Method for Improving Optical Purity of 2-Hydroxycarboxylic
Acid or Derivative Thereof
Technical Field
[ OOOl]
The present invention relates to a method for improving
optical purity of an optically active 2-hydroxycarboxylic
acid or a derivative thereof that is useful as a raw material
for producing medicines, agrochemicals, and industrial
products.
Background Art
[0002]
Optically active 2-hydroxycarboxylic acids are useful
compounds as reagents or raw materials in the manufacture of
medicines, agrochemicals, and industrial products. For
example, 2-hydroxycarboxylic acid can be used as an important
raw material of (R) -2- (3-(N- (benzoxazol-2-yl)- N- [3- (4-
methoxyphenoxy)propyllaminomethyl]phenoxy)butyric acid of the
following formula that is a selective PPARa-activating agent
and is useful as a preventive and/or a therapeutic agent for
hyperiipidemia, arteriosclerosis, diabetes, diabetes
complications, inflammation, and cardiac disorders (Patent
Document 1). In the manufacture of the above-described
compound, optical purity of 2-hydroxybutyric acid serving as
a synthesis intermediate, or a derivative thereof directly
and considerably affects optical purity of the final product.
Therefore, a pharmaceutical ingredient having higher optical
purity is desired (Patent Documents 2 to 6).
[00031
[00041
Such an optically active 2-hydroxybutyric acid
derivative is, commercially available (Aldrich), but very
expensive. Hitherto, there have been knot~n several methods
for manufacturing optically active 2-hydroxycarboxylic acid
ester derivatives as shown in the following reaction schemes:
(1) Method for manufacturing an optically active 2-
hydroxybutyric acid ester by asymmetric reduction of 2-keto
butyric acid ester using a baker's yeast (Non-Patent Document
11,
(2) Method for manufacturing an optically active 2-
hydroxybutyric acid ester using L-methionine as a starting
material (Non-Patent Documents 2 and 3 ) ,
(3) Method for manufacturing an optically active 2-
hydroxycarboxylic acid ester derivative by asymmetric
reduction of an acrylic acid derivative (Non-Patent Document
4), and
(4) Method for manufacturing an optically active 2-
hydroxycarboxylic acid derivative using an aldehyde as a
starting material via optically active cyanohydrin (Patent
Document 7).
[0005]
1) 0 Baker's yeast OH
P
OH
4C02Et *cQE~ + 4C02Et
Free baker's yeast; 75% e.e./42%
Immobilized baker's yeast; 66% e.e./42%
2) 0 0 BnOH 0
TsOH
/ ' d O H +OH +OH ~nzene* +OBn
Nth 80°C NH* O"C+rt OH reflux, 5h OH
3) Asymmetric
reduction Hydrolysis
DuPHOS-Rh HCI/R"OH *
OCoR BOpsi Hz OCOR OH
--.,
-R = H; C,: alkyl group, orawl gzup,
R' = acetyfgroup or benzoyi group
R" = Me, Et
4) HCN
R-CHO
VO-salen-complex c.HCI - 2
R CN R C%H
R = C,.,, alkyl group, alkenyl group,
or alkynyl group, or aryl group 68%, 88% ee(2 steps)
However, in method (I), the optical purity (S
configuration) and the chemical yield of the resultant 2-
hydroxybutyric acid ester are 75% e.e. and 42% respectively
when free baker's yeast is used, and are 66% e.e. and 42%
respectively when immobilized baker's yeast is used.
Therefore, neither of them is suitable for manufacturing a 2-
hydroxybutyric acid ester with high optical purity. Thus,
method (1) is not an industrially available manufacturing
method. In addition, a 2-keto butyric acid ester is
chemically unstable and is expensive, which is problematic.
Furthermore, optically active 2-hydroxycarboxylic acid ester
having R configuration cannot be yielded through method (1).
[0007]
In method (2), a target optically active 2-
hydroxybutyric acid ester can be manufactured using
inexpensive L-methionine as a starting material. However,
three steps are required for the manufacture of the target
product, and the total yield is as low as 32%. Furthermore,
method (2) is not efficient, since, for example, a large
amount of solvent is required for the reaction and posttreatment
of reaction. Also, since the manufacturing method
involves a step of forming an unstable diazonium salt, it is
difficult to control the reaction conditions. As a result,
consistent yield and optical purity of the target product may
not be obtained, and the optical purity may be significantly
lowered depending on the manufacturing scale.
[0008]
In method ( 3 ) , a target product having high optical
purity can be yielded through asymmetrically reducing double
bonds in a 2-acyloxyacrylic acid ester derivative through
hydrolysis with acid in the presence of an asymmetric
catalyst. However, cumbersome operations are required for
producing a 2-acyloxyacrylic acid ester derivative serving as
a starting substrate. In addition, method (3) is not an
industrially advantageous manufacturing method, involving
problems such as preparation of an expensive asymmetric
ligand and carrying out reduction under high pressure
hydrogen.
[0009]
In method ( 4 1 , a 2-hydroxy carboxylic acid derivative
is manufactured in two steps, i.e., conversion of an aldehyde
into asymmetric cyanohydrin and subsequent hydrolysis. This
requires a cumbersome preparation of an asymmetric ligand
serving as an asymmetric catalyst. With regard to optical
purity, the optical purity and the chemical yield of the
target are likely to vary depending on the substituent of the
reaction substrate.
[OOlO]
In a known alternative method, racemic 2-hydroxy
butyric acid is transformed into a corresponding diastereomer
salt by using brucine, and the salt is subjected to optical
resolution (Non-Patent Document 5). The document does not
disclose optical purity. Also reported is a kinetic optical
resolution of 2-hydroxycarboxylic acid by using recombinant E.
coli (Non-Patent Document 6). However, the method is not
industrially practical.
[OOll]
Furthermore, it is reported the optical purity of an
inorganic salt of 2-hydroxyhexanoic acid (Non-Patent Document
7). However, it is not known that a 2-hydroxycarboxylic acid
having high optical purity and a derivative thereof can be
produced from the thus-formed inorganic salt.
Prior Art Documents
Patent Documents
[0012]
Patent Document 1: WO 2005/23777
Patent Document 2: WO 2006/90768
Patent Document 3: WO 2006/93142
Patent Document 4: WO 2006/129649
Patent Document 5: WO 2007/13555
Patent Document 6: WO 2007/23906
Patent Document 7: Japanese PCT Kohyo Patent Application
2004-533490
Non-Patent Documents
[00131
Non-Patent Document 1: J. Org. Chem., 1988, 53, 2589-2593
Non-Patent Document 2: J. Org. Chem., 1986, 51, 1713-1719
Non-Patent Document 3: Chirality, 1996, 51, 225-233
Non-Patent Document 4: J. Am. Chem. Soc., 1988, 120,
4315-4353
Non-Patent Document 5: Nippon Kagaku Kaishi, 1956, 77, 2, 284
Non-Patent Document 6: Tetrahedron: Asymmetry, 2007, 18,
2394-2398
Non-Patent Document 7: J. Chem. Soc., 1954, 177, 1460-1464
Summary of the Invention
Problems to be Solved by the Invention
[0014]
An object of the present invention is to provide a
method for improving optical purity of an optically active 2-
hydroxycarboxylic acid or a derivative thereof, which is
useful as a raw material in the manufacture of medicines,
agrochemicals, and industrial products.
[0015]
In view of the foregoing, the present inventor has
conducted intensive studies to explore a method for improving
optical purity of an optically active 2-hydroxycarboxylic
acid or a derivative thereof. As a result, the present
inventor has found that the optical purity of optically
active 2-hydroxycarboxylic acid or derivative thereof can be
improved by reacting an optically active 2-hydroxycarboxylic
acid with at least one optically inactive base selected from
the group consisting of an alkali metal alkoxide and a
secondary amine, in the presence of a solvent, and
recrystallizing the reaction product. The present invention
has been accomplished on the basis of this finding. As used
herein, the term "2-hydroxycarboxylic acid derivative" refers
to a salt or an ester of a 2-hydroxycarboxylic acid.
[00161
Accordingly, the present invention is directed to the
following.
[0017]
(1) A method for improving optical purity of a
hydroxycarboxylic acid of the following formula (la) or (lb)
or a derivative thereof, the method comprising the steps of:
reacting the hydroxycarboxylic acid of the following
formula (la) or (lb) with at least one optically inactive
base selected from the group consisting of an alkali metal
alkoxide and a secondary amine in the presence of a solvent,
and, subsequently,
performing recrystallization, to thereby form a
hydroxycarboxylic acid salt of the following formula (IIIa)
or (IIIb) .
[0018]
(2) A method for improving optical purity of a
hydroxycarboxylic acid of the following formula (la) or (lb)
or a derivative thereof, the method comprising:
a first step of reacting the hydroxycarboxylic acid of
the following formula (la) or (lb) with at least one
optically inactive base selected from the group consisting of
an alkali metal alkoxide and a secondary amine in the
presence of a solvent and, subsequently, performing
recrystallization, to thereby form a hydroxycarboxylic acid
salt of the following formula (IIIa) or (IIIb), and
a second step of reacting the hydroxycarboxylic acid
salt with an organic acid or an inorganic acid, to thereby
form the hydroxycarboxylic acid of formula (la) or (lb).
[0019]
(3) A method for improving optical purity of a
hydroxycarboxylic acid of the following formula (la) or (lb)
or a derivative thereof, the method comprising:
a first step of reacting the hydroxycarboxylic acid of
the following formula (la) or (lb) with at least one
optically inactive base selected from the group consisting of
an alkali metal alkoxide and a secondary amine in the
presence of a solvent and, subsequently, performing
recrystallization, to thereby form a hydroxycarboxylic acid
salt of the following formula (IIIa) or (IIIb),
a second step of reacting the hydroxycarboxylic acid
salt with an organic acid or an inorganic salt, to thereby
form the hydroxycarboxylic acid of formula (la) or (lb), and
a third step of esterifying the hydroxycarboxylic acid
formed in the second step.
[00201
(4) A method for improving optical purity of a
hydroxycarboxylic acid of the following formula (la) or (lb)
or a derivative thereof, the method comprising the steps of:
reacting the hydroxycarboxylic acid of the following
formula (la) or (lb) with at least one optically inactive
base selected from the group consisting of an alkali metal
alkoxide and a secondary amine in the presence of a solvent
and, subsequently, performing recrystallization, to thereby
form a hydroxycarboxylic acid salt of the following formula
(IIIa) or (IIIb), and
esterifying the hydroxycarboxylic acid salt.
[00211
( l a ) ( I I . ) ( Wa ) ( I I I )~
[0022]
, wherein R' represents a C1-8 alkyl group, and R~ represents
an alkali metal or a secondary amine.
[0023]
(5) More specifically, the method as described in any
one of (1) to (4) above, wherein RI is an ethyl group.
LOO241
(6) More specifically, the method as described in any
one of (1) to (5) above, wherein the optically inactive base
is a sodium alkoxide.
[00251
(7) The method as described in (6) above, wherein the
sodium alkoxide is sodium methoxide.
[00261
(8) The method as described in any one of (1) to (7)
above, wherein the optically inactive base is
dicyclohexylamine.
[0027]
(9) The method as described in any one of ( 1 ) to ( 8 )
above, wherein recrystallization is performed by using a
solvent containing at least one solvent selected from the
group consisting of an ester, an ether and an alcohol.
[0028]
(10) A method for producing a compound of the following
formula (A), the method comprising a method as recited in any
one of (1) to (9) above.
[00291
[0030]
, wherein R' represents a C1-8 alkyl group.
[00311
(11) The method as described in (10) above, wherein the
formula (A) is (R) -2- (3-{N-( benzoxazol-2-yl)- N- [3- (4-
methoxyphenoxy)propyl]aminomethyl)phenoxy)butyric acid.
Effects of the Invention
LOO321
According to the method of the present invention, the
optical purity of an optically active 2-hydroxycarboxylic
acid or a derivative thereof that are useful as raw materials
in the manufacture of medicines, agrochemicals, and
industrial products can be improved.
Modes for Carrying Out the Invention
[0033]
The compound of the present invention of the abovedescribed
formula (la) or (lb), hereinafter also referred to
as "carboxylic acid (la) or (lb)", can be produced in
accordance with the following scheme 1. The compound of the
following formula (IIIa) or (IIIb), hereinafter also referred
to as "a carboxylic acid salt (IIIa) or (IIIb)", can be
produced by reacting the carboxylic acid (la) or (lb) of the
present invention with a optically inactive base. The
compound of the following formula (IVa) or (IVb), hereinafter
also referred to as "ester (IVa) or (IVb)", can be produced
by esterifying the carboxylic acid (la) or (lb) of the
present invention. These compounds can serve as an
intermediate of synthesis of pharmaceutically useful
compounds. In production of the carboxylic acid (la) or (lb),
the compound of the following formula (IIa) or (IIb),
hereinafter also referred to as "amino acid (IIa) or (IIb)",
may be used as a rap7 material. The method for producing the
carboxylic acid (la) or (lb) is not limited to these methods,
and the carboxylic acid (la) or (lb) may be produced through
any known method.
LOO341
( IIa ( l a ) (Ma )
or + or + or
reaction step 1 reaction step 2
0
-. - - -
N H2 6~
(lib )
OH OH
reaction-step 4
- --
6H 6H
, wherein R' represents C1-8 alkyl group, and R' represents an
alkali metal or a secondary amine
to0361
As the Cl-8 alkyl group of R', a C1-6 alkyl group is
preferable, and a C1.3 alkyl group is more preferable. The
alkyl group may be linear or branched, and linear form is
preferable. Specific examples include a methyl group, an
ethyl group, an n-propyl group, an isopropyl group, and the
like. Among them, an ethyl group is preferable.
[0037]
Hereinafter, each reaction step is described based on
scheme 1.
[0038]
[Reaction Step 11
This step is for converting an amino group in the amino
acid (IIa) or (IIb) into a hydroxyl group with
stereoretention of the amino group, to thereby produce the
carboxylic acid (la) or (lb).
[0039]
The reagents, the solvents and the reaction conditions
employed in reaction step 1 are not specifically limited.
For example, the method described in "Chirality, 1996, 51,
225-233" or "Tetrahedron, 1976, 32, 1101-1106" may be
employed. There may be also employed hydroxylation via
diazotization of amine with a diazotization reagent in the
presence or absence of a solvent. No particular limitation
is imposed on the diazotization reagent, and examples thereof
include sodium nitrite, nitrous acid, and the like.
[00401
If necessary, the carboxylic acid (la) or (lb) yielded
in step 1 may be isolated and/or purified through a
purification method generally employed in synthetic organic
chemistry, such as filtration, extraction, washing, drying,
concentration, recrystallization, and a variety of
chromatography techniques. Alternatively, the carboxylic
acid may be used in the subsequent step without any further
purification.
[00411
[Reaction Step 21
In reaction step 2, the carboxylic acid (la) or (lb) is
reacted with at least one optically inactive base selected
from the group consisting of an alkali metal alkoxide and a
secondary amine in the presence of a solvent, and then
performing recrystallization, to thereby form a carboxylic
acid salt (IIIa) or (IIIb), having an improved optical purity.
[0042]
The alkali metal alkoxide and the secondary amine may
be used singly or in combination of two or more species.
Also, the alkali metal alkoxide may be used in combination
with the secondary amine.
[0043]
No particular limitation is imposed on the alkali metal
alkoxide, so long as it is optically inactive. A
commercially available alkali metal alkoxide as is may be
used. Alternatively, an alkali metal, an alkali metal
hydride, or an alkali metal amide is reacted with alcohol,
and the reaction product may be used as the alkali metal
alkoxide. Examples of the alkali metal alkoxide include C1-6
alkoxides of lithium, potassium, sodium, and the like. The
C1-6 alkoxide may be any of linear, branched, and cyclic.
Specific examples include sodium alkoxides such as sodium
methoxide, sodium ethoxide, sodium tert-butoxide, and sodium
phenoxide; and potassium alkoxides such as potassium
methoxide, potassium ethoxide, potassium tert-butoxide, and
potassium phenoxide. Among them, sodium alkoxides are
preferable, and sodium methoxide is more preferable.
[0044]
No particular limitation is imposed on the secondary
amine, but a dialkyl amine is preferable. A variety of
dialkyl amines that have the same kind of alkyl groups or a
different kind of alkyl groups may be used. The alkyl group
may be linear, branched, and cyclic, so long as it is
optically inactive, and a cyclic alkyl group is preferable.
As the dialkyl amine, a di(C1-8 alky1)amine is preferable, a
di(C3-6 alky1)amine is more preferable, and di(C3-6 cyclic
alky1)amine is still more preferable. Specific examples
include dimethylamine, diethylamine, dipropylamine,
diisopropylamine, dicylohexylamine, N-ethylmethylamine, Nmethylpropylamine,
N-isopropylmethylamine, Nmethylcyclohexylamine,
N-ethylpropylamine, Nethylisopropylamine,
N-ethylcyclohexylamine, Npropylisopropylamine,
N-propylcyclohexylamine, Nisopropylcyclohexylamine,
and the like. Among these,
dicyclohexylamine is preferable.
[00451
No particular limitation is imposed on the amount of
the optically inactive base used in the invention, so long as
a salt of the carboxylic acid (la) or (lb) with the base (1 :
1 by mole) can be formed and precipitated as crystals. From
the standpoint of further improving the optical purity, from
0.7 to 1.5 mol eq. to the carboxylic acid (la) or (lb) is
preferable, and from 90.9 to 1.2 mol eq. is more preferable.
[00461
No particular limitation is imposed on the solvent used
in the reaction with the optically inactive base, so long as
it can dissolve the carboxylic acid (la) or (lb). Examples
of the solvent include alcohols such as methanol, ethanol,
and isopropanol; and ethers such as tetrahydrofuran, diethyl
ether, dioxane, methyl tert-butyl ether (MTBE), and
cyclopentyl methyl ether. Among them, ethers are preferable.
These solvents may be used singly or in combination of two or
more species. In addition, the below-mentioned solvent used
for recrystallization may also be employed here. The amount
of the solvent is appropriately tuned, and preferably from 10
to 50 (v/w) times as much as the weight of the carboxylic
acid (la) or (lb), and more preferably from 15 to 35 (v/w)
times as much. As used herein, 'v/w" means a volume/weight
ratio on L/kg basis.
[00471
The reaction temperature may be appropriately selected
depending on the types of the optically inactive base to be
employed, and is preferably from -20°C to 100°C, and more
preferably from -lO°C to 80°C. The reaction time is
preferably from 10 to 300 minutes, and more preferably from
20 to 120 minutes.
[0048]
After the reaction is terminated, the salt precipitated
from the reaction mixture may be collected through filtration,
and optionally subsequent washing and solvent evaporation, to
form the carboxylic acid salt (IIIa) or (IIIb) . In the
present invention, the carboxylic acid salt (IIIa) or (IIIb)
can be employed in the subsequent recrystallization as
described hereafter, without isolating the carboxylic acid
salt (IIIa) or (IIIb). Examples of the recrystallization
method include the following:
i) A method in which the carboxylic acid (la) or (lb)
and an optically inactive base are dissolved in a solvent,
followed by subjecting them to a reaction and optional
cooling; and
ii) A method in which the carboxylic acid salt (IIIa)
or (IIIb) is heated and dissolved in a solvent, optionally
with addition of a poor solvent or solvent substitution with
a poor solvent, and/or optionally followed by cooling.
[00491
No particular limitation is imposed on the solvent used
in the recrystallization. Examples of the solvent include
halogenated hydrocarbons such as dichloromethane and
chloroform; ethers such as tetrahydrofuran, diethyl ether,
dioxane, methyl tert-butyl ether (MTBE), and
cyclopentylmethyl ether; aromatic hydrocarbons such as
benzene, toluene, and xylene; alcohols such as methanol,
ethanol, and isopropanol; esters such as ethyl acetate and
isopropyl acetate; nitriles such as acetonitrile and
propionitrile; aprotic polar solvents such as
dimethylformamide and dimethyl sulfoxide; and hydrocarbons
such as n-hexane and n-heptane. Among them, the solvent
preferably contains at least one member selected from the
group consisting of an ester, an ether, and an alcohol, and
more preferably contains at least one member selected from
the group consisting of methyl tert-butyl ether,
cyclopentylmethyl ether, methanol, ethanol, isopropanol,
ethyl acetate, and propyl acetate. These solvents may be
used singly or in combination of two or more. When solvents
are used in combination, although not limiting, a preferable
combination is alcohol/hydrocarbon and alcohol/ester, and a
more preferable combination is isopropanol/n-heptane,
ethanol/n-heptane, or methanol/methyl tert-butyl ether. When
the carboxylic acid salt is an alkali metal salt, the amount
ratio (v/v) is preferably from 1/23 to 4/1, more preferably
from 1/4 to 2/1. When the carboxylic acid salt is an amine
salt, the amount ratio (v/v) is preferably from 1/2 to 1/12,
and more preferably from 1/5 to 1/10.
[00501
The amount of the solvent used for recrystallization is
preferably from 3 to 65 (v/w) times as much as the weight of
the carboxylic acid salt (IIIa) or (IIIb), and more
preferably from 10 to 15 (v/w) times as much.
[0051]
No particular limitation is imposed on the temperature
at which the compound is dissolved upon recrystallization,
and the temperature is preferably, for example, from 20°C to
100°C, more preferably from 50°C to 80°C. The cooling
temperature is preferably, for example, from 20 to 30°C. If
necessary, the cooling may be performed under stirring.
[0052]
[Reaction Step 31
In reaction step 3, the carboxylic acid salt (IIIa) or
(IIIb) having an improved optical purity is reacted with an
organic acid or an inorganic acid, to thereby produce the
carboxylic acid (la) or (lb) having an improved optical
purity.
[0053]
This step can be performed in a solvent. No particular
limitation is imposed on the solvent, so long as it can
dissolve the carboxylic acid salt (IIIa) or (IIIb) . Examples
of the solvent include alcohols such as methanol, ethanol,
isopropanol, and n-butanol; aromatic hydrocarbon such as
benzene, toluene, and xylene; ethers such as tetrahydrofuran,
diethyl ether, dioxane, methyl tert-butyl ether (MTBE), and
cyclopentylmethyl ether; esters such as ethyl acetate and
isopropyl acetate; nitriles such as acetonitrile and
propionitrile; hydrocarbons such as n-hexane and n-heptane;
and water. These solvents may be used singly or in
combination of two or more species. The amount of the
solvent used in the invention may be tuned depending on the
solubility of the carboxylic acid salt (IIIa) or (IIIb), as
appropriate. The amount of the solvent is preferably from 1
to 20 (v/w) times as much as the weight of the carboxylic
acid salt (IIIa) or (IIIb), and more preferably from 1 to 10
(v/w) times as much.
LOO541
Non-limiting examples of the inorganic acid include
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric
acid, nitric acid, and phosphoric acid. Non-limiting
examples of the organic acid include methanesulfonic acid,
ethanesulfonic acid, and p-toluenesulfonic acid. The amount
of the acid to be employed is preferably from 1 to 5 mol eq.
to the carboxylic acid salt (IIIa) or (IIIb), and more
preferably from 1 to 2 mol eq.
LOO551
The reaction temperature is preferably from -20°C to
80°C, and more preferably from O°C to 40°C. The reaction time
is preferably from 0.1 to 12 hours, and more preferably from
0.1 to 2 hours.
[00561
After the reaction, if necessary, a solvent and water
are added to the reaction mixture for phase separation, and
the organic layer is concentrated, thereby providing the
carboxylic acid (la) or (lb) having an improved optical
purity. The aforementioned solvents may also be employed.
According to the present invention, the carboxylic acid (la)
or (lb) may be employed in a subsequent step, without
isolating the carboxylic acid (la) or (lb).
[OD571
[Reaction Step 41
In reaction step 4, an ester (IVa) or (rvb) is produced
by condensing the carboxylic acid (la) or (lb) having an
improved optical purity with a monovalent aliphatic alcohol
by using a condensation agent in a solvent in the presence or
absence of a condensation accelerator. Alternatively, the
ester (IVa) or (IVb) may be produced by reacting the
carboxylic acid (la) or (lb) with a monovalent aliphatic
alcohol in a solvent in the presence of an acid catalyst,
which is a common technique for producing an ester. Still
alternatively, the ester (IVa) or (IVb) may be produced by
converting the carboxylic acid (la) or (lb) into a reactive
derivative in a solvent and reacting the derivative with a
monovalent aliphatic alcohol, which is a common method for
producing an ester. The monovalent aliphatic alcohol is
preferably a aliphatic monoalcohol, more preferably a C1-6
aliphatic monoalcohol, and may have a linear chain or
branched chain. Specific examples include methanol, ethanol,
n-propanol, n-butanol, and the like. Among them, n-butanol
is preferable. Scheme 1 shows a specific example in which nbutanol
is used as the aliphatic alcohol in'the
esterification reaction.
[00581
on-limiting examples of the solvent include halogen
hydrocarbons such as 1,2-dichloroethane, chloroform, and
dichloromethane; esters such as ethyl acetate and isopropyl
acetate; aromatic hydrocarbons such as toluene and benzene;
ethers such as tetrahydrofuran and l,4-dioxane; nitriles such
as acetonitrile and propionitrile; amides such as N,Ndimethylformamide
and N-methylpyrrolidone; and water. These
solvents may be used singly or in combination of two or more
species.
[a0591
Non-limiting examples of the condensation accelerator
include DMAP, HOAt, HOBt, HODhbt, HONB, HOPfp, HOPht, HOSu,
and the like. Non-limiting examples of the condensation
agent include DCC, DIPCI, WSCI, WSCqHC1, DEPC, BOP, PyBOP,
TBTU, and the like.
[00601
Non-limiting examples of the acid include inorganic
acids such as hydrochloric acid, hydrobromic acid, hydriodic
acid, sulfuric acid, nitric acid, and phosphoric acid; and
organic acids such as methane sulfonate, ethane sulfonate,
and p-toluene sulfonate. Non-limiting examples of the
reactive derivative include an acid halide, a mixed acid
anhydride with pivalic acid; and a p-nitrophenyl ester. The
reaction temperature is from -20°C to 150°C, and more
preferably from 80°C to 130°C. The reaction time is
preferably from 5 minutes to 24 hours, and more preferably
fro111 10 minutes to 12 hours.
[0061]
[Reaction Step 51
In reaction step 5, the ester (IVa) or (IVb) is
produced by reacting the carboxylic acid salt (IIIa) or
(IIIb) having an improved optical purity with a monovalent
aliphatic alcohol in a solvent in the presence of an acid
catalyst, or with a monovalent halogenated aliphatic
hydrocarbon under basic conditions. The monovalent
halogenated aliphatic hydrocarbon is preferably a Cl+ alkyl
halide, more preferably a C1-6 alkyl halide, and the alkyl
group may have a linear chain or branched chain. Examples of
the halogen include fluorine, chlorine, bromine, and iodine.
Specific examples of the monovalent halogenated aliphatic
hydrocarbon include methyl bromide, ethyl chloride, isopropyl
chloride, n-butyl chloride, and the like. Examples of the
monovalent aliphatic alcohol include those as described above,
and preferable embodiments are as descrihed above, too.
Scheme 1 shows specific exanlple in which n-butyl chloride and
n-butanol are in the esterification reaction.
LO0621
As the solvent and the acid catalyst used in the
esterification, those commonly used in esterification may be
used without limitation. For example, solvents and acid
catalysts similar to those employed in the above-described
reaction processes 3 and 4 may be used. Examples of the base
catalyst include sodium hydroxide and potassium hydroxide.
The amount of the solvent used in the invention, the acid
catalyst and the base catalyst, the reaction temperature, and
the reaction time may be the same as employed in the abovedescribed
reaction steps 3 and 4.
[00631
Note that the compound of formula (A) (for example,
(R) -2- (3-IN- (benzoxazol-2-yl) -N- 13- (4-
methoxyphenoxy)propyl]aminomethyl}phenoxy)butyric acid) is
produced by Lhe method described in, for example, WO
2005/23777, WO 2006/90768, and WO 2006/93142, by using 2-
hydroxycarboxylic acid of formula (la) or (lb) or a
derivative thereof in the above-described reaction step. In
one embodiment, a hydroxyl group in the ester (IVa) or (IVb)
formed in the above-described reaction step is transformed
into a trifluoromethanesulfonyloxy group, which is reacted
with the compound of the following formula (B) in the
presence of a base, to thereby form a corresponding phenyl
ether. Then, the conipound is de-esterified. The entire
content of all patent documents and non-patent docu~~lents
cited in the present specification is incorporated by
reference herein.
[00641
[F61
[00651
The ester (IVa) or (IVb) formed in reaction steps 4 and
5 may be isolated and purified by a purification technique
commonly employed in organic synthetic chemistry such as
filtration, extraction, washing, drying, concentration,
recrystalljzation, or a variety of chromatography techniques,
if required.
LO0661
Isomers of the target compound can be isolated through
applying a conventional method employing difference in
physical and chemical properties between the isomers. A
racemic mixture can be transformed into an optically pure
isomer through a conventional optical resolution technique
such as optical resolution of a diastereomer salt with a
general optically active acid such as tartaric acid; or
through optically active column chromatography. Also, a
diastereomer mixture can be separated through fractionated
crystallization or a variety of chromatography techniques.
Alternatively, an optically active compound may be produced
by using an appropriate optically active raw material.
Examples
[00671
The present invention will next be described in detail
by way of examples, which should not be construed as llmiting
the invention thereto. The symbols used in the following
Examples have the following meanings.
s: singlet
d: doublet
t: triplet
m: multiplet
J: couplj ng constant
Hz: Hertz
CDC13: Deuterated chloroform
e.e.: enantiomeric excess
GC: gas chromatography
MTBE: methyl tert-butyl ether
DCHA: dicyclohexylamine
I00681
Production Example 1:
Method of synthesizing (S)-2-hydroxybutyric acid
(S) -2-Aminobutyric acid (20.0 g, 194 mmol) was
dissolved in 1N sulfuric acid (228 mL) . At -5OC, an aqueous
solution of sodium nitrite (26.8 g, 338 mmol) (68 mL) was
added dropvise thereinto, and stirred for 0.5 hours. The
mixture was further stirred for 2 hours at room temperature.
The reaction mixture was cooled to O°C, and sulfuric acid rias
added such that the pH of the reaction mixture became I. The
resultant mixture was stirred for 12 hours at room
temperature. To the reaction mixture, sodium chloride (120
g) and MTBE (120 mL) w e r e added, and the mixture was s t i r r e d
for 30 minutes and subjected t o e x t r a c t i o n with MTBE. The
organic layer was washed with s a t u r a t e d s a l i n e , d r i e d over
anhydrous sodium s u l f a t e , and concentrated under reduced
pressure, thereby providing the t i t l e compound (13.8 g, 69%)
as a pale yellow s o l i d .
'H NMR (400MHz, CDC13) 6 1.00 (t, J = 7.6 Hz, 3H), 1.68-1.79
(m, 1 H ) , 1.84-1.93 (m, l H ) , 4.24 (dd, J = 6.8, 4.4 Hz, 1H) .
[0069]
Example 1
1. SynLhesis of dicyclohexylamirie (DCHA) s a l t
(S)-2-Hydroxybutyric acid (6.44 g) was dissolved i n
MTBE (200 mL) . Under s t i r r i n g , DCHA (12.3 g, 1.1 e q . ) was
added dropwise t h e r e i n t o . After s t i r r i n g a t 25'C f o r 1.5
hours, the s o l i d was recovered through f i l t r a t i o n and washed
with MTBE (30 mL x 3 ) . The r e s u l t a n t s o l i d was d r i e d a t 70°C
under reduced pressure up t o a constant mass, thereby
yieldinq a c o l o r l e s s s o l i d (16.2 9, 92%).
[00701
2. Synthesis of sodium (Na) s a l t
(S)-2-Hydroxybutyric acid (4.00 y) was dissolved i n
MeOH (60 mL) . While the solution xias s t i r r e d under i c e
cooling, MeONa (38.4 g, 1.0 eq.) was added. After s t i r r i n g
f o r 30 minutes, the reaction mixture was concentrated under
reduced pressure, t o thereby form a c o l o r l e s s s o l i d . The
r e s u l t a n t s o l i d w a s suspended i n and washed with MTBE ( i n
appropriate amount), and the s o l i d was recovered through
filtration and washed with MTBE (appropriate amount). The
resultant solid was dried at room temperature under reduced
pressure up to a constant mass, thereby yielding a colorless
solid (4.29 g, 89%) .
[00711
3. Recrystallization
The DCHA salt (A) or Na salt (B) were heated and
dissolved in a solvent, and the solution was returned to room
temperature under stirring. After overnight. stirring,
crystals were recovered through filtration and washed with
the solvent used (A; 2 mL x 3, B; 1 mL). The resultant
crystals were dried at 25OC under reduced pressure up to a
constant mass (See Table 1. In entries 4, 6 to 9, crystals
were dissolved in alcohol, and a poor solvent was added).
[0072]
4. Determination of optical purity
To a (S) -2-hydroxybutyric acid salt (1.75 mmol) formed
through the recrystallization, n-BuOH (1 mL) containing
sulfuric acid (50 pL) was added, and the mixture was stirred
for 6 hours at 110°C. The mixture was brought back to room
temperature, and 0.5N HC1 (6 mL) and AcOEt (3 mL) were added,
follovred by sufficient mixing. The organic layer (2 mL) was
dried over sodium sulfate. Thereafter, the supernatant was
filtered over a Millipore filter. An aliquot (1 mL) thereof
was used as a sample for GC measurement, and was diluted with
a solvent as appropriate, whereby the optical purity of the
sample was measured. The conditions for the GC measurement
are as follor-IS.
100131
Measurement conditions
Detector: hydrogen flame ionization detector
Column: InertCap CHIRAMIX manufactured by GL Sciences
Column temperature: injected at a constant temperature around
100°C and held for 20 minutes. Thereafter, the temperature
elevated to 140°C by 2'C per minute.
Inlet temperature: 230°C
Detector temperature: 250°C
Carrier gas: helium
Flowrate: 1.0 mL/min
Split ratio: 20 : 1
I00741
The relative retention time of (S)-2-hydroxybutyric
acid is 0.96 minutes.
[00751
[Table 11
*: A: dicyclohexylamine salt (97.6% e.e.), B:sodium salt (96.5%
e.e.1.
[a0761
Example 2:
Synthesis of (S)-butyl 2-hydroxybutanoate
To a suspension of sodium (S) -2-hydroxybutyrate (18.0 g,
0.14 mol, 93.4% e.e.) obtained by the same process as
employed in Example 1 in n-butanol (140 mL), n-butanol (40
mL) containing sulfuric acid (11.2 g, 0.11 mol) v7as slowly
added at room temperature. The resultant mixture was heated
to llO°C, stirred for 1.5 hours, and ice-cooled to O°C. A 10%
aqueous solution of potassium bicarbonate (180 mL) was slowly
added thereto at 2.0 to 14.S°C, and the mixture was stirred
for 0.5 hours. The resultant organic layer was washed with
saturated saline, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure, to thereby provide
colorless oil (17.5 g, 79%, 98.9% e.e.1 .
Industrial Applicability
[DO771
The present invention provides a method for improving
optical purity of 2-hydroxycarboxylic acid of the abovedescribed
formula (la) or (lb) or a derivative thereof. The
present invention enables production of an important raw
material of (R) -2- (3-{N- (benzoxazol-2-yl) -N-[3- (4-
methoxyphenoxy)propyllaminomethyllphenoxy)butyric acid of
formula (A), which is useful as a preventive and/or a
therapeutic agent for hyperlipidemia, arteriosclerosis,
diabetes, diabetes complications, inflammation, and cardiac
disorders. Thus, the present invention has industrial
applicability. The compound of formula (A) (for example,
(R) -2- (3-{N- (benzoxazol-2-yl)- N- [3- (4-
methoxyphenoxy)propyl]aminomethyl]phenoxy)butyric acid) can
be manufactured by using 2-hydroxycarboxylic acid of the
above-described formula (la) or (lb) or a derivative thereof
through a method described in WO 2005/23777, WO 2006/90768,
WO 2006/93142, or the like.
1. A method for improving optical purity of a
hydroxycarboxylic acid of the follor~ring formula (la) or (lb)
or a derivative thereof, the method comprising the steps of:
reacting the hydroxycarboxylic acid of the following
formula (la) or (lb):
, wherein R' represents a C1-8 alkyl group, with at least one
optically inactive base selected from the group consisting of
an alkali metal alkoxide and a secondary amine in the
presence of a solvent and, subsequently,
performing recrystallization, to thereby form a
hydroxycarboxylic acid salt of the following formula (IIIa)
or (IIIb) :
( IIIa ) ( Illb )
, wherein R' has the same meaning as defined above, and R'
represents an alkali metal or a secondary amine.
2. A method for improving optical purity of a
hydroxycarboxylic acid of the following formula (la) or (lb)
or a derivative thereof, the method comprising a first step
of:
reacting the hydroxycarboxylic acid of the following
formula (la) or (lb) :
, wherein R' represents a C1.* alkyl group, with at least one
optically inactive base selected from the group consisting of
an alkali metal alkoxide and a secondary amine in the
presence of a solvent and, subsequently, performing
recrystallization, to thereby form a hydroxycarboxylic acid
salt of the following formula (IIIa) or (IIIb) :
( IIIa ) ( IIIb )
, wherein R1 has the same meaning as defined above, and R'
represents an alkali metal or a secondary amine, and a second
step of:
reacting the hydroxycarboxylic acid salt with an
organic acid or an inorganic acid, to thereby form the
hydroxycarboxylic acid of formula (la) or (lb)
3. A method for improving optical purity of a
hydroxycarboxylic acid of the following formula (la) or (lb)
or a derivative thereof, the method comprising a first step
of:
reacting the hydroxycarboxylic acid of the following
formula (la) or (lb) :
, wherein R' represents a C1-8 alkyl group, with at least one
optically inactive base selected from the group consisting of
an alkali metal alkoxide and a secondary amine in the
presence of a solvent and, subsequently, performing
recrystallization, to thereby form a hydroxycarboxylic acid
salt of the follob~ing formula (IIIa) or (IIIb):
( IIIa ) ( IIlb )
, wherein R' has the same meaning as defined above, and R~
represents an alkali metal or a secondary amine,
a second step of reacting the hydroxycarboxylic acid
salt with an organic acid or an inorganic acid to thereby
obtain a hydroxycarboxylic acid of the following formula (la)
or ( l b ) , and
a step of esterifying the hydroxycarboxylic acid formed
in the second step.
4. A method for improving optical purity of a
hydroxycarboxylic acid of the following formula (la) or (lb)
or a derivative thereof, the method comprising the steps of:
reacting the hydroxycarboxylic acid of the following
formula (la) or (lb):
, wherein R' represents a CI-8 alkyl group, krith at least one
optically inactive base selected from the group consisting of
alkali metal alkoxide and secondary amine in the presence of
a solvent and, subsequently, performing recrystallization, to
thereby form a hydroxycarboxylic acid salt of the following
formula (IIIa) or (IIIb) :
( IIIa ) (Illb )
, wherein R' has the same meaning as defined above, and R~
represents an alkali metal or a secondary amine, and
esterifying the hydroxycarboxylic acid salt.
5. A method according to any one of claims 1 to 4,
wherein R' is an ethyl group.
6. A method according to any one of claims 1 to 5,
wherein the optically inactive base is a sodium alkoxide.
7. A method according to claim 6, wherein the sodium
alkoxide is sodium methoxide.
8. A method according to any one of claims 1 to 7,
wherein the optically inactive base is dicyclohexylamine
9. A method according to any one of claims 1 to 8,
wherein recrystallization is performed using a solvent
containing at least one member selected from the group
consisting of an ester, an ether, and an alcohol.
10. A method for producing a compound of the following
formula (A) :
, wherein R' represents a C1-8 alkyl group,
the method comprising a method as recited in any one of
claims 1 to 9.
11. A method according to claim 10, wherein formula (A)
is (R) -2- (3-{N- (benzoxazol-2-yl) -N- [3- (4-
methoxyphenoxy)propyllaminomethyl)phenoxybutyric acid.