Description
Title of Invention
METHOD FOR PRODUCING OPTICALLY ACTIVE
b-HYDROXY-a-AMINOCARBOXYLICACID ESTER
Technical Field
The present invention relates to a novel method for producing an
optically active b-hydroxy-craminocarboxylic acid ester, the method comprising
performing an asymmetric reduction reaction of a b-keto-craminocarboxylic acid
ester by use of a ruthenium complex as catalyst.
Background Art
Optically active b-hydroxya-aminocarboxylic acid esters are important
as synthetic intermediates of ceramides, which are key molecules of the
moisturizing effect on the stratum corneum, and are compounds which can serve
as not only intermediates of pharmaceuticals and the Hke, but also important
intermediates for producing functional materials and the like necessary in the
chemical industries and the like. For this reason, methods for producing an
optically active b-hydroxy-craminocarboxylic acid ester have been studied and
reported so far (see JP-H06-080617Aor WO2008/041571A).
JP-H06-080617A discloses a method in which a syn isomer of an
optically active b-hydroxya-aminocarboxylic acid ester is selectively synthesized
by a catalytic asymmetric hydrogenation reaction using a rutheniunroptically
active phosphine complex, and further the hydroxyl group at the b-position is
optically inverted to obtain the anti isomer.
WO2008/041571A discloses a method in which an anti isomer is
selectively obtained by conducting a catalytic asymmetric hydrogen transfer
reaction using a ruthenium-optically active diamine complex.
Meanwhile, many asymmetric reactions including asymmetric reduction
have been developed, and many asymmetric reactions have been reported in
which an asymmetric metal complex having an optically active phosphine Ugand
is used. Moreover, for example, many reports indicate that complexes in which
an optically active nitrogen compound is coordinated to a transition metal such
as ruthenium, rhodium, or iridium have excellent performances as catalysts for
asymmetric synthesis reactions (see Che Rev., (1992), p. 1051; J . Am. Chem.
Soc, 117 (1995), p. 7562; J . Am. Chem. Soc, 118 (1996), p. 2521; and J . Am.
Chem. Soc, 118 (1996), p. 4916).
Summary of Invention
However, optically active b-hydroxy-a-aminocarboxylic acid esters are
obtained only after many steps in the production of the optically active
b-hydroxy-craminocarboxylic acid esters based on any of the methods reported so
far. In addition, even when the ester can be produced in one step by utilizing an
asymmetric reduction reaction, the production has such problems that long
reaction time is necessary, that the stereo selectivity is low, and that the large
amount of the catalyst necessary for the reaction complicates the operation for
removing the catalyst. Specifically, the method disclosed in Patent Literature 1
requires an extra step, because a syn isomer is first obtained selectively, and the
hydroxyl group at the b-position has to be optically inverted to obtain an anti
isomer. In addition, although the anti isomer can be obtained selectively in the
method disclosed in Patent Literature 2, the time required for the reaction in this
method is as long as several days, and if the reaction time is shortened, the
amount of the catalyst is increased. Hence, the method is disadvantageous from
the industrial viewpoint.
An object of the present invention is to solve these problems.
To solve the above-described problems, the present inventors have
conducted earnest study. As a result, the present inventors have found that the
use of the following ruthenium complex as a catalyst makes it possible to
efficiently produce an optically active b-hydroxy-craminocarboxylic acid ester by
an asymmetric reduction of a b-keto-craminocarboxylic acid ester under a mild
conditions in an anti isomer-selective manner. Specifically, the ruthenium
complex is such that the aromatic compound (arene) moiety is coordinated to a
ruthenium atom, and that a hetero atom such as an oxygen atom or a sulfur atom
is introduced to a chain moiety linking the aromatic compound (arene) moiety
and a diamine moiety, or the aromatic compound (arene) moiety and the diamine
moiety are is linked with each other through a carbon chain. Moreover, the
ruthenium complex has a tridentate ligand whose two nitrogen atoms in the
diamine ligand are bonded to the ruthenium atom by covalent bonding or
coordination bonding, and whose aromatic compound (arene) moiety linked to the
diamine is also coordinated to the ruthenium atom. In addition, in the
ruthenium complex, a hetero atom such as an oxygen atom or a sulfur atom is
introduced to the chain moiety Unking the aromatic compound (arene) moiety
and the diamine moiety, or the chain moiety Unking the aromatic compound
(arene) moiety and the diamine moiety are linked with each other through a
carbon chain. This finding has led to the completion of the present invention.
Specifically, the present invention encompasses the following content
[l] A method for producing an optically active b-hydroxy-craminocarboxylic acid
ester, comprising performing an asymmetric reduction reaction of a
b-keto-a-aminocarboxylic acid ester in the presence of a ruthenium complex and
a hydrogen donor, wherein
the ruthenium complex is represented by the following general formula
(1) or (l)':
(where
1 represents an alkyl group having 1 to 10 carbon atoms, a halogenated
alkyl group having 1 to 10 carbon atoms, a 10-camphoryl group; an amino group
which may be substituted with one or two alkyl groups having 1 to 10 carbon
atoms; or an aryl group (provided that the aryl group may be substituted with
one or more selected from alkyl groups having 1 to 10 carbon atoms, halogenated
alkyl groups having 1 to 10 carbon atoms, halogen atoms, cyano groups (-CN),
amino groups, alkylamino groups (-NR20R21), 5- or 6-membered cyclic amino
groups, acylamino groups (-NH-COR 20), hydroxyl groups, alkoxy groups ( R20),
acyl groups (-C R20), carboxyl groups, alkoxycarbonyl groups (-COOR20),
phenoxycarbonyl groups, mercapto groups, alkylthio groups (-SR20), silyl groups
(-SiR R 1R22), and nitro groups (-NO2)),
R20, R2 , and R22 each independently represent a hydrogen atom, an alkyl
group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon
atoms,
Y represents a hydrogen atom,
X represents a trifluoromethanesulfonyloxy group, a
p-toluenesulfonyloxy group, a methanesulfonyloxy group, a benzenesulfonyloxy
group, a hydrogen atom, or a halogen atom,
Q © represents a counter anion,
j and k each represent 0 or 1, provided that cases where j+k=l are
excluded,
R2 and R3 each independently represent a hydrogen atom; an alkyl group
having 1 to 10 carbon atoms; a phenyl group (provided that the phenyl group
may be substituted with one or more selected from alkyl groups having 1 to 10
carbon atoms, alkoxy groups having 1 to 10 carbon atoms, and halogen atoms); or
a cycloalkyl group having 3 to 8 carbon atoms, or R2 and R3 may together form a
ring,
R11, R12, R13, R14, and R15 each independently represent a hydrogen atom,
an alkyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10
carbon atoms,
R 6, R17, R18, and R19 each independently represent a hydrogen atom, a
hydroxyl group, an alkyl group having 1 to 10 carbon atoms, or an alkoxy group
having 1 to 10 carbon atoms, or R 6, R17, and the carbon atom to which R16 and
R17 are bonded and/or R18, R19, and the carbon atom to which R18 and R19 are
bonded may form a carbonyl group(s),
Z represents an oxygen atom, a sulfur atom, or a methylene,
n i represents 1 or 2, and represents any integer of 1 to 3, and
each * indicates an asymmetric carbon atom (provided that when R2
and/or R3 is/are a hydrogen atom(s), the carbon atom to which the hydrogen atom
is bonded is not an asymmetric carbon atom)),
the b-keto-a-aminocarboxylic acid ester is represented by the following
general formula (2)·
(where
R23 represents a hydrocarbon group which has 11 to 21 carbon atoms and
which may be substituted with one or more hydroxyl groups,
R24 represents a hydrogen atom or a hydrocarbon group having 1 to 10
carbon atoms, and
R25 and R26, which may be the same or different, each represent a
hydrogen atom, an alkyl group which has 1 to 10 carbon atoms and which may be
substituted with one or more selected from halogen atoms and hydroxyl groups,
an acyl group which has 1 to 24 carbon atoms and which may be substituted with
one or more selected from halogen atoms and hydroxyl groups, or an
amino-protecting group, or R25 and R26 may form, together with the adjacent
nitrogen atom, a heterocycle which may be substituted with one or more hydroxyl
groups), and
the optically active b-hydroxy-a-aminocarboxylic acid ester is
represented by the following general formula (3) or (4)·
(3)
OH O
R 23
25 ' 26
(4)
(where
each * indicates an asymmetric carbon atom, and
R23, R24, R25, and R26 are the same as those described above).
In a preferable embodiment, a major product of the optically active
b-hydroxy-a-aminocarboxylic acid ester is a (2R,3R) isomer represented by
general formula (4),
the formation ratio (2R,3R) isomer :(2S,3R) isomer is 85 15 to IOO , and
the reaction is completed within a reaction time of 10 hours.
In another preferable embodiment, a major product of the optically
active b-hydroxy-a-aminocarboxylic acid ester is a (2R,3R) isomer represented by
general formula (4),
the formation ratio (2R,3R) isomer :(2S,3R) isomer is 85:15 to 100 ; and
the reaction is completed within a reaction time of 20 hours when the
molar ratio of the ruthenium complex represented by general formula (l) to the
b-keto-a-aminocarboxylic acid ester represented by general formula (2) is 1/500 to
1/10000.
[0012]
The present invention provides a method for producing an optically
b-hydroxy-a-aminocarboxylic acid ester, which is important as a synthetic
intermediate of ceramides, pharmaceuticals, agricultural chemicals, and the like,
through simple steps and at low costs.
The ruthenium complex of the present invention has a hetero atom
introduced to the chain moiety linking the aromatic compound (arene) moiety
and the diamine moiety coordinated to the ruthenium, has an extremely high
catalytic activity, and is useful as a catalyst for various kinds of hydrogenation
such as reduction of ester groups. Moreover, the ruthenium complex of the
present invention has an optically active ligand, and hence is capable of
achieving an excellent stereo selectivity and a high enantiomeric excess. The
use of this ruthenium complex of the present invention in the method for
producing an optically active b-hydroxy-a-aminocarboxylic acid ester makes it
possible to synthesize an anti isomer of an optically active
b-hydroxy-craminocarboxylic acid ester at a high optical purity and in a high
yield more simply and efficiently than conventional cases.
Description of Embodiments
Hereinafter, the present invention will be described in further detail.
In the present invention, an optically active
B-hydroxy-craminocarboxylic acid ester is produced by performing an asymmetric
reduction reaction of a b-keto-a-aminocarboxylic acid ester in the presence of a
ruthenium complex and a hydrogen donor, wherein
the ruthenium complex is represented by the following general formula
(l) or (l)':
(where
1 represents an alkyl group having 1 to 10 carbon atoms! a halogenated
alkyl group having 1 to 10 carbon atoms, a 10-camphoryl group, an amino group
which may be substituted with one or two alkyl groups having 1 to 10 carbon
atoms, or an aryl group (provided that the aryl group may be substituted with
one or more selected from alkyl groups having 1 to 10 carbon atoms, halogenated
alkyl groups having 1 to 10 carbon atoms, halogen atoms, cyano groups (-CN),
amino groups, alkylamino groups (-NR20R2 1), 5- or 6-membered cyclic amino
groups, acylamino groups (-NH-COR 20), hydroxyl groups, alkoxy groups (-OR20),
acyl groups (-C R20), carboxyl groups, alkoxycarbonyl groups (-COOR20),
phenoxycarbonyl groups, mercapto groups, alkylthio groups (-SR20), silyl groups
(-SiR R 1R22), and nitro groups (-NO2)),
R20, R21, and R22 each independently represent a hydrogen atom, an alkyl
group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon
atoms,
Yrepresents a hydrogen atom,
X represents a trifluoromethanesulfonyloxy group, a
p-toluenesulfonyloxy group, a methanesulfonyloxy group, a benzenesulfonyloxy
group, a hydrogen atom, or a halogen atom,
Q represents a counter anion,
j and k each represent 0 or 1, provided that cases where j+k=l are
excluded,
2 and R3 each independently represent a hydrogen atom; an alkyl group
having 1 to 10 carbon atoms; a phenyl group (provided that the phenyl group
may be substituted with one or more selected from alkyl groups having 1 to 10
carbon atoms, alkoxy groups having 1 to 10 carbon atoms, and halogen atoms); or
a cycloalkyl group having 3 to 8 carbon atoms, or R2 and R3 may together form a
ring,
R , R12, R13, R14, and R15 each independently represent a hydrogen atom,
an alkyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10
carbon atoms,
R16, R17, R18, and R19 each independently represent a hydrogen atom, a
hydroxyl group, an alkyl group having 1 to 10 carbon atoms, or an alkoxy group
having 1 to 10 carbon atoms, or R16 , R 7 , and the carbon atom to which R16 and
R17 are bonded and/or R18, R19, and the carbon atom to which R18 and R19 are
bonded may form a carbonyl group(s),
Z represents an oxygen atom, a sulfur atom, or a methylene,
n i represents 1 or 2, and 2 represents any integer of 1 to 3, and
each * indicates an asymmetric carbon atom (provided that when R2
and/or R3 is/are a hydrogen atom(s), the carbon atom to which the hydrogen atom
is bonded is not an asymmetric carbon atom)),
the b-keto-a-aminocarboxylic acid ester is represented by the following
general formula (2):
(2)
(where
R23 represents a hydrocarbon group which has 11 to 21 carbon atoms and
which may be substituted with one or more hydroxyl groups,
R24 represents a hydrogen atom or a hydrocarbon group having 1 to 10
carbon atoms, and
R25 and R26, which may be the same or different, each represent a
hydrogen atom, an alkyl group which has 1 to 10 carbon atoms and which may be
substituted with one or more selected from halogen atoms and hydroxyl groups,
an acyl group which has 1 to 24 carbon atoms and which may be substituted with
one or more selected from halogen atoms and hydroxyl groups, or an
amino-protecting group, or R25 and R26 may form, together with the adjacent
nitrogen atom, a heterocycle which may be substituted with one or more hydroxyl
groups), and
the optically active b-hydroxy-a-aminocarboxylic acid ester is
represented by the following general formula (3) or (4):
(3)
OH O
R 2 (4)
(where
each * indicates an asymmetric carbon atom, and
R23, R24, R25, and R26 are the same as those described above).
Hereinafter, the ruthenium complex represented by general formula (l)
and a method for synthesizing the ruthenium complex are described first.
Subsequently, a description is given of the b-keto-a-aminocarboxylic acid ester
represented by general formula (2) and the b-hydroxy-a-aminocarboxylic acid
esters represented by general formulae (3) and (4). Then, a description is given
of a process for producing the b-hydroxy-a-aminocarboxylic acid esters
represented by general formulae (3) and (4) by carrying out an asymmetric
reduction reaction of the b-keto-a-aminocarboxylic acid ester represented by
general formula (2) by use of the ruthenium complex represented by general
formula (l) as a catalyst.

The ruthenium complex represented by general formula (l) is such that
an aromatic compound (arene) moiety is coordinated to a ruthenium atom, and
that a hetero atom such as an oxygen atom or a sulfur atom is introduced to a
chain moiety linking the aromatic compound (arene) moiety and a diamine
moiety, or the aromatic compound (arene) moiety and the diamine moiety are
linked through a carbon chain.
In addition, the ruthenium complex represented by general formula (l)
has a tridentate ligand whose two nitrogen atoms in the diamine ligand are
bonded to the ruthenium atom by covalent bonding or coordination bonding, and
whose aromatic compound (arene) moiety linked to the diamine is also
coordinated to the ruthenium atom. In addition, in the ruthenium complex, a
hetero atom such as an oxygen atom or a sulfur atom is introduced to the chain
moiety linking the aromatic compound (arene) moiety and the diamine moiety.
Each sign * in general formula (l) indicates that the carbon atom to
which the sign * is attached may be an asymmetric carbon atom. When the
carbon atom is an asymmetric carbon atom, the ruthenium complex may be an
optically active compound, a mixture of optically active compounds, or a racemic
mixture (including a racemic compound), in terms of the asymmetric carbon
atom. In a preferred mode of the present invention, the ruthenium complex is
an optically active compound, when any of these carbon atoms is an asymmetric
carbon atom.
However, as described later, when 2 and/or R3 is/are a hydrogen atom(s),
the carbon atom to which the hydrogen atom is bonded is not an asymmetric
carbon atom.
In general formula (l) of the present invention, R1 represents
an alkyl group having 1 to 10 carbon atoms;
a halogenated alkyl group having 1 to 10 carbon atoms,
a 10 camphoryl group,
an amino group which may be substituted with one or two alkyl groups
having 1 to 10 carbon atoms, or
an aryl group (provided that the aryl group may be substituted with one
or more selected from alkyl groups having 1 to 10 carbon atoms, halogenated
alkyl groups having 1 to 10 carbon atoms, halogen atoms, cyano groups (-CN),
amino groups, alkylamino groups (-NR2 R21), 5 or 6-membered cyclic amino
groups, acylamino groups (-NH-COR 20), hydroxyl groups, alkoxy groups (-OR20),
acyl groups (-COR 20), carboxyl groups, alkoxycarbonyl groups (-COOR20),
phenoxycarbonyl groups, mercapto groups, alkylthio groups (-SR20), silyl groups
(-SiR20R 1R22), and nitro groups (-N02)).
Examples of the alkyl group having 1 to 10 carbon atoms represented by
R1 in general formula (l) of the present invention include linear or branched
alkyl groups having 1 to 10 carbon atoms, and preferably 1 to 5 carbon atoms.
Specific examples of the alkyl groups include a methyl group, an ethyl group, a
n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a s-butyl
group, a t-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a
n-octyl group, a n-nonyl group, a n-decyl group, and the like.
Examples of the halogenated alkyl group having 1 to 10 carbon atoms
represented by R1 in general formula (l) of the present invention include alkyl
groups having 1 to 10 carbon atoms which are the same as the above-described
linear or branched alkyl groups such as a methyl group, an ethyl group, a
n-propyl group, an isopropyl group, a n-butyl group, and a n-hexyl group, except
that the alkyl groups are substituted with one or more halogen atoms such as
fluorine atoms, chlorine atoms, and bromine atoms. Examples of the
halogenated alkyl groups include perfluoroalkyl groups such as a trifluoromethyl
group, a pentafluoroethyl group, and a heptafluoropropyl group.
Examples of the alkyl group which has 1 to 10 carbon atoms and which
may be included in the amino group represented by R1 in general formula (l) of
the present invention include linear or branched alkyl groups having 1 to 10
carbon atoms, and preferably 1 to 5 carbon atoms. Specific examples of the
alkyl group include a methyl group, an ethyl group, a n-propyl group, an
isopropyl group, a n-butyl group, an isobutyl group, a s-butyl group, a t-butyl
group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a
n-nonyl group, and a n-decyl group.
Examples of the aryl group in general formula (l) of the present
invention (provided that the aryl group may be substituted with one or more
selected from alkyl groups having 1 to 10 carbon atoms, halogenated alkyl groups
having 1 to 10 carbon atoms, halogen atoms, cyano groups (-CN), amino groups,
alkylamino groups (-NR20R21), 5- or 6-membered cyclic amino groups, acylamino
groups (-NH-COR 20), hydroxyl groups, alkoxy groups ( R20), acyl groups
(-C R20), carboxyl groups, alkoxycarbonyl groups (-COOR20), phenoxycarbonyl
groups, mercapto groups, alkylthio groups (-SR20), silyl groups (-SiR 0R2 R22), and
nitro groups (-NO2)) include monocyclic, polycyclic, or condensed cyclic aryl
groups having 1 to 20 carbon atoms, and preferably 6 to 12 carbon atoms, such as
a phenyl group and a naphthyl group.
Examples of the aryl groups include a phenyl group, 0-, nr, and p-tolyl
groups, 0-, nr, and p-ethylphenyl groups, 0-, nr, and p-isopropylphenyl groups,
o-,nv, and p-t-butylphenyl groups, a 2,4,6-trimethylphenyl group, a 3,5-xylyl
group, a 2,4,6-triisopropylphenyl group, 0-, m-, and p-trifluoromethylphenyl
groups, 0-, m-, and p-fluorophenyl groups, 0-, m-, and p-chlorophenyl groups, a
pentafluorophenyl group, and the like.
Note that R20, R2 1, and R22 each independently represent a hydrogen
atom, an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3
to 10 carbon atoms. R20, R21, and R22 are described later.
Hereinafter, a lurther description is given of the alkyl groups having 1 to
10 carbon atoms, the halogenated alkyl groups having 1 to 10 carbon atoms, the
halogen atoms, the alkylamino groups (-NR2 2 1), the 5- or 6-membered cyclic
amino groups, the acylamino groups (-NH-COR 20), the alkoxy groups (-OR20), the
acyl groups (-C R20), the alkoxycarbonyl groups (-COOR20), the alkylthio groups
(-SR20), and the silyl groups (-SiR20R21R22), which may be selected as the
substituent in the aryl group.
Examples of the alkyl group having 1 to 10 carbon atoms which may be
selected as the substituent in the aryl group include the alkyl groups described
above. Examples of the halogenated alkyl group having 1 to 10 carbon atoms
which may be selected as the substituent in the aryl group include the
halogenated alkyl groups described above, and an example of which is a
perfluoroalkyl group.
Examples of the halogen atom which may be selected as the substituent
in the aryl group include a fluorine atom, a chlorine atom, and the like.
Examples of the alkylamino group which may be selected as the
substituent in the aryl group and which is represented by -NR 0R2 1 (where R20
and R21 each independently represent a hydrogen atom, an alkyl group having 1
to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms) include
monoalkylamino groups and dialkylamino groups such as an N-methylamino
group, an N,N-dimethylamino group, an N,N-diisopropylamino group, and an
N-cyclohexylamino group.
Examples of the 5- or 6-membered cyclic amino group which may be
selected as the substituent in the aryl group include 5- or 6- membered
unsaturated or saturated heterocyclic groups having one or two nitrogen atoms
such as a pyrrolidinyl group, a piperidino group, and a morpholyl group.
Examples of the acylamino group which may be selected as the
substituent in the aryl group and which is represented by -NH-COR 20 (where R20
represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a
cycloalkyl group having 3 to 10 carbon atoms) include a formylamino group, an
acetylamino group, a propionylamino group, a pivaloylamino group, a
pentanoylamino group, a hexanoylamino group, and the like.
Examples of the alkoxy group which may be selected as the substituent
in the aryl group and which is represented by -OR20 (where R20 represents a
hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group
having 3 to 10 carbon atoms) include a methoxy group, an ethoxy group, a
n-propoxy group, an isopropoxy group, a n-butoxy group, a s-butoxy group, an
isobutoxy group, a t-butoxy group, a n-pentyloxy group, a 2-methylbutoxy group,
a 3-methylbutOxy group, a 2,2-dimethylpropyloxy group, a n-hexyloxy group, a
2-methylpentyloxy group, a 3-methylpentyloxy group, a 4-methylpentyloxy group,
a 5-niethylpentyloxy group, a cyclohexyloxy group, and the like.
Examples of the acyl group which may be selected as the substituent in
the aryl group and which is represented by -COR 20 (where R20 represents a
hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group
having 3 to 10 carbon atoms) include a formyl group, an acetyl group, a propionyl
group, a butyryl group, a pivaloyl group, a pentanoyl group, a hexanoyl group,
and the like.
Examples of the alkoxycarbonyl group which may be selected as the
substituent in the aryl group and which is represented by -COOR20 (where R20
represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a
cycloalkyl group having 3 to 10 carbon atoms) include a methoxycarbonyl group,
an ethoxycarbonyl group, a n-propoxycarbonyl group, an isopropoxycarbonyl
group, a n-butoxycarbonyl group, a t-butoxycarbonyl group, a pentyloxycarbonyl
group, a hexyloxycarbonyl group, a 2-ethylhexyloxycarbonyl group, and the like.
Examples of the alkylthio group which may be selected as the
substituent in the aryl group and which is represented by -SR20 (where R20
represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a
cycloalkyl group having 3 to 10 carbon atoms) include a methylthio group, an
ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group,
a s-butylthio group, an isobutylthio group, a t-butylthio group, a pentylthio group,
a hexylthio group, a cyclohexylthio group, and the like.
Examples of the silyl group which may be selected as the substituent in
the aryl group and which is represented by -SiR20R 1R22 (where R20, R21, and R22
each independently represent a hydrogen atom, an alkyl group having 1 to 10
carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms) include a
trimethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, a
t-butyldiphenylsilyl group, a triphenylsilyl group, and the like.
Here, examples of the alkyl group having 1 to 10 carbon atoms in each of
the above-described definitions of R20, R2 , and R22 include the alkyl groups
described above. Examples of the cycloalkyl group having 3 to 10 carbon atoms
in each of the above-described definitions of R20, R2 , and R22 include monocyclic,
polycyclic, or condensed cyclic, saturated or unsaturated, 3- to 7-membered
cycloalkyl groups having 3 to 10 carbon atoms.
In general formula (l) of the present invention, Y represents a hydrogen
atom, and X represents a trifluoromethanesulfonyloxy group, a
p-toluenesulfonyloxy group, a methanesulfonyloxy group, a benzenesulfonyloxy
group, a hydrogen atom, or a halogen atom, and preferably a halogen atom. A
specific preferred example of X is a chlorine atom.
Q© in the formula (l)' represents a counter anion. Specific examples of the counter
anion include borate ions such as a tetrafluoroborate ion (BF4 ), a tetraphenylborate
ion (B(C F ) ), and a BArF ion (B(3,5-(CF )2C6F3)4 ) and ions such as SbF , CF3COO ,
CH3COO , PFe , NO , CIO4 , SCN-, OCN\ Re0 4 and M0O4
The hydrogen atom represented by each of Y and X in general formula
(l) may be not only an ordinary hydrogen atom, but also an isotope atom of
hydrogen. Apreferred isotope atom is a deuterium atom.
In general formula (l), k and j each represent an integer of 0 or 1,
provided that cases where j+k=l are excluded. In other words, when k is 1, j is
also 1, whereas when k is 0, j is also 0.
Meanwhile, R2 and R3 in general formula (l) of the present invention
each independently represent
a hydrogen atom;
an alkyl group having 1 to 10 carbon atoms;
a phenyl group (provided that the phenyl group may be substituted with
one or more selected from alkyl groups having 1 to 10 carbon atoms, alkoxy
groups having 1 to 10 carbon atoms, and halogen atoms); or
a cycloalkyl group having 3 to 8 carbon atoms.
Alternatively, R2 and R3 may together form a ring.
Examples of the alkyl group having 1 to 10 carbon atoms represented by
each of R2 and R3 in general formula (l) of the present invention include linear or
branched alkyl groups having 1 to 10 carbon atoms, and preferably 1 to 5 carbon
atoms. Specific examples of the alkyl groups include a methyl group, an ethyl
group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a
s-butyl group, a t-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl
group, a n-octyl group, a n-nonyl group, a n-decyl group, and the like.
The phenyl group represented by each of R2 and R3 in general formula (l)
of the present invention may be substituted with one or more selected from alkyl
groups having 1 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms,
and halogen atoms. Examples of the alkyl groups having 1 to 10 carbon atoms
include the alkyl groups described above. Examples of the alkoxy groups having
1 to 10 carbon atoms include linear or branched alkoxy groups having 1 to 10
carbon atoms, and preferably 1 to 5 carbon atoms. Specific examples of the
alkoxy groups include a methoxy group, an ethoxy group, a n-propoxy group, an
isopropoxy group, a n-butoxy group, an isobutoxy group, a s-butoxy group, a
t-butoxy group, a n-pentyloxy group, a n-hexyloxy group, a n-heptyloxy group, a
n-octyloxy group, a n-nonyloxy group, a n-decyloxy group, and the like.
Examples of the halogen atom include a fluorine atom, a chlorine atom, and a
bromine atom.
Examples of the cycloalkyl group having 3 to 8 carbon atoms represented
by each of R2 and R3 in general formula (l) of the present invention include
monocyclic, polycyclic, or cross-linked cycloalkyl groups having 3 to 8 carbon
atoms, and preferably 5 to 8 carbon atoms. Specific examples of the cycloalkyl
groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a
cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like. These
cycloalkyl groups may be substituted with alkyl groups or the like such as methyl
groups, isopropyl groups, and t-butyl groups.
In addition, when R2 and R3 in general formula (l) of the present
invention together form a ring, R2 and R3 together represent a linear or branched
alkylene group having 2 to 10 carbon atoms, and preferably 3 to 10 carbon atoms,
and the alkylene group, together with the adjacent carbon atoms, forms a 4- to
8-membered, preferably 5- to 8-membered cycloalkane ring. Preferred examples
of the cycloalkane ring include a cyclopentane ring, a cyclohexane ring, and a
cycloheptane ring. These rings may have alkyl groups and the like, such as
methyl groups, isopropyl groups, and t-butyl groups, as substituents.
In the present invention, R1 , R12, R13, R 4, and R15 in the arene moiety
represented by general formula (l) each independently represent
a hydrogen atom;
an alkyl group having 1 to 10 carbon atoms; or
an alkoxy group having 1 to 10 carbon atoms.
Examples of the alkyl group having 1 to 10 carbon atoms include the
alkyl groups described above. Specific examples of the alkyl groups include a
methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl
group, an isobutyl group, a s-butyl group, a t-butyl group, a n-pentyl group, a
n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group,
and the like.
Examples of the alkoxy group having 1 to 10 carbon atoms include the
linear or branched alkoxy groups described above. Specific examples of the
alkoxy groups include a methoxy group, an ethoxy group, a n-propoxy group, an
isopropoxy group, a n-butoxy group, an isobutoxy group, a s-butoxy group, a
t-butoxy group, a n-pentyloxy group, a n-hexyloxy group, a n-heptyloxy group, a
n-octyloxy group, a n-nonyloxy group, a n-decyloxy group, and the like.
R 6 , R17, R18, and R19 which represent substituents introduced to the
carbon atoms in the chain moiety linking the arene moiety and the diamine
moiety in general formula (l) each independently represent
a hydrogen atom,'
a hydroxyl group,'
an alkyl group having 1 to 10 carbon atoms,' or
an alkoxy group having 1 to 10 carbon atoms.
Examples of the alkyl group having 1 to 10 carbon atoms include the
alkyl groups described above. Specific examples of the alkyl groups include a
methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl
group, an isobutyl group, a s-butyl group, a t-butyl group, a n-pentyl group, a
n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group,
and the like.
Examples of the alkoxy group having 1 to 10 carbon atoms include the
linear or branched alkoxy groups described above. Specific examples of the
alkoxy groups include a methoxy group, an ethoxy group, a n-propoxy group, an
isopropoxy group, a n-butoxy group, an isobutoxy group, a s-butoxy group, a
t-butoxy group, a n-pentyloxy group, a n-hexyloxy group, a n-heptyloxy group, a
n-octyloxy group, a n-nonyloxy group, a n-decyloxy group, and the like.
Preferred examples of the -(-C(R16)R1 -)nr group include a -CHz- group, a
-CH(CH3)- group, a -CO- group, and the like, but the -(-C(R16)R -)nr group is not
limited to these groups.
Preferred examples of the -(-C(R1 )R1 -)n2- group include a -CH2- group, a
-CH(CH3)- group, a -CO- group, and the like, but the -(-C(R )R 9-)n2- group is not
limited to these groups.
Z in general formula (l) is an oxygen atom (-0-), a sulfur atom (-S-), or a
methylene (-CH2-).
In addition, ni represents 1 or 2, and preferably 1, and represents any
integer of 1 to 3, and preferably 2.

The above-described ruthenium complex can be synthesized, for example,
by the method shown in the following scheme 1:
Scheme 1
In scheme 1, R , R2, R3, R11 to R 5, and R16 to R 9 represent the
substituents as described above, Y represents a hydrogen atom or a deuterium
atom, and Z represents an oxygen atom, a sulfur atom, or a methylene. In a
ruthenium arene dimer (a), W represents a halogen atom, an alkanesulfonyloxy
group which may be substituted with one or more halogen atoms, or an
arenesulfonyloxy group which may be substituted with an alkane(s), and V
represents a halogen atom ni represents 1 or 2, and represent any integer of
1 to 3.
As shown in scheme 1, a thioether formation or ether formation reaction
is conducted simultaneously with the complexation by reacting, in the presence
of an appropriate base, the ruthenium arene dimer (a) having halogen atoms or
the like in terminals of substituents on the arenes with a diamine (b) having a
hydroxyl group or a thiol group in a terminal of a chain moiety bonded to the
nitrogen atom to which the sulfonyl group is not bonded. Thus, a
rutheniunrdiamine complex (d), which is the target complex, can be synthesized
directly or through an amide complex (c). When the synthesis is conducted
through the amide complex (c), the amide complex (c) can be converted to the
diamine complex (d) by adding an appropriate acid to the amide complex (c).
Examples of the halogen atom, the alkanesulfonyloxy group which may
be substituted with one or more halogen atoms, and the arenesulfonyloxy group
which may be substituted with an alkane(s), which are represented by Win the
ruthenium arene dimer (a), include a chlorine atom, a bromine atom, an iodine
atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a
benzenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like.
In addition, the halogen atoms represented by Vs each represent any one of a
chlorine atom, a bromine atom, and an iodine atom, and all of the Vs may be the
same halogen atoms, or the Vs may be a combination of different halogen atoms.
In the diamine (b), Z is an oxygen atom, a sulfur atom, or a methylene,
and Y represents a hydrogen atom.
Examples of a base used for synthesizing the amide complex (c) include
inorganic bases such as LiOH, NaOH, KOH, K2CO3, and CS2CO3; and metal
alkoxides such as sodium methoxide and potassium methoxide. The amount of
the base added is 2 mol or more relative to 1 mol of ruthenium atoms. A solvent
used in this case is not particularly limited, and preferred examples thereof
include ethers such as diethyl ether and tetrahydrofuran; aromatic hydrocarbons
such as toluene and xylene; halogen-containing hydrocarbon solvents such as
dichloromethane and 1,2-dichloroethane; aprotic polar solvents such as
acetonitrile and N,N-dimethylformamide. and the like, and particularly
preferred examples thereof include dichloromethane and toluene. In addition,
water may be used as another solvent, and this reaction can be carried out as a
reaction of a two-layer system of water with an organic solvent. In this case, it
is preferable to carry out the reaction by using a phase transfer catalyst.
Examples of the phase transfer catalyst used here include tetrabutylammonium
chloride, tetrabutylammonium bromide, tetrabutylammonium iodide,
tetraethylammonium chloride, tetraethylammonium bromide,
tetraethylammonium iodide, triethylbenzylammonium chloride,
triethylbenzylammonium bromide, triethylbenzylammonium iodide, and the
like.
Examples of the acid (X-Y) used for the conversion from the amide
complex (c) to the diamine complex (d) include hydrochloric acid, hydrobromic
acid, hydroiodic acid, and the like.
The solvent in which this reaction is carried out is not particularly
limited. After the synthesis of the amide complex (c), the conversion from the
amide complex (c) to the diamine complex (d) can be carried out, without
isolation of the amide complex (c), by performing a reaction directly in the same
system in the presence of the same solvent. Alternatively, the conversion to the
diamine complex (d) may be carried out by isolating the amide complex (c), and
then performing a reaction using an appropriate different solvent.
Preferred examples of the base used for the direct synthesis of the
diamine complex (d) include tertiary organic amines such as trimethylamine,
triethylamine, triisopropylamine, and diisopropylethylamine, and particularly
preferred examples thereof include triethylamine and diisopropylethylamine.
In this case, the amount of the base added is equimolar or more relative to the
ruthenium atoms.
The solvent used in this case is not particularly limited. Preferred
examples of the solvent include ethers such as diethyl ether and tetrahydrofuran;
alcohols such as methanol, ethanol, and isopropanol; aromatic hydrocarbons such
as toluene and xylene, halogen-containing solvents such as dichloromethane and
1,2-dichloroethane, aprotic polar solvents such as acetonitrile and
N,N-dimethylformamide, and the like, and particularly preferred examples
thereof include dichloromethane and isopropanol.
Alternatively, in another method for synthesizing the complex of the
present invention, a ruthenium arene dimer (e) having hydroxyl groups or thiol
groups in terminals of substituents of the arenes and a diamine (f) having a
halogen atom or the like in a terminal of a chain moiety bonded to the nitrogen
atom to which a sulfonyl group is not bonded can also be used as raw materials,
as shown in the following scheme 2.
Scheme 2
(in scheme 2, each sign has the same meaning as that in scheme l).
In this scheme 2, the combination of positions of the hydroxyl group or
thiol group and the leaving group such as a halogen atom is inversed as
compared with that in scheme 1. Also in this case, a thioether formation or
ether formation reaction is conducted simultaneously with the complexation by
reacting these substances in the presence of an appropriate base. Thus, the
ruthenium-diamine complex (d) or a cationic diamine complex (g), which are the
target complexes, can be similarly synthesized directly or through the amide
complex (c). When the synthesis is conducted through the amide complex (c),
the amide complex (c) can be converted to the complex (d) or (g) by adding an
appropriate acid to the amide complex (c). The base, solvent, and the like used
in this reaction are the same as those described above.
Moreover, the complex of the present invention can also be produced by a
method as shown in the following scheme 3.
Scheme 3
(I) A compound (h) having a 1,4-cyclohexadiene skeleton is synthesized
by a Diels-Alder reaction.
(II) Acompound (i) having a leaving group in its terminal is synthesized
by tosylation or the like of the compound (h) obtained in (I).
(III) A diamine (j) having a cyclohexadiene skeleton is synthesized by a
reaction of the compound (i) with TsDPEN
(N-(p-toluenesulfonyl)-l,2-diphenylethylenediamine).
(IV) The target monomer complex can be obtained by a reaction of the
obtained diamine (j) with ruthenium trichloride through a ruthenium dimer (k).
By this method, the ruthenium complex represented by general formula
(l) can be produced.
The use of such a ruthenium complex as a catalyst makes it possible to
produce an optically active b-hydroxy-c -aminocarboxylic acid ester in a high yield
at a high catalytic efficiency with a high selectivity.
Note that the preparation of the ruthenium complex of the present
invention is generally carried out at 120°C or below, and preferably 100°C or
below.
In addition, as for an asymmetric reduction reaction described below, the
reaction may be carried out by using the isolated amide complex (c) or diamine
complex (d) as a catalyst, or the reaction may be carried out by using the reaction
liquid of the complex preparation as it is without isolation of the complex (an in
situ method).
<6-Keto-a-aminocarboxylic Acid Ester>
In the b-keto-a-aminocarboxylic acid ester represented by general
formula (2), R23 represents a hydrocarbon group which may be substituted with
one or more hydroxyl groups and which has 11 to 21 carbon atoms, preferably 11
to 18 carbon atoms, and further preferably 11 to 15 carbon atoms. The
hydrocarbon group (which may be substituted with one or more hydroxyl groups)
may be acyclic or cyclic. When the hydrocarbon group is acyclic, the
hydrocarbon group may be a linear or branched saturated hydrocarbon group or
a linear or branched unsaturated hydrocarbon group, and is preferably a linear
saturated hydrocarbon group. When the hydrocarbon group is cyclic, the
hydrocarbon group may likewise be a saturated cyclic hydrocarbon group or an
unsaturated cyclic hydrocarbon group, and is preferably a saturated cyclic
hydrocarbon group. R23 is preferably a linear saturated fatty acid group having
11 to 15 carbon atoms, for example. Specifically, R23 is preferably a pentadecyl
group, a 1-hydroxypentadecyl group, or a dodecyl group. R23 is particularly
preferably a pentadecyl group or a 1-hydroxypentadecyl group, from the
viewpoint of usefulness of the compound (2).
In the b-keto-craminocarboxylic acid ester represented by general
formula (2), R24 represents a hydrogen atom or a hydrocarbon group having 1 to
10 carbon atoms, preferably a hydrogen atom, or a hydrocarbon group having 1 to
5 carbon atoms, and further preferably a hydrocarbon group having 1 to 4 carbon
atoms. The hydrocarbon group may be acyclic or cyclic. When the hydrocarbon
group is acyclic, the hydrocarbon group may be a linear or branched saturated
hydrocarbon group or a linear or branched unsaturated hydrocarbon group, and
is preferably a linear saturated hydrocarbon group. When the hydrocarbon
group is cyclic, the hydrocarbon group may likewise be a saturated cyclic
hydrocarbon group or an unsaturated cyclic hydrocarbon group, and is preferably
a saturated cyclic hydrocarbon group. R24 is preferably a saturated hydrocarbon
group having 1 to 4 carbon atoms. Specifically, R24 is preferably a methyl group,
an ethyl group, a propyl group, an isopropyl group, an isobutyl group, or a
tert-butyl group. From the viewpoint of the easiness of synthesis of the raw
material, R24 is further preferably a methyl group, an ethyl group, or a propyl
group, and particularly preferably a methyl group.
In the b-keto-a-aminocarboxylic acid ester represented by general
formula (2), R25 and R26 may be the same or different, and are preferably
different from each other. R25 and R26 each represent a hydrogen atom, an alkyl
group which has 1 to 10 carbon atoms and which may be substituted with one or
more selected from halogen atoms and hydroxyl groups, an acyl group which has
1 to 24 carbon atoms and which may be substituted with one or more selected
from halogen atoms and hydroxyl groups, or an amino-protecting group.
When any of R25 and R26 is an alkyl group having 1 to 10 carbon atoms
(which may be substituted with one or more halogen atoms or one or more
hydroxyl groups), an alkyl group having 1 to 5 carbon atoms, and particularly
preferably 1 to 3 carbon atoms is preferably selected as the alkyl group. In
addition, the alkyl group may be linear or branched, and is preferably linear.
Specific examples of the alkyl group include those described as the specific
examples of the alkyl group having 1 to 10 carbon atoms described above.
When any of R25 and R26 is an acyl group having 1 to 24 carbon atoms
(which may be substituted with one or more halogen atoms or one or more
hydroxyl groups), an acyl group having preferably 1 to 2 1 carbon atoms, and
particularly preferably 1 to 18 carbon atoms is selected as the acyl group. In
addition, the acyl group may be a saturated acyl group or an unsaturated acyl
group, and is preferably a saturated acyl group. Specific preferred examples of
the acyl group include a formyl group, an acetyl group, a trifluoroacetyl group, a
trichloroacetyl group, a monochloroacetyl group, a benzoyl group, an
octadecanoyl group, a 2-hydroxyoctadecanoyl group, and a 2-oxooctadecanoyl
group.
When any of 25 and R26 is an amino-protecting group, a group described
in Protective Groups in Organic Synthesis 3rd ed. (Theodora W. Greene and
Peter G. M. Wuts Ed., Wiley-Interscience: New York, 1999) can be selected as the
amino-protecting group, for example. Specific preferred examples of the
amino-protecting group include alkoxycarbonyl groups such as a
methoxycarbonyl group, an ethoxycarbonyl group, a benzyloxycarbonyl group,
and a tert-butoxycarbonyl group, and sulfonyl groups such as a
p-nitrobenzenesulfonyl group.
In the b-keto-a-aminocarboxylic acid ester represented by general
formula (2), R25 and R26 may form, together with the adjacent nitrogen atom, a
heterocycle which may be substituted with one or more hydroxyl groups. When
the heterocyclic is formed, for example, a phthaloyl group is selected as R25 and
R26, and a phthalimide group is formed together with the adjacent nitrogen atom.
As for R25 and R26, it is preferable that one of R25 and R26 be an acyl group
which has 1 to 24 carbon atoms and which may have a substituent(s), and the
other be a hydrogen, or that R25 and R26, together with the adjacent nitrogen
atom, form a heterocycle.
More preferably, one of R25 and R26 is an acyl group which has 1 to 24
carbon atoms and which may be substituted with one or more selected from
halogen atoms and hydroxyl groups, and the other is a hydrogen. In this case,
the acyl group which has 1 to 24 carbon atoms and which may be substituted
with one or more selected from halogen atoms and hydroxyl groups is preferably
a formyl group, an acetyl group, a benzoyl group, or an octadecanoyl group, from
the viewpoint of easiness of deprotection.
As for a method for producing the compound (2), the compound (2) can be
produced by known methods such as a method in which a b-keto ester is treated
with sodium nitrite, followed by oximation at the a position, and then an amino
group is formed by reduction of only the oxime.

In the optically active b-hydroxy-craminocarboxylic acid ester
represented by general formula (3) or (4), the definitions of 23, R24, R25, and R26
are the same as those described above.
In general formula (3) and (4), each * indicates an asymmetric carbon
atom. Since the compound (3) or (4) has two asymmetric carbon atoms, two
diastereomers are present. A compound having a relative configuration as that
of the compound (3) or (4) is referred to as an anti isomer. The other
diastereomer is referred to as a syn isomer, and represented by the following
general formula (5) or (6) :
(where each * indicates an asymmetric carbon atom, and R23, R24, R25, and R26 are
the same as those described above).
The present invention relates to a method for obtaining an optically
active b-hydroxy-o-aminocarboxylic acid ester, in particular, an anti isomer of an
optically active b-hydroxy-craminocarboxylic acid ester represented by general
formula (3) or (4). It is particularly desirable to selectively obtain, of the anti
isomers, the anti isomer of general formula (4), because the anti isomer of
general formula (4) is an important intermediate of optically active ceramides
useful as cosmetics components.

The present invention relates to a method for producing a compound
represented by general formula (3) or general formula (4), the method comprising
performing an asymmetric reduction reaction of a compound represented by
general formula (2) by use of a ruthenium complex represented by general
formula (l) (hereinafter also simply referred to as a ruthenium complex) as a
catalyst. Note that the present invention makes it possible to more selectively
produce, of the anti isomers, the compound represented by general formula (4),
because the compound represented by general formula (4) is an important
intermediate of optically active ceramides having a naturally occurring
configuration useful as cosmetics components. In the production method of the
present invention, the compound represented by general formula (3) or general
formula (4) can be obtained by an asymmetric reduction reaction which is
conducted by preparing a reaction solution containing the ruthenium complex
represented by general formula (l), the compound represented by general
formula (2), and a hydrogen donor, and then allowing a reaction therebetween to
proceed by, for example, heating this reaction solution or other procedures.
Note that these materials may be added to the reaction solution in any order in
the preparation of the reaction solution. In addition, in the production method,
the reaction may be conducted by adding the hydrogen donor at once, or by
adding the hydrogen donor continuously or intermittently. In addition, a
common catalyst other than the ruthenium complex represented by general
formula (l) may be contained as appropriate.
In addition, of the optically active b-hydroxy-a-aminocarboxylic acid
esters represented by the general formula (3) and (4), the (2R,3R) isomer
represented by general formula (4) is easily obtained as the major product in the
production method of the present invention. Moreover, it is possible to achieve a
formation ratio (2E,3R) isomer :(2S,3R) isomer of 85^15 to IOO , more preferably
95:5 to lOOO. In other words, this production method makes it possible to
obtain the anti isomer of an optically active b-hydroxy-craminocarboxylic acid
ester with a high stereo selectivity.
Detailed conditions are described below.
The amount of the ruthenium complex used in the production method of
the present invention is generally 1 to 1/100000 in terms of molar ratio relative
to the b-keto-a-aminocarboxylic acid ester represented by general formula (2).
However, the above-described reaction can be sufficiently and easily completed in
the present invention, even when the molar ratio is 1/250 to 1/10000, or further
1/500 to 1/10000.
The hydrogen donor used in the production method of the present
invention is not limited, as long as the hydrogen donor is capable of donating
hydrogen to the b-keto-a-aminocarboxylic acid ester represented by general
formula (2) during the reaction. Here, examples of usable hydrogen donors
include metal hydrides such as borohydride compounds, and those generally used
as hydrogen donors in hydrogen transfer reduction reaction, such as formic acid,
salts thereof, and isopropanol. Specific examples of usable hydrogen donors
include alcohols such as methanol, ethanol, n-propanol, and isopropanol; formic
acid; sodium formate; ammonium formate; hydrogen; and the like. The amount
of the hydrogen donor used may be any, as long as the amount is an equimolar
amount or more to the catalyst in terms of hydride. Moreover, hydrogen gas can
also be used as the hydrogen donor. The amount of hydrogen gas is preferably 1
to 100 equivalents, and particularly 1 to 10 equivalents to the
b-keto-craminocarboxylic acid ester, in view of the reactivity. In addition,
because of easiness of handling, formic acid or hydrogen is preferably used, and
formic acid is most preferably used.
The reaction pressure is not particularly limited, and the reaction is
carried out at generally 0.05 to 0.2 MPa, and preferably normal pressure.
Meanwhile, when hydrogen gas is used as the hydrogen donor, the
pressure is preferably 5 MPa or less, in general.
In the production method of the present invention, the reaction is
preferably carried out in the coexistence of a base. Examples of the base which
can be added for use in this reaction include inorganic bases such as sodium
hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate;
alkoxides such as sodium methoxide, sodium ethoxide, and sodium tert-butoxide;
and bases such as ammonia and organic amines having 3 to 30 carbon atoms.
Because of easiness of handling, it is preferable to add organic amines having 3
to 30 carbon atoms, and preferably 6 to 24 carbon atoms. Specific examples of
the organic amines include triethylamine, tributylamines (for example,
n-tributylamine), diisopropylethylamine, isopropyldimethylamine,
trimethylamine, n-trioctylamine, iso-trioctylamine,
l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene,
l,4-diazabicyclo[2.2.2]octane, and the like. Preferred examples thereof include
triethylamine, tributylamine, diisopropylethylamine, n-trioctylamine,
l,8-diazabicyclo[5.4.0]undec -7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine,
morpholine, 1-ethylpiperidine, 1-methylpiperidine, dicyclohexylmethylamine,
dimethylaniline and diethylaniline and so on, and more preferred examples
thereof include triethylamine, tributylamine diisopropylethylamine and
dicyclohexylmethylamine. The amount of the coexistent base is not particularly
limited, and is 1 to 100 equivalents, and preferably 1 to 10 equivalents to the
b-keto-craminocarboxylic acid ester represented by formula (2). Moreover, a
mixture of multiple bases may be used. In this case, the mixing ratio is not
particularly limited.
When the hydrogen donor is formic acid, it is particularly preferable to
use an organic amine as the base, among combinations of the above-described
hydrogen donors and the above-described bases. In this case, formic acid and
the amine are added to the reaction system separately, or an azeotrope of formic
acid and an organic amine prepared in advance may be used. Preferred
examples of the azeotrope of formic acid and an organic amine include an
azeotrope of formic acid and triethylamine (5:2), and the like.
In this production method, the reaction temperature is -20°C to 180°C,
preferably 0°C to 120°C, and further preferably 30°C to 100°C. A too-low
reaction temperature leads to an uneconomical result, because the time to
complete this reaction may be increased, or a large amount of the unreacted raw
material may remain, in some cases. Meanwhile, a too-high reaction
temperature is not preferable, because decomposition of the raw materials, the
catalyst, or the like may occur in some cases. Accordingly, the reaction solution
may be heated as appropriate in the production method of the present invention.
By setting the temperature of the reaction solution to 0°C to 120°C, the
asymmetric reduction reaction can be completed in 30 minutes to 72 hours. In
particular, by setting the temperature of the reaction solution to 30 to 100°C, the
asymmetric reduction reaction can be completed in 2 hours to 48 hours. The
heating temperature and the reaction time can be adjusted depending on the
optically active compound to be obtained. More particularly, by appropriately
setting reaction conditions, the reaction time can be 20 hours or shorter, in
particular 10 hours or shorter.
When the hydrogen donor is liquid, the hydrogen donor can be used as
the reaction solvent for the reaction, in general. It is also possible to use, as an
auxiliary solvent, one of or a mixture of non-hydrogen-donating solvents such as
toluene, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide,
acetone, and methylene chloride, in order to dissolve the raw materials. In a
case where a formic acid salt is used or in similar cases, it is also possible to carry
out the reaction of a two-layer system by using water as an auxiliary solvent to
dissolve the formic acid salt, in combination with an organic solvent. In this
case, a phase transfer catalyst may be used in combination to accelerate the
reaction. In addition, when hydrogen gas is used, the solvent is preferably an
alcohol solvent such as methanol, ethanol, isopropanol, trifluoroethanol, or
hexafluoro-2-propanol.
The reaction solvent is not particularly limited, as long as the solvent
does not inhibit the reaction. Specific examples of the reaction solvent include
hydrocarbons such as pentane, hexane, heptane, and cyclohexane; esters such as
methyl acetate, ethyl acetate, and butyl acetate! aromatic hydrocarbons such as
benzene, toluene, and xylene; nitriles such as acetonitrile; ethers such as diethyl
ether, diisopropyl ether, methyl cyclopentyl ether, tetrahydrofuran, and dioxane;
amides such as N,N-dimethylformamide and N,N-dimethylacetamide» dimethyl
sulfoxide; and halogenated hydrocarbons such as methylene chloride,
chloroform, chlorobenzene, and 1,2-dichloroethane. The reaction solvent is
preferably heptane, cyclohexane, methyl acetate, ethyl acetate, butyl acetate,
toluene, acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide,
methylene chloride, or chlorobenzene, and more preferably tetrahydrofuran,
dioxane, methyl acetate, ethyl acetate, or butyl acetate.
When a mixture solvent of two or more of these solvents is used, the
mixing ratio is not particularly limited. The amount of the solvent used can be
selected as appropriate depending on the reaction conditions, and the like. If
necessary, the reaction is carried out with stirring.
Furthermore, to increase an sin ratios in the present reaction, adding
dropwise a solution of a substrate to a solution of a catalyst for a long time is
effective. In this case, a solvent in which the catalyst is dissolved can be the
same as the above mentioned solvents. Additionally, the formic acid and amines
which are used in the reaction may be added into the solution of the catalyst
previously. Also, the formic acid and amines may be mixed with the solution of
the substrate to add dropwise the substrate together with the formic acid and
amines to the solution of the catalyst. A time required for adding dropwise the
substrate, which is a time required for the completion of the reaction, is, but not
be limited to, from 1 hour to 60 hours, preferably 5 hours to 15 hours.
The concentration of the b-keto-oraminocarboxylic acid ester represented
by general formula (2) in the reaction solution is, for example, 100 to 0.1%(w/v),
and preferably 100 to 10%(w/v), but is not particularly limited. In addition, the
concentration can be changed as appropriate depending on the reaction solvent
used.
After completion of the reaction, the target b-hydroxy-craminocarboxylic
acid ester can be obtained by one of or an appropriate combination of ordinary
employed purification methods such as extraction, filtration, crystallization,
distillation, and various kinds of chromatography.
Note that, after completion of the reaction asymmetric reduction, the
target ruthenium complex can be separated by an ordinary crystallization
technique such as concentration of the reaction liquid or addition of a poor
solvent. In addition, when a hydrogen halide salt is by-produced in the
above-described preparation, a washing operation with water may be conducted,
if necessary. In this case, the operation can be carried out easily, because the
amount of the ruthenium complex represented by general formula (l) and used
in the present invention is very small.
Examples
Hereinafter, the present invention will be described in detail on the basis
of Examples. However, the present invention is not limited to these Examples.
Note that the NMR spectra used for identification and purity
determination of complexes in the following Examples and the like were
measured with a Mercury Plus 300 4 n model apparatus manufactured by Varian
Technologies Japan Ltd., or Bruker BioSpin Avance III 500 System. Meanwhile,
the GC analyses were conducted by using Chirasil-DEX CB (0.25 mm x 25 m,
0.25 mh ) (manufactured by Varian, Inc.) or InertCapPure-WAX (0.25 mm x 30 m,
0.25 m ) (manufactured by GL Sciences Inc.). The HPLC analyses were
conducted by using CHIRALCEL OJ-H (0.46 mm x 25 cm) (manufactured by
Daicel Chemical Industries, Ltd.), ODS-3V (4.6 mm x 25 cm, 5 m) (GL Sciences
Inc.) , or CHIRALPAKAD (4.6 mm x 25 cm).
Note that abbreviations in Examples have the following meanings.
TsDPEN- N-(p-toluenesulfonyl)- 1,2-diphenylethylenediamine;
TIPPsDPEN:
N-(2,4,6-triisopropylbenzenesulfonyl)- 1,2-diphenylethylenediamine
o-TFTsDPEN:
N-(2-trifluoromethylmethylbenzenesulfonyl)- 1,2-diphenylethylenediamine
MESsDPEN:
N-(2,4,6-trimethylbenzenesulfonyl)- 1,2-diphenylethylenediamine
TsCYDN: N-(p-toluenesulfonyl)- 1,2-cyclohexanediamine
DIPEA diisopropylethylamine
DPPE: diphenylphosphinoe thane
Note that the diamines in complexes represent those from which one or
two hydrogen atoms were eliminated.
S/C represents a value of the number of moles of the substrate/the
number of moles of the catalyst.
The following Synthesis 1 to Synthesis 9 show synthesis methods for
obtaining ruthenium complexes represented by general formula (l).
[Synthesis l ]
Production of
N-((lR,2R)-l,2-diphenyl-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethylamino)ethyl)-4-
methylbenzenesulfonamide
The target compound (B) was produced by the following reaction.
In a 50-ml Schlenk tube, 5.0 g (13.65 mmol) of (R,R)-TsDPEN and 2.85 g
(2.07 ml) (13.65 mmol) of alkyl bromide (A) were mixed with each other in 10 ml
of DMSO, and the reaction was allowed to proceed at 60°C for 29 hours. Then,
50 ml of dichloromethane and 50 ml of a saturated aqueous NaHCOs solution
were added to the reaction mixture. After stirring, the organic layer was
separated, and further washed twice with 50 ml of a saturated aqueous NaHC03
solution. The dichloromethane was recovered, and the residue was purified by
silica gel column chromatography. Thus, 4.94 g of the target compound (B) was
obtained. Yield: 72%.
Ή -NMR (CDCls, 300 MHz) -
1.43-1.80 (m, 6H), 2.32 (s, 3H), 2.42-2.70 (m, 2H), 3.40-3.55 (m, 2H), 3.70-3.85 (m,
2H), 3.77 (d, 1H), 4.30 (m, 1H), 4.45 (d, 1H), 6.93-7.38 ( , 14H)
[Synthesis 2]
Production of
N-((lR 2R)-2-(2-hydroxyethylamino)-l,2-diphenylethyl)-4-methylbenzenesulfona
mide
The target diamine (C) was produced by the following reaction.
To 5.69 g of the above-described compound (B) obtained in Synthesis 1,
135 ml of ethanol and 34.5 ml of a 1M aqueous HCl solution were added, and the
reaction was allowed to proceed at 40°C for 2 hours. Then, the reaction mixture
was neutralized by adding 3.45 g of NaHCC 3 thereto. Then, 75 ml of water and
150 ml of diethyl ether were added to the solution, and phase separation was
conducted. Then, 50 ml of water was added thereto, and ether was removed
with an evaporator. As a result, white crystals were precipitated. After the
mixture was ice cooled, the crystals were filtered, washed with water, and then
dried under reduced pressure at 70°C. Thus, 4.33 g of the target diamine (C)
was obtained. Yield: 92%.
Ή -NMR (CDCI3, 300 MHz) d·
2.31 (s, 3H), 2.50-2.62 (m, 2H), 3.58-3.75 (m, 2H), 3.79 (d, 1H), 4.40 (d, 1H),
6.82-7.41 (m, 14H)
[Synthesis 3]
Production of (4-methylcyclohexa-l,4-dienyl)methanol
The target compound (F) was produced by the following reaction.
In a 500 L four-necked flask, 1.73 g (7.93 mmol) of CoBr2, 8.4 g (26.3
mmol) of Znl2, 3.47 g (8.8 mmol) of DPPE, and 370 ml of dichloromethane were
placed. After nitrogen substitution, the mixture was stirred at 30°C for 30
minutes. Then, 78 ml (53. 1 g, 780 mmol) of isoprene, 41ml (39.3 g, 701 mmoD of
propargyl alcohol, and 2.2 g (8.53 mmol) of BU4NBH4 were added thereto, and the
reaction was allowed to proceed at 30°C for 7 hours. Then, the dichloromethane
solution was recovered, and the residue was distilled under reduced pressure at
160°C. Thus, 27.7 g of the target diene mixture (F) was obtained (32% yield).
The purity of the target diene in this mixture was approximately 98% based on
gas chromatography (GC).
Ή -NMR (CDCI3, 300 MHz) :
1.67 (s, 3H), 2.55-2.70 (m, 4H), 4.02 (s, 2H), 5.44 ( , 1H), 5.68 (m, 1H)
[Synthesis 4]
Production of [RuC (l (bromomethyl)-4-methylbenzene)]2)
The target complex compound (G) was produced by the following
reaction.
In 40 ml of 2-methoxyethanol and 4 ml of water, 4.75 g (38.2 mmol) of the
above-described diene (F) obtained in Synthesis 3, 2.0 g (7.65 mmol) of
ruthenium trichloride trihydrate, and 0.643 g (7.65 mmol) of NaHC were
dissolved, and the reaction was allowed to proceed at 130°C for 1.5 hours. After
that, the solvent was removed by distillation with an evaporator. To the residue,
52 ml of a concentrated aqueous hydrobromic acid solution and 4 ml of
concentrated sulfuric acid were added, followed by stirring at 100°C for 4 hours.
After the reaction, dichloromethane, water, and 2-methoxyethanol were added to
the solution. The mixture was stirred, and allowed to stand. Then, the
precipitated crystals were filtered. Thus, 1.9 g of the target complex (G) was
obtained. Yield: 7 9 /0.
Ή -NMR (DMSO-de, 300 MHz)
2.23 (s, 3H), 4.40 (s, 2H), 5.84 (d, 2H), 6.15 (d, 2H)
[Synthesis 5
Production of RuCl((R,R)-0-HT-TsDPEN)
The target complex RuCl((R,R)-(>HT-TsDPEN) was produced by the
following reaction.
c
The above-described arene dimer (G) (1.6 g, 2.24 mmol) obtained in
Synthesis 4, 1.53 g (3.73 mmol) of diamine (C) produced in Synthesis 2, 1.19 g
(3.73 mmol) of triethylbenzylammonium iodide (EtsBnNI), 52.8 ml of
dichloromethane, and 52.8 ml of water were mixed with each other, and stirred
at 35°C. To this mixture, 1.78 g (26.9 mmol) of KOH was added, and the
reaction was allowed to proceed for 3 hours. The organic layer turned to be a
violet solution. After the mixture was allowed to stand, the aqueous layer was
removed. To the organic layer, 50 ml of water was added. The mixture was
stirred, and allowed to stand, followed by phase separation. This phase
separation operation was conducted three times. Thereafter, 65 ml of a 0.1 M
aqueous HCl solution was added thereto, followed by stirring for 30 minutes.
Then, the solution was neutralized by adding 0.034 g of NaHCOs, and the
mixture was allowed to stand. The dichloromethane layer alone was separated,
and evaporated to dryness. The residue was purified with a silica gel column
(eluent: CHCl3/MeOH=20/l). Thus, 1.1 g of the target complex
RuCl((R,R)-OHT-TsDPEN) was obtained. Yield: 45% (the purity was
approximately 95% based on liquid chromatography (HPLC)).
Ή -NMR (CD2CI2, 300 MHz)
2.25 (s, 3H), 2.52 (s, 3H), 3.13 (m, IH), 3.60 ( , IH), 3.80-4.00 (m, 4H), 4.48 (d,
J=15.0 Hz, IH), 4.52 (brs, IH), 4.95 (d, J=15.0 Hz, IH), 5.45 (d, J=5.2 Hz, IH),
5.75 (d, J=6.2 Hz, IH), 6.05 (d, J=5.2 Hz, IH), 6.60 (d, J=6.9 Hz, 2H), 6.65-6.70 (m,
4H), 6.88 (d, J=8.0 Hz, 2H), 7.08-7.18 (m, 4H), 7.23 (d, J=8.0 Hz, 2H)
HRMS (ESI):
[M-C1]+ calcd for C31H33N2O3RUS: 615.1258; found: 615.1258
[Synthesis 6]
Production of 2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethanol and
2-((5-methylcyclohexa- l,4-dienyl)methoxy)ethanol
(1,4type)
In 460 ml of THF, 7.74 g (0.019 mol) of l,2-bis(diphenylphosphino)ethane,
4.05 g (0.019 mol) of cobalt bromide, 11.82 g (0.037 mol) of zinc iodide, and 2.42 g
(0.037 mol) of zinc were dissolved, and the mixture was stirred at 70°C for 15
minutes. After cooling to room temperature, 74.89 g (1.10 mol) of isoprene was
added thereto, and then 92.70 g (0.93 mol) of an alkyne alcohol was added
dropwise slowly, with cooling in a water bath. After stirring at 35°C for 1 hour,
the solvent was removed by distillation under reduced pressure. To the
obtained residue, 460 ml of toluene and 460 ml of water were added (stirring: 10
minutes, allowing to stand: 10 minutes). Under nitrogen atmosphere, filtration
was conducted through Celite, and then the obtained solution was phase
separated. The solvent was removed by distillation under reduced pressure.
The obtained crude product was purified by Claisen distillation (101 to 113°C/3
torr). Thus, 106.6 g of the diene alcohols were obtained as a colorless oily
substance. Yield: 68.5% (l,4-type/l,5-type=91/9).
Ή -NIvIR (CDCI3, 300 MHz) d :
1.68 (s, 3H), 2.31 (brs, 1H), 2.64 (brs, 4H), 3.48-3.52 (m, 2H), 3.70-3.75 (m, 2H),
3.93 (s, 2H), 5.43-5.45 (m, 1H), 5.70-5.71 (m, 1H);
HRMS(ESI):
[M+H]+ calcd for CioHi 0 2: 167. 1430; found: 167. 1432
[Synthesis 7]
Production of 2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethyl
4-methylbenzenesulfonate and 2-((5-methylcyclohexa- l,4-dienyl)methoxy)ethyl
4-methylbenzenesulfonate
(1,4type) (1,4type)
+ +
In 400 ml of toluene, 100.00 g (0.59 mol) of the diene alcohols obtained in
Synthesis 6, 90.29 g (0.89 mol) of triethylamine, 73.20 g (0.89 mol) of
1-methylimidazole were dissolved. To this solution cooled in an ice bath, a
toluene solution (400 ml) of 130.33 g (0.68 mol) of p-toluenesulfonyl chloride was
added dropwise slowly, followed by stirring at room temperature for 1 hour.
Water was added thereto, and phase separation was conducted. The obtained
organic layer was washed with 15% sulfuric acid, water, and saturated aqueous
sodium hydrogen carbonate in this order. The solvent was removed by
distillation under reduced pressure. Thus, 188.01 g of the target tosylates were
obtained as a colorless oily substance. Yield: 98.1% (l,4-type/l,5-type=91/9).
Ή -NMR (CDC13, 300 MHz) d
1.67 (s, 3H), 2.44 (s, 3H), 2.58 (brs, 4H), 3.58-3.55 (m, 2H), 3.84 (s, 2H), 4.18-4.14
(m, 2H), 5.41-5.40 (m, 1H), 5.64-5.63 (m, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.80 (d,
J=8.3 Hz, 1H);
HRMS (ESI):
[M+H]+ calcd for C17H22O4S: 323.1312; found: 323.1325
[Synthesis 8]
Production of
2,4,6-triisopropyl-N-((lR,2R)-2-(2-((4-methylcyclohexa-l,4-dienyl)methoxy)etheyl
amino)- l,2-diphenylethy)benzenesulfonamide
In 25 ml of toluene, 6.03 g (18.82 mmol) of the above-described tosylates
obtained in Synthesis 7 were dissolved. To this solution, 2.43 g (18.82 mmol) of
DIPEA and 9.00 g (18.80 mmol) of (R,R)-TIPPsDPEN were added, foUowed by
stirring at 135°C for 13 hours. After that, the solvent was removed by
distillation under reduced pressure. The obtained residue was purified by silica
gel column chromatography (toluene/ethyl acetate=20/l 15/l). Thus, 10.53 g of
the title compound was obtained as a colorless oily substance. Yield: 89.0%.
Ή -NMR (CDCI3, 300 MHz)
1.06 (d, J=6.9 Hz, 3H), 1.21 (d, J=6.9 Hz, 3H), 1.87 (brs, 1H), 1.68 (s, 3H), 2.60
(brs, 4H), 2.71-2.48 (m, 2H), 3.52-3.34 ( , 2H), 3.55 (d, J=8.9 Hz, 1H), 3.77 (s, 2H),
3.95 (septet, J=6.7 Hz, 3H), 4.40 (d, J=8.9 Hz, 1H), 5.44 (m, 1H), 5.64 (m,
1H),6.52 (brs, 1H), 6.74-7.28 (m, 12H);
HRMS(ESI):
[M+H]+ calcd for C39H53N2O3S: 629.3771; found: 629.3771
[Synthesis 9]
Production of RuCl((R,R)-OHT-TIPPsDPEN)
In 8 ml of methanol, 2.02 g (3.21 mmol) of the above-described
sulfonamide obtained in Synthesis 8 was dissolved. Under ice-cooling, 0.67 g
(6.42 mmol) of a 1 M hydrochloric acid solution in methanol was added thereto,
followed by stirring at room temperature for 20 minutes. Then, the solvent was
removed by distillation under reduced pressure. The obtained residue was
dissolved in 30 ml of 3-methoxypropanol and 18 ml of water. To this solution,
0.72 g (2.75 mmol) of ruthenium trichloride trihydrate was added, followed by
stirring at 120°C for 1 hour. The solvent was removed by distillation under
reduced pressure. To the obtained residue, 35 ml of IPA and 0.72 g (7.15 mmol)
of triethylamine were added, followed by stirring at 60°C for 1 hour. The
solvent was removed by distillation under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(chloroform/methanol=97/3 20/l). Thus, 1.28 g of the target Ru complex was
obtained. Yield: 52.3%.
Ή -NMR (CD2CI2, 500 MHz)
1.0-1.2 (m, 18H), 1.70 (m, IH), 2.41 (s, 3H), 2.60 (m, IH), 3.05 (m, IH), 3.35 (m,
IH), 3.68 (m, IH), 3.75 (t, IH), 3.85 (m, 2H), 4.18 (d, IH), 4.25 (d, IH), 4.85 (brs,
IH), 5.02 (d, IH), 5.30 (d, IH), 5.48 (d, IH), 5.63 (d, IH), 6.35 (d, IH), 6.40-6.70 (m,
10H), 6.90-7.05 (m, 3H);
HRMS (ESI):
[M+H]+ calcd for C39H50N2O3SCIRU: 763.2269; found - 763.2257
[Synthesis 10]
Production of
N-((lR,2R)-2-(2-((4-methylcyclohexa-l,4-dienyl)methoxy)ethylamino)-l,2-diphen
ylethyl)-2-(trifluoromethyl)benzenesulfonamide hydrochloride
In 31.6 ml of toluene, 8.07 g (26.1 mmol) of the above-described tosylates
obtained in Synthesis 7 were dissolved. To this solution, 3.38 g (26.2 mmol) of
DIPEA, 10.00 g (23.8 mmol) of (R,R)-0-TFTsDPEN and 4.34 g (26.2 mmol) of
potassium iodide were added, followed by stirring at 135°C for 6 hours. The
reaction solution was concentrated and purified with a silica gel column
chromatography to obtain 10.1 g of diamine (Yield: 74.5 %). Then, 110 ml of
dichloromethane and 65.3 ml of HCl in methanol solution (IN) were added to
10.1 g (17.7 mmol) of the diamine, followed by stirring for 0.5 hours, and the
solvent was removed to obtain 11. 1 g of the target diamine hydrochloride. Yield:
93.9%
Ή - M DMSO,300MHz)
1.62(m, 3H), 2.60(s, 3H), 2.78-3. 12(m, 2H), 3.52-3.70(m, 2H), 3.86(s, 2H) ,4.75(m,
1H), 4.92(m, 1H), 5.40(m, 1H), 5.68(m, 1H), 6.75-7.35(m, 10H), 7.40(t, 1H), 7.50(t,
1H), 7.60(d, 1H), 7.75(d, 1H), 8.90(m, 1H), 8.98(brd, 1H), 9.92(brd, 1H);
-57.16;
HRMS (ESI):
[M-C1]+ calcd for HCl 571.2237; found: 571.2244
[Synthesis ll]
Production of RuCl((R,R)-0-HT- 0-TFTs-DPEN)
In 66 ml of 3-methoxypropanol and 22 ml of water, 5.0 g (8.25 mmol) of
the diamine hydrochloride obtained in Synthesis 10 was dissolved. After that,
to the solution, 1.79 g (6.86 mmol) of rutheniumchloride trihydrate and 0.58 g
(6.86 mmol) of sodium hydrogencarbonate were added, followed by stirring at
120°C for 2 hours. After collecting 50 ml of 3-methoxypropanol from the
solution, to the solution, 75 ml of MIBK and 2.78 g (27.45 mmol) of triethylamine
were added, followed by stirring at 60°C for 1 hour. Then, a 0.3 M hydrochloric
acid was added to the solution, and phase separation was conducted, followed by
washing an obtained organic phase with water twice. After about 60 ml of the
solvent was collected, 85 ml of heptane was added, and precipitation was
conducted. The precipitated crystals were filtered, and then 4.60 g of the target
Ru complex was obtained. Yield: 95.2%.
1H-NMR(CD2Cl2,300MHz)
2.50 (s, 3H), 3.15 - 3.20 ( , IH), 3.70 - 3.82 (m, 2H), 4.00 (m, 2H), 4.15 (m, IH),
4.40 (m, IH), 4.80 (m, IH), 5.10 (d, IH), 5.45 (d, IH), 5.62 (d, IH), 5.70 (d, IH),
6.38 (d, IH), 6.50-7.50(m, 14H);
1 F-NMR(DMSO) d:
-58.45
HRMS(ESI):
[M+H]+ calcd for C31H30CIN2O3F3RUS: 705.7034; found: 705.0758
[Synthesis 12]
Production of 2,4,6-trimethyl-N-((lR,2R)-2-(2-((4-methyl
cyclohexa-l,4-dienyl)methoxy)ethylamino)-l,2-diphenylethyl)benzenesulfonamid
e
In 5 ml of toluene, 1.0 g (3.0 mmol) of the above-described tosylates
obtained in Synthesis 7 was dissolved. To this solution, 0.39 g (3.0 mmol) of
DIPEA and 1.3 g (3.3 mmol) of (R,R)-MESsDPEN were added, followed by
stirring at 120°C for 8 hours. After that, the solvent was removed by distillation
under reduced pressure. The obtained residue was purified with a silica gel
column chromatography (toluene/ethyl acetate=4/l). Thus, 0.71 g of the title
compound was obtained as a colorless oily substance. Yield: 44.7 %.
[Synthesis 13]
Production of RuCl((R,R)-OHT-MESs-DPEN)
In 5 ml of methanol, 0.67 g (1.2 mmol) of the above-described
sulfonamide obtained in Synthesis 12 was dissolved. Under ice-cooling, 0.25 g
(2.4 mmol) of a 1 M hydrochloric acid solution in methanol was added thereto,
followed by stirring at room temperature for 20 minutes. Then, the solvent was
removed by distillation under reduced pressure. The obtained residue was
dissolved in 20 ml of 2-methoxyethanol, 2 ml of water and 0.09 g (1.2 mmol) of
sodium hydrogencarbonate. To this solution, 0.36 g (1.35 mmol) of
rutheniumchloride trihydrate was added, followed by stirring at 120°C for 3
hours. The solvent was removed by distillation under reduced pressure. To
the obtained residue, 40 ml of ethanol, 0.5 g (4.94 mmol) of triethylamine were
added, followed by stirring at 80°C for 2 hour. The solvent was removed by
distillation under reduced pressure. The obtained residue was purified with a
silica gel column chromatography (chloroform/methanol=20/l). Thus, 0.13 g of
the target Ru complex was obtained. Yield- 16.0 %.
H-NMR(CD2Cl2,500MHz) :
1.95 (s, 3H), 2.45(s, 6H), 2.46(s, 3H), 3.05(m, 1H), 3.70(m, 1H), 3.80(d, 1H),
3.85(m, 2H), 3.95(d, 1H), 4.25(d, 1H), 4.75(m, 1H), 5.00(d, 1H), 5.40(d, 1H), 5.50(d,
1H), 5.60(d, 1H), 6.30(s, 2H), 6.53(d, 1H), 6.40-7.00(m, 10H);
HRMS(ESI):
[M+H]+ calcd for C33H37CIN2O3KUS: 679.1335; found: 679.1327
[Synthesis 14]
Production of 4-methyl-N-((lR,2R)-2-(2-((4-methyl
cyclohexa-l,4-dienyl)methoxy)ethylamino)cyclohexyl)benzenesulfonamide
hydrochloride
In 26 ml of toluene, 5.06 g (16.4 mmol) of the above-described tosylates
obtained in Synthesis 7 were dissolved. To this solution, 2.12 g (16.4 mmol) of
DIPEA, 4.00 g (14.9 mmol) of (R,R)-TsCYDN and 2.72 g (16.4 mmol) of potassium
iodide were added, followed by stirring at 135°C for 20 hours. The reaction
solution was concentrated and purified with a silica gel column to obtain 2.9 g of
diamine (Yield: 46.9 %). Then, 42 ml of dichloromethane and 24.6 ml of HCI in
methanol solution (IN) were added to 2.8 g (6.69 mmol) of the diamine, followed
by stirring for 0.5 hours, and the solvent was removed to obtain 2.9 g of the
target diamine hydrochloride. Yield: 94.7 %
H-NMRiDMSO,300MHz) :
0.95-1.30(m, 4H), 1.50(m, 2H), 1.63(s, 3H), 2.10(m, 2H), 2.40(s, 3H), 2.60(m, 2H),
2.95(brd, IH), 3.18(m, 2H), 3.60(m, 2H), 3.90(s, 2H), 5.40(m, IH), 5.70(m, IH),
7.40(d, IH), 7.75(d, IH), 8.15(d, IH), 8.23(brd, IH), 9.10(brd, IH)
HRMS(ESI):
[M-C1]+ calcd for C23H34N2O3S: 419.2363; found: 419.2365
[Synthesis 15]
Production of RuCl((R,R)-OHT-Ts-cydn)
In 15 ml of 3-methoxypropanol and 3 ml of water, 0.5 g (l.l mmol) of the
diamine hydrochloride obtained in Synthesis 14 was dissolved. After that, to
the solution, 0.25 g (0.96 mmol) of rutheniumchloride trihydrate and 0.08 g (0.96
mmol) of sodium hydrogencarbonate were added, followed by stirring at 120°C
for 1 hour. After collecting 12 ml of 3-methoxypropanol from the solution, to the
solution, 13 ml of MIBK and 0.39 g (3.82 mmol) of triethylamine were added,
followed by stirring at 60°C for 1 hour. Then, a 0.3 M hydrochloric acid was
added to the solution, and phase separation was conducted, followed by washing
an obtained organic phase with water twice. After about 10 ml of the solvent
was collected, 15 ml of heptane was added, precipitation was conducted. The
precipitated crystals were filtered, and then 0.24 g of the target Ru complex was
obtained. Yield: 45.5 %.
H-NMR(CD 2Cl2,500MHz)
0.65-1.05 (m, 4H), 1.90 (m, 1H), 1.15 (m, 1H), 2.08 (m, 1H), 2.70 (m, 1H), 2.75 (s,
1H), 2.77 (s, 1H), 2.60 (m, 1H), 3.60-3.70 (m, 2H), 3.80 (m, 1H), 4.00 (m, 1H), 4.25
(m, IH), 4.35 (d, IH), 4.92 (d, IH), 5.25 (d, IH), 5.50 (d, IH), 5.67 (d, 1H),5.83 (d,
IH), 7.20 (d, IH), 7.80 (d, IH);
HRMS(ESI):
[M-C1]+ calcd for C2 3i 20 uS 517.1093; found-' 517.1101
[Example l ]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R)-OHT-TsDPEN) (6.5 mg, 0.01 mmol)
produced in Synthesis 5 and methyl 2-acetylamino-3-oxooctadecanoate (0.93 g,
2.50 mmol) in 1,4-dioxane (4.6 ml), triethylamine (0.758 g, 7.5 mmol) and formic
acid (0.345 g, 7.5 mmol) were added. Then, the mixture was heated to 90°C, and
stirring was continued for 6 hours. A sample was taken out, and anaylzed by
HPLC. As a result, the conversion was 99%. In addtion, the ratio between the
anti isomer ((2R,3R) isomer) and the syn isomer((2S,3R) isomer) was as followes^
anti isomer^syn isomer=90.5 '9.5.
After cooling to 20°C, the reaction liquied was washed wtih water, and
drived over magnesium sulfate. The solvent was recovered under reduced
pressure. Thus, the titled compound was obtained. The obtained crude
product was analyzed by cmparison with a standard substance. As a result, the
content of the titled compound was 0.88 g, and the yield thereof was 95%. In
addtion, the optical purity of the anti isomer was 97%ee.
[Example 2]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R)-OHT-TIPPsDPEN) (7.6 mg, 0.01 mmol)
produced in Synthesis 9 and methyl 2-acetylamino 3-oxooctadecanoate (0.93 g,
2.50 mmol) in 1,4-dioxane (4.6 ml), triethylamine (0.758 g, 7.5 mmol) and formic
acid (0.345 g, 7.5 mmol) were added. The mixture was heated to 90°C, and
stirring was continued for 6 hours. A sample was taken out, and analyzed by
HPLC. As a result, the conversion was 70%. In addition, the ratio between the
anti isomer ((2R,3R) isomer) and the syn isomer ((2S,3R) isomer) was as follows:
anti isomer syn isomer=92.5 7.5. In addition, the optical purity of the anti
isomer was 97%ee.
[Comparative Example]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl[(R,R)TsDPEN)](p-cymene) complex (6.4 mg, 0.01
mmol) and methyl 2-acetylamino-3 _oxooctadecanoate (0.93 g, 2.50 mmol) in
1,4 dioxane (4.6 ml), triethylamine (0.758 g, 7.5 mmol) and formic acid (0.345 g,
7.5 mmol) were added. The mixture was heated to 90°C, and stirring was
continued for 6 hours. A sample was taken out, and analyzed by HPLC. As a
result, the conversion was 65%. In addition, the ratio between the anti isomer
((2R,3R) isomer) and the syn isomer ((2S,3R) isomer) was as follows anti
isomer^syn isomer=81. 5:18.5. In addition, the optical purity of the anti isomer
was 97%ee.
Table 1 shows the results of Examples 1 and 2, as well as Comparative
Example.
Table 1
Here, De in this specification represents the mass ratio of (anti isomer-syn
isomer)/(anti isomer+syn isomer).
From the contents of Examples 1 and 2 and Comparative Example, it was
found that when the reaction conditions (s/c, temperature, and reaction time) were
the same, the conversion was remarkably increased by selecting the ruthenium
complex used for the invention of the present application. In addition, it was also
found that the anti isomer was obtained with high stereo selectivity.
[Examples 3 to 5]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
Different amines were added respectively to solutions each containing
RuCl((R,R)-0-HT-TsDPEN) (6.5 mg, 0.01 mmol) produced in Synthesis 5 and
methyl 2-acetylamino_3-oxooctadecanoate (0.93 g, 2.50 mmol) in tetrahydrofuran
(4.6 ml). Then, formic acid (0.345 g, 7.5 mmol) was further added to this mixture,
and stirring was continued at 30°C for 20 hours.
Table 2 shows the results.
Table 2
EteN: Triethylamine
nBueN: Tri-n-butylamine
EtN(iPr 2: Diisopropylethyl
Examples 3 to 5 showed that the use of tertiary organic amines made it
possible to complete the reaction even under a mild temperature condition (30°C) in
a relatively short reaction time (20 hours), and to achieve high ratios of anti^syn.
[Examples 6 to 15]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
Different amines were added respectively to solutions each containing
RuCl((R,R)-0-HT-TsDPEN) (5.2 mg, 0.008 mmol) produced in Synthesis 5 and
methyl 2-acetylamino-3-oxooctadecanoate (1.48 g, 4.00 mmol) in tetrahydrofuran
(14.8 ml). Then, formic acid (0.552 g, 12.0 mmol) was further added to this mixture,
and stirring was continued at 60°C for 20 hours.
Table 3 shows the results.
Table 3
1-Me-pyrrolidine: 1-methylpyrrolidine
(i-Oct) 3 : trriso-octylamine
iPrMe2N isopropyldimethylamine
1-Et-piperidine : 1-ethylpiperidine
l-Me-pipieridine: 1-methylpiperidine
Cy2Me dicyclohexylmethylamine
From the results of Examples 6 to 15, it was found that the use of a primary,
secondary or tertiary organic amine, made it possible to complete the reaction for a
relatively short reaction time (20 hours) and to achieve relatively high anti^syn
ratios by a somewhat higher temperature condition (60°C) than in Example 3 to 5,
even if the amount of the catalysts was small (the substrate^catalyst (S/C) ratio was
500).
[Example 16]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R)-(>HT-TsDPEN) (2.6 mg, 0.004 mmol)
(S/C=1,000) produced in Synthesis 5 and methyl 2-acetylamino-3-oxooctadecanoate
(1.48 g, 4.00 mmol) in ethyl acetate (14.8 ml), triethylamine (1.21 g, 12.0 mmol) was
added. Furthermore, formic acid (0.552 g, 12.0 mmol) was added to the solution,
and stirring was continued at 60°C for 20 hours. A sample was taken out, and
anaylzed by HPLC. As a result, the conversion was 97%. In addtion, the ratio
between the anti isomer ((2R,3R) isomer) and the syn isomer ((2S,3R) isomer) was as
followes- anti isomer:syn isomer=88.3 :11.7.
[Example 17]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R)-OHT-TsDPEN) (2.6 mg, 0.004 mmol)
(S/C=1,000) produced in Synthesis 5 and methyl 2-acetylamino-3-oxooctadecanoate
(1.48 g, 4.00 mmol) in methyl acetate (14.8 ml), triethylamine (1.21 g, 12.0 mmol)
was added. Furthermore, formic acid (0.552 g, 12.0 mmol) was added to the
solution, and stirring was continued at 60°C for 20 hours. A sample was taken out,
and anaylzed by HPLC. As a result, the conversion was 94%. In addtion, the
ratio between the anti isomer ((2R.3R) isomer) and the syn isomer((2S,3R) isomer)
was as followes^ anti isomer^syn isomer=88.5 11.5.
From the results of Examples 16 and 17, it was found that the use of
suitable solvents such as ethyl acetate and methyl acetate made it possible to
complete the reaction for a relatively short reaction time_(20 hour s)- and-to achie-ve
relatively high anti -syn ratios by a temperature condition of 60°C, even if a
condition where the amount of the catalysts was very small (the substrate ^catalyst
(S/C) ratio was 1,000).
[Example 18]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R)O-HT-TsDPEN) (2.6 mg, 0.004 mmol)
(S/C=1,000) produced in Synthesis 5 and methyl 2-acetylamino-3-oxooctadecanoate
(1.48 g, 4.00 mmol) in ethyl acetate (14.8 ml), diisopropylethylamine (1.55 g, 12.0
mmol) was added. Furthermore, formic acid (0.552 g, 12.0 mmol) was added to the
solution, and stirring was continued at 60°C for 20 hours. Asample was taken out,
and anaylzed by HPLC. As a result, the conversion was 100%. In addtion, the
ratio between the anti isomer ((2R,3R) isomer) and the syn isomer ((2S,3R) isomer)
was as followes- anti isomer^syn isomer=87.8 :12.2 (75.7%de).
[Example 19]
Production of methyl (2R,3R)-2-acetylamino-3 hydroxyoct adecanoate
A solution of RuCl((R,R)-0-HT-TsDPEN) (2.6 mg, 0.004 mmol) (S/C=1,000)
produced in Synthesis 5 and diisopropylethylamine (1.55 g, 12.0 mmol) in ethyl
acetate (14.8 ml), was heated to 60°C and stirred. Then, to the solution, a solution
of methyl 2-acetylamino-3-oxooctadecanoate (1.48 g, 4.00 mmol) and formic acid
(0.552 g, 12.0 mmol) in 5 ml THF were added dropwise over 10 hours, and stirring
was continued for 10 hours. A sample was taken out, and anaylzed by HPLC. As
a result, the conversion was 100%. In addtion, the ratio between the anti isomer
((2R,3R) isomer) and the syn isomer((2S,3R) isomer) was as followes: anti
isomer:syn isomer=91. 7:8.3 (83.3% de).
Having reviewed Example 18 and Example 19, it was found that the slowly
adding dropwise the solution of the substrate to the solution of the catalyst in the
reaction of Example 19 made it possible to further increase an syn ratios,
compared to the reaction of Example 18, in which all substrates are mixed with the
solution of the catalyst from the start.
[Example 20]
of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R)-0-HT-o-TFTs-DPEN) (2.8 mg, 0.004 mmol)
(S/C=1,000) produced in Synthesis 11 and methyl 2-acetylamino-3 _oxooctadecanoate
(1.48 g, 4.00 mmol) in methyl acetate (14.8 ml), diisopropyl ethylamine (1.55 g, 12.0
mmol) was added. Furthermore, formic acid (0.552 g, 12.0 mmol) was added to the
solution, and stirring was continued at 60°C for 20 hours. A sample was taken out,
and anaylzed by HPLC. As a result, the conversion was 92%. In addtion, the
ratio between the anti isomer ((2R,3R) isomer) and the syn isomer((2S,3R) isomer)
was as followes- anti isomer syn isomer=91.0 :9.0 (82.0%de).
[Example 21]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R) -HT MESs-DPEN) (2.7 mg, 0.004 mmol)
(S/C= 1,000) produced in Synthesis 13 and methyl
2-acetylamino-3-oxooctadecanoate (l.48g, 4.00 mmol) in methyl acetate (14.8 ml),
diisopropylethylamine (1.55 g, 12.0 mmol) was added. Furthermore, formic acid
(0.552 g, 12.0 mmol) was added to the solution, and stirring was continued at 60°C
for 20 hours. A sample was taken out, and anaylzed by HPLC. As a result, the
conversion was 95%. Then, additionally stirring was continued for 20 hours, and a
sample was taken out again, and anaylzed by HPLC. As a result, the conversion
was 100%. In addtion, the ratio between the anti isomer ((2R,3R) isomer) and the
syn isomer((2S,3R) isomer) was as followes- anti isomer syn isomer=91. 6-8.4
(83.3%de).
[Example 22]
Production of methyl (2R,3R)-2-acetylamino-3-hydroxyoctadecanoate
To a solution of RuCl((R,R)-OHT-Ts-cydn) (2.7 mg, 0.004 mmol)
(S/C=1,000) produced in Synthesis 15 and methyl
2-acetylamino 3-oxooctadecanoate (1.48 g, 4.00 mmol) in methyl acetate (14.8 ml),
diisopropyl ethylamine (1.55 g, 12.0 mmol) was added. Furthermore, formic acid
(0.552 g, 12.0 mmol) was added to the solution, and stirring was continued at 60°C
for 20 hours. A sample was taken , nd anaylzed y_HPLC.— s a- resu t th
conversion was 89%. Then, additionally stirring was continued for 20 hours, and a
sample was taken out again, and anaylzed by HPLC. As a result, the conversion
was 98%. In addtion, the ratio between the anti isomer ((2R,3R) isomer) and the
syn isomer((2S,3R) isomer) was as followes- anti isomer^syn isomer=89.0 11.0
(78.1%de).
It is possible to selectively produce an optically active
8-hydroxy-a-aminocarboxylic acid ester useful as a raw material for producing
pharmaceuticals and functional materials and as the like.
Claims
1. A method for producing an optically active b-hydroxy-craminocarboxylic
acid ester, comprising performing an asymmetric reduction reaction of a
b-keto-a-aminocarboxylic acid ester in the presence of a ruthenium complex and a
hydrogen donor, wherein
the ruthenium complex is represented by the following general formula (l)
or (1)':
(where
R1 represents an alkyl group having 1 to 10 carbon atoms! a halogenated
alkyl group having 1 to 10 carbon atoms, a 10-camphoryl group; an amino group
which may be substituted with one or two alkyl groups having 1 to 10 carbon atoms;
or an aryl group (provided that the aryl group may be substituted with one or more
selected from alkyl groups having 1 to 10 carbon atoms, halogenated alkyl groups
having 1 to 10 carbon atoms, halogen atoms, cyano groups (-CN), amino groups,
alkylamino groups (-NR20R2 1), 5- or 6-membered cyclic amino groups, acylamino
groups (-NH-COR 20), hydroxyl groups, alkoxy groups ( R20), acyl groups (-C R20) ,
carboxyl groups, alkoxycarbonyl groups (-COOR20) , phenoxycarbonyl groups,
mercapto groups, alkylthio groups (-SR20), silyl groups (-SiR 0R2 R22), and nitro
groups (-NO2)),
R20, R2 1, and R22 each independently represent a hydrogen atom, an alkyl
group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon
atoms,
Y represents a hydrogen atom,
X represents a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy
group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a hydrogen atom,
or a halogen atom,
Q © represents a counter anion,
j and k each represent 0 or 1, provided that cases where j+k=l are excluded,
R2 and R3 each independently represent a hydrogen atom; an alkyl group
having 1 to 10 carbon atoms! a phenyl group (provided that the phenyl group may
be substituted with one or more selected from alkyl groups having 1 to 10 carbon
atoms, alkoxy groups having 1 to 10 carbon atoms, and halogen atoms); or a
cycloalkyl group having 3 to 8 carbon atoms, or R2 and R3 may together form a ring,
R11, R12, R13, R14, and R15 each independently represent a hydrogen atom, an
alkyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon
atoms,
R16, R17, R18, and R1 each independently represent a hydrogen atom, a
hydroxyl group, an alkyl group having 1 to 10 carbon atoms, or an alkoxy group
having 1 to 10 carbon atoms, or R16, R17 , and the carbon atom to which R16 and R17
are bonded and/or R18, R19 , and the carbon atom to which R18 and R19 are bonded
may form a carbonyl group(s),
Z represents an oxygen atom, a sulfur atom, or a methylene,
ni represents 1 or 2, and represents any integer of 1 to 3, and
each * indicates an asymmetric carbon atom (provided that when R2 and/or
R3 is/are a hydrogen atom(s), the carbon atom to which the hydrogen atom is bonded
is not an asymmetric carbon atom)),
the b-keto-ci-aminocarboxylic acid ester is represented by the following
general formula (2) ·
( 2 )
(where
R23 represents a hydrocarbon group which has 11 to 21 carbon atoms and
which may be substituted with one or more hydroxyl groups,
R24 represents a hydrogen atom or a hydrocarbon group having 1 to 10
carbon atoms, and
R25 and R26, which may be the same or different, each represent a hydrogen
atom, an alkyl group which has 1 to 10 carbon atoms and which may be substituted
with one or more selected from halogen atoms and hydroxyl groups, an acyl group
which has 1 to 24 carbon atoms and which may be substituted with one or more
selected from halogen atoms and hydroxyl groups, or an amino-protecting group, or
R25 and R26 may form, together with the adjacent nitrogen atom, a heterocycle
which may be substituted with one or more hydroxyl groups), and
the optically active b-hydroxyu-aminocarboxylic acid ester is represented
by the following general formula (3) or (4)·
(where
each * indicates an asymmetric carbon atom, and
R23, R24, R25, and R26 are the same as those described above).
2. The production method according to claim 1, wherein formic acid is used as
the hydrogen donor.
3. The production method
carried out in the coexistence of a base.
4. The production method according to any one of claims 1 to 3, wherein the
base used for carrying out the asymmetric reduction reaction is an organic amine
having 3 to 30 carbon atoms.
5. The production method according to any one of claims 1 to 4, wherein a
major product of the optically active b-hydroxy-a-aminocarboxylic acid ester is a
(2R,3R) isomer represented by general formula (4),
the formation ratio (2R,3R) isomer (2S,3R) isomer is 85^15 to 100 ; and
the reaction is completed within a reaction time of 10 hours.
6. The production method according to any one of claims 1 to 4, wherein a
major product of the optically active b-hydroxy-a-aminocarboxylic acid ester is a
(2R,3R) isomer represented by general formula (4),
the formation ratio (2R,3R) isomer :(2S,3R) isomer is 85:15 to 100 0; and
the reaction is completed within a reaction time of 20 hours when the molar
ratio of the ruthenium complex represented by general formula (l) to the
b-keto-a-aminocarboxylic acid ester represented by general formula (2) is 1/500 to
1/10000.
7. The production method according to any one of claims 1 to 5, wherein the
molar ratio of the ruthenium complex represented by general formula (l) to the
b-keto-c -aminocarboxylic acid ester represented by general formula (2) is 1/250 to
1/10000.
8. The production method according to any one of claims 4 to 6, wherein at
least one of triethylamine, tributylamine, and diisopropylethylamine is used as the
organic amine.