to the
sixteenth aspect is a method of realizing the temperature
change by cooling the solution. By cooling the solution, it is
possible to change the solution temperature and crystallize or

23
extract the carrier for separation itself or the carrier for
separation bound to the compound.
According to a seventeenth aspect, in the method of
separating a compound according to any one from the sixth to
eighth aspects or from, the tenth to eleventh .aspects, .the
solidification process is carried out by a means of adding a
poor solvent in which the solubility of the carrier for
separation is low to the carrier for separation bound to the
other compound.
According to an eighteenth aspect, in the method of
separating a compound according to any one from the seventh to
eighth aspects or from the tenth to eleventh aspects, the
extraction process is carried out by a means of adding a
solvent capable of dissolving the carrier for separation bound
with the other compound.
According to a nineteenth aspect, in the carrier for
separation according to the first aspect, in which the other
compound is an amino acid; the reaction site A is an atomic
group capable of binding to an amino acid; Ri and R2, which may
be identical or different, are groups containing a
carbohydrate group having a carbon number of which is in the
range of 14 to 30 which may have a substituent; or an acyl
group having a carbon number in the range of 14 to 30 which
may have substituent.
According to a twentieth aspect, in the carrier for
separation according to the nineteenth aspect, the reaction
site'A is an atomic group having a hydroxyl group, a thiol

24
group, an amino group or a carboxyl group capable of binding
with an amino acid.
According to a twenty-first aspect, a method of
synthesizing oligopeptide includes a dissolution process of
dissolving, the carrier for .separation according to the
nineteenth or twentieth aspect in a soluble solvent to prepare
a carrier solution; a binding process of obtaining the carrier
for separation bound to oligopeptide by binding amino acid to
the reaction site A of the carrier for separation followed by
sequentially binding other amino acids to the amino acid which
has been bound to the carrier for separation; a
crystallization process of crystallizing the carrier for
separation while the oligopeptide is bound thereto; or a
selection process of selectively extracting and/or selectively
crystallizing the carrier for separation into a specific phase
while the oligopeptide being is bound thereto; and an excision
process of excising the oligopeptide from the carrier for
separation bound to the oligopeptide after the crystallization
process and the selection process.
Since the oligopeptide synthesis method according to
twenty-first aspect can perform the synthetic reaction in the
liquid phase, the reaction efficiency and volumetric
efficiency are extremely high, so that even oligopeptides, the
synthesis of which by the solid phase reaction method is
difficult, can be synthesized. Furthermore, the carrier for
separation in the state bound to oligopeptide contained in the
liquid phase after the completion of reaction can be

25
efficiently separated in high purity. Furthermore, since a
solid phase reagent can be used when the oligopeptide is
excised from the carrier for separation bound to oligopeptide,
it is easy to eliminate the solid phase reagent different from
the- case, of excision with a soluble reagent. _. .
Therefore, the oligopeptide synthesis method according to
the twenty-first aspect enables various peptides to be easily
and speedily synthesized, and provided. This oligopeptide can
be used also as a material for synthesis of existing
oligopeptides, enabling the number of processes of peptide
synthesis to be reduced a greatly.
Herein, the carrier for separation used in the
oligopeptide synthesis method of the twenty-first aspect has,
as shown in formula (1), an atomic group having a hydroxyl
group, a thiol group, an amino group or a carboxyl group as A
to bind to an amino acid. Thus, this carrier for separation
can sequentially bind a plurality of amino acids via the
atomic group A so as to synthesize oligopeptide. Furthermore,
since the bond between this atomic group A and the
oligopeptide is relatively easily cleaved, a solid phase
reagent can be used when the oligopeptide is excised from the
carrier for separation.
This amino acid may be an amino acid having no protective
group, or may be a protected amino acid having protective
groups such as a Fmoc (9-fluorenylmethoxycarbonyl) group and
Cbz (benzyloxycarbonyl) group. Therefore, synthesized
oligopeptides include, besides unmodified oligopeptides,

26
modified oligopeptides having the protective group of an amino
acid side chain residue, amino protective group of terminal
amino acid, and carboxyl protective group.
According to a twenty-second aspect, in the oligopeptide
synthesis method according to the twenty-first aspect, in
which the crystallization process or the selection process is
performed by a means of changing the composition of a solution
in which the carrier for separation dissolves and/or a means
of changing the temperature .of a solution in which the carrier
for separation dissolves.
The oligopeptide synthesis method of the twenty-first
aspect is a method of crystallizing or extracting the carrier
for separation bound to the oligopeptide by changing the
composition and/or temperature of a solution in which the
carrier for separation dissolves.
According to a twenty-third aspect, in the oligopeptide
synthesis method according to the twenty-first or twenty
second aspect, the excision process is performed by adding a
solid phase reagent to a solution in which the carrier for
separation dissolves.
..According a twenty-fourth aspect, in the oligopeptide
synthesis method according to the twenty-third aspect, the
solid phase reagent is a solid acid reagent.
The oligopeptide synthesis method according to the
twenty-third aspect is a method of excising oligopeptide from
the carrier for separation by adding a solid phase reagent
such as a solid acid, solid base and solid reducing agent to a

27
solution in which the carrier for separation dissolves; and
the oligopeptide synthesis method according to the twenty-
fourth aspect is a method especially using a solid acid
reagent as a solid phase reagent. The excised oligopeptide and
solid phase reagent used in excision can be.easily separated
by filtration.
Effects of the Invention
The carrier for separation of the present invention
enables a chemical reaction to be performed in a liquid phase,
a specific compound contained in a liquid phase after the
completion of the reaction to be reacted with and bound to the
reaction site A, and other compounds to be selectively
separated from the liquid phase. Therefore, the objective
compound can be efficiently separated in high purity.
Furthermore, the carrier for separation of the present
invention is not a polymer, but a simple compound so that it
enables the separated compound to be evaluated readily by
structural analysis or the like while the compound is bound to
the carrier. Therefore, confirmation of a compound, etc. can
be performed without going through a separation process, so
that the. carrier for separation of the present invention can
shorten the time required for chemical synthesis and realize
promotion of research in the research and development scene.
Furthermore, the carrier for separation of the present
invention enables the compound which is reacted with and bound
to the reaction site A to be easily separated from the
carrier. Thus,' the objective compound can be obtained

28
efficiently in a shorter time compared with the case of
performing conventional complicated processes such as chemical
treatment, biochemical treatment, light irradiation and the
application of electric stimuli.
.Furthermore, the. carrier for separation of the... present
invention is capable of reversibly recreating the soluble
state and insoluble (crystallized) state, or dissolving in a
specific phase of liquid separated into multiple phases
selectively in high concentration (selective partition) under
substantially the same conditions, even when the chemical
structure of other compound bound to the carrier changes by
sequential chemical reactions. Therefore, it is unnecessary to
investigate separation conditions based on specific
characteristics, etc. of respective compounds.
Furthermore, the carrier for separation of the present
invention shows superior solubility toward many organic
solvents, so that it can be widely used without selecting the
type of liquid in which the objective compound dissolves.
Therefore, since the carrier for separation of the
present invention has the above-described effects, it is
unnecessary to examine crystallization conditions or partition
conditions based on specific properties, etc. of respective
compounds. Thus, the carrier for separation of the present
invention not only enables the process development to be made
readily, but also enables, for example, the research and
development of drugs, etc. by compound library synthesis or
the like to be promoted, so as to be able to eventually *

29
contribute to the technical innovation in the biochemical
industry and chemical industry.
Furthermore, the method for separation of a compound
according to the present invention enables a specific compound
to be selectively separated. That is, it.enables only, the
specific objective compound to be separated while
ingredient(s) soluble in a liquid phase are left therein, so
as to be able to avoid a complicated excision process.
Furthermore, the method for separation of a compound
according to the present invention can be widely applied
without selecting the type of organic solvents since the
carrier to be used shows superior solubility toward many
organic solvents.
Therefore, the method for compound separation of the
present invention can become an innovative technique in the
separation and purification of biochemical substances, search
for drug candidate substances, and constitution of a novel
chemical synthetic reaction method and peptide continuous
synthesis method, etc.
Furthermore, the present invention can synthesize various
oligopeptides simply and quickly using a carrier for
separation of the structure having one atomic group serving as
the reaction site to bind to an amino acid on the benzene ring
and one each of long chain groups having more than a specified
number of carbon atoms at each of the ortho-position and the
para-position of the atom group through an oxygen atom,
respectively. . . .

30
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a process chart showing the separation method
using a carrier for separation.
PREFERRED MODE FOR CARRYING OUT THE INVENTION
Hereinafter, preferred embodiments of the present
invention are described in detail.
Carrier for Separation
The carrier for separation of the present invention
represented by the following formula (1) has a reaction site A
to bind with other compound, and this reaction site A binds to
the other compound through any one of a carbon atom, oxygen
atom, sulfur atom or nitrogen atom so as to separate the other
compound.

(in the formula,
A is a reaction site having more than 1 atom selected
from the group consisting of carbon, oxygen, sulfur and
nitrogen atoms;
X, Y and Z are each independently selected from any one
of the group consisting of a hydrogen, a halogen, a
hydrocarbon group having a carbon number in the range of 1 to
10 which may have substituent, an acyl group having a carbon
number in the range of 1 to 10 which may have a substituent, a

31
benzyl group, 'and a phenyl group;
Ri and R2, which may be identical or different, are groups
containing more than 1 of either a hydrocarbon group having a
carbon number in the range of 14 to 60 which may be
substituted or an acyl group having a carbon number in the
range of 14 to 60 which may be substituted. )
Reaction site A
The reaction site A to bind to other compound on the
carrier for separation of the present invention includes at
least one atom selected from the group consisting of a carbon
atom, oxygen atom, sulfur atom and nitrogen atom, and may
contain a plurality of the same atom.
The size of the reaction site A is not particularly
limited, and may be sufficient as long as the reaction site A,
in its part, has a portion serving as a reaction site capable
of binding to other compound. Furthermore, although the
position in which the reaction site to bind to other compound
is present in the reaction site A is not particularly limited,
it is preferably present at the terminal end of the reaction
site A to make the reaction proceed readily.
The reaction site A binds to other compound through any
one selected from the group consisting of a carbon atom,
nitrogen atom, sulfur atom and nitrogen atom. Although, in the
reaction site A, the structure of the reaction site having any
one selected from the group consisting of a carbon atom,
nitrogen atom, sulfur atom and nitrogen atom to bind to other
compound is not particularly limited, for example, a- hydroxyl

32
group, amino group, carboxyl group, thiol group, etc. can be
exemplified.
The carrier for separation of the present invention may
be one having an atomic group A serving as a reaction site to
bind to an amino acid. The. atomic group A is not particularly
limited.
The carrier for separation of the present invention may
be one having a hydroxyl group, thiol group, amino group or
carboxyl group to bind to the amino acid so as to have an
atomic group A serving as a reaction site to bind to the amino
acid.
If this is the case, the size of the atomic group A is
not particularly limited and may be sufficient as long as a
part of the atomic group A has a hydroxyl group, thiol group,
amino group or carboxyl group. Furthermore, the position in
which the hydroxyl group, thiol group, amino group or carboxyl
group is present in the atomic group A is not particularly
limited, but it is preferably present at the terminal of the
atomic group A for making the reaction proceed readily.
Furthermore, the number of reaction sites A in the
carrier for separation of the present invention is only one on
the benzene ring. Since the carrier for separation of the
present invention has only one reaction site A, when
separating a compound having one reactive part capable of
binding to the reaction site A, the reaction ratio of the
carrier for separation to the compound becomes 1:1.
Therefore, in this case, subsequent structure analysis or the •

33
like becomes easy.
The carrier for separation of the present invention is of
a structure having long-chain groups Ri and R2 of more than a
specified number of carbon atoms at each of the ortho position
and the para position of the reaction.site A .through an oxygen
atom, respectively.
Herein, Ri and R2, which may be the same or different, are
groups containing more than 1 of either a hydrocarbon group
having a carbon number in the range of 14 to 60 or an acyl
group having a carbon number in the range of 14 to 60. The
carbon number of the hydrocarbon group is preferably in the
range of 14 to 50, more preferably in the range of 16 to 40,
and most preferably in the range of 18 to 30. The carbon
number of the acyl group is preferably in the range of 14 to
50, more preferably in the range of 16 to 40, and most
preferably in the range of 18 to 30. Specifically, alkyl
groups such as octadecyl, icosyl and docosyl groups having a
carbon number in the range of 18 to 22, and acyl groups such
as stearoyl, icosanoyl and docosanoyl groups having a carbon
number in the range of 18 to 22 can be exemplified.
Furthermore, when the atomic group A has a reactive site
to bind with the amino acid, Ri and R2, which may be the same
or different, are groups containing more than 1 of either
hydrocarbon group having a carbon number in the range of 14 to
30 or an acyl group having a carbon number in the range of 14
to 30. The carbon number of the hydrocarbon group is more
preferably in the range of 18 to 22. The carbon number of the

34
acyl group is more preferably in the range of 18 to 22.
Specifically, alkyl groups such as octadecyl, icosyl and
docosyl groups having a carbon number in the range of 18 to
22, and acyl groups such as stearoyl, icosanoyl and docosanoyl
groups having a carbon number in the range of 18 to 22 can be
exemplified.
The carrier for separation of the present invention is
carrier in which X, Y and Z on the benzene ring are
respectively any one independently selected from the group
consisting of a hydrogen, a halogen, hydrocarbons, which may
have a substituent, having carbon number in the range of 1 to
10, acyl groups, which may have a substituent, having a carbon
number in the range of 1 to 10, a benzyl group and a phenyl
group. In the case of hydrocarbon groups which may have a
substituent, the carbon number of which is preferably in the
range of 1 to 8, more preferably in the range of 1 to 6. In
the case of acyl groups, which may have a substituent, the
carbon number of which is preferably in the range of 2 to 8,
and more preferably in the range of 2 to 6.
The method of preparing the carrier for separation of the
present invention is not particularly limited. For example, a
method is cited in which after a 2,4-dihydroxybenzaldehyde
derivative and alkyl bromide are heated in the presence of
basic catalysts such as potassium carbonate to obtain an
alkyletherified benzaldhyde derivative, the aldehyde is
dissolved in a suitable solvent and reduced using reducing
agents such as' sodium bicarbonate to benzyl alcohol so as to

35
obtain the carrier for separation.
Property of the Carrier for Separation
The carrier for separation of the present invention has
properties to reversibly change from a liquid phase state to a
solid phase state according to changes in the composition
and/or temperature of a solution in which the carrier is
dissolved or a liquid phase in which the carrier melts so as
to crystallize or solidify while the carrier is bound to other
compound.
Furthermore, the carrier for separation of the present
invention also has properties to be selectively extracted
and/or selectively crystallized in a specific phase according
to changes in the composition and/or temperature of a solution
in which the carrier is dissolved while the carrier is bound
to other compound. Thus, it can be selectively extracted
and/or crystallized in a specific phase of liquid phases
divided into more than two phase.
Furthermore, the carrier for separation of the present
invention is a carrier capable of reversibly changing from a
liquid phase to a solid phase according to changes in the
composition and/or temperature of a solution in which the
carrier is dissolved or a liquid phase in which the carrier
melts so as to also have properties to bind to other compound
after becoming a solid phase state.
Method of Separating Compound
Methods of separating a compound of the present invention
include the following three methods:- (1) -a method of

36
performing crystallization and/or extraction after dissolving
the carrier for separation of the present invention in a
soluble solvent, and binding the objective specific compound
to the carrier for separation; (2) a method in which, after
melting the carrier, for separation of the present invention
itself to a liquid phase and binding the objective specific
compound to the carrier in a liquid phase, the carrier for
separation bound to the compound is solidified; and (3) a
method in which, after dissolving the carrier for separation
of the present invention in a soluble solvent and subsequently
crystallizing (solidifying) it, the objective specific
compound is captured by binding to the crystallized carrier.
Hereinafter, each method is separately explained.
(1) (i) Method of performing crystallization and/or extraction
after dissolving the carrier for separation of the present
invention in a soluble solvent and binding the objective
specific compound to the carrier for separation
The method of separating a compound, in which the carrier
for separation of the present invention is dissolved in a
soluble solvent and first the objective compound is bound to
the carrier for separation, includes: a dissolving process of
dissolving the carrier for separation of the present invention
in a soluble solvent to prepare a carrier solution; a first
binding process of binding other compound to the reaction site
A of the carrier for separation; a crystallization process of
crystallizing the carrier bound to the other compound or a
selection process of selectively-extracting and/or selectively

37
crystallizing the carrier for separation in a specific phase
while the other compound being bound thereto.
Dissolution Process
The dissolution process of the present separation method
is a process of dissolving the,carrier for separation of the...
present invention in a soluble solvent to prepare a carrier
solution. Soluble solvents used in the dissolution process are
not particularly limited as long as they are capable of
dissolving the carrier for separation of the present
invention. For example, a halogenated hydrocarbon, linear
ether, cyclic ether, cyclic or linear hydrocarbon having a
number of carbon atoms in the range of 4 to 40 can be
exemplified. More specifically, for example, dichloromethane,
tetrahydrofuran, cyclohexane, methylcyclohexane, decalin, etc.
can be exemplified. These solvents may be used by mixing one
or more than 2 types thereof.
Although the concentration of the carrier for separation
of the present invention when dissolving it in a soluble
solvent can be appropriately selected according to the
properties of the solvent to be used, a carrier for separation
and a compound to be bound to the crystallized carrier for
separation, it is usually in the range of 0.01 to 0.5 g/ml.
First Binding Process
The binding process in the present separation method is a
process of obtaining a complex compound of the carrier for
separation and other compound by binding the other compound to
the reaction site A of the carrier for separation. Binding

38
methods in the binding process are not particularly limited so
far as they are methods of binding the other compound having a
portion capable of reacting with the reaction site A to the
reaction site A of the carrier for separation dissolved in a
soluble solvent in the previous process, so that various
chemical reactions in liquid phase can be used. For example,
methods of binding by forming the ester bond and amide bond
can be exemplified.
Second Binding Process
The present separation method may be a method including,
after the above-described first binding process, a second
binding process to further bind another compound to the other
compound which has been bound to the reaction site A of the
carrier for separation. In the present separation method, it
is possible to bind a plurality of other compounds
sequentially by chemical reactions to the reaction site A as a
point of origin.
Compounds used when performing the sequential chemical
reactions are not particularly limited so far as they are
compounds capable of reacting with and binding to the compound
which has been already bound to the reaction site A of the
carrier for separation as a point of origin. Furthermore, the
sequential chemical reactions may be performed in the same
liquid phase containing the carrier for separation which has
already become a complex compound with other compounds or in a
different liquid phase after once solidifying (crystallizing)
to separate the carrier for separation which has become a

39
complex compound.
Impurity Eliminating Process
In the present separation method, it is preferable to
include an impurity elimination process for eliminating
-- impurities before performing the following crystallization
process or selection process. In the following crystallization
process or selection process, impurities contained in solution
may be sometimes crystallized or extracted together with the
carrier. Especially, when a means of distilling off all
solvents is used as a crystallization process, impurities are
precipitated together with crystals of the carrier for
separation bound to the compound as the crystallization
objective. Therefore, by previously eliminating impurities
before performing the crystallization process or selection
process, it is possible to raise the purity of the
subsequently obtained crystals of the carrier for separation
bound with the compound as the separation objective.
Although methods of eliminating impurities are not
particularly limited, for example, a method of washing a whole
solution in which a complex compound of the compound as a
separation objective and the carrier for separation is
dissolved with a solvent can be exemplified.
Crystallization Process
The crystallization process in the present separation
method is a process of crystallizing a compound bound to the
carrier for separation in a first binding process, a previous
process, or further in'a second binding process while the

40
compound is accompanied with the carrier for separation.
Although the crystallization process of the present separation
method is not particularly limited, so far as it enables the
crystallization of the compound as a separation objective
while the compound is-bound to the carrier for separation, for...
example, a means of changing the solution composition and/or
the solution temperature can be preferably used.
Selection Process
The selection process of the present separation method is
a process of selectively extracting (as a liquid) or
selectively crystallizing a compound bound to the carrier for
separation in a first binding process, a previous process, or
further in a second binding process in a specific liquid phase
while the compound is accompanied with the carrier. That is,
in the separation method including the selection process, the
liquid phase is in a state of multi-phase including more than
two phases, so that the carrier for separation accompanied by
a compound is selectively extracted (as a liquid) and/or
crystallized in a specific liquid phase of multiple phases.
Although the selection process in the present separation
method is not particularly limited, so far as the selection
process enables a specific compound, which becomes a
separation objective, to be extracted and/or crystallized
while the compound is bound to the carrier for separation, for
example, a means of changing the solution composition and/or a
means of changing the solution temperature can be preferably
used.

41
Means of Changing Composition
A means of changing the solution composition preferably
used in the crystallization process or selection process of
the present separation method is not particularly limited so
far as it enables the composition of the solution in which a
complex of the compound as a separation objective and the
carrier for separation is dissolved to be altered.
In the present separation method, as a preferable means
of changing the solution composition, for example, a means of
further adding a solvent having a high affinity toward the
soluble solvent used to dissolve the carrier for separation in
the dissolution process is exemplified. When adding a solvent
having a high affinity toward the soluble solvent, a liquid
phase is maintained as a single phase without causing phase
separation.
A high-affinity solvent may be the same as or different
from the solvent used as a soluble solvent. For example, when
dichloromethane, tetrahydrofuran, etc. is used as the soluble
solvent, acetonitrile, dimethylformamide, methanol, etc. can
be used.
In the present separation method, as another preferable
means of changing the solution composition, for example, a
means of further adding a solvent having a low affinity toward
the soluble solvent used to dissolve the carrier for
separation in the dissolution process can be exemplified. When
adding a solvent having low affinity toward the soluble
solvent, the liquid causes phase separation into-a double

42
phase. Thereby, the carrier for separation itself or the
carrier for separation bound with a compound is transferred
selectively to a specific phase.
For example, by dissolving the carrier for separation in
cyclohexane, dissolving other compound and the other arbitrary
reaction reagent or the like in dimethylformamide, and mixing
the two solutions, and subsequently, after passing through a
first binding process or furthermore a second binding process,
by adding a small amount of an aqueous solution of propylene
carbonate and ammonium salt corresponding to a low affinity
solvent, the carrier for separation bound with the other
compound can be selectively dissolved in the cyclohexane
phase.
Furthermore, as yet another preferable means of changing
the solution composition, for example, a means of
concentrating the solvent of a solution, in which the complex
compound of the compound as a separation objective and the
carrier for separation is dissolved, is exemplified. Herein,
concentration refers to partial or complete distillation of
the solvent. In addition, when the carrier for separation
bound with a compound is crystallized by the complete
distillation of the solvent, impurities and so on contained in
the solution may be crystallized together, so that it is
preferable to include a process of eliminating impurities
before performing the crystallization process.
Means of Changing Temperature
A means of changing solution temperature preferably used

43
in the crystallization process or selection process of the
present separation method is not particularly limited so far
as they are means capable of changing the temperature of the
solution in which the complex compound of the compound to be
.the separation objective and the carrier for separation is
dissolved. In the present separation method, for example, a
means of cooling the solution can be exemplified. For example,
when cyclohexane is used as a soluble solvent to dissolve the
carrier for separation, the complex compound can be
crystallized by cooling the solution to 5°C. In addition, when
a means of cooling the solvent is used as a means of changing
the solution temperature, it becomes possible to facilitate
the crystal growth by adding crystallization nuclei such as
ODS particles (silica gel to the surface of which octadecyl
group being bound) and glass beads.
Excision Process
In the method of separating a compound of the present
invention, it is preferable to include a process of separating
the complex compound of a compound to be the separation
objective and the carrier for separation obtained in the
crystallization process or the selection process into the
compound and the carrier for separation.
Methods for separation into the compound and carrier for
separation are not particularly limited so far as they are
capable of cleaving the bond between the compound and the
carrier for separation. For example, when a para-alkoxybenzyl
bond is formed, it is possible to cleave the bond by the acid

44
treatment.
(1) (ii) A method of performing crystallization and/or
extraction after dissolving the carrier for separation of the
present invention in a soluble solvent and sequentially
binding amino acids to the carrier.
The method for separation of a compound of the present
invention can be utilized as a synthesis method of a peptide
using amino acids as the other compound.
The oligopeptide synthesis method of the present
invention is a method including a dissolution process of
dissolving the carrier for separation of the present invention
in a soluble solvent to prepare a carrier solution; a binding
process of obtaining the carrier for separation bound with an
oligopeptide by binding an amino acid to the atomic group A of
the carrier for separation, and sequentially binding other
amino acids to the amino acid which has been bound to the
carrier for separation; a crystallization process of
crystallizing the carrier for separation while the
oligopeptide is bound to the carrier for separation or a
selection process of selectively extracting and/or selectively
crystallizing the carrier for separation in a specific phase
while the oligopeptide is bound to the carrier for separation;
and an excision process of excising the oligopeptide from the
carrier for separation bound with the oligopeptide after the
crystallization process or the selection process.
Except that amino acids as other compounds are
sequentially bound to the carrier for separation"so as to make

45
the carrier for separation to hold a peptide, the present
method is common to the method (1) (i), in which
crystallization and/or extraction are performed after the
carrier for separation of the present invention is dissolved
in a soluble solvent and the objective specific compound is
bound to the carrier for separation, with respect of the
dissolution process, impurity elimination process, and
selection process (a means of changing the solution
composition, a means of changing the solution temperature).
Regarding the processes, see the above descriptions.
Binding Process
In the binding process, after binding an amino acid to
the atomic group A which is the reaction site of the carrier
for separation to obtain a complex compound of the amino acid
and the carrier for separation, other amino acids are
sequentially bound to the amino acid which has been bound to
the atomic group A so as to obtain a complex compound of
oligopeptide and the carrier for separation. That is, in the
binding process, a plurality of amino acids are sequentially
bound in a desired order with the atomic group A as a point of
origin to obtain a complex compound of oligopeptide and the
carrier for separation. The sequential binding may be
performed in the same liquid phase containing the carrier for
separation which has become a complex compound with the amino
acid or oligopeptide, or in a different liquid phase once
after the carrier for separation which has become a complex
compound is solidified (crystallized) and separated.

46
Although the amino acids to be bound in this binding
process are not particularly limited, protected amino acids
used in the conventional solid phase reaction method such as
Fmoc-amino acids and Cbz-amino acids can be used. Furthermore,
- the number of. amino acids, to ba. bound, to the carrier for
separation is not particularly limited, but preferably is in
the range of 2 to 5.
Crystallization Process
In the crystallization process, the oligopeptide which
has been bound to the carrier for separation in the previous
binding process is crystallized while the oligopeptide is
accompanied by the carrier for separation. In this
crystallization process, any means may be used as far as the
carrier for separation can be crystallized while the carrier
for separation is bound with oligopeptide such as, for
example, a means of changing the solution composition and/or a
means of changing the solution temperature can be preferably
used. In addition, when crystallization is performed after
deprotecting the amino acid, it is possible to make the
complex compound to crystallize easily by adding a weak acid
such as formic acid to form the salt.
Excision Process
In the excision process, the oligopeptide is excised from
a complex compound of oligopeptide with the carrier for
separation obtained in the crystallization process or
selection process. In the excision process, although a soluble
reagent such as trifluoroacetic acid may be used;- it is not

47
easy to separate the acid from the excised oligopeptide, so
that a solid phase reagent is preferably used. Solid phase
reagents used in the excision process are not particularly
limited so far as they are capable of excising oligopeptide
from the complex compound, so that, for example, a solid acid,
solid base and solid reducing agent can be used. Among them,
as the solid acid reagent, for example, an acidic ion-exchange
resin, acidic metal oxide, acidic combined metal oxide, metal
sulfate, metal phosphate, crystalline metalosilicate, zeolite,
silica alumina, etc. can be exemplified. More specifically,
for example, a zeolite catalyst and montmorillonite can be
exemplified.
(2) Method of solidifying the carrier for separation of the
present invention after melting the carrier for separation
itself to a liquid phase and binding a specific objective
compound thereto in a liquid phase
The separation method in which the carrier for separation
itself of the present invention is melted to a liquid phase
and reacted with a specific compound in the liquid phase
includes a melting process of heating the carrier for
separation of the present invention above the melting point to
melt it to a liquid phase; a reaction process of reacting
other compound with the reaction site A of the melted carrier
for separation so as to bind the compound thereto; and a
solidification process of solidifying the carrier for
separation while the other compound is bound thereto.
Melting Process ^ - ■

48
The melting process in the present separation method is
not particularly limited so far as it is a process of heating
the carrier for separation above the melting point to melt the
carrier itself to a liquid phase.
Reaction Process ................
The reaction process in the present separation method is
a method of binding other compound to the reaction site A of
the carrier for separation to obtain the complex compound of
the carrier for separation and the other compound. The binding
method in the reaction process is not particularly limited so
far as it is a method of binding the other compound having a
part capable of reacting with the reaction site A of the
carrier for separation which has been fluidized in the
previous process, so that, similar to the above-described
first binding process, various chemical reactions in a liquid
phase can be used. For example, a method of binding by forming
the ester bond and amide bond can be exemplified. Also in the
reaction process, for the purpose of maintaining the liquid
phase, it is preferable to maintain the reaction temperature
higher than the melting point of the carrier for separation.
Second Binding Process
The present separation process may include, after the
above-described reaction process, a second binding process of
further binding another compound to the other compound which
has been bound to the reaction site A of the carrier for
separation. The second binding process can be performed under
similar conditions as those of the above-described second

49
binding process.
Impurity Eliminating Process
Furthermore, in the present separation method, it is
preferable to include an impurity eliminating process for
eliminating impurities before performing the.following
solidification process similar to the above-described
separation method.
Solidification Process
The solidification process in the present separation
method is process in which after implementing the reaction
process or furthermore a second binding process to the melted
and fluidized carrier for separation to bind the other
compound, etc., the carrier for separation is solidified to a
solid phase while these compounds are bound to the carrier for
separation. Although the method of solid phase transition in
the solidification process is not particularly limited, it is
preferable to perform the solid phase transition by a means of
adding a poor solvent, in which the solubility of the complex
compound of a compound to be the separation objective and the
carrier for separation is low, to the complex compound because
of easy operation.
Washing Process
Although, in the present separation method, separation of
the objective specific compound is completed by a solid phase
obtained in the above-described solidification process, a
washing process may be arbitrarily implemented. The washing
" process is a process' of washing the solid carrier for

50
separation bound to the other compound with a poor solvent in
which the solubility of this solid is low.
Impurity Elimination Process
In the present separation method, it is preferable to
further include.the.impurity elimination process to eliminate
impurities before performing the following extraction process
similar to the above-described separation method.
Extraction Process
In the present separation method, it is preferable to
include an extraction process of selectively extracting the
complex compound of a compound to be the separation objective
and the carrier for separation into a specific solvent after
the abovementioned solidification process or washing process.
Although the extraction process is not particularly limited,
it is preferable to perform the extraction process by a means
of adding a solvent capable of dissolving the complex compound
of a compound to be the separation objective and the carrier
for separation.
Excision Process
Furthermore, in the present separation method, it is
preferable to include a process to separate the complex
compound of a compound to be the separation objective and the
carrier for separation into the compound and the carrier for
separation after the above-described solidification process or
extraction process, similar to the aforementioned separation
method. When ending the operation with the solidification
process, the excision process may be included after the

51
solidification process, and when implementing procedures up to
the extraction process, the excision process may be included
after the extraction process.
(3) Method of binding and capturing the objective specific
compound (with the carrier for separation) after dissolving
the carrier for separation of the present invention in a
soluble solvent and subsequently crystallizing (solidifying)
the same
The method for separation of a compound in which the
carrier for separation of the present invention is dissolved
in a soluble solvent and subsequently crystallized
(solidified) before binding the objective compound to the
carrier for separation includes: a dissolution process of
dissolving the carrier for separation of the present invention
in a soluble solvent to prepare a carrier solution; a
crystallization process of crystallizing the carrier for
separation; and a capturing process of capturing other
compound by binding the other compound to the reaction site A
of the crystallized carrier for separation.
Dissolution Process
The dissolution process in the present separation method
can be performed by the same procedure as in the above-
described dissolution process.
Crystallization Process
The crystallization process in the present separation
method is a process of crystallizing (solidifying) the carrier
for separation' itself. Although the crystallization process in

52
the present separation method is not particularly limited, so
far as it is capable of crystallizing (solidifying) the
carrier for separation, for example, a means of changing the
composition of a solution in which the carrier for separation
itself is dissolved and/or a means of changing the temperature
of a solution in which the carrier for separation itself is
dissolved can be preferably used.
Impurity Eliminating Process
Furthermore, in the present separation method, it is
preferable to include an impurity eliminating process before
implementing the following capturing process, similar to the
above-described separation method.
Capturing Process
The capturing process in the present separation method is
a process of binding a specific other compound having a part
reactive to the reaction site A of the carrier for separation,
which has been crystallized (solidified) in the previous
process, to the reaction site A so as to obtain the complex
compound of the carrier for separation and the other compound.
The capturing process in the present separation method is not
particularly limited, so far as it is a process (method) of
binding the reaction site A and a specific other compound. For
example, amide binding and ester binding can be exemplified.
Excision Process
Furthermore, in the present separation method, similar to
the above-described separation method, it is preferable to
include a process of separating the complex compound of a

53
compound to be the separation objective and the carrier for
separation obtained in the capturing process into the compound
and the carrier for separation.
.EXAMPLES
Next, the present invention is further described in
detail with reference to Examples, but it is not to be
construed as being limited thereto.
Example 1
Synthesis of Carrier for Separation
Hereinafter, a synthesis process chart of the carrier for
separation of the present invention (compounds 2 and 5 in the
figure) is shown. Numerals in the figures represent the
compound numbers.

Synthesis of 2,4-bisoctadecyloxyphenylmethanol (Compound 2)
After 2,4-dihydroxybenzaldehyde (compound 1) (1 g (0.0072
mol)) and octadecyl bromide (4.82 g (0.0145 mol)) were
dissolved in dimethylformamide (DMF) (20 ml), potassium
carbonate (5 g (0.0372 mol)) was added, and the resulting
mixture was stirred under a- nitrogen atmosphere at 100°C- for 6 -

54
hours. The reaction liquid thus obtained was extracted with
hexane (3 x 100 ml), and subsequently this hexane solution was
concentrated under vacuum. Methanol (MeOH) (200 ml) was added
to the residue, and crystals thus produced were separated by
filtration. After crystals thus obtained were dissolved in
tetrahydrofuran (THF) (80 ml) and methanol (MeOH) (30 ml),
sodium borohydride (0.7 g (0.0184 mol)) was added to the
solution under stirring in an ice bath, and after stirring
further for 1 hour, acetone (20 ml) was added to the mixture
to terminate the reaction. Subsequently, after concentration
under vacuum, water (50 ml) was added to the residue. The
reaction solution thus obtained was extracted with hexane (3 x
100 ml), dried over anhydrous magnesium sulfate, and the
solvent was distilled off under vacuum. Furthermore, methanol
(MeOH) (200 ml) was added to the residue, and crystals thus
produced were separated by filtration to obtain the objective
compound 2 (2,4-bisoctadecyloxyphenylmetanol). The yield was
71%.
^-NMR (400 MHz, CDC13)
6 7.12 (d, J = 8.05, 1H), 6.45 (d, J = 2.20, 1H), 6.41
(dd, J = 8.05, 2.20, 1H), 4.60 (d, J = 6.59, 2H), 3.97 (t, J =
6.59, 2H), 3.93 (t, J = 6.59, 2H), 1.86 - 1.69 (m, 4H), 1.52 -
1.15 (m, 60H), 0.93 - 0.83 (m, 6H)
13C-NMR (75 MHz, CDC13)
5 160.1, 158.2, 129.5, 121.7, 104.4, 99.8, 68.1, 68.0,
61.9, 31.9, 29.7, 29.6, 29.4, 29.3, 29.2, 26.1, 26.0, 22.7,
14.1 ■ -

55
Evaluation of Solubility
The compound 2 (2,4-bisoctadecyloxyphenylmethanol) thus
obtained was measured for solubility in hexane, cyclohexane,
dichloromethane and tetrahydrofuran, respectively, when used
as solvents at 25°C. Results are shown in. Table,1.
Table 1

Solubility at 25°C (mg/ml)
Solvent Example 1
(Compound 2) Comparative Example 1
(Compound 6)
Hexane 46.6 3
Cyclohexane 145 10
Dichloromethane 242 46
Tetrahydrofuran 370 184
Comparative Example 1
3,4,5-Tris-octadecyloxybenzylalcohol (compound 6) having
the following chemical formula was measured for solubility in
various solvents at 25°C similar to as in Example 1. Results
are shown in Table 1.

As shown in Table 1, compound 2 (2,4-
bisoctadecyloxyphenylmethanol), one of the carriers for
separation of the present invention is higher in solubility in
commonly used solvents than the conventional compound 6
(3, 4, 5-tris-octadecyloxybenzylalcohol). Thus, the carrier for
separation of the present invention can aim at improving the
productivity.

56
Example 2
Synthesis of 2,4-bis-(2-decyl-tetradecyloxy)-phenylmethanol
(compound 5)
2-Decyl-l-tetradecanol (compound 3) (9.7 g (0.0274 mol))
■-• and pyridine (10.6 g (0.134 mol)) were dissolved in
dichloromethane (100 ml), and tosyl chloride (15.5 g (0.0813
mol)) was added under stirring in an ice bath. After stirring
for 3 hours at room temperature, ice water (20 ml) was added
to the mixture to terminate the reaction. Hexane (200 ml) was
added to the obtained reaction solution, and after washing the
organic layer with 1 N HC1 (3 x 100 ml), it was washed with a
saturated sodium bicarbonate aqueous solution (3 x 100 ml),
and further with a saturated NaCl solution three times. After
drying over anhydrous magnesium sulfate, the solvent was
distilled off under vacuum to obtain compound 4 (toluene-4-
sulfonic acid 2-decyl-l-tetradecyl ester). The yield was 88 %.
XH-NMR (300 MHz, CDC13)
5 7.78 (d, J = 8.25, 2H), 7.33 (d, J = 8.44, 2H) , 3.91
(d, J = 5.14, 2H), 2.44 (s, 3H), 1.65 - 1.51 (m, 1H), 1.38 -
1.02 (m, 40H), 0.90 - 0.78 (m, 6H)
After 2,4-dihydroxybenzaldehyde (293 mg (0.0021 mol)) and
the above-obtained compound 4 (toluene-4-sulfonic acid 2-
decyl-1-tetradecyl ester) (2.8 g (0.0055 mol)) were dissolved
in dimethylformamide (DMF) (20 ml), potassium carbonate (1.5 g
(0.0109 mol)) was added, and the resulting mixture was stirred
under a nitrogen atmosphere at 100°C for 16 hours. The
reaction solution thus obtained was extracted with hexane (3 x

57
100 ml), and the obtained hexane solution was washed with a
saturated NaCl aqueous solution (3 x 100 ml). Subsequently,
after the hexane solution was dried over anhydrous magnesium
sulfate and concentrated under vacuum, the residue was
- dissolved in tetrahydrofuran (THE) (100 ml) and methanol
(MeOH) (40 ml), and sodium borohydride (240 mg (0.0063 mol))
was added to the solution under stirring in an ice bath. After
the mixture was stirred further for 1 hour, acetone (20 ml)
was added to terminate the reaction. After the concentration
under vacuum, water (50 ml) was added, and the reaction
solution was extracted with hexane (3 x 100 ml). Furthermore,
after the combined hexane extracts were dried over anhydrous
magnesium sulfate, the solvent was distilled off under vacuum,
and the residue was purified by fractionation using silica gel
chromatography (developing solution, hexane : ethyl acetate =
20 : 1) to obtain the objective compound 5 (2,4-bis-(2-decyl-
tetradecyloxy)-phenylmethanol. The yield was 70%.
^-NMR (300 MHz, CDC13)
6 7.13 (d, J = 8.07, 1H), 6.47 - 6.38 (m, 2H), 4.61 (d, J
= 6.42, 2H), 3.84 (dd, J = 17.87, 6.42, 4H), 1.86 - 1.63 (m,
2H), 1.52 - 1.13 (m, 80H), 0.97 - 0.75 (m, 12H)
Example 3
Separation Method Using Carrier for Separation
Hereinafter, a process chart of the separation method
using the carrier for separation (compound 2) obtained in
Example 1 is shown. Numerals in the figures represent the
compound numbers.

58

First. Binding Process.
Compound 2 (2,4-bis-octadecyloxyphenylmethanol), the
carrier for separation of the present invention obtained in
Example 1 (1 g (1.5502 mmol)), 4-iodobenzoic acid (0.77 g
(3.1046 mmol)) and dimethylaminopyridine (100 mg (0.8195
mmol)) were dissolved in dichloromethane (50 ml), and
diisopropylcarbodiimide (0.98 g (7.7778 mmol)) was further
added, and the resulting mixture was stirred for 2 hours at
room temperature. Subsequently, after distilling off the
solvent under vacuum, methanol (MeOH) (200 ml) was added to
the residue, and crystals were filtered to obtain 4-iodo-
benzoic acid 2,4-bis-octadecyloxybenzyl ester (compound 7).
The yield was 81%.
1H-NMR (300 MHz, CDC13)
6 7.78 - 7.71 (m, 4H), 7.27 (d, J = 8.4, 1H), 6.48 - 6.42
(m, 2H) , 5.32 (s, 2H) , 4.02 - 3.87 (m, 4H) , 1.51 - 1.13 (m,
64H) , 0.95 - 0.80 (m, 6H)
Second Binding Process (process of coupling other compound to
the compound bound to carrier)
To the above-obtained compound 7 (4-iodo-benzoic acid
2,4-bis-octadecyoxybenzylester) (251 mg (0.2868 mmol)),
palladium acetate (II) (3.2 mg (0.0151 mmol)) and tri-o-
tolylphosphine (8.7 mg (0.0286 mmol)) was added

59
dimethylformamide (DMF) (20 ml), and the mixture was stirred
for 10 min. To the mixture thus obtained were added potassium
phosphate (183 mg (0.8632 mmol)), 2-naphthaleneboronic acid
(148 mg (0.8605 mmol)) and cyclohexane (20 ml), and the
mixture was stirred at 80°C for 20 hours. Upon cooling the
reaction solution to room temperature, it became a two-layer
solution. After recovering only the upper layer and
concentrating it under vacuum, crystals formed were filtered
by adding methanol (MeOH) (200 ml) to obtain compound 8 (4-
naphthalen-2-yl-benzoic acid 2,4-bis-octadecyloxybenzylester)
formed by coupling another compound to the compound bound to
the carrier for separation. The yield was 80%.
^-NMR (300 MHz, CDC13)
5 8.16 (d, J = 8.3, 2H), 8.06 (s, 1H), 7.97 - 7.82 (m,
3H), 7.80 - 7.69 (m, 3H), 7.57 - 7.44 (m, 2H), 7.33 (d, J =
8.8, 1H) , 6.53 - 6.41 (m, 2H), 5.38 (s, 2H), 4.04 - 3.88 (m,
4H), 1.51 - 1.12 (m, 64H), 0.95 - 0.79 (m, 6H)
Separation Process
After the above-obtained compound 8 (4-naphthalen-2-yl-
benzoic acid 2,4-bis-octadecyloxybenzylester) (100 mg) was
dissolved in dichloromethane (30 ml), trifluoroacetic acid
(0.3 ml) was added, and the mixture was stirred at room
temperature for 30 min. Subsequently, after distilling off the
solvent under vacuum and adding methanol (MeOH) (100 ml) to
the residue, crystals were removed by filtration. The filtrate
was distilled off under vacuum to obtain 4-naphthalen-2-yl-
benzoic acid. The yield was 95%.

60
Evaluation of Separation Efficiency
By stirring the obtained compound 7 (4-iodo-benzoic acid
2,4-bis-octadecyloxybenzyl ester) in solvents listed in Table
2 and for the times shown in Table 2, separation of the
compound from the carrier was performed to.obtain the reaction
rate. In this case, the reaction rate was calculated by
assessing the disappearance of material by HPLC. Results are
shown in Table 2.
Table 2

Reaction rate (%)*
Excision reaction system Example 3
(compound 7) Comparative example 2
(compound 9)
1% Trifluoroacetic
acid/dichloromethane 30 min 100 1 10% Trifluoroacetic
acid/dichloromethane 120 min 100 12
50% Trifluoroacetic
acid/dichloromethane 120 min 100 100
* Material consumption evaluated by HPLC measurement
Comparative example 2
Regarding compound 9 (4-iodo-benzoic acid 3,4,5-tris-
octadecyloxybenzyl ester) having the following formula 6,
which was prepared by condensing 4-iodobenzoic acid to
compound 6 (3,4,5-tris-octadecyloxybenzyl alcohol), the
separation reaction rate was measured under various conditions
similar to in Example 2. Results are shown in Table 2.

As shown in Table 2, compound 7 (4-iodo-benzoic acid 2,4-

61
bis-octadecyloxybenzyl ester), one of complex compounds of the
carrier for separation of the present invention and other
compound, enables the separation process to be terminated
under more moderate conditions and in a shorter time when
compared with compound 9 (4-iodo-benzoic acid 3,4,5-tris-
ocatadecyloxybenzyl ester), one of condensation products of
the conventional carrier with the other compound. Therefore,
the carrier for separation of the present invention can be
applied even to acid-labile compound.
Example 4
The synthesis reaction was performed similar to Example
1, except for using 1-bromodocosane (5.64 g (0.0145 mol)) in
place of octadecyloxybromide to obtain the objective compound
(2,4-bis-docosanoxyphenyl methanol). The yield was 72%.
NMR measurement results are shown below.
^-NMR (400 MHz, CDC13)
5 7.12 (d, J = 8.29, 1H), 6.45 (d, J = 2.20, 1H), 6.41
(dd, J = 8.29, 2.20, 1H), 4.60 (d, J = 6.59, 2H), 3.97 (t, J =
6.59, 2H), 3.93 (t, J = 6.59, 2H), 2.26 (t, J = 6.59, 1H),
1.78 (m, 4H), 1.44 (m, 72H), 0.88 (t, J= 6.83, 6H)
As a result of measuring the solubility of the obtained
compound toward (in) tetrahydrofuran similar to Example 1, the
solubility at 25°C was 236 mg/ml.
Synthesis was performed similarly to in the first binding
process of Example 3, except for using the above-described
compound (1.17 g) in place of 2,4-bis-octadecyloxyphenyl
methanol to obtain 4-iodo-benzoic acid 2,4-bis-

62
docosanoxybenzyl ester. The yield was 80%.
1H-NMR (300 MHz, CDC13)
5 7.78 - 7.71 (m, 4H) , 7.27 (d, J = 8.4, 1H) , 6.48 - 6.42
(m, 2H), 5.32 (s, 2H) , 4.02 - 3.87 (m, 4H), 1.86 - 1.65 (m,
4H) , 1.51 -.1.13. (m, . 7.6H) , 0.95 -.0.80 (m,. 6H)
The above-obtained compound was evaluated for the
separation efficiency, similar to Example 3, when it was
stirred in dichloromethane containing 1% trifluoroacetic acid
for 30 min. As a result, the reaction rate was 100%.
Example 5
Separation Method Using Carrier for Separation (reaction
using microwave)
Hereinafter, a process chart of the separation method
using the carrier for separation (compound 2) obtained in
Example 1 is shown. Numerals in the figures represent the
compound numbers.

First Binding Process
Compound 2 (2,4-bis-octadecyloxyphenylmethanol), the
carrier for separation of the present invention obtained in
Example 1 (1 g (1.5502 mmol)), 4-bromobenzoic acid (0.62 g
(3.1046 mmol)) and dimethylaminopyridine (100 mg (0.8195
mmol)) were dissolved in dichloromethane (50 ml), and
diisopropylcarbodiimide (0.98 g (7.7778 mmol)) was further
added, and the resulting mixture was stirred for 2 hours at

63
room temperature. Subsequently, after distilling off the
solvent under vacuum, methanol (MeOH) (200 ml) was added to
the residue, and crystals were filtered to obtain compound 10
(4-bromo-benzoic acid 2,4-bis-octadecyloxybenzyl ester). The
yield was 84%.
Second Binding Process (process of coupling other compound to
the compound bound to carrier)
To the above-obtained compound 10 (4-bromo-benzoic acid
2,4-bis-octadecyoxybenzyl ester) (24.8 mg (0.03 mmol)) and
[1,1-bis-(diphenylphosphino)ferrocene]palladium (II) chloride
(1.1 mg (0.0015 mmol)) was added dimethylformamide (DMF) (5
ml), and the mixture was stirred for 10 min. To the resulting
mixture were added potassium phosphate (19.0 mg (0.09 mmol)),
3-methoxycarbonyl boronic acid (13.5 mg (0.075 mmol)) and
cyclohexane (5 ml), and the mixture was irradiated with a
microwave at 50 W for 10 min. After the irradiation, the
mixture was cooled to room temperature to separate it to two
phases. The upper layer was removed, and the solvent was
distilled off under vacuum. Methanol (30 ml) was added to the
residue, and crystals were filtered to obtain compound 11
(biphenyl-3,4'-dicarboxylic acid 4'-(2,4-bis-octadecyloxy-
benzyl) ester methyl ester. The yield was 99%.
Example 6
Separation Method Using Carrier for Separation (flow synthetic
reaction using microwave)
Fig. 1 shows a process chart of the separation method
using the carrier for separation (compound 2) obtained in - -.-

64
Example 1. Numerals in the figures represent compound numbers.
First Binding Process
Compound 2 (2,4-bis-octadecyloxyphenylmethanol), which is
the carrier for separation of the present invention obtained
in Example 1 (1 g (1..5502 mmol) , 2-iodo-benzoic acid (0.77 g
(3.1046 mmol)) and dimethylaminopyridine (100 mg (0.8195
mmol)) were dissolved in dichloromethane (50 ml), and
diisopropylcarbodiimide (0.98 g (7.7778 mmol)) was further
added, and the resulting mixture was stirred for 2 hours at
room temperature. Subsequently, after distilling off the
solvent under vacuum, methanol (MeOH) (200 ml) was added (to
the residue), and crystals were filtered to obtain compound 12
(2-iodo-benzoic acid 2,4-bis-octadecyloxybenzyl ester). The
yield was 79%.
Second Binding Process (process of coupling other compound to
the compound bound to carrier)
The above-obtained compound 12 (2-iodo-benzoic acid 2,4-
bis-octadecyoxybenzyl ester) (26.2 mg (0.03 mmol)) was
dissolved in cyclohexane (4 ml). Separately, to
dimethylformamide (4 ml) were added ethinylbenzene (30.6 mg
(0.3 mmol)), dichloro-bis(triphenylphosphin)palladium (II)
(4.2 mg (0.006 mmol)), triethylamine (30.3 mg (0.3 mmol)) and
copper iodide (0.5 mg (0.003 mmol)), and the mixture was
stirred. To the resulting mixture was added a cyclohexane
solution of the above-obtained compound 12, and after air was
replaced with nitrogen, flow synthesis was performed by the
method shown in Fig. 1. In this case, the tube was made of 1 .

65
mm diameter Teflon (trademark), a tube of 170 cm being
embedded in the microwave irradiation unit. While vigorously
stirring the supply unit, the solution was supplied from the
supply unit toward the recovery unit under microwave
irradiation at 150 W and at flow rate of 3 ml/min. After
running the entire solution, compound 13 (2-stilbenezoic acid
2,4-bis-octadecyloxybenzyl ester) was obtained from the upper
layer of the recovery unit. The yield was 90%.
Example 7
Fmoc-dipeptide Synthesis Using the Carrier for Separation of
the Present Invention
Dissolution of Carrier for Separation
2,4-Bis-dococyloxybenzyl alcohol represented by the
following formula (2) (JITSIBO Co. Ltd, trade name: Hiver-Kb-
OH) (hereinafter abbreviated as "Kb") was used as a carrier
for separation, and 3800 mg (5 mmol) thereof was dissolved in
dichloromethane (200 ml) to prepare a carrier solution.

Binding of the First Amino Acid to Carrier for Separation
To the above-obtained carrier solution were added Fmoc-
glycine (Gly)-OH (2300 mg (7.5 mmol)), dimethylaminopyridine
(120 mg (1 mmol)) and diisopropylcarbodiimide (1.5 ml (10
mmol)) respectively, and the mixture was stirred for 30 min at
room temperature. Completion of the reaction was confirmed by
TLC (thin layer chromatography). After the reaction,

66
acetonitrile (200 ml) was added to the reaction mixture, and
the solvent was distilled off slowly under vacuum. Crystals
thus obtained were filtered with a Kiriyama funnel to obtain
the objective compound Kb-Gly-Fmoc. The yield was 92%.
Furthermore, to a solution of this compound (3640 mg (3.5
mmol)) dissolved in dichloromethane (200 ml) was added DBU
(1,8-diazabicyclo(5,4,0)undecene-7) (580 ul), and the mixture
was stirred to react for 1 hour at room temperature. After the
reaction was completed, formic acid (580 ul) and acetonitrile
(200 ml) were added to the solution, respectively, and the
solvent was distilled off slowly under vacuum. Crystals thus
obtained were filtered with a Kiriyama funnel to obtain the
objective compound Kb-Gly-H.
Binding of Second Amino Acid to Carrier for Separation
To a solution of the above-obtained Kb-Gly-H (2100 mg
(2.6 mmol)) dissolved in dichloromethane (100 ml) were added
Fmoc-alanine (Ala)-OH-H20 (1000 mg (3 mmol)), HBTU (2-(lH-
benzotriazol-1-yl)-1,1,3,3-
tetramethyluroniumhexafluorophosphate) (1140 mg (3 mmol)),
HOBt (1-hydroxybenzotriazole (400 mg (3 mmol)),
dimethylformamide (20 ml), and diisopropylethylamine (550 ul
(3 mmol)), respectively, and the mixture was stirred to react
for 1 hour at room temperature. After the reaction,
acetonitrile (200 ml) was added, and the solvent was distilled
off slowly under vacuum. Crystals thus obtained were filtered
with a Kiriyama funnel to recover the objective compound Kb-
Gly-Ala-Fmoc. The yield was 93%.

67
1H-NMR (300 MHz, CDC13)
6 7.76 (2H, d, J = 7.2 Hz), 7.58 (2H, d, J = 7.2 Hz),
7.40 (2H, t, J = 7.2 Hz), 7.31 (2H, t, J = 7.2 Hz), 7.18 (1H,
d, J = 7.9 Hz), 6.47 - 6.40 (3H, m), 5.32 (1H, br), 5.17 (2H,
s) , 4.51 .- 4.16 (4H, m) , 4.09 - 3.99 (2H, m) , 3.98 - 3.87, (4H,
m), 1.84 - 1.53 (7H, m), 1.47 - 1.19 (76H, m) 0.88 (6H, m)
Excision of Fmoc-dipeptide Bound to the Carrier for Separation
of the Present Invention by Solid Phase Reagent
To a solution of the above-obtained Kb-Gly-Ala-Fmoc (1000
mg (0.90 mmol)) dissolved in dichloromethane (25 ml) was added
a solid acid reagent (Sigma-Aldrich, Inc., trade name:
Montmorillonite K10) (1000 mg), and the mixture was stirred to
react at room temperature for 3.5 hours. Completion of the
reaction was confirmed by TLC (thin layer chromatography).
After the reaction, methanol (60 ml) was added, and the
solvent was distilled off slowly under vacuum. The obtained
crystalline Kb and the solid acid reagent were filtered with a
Kiriyama funnel to recover the filtrate. The solvent of this
filtrate was distilled off under vacuum, and the residue was
dried under vacuum to recover the objective compound, Fmoc-
Ala-Gly-OH. The yield was 69%.
As can be clearly seen from Example 7, the use of the
carrier for separation represented by the above-described
formula (2) enables Fmoc-dipeptide to be efficiently
synthesized on the carrier for separation, and enables the
carrier for separation bound with this Fmoc-dipeptide to be
isolated. Furthermore, the treatment with a solid acid reagent

68
enables Fmoc-dipeptide to be excised from the carrier for
separation.
Example 8
Synthesis of Fmoc-tripeptide Using the Carrier for Separation
of the Present Invention
Dissolution of Carrier for Separation
Similar to Example 1, Kb was used as a carrier for
separation, and 300 mg (5 mmol) thereof was dissolved in
cyclohexane (100 ml) to prepare a carrier solution.
Binding of First Amino Acid to Carrier for Separation
To the above-obtained carrier solution were added Fmoc-
Leu-OH (2640 mg (7.5 mmol)), dimethylaminopyridine (120 mg (1
mmol)) and diisopropylcarbodiimide (1.5 ml (10 mmol)) in
dimethylformamide (100 ml) respectively, and the mixture was
stirred to react at 55°C for 1 hour. Completion of the
reaction was confirmed by TLC. After the reaction, the mixture
was cooled to room temperature to become a two-layer solution,
so that the upper layer solution containing Kb-Leu-Fmoc was
recovered. To this upper layer solution was added
dimethylformamide containing 1% DBU (70 ml) to form a two-
layer solution, and the mixture was stirred to react at room
temperature for 30 min. Completion of the reaction was
confirmed by TLC. After the reaction, the upper layer solution
containing Kb-Leu-H was recovered.
Binding of Second Amino Acid to Carrier for Separation
To the above-obtained upper layer solution were added
Fmbc-Leu-OH (2640 mg (7.5 mmol)), HBTU (2850 mg (7.5 mmol)),

69
HOBt (1000 mg (7.5 mmol)) and diisopropylethylamine (1375 pi
(7.5 mmol)) in dimethylformamide (70 ml), respectively, and
the mixture was stirred to react at 55°C for 1 hour.
Completion of the reaction was confirmed by TLC. After the
reaction, the mixture was cooled to room temperature to become
a two-layer solution, so that the upper layer solution
containing Kb-Leu-Leu-Fmoc was recovered. To this upper layer
solution was added dimethylformamide containing 1% DBU (70 ml)
to form a two-layer solution, and the mixture was stirred to
react at room temperature for 30 min. Completion of the
reaction was confirmed by TLC. After the reaction, the upper
layer solution containing Kb-Leu-Leu-H was recovered.
Binding of Third Amino Acid to Carrier for Separation
To the above-obtained upper layer solution were added
Fmoc-Gly-OH (2230 mg (7.5 mmol)), HBTU (2850 mg (7.5 mmol)),
HOBt (1000 mg (7.5 mmol)) and diisopropylethylamine (1375 ul
(7.5 mmol)) in dimethylformamide (70 ml), respectively, and
the mixture was stirred to react at 55°C for 1 hour.
Completion of the reaction was confirmed by TLC. After the
reaction, when the reaction mixture was cooled to room
temperature, it formed a two-layer solution, so that the upper
layer solution containing Kb-Leu-Leu-Gly-Fmoc was recovered.
After distilling off the solvent of this upper layer solution
under vacuum slowly, methanol (300 ml) was added. Crystals
thus obtained were filtered with a Kiriyama funnel to recover
the objective compound Kb-Leu-Leu-Gly-Fmoc. The yield was 48%.
XH-NMR (300 MHz, CDC13) '

70
6 7.74 (2H, d, J = 7.5 Hz), 7.58 (2H, d, J = 7.5 Hz),
7.38 (2H, dt, J = 0.6, 7.5 Hz), 7.29 (2H, dt, J = 0.9, 7.5
Hz), 7.14 (1H, d, J = 8.7 Hz), 6.43 - 6.31 (3H, m) , 6.28 -
6,21 (1H, m), 5.37 (1H, br), 5.15 (1H, d, J = 11.7 Hz), 5.06
(1H, d,- J = 11.7 Hz), 4.62 - 4.55 (1H, m), 4.49 - 3.34 (3H,
m), 4.20 (1H, t, J = 6.8 Hz), 3.95 - 3.81 (6H, m), 1.81 - 1.36
(10H, m), 1.34 - 1.14 (76H, m), 0.92 - 0.80 (18H, m)
As can be clearly seen from Example 8, the use of a
carrier for separation represented by the above-described
formula (2) enables Fmoc-tripeptide to be efficiently
synthesized on the carrier for separation, and enables the
carrier for separation bound to Fmoc-tripeptide to be
separated. Especially, this Fmoc-tripeptide contains a Leu-Leu
bond so as to be difficult to be synthesized by the solid
phase reaction method. It is also possible to excise Fmoc-
tripeptide from the carrier for separation by the treatment
with a solid phase reagent.
Comparative Example 3
Excision of Fmoc-dipeptide Bound to Another Carrier for
Separation by Solid Phase Reagent
3,4,5-Tris-octadecyloxybenzyl alcohol represented by the
following formula (3) (hereinafter abbreviated as "Ka") was
used as a carrier for separation to recover Ka-Gly-Ala-Fmoc
similarly as in Example 1. To a solution of Ka-Gly-Ala-Fmoc
(1160 mg (0.92 mmol)) dissolved in dichloromethane (25 ml) was
added a solid acid reagent, (Sigma-Aldrich, Inc., trade name:
Montmorillonite K10) (1000 mg), and the mixture was stirred to

71
react at room temperature for 3.5 hours. After the reaction,
methanol (60 ml) was added, and the solvent was distilled off
slowly under vacuum. The obtained crystals and the solid acid
reagent were filtered with a Kiriyama funnel to recover the
filtrate. - Although the solvent of this filtrate was distilled
off under vacuum and the residue was dried under vacuum, the
objective compound Fmoc-Ala-Gly-OH could not be obtained.

As can be clearly seen from comparative example 3, when
the carrier for separation represented by the above-described
formula (3) was used, Fmoc-dipeptide could not be obtained.
This is apparently due to the bond between the carrier for
separation Ka and dipeptide which is comparatively difficult
to be cleaved, so that it was not cleaved by the solid acid
reagent.
Comparative Example 4
Excision of Fmoc-dipeptide Bound to Solid Phase Carrier by
Solid Phase Reagent
Chloro-trityl(2-chloro)resin (Watanabe Chemical Industry)
(hereinafter abbreviated as "CTC") (1.45 mmol) was used as a
solid phase carrier, and CTC-Gly-Ala-Fmoc was synthesized by
the solid phase reaction method. In addition, to a solution of
CTC-Gly-Ala-Fmoc (580 mg, supported amount 0.84 mmol)
dissolved in dichloromethane (25 ml) was added a solid acid
reagent (Sigma-Aldrich, Inc., trade name: Montmorilloni-te K10)

72
(1000 mg), and the mixture was stirred to react at room
temperature for 3.5 hours. After the reaction, methanol (60
ml) was added, and the solvent was distilled off slowly under
vacuum. The obtained crystals and the solid acid reagent were
filtered with a Kiriyama funnel to recover the filtrate.
Although the solvent of this filtrate was distilled off under
vacuum and the residue was dried in vacuo, the objective
compound Fmoc-Ala-Gly-OH could not be obtained.
As can be clearly seen from comparative example 4, when
the solid phase carrier was used, Fmoc-dipeptide could not be
obtained. This is apparently due to the insolubility of both
the solid phase carrier and solid acid reagent in the reaction
solution, so that they have no chance to interact each other,
resulting in failure of bond cleavage.
Example 9
Tripeptide Synthesis by Solid Phase Reaction Using Fmoc-
dipeptide
Tripeptide synthesis on solid phase carrier
Similar to comparative example 4, CTC-phenylalanine
(Phe)-H was synthesized by the solid phase reaction method
using CTC as a solid phase carrier. Furthermore, similar to
Example 7, Fmoc-Ala-Gly-OH was synthesized. Then, to
dichloromethane (2 ml) were added CTC-Phe-H (110 mg (0.145
mmol)), Fmoc-Ala-Gly-OH (160 mg (0.4 mmol)), HBTU (165 mg (0.4
mmol)), HOBt (60 mg (0.4 mmol)), dimethylformamide (1 ml) and
diisopropylethylamine (75 ul (0.4 mmol)), respectively, and
the mixture was stirred to react at room temperature for 2

73
hours. After the reaction, the solid phase was washed with
dimethylformamide (3 x 2 ml) , methanol (3 x 2 ml) and
dichloromethane (3x2 ml), respectively. Subsequently, to the
above solid phase was added the previously prepared Fmoc
de-protection solution (dimethylformamide : piperidine : DBU =
96 : 2 : 2) (2 ml), and the mixture was stirred to react at
room temperature for 1 hour to obtain CTC-Phe-Gly-Ala-H.
Excision of Tripeptide Bound to Solid Phase Carrier
The above-obtained CTC-Phe-Gly-Ala-H was washed with
dimethylformamide (3x2 ml), methanol (3x2 ml), and
dichloromethane (3 x 2 ml), respectively. Subsequently, the
previously prepared excision fluid (dichloromethane containing
1% trichloroacetic acid) (20 ml) was added, and the resulting
mixture was stirred to react for 30 minutes at room
temperature. After the reaction, the solution was filtered
through a Kiriyama funnel to recover the filtrate. The solvent
of this filtrate was distilled off under vacuum, and the
residue was dried in vacuo to obtain the objective compound H-
Ala-Gly-Phe-OH. As a result of high-performance liquid
chromatography, purity was 94%.
As can be clearly seen from Example 9, the use of Fmoc-
dipeptide synthesized using a carrier for separation
represented by the above-described formula (2) as a material
of the solid phase reaction method enables tripeptide to be
synthesized in a fewer number of processes, rapidly, and in
high purity.
Comparative Example 5

74
Tripeptide Synthesis by Solid Phase Reaction Method
Tripeptide Synthesis on Solid Phase Carrier
Similar to comparative example 4, CTC-Phe-H was
synthesized by the solid phase reaction method using CTC as a
solid phase carrier. Then, to dichloromethane (2 ml) were
added CTC-Phe-H (110 mg (0.145 mmol)), Fmoc-Gly-OH (120 mg
(0.4 mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4
mmol)), dimethylformamide (1 ml) and diisopropylethylamine (75
ul (0.4 mmol)), respectively, and the mixture was stirred to
react at room temperature for 2 hours. After the reaction, the
solid phase was washed with dimethylformamide (3 x 2-ml),
methanol (3 x 2 ml) and dichloromethane (3 x 2 ml),
respectively. Subsequently, to the solid phase was added the
previously prepared Fmoc deprotection solution
(dimethylformamide : piperidine : DBU = 96 : 2 : 2) (2 ml),
and the mixture was stirred to react at room temperature for 1
hour to obtain CTC-Phe-Gly-H. This CTC-Phe-Gly-H was dissolved
in dichloromethane (2 ml), and Fmoc-Ala-OH-H20 (130 mg (0.4
mmol)), HBTU (165 mg (0.4 mmol)), HOBt (60 mg (0.4 mmol)),
dimethylformamide (1ml) and diisopropylethylamine (75 ul (0.4
mmol)) were added, respectively, and the mixture was stirred
to react at room temperature for 2 hours. After the reaction,
the solid phase was washed with dimethylformamide (3 x 2 ml),
methanol (3 x 2 ml), and dichloromethane (3 x 2 ml),
respectively. Subsequently, to the solid phase was added the
previously prepared Fmoc deprotection solution
(dimethylformamide : piperidine : DBU = 96 : 2 : 2) (2 ml),

75
and the mixture was stirred to react at room temperature for 1
hour to obtain CTC-Phe-Gly-Ala-H.
Excision of Tripeptide Bound to Solid Phase Carrier
The above-obtained CTC-Phe-Gly-Ala-H was washed with
dimethylformamide (3 x 2 ml), methanol (3x2 ml), and
dichloromethane (3x2 ml), respectively. Subsequently, the
previously prepared excision solution (dichloromethane
containing 1% trichloroacetic acid) (20 ml) was added, and the
resulting mixture was stirred to react for 30 minutes at room
temperature. After the reaction, the solution was filtered
through a Kiriyama funnel to recover the filtrate. The solvent
of this filtrate was distilled off under vacuum, and the
residue was dried in vacuo to obtain the objective compound H-
Ala-Gly-Phe-OH. As a result of high-performance liquid
chromatography, purity was 8 8%.
As can be clearly seen from comparative example 5, the
tripeptide could be synthesized as usual by a conventional
solid phase reaction method, but purity of the product was
lower compared with Example 9. This is probably due to, for
example, a partial failure of the reaction of CTC-Phe-H with
Fmoc-Gly-OH and instead due to the reaction of CTC-Phe-H with
the subsequently added Fmoc-Ala-OH-H20, resulting in the
synthesis of a dipeptide, H-Ala-Phe-OH, or due to a partial
failure of the reaction of CTC-Phe-Gly-H with Fmoc-Ala-OH-H20,
resulting in the synthesis of a dipeptide, H-Gly-Phe-OH.
INDUSTRIAL APPLICABILITY • ■ ■

76
The carrier for separation and the method of separating a
compound according to the present invention enable the
research and development of drugs, etc. by compound library
synthesis or the like to be promoted, so as to be able to
eventually contribute to technical innovation-in the
biochemical industry and chemical industry. Furthermore, the
present invention is able to become an innovative technique in
the separation and purification of biochemical substances, the
search for drug candidate substances, and the constitution of
novel chemical synthetic reaction methods and continuous
synthesis method of peptides, etc.

77
CLAIMS
1. A carrier for separation represented by the following
chemical formula (1) having a reaction site A to bind with
other compound, wherein
the reaction site A binds to the other compound via any
one selected from the group consisting of a carbon atom,
oxygen atom, sulfur atom and nitrogen atom so as to separate
the other compound;

(In the formula,
wherein A is a reaction site having at least one atom
selected from the group consisting of carbon, oxygen, sulfur
and nitrogen;
X, Y and Z are each independently any one group selected
from the group consisting of a hydrogen, a halogen, a
hydrocarbon group having a carbon number in the range of 1 to
10 which may have a substituent, an acyl group having a carbon
number in the range of 1 to 10 which may have a substituent, a
benzyl group and a phenyl group;
Ri and R2 are groups, which may be identical or different,
containing at least 1 of a hydrocarbon group having a carbon
number in the range of 14 to 60 which may have a substituent,

78
and an acyl group having a carbon number in the range of 14 to
60 which may have a substituent.)
2. The carrier for separation according to claim 1, wherein
the carrier for separation is one to be selectively extracted
and/or selectively crystallized in a specific phase according
to changes in the composition and/or temperature of a solution
in which the carrier is dissolved while the other compound
being is bound to the carrier.
3. The carrier for separation according to claim 1, wherein
the other compound is an amino acid; the reaction site A is an
atomic group capable of binding to the amino acid; and the Ri
and R2, which are one of identical and different, are groups
containing one of a hydrocarbon group having a carbon number
in the range of 14 to 30 which may have a substituent, and an
acyl group having a carbon number in the range of 14 to 30
which may have a substituent.
4. The carrier for separation according to claim 3, wherein
the reaction site A is an atomic group having hydroxyl group,
thiol group, amino group or carboxyl group capable of binding
to an amino acid.
5. A method of separating a compound comprising: a
dissolution process for dissolving the carrier for separation
according to claim 1 in a soluble solvent to prepare a carrier

79
solution;
a first binding process for binding other compound to the
reaction site A of the carrier for separation; and
crystallization process for crystallizing the carrier for
separation while the other compound is bound to the carrier,
or a selection process for selectively extracting the carrier
for separation in a specific phase while the other compound is
bound to the carrier and/or selectively crystallizing the
carrier for separation in a specific phase while the other
compound is bound to the carrier.
6. The method of separating a compound according to claim 5
comprising, after the first binding process, a second binding
process for further binding another compound to the other
compound which was bound to the reaction site A of the carrier
for separation.
7. The method of separating a compound according to claim 5
or 6 further comprising, after the crystallization process or
the selection process, an excision process for excising the
other compound from the carrier for separation to which the
other compound was bound.
8. The method of separating a compound according to any one
of claims 5 to 7 further comprising, before the
crystallication process or the selection process, a process
for eliminating impurities from a solution in which the

80
carrier for separation is dissolved or a liquid phase in which
the carrier for separation melts.
9. The method of separating a compound according to any one
of claims 5 to 8, wherein the crystallization process or the .....*.-■
selection process is performed by a means of changing the
composition of a solution in which the carrier for separation
dissolves and/or a means of changing the temperature of a
solution in which the carrier for separation dissolves.
10. A method for synthesizing an oligopeptide comprising: a
dissolution process for dissolving the carrier for separation
according to claim 3 or 4 in a soluble solvent to prepare a
carrier solution;
a binding process for obtaining the carrier for
separation bound with an oligopeptide by binding an amino acid
to the reaction site A of the carrier for separation and
sequentially binding other amino acids to the amino acid which
has been bound to the carrier for separation;
a crystallization process for crystallizing the carrier
for separation while the oligopeptide is bound to the carrier,
or a selection process for selectively extracting and/or
selectively crystallizing the carrier for separation into a
specific phase while the oligopeptide is bound to the carrier;
and
after the crystallization process or the selection
process, an excision process'for excising the oligopeptide

81
from the carrier for separation to which the oligopeptide has
been bound.
11. The method for synthesizing oligopeptide according to
claim 10, wherein the crystallization-process or the selection
process is performed by a means of changing the composition of
a solution in which the carrier for separation dissolves
and/or a means of changing the temperature of a solution in
which the carrier for separation dissolves.
12. The method for synthesizing oligopeptide according to
claim 10 or 11, wherein the excision process is performed by
adding a solid phase reagent to a solution in which the
carrier for separation is dissolved.
13. The method for synthesizing oligopeptide according to
claim 12, wherein the solid phase reagent is a solid acid
reagent.

Disclosed are a carrier for use for separation purpose and a
method for separation of a compound which enable a chemical
reaction to be performed in a liquid phase, enable a compound
of interest to be separated from the liquid phase after the
completion of the reaction readily, enable the separated
compound to be evaluated by structural analysis or the like
while the compound being bound to the carrier, and enable the
compound to be separated from the carrier readily. A carrier
for separation which has a reaction site capable of reacting
with other compound on a benzene ring, and a long-chain group
having a specified carbon atom(s) at each of the ortho-position
and the para-position of the reaction site through an
oxygen atom.

Documents:

01161-kolnp-2008-abstract.pdf

01161-kolnp-2008-claims.pdf

01161-kolnp-2008-correspondence others.pdf

01161-kolnp-2008-description complete.pdf

01161-kolnp-2008-drawings.pdf

01161-kolnp-2008-form 1.pdf

01161-kolnp-2008-form 3.pdf

01161-kolnp-2008-form 5.pdf

01161-kolnp-2008-international publication.pdf

01161-kolnp-2008-international search report.pdf

01161-kolnp-2008-pct priority document notification.pdf

1161-KOLNP-2008-(04-05-2012)-ABSTRACT.pdf

1161-KOLNP-2008-(04-05-2012)-AMANDED CLAIMS.pdf

1161-KOLNP-2008-(04-05-2012)-ASSIGNMENT.pdf

1161-KOLNP-2008-(04-05-2012)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(04-05-2012)-DESCRIPTION (COMPLETE).pdf

1161-KOLNP-2008-(04-05-2012)-DRAWINGS.pdf

1161-KOLNP-2008-(04-05-2012)-FORM-1.pdf

1161-KOLNP-2008-(04-05-2012)-FORM-13.pdf

1161-KOLNP-2008-(04-05-2012)-FORM-2.pdf

1161-KOLNP-2008-(04-05-2012)-FORM-3.pdf

1161-KOLNP-2008-(04-05-2012)-FORM-5.pdf

1161-KOLNP-2008-(04-05-2012)-OTHERS.pdf

1161-KOLNP-2008-(04-05-2012)-PETITION UNDER RULE 137-1.pdf

1161-KOLNP-2008-(04-05-2012)-PETITION UNDER RULE 137.pdf

1161-KOLNP-2008-(06-12-2012)-CLAIMS.pdf

1161-KOLNP-2008-(06-12-2012)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(06-12-2012)-FORM-13.pdf

1161-KOLNP-2008-(06-12-2012)-OTHERS.pdf

1161-KOLNP-2008-(08-03-2013)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(10-04-2013)-ABSTRACT.pdf

1161-KOLNP-2008-(10-04-2013)-CLAIMS.pdf

1161-KOLNP-2008-(10-04-2013)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(10-04-2013)-FORM-1.pdf

1161-KOLNP-2008-(10-04-2013)-FORM-2.pdf

1161-KOLNP-2008-(10-04-2013)-OTHERS.pdf

1161-KOLNP-2008-(13-03-2012)-ENGLISH TRANSLATION.pdf

1161-KOLNP-2008-(13-03-2012)-EXAMINATION REPORT REPLY RECEIVED.pdf

1161-KOLNP-2008-(13-12-2012)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(13-12-2012)-OTHERS.pdf

1161-KOLNP-2008-(18-03-2013)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(18-11-2013)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(20-12-2013)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(20-12-2013)-OTHERS.pdf

1161-KOLNP-2008-(30-10-2012-RI)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(30-10-2012-RI)-OTHERS.pdf

1161-KOLNP-2008-(31-07-2012)-ABSTRACT.pdf

1161-KOLNP-2008-(31-07-2012)-AMANDED CLAIMS.pdf

1161-KOLNP-2008-(31-07-2012)-CORRESPONDENCE.pdf

1161-KOLNP-2008-(31-07-2012)-DESCRIPTION (COMPLETE).pdf

1161-KOLNP-2008-(31-07-2012)-DRAWINGS.pdf

1161-KOLNP-2008-(31-07-2012)-FORM-13.pdf

1161-KOLNP-2008-(31-07-2012)-FORM-2.pdf

1161-KOLNP-2008-(31-07-2012)-OTHERS.pdf

1161-kolnp-2008-form 18.pdf

abstract-01161-kolnp-2008.jpg


Patent Number 260022
Indian Patent Application Number 1161/KOLNP/2008
PG Journal Number 14/2014
Publication Date 04-Apr-2014
Grant Date 31-Mar-2014
Date of Filing 19-Mar-2008
Name of Patentee JITSUBO CO., LTD.
Applicant Address 2-24-16, NAKACHO KOGANEI-SHI, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 CHIBA, KAZUHIRO C/O NATIONAL UNIVERSITY CORPORATION, TOKYO UNIVERSITY OF AGRICULTURE AND TECHNOLOGY, 8-1, HARUMICHO 3-CHOME,, FUCHU-SHI, TOKYO 183-8538
2 KONO, YUSUKE C/O JITSUBO CO., LTD., 2-24-16, NAKACHO, KOGANEI-SHI, TOKYO 184-8588
3 KIM, SHOKAKU C/O JITSUBO CO., LTD., 2-24-16, NAKACHO, KOGANEI-SHI, TOKYO 184-8588
PCT International Classification Number C07C 51/487
PCT International Application Number PCT/JP2006/318594
PCT International Filing date 2006-09-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2006-183688 2006-07-03 Japan
2 2005-272905 2005-09-20 Japan
3 2006-024725 2006-02-01 Japan