U.S. patent application number 15/472831 was filed with the patent office on 2018-03-01 for amylose derivative and optical isomer separating agent containing same.
This patent application is currently assigned to DAICEL CORPORATION. The applicant listed for this patent is DAICEL CORPORATION. Invention is credited to Geng LI, Yoshio OKAMOTO, Jun SHEN, Zhongzheng YANG.
Application Number | 20180056270 15/472831 |
Document ID | / |
Family ID | 61225715 |
Filed Date | 2018-03-01 |
United States Patent
Application |
20180056270 |
Kind Code |
A1 |
SHEN; Jun ; et al. |
March 1, 2018 |
AMYLOSE DERIVATIVE AND OPTICAL ISOMER SEPARATING AGENT CONTAINING
SAME
Abstract
Provided are a novel amylose derivative which exhibits excellent
optical isomer separability and which is suitable as an optical
isomer separating agent; and an optical isomer separating agent
containing the amylose derivative. A task is attained by an amylose
derivative having a constituent unit represented by formula (I)
below; In below formula (I), R.sup.1 is a substituent group
represented by any of formulae 1 to 3 below, and R.sup.2 is a
substituent group represented by any of formulae a to g below.
R.sup.1 and R.sup.2 are different substituent groups. A combination
of R.sup.1 and R.sup.2 in which R.sup.1 is a substituent group
represented by structural formula 3 and R.sup.2 is a substituent
group represented by structural formula c is excluded from the
formula (I). ##STR00001##
Inventors: |
SHEN; Jun; (Harbin, CN)
; YANG; Zhongzheng; (Harbin, CN) ; LI; Geng;
(Harbin, CN) ; OKAMOTO; Yoshio; (Harbin,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DAICEL CORPORATION |
Osaka |
|
JP |
|
|
Assignee: |
DAICEL CORPORATION
Osaka
JP
|
Family ID: |
61225715 |
Appl. No.: |
15/472831 |
Filed: |
March 29, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 20/3085 20130101;
C08B 33/02 20130101; B01J 20/29 20130101; B01J 20/24 20130101; B01J
2220/80 20130101 |
International
Class: |
B01J 20/24 20060101
B01J020/24; C08B 33/02 20060101 C08B033/02; B01J 20/29 20060101
B01J020/29; B01J 20/30 20060101 B01J020/30 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 26, 2016 |
JP |
2016-165637 |
Claims
1. An amylose derivative having a constituent unit represented by
formula (I) below: ##STR00015## (In formula (I), R.sup.1 is a
substituent group represented by any of structural formulae 1 to 3
below, R.sup.2 is a substituent group represented by any of
structural formulae a to g below, and two R.sup.2 groups are the
same substituent group. R.sup.1 and R.sup.2 are different
substituent groups. A combination of R.sup.1 and R.sup.2 in which
R.sup.1 is a substituent group represented by structural formula 3
and R.sup.2 is a substituent group represented by structural
formula c is excluded from the formula (I).) ##STR00016##
2. The amylose derivative according to claim 1, wherein R.sup.1 is
a substituent group represented by the structural formula 1 and
R.sup.2 is a substituent group represented by any of the structural
formulae a, b, e and f in the constituent unit represented by the
formula (I).
3. The amylose derivative according to claim 1, wherein R.sup.2 is
a substituent group represented by the structural formula 2 and
R.sup.2 is a substituent group represented by any of the structural
formulae a, c, d, e and g in the constituent unit represented by
the formula (I).
4. The amylose derivative according to claim 1, wherein R.sup.1 is
a substituent group represented by the structural formula 3 and
R.sup.2 is a substituent group represented by any of the structural
formulae a, b, d, e and f in the constituent unit represented by
the formula (I).
5. An optical isomer separating agent, which is constituted from a
carrier and the amylose derivative according to claim 1 which is
carried by the carrier.
6. A method for producing an amylose derivative, the method
comprising: a 2-position and 6-position protection step in which
hydroxyl groups at the 2-position and 6-position of an amylose
constituent unit are protected by protecting groups; a 3-position
modification step in which a hydroxyl group at the 3-position of
the constituent unit, whose 2-position and 6-position are
protected, is modified by a first substituent group represented by
formula (II-1) below; a 2-position and 6-position deprotection step
in which protecting groups at the 2-position and 6-position of the
constituent unit, whose 3-position is modified, are removed; and a
2-position and 6-position modification step in which hydroxyl
groups at the 2-position and 6-position, from which protecting
groups have been removed, are modified by a second substituent
group represented by formula (II-2) below: --CO--NH--R.sup.3 (II-1)
where, R.sup.3 is a substituent group represented by any of
formulae 1 to 3, ##STR00017## --CO--NH--R.sup.4 (II-2) where,
R.sup.4 is a substituent group represented by any of formulae a to
g. However, R.sup.3 in formula II-1 and R.sup.4 in formula II-2 are
different substituent groups, ##STR00018##
7. The method for producing an amylose derivative according to
claim 6, wherein R.sup.3 is a substituent group represented by
structural formula 1 in a first substituent group represented by
the formula (II-1) and R.sup.4 is a substituent group represented
by any of structural formulae a, b, e and f in a second substituent
group represented by the formula (II-2).
8. The method for producing an amylose derivative according to
claim 6, wherein R.sup.3 is a substituent group represented by
structural formula 2 in a first substituent group represented by
the formula (II-1) and R.sup.4 is a substituent group represented
by any of structural formulae a, c, d, e and g in a second
substituent group represented by the formula (II-2).
9. The method for producing an amylose derivative according to
claim 6, wherein R.sup.3 is a substituent group represented by
structural formula 3 in a first substituent group represented by
the formula (II-1) and R.sup.4 is a substituent group represented
by any of structural formulae a, b, d, e and f in a second
substituent group represented by the formula (II-2).
Description
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The present invention relates to an amylose derivative that
is useful for separating optical isomers, and to an optical isomer
separating agent containing same.
Description of the Related Art
[0002] Polysaccharide derivatives obtained by modifying hydroxyl
groups present in polysaccharides, such as cellulose and amylose,
with a variety of substituent groups are known to exhibit high
optical resolution capability as chiral stationary phases in
chromatography, and many types of polysaccharide derivative have
been synthesized in the past.
[0003] One synthesis example of a polysaccharide derivative that is
useful as this type of optical isomer separating agent is a
synthesis example in which substituent groups are introduced
separately at the 2-position, 3-position and 6-position by means of
a process in which a hydroxyl group at the 6-position of a
polysaccharide is protected by means of trityl chloride, and then
deprotected (see Bull. Chem. Soc. Jpn., 66, 2225-2232, 1993).
[0004] However, separately substituting at the 2-position and
3-position, which have similar reactivity, was difficult when
substituting hydroxyl groups in polysaccharides. With regard to
this matter, examples have been reported in which cellulose
derivatives in which different substituent groups are introduced at
the adjacent 2-position and 3-position (3-allyl cellulose, 3-methyl
cellulose and 3-methyl-2,6-acetyl cellulose) are synthesized (see
Macromol. Biosci 1, 49-54, 2001).
[0005] However, no derivatives are known in which the same type of
substituent group is introduced at the 2-position and 6-position
but a different type of substituent group is introduced at the
3-position of amylose when using amylose as a polysaccharide.
LIST OF PRIOR ART DOCUMENTS
[0006] Ref. 1: Bull. Chem. Soc. Jpn., 66, 2225-2232, 1993 [0007]
Ref. 2: Macromol. Biosci. 1, 49-54, 2001 [0008] Ref. 3: J.
Chromatogr. A 363, 173-186, 1986 [0009] Ref. 4: Chirality 9, 63-68,
1997 [0010] Ref. 5: Chem. Lett. 9, 1857-1860, 1987
SUMMARY OF THE INVENTION
[0011] The present invention provides a novel amylose derivative
which exhibits excellent optical isomer separability and which is
suitable as an optical isomer separating agent; and an optical
isomer separating agent containing the amylose derivative.
[0012] The present invention provides an amylose derivative having
a constituent unit represented by formula (I) below.
[0013] In an amylose derivative having a constituent unit
represented by formula (I) below, hydroxyl groups at the 2-position
and 6-position of amylose are substituted by the same type of
substituent group, and the hydroxyl group at the 3-position of
amylose is substituted by a different type of substituent group
from that substituted at the 2-position and 6-position.
##STR00002##
(In formula (I), R.sup.1 is a substituent group represented by any
of structural formulae 1 to 3 below, R.sup.2 is a substituent group
represented by any of structural formulae a to g below, and two
R.sup.2 groups are the same substituent group. R.sup.1 and R.sup.2
are different substituent groups. A combination of R.sup.1 and
R.sup.2 in which R.sup.1 is a substituent group represented by
structural formula 3 and R.sup.2 is a substituent group represented
by structural formula c is excluded from the formula (I).)
##STR00003##
[0014] In addition, as a method for producing an amylose derivative
represented by formula (I), the present invention provides a method
for producing an amylose derivative, the method including a
2-position and 6-position protection step in which hydroxyl groups
at the 2-position and 6-position of an amylose constituent unit are
protected by protecting groups; a 3-position modification step in
which a hydroxyl group at the 3-position of the constituent unit,
whose 2-position and 6-position are protected, is modified by a
first substituent group represented by formula (II-1) below; a
2-position and 6-position deprotection step in which protecting
groups at the 2-position and 6-position of the constituent unit,
whose 3-position is modified are removed; and a 2-position and
6-position modification step in which hydroxyl groups at the
2-position and 6-position, from which protecting groups have been
removed, are modified by a second substituent group represented by
formula (II-2) below (however, R.sup.3 in formula II-1 and R.sup.4
in formula II-2 are different substituent groups).
--CO--NH--R.sup.3 (II-1)
[0015] In the formula, R.sup.3 is a substituent group represented
by any of formulae 1 to 3.
##STR00004## --CO--NH--R.sup.4 (II-2)
In the formula, R.sup.4 is a substituent group represented by any
one of formulae a to g.
##STR00005##
[0016] In addition, the present invention relates to an optical
isomer separating agent containing this polysaccharide
derivative.
[0017] In addition, in cases where R.sup.2 is a substituent group
represented by any of structural formulae a, b, e and f when
R.sup.1 is a substituent group represented by structural formula 1
in the constituent unit represented by formula (I), cases where
R.sup.2 is a substituent group represented by any of structural
formulae a, c, d, e and g when R.sup.1 is a substituent group
represented by structural formula 2 in the constituent unit
represented by formula (I) and cases where R.sup.2 is a substituent
group represented by any of structural formulae a, b, d, e and f
when R.sup.1 is a substituent group represented by structural
formula 3 in the constituent unit represented by formula (I), the
present invention is significantly more effective from the
perspective of providing an amylose derivative which exhibits
excellent optical isomer separability and which is suitable as an
optical isomer separating agent.
[0018] In addition, the present invention provides an optical
isomer separating agent that contains this amylose derivative, and
can therefore provide an optical isomer separating agent that
contains an amylose derivative which exhibits excellent optical
isomer separability and which is suitable as an optical isomer
separating agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a diagram showing a .sup.1H NMR spectrum in
pyridine-d.sub.5 of amylose derivative 1f at 80.degree. C.;
[0020] FIG. 2 is a diagram showing a chromatogram obtained by
separating racemate 5 using amylose derivative 1f; and
[0021] FIG. 3 is a diagram showing chromatograms obtained by
separating racemate 5 using amylose 3-(4-chlorophenyl carbamate)
derivatives (2a, 2c, 2d, 2e and 2g).
DESCRIPTION OF THE EMBODIMENTS
[0022] The amylose derivative of the present invention has a
constituent unit in which the hydrogen atoms in the hydroxyl groups
at the 2-position and 6-position of amylose are substituted by
substituent groups that are different from that substituted for the
hydrogen atom in the hydroxyl group at the 3-position of amylose,
as shown by formula (I).
##STR00006##
(In formula (I), R.sup.1 is a substituent group represented by any
of structural formulae 1 to 3 below, R.sup.2 is a substituent group
represented by any of structural formulae a to g below, and the two
R.sup.2 groups are the same substituent group. R.sup.1 and R.sup.2
are different substituent groups. A combination of R.sup.1 and
R.sup.2 in which R.sup.1 is a substituent group represented by
structural formula 3 and R.sup.2 is a substituent group represented
by structural formula c is excluded from the formula (I).)
##STR00007##
[0023] In the present invention, the asterisks (*) shown in
structural formulae 1 to 3 and structural formulae a to g denote
the position of substitution of a hydrogen atom of a hydroxyl group
in amylose.
[0024] The average degree of polymerization of amylose (the average
number of pyranose or furanose rings in 1 molecule of amylose) is
preferably 5 or more, and more preferably 10 or more, with no
particular upper limit, but this average degree of polymerization
is preferably 1000 or less from the perspective of ease of
handling, and is more preferably 5 to 1000, further preferably 10
to 1000, and particularly preferably 10 to 500.
[0025] In the amylose derivative of the present invention, hydroxyl
groups in the constituent unit represented by formula (I) are
substituted by --CO--NH--R groups.
[0026] R is represented by R.sup.1 at the 3-position of amylose,
and R is represented by R.sup.2 at the 2-position and 6-position of
amylose.
[0027] R.sup.1 and R.sup.2 are different substituent groups and the
two R.sup.2 groups are the same type of substituent group, but in
the present invention, this excludes a case in which when R.sup.1
is a substituent group represented by structural formula 3, R.sup.2
is a substituent group represented by structural formula c.
[0028] In the structural unit represented by formula (I), as long
as an optical resolution effect can be achieved by substituent
groups represented by R.sup.1 and R.sup.2, it is possible for not
all the hydroxyl groups at these positions in this constituent unit
to be substituted. In the structural unit represented by formula
(I), the rate of introduction of substituent groups represented by
R.sup.1 and R.sup.2 into the amylose derivative of the present
invention is preferably 70% to 100%, more preferably 80% to 100%,
and particularly preferably 100%.
[0029] Moreover, this rate of introduction (%) is defined as
follows. In the amylose derivative of the present invention, this
rate of introduction is the ratio of the total number of
substituent groups represented by the formulae mentioned above in
the amylose derivative of the present invention relative to the
total number of hydroxyl groups in the constituent unit mentioned
above when the substituent groups represented by the formulae
mentioned above in the amylose derivative of the present invention
are deemed to have been substituted by hydroxyl groups in the
constituent unit mentioned above. The rate of introduction can be
determined by using a publicly known analytical method such as NMR
or elemental analysis, which can identify the type and/or bonding
position of substituent groups, and can also be determined
according to the type and bonding position of substituent
groups.
[0030] In cases, for example, where substituent groups represented
by the formulae mentioned above substitute only hydroxyl groups in
the amylose derivative of the present invention, this rate of
introduction is a numerical value obtained by multiplying, by 100,
the ratio of the number of substituent groups represented by
R.sup.1 and R.sup.2 relative to the total number of hydroxyl groups
in the amylose following the substitution.
[0031] In the constituent unit represented by formula (I), in cases
where R.sup.1 is a substituent group represented by structural
formula 1, R.sup.2 is preferably a substituent group represented by
any of structural formulae a, b, e and f, more preferably a
substituent group represented by any of structural formulae a, e
and f, and particularly preferably a substituent group represented
by structural formula a.
[0032] In the constituent unit represented by formula (I), in cases
where R.sup.1 is a substituent group represented by structural
formula 2, R.sup.2 is preferably a substituent group represented by
any of structural formulae a, c, d, e and g, more preferably a
substituent group represented by any of structural formulae c and
e, and particularly preferably a substituent group represented by
structural formula c.
[0033] In the constituent unit represented by formula (I), in cases
where R.sup.1 is a substituent group represented by structural
formula 3, R.sup.2 is preferably a substituent group represented by
any of structural formulae a, b, d, e and f, more preferably a
substituent group represented by any of structural formulae a and
d, and particularly preferably a substituent group represented by
structural formula a.
[0034] Moreover, because the separation behavior of racemates
differs according to the type of racemate to be separated and the
type of substituent group R.sup.1 and R.sup.2 in the amylose
derivative, it is possible to select the type of substituent group
R.sup.1 and R.sup.2 according to the type of racemate to be
separated.
[0035] In the constituent unit represented by formula (I), R.sup.1
and R.sup.2 are different substituent groups.
[0036] Therefore, a combination in which R.sup.2 is a substituent
group represented by structural formula d when R.sup.1 is a
substituent group represented by structural formula 1, a
combination in which R.sup.2 is a substituent group represented by
structural formula f when R.sup.1 is a substituent group
represented by structural formula 2 and a combination in which
R.sup.2 is a substituent group represented by structural formula g
when R.sup.1 is a substituent group represented by structural
formula 3 are excluded from the present invention.
[0037] The amylose derivative of the present invention can be
produced using the following method.
[0038] That is, the amylose derivative of the present invention can
be produced using a method that includes a 2-position and
6-position protection step in which hydroxyl groups at the
2-position and 6-position of an amylose constituent unit are
protected by protecting groups; a 3-position modification step in
which a hydroxyl group at the 3-position of the constituent unit,
whose 2-position and 6-position are protected, is modified by a
first substituent group represented by formula (II-1) below; a
2-position and 6-position deprotection step in which protecting
groups at the 2-position and 6-position of the constituent unit,
whose 3-position is modified are removed; and a 2-position and
6-position modification step in which hydroxyl groups at the
2-position and 6-position, from which protecting groups have been
removed, are modified by a second substituent group represented by
formula (II-2) below.
--CO--NH--R.sup.3 (II-1)
In the formula, R.sup.3 is a substituent group represented by any
of formulae 1 to 3.
##STR00008## --CO--NH--R.sup.4 (II-2)
[0039] In the formula, R.sup.4 is a substituent group represented
by any one of formulae a to g.
##STR00009##
[0040] In formulae (II-1) and (II-2), a combination in which
R.sup.4 is a substituent group represented by structural formula d
when R.sup.3 is a substituent group represented by structural
formula 1, a combination in which R.sup.4 is a substituent group
represented by structural formula f when R.sup.3 is a substituent
group represented by structural formula 2 and a combination in
which R.sup.4 is a substituent group represented by structural
formula g when R.sup.3 is a substituent group represented by
structural formula 3 are excluded from the present invention.
[0041] The 2-position and 6-position protection step can be carried
out using, for example, the method disclosed in Macromol. Biosci 1,
49-54, 2001. Specifically, it is possible to dissolve in a mixture
of N,N-dimethylacetamide (DMAc) and lithium chloride (LiCl) (at
approximately 100.degree. C.), add imidazole (at a quantity of
approximately 2.4 equivalents relative to the number of hydroxyl
groups at the 2-position and 6-position) and TMDS-Cl
(thexyldimethylsilyl chloride: at a quantity of approximately 2
equivalents relative to the number of hydroxyl groups at the
2-position and 6-position) dropwise incrementally to the solution
(at approximately 100.degree. C.), and allow a reaction to progress
for approximately 24 hours.
[0042] In this way, hydroxyl groups at the 2-position and
6-position of amylose are substituted by thexyldimethylsilyl
groups.
[0043] Following the 2-position and 6-position protection step, the
method has a 3-position modification step in which the hydroxyl
group at the 3-position of the constituent unit, whose 2-position
and 6-position are protected, is modified by a first substituent
group represented by formula (II-1) above.
[0044] In order to effect modification by the first substituent
group represented by formula (II-1), modification of the hydroxyl
group at the 3-position by the first substituent group may be
carried out by reacting an isocyanate having a structure
represented by formula (II-1) above with the hydroxyl group at the
3-position of amylose using an appropriate solvent or the like
under appropriate conditions (for example, in pyridine at
approximately 80.degree. C.)
[0045] In this way, the hydroxyl group at the 3-position of amylose
can be substituted by the first substituent group represented by
formula (II-1).
[0046] An example of the 2-position and 6-position deprotection
step in which protecting groups at the 2-position and 6-position of
the constituent unit whose 3-position is modified are removed is a
step of dispersing amylose, in which the 2-position and 6-position
are modified by protecting groups and in which the 3-position is
modified by the substituent group represented by formula (II-1), in
an appropriate solvent (for example, THF), adding tetrabutyl
ammonium fluoride (TBAF: approximately 50.degree. C.) to this
solution, and allowing a reaction to progress for approximately 24
hours.
[0047] Next, an example of the 2-position and 6-position
modification step in which hydroxyl groups at the 2-position and
6-position, from which protecting groups have been removed, are
modified by a second substituent group represented by formula
(II-2) is a step of reacting an isocyanate having a structure
represented by formula (II-2) above with the hydroxyl groups at the
2-position and 6-position of amylose using an appropriate solvent
or the like under appropriate conditions (for example, for
approximately 14 hours in pyridine at approximately 80.degree. C.)
in order to effect modification of the 2-position and 6-position by
the substituent group represented by formula (II-2), in the same
way as in the 3-position modification step.
[0048] In this way, the hydroxyl group at the 3-position of amylose
can be substituted by the second substituent group represented by
formula (II-2).
[0049] In cases where R.sup.3 is a substituent group represented by
structural formula 1 in the first substituent group represented by
formula (II-1), R.sup.4 is preferably a substituent group
represented by any of structural formulae a, b, e and f, more
preferably a substituent group represented by any of structural
formulae a, e and f, and particularly preferably a substituent
group represented by structural formula a in the second substituent
group represented by formula (II-2).
[0050] In cases where R.sup.3 is a substituent group represented by
structural formula 2 in the first substituent group represented by
formula (II-1), R.sup.4 is preferably a substituent group
represented by any of structural formulae a, c, d, e and g, more
preferably a substituent group represented by any of structural
formulae c and e, and particularly preferably a substituent group
represented by structural formula c in the second substituent group
represented by formula (II-2).
[0051] In cases where R.sup.3 is a substituent group represented by
structural formula 3 in the first substituent group represented by
formula (II-1), R.sup.4 is preferably a substituent group
represented by any of structural formulae a, b, d, e and f, more
preferably a substituent group represented by any of structural
formulae a and d, and particularly preferably a substituent group
represented by structural formula a in the second substituent group
represented by formula (II-2).
[0052] The optical isomer separating agent of the present invention
contains the amylose derivative of the present invention. The
optical isomer separating agent of the present invention may be
constituted only from the amylose derivative of the present
invention, but may also be constituted from a carrier such as
silica gel and the amylose derivative of the present invention
supported on this carrier, and may be in the form of a single body
housed integrally in a column or in the form of particles filled in
a column. The optical isomer separating agent of the present
invention may be produced from a publicly known optical isomer
separating agent that contains an amylose derivative in addition to
using the amylose derivative of the present invention.
[0053] More specifically, an optical isomer separating agent can be
produced by supporting the amylose derivative of the present
invention on a carrier, pulverizing the amylose derivative per se
or obtaining spherical particles of the amylose derivative using a
publicly known method (for example, see Japanese Patent Application
Publication No. H7-285889). Moreover, "supporting" in this case
means that the amylose derivative is immobilized on a carrier. The
method for supporting the amylose derivative can be a publicly
known supporting method, and can be a method such as physical
adsorption between the amylose derivative and a carrier, chemical
bonding between the amylose derivative and a carrier, chemical
bonding between the amylose derivative, chemical bonding between
the amylose derivative and/or a carrier and a third component,
irradiation of the amylose derivative with light, or a radical
reaction (for example, see Japanese Patent Application Publication
No. H6-93002).
[0054] Examples of carriers include porous organic carriers and
porous inorganic carriers, and the use of a porous inorganic
carrier is preferred. The average particle diameter of the porous
carrier is preferably 1 nm to 100 .mu.m, and more preferably 5 nm
to 5 .mu.m. Suitable porous organic carriers include polymeric
substances comprising polystyrene, polyacrylamide, polyacrylates
and the like, and suitable porous inorganic carriers include silica
gel, alumina, zirconia, magnesia, glass, kaolin, titanium oxide,
silicates and hydroxyapatite. In addition, the form of the porous
inorganic carrier may, in addition to a particulate carrier, be a
mesh-like inorganic-based carrier such as an organic-inorganic
composite material or a cylindrical integrated inorganic-based
carrier able to be held in a column, such as those disclosed in
Japanese Patent Application Publication Nos. 2005-17268 and
2006-150214.
[0055] A particularly preferred carrier is silica gel, and the
particle diameter of the silica gel is 1 .mu.m to 1 mm, preferably
1 to 300 .mu.m, and more preferably 1 to 100 .mu.m. In addition, it
is possible to use a carrier that has been subjected to a treatment
for improving affinity with the polysaccharide derivative or a
treatment for modifying the characteristics of the surface of the
carrier per se. Examples of surface treatment methods include
silanization treatment using an organic silane compound such as
aminopropylsilane and surface treatment methods involving plasma
polymerization. The quantity of amylose derivative supported on the
character is preferably 1 to 100 parts by mass, more preferably 5
to 60 parts by mass, and particularly preferably 10 to 40 parts by
mass, relative to 100 parts by mass of the optical isomer
separating agent.
EXAMPLES
[0056] Examples are given below, but the present invention is not
limited to these examples.
[Synthesis Examples] Synthesis of Amylose Derivatives (1a to 1g, 2a
to 2g and 3a to 3g)
[0057] Substitution was carried out by position-specific
substitution of the 2-position, 6-position and 3-position of
amylose by phenyl carbamate groups. This method was carried out in
accordance with the method disclosed in Macromol Biosci 1, 49-54,
2001.
[0058] The specific reaction order is as follows.
##STR00010## ##STR00011##
[0059] In order to selectively protect the 2-position and
6-position of amylose, 3.0 g of amylose was dissolved in a mixture
of DMAc (dimethylacetamide) and LiCl (lithium chloride) (at
100.degree. C.), and imidazole (at a quantity of 2.4 equivalents
relative to the number of hydroxyl groups at the 2-position and
6-position) and TMDS-Cl (thexyldimethylsilyl chloride: at a
quantity of 2 equivalents relative to the number of hydroxyl groups
at the 2-position and 6-position) were added dropwise incrementally
to the solution (at 100.degree. C.)
[0060] A reaction was then allowed to progress for 24 hours so as
to protect the hydroxyl groups at the 2-position and 6-position of
amylose with thexyldimethylsilyl ether.
[0061] The reaction mixture was added to an excess of a phosphate
buffer solution (which was obtained by dissolving 1.79 g of
K.sub.2HPO.sub.4 and 0.89 g of KH.sub.2PO.sub.4 in 250 mL of
distilled water).
[0062] After thoroughly washing the obtained precipitated product
with ethanol and water, a product was obtained as an insoluble
component (yield: 80% to 100%).
[0063] The obtained 2, 6-di-O-thexyldimethylsilylamylose was
reacted with phenyl isocyanate, 4-chlorophenyl isocyanate or
3,5-dichlorophenyl isocyanate in pyridine at 80.degree. C. so as to
convert the hydroxyl group at the 3-position of amylose into the
corresponding phenyl carbamate group. The yield of product obtained
as methanol-insoluble components was 85% to 100%.
[0064] Next, the obtained 2,
6-di-O-thexyldimethylsilyl-3-(phenylcarbamoyl,
4-chlorophenylcarbamoyl or 3, 5-dichlorophenylcarbamoyl) amylose
was dispersed in THF, tetrabutylammonium fluoride trihydrate: TBAF)
(as a catalyst at a quantity of 20 wt % relative to the THF), and
the obtained mixture was stirred for 24 hours at 50.degree. C. so
as to deprotect the thexyldimethylsilyl ether groups.
[0065] Next, by reacting the hydroxyl groups at the 2-position and
6-position of the produced amylose with an excess of phenyl
isocyanate, 4-chlorophenyl isocyanate or 3,5-dichlorophenyl
isocyanate for 14 hours at 80.degree. C., these hydroxyl groups
were substituted by phenyl carbamate groups.
[0066] By carrying out this procedure, 18 types of amylose
derivative (amylose derivatives 1a to 1g, 2a to 2g and 3a to 3g)
were obtained as methanol-insoluble components (the yield was 85%
to 1000).
[0067] The obtained 18 types of amylose derivative were
combinations of R.sup.1 and R.sup.2 shown below, excluding cases in
which R.sup.1 and R.sup.2 are the same.
##STR00012##
[Preparation of Chiral Stationary Phase]
[0068] 0.35 g of each of the 18 types of amylose derivative was
dissolved in 8 mL of THF and coated on 1.40 g of silica gel that
had been treated with aminopropylsilane, in accordance with the
disclosures in J. Chromatogr. A 363, 173-186, 1986. The silica gel
was wide pore silica gel (average particle diameter 7 .mu.m,
average pore diameter 100 nm: Daiso gel SP-1000).
[0069] Each of the silica gels was charged in a stainless steel
column (25.times.0.20 cm i.d.) using a slurry method.
[0070] The number of theoretical plates in each filled column was
1800 to 2800 for a flow rate of 0.1 mL/min using benzene
(hexane/2-propanol (90/10, v/v)) as an eluant.
[0071] The dead time (t.sub.0) was calculated using
1,3,5-tributylbenzene as a non-retentive compound.
[0072] Tests involving the use of chromatography were carried out
at room temperature using a JASCO PU-2089 chromatographic apparatus
equipped with UV-Vis (JASCO UV-2070) and circular dichroism (JASCO
CD-2095) measurement devices.
[0073] A racemate solution (3 mg/mL) was injected into an
intelligent sampler (JASCO AS-2055).
[0074] A .sup.1H-NMR spectrum (500 MHz) was measured at 80.degree.
C. in pyridine-d.sub.5 using a Bruker-500 spectrometer (Bruker,
USA).
[0075] Thermogravimetric analysis (TGA) was carried out using a TGA
Q50 apparatus (TA, USA).
[Results of .sup.1H-NMR Analysis and Thermogravimetric
Analysis]
[0076] .sup.1H-NMR analysis results for amylose 1f (in which the
3-position was substituted by the substituent group represented by
structural formula 1, and the 2-position and 6-position were
substituted by the substituent group represented by structural
formula f; similar nomenclature is used below) are shown in FIG. 1.
Characteristic peaks were observed in amylose derivative 1f.
[0077] The other amylose derivatives were also subjected to
.sup.1H-NMR analysis, and the structures thereof were confirmed in
the same way.
[0078] Elemental analysis results for several of the amylose
derivatives are shown in Table 1. The results show good conformity
between theoretical values and measured values.
TABLE-US-00001 TABLE 1 Calculated (%).sup.a Found (%) Derivatives C
H N C H N 1b 64.46 6.11 7.27 64.23 6.12 6.92 1c 65.44 6.49 6.94
64.89 6.31 6.64 1e 56.32 4.73 6.79 55.96 4.47 6.25 1g 50.67 3.96
6.11 50.21 3.62 5.98 2b 60.83 5.60 6.87 60.27 5.68 6.52 2c 61.92
5.98 6.56 61.36 5.77 6.39 2e 53.35 4.32 6.44 53.18 4.12 6.21 2g
48.26 3.63 5.82 48.08 3.22 5.38 3b 57.59 5.14 6.50 57.24 5.01 6.25
3c 58.76 5.53 6.23 58.18 5.21 6.04 3d 56.32 4.73 6.79 56.05 4.68
6.58 4e 50.67 3.96 6.11 50.26 4.05 5.88 .sup.aEsimated based on a
repeated glucose unit.
[Results of Racemate Separation by HPLC, and Discussion]
[0079] 10 types of racemate represented by 4 to 13 below were
analyzed by means of HPLC using fillers obtained using the amylose
derivatives prepared in the manner described above.
##STR00013## ##STR00014##
[0080] FIG. 2 is a chromatogram obtained by separating
trans-stilbene oxide (racemate 5) using a filler coated with
amylose derivative 1f. The enantiomers were separated at retention
times t.sub.1 and t.sub.2. The dead time (t.sub.0) was 8.28 minutes
when 1,3,5-tri-tert-butylbenzene was used.
[0081] The retention coefficients (k.sub.1'
((t.sub.1-t.sub.0)/t.sub.0) and k.sub.2'
((t.sub.2-t.sub.0)/t.sub.0)) were 0.33 and 1.15 respectively, and
the separation coefficient .alpha. (k.sub.2'/k.sub.1') was 3.48. As
is clear from FIG. 2, racemate 5 was sufficiently separated.
[0082] The results obtained when separating racemates 4 to 13 using
fillers coated with amylose derivatives 1a to 1g, 2a to 2g and 3a
to 3g are summarized in Tables 2 to 4.
[0083] The HPLC conditions are as shown in the tables.
[0084] Moreover, the tables show results obtained when separating
the racemates using fillers obtained using Chiralpak AD (amylose
tris(3,5-dimethylphenyl carbamate)) as a chiral selector.
[0085] Going from left to right in the tables, the
electron-withdrawing effect of the substituent groups
increases.
<Amylose Derivatives 1a to 1g (1d is a Reference
Example)>
[0086] Results obtained when separating the racemates using fillers
obtained using amylose derivatives 1a to 1g are summarized in Table
2A and 2B below.
TABLE-US-00002 TABLE 2A 1a.sup.a 1b.sup.a 1c.sup.a 1d.sup.b
Racemates k1' .alpha. k1' .alpha. k1' .alpha. k1' .alpha. 4 0.42(+)
1.71 0.58(+) 1.19 0.62(+) 1.63 0.77(+) 1.28 5 0.27(+) 2.48 0.28(+)
1.61 0.52(+) 2.50 0.39(+) 1.46 6 2.57(-) 1.35 2.25(-) ~1 3.90(-)
1.17 3.72(+) ~1 7 0.56 1.0 0.70 1.0 0.74 1.0 1.19(-) ~1 8 0.83 1.0
0.84 1.0 1.72 1.12 0.61 1.0 9 0.42(+) ~1 0.62(+) 1.29 0.34(+) ~1
1.80(-) 1.28 10 1.06(+) 1.67 1.03(+) 1.11 1.20(+) ~1 2.21(+) 1.51
11 0.28 1.0 0.25 1.0 0.55 ~1 12 7.50(+) 1.05 9.13(+) ~1 11.55(+) ~1
13 1.11(+) 1.23 0.84 1.0 1.11 1.0 .sup.a,bColumn: 25 cm .times.
0.20 cmID, Flow eate: 0.1 mL/min. .sup.bData taken from ref. 4 The
signs in parentheses represent the circular dichroism detection at
254 nm of the first-eluted enantiomer. The signs in parentheses
represent the optical rotation of the first-eluted enantiomer.
TABLE-US-00003 TABLE 2B Race- 1e.sup.a 1f.sup.a 1g.sup.a Chiralpak
AD.sup.c mates k1' .alpha. k1' .alpha. k1' .alpha. k1' .alpha. 4
0.72(+) 1.60 0.65(+) 1.32 0.69(+) 1.45 0.53(+) 1.58 5 0.30(+) 2.43
0.33(+) 3.48 0.41(+) 1.49 0.42(+) 3.04 6 3.18(-) 1.24 2.55(-) 1.22
4.72 1.0 3.14(-) 1.21 7 0.71 1.0 0.98(-) ~1 1.06 1.0 0.61(-) ~1 8
0.58 1.0 0.43 1.0 0.36 1.0 1.30(+) 1.15 9 0.48(+) ~1 1.19(+) ~1
0.56(+) ~1 0.25(-) ~1 10 1.32(+) 1.63 1.37(+) ~1 1.39(+) ~1 0.93(+)
1.12 11 0.26 1.0 0.20(+) ~1 0.29(+) ~1 12 2.78(+) ~1 5.89(+) 1.07
7.02 1.0 13 0.18 1.0 0.89 1.0 0.87 1.0 .sup.aColumn: 25 cm .times.
0.20 cmID, Flow eate: 0.1 mL/min. .sup.cData taken from ref. 5
Column: 25 cm .times. 0.46 cmID, Flow eate: 0.5 mL/min. Eluent:
hexane/2-propanol = 90/10, v/v The signs in parentheses represent
the circular dichroism detection at 254 nm of the first-eluted
enantiomer. The signs in parentheses represent the optical rotation
of the first-eluted enantiomer.
[0087] Among amylose derivatives 1a to 1g, amylose derivative 1a
(2,6-bis(3-methylphenyl carbamate) exhibited the best optical
resolution performance for the racemates. Separation was
particularly good for racemates 4, 5, 6, 10, 12 and 13. This shows
that a compound in which 3-methylphenyl carbamate, which is an
electron donor, is substituted at the 2-position and 6-position and
phenyl carbamate is substituted at the 3-position is effective for
identifying a chiral drug such as racemate 13.
[0088] Fillers obtained using amylose derivatives 1a and 1e showed
good separation results for racemate 10. This may be due to the
introduction of a phenyl carbamate group, which is an aromatic
ring, at the 2-position and 6-position, which are
meta-positions.
[0089] Others among amylose derivative 1 also exhibited good
separation performance for the racemates. In particular, cases in
which Chiralpak AD was used could not separate racemate 9, but
amylose derivative 1b exhibited excellent separation of racemate
9.
<Amylose Derivatives 2a to 2g (2f is a Reference
Example)>
[0090] In amylose derivatives 2a to 2g, a 4-chlorophenyl carbamate
group was introduced at the 3-position of amylose.
[0091] Results for separation of the racemates by fillers obtained
using these amylose derivatives are summarized in Table 3A and 3B
below.
TABLE-US-00004 TABLE 3A 2a.sup.a 2b.sup.a 2c.sup.a 2d.sup.a
Racemates k1' .alpha. k1' .alpha. k1' .alpha. k1' .alpha. 4 0.99(+)
1.51 0.68(+) 1.24 0.77(+) 1.79 0.83(+) 1.37 5 0.52(+) 2.48 0.37(+)
2.43 0.66(+) 2.86 0.47(+) 1.79 6 4.79(-) 1.20 2.70(-) ~1 4.29(-)
1.12 4.08(-) ~1 7 1.51(-) ~1 0.84 1.0 1.01 1.0 1.14 1.0 8 0.61 1.0
0.77 1.0 1.40(-) 1.19 0.8 1.0 9 1.05(+) 1.15 0.83(+) ~1 0.38(+) ~1
1.35(+) 1.39 10 1.93(+) 1.52 1.17(+) ~1 1.46(+) 1.21 1.91(+) 1.54
11 0.39(+) ~1 0.30 1.0 0.55 1.0 0.35 1.0 12 7.51(+) 1.05 9.55(+) ~1
15.26(-) 1.11 10.80(+) 1.08 13 1.53 1.0 0.80 1.0 1.16 1.0 1.11 1.0
.sup.aColumn: 25 cm .times. 0.20 cmID, Flow eate: 0.1 mL/min. The
signs in parentheses represent the circular dichroism detection at
254 nm of the first-eluted enantiomer. The signs in parentheses
represent the optical rotation of the first-eluted enantiomer.
TABLE-US-00005 TABLE 3B Race- 2e.sup.a 2f.sup.b 2g.sup.a Chiralpak
AD.sup.c mates k1' .alpha. k1' .alpha. k1' .alpha. k1' .alpha. 4
0.61(+) 1.59 0.79(+) 1.37 1.04(+) 1.49 0.53(+) 1.58 5 0.41(+) 2.10
0.53(+) 3.02 0.54(+) 1.33 0.42(+) 3.04 6 3.52(-) 1.20 5.14(-) 1.40
6.72(-) ~1 3.14(-) 1.21 7 0.84(-) ~1 1.85(-) 1.18 1.59 1.0 0.61(-)
~1 8 0.92 1.0 0.67 1.17 0.60 1.0 1.30(+) 1.15 9 0.55(+) ~1 1.32(-)
~1 0.60 1.0 0.25(-) ~1 10 1.47(+) 1.56 0.88(+) 1.37 1.88(+) 1.13
0.93(+) 1.12 11 0.37(+) ~1 0.42(+) ~1 12 6.93(+) ~1 8.79(+) ~1 13
1.02(+) 1.27 1.49 1.0 .sup.a,bColumn: 25 cm .times. 0.20 cmID, Flow
eate: 0.1 mL/min. .sup.bData taken from ref. 4 .sup.cData taken
from ref. 5 Column: 25 cm .times. 0.46 cmID, Flow eate: 0.5 mL/min.
Eluent: hexane/2-propanol = 90/10, v/v The signs in parentheses
represent the circular dichroism detection at 254 nm of the
first-eluted enantiomer. The signs in parentheses represent the
optical rotation of the first-eluted enantiomer.
[0092] Amylose derivatives 2a, 2c, 2d and 2e exhibited good
separation of 5 racemates. However, differences in racemate
separation occurred, depending on the type of amylose derivative.
For example, racemate 8 was separated by amylose derivative 2c.
Racemate 9 was separated by amylose derivatives 2a and 2d. Amylose
derivative 2c (2,6-bis(3,5-dimethylphenyl carbamate) exhibited
relatively high separation performance for racemates 4 to 8 and 12
in particular.
[0093] A chromatogram showing separation results for racemate 5 is
shown in FIG. 3.
[0094] In light of these results, it is thought that the presence
or absence of electron-withdrawing groups in phenyl groups affects
separation.
[0095] Amylose derivative 2e exhibited the best separation for
racemate 13.
<Amylose Derivatives 3a to 3g (3g is a Reference
Example)>
[0096] In amylose derivatives 3a to 3g, 3,5-dichlorophenylcarbamate
is introduced at the 3-position of amylose and electron-donating
groups or electron-withdrawing groups are introduced at the
2-position and 6-position of amylose. Results for separation of
racemates by fillers obtained using these amylose derivatives are
summarized in Table 4A and 4B below.
TABLE-US-00006 TABLE 4A 3a.sup.a 3b.sup.a 3c.sup.a 3d.sup.a
Racemates k1' .alpha. k1' .alpha. k1' .alpha. k1' .alpha. 4 0.66(+)
1.61 0.74(+) 1.86 0.27(+) 2.11 0.80(+) 1.71 5 0.48(+) 2.35 0.40(+)
2.30 0.21(+) 2.71 0.56(+) 2.43 6 4.04(-) 1.36 3.43(-) 1.19 2.29(-)
~1 4.23(-) 1.30 7 0.95(-) ~1 1.01 1.0 0.47 1.0 1.12 1.0 8 0.93 1.0
0.72 1.0 0.59 1.0 0.70 1.0 9 0.54(+) ~1 0.40(+) 1.28 0.08 1.0
0.74(+) 1.20 10 1.63(+) 1.33 1.57(+) 1.23 0.60(+) ~1 2.43(+) 1.31
11 0.40(+) ~1 0.29(+) ~1 0.18(+) ~1 0.34(+) ~1 12 7.84(+) 1.03
11.72(+) ~1 7.80(-) ~1 11.66(+) ~1 13 1.19(+) 1.27 1.11 1.0 0.65
1.0 1.42 1.0 .sup.aColumn: 25 cm .times. 0.20 cmID, Flow eate: 0.1
mL/min. The signs in parentheses represent the circular dichroism
detection at 254 nm of the first-eluted enantiomer. The signs in
parentheses represent the optical rotation of the first-eluted
enantiomer.
TABLE-US-00007 TABLE 4B Race- 3e.sup.a 3f.sup.a 3g.sup.b Chiralpak
AD.sup.c mates k1' .alpha. k1' .alpha. k1' .alpha. k1' .alpha. 4
0.88(+) 1.48 0.40(+) 1.65 0.84(+) 1.34 0.53(+) 1.58 5 0.49(+) 2.16
0.25(+) 2.52 0.50(+) 1.32 0.42(+) 3.04 6 5.09(-) 1.16 1.51(-) 1.26
6.08(-) ~1 3.14(-) 1.21 7 1.40(-) ~1 0.76 1 1.26(-) ~1 0.61(-) ~1 8
0.58 1.0 0.35 1.0 0.37 1.0 1.30(+) 1.15 9 0.90(+) 1.14 0.54(+) ~1
0.63(+) ~1 0.25(-) ~1 10 1.84(+) 1.24 0.74(+) ~1 1.62(+) 1.10
0.93(+) 1.12 11 0.35(+) ~1 0.18(+) ~1 12 7.76(+) 1.06 9.06(+) ~1 13
1.55(+) 1.28 0.50 1.0 .sup.a,bColumn: 25 cm .times. 0.20 cmID, Flow
eate: 0.1 mL/min. .sup.bData taken from ref. 4 .sup.cData taken
from ref. 5 Column: 25 cm .times. 0.46 cmID, Flow eate: 0.5 mL/min.
Eluent: hexane/2-propanol = 90/10, v/v The signs in parentheses
represent the circular dichroism detection at 254 nm of the
first-eluted enantiomer. The signs in parentheses represent the
optical rotation of the first-eluted enantiomer.
[0097] Fillers obtained using amylose derivatives 3a, 3b, 3d and 3e
exhibited good separation performance for 5 or 6 racemates.
[0098] Amylose derivative 3a exhibited high separation performance
for racemates 6, 10 and 13. Amylose derivative 3b exhibited high
separation performance for racemate 9. Amylose derivative 3e
exhibited high separation performance for racemates 12 and 13.
Racemate 9, which could not be separated using Chiralpak AD, could
be separated by fillers obtained using amylose derivatives 3b, 3d
and 3e. Amylose derivatives 3a and 3e were able to separate
propranolol (13).
[0099] A filler obtained using amylose derivative 3c (3,5-dimethyl
group) exhibited good separation performance for racemates 4 and
5.
[0100] Amylose derivatives 3a to 3f exhibited better separation
performance for racemates 4, 6, 9 and 10 than Chiralpak AD.
[0101] In fillers obtained using amylose derivatives 1a to 1g, 2a
to 2g and 3a to 3g, the fact that racemates 6 and 12 have a higher
retention coefficient k.sub.1' than other racemates means that
interactions between the phenyl carbamate groups in the amylose
derivatives and these racemates are strong, and means that the
effect of substituent groups on the phenyl carbamate groups at the
2-position and 6-position may be hardly exerted.
[0102] When used in an optical isomer separating agent, the amylose
derivative of the present invention exhibits similar or better
applicability in comparison with existing optical isomer separating
agents and exhibits higher optical separation performance than
existing optical isomer separating agents depending on the type of
racemate to be subjected to optical resolution. Therefore, the
amylose derivative and optical isomer separating agent of the
present invention enable separation of optical isomers that could
not be satisfactorily separated using existing optical isomer
separating agents, and can be used to develop, for example, new
drugs in which such optical isomers are used.
[0103] While the present invention has been described with
reference to exemplary embodiments, it is to be understood that the
invention is not limited to the disclosed exemplary embodiments.
The scope of the following claims is to be accorded the broadest
interpretation so as to encompass all such modifications and
equivalent structures and functions.
[0104] This application claims the benefit of Japanese Patent
Application No. 2016-165637, filed on Aug. 26, 2016, which is
hereby incorporated by reference herein in its entirety.
* * * * *