TECHNICAL FIELD
[0001] The present invention relates to a method for producing an optically active
alcohol compound.
BACKGROUND ART
[0002] It is conventionally known that optically active alcohol compounds have
been used as production intermediates for pharmaceuticals, agricultural chemicals, and
15 electronic materials. In particular, 3-amino-1 -(3-alkoxy)phenylpropan-1 -ol derivatives
of Formula (1) have been known as important compounds for medical products for eye
disease (for example, see Patent Document!).
X)'
(1)
[0003] As the method for producing the compound (I) , a method for producing
20 3-amino-l-(3-alkoxy) phenylpropan-1-ol derivatives by carrying out a reduction reaction
of 3-amino-l-(3-alkoxy)phenylpropan-l-one of Formula (2) in the presence of an
asymmetric reduction catalyst such as (-)-B-chlorodiisopinocampheylborane[(-)-DIPCl]
has been known (for example, refer to Patent Document 1).
° T 2)DBU f i U I
O k/i OH
(2) (1)
25 (in the above formula, Fmoc is 9-fluorenylmethyloxycarbonyl, DIPEA is
2
N,N-diisopropylethylamine, and DBU is diazabicycloundecene.)
Prior Art Documents
Patent Documents
[0004] Patent Document 1: International Publicaiton WO 2009/045479
5 Pamphlet
SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
10 [0005] In the method described in Patent Document 1, the stereoselectivity of the
compound of Formula (1) obtained from the reduction reaction of the compound of
Formula (2) is 96.1 ;3.9. This selectivity is insufficient for using the compound of
Formula (1) as a medical product. An additional operation for improving the optical
purity is required and thus this method is hardly an industrially suitable production
15 method.
Means for Solving the Problem
[0006] In view of the above circumstances, the inventors of the present invention
have extensively studied for a purpose of providing industrially useful production method
of the optically active alcohol compound in higher yield and higher selectivity. As a
20 result, the inventors of the present invention have found a production method in which
the optically active alcohol compound can be obtained in extremely high stereoselectivity
and high yield and have accomplished the present invention.
[0007] Namely, the present invention relates to the following aspects [1] to [21].
[1]
25 A method for producing an optically active alcohol compound of Formula (8):
(8) OH
[in the formula, R1 is a hydrogen atom, Ci.6 alkyl, (C[-6) alkyl optionally substituted with
R3, -C(0)Rs, or -Si(RI2a)(Rl2b)R12; and
R2 is cyano or -CH2N(R5)R4;
R is Ci-6 alkoxy, phenyl, or C3.8 cycloalkyl;
R4 is a hydrogen atom, -C(0)R6, or -C(0)OR7;
5 R5 is a hydrogen atom or C\.s alkyl, or R optionally forms a 5- to 7-membered ring
together with a nitrogen atom to which R4 and R5 are bonded by forming a C4.6 alkylene
chain together with R , and in this case the alkylene chain is optionally substituted with
one or more selected from the group consisting of C[-6 alkyl, {C\.e) alkyl optionally
substituted with Y, phenyl, and an oxo group, or the alkylene chain optionally forms
10 phenyl together with carbon atoms to which two substituents each bond when the two
substituents exist at adjacent positions on the alkylene chain;
R6 is Cj-6 alkyl, (Ci-6) alkyl optionally substituted with a halogen atom, or phenyl;
R7 is C1.6 alkyl or-CH2R13;
R is a hydrogen atom, Cj.6 alkyl, (Ci-e) alkyl optionally substituted with a halogen
15 atom, phenyl, or phenyl substituted with (Z)p;
R12, R12a, and Rt2b each are independently Ci-6 alkyl or phenyl;
R is phenyl or 9-fluorenyI;
Y is a halogen atom;
Z is a halogen atom or Ci-6 alkoxy; and
20 p is an integer of 1,2, 3, 4, or 5];
the method characterized by comprising the step of:
reacting a compound of Formula (3):
(3) O
(in the formula, R1 and R2 are the same meaning as Formula (8));
25 with a reducing agent in the presence of an optically active ruthenium catalyst selected
from the group consisting of a compound of Formula (4):
OCH;
Ar2
^ //
H3Cd (4)
(in the formula, Ar is 3,5-dimethylphenyI), a compound of Formula (5):
-OCH3
OCH3
(in the formula, Ar is 3,5-dimethylphenyl), and a compound of Formula (6):
H3Q
H2 fc|
(6)
(in the formula, Ts is paratoluenesulfonyl) or an optically active oxazaborolidine
compound of Formula (7),
12]
The method for producing the optically active alcohol compound described in the
aspect [1], in which
1 1 X
R is a hydrogen atom, (Cj-e) alkyl optionally substituted with R , -C(0)R -, or
5
-Si(RI2a)(RI2b)R12.
[3]
The method for producing the optically active alcohol compound described in the
aspect [2], in which the reaction is carried out in the presence of the optically active
5 ruthenium catalyst of Formula (4).
[4]
The method for producing the optically active alcohol compound described in the
aspect [3], in which
R2 is -CH2N(R5)R4;
10 R4 is -C(0)R6 or -C(0)OR7;
R6 is Ci-6 alkyl or (Ci-e) alkyl optionally substituted with a halogen atom; and
R8 is a hydrogen atom, C\.$ alkyl, or (Ci-6) alkyl optionally substituted with a
halogen atom.
[5]
15 The method for producing the optically active alcohol compound described in the
aspect [4], in which
R1 is (Cw) alkyl optionally substituted with R3, or ~Si(RI2a)(R12b)R12;
R2 is -CH2N(R5)R4;
R3 is phenyl, or C3.8 cycloalkyl;
20 R4 is -C(0)R6 or -C(0)OR7;
R5 is a hydrogen atom, or R5 optionally forms a 5-membered ring together with a
nitrogen atom to which R4 and R5 are bonded by forming a C4 alkylene chain together
with R4, and in this case the alkylene chain is optionally substituted with an oxo group, or
the alkylene chain optionally forms phenyl together with the carbon atoms to which two
25 substituents each bond when the two substituents exist at adjacent positions on the
alkylene chain;
R6 is (Cj-6) alkyl optionally substituted with a halogen atom; and
R13 is 9-fluorenyI.
[6]
6
The method for producing the optically active alcohol compound described in the
aspect [5], in which
R1 is (Ci-e) alkyl optionally substituted with R3;
R3 is C3.8 cycloalkyl;
5 R4 is -C(0)OR7;
R5 is a hydrogen atom; and
R7 is Q.6 alkyl.
[7]
The method for producing the optically active alcohol compound described in any
10 one of the aspects [3] to [6], in which the reducing agent is hydrogen gas.
[8]
The method for producing the optically active alcohol compound described in the
aspect [2], in which the reaction is carried out in the presence of the optically active
ruthenium catalyst of Formula (6).
15 [9]
The method for producing the optically active alcohol compound described in the
aspect [8], in which
R6 is Ci-6 alkyl or (C].6) alkyl optionally substituted with a halogen atom.
[10]
20 The method for producing the optically active alcohol compound described in the
aspect [9], in which
R is a hydrogen atom, (Ci-6)aikyl optionally substituted with R , -C(0)R , or
-Si(R12a)(R12b)R!2;
R5 is a hydrogen atom, or R5 optionally forms a 5-membered ring together with a
25 nitrogen atom to which R4 and R5 are bonded by forming a C4 alkylene chain together
with R4, and in this case the alkylene chain is optionally substituted with an oxo group, or
the alkylene chain optionally forms phenyl together with the carbon atoms to which two
substituents each bond when the two substituents exist at adjacent positions on the
alkylene chain;
7
R6 is (Cj-6) alkyl optionally substituted with a halogen atom;
R7isCi.6alkyl;
R8 is phenyl; and
R13 is 9-fluorenyl.
5 [11]
The method for producing the optically active alcohol compound described in the
aspect [10], in which
R1 is Ci-6 alkyl optionally substituted with R3;
R2 is cyano; and
10 R3 is C3.8 cycloalkyl.
[12]
The method for producing the optically active alcohol compound described in any
one of the aspects [8] to [11], in which the reducing agent is formic acid.
[13]
15 A compound of Formula (3'):
R i 0 — ^ Y R2
(3') O
(in the formula, R is C| alkyl substituted with R ;
R2 is cyano; and
R3 is cyclohexyl).
20 [14]
A method for producing a compound of Formula (3"):
(3") O
(in the formula, R1 is a cyclohexylmethyl group; and
R2 is -CH2NHC(0)0(C4H9-t) or -CH2NHC0CF3);
25 the method characterized by comprising the step of:
reacting an alcohol compound of Formula (44):
R'O
(in the formula, R and R are the same meaning as Formula (3")) with an oxidizing
agent in the presence of N-hydroxy-2-azaadamantane of Formula (43):
5 (43)
[15]
The method for producing the optically active alcohol compound described in any
one of the aspects [1] to [12], in which
R1 is methyl substituted with one R3; and
10 R3 is cyclohexyl.
[16]
The method for producing the optically active alcohol compound described in any
one of the aspects [1] to [12], in which
R1 is methyl substituted with one R3; and
15 R3 is phenyl.
[17]
The method for producing the optically active alcohol compound described in any
one of the aspects [1] to [12], in which
R1 is -Si(RI2a)(R12b)R12.
20 [18]
The method for producing the optically active alcohol compound described in any
one of the aspects [1] to [12], in which
R is methyl substituted with one R ; and
9
R3 is Ci-6 alkoxy.
[19]
The method for producing the optically active alcohol compound described in any
one of the aspects [1] to [12], in which
5 R2 is -CH2N(R5)R4;
R4 is -C(0)R6 or -C(0)OR7;
R5 is a hydrogen atom;
R6 is (Ci-6) alkyl optionally substituted with a halogen atom; and
R7 is C,.6 alkyi.
10 [20]
The method for producing the optically active alcohol compound described in any
one of the aspects [1] to [12], in which
R iscyano.
[21]
15 The method for producing the optically active alcohol compound described in any
one of the aspects [1] to [12], in which
R2 is cyano or -CH2N(R5)R4.
Effects of the Invention
[0008] According to the present invention, the optically active alcohol
20 compound of Formula (8) that is useful as medical products can be produced in high
selectivity and in large amounts and thus the present invention has a high utility value as
an industrial production method.
MODES FOR CARRYING OUT THE INVENTION
25
[0009] Hereinafter, the present invention will be described in further detail.
In this specification, "n-" means normal; "i-" means iso; "s-" means secondary; "t-"
or "-t" means tertiary; "c-" means cyclo, "o~" means ortho; "m-" means meta; "p-" means
para; "Bu" means butyl; "Bz" means benzoyl; "Bn" means benzyl; "Fmoc" means
10
9-fluorenylmethyloxycarbonyI; "Boc" means tert-butoxycarbonyl; "TBS" means a
tert-butyldimethylsilyl group; "DBU" means diazabicycloundecene; and "MOM" means
methoxymethyl.
In this specification, the compound of Formula (X) is described in an abbreviated
5 manner as the "compound (X)".
[0010] Specific examples of each substituent described in this specification are
described below.
In this specification, Ca.b alkyl is a linear or branched hydrocarbon group in which
the number of carbon atoms is a to b. Specific examples of the Ca-b alkyl may include
10 methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group,
t-butyl group, s-butyl group, n-pentyl group, l-methylbutyl group, 2-methylbutyl group,
3-methylbutyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl
group, neopentyl group, n~hexyl group, 1 -methylpentyl group, 2-methylpentyl group,
3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group,
15 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group,
2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethyIbutyl group,
1,1,2-uimethylpropyI group, 1-ethyl-l-methylpropyl group, 1 -ethyl-2-methylpropyl
group, 1-heptyl group, 1-octyl group, 1-nonyl group, 1-decanyl group, 1-undecanyl group,
and 1-dodecanyl group. The group is selected in a range of the specified number of
20 carbon atoms.
In this specification, Ca-b cycloalkyl is a cyclic hydrocarbon group in which the
number of carbon atoms is a to b, and a single ring structure or a multi-ring structure can
be formed. Each ring may be optionally substituted with an alkyl group in a range of
the specified carbon number. Specific examples of the Ca-b cycloalkyl may include
25 cyclopropyl group, 1 -methylcyclopropyl group, 2-methylcyclopropyl group,
2,2-dimethyl-cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl
group. The group is selected in a range of the specified number of carbon atoms.
In this specification, Ca.b alkoxy is an alkyl-O- group, in which the alkyl is the same
meaning as described above and the number of carbon atoms is a to b. Specific
11
examples of the Ca-b alkoxy may include methoxy group, ethoxy group, n-propyloxy
group, i-propyloxy group, n-butyloxy group, s-butyloxy group, i-butyloxy group,
t-butyloxy group, n-pentyloxy group, and n-hexyloxy group. The group is selected in a
range of the specified number of carbon atoms.
5 [0011] In this specification, (Ca.b) alkyl optionally substituted with R is an alkyl
group having the number of carbon atoms of a to b, having the same meaning as
described above, and formed by substituting the hydrogen atom bonded to the carbon
atom with an optional substituent R3 at any position and any number. The group is
selected in a range of the specified number of carbon atoms. In this case, when two or
10 moreofthesubstituentsR exist on each (Ca.b) alkyl group, each R may be the same as
or different from each other.
[0012] In this specification, -N(R5)R4 described by "R5 optionally forms a 5- to
7-membered ring together with a nitrogen atom to which R4 and R5 are bonded by
forming a C4.6 aikylene chain together with R , and in this case, the aikylene chain is
15 optionally substituted with one or more selected from the group consisting of Ci-g alkyl,
(Cj-s) alkyl optionally substituted with Y, phenyl, and an oxo group, or the aikylene chain
optionally forms phenyl together with the carbon atoms to which two substituents each
bond when the two substituents exist at adjacent positions on the aikylene chain" may
include the following groups.
CN* 0
20
*N
[0013] The method for producing the optically active alcohol compound (8) made
from the compound (3) as the starting material in the present invention will be described
in detail.
12
R10 R10
(3) (8)
[0014] (i) The optically active alcohol compound (8) (in the formula, R and R
mean the same as the formula described above) can be synthesized by reacting the
compound (3) (in the formula, R1 and R2 are the same meaning as the formula described
above) with the reducing agent in the presence of the asymmetric reduction catalyst.
As the usable asymmetric reduction catalyst, for example, an optically active
ruthenium catalyst can be used. Preferable examples of the optically active ruthenium
may include commercially available RUCY (registered trademark)-XylBINAP (sold by
TAKASAGO INTERNATIONAL CORPORATION) of Formula (4):
X>CH3
10 H3Cd (4)
(in the formula, Ar is 3,5-dimethylphenyl) or RuCi2[(S)-xyIbinap][(S)-daipen] (sold
by TAKASAGO INTERNATIONAL CORPORATION) of Formula (5):
Ct
OCH<
OCH3
(in the formula, Ar is 3,5-dimethyIphenyl).
15 The amount of the asymmetric reduction catalyst to be used is 1/100,000 moI% to
100 mol% and preferably 0.01 moI% to 5 moI% relative to the compound (3).
13
[0015] A base can be added for the reaction. Examples of the base to be used
may include alkali metal salts of alcohols. Specific Examples of the alkali metal salts of
alcohols may include CH3ONa, C2H5ONa, and t-BuOK and t-BuOK is the most
preferable.
5 The amount of the base to be added may be the same amount or more relative to the
asymmetric reduction catalyst to be used and is preferably 10 to 20 equivalents relative to
the catalyst.
[0016] The solvent used for the reaction is not limited as long as the solvent does
not inhibit the reaction progress. Examples of the solvent may include water, aprotic
10 polar organic solvents (such as N,N-dimethylformamide, dimethylsulfoxide,
N,N-dimethylacetamide, tetramethylurea, sulfoiane, N-methyl-2-pyrrolidone, and
N,N-dimethyIimidazoIidinone), ether solvents (such as diethyl ether, diisopropyl ether,
t-butyl methyl ether, tetrahydrofuran, and dioxane), aliphatic hydrocarbon solvents (such
as pentane, n-hexane, c-hexane, octane, decane, decalin, and petroleum ether), aromatic
15 hydrocarbon solvents (such as benzene, chlorobenzene, o-dichlorobenzene, nitrobenzene,
toluene, xylene, mesitylene, and tetralin), halogenated hydrocarbon solvents (such as
chloroform, dichloromethane, dichloroethane, and carbon tetrachloride), lower aliphatic
acid ester solvents (such as methyl acetate, ethyl acetate, butyl acetate, and methyl
propionate), alkoxy alkane solvents (such as dimethoxyethane and diethoxyethane),
20 alcohol solvents (such as methanol, ethanol, 1-propanol, and 2-propanol), and carboxylic
acid solvents (such as acetic acid). Among them, the alcohol solvents are preferable.
The alcohol solvents to be used may be used singly or in combination of two or more of
them. The mixture of ethanol and 2-propanol is preferably used. The mixture can be
used in any mixing ratio and the most preferable mixing ratio is ethanol:2-porpanol = 1:1
25 in a mass ratio.
[0017] The reaction temperature is preferably about 10°C to about 40°C and more
preferably about 20°C to about 30°C.
[0018] The reducing agent that can be used in this reaction is not particularly
limited as long as the reducing agent is used as a reagent. Examples of the reducing
14
agent may include hydrogen gas.
The reaction can be carried out at any hydrogen pressure. The preferable hydrogen
pressure is in a range of 0.1 MPa to 1.0 MPa and more preferably 0.5 MPa.
[0019] (ii) The optically active alcohol compound (8) can be synthesized by
5 reacting the compound (3) with the reducing agent in the presence of a hydrogen transfer
type asymmetric reduction catalyst.
Examples of the hydrogen transfer type asymmetric reduction catalyst that can be
used in the reaction may include commercially available RuCl[(R,R)-Tsdpen](p-cymene)
(sold by KANTO CHEMICAL CO., INC.) of Formula (6).
HA
The amount of the hydrogen transfer type asymmetric reduction catalyst to be used
is 1/100,000 moi% to 100 moI% and preferably 0.01 mol% to 20 mol% relative to the
compound (3).
[0020] In this reaction, hydrogen gas is not required to be fed as the reducing
15 agent and a reaction reagent can be used as a hydrogen source. Examples of the
reaction reagent to be the hydrogen source may include a mixed solution of formic acid
and triethylamine, and 2-propanol. In this reaction, the mixed solution of formic acid
and triethylamine is preferable. The amount of formic acid and triethylamine to be used
may be any amount relative to the compound (3). Formic acid may be used in an
20 amount of 3 equivalents to 9 equivalents, and triethylamine may be used in an amount of
2 equivalents to 8 equivalents. The most desirable amounts are 3.1 equivalents of
formic acid and 5.2 equivalents of triethylamine.
[0021] The mixed solution of formic acid and triethylamine described above can
be also used as a reaction solvent. Another solvent, however, can be added and used as
25 long as this solvent does not inhibit the reaction progress. This solvent is not
particularly limited and examples of this solvent may include water, aprotic polar organic
15
solvents (such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide,
tetramethylurea, sulfolane, N-methyl-2-pyrrolidone, and N,N-dimethylimidazolidinone),
ether solvents (such as diethyl ether, diisopropyl ether, t-butyl methyl ether,
tetrahydroforan, and dioxane), aliphatic hydrocarbon solvents (such as pentane, n-hexane,
5 c-hexane, octane, decane, decalin, and petroleum ether), aromatic hydrocarbon solvents
(such as benzene, chlorobenzene, o-dichlorobenzene, nitrobenzene, toluene, xylene,
mesityiene, and tetralin), haiogenated hydrocarbon solvents (such as chloroform,
dichloromethane, dichloroethane, and carbon tetrachloride), lower aliphatic acid ester
solvents (such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate), and
10 alkoxy alkane solvents (such as dimethoxyethane and diethoxyethane). In this reaction,
the solvent to be used is preferably the aprotic polar organic solvents. Among them,
dimethylformamide is the most preferable. The amount of the solvent to be used can be
any amount. The most appropriate amount is an amount two times larger than the
amount of the compound (3) in mass.
15 [0022] The reaction temperature is preferably 20°C to 30°C.
[0023] (iii) The optically active alcohol compound (8) can be synthesized by
reacting the compound (3) with the reducing agent in the presence of an optically active
oxazaborolidine compound.
Examples of the usable optically active oxazaborolidine compound may include a
20 commercially available optically active oxazaborolidine compound of Formula (7).
The amount of the optically active oxazaborolidine compound to be used 1/100,000
mol% to 100 mol% and preferably 1 moI% to 30 mol% relative to the compound (3).
[0024] The reducing agent that can be used in this reaction is not particularly
25 limited as long as the reducing agent is used as a reagent. Examples of the reducing
16
agent may include a borane-dimethylsulfide complex and a borane-tetrahydrofuran
complex.
The amount of the reducing agent to be used may be any amount of 0.6 equivalent to
2 equivalents relative to the compound (3).
5 [0025] The solvent used for the reaction is not limited as long as the solvent does
not inhibit the reaction. Examples of the solvent may include ether solvents (such as
diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, and dioxane),
aliphatic hydrocarbon solvents (such as pentane, n-hexane, c-hexane, octane, decane,
decalin, and petroleum ether), aromatic hydrocarbon solvents (such as benzene,
10 chlorobenzene, o-dichlorobenzene, nitrobenzene, toluene, xylene, mesitylene, and
tetralin), and halogenated hydrocarbon solvents (such as chloroform, dichloromethane,
dichloroethane, and carbon tetrachloride). The aromatic hydrocarbon solvents are
preferable and, among them, toluene is the most preferable.
[0026] With respect to the reaction temperature, the reaction can be carried out at
15 any temperature of-50°C to 40°C. In the present invention, however, the reaction
temperature is preferably about 20°C.
[0027] With respect to the production method of the invention in the present
specification, the compound (3), which is a ketone derivative used for the reduction
reaction, includes known compounds. Although some of the ketone derivatives can be
20 obtained as reagents, the method for producing the compound (3) will be described
below.
[0028] Among the compounds (3), a method for synthesizing the following
specific compound (14) will be described below.
( 1 4 )
25 [0029] The compound (14) can be synthesized by oxidizing the compound (13)
being the known compound.
[0030] As described below, for example, a method of using an oxidizing agent in
the presence of potassium 2-iodo-benzenesulfonate (9) as an oxidation catalyst can be
5 selected as the method.
FT ^ ^ S O gK
(9)
(In the formula, R is a hydrogen atom or Ci-io aikyl)
[0031 ] The substituent R in potassium 2-iodo-benzenesulfonate (9) is desirably a
hydrogen atom or a methyl group. Potassium 2-iodo-benzenesulfonate (9) is a known
10 compound and some of the compounds can be obtained as a reagent from JUNSEI
CHEMICAL CO., LTD. or other suppliers.
Potassium 2-iodo-benzenesulfonate (9) is preferably used in a range of an amount of
0.01 mol% to 20 mol% relative to the compound (13).
[0032] The oxidizing agent is not particularly limited as long as the oxidizing
15 agent can oxidize the iodine group of the compound (9) to pentavalent iodine. The
oxidizing agent may be either an inorganic oxidizing agent or an organic oxidizing agent.
In the present invention, among them, potassium monopersulfate compound salt
[OXONE (registered trademark)] is preferable. The amount of OXONE (registered
trademark) to be used is not particularly limited. In the present invention, the amount is
20 preferably 1.5 to 2.0 times larger in mole than the amount of the compound (13).
[0033] With respect to the reaction temperature of the oxidation reaction, the
reaction can be carried out at 20°C to 100°C as needed. In the present invention, the
reaction temperature is more preferably 70°C.
[0034] The solvent used for the oxidation reaction is not limited as long as the
18
solvent does not inhibit the reaction progress. Examples of the solvent may include
ether solvents (such as diethyl ether, diisopropyl ether, t-butyl methyl ether,
tetrahydrofuran, and dioxane), aliphatic hydrocarbon solvents (such as pentane, n-hexane,
c-hexane, octane, decane, decalin, and petroleum ether), aromatic hydrocarbon solvents
5 (such as benzene, chlorobenzene, o-dichlorobenzene, nitrobenzene, toluene, xylene,
mesitylene, and tetralin), halogenated hydrocarbon solvents (such as chloroform,
dichloromethane, dichloroethane, and carbon tetrachloride), ketone solvents (such as
acetone, methyl ethyl ketone, methyl butyl ketone, and methyl isobutyl ketone), lower
aliphatic acid ester solvents (such as methyl acetate, ethyl acetate, butyl acetate, and
10 methyl propionate), alkoxy alkane solvents (such as dimethoxyethane and
diethoxyethane), and nitrile solvents (such as acetonitrile, propionitrile and butyronitrile).
Among them, for example, ethyl acetate and acetonitrile are preferable.
[0035] Some of the compounds (3) except the compound (14) are known
compounds that are available as reagents. The other compounds of the compound (3)
15 can also be synthesized in accordance with the method described above.
[0036] Among the compounds (3), for example, a method for producing the
compound (2), in which R is a cyclohexylmethyl group and R is a CFhNHFmoc group,
is described in Patent Document 1. More specifically, the compound (2) can be
produced by the reaction using a manganese compound as an oxidizing agent to the
20 compound (42). The compound (2) can also be produced from the compound (42) by
the reaction using oxidizing agent in the presence of the N-hydroxyl compound of
Formula (43).
OH K^J O
<42) (2>
(43)
19
[0037] The N-hydroxyl compound (43) can be obtained as AZADOL [(registered
trademark), sold by Wako Pure Chemical Industries, Ltd.] being the commercial product.
The amount of the N-hydroxyl compound (43) to be used is preferably 0.1 mol% to
50 mol% and more preferably 1 mol% to 10 mol% relative to the alcohol compound
(compound (42)) being the substrate.
[0038] Examples of the oxidizing agent in the above reaction may include organic
or inorganic compounds containing an oxygen atom. Typical examples may include
peroxygen acids such as peracetic acid, hydrogen peroxide (H202), hypohalites, halites,
halides, diacetoxyiodoallenes, oxygen, or a combination thereof. Alkali metal
hypohalites and alkaline earth metal hypohalites are preferable as the hypohalites and
examples of the hypohalites may include LiOCl, NaOCI, KOC1, LiOBr, NaOBr, and
KOBr. Specifically, the oxidizing agent is preferably the alkali metal hypohalite.
Among them, sodium hypochlorite (NaOCI) is preferable in the present invention.
[0039] With respect to the reaction temperature, the reaction can be carried out at
room temperature. The reaction, however, can be carried out at a temperature in a range
of 10°C to 40°C, in a range of 0°C to 100°C, and at -10°C to 200°C as needed. With
respect to the reaction pressure, normal pressure (atmospheric pressure) can be sufficient
for the reaction. The reaction, however, can be carried out in a reduced pressure state
and a pressurized state in a range of 0.01 MPa to 10 MPa.
The reaction time is 1 minute to 100 hours and preferably 5 minutes to 24 hours.
[0040] The solvent used for this oxidation reaction is not limited as long as the
solvent does not inhibit the reaction progress. Examples of the solvent may include
water, aprotic polar organic solvents (such as dimethylformamide, dimethylsulfoxide,
dimethylacetamide, tetramethylurea, sulfolane, N-methyl-2-pyrrolidones and
N,N-dimethyl imidazolidinone), ether solvents (such as diethyl ether, diisopropyl ether,
t-butyl methyl ether, tetrahydrofuran, and dioxane), aliphatic hydrocarbon solvents (such
as pentane, hexane, c-hexane, octane, decane, decalin, and petroleum ether), aromatic
hydrocarbon solvents (such as benzene, chlorobenzene, o-dichlorobenzene, nitrobenzene,
toluene, xylene, mesitylene, and tetralin), halogenated hydrocarbon solvents (such as
20
chloroform, dichloromethane, dichloroethane, and carbon tetrachloride), ketone solvents
(such as acetone, methyl ethyl ketone, methyl butyl ketone, and methyl isobutyl ketone),
lower aliphatic acid ester solvents (such as methyl acetate, ethyl acetate, butyl acetate,
and methyl propionate), alkoxy alkane solvents (such as dimethoxyethane and
5 diethoxyethane), nitrile solvents (such as acetonitrile, propionitrile and butyronitrile), and
carboxylic acid solvents (such as acetic acid). Among them, for example, toluene is
preferable.
[0041] To the reaction liquid mixture, a buffering agent such as an inorganic salt
or an organic salt can be added. Examples of the buffering agent to be used may include
10 carbonates of alkali metals or alkaline earth metals, hydrogen carbonates of alkali metals
or alkaline earth metals, hydroxides of alkali metals or alkaline earth metals, and
phosphates of alkali metals or alkaline earth metals. The buffering agent is desirably the
hydrogen carbonates of alkali metals or alkaline earth metals.
[0042] When toluene is used as the reaction solvent, an aqueous solution of
15 sodium hypochlorite being an oxidizing agent can be used and oxidation can be carried
out in a two-phase reaction system.
Examples
[0043] Hereinafter, the present invention will be more specifically described with
reference to Examples and Comparative Examples. The present invention, however, is
20 not limited to the following Examples. The following devices and conditions were used
for measurements using nuclear magnetic resonance spectrum (!H-NMR), liquid
chromatography (LC), and liquid chromatography-mass measurement spectrometry
(LC-MS),
"OXONE" used in Examples is a "potassium monopersulfate compound salt" and
25 registered trademark.
In the description of Examples, for example, a "solution of 10 g of a compound (X)
in 100 g of an organic solvent" means the solution in which 10 g of the compound (X) is
dissolved or dispersed in 100 g of the organic solvent.
[0044] [I] 'H-NMR
21
Model: AVANCE III 500 (manufactured by BRUKER Corporation, 500 MHz)
Measurement solvent: CDCI3
[2] LC (liquid chromatography)
(1) LC conditions example 1: Method name LC-1 (used for measurement of conversion
5 of reaction and quantitative analysis)
LC: Shimadzu 20A (manufactured by Shimadzu Corporation)
Column: YMC-Pack Pro CI8 RS
250 x 4.6 mm, I. D. 5 urn
Oven Temperature: 30°C
10 Eluent: CH3CN, H20
CH3CN = 10% (0 min.) -» 100% (15 min.) -> 100% (25 min.) -> 10% (25.01 min.)
~> 10% (30 min.)
Time program in the parentheses is a total time from the start of analysis.
Flow rate: 1.2mL/min.
15 Detector: UV 210 nm
(2) LC conditions example 2: Method name LC-2 (used for analysis of optical purity)
LC: Agilent 1200 (manufactured by Agilent Technologies Co., Ltd.)
Column: CHIRALPAKIA
250 x 4.6 mm, I. D. 5 urn
20 Oven Temperature: 25°C
Eluent: Heptane/EtOH/ethanesulfonic acid = 95/5/0.1 (v/v/v)
Flow rate: 1 mL/min.
Detector: UV 210 nm
(3) LC conditions example 3: Method name LC-3 (used for analysis of optical purity)
25 LC: Agilent 1200
Column: CHIRALPAK IA
250 x 4.6 mm, I. D. 5 um, two columns are connected
Oven Temperature: 25°C
Eluent: Heptane/EtOH/Trifluoroacetic acid = 96/4/0.1 (v/v/v)
22
Flow rate: 1 mL/min.
Detector: UV 210 nm
(4) LC conditions example 4: Method name LC-4 (used for analysis of optical purity)
LC: Agilent 1200
5 Column: CHIRALPAKIA
250 x 4.6mm, I. D. 5 pm
Oven Temperature: 25°C
Eluent: Heptane/EtOH/Ethanesulfonic acid - 90/10/0.1 (v/v/v)
Flow rate: 1 mL/min.
10 Detector: UV 210 nm
[3] LC-MS
LC-MS: Waters 2695, MICROMASS QUATTRO MICRO API
Eluent: CH3CN, 5 mM ammonium acetate aqueous solution
With respect to the analytical conditions, the analysis was carried out in the same
15 method as LC-1 except Eluent.
[0045] Example 1: Synthesis of compound (11)
r^Y^O^^Y^-"NH8ot; ~ * f
/ V N o ^ l N ' / u - -V ^ N H e o c
(10) (11)
[0046] The solution of 40 g of the compound (10) synthesized in accordance with
the method described in Patent Document 1 in 400 g of toluene was cooled to 0°C.
20 After completion of the cooling, 1.7 g ofN-hydroxy-2-azaadamantane [AZADOL
(registered trademark), sold by Wako Pure Chemical Industries, Ltd.] was added to the
reaction solution. After completion of the addition, the reaction solution was stirred at
the same temperature for 5 minutes. After completion of the stirring, 241 g of 5% by
mass sodium hydrogen carbonate aqueous solution, and then 120 g of 14% by mass
25 sodium hypochlorite aqueous solution were added dropwise to the reaction solution at the
same temperature. After completion of the dropwise addition, the reaction solution was
continuously stirred for 1 hour at 10°C to 15°C. After completion of the stirring, 1.7 g
23
of N-hydroxy-2~azaadamantane [AZADOL (registered trademark), sold by Wako Pure
Chemical Industries, Ltd.] was added to the reaction solution at 15°C to 20°C. After
completion of the addition, 240 g of 5% by mass sodium hydrogen carbonate aqueous
solution, and then 120 g of 14% by mass sodium hypochlorite aqueous solution were
5 added dropwise to the reaction solution at 10°C to 15°C. After completion of the
dropwise addition, the reaction solution was stirred at 10°C to 15°C for 2 hours. After
completion of the stirring, the disappearance of the compound (10) being the starting
material was ascertained by LC, and thereafter, 500 g of 10% by mass sodium thiosulfate
aqueous solution and then 220 g of 3.7% by mass hydrochloric acid aqueous solution
10 were added dropwise at 7°C to 15°C to the reaction solution. After completion of the
dropwise addition, the reaction solution was stirred at 15°C to 20°C for 30 minutes, and
thereafter the organic phase was separated by a liquid separation operation. 420 g of
toluene was added to the aqueous phase obtained after the liquid separation, and the
resultant mixture was stirred for 10 minutes. Thereafter, the organic phase was
15 separated by the liquid separation operation. The obtained organic phases were
combined and 500 g of 10% by mass sodium hydrogen carbonate aqueous solution was
added. The resultant mixture was stirred for 10 minutes and the mixture was separated.
To the obtained organic phase, 500 g of water was added and the resultant mixture was
stirred for 30 minutes. Thereafter, the mixture was separated and 500 g of 20% by mass
20 sodium chloride aqueous solution was further added to the obtained organic phase and the
resultant mixture was stirred for 10 minutes, followed by separating the mixture. To the
obtained organic phase, 60 g of sodium sulfate was added and the resultant mixture was
stirred for 30 minutes, followed by filtering the mixture. Thereafter, the filtrate was
concentrated under reduced pressure to give 37.2 g of the crude product of the compound
25 (11) as a brown oily substance.
Analysis conditions of LC at the time of ascertainment of starting material
disappearance: LC-1
[0047] Purification of compound (11)
The crude product of the compound (11) obtained by the method described above
24
was purified by column chromatography in accordance with the following conditions.
20.6 g of the compound (11) in which the area percentage obtained by the LC
measurement is increased from 78% to 90% was obtained as a brown oily substance.
Column used: Hi-Flash Column, 40 urn, 60 A, 415 g
5 Gradient composition: n-hexane/ethyl acetate = 9/1 -> 7/1 -> 5/1 -» 3/1 (volume
ratio, the same applied hereafter).
Flow rate: 70 mL/min
[0048] The purified product obtained by column chromatography was purified by
recrystallization. The conditions of the recrystallization will be described below. To
10 20.6 g of the column chromatography-purified compound (11) obtained by the method
described above, 20.66 g of toluene and 122.4 g of n-hexane were added. After
completion of the addition, the slurry solution of the compound (11) was heated to 45°C
to completely dissolve the compound (11) in the solvent. When the temperature of the
solution reached 42°C, 5 mg of a seed crystal of the compound (11) was added. After
15 completion of the addition, occurrence of white turbidity in the solution was ascertained,
and thereafter the solution was cooled to 2°C over 30 minutes. After completion of the
cooling, the solution was stirred at 0°C to 2°C for 30 minutes. After completion of the
stirring, the precipitated crystal in the solution was separated by filtration operation to
give 13.9 g of the compound (11) as a white crystal. The yield from the compound (10)
20 was 67.6% and the area percentage obtained by the LC measurement was 97.5%.
As the seed crystal of the compound (11), the crystal obtained after separately
storing a part of the column chromatography-purified product in a frozen state at -15°C
for 12 hours was used.
'H-NMR of the compound (11) (500 MHz, ppm, in CDC13) 5: 1.00-1.10 (m, 2H),
25 1.19-1.25 (m, 1H), 1.25-1.35 (m, 2H), 1.40-1.50 (s, 9H), 1.68-1.75 (m, 1H), 1.75-1.85 (m,
3H), 1.85-1.90 (m, 2H), 3.16-3.21 (t, 2FI), 3.51-3.58 (dd, 2H), 3.78-3.82 (d, 2H),
5.10-5.20 (t, 1H), 7.09-7.12 (dd, 1H), 7.34-7.38 (dd, 1H), 7.44-7.48 (s, 1H), 7.49-7.53 (d,
1H)
LC-MS (ESI +) m/z: 362 (M+H+)
25
LC conditions: LC-1
[0049] Example 2: Asymmetric reduction reaction of compound (11)
O L. J OH
(113 ~ (12)
[0050] To the solution of 0.20 g of the compound (11) in 1.0 g of ethanol and 1.0
g of 2-propanoI, 6.5 mg of potassium tert-butoxide and 3.8 mg of (S)RUCY (registered
trademark)-XylBINAP (sold by TAKASAGO INTERNATIONAL CORPORATION
(compound of Formula (4)) were added. After completion of the addition, the inside of
the vessel of the reaction solution was purged with hydrogen gas, and thereafter the
reaction solution was stirred under a hydrogen pressure of 0.5 MPa at a reaction
temperature of 25°C for 1.5 hours. After completion of the stirring, the disappearance
of the starting material in the reaction solution was ascertained by LC. After completion
of the ascertainment, the reaction solution was concentrated under reduced pressure and
diluted with acetonitrile using a 25 mL measuring flask. As a result of the quantitative
analysis of the acetonitrile solution, the yield of the compound (12) was 99.7%. LC
analysis under LC-2 conditions provides a stereoselectivity of the reduction reaction of
100:0.
Analysis conditions of LC at the time of ascertainment of starting material
disappearance: LC-1
[0051] The quantitative analysis conditions of LC at the time of calculating the
yield of the compound (12) were in accordance with the method described below.
Standard substance: The purified compound (10) [racemic substance of compound
(12)] synthesized in accordance with the method described in Patent Document 1 was
used as the standard substance.
Purification method: The solution of 6.06 g of the compound (10) in 7.0 g of toluene
and 30 g of n-hexane was cooled to 0°C and stirred for 1 hour. After completion of the
stirring, the precipitated white crystal in the solution was separated by a filtration
operation. The obtained crystal was dried under reduced pressure to give 2.0 g of the
26
compound (10) as a white crystal. The area percentage of the obtained crystal by the
LC measurement was 99.2%.
LC conditions: LC-1
'H-NMR of the compound (10) (500 MHz, ppm, in CDC13) 5: 1.01-1.10 (m, 2H),
5 1.18-1.25 (m, IH), 1.25-1.35 (m, 2H), 1.41 (s, 9H), 1.68-1.73 (m, IH), 1.73-1.82 (m, 3H),
1.82-1.90 (m, 4H), 3.14-3.20 (m, 2H), 3.45-3.52 (m, IH), 3.73-3.78 (d, 2H), 4.69-4.74 (m,
IH), 4.85-4.94 (t, IH), 6.78-6.80 (d, IH), 6.88-6.94 (m, 2H), 7.20-7.30 (dd, IH)
LC-MS (ESI+) m/z: 386 (M+Na+)
[0052] The stereoselectivity of the compound (12) was calculated in accordance
10 with the method described below. That is, as a result of the analysis of the compound
(10) synthesized in accordance with the method described in Patent Document 1 by LC
under the LC-2 conditions, the peaks having retention times of 10.9 minutes and 14.2
minutes were ascertained. For the compound (12) obtained by the reaction, only the
peak having a retention time of 10.9 minutes was able to be ascertained.
15 [0053] The steric configuration of the obtained compound (12) was determined
by deriving the compound (12) into the compound (1) in accordance with the method
described below.
15 mL of the solution of the compound (12) obtained in Example 2 described above
acetonitrile [as a result of the quantitative analysis described above, the compound (12)
20 was contained in the solution in an amount of 60 mg] was concentrated under reduced
pressure. The obtained compound (12) was dissolved into 1.0 g of methylene chloride,
0.61 g of water, and 0.97 g of trifluoroacetic acid were further added to this solution.
After completion of the addition, the solution was stirred at 23°C for 1 hour. After
completion of the stirring, the solution was heated to 50°C and continuously stirred at the
25 same temperature for 2 hours. After completion of the stirring, the disappearance of the
compound (12) and generation of the compound (1) were ascertained by LC under LC-1
conditions. Thereafter, the reaction liquid was concentrated under reduced pressure and
the resultant residue was analyzed by LC under LC-2 conditions.
According to the description in Patent Document 1, the retention times of the
27
compound (1) (R form) and the enantiomeric isomer of the compound (1) (S form) each
analyzed by LC under LC-2 conditions are 29.485 minutes and 37.007 minutes,
respectively. It was previously ascertained that analysis of the racemic form of the
compound (1) synthesized in accordance with the method described in Patent Document
5 1 under the LC-2 conditions resulted in detection of the peaks of the compound (1) being
the R form having a retention time of 34.8 minutes and the enantiomeric isomer of S
form having a retention time of 40.7 minutes and the peak having a retention time of 34.8
minutes was the Compound (1). The configuration of the compound (1) was clarified to
be (R) because the retention time of the compound (1) obtained in Example 2 was 34.9
10 minutes.
[0054] Example 3: Synthesis of compound (14)
OH K^J O
(13) (14)
[0055] To the solution of 30.0 g of the compound (13) synthesized in accordance
with the method described in Patent Document 1 in 150 g of acetonitrile, 1.25 g of water,
15 403 mg of potassium 2-iodo-5-methylbenzenesulfonate and 60.7 g of OXONE (registered
trademark, potassium monopersulfate compound salt) were sequentially added at 20°C to
25°C. After completion of the addition, the reaction solution was stirred at 74°C for 4.5
hours. After completion of the stirring, 1.0 g of water, 200 mg of potassium
2-iodo-5-methylbenzenesulfonate, and 7.2 g of OXONE were sequentially added at the
20 same temperature to the reaction solution. After completion of the addition, the reaction
solution was continuously stirred at the same temperature for 4 hours. After completion
of the stirring, the disappearance of the compound (3) being the starting material was
ascertained by LC, and the reaction solution was cooled to 20°C. Thereafter, insoluble
substance in the reaction solution was separated by filtration with Celite. To the filtrate
25 obtained after the filtration, 1.0 g of water, 200 mg of potassium
2-iodo-5-methylbenzenesulfonate and 60 g of OXONE were sequentially added. After
completion of the addition, the reaction solution was stirred at 75°C for 3.5 hours. After
28
completion of the stirring, the reaction solution was cooled to 20°C, and thereafter
insoluble substance in the reaction solution was separated by filtration with Celite. The
filtrate obtained after the filtration was concentrated under reduced pressure. To the
obtained residue, 300 g of toluene, 60 g of water, and 2.0 g of sodium chloride were
5 added and after the resultant mixture was stirred for 60 minutes, the aqueous phase was
separated and disposed. To the obtained organic phase, sodium sulfate (30 g) was added
and the resultant mixture was stirred at 20°C for 1 hour, followed by separating the
mixture by filtration. The solvent in the obtained organic phase was distilled away
under reduced pressure to give 31.5 g of the crude product of the compound (14) as a
10 brown oily substance.
Analysis condition of LC at the time of ascertainment of starting material
disappearance: LC-1
[0056] Purification of compound (14)
The crude product of the compound (14) obtained by the method described above
15 was purified by column chromatography in accordance with the following conditions.
13.9 g of the compound (14) in which the area percentage obtained by the LC
measurement was increased from 56% to 97% was obtained as a brown crystal.
Column used: Hi-Flash Column, 40 urn, 60 A, 265 g
Gradient composition: n-hexane/ethyl acetate = 10/1 —> 8/1 -^ 5/1 -» 3/1 (flow rate
20 65 mL/min)
[0057] The compound (14) obtained by purifying with the column
'chromatography was further purified by recrystallization. Specifically, 13.3 g of the
column chromatography-purified compound (14) obtained by the method described
above was dissolved in 19.34 g of toluene at 60°C. After the dissolution, 18.62 g of
25 n-hexane was added to the solution. After completion of the addition, the solution was
cooled. When the internal temperature reached 40°C, 5 mg of the crystal of the
compound (14) obtained after separately storing a part of the column chromatography
purified product in a frozen state at -15°C for 12 hours was added as the seed crystal.
After completion of the addition, the solution was continuously cooled. When the
29
internal temperature reached 27°C, 15.47 g of toluene and 8.17 g of n-hexane were added.
After completion of the addition, the solution was further continuously stirred at about
20°C for 1 hour. After completion of the stirring, the crystal precipitated in the solution
was separated by filtration to give 7.74 g of the compound (14) as a white crystal. The
5 yield from the compound (13) was 24% and the area percentage obtained by the LC
measurement was 99.8%.
[0058] The obtained crystal was further purified with a preparative TLC.
Specifically, first, 0.40 g of the crystal of the compound (14) obtained by the method
described above was dissolved in 2 g of dichloromethane. Each half amount of the
10 solution was charged to the two preparative TLC plates (Merck Kieselgel 60 F254 20 x
20 cm, thickness 2 mm) and development was carried out two times with hexane/ethyl
acetate = 2/1 (volume ratio), 0.15 g of the compound (14) was obtained as a yellow
solid from the part whose Rf value is about 0.6 to about 0.7. The yield from the crystal of
the compound (14) was 38% and the area percentage of the obtained compound (14)
15 obtained by the LC measurement was 100%.
!H-NMR of compound (14) (500 MHz, ppm, in CDCI3) 5: 1.06-1.12 (dt, 2H),
1.20-1.25 (m, 1H), 1.28-1.35 (m,2H), 1.68-1.74 (m,2H), 1.75-1.80 (m, 1H), 1.80-1.85
(m, 1H), 1.85-1.91 (m, 2H), 3.79-3.85 (d, 2H), 4.48 (s, 2H), 7.16-7.20 (m, 1H), 7.38-7.45
(m, 3H)
20 LC-MS (ESI +) m/z: 275 (M+NH4+)
[0059] Example 4: Asymmetric reduction reaction of compound (14)
(15)
[0060] To a mixed solution of 80.5 mg of triethylamine, 22.7 mg of formic acid,
and 86.1 mg of N,N-dimethylformamide, 5.0 mg of RuCI[(R,R)-Tsdpen](p-cymene) (sold
25 by KANTO CHEMICAL CO., INC.) (the compound of Formula (6)) was added at 20°C.
After completion of the addition, 40.0 mg of the compound (14) was added to the
reaction solution at the same temperature. After completion of the addition, the reaction
30
solution was stirred at 30°C for 2 hours. After completion of the stirring, the
disappearance of the compound (14) in the reaction solution was ascertained by LC under
the LC-1 conditions, and thereafter the reaction liquid was diluted with acetonitrile using
a 20 mL measuring flask. As a result of the quantitative analysis of the acetonitrile
5 solution by LC, the yield of the compound (15) was 99.3%. [0061] The solvent of 5
mLof the obtained acetonitrile solution was distilled away under reduced pressure, and
thereafter the obtained compound (15) was diluted with 1.5 mL of the mobile phase in the
LC-2 conditions. Analysis of the diluted compound (15) by LC under the LC-2
conditions provided the stereoselectivity of the reduction reaction of 98.95:1.05.
10 [0062] The yield of the compound (15) was calculated from the quantitative
analysis by LC. LC-1 was used as the analysis conditions of LC. As the standard
substance used in this quantitative analysis, the compound (13) [racemic substance of
compound (15)] synthesized in accordance with the method described in Patent
Document 1 purified with a silica gel column under the following conditions was used.
15 Column used: Hi-Flash Column, 40 urn, 60 A, 250 g
Gradient composition: n-hexane/ethyl acetate = 8/1 -» 5/1 ~> 3/1 (flow rate 90
mL/min)
[0063] 'H-NMR of compound (15) (500 MHz, ppm, in CDC13) 8: 1.01-1.10 (m,
2H), 1.14-1.36 (m, 3H), 1.68-1.90 (m, 6H), 2.50-2.60 (m, 1H), 2.75-2.80 (m, 2H),
20 3.70-3.80 (m, 2H), 5.00 (t, 1H), 6.80-6.95 (m, 3H), 7.30-7.35 (m, 1H)
LC-MS (ESI +) m/z: 277 (M+NH+)
[0064] The steric configuration of the obtained compound (15) was determined
by deriving the compound (15) into the compound (1) in accordance with the method
described below. That is, acetonitrile (5 mL) [10 mg of the compound (15) is contained
25 in the acetonitrile solution] was concentrated under reduced pressure and the residue was
dissolved in 0.6 g of terrahydrofuran. The obtained solution was cooled. When the
internal temperature reached 0°C, 93 mg of borane-dimethylsulfide complex was added.
After completion of the addition, the reaction solution was heated to 70°C and stirred at
the same temperature for 3 hours. After completion of the stirring, the disappearance of
31
the compound (15) and generation of the compound (1) in the solution were ascertained
by LC under LC-1 conditions. After completion of the ascertainment, the reaction
solution was concentrated under reduced pressure. The obtained residue was analyzed
in accordance with the analysis conditions described in Example 2. As a result, the
5 compound (1) was clarified to be the (R) form because the retention time of the actually
obtained compound (1) was 36.9 minutes.
(It was previously ascertained that analysis of the racemic form of the compound (1)
synthesized in accordance with the method described in Patent Document 1 under the
LC-2 conditions resulted in detection of the peaks having retention times of 36.9 minutes
10 and 40.9 minutes).
[0065] Example 5: Synthesis of compound (2)
cr° IT- —• cr^i
(16) (2)
[0066] To the solution of 3.04 g of the compound (16) synthesized in accordance
with the method described in Patent Document 1 in 20 g of tetrahydrofuran, 10 g of water
15 and 3.31 g of potassium carbonate were added. After completion of the addition, the
reaction mixture was cooled to 5°C. Thereafter, the solution of 3.26 g of
9-fluorenylmethoxycarbonyl chloride in 20 g of tetrahydrofuran was added dropwise at
about 5°C. After completion of the dropwise addition, the reaction mixture was stirred
at room temperature for 1 hour. After completion of the stirring, the disappearance of
20 the starting material in the reaction mixture was ascertained by LC. After ascertaining
the disappearance of the starting material, 35 g of 1 mol/L hydrochloric acid aqueous
solution was added dropwise to the reaction mixture at a temperature in a range of 0°C to
10°C. After completion of the dropwise addition, the reaction mixture was concentrated
and thereafter the residue was extracted two times with 50 g and 30 g of ethyl acetate.
25 After combining the obtained organic phases, the combined organic phase was
dehydrated and dried by adding 30 g of 20% by mass sodium chloride aqueous solution
and then 10 g of sodium sulfate in this order. Thereafter, the solvent was distilled away
32
under reduced pressure to give 6.00 g of a yellow oily substance. The obtained oily
substance was dissolved in 60 g of toluene and 0.175 g of N-hydroxy-2-azaadamantane
[AZADOL (registered trademark), sold by Wako Pure Chemical Industries, Ltd.] was
added at 0°C. After completion of the addition, 25 g of 5% by mass sodium hydrogen
5 carbonate aqueous solution, and then 12 g of 14% by mass sodium hypochlorite aqueous
solution were added dropwise to the reaction solution at about 0°C. After completion of
the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours.
Thereafter, 0.09 g of N-hydroxy-2-azaadamantane [AZADOL (registered trademark),
sold by Wako Pure Chemical Industries, Ltd.], 12 g of 5% by mass sodium hydrogen
10 carbonate aqueous solution, and then 6.15 g of 14% by mass sodium hypochlorite
aqueous solution were added dropwise. After completion of the dropwise addition, the
reaction mixture was stirred for 1 hour and thereafter the disappearance of the starting
material in the reaction mixture was ascertained by LC. Thereafter, 70 g of 10% by
mass sodium thiosulfate aqueous solution and then 22 g of 1 mol/L hydrochloric acid
15 aqueous solution were added dropwise. After completion of the dropwise addition, the
reaction mixture was stirred at room temperature for 20 minutes and thereafter extracted
with toluene (50 g). After combining the obtained organic phases, the resultant organic
phase was washed with 100 g of 10% by mass sodium hydrogen carbonate aqueous
solution. Thereafter, the organic phase was dehydrated and dried by adding 100 g of
20 10% by mass sodium chloride aqueous solution and then 10 g of sodium sulfate in this
order. Thereafter, the solvent was distilled away under reduced pressure to give 5.58 g
of the crude product of the compound (2) being the target product as a brown oily
substance.
Analysis conditions of LC at the time of ascertainment of starting material
25 disappearance: LC-1
[0067] Purification of compound (2)
The crude product of the compound (2) obtained by the method described above was
purified by column chromatography in accordance with the following condition (A).
Subsequently, 2 g of the obtained compound (2) was purified again by column
33
ciiromatography in accordance with the following condition (B). 1.1 g of the compound
(2) was obtained as yellow oily substance by column chromatography purification carried
out two times. The yield from the compound (16) was 20% and the area percentage of
the obtained compound (2) obtained by the LC measurement was 88%.
5 Condition (A)
Column used: Hi-Flash Column, 40 um, 60 A, 120 g
Gradient composition: n-hexane/ethyl acetate ~ 88/12 -> 85/15 (flow rate 60
mL/min)
Condition (B)
10 Column used: Hi-Flash Column, 40 u_m, 60 A, 120 g
Solvent composition: n-hexane/ethyl acetate = 9/1 (flow rate 60 mL/min)
[0068] lH-NMR of compound (2) (500 MHz, ppm, in CDC13) 8: 7.74 (d, J - 7.8
Hz, 2H), 7.57 (d, J - 7.8 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.47 (s-like, 1H), 7.37 (dd, J =
7.8, 7.8 Hz, 2H), 7.36 (dd, J = 7.8 Hz, 1H), 7.28 (dd, J - 7.8, 7.8 Hz, 2H), 7.11 (d-like, J
15 - 7.8 Hz, 1H), 4.37 (d, J = 6.9 Hz, 2H), 4.19 (t, J = 6.9 Hz, 1H), 3.79 (d, J - 6.0 Hz, 2H),
3.62 (q, J - 5.7 Hz, 2H), 3.22 (t, J = 5.7 Hz, 2H), 1.88-1.86 (m, 2H), 1.84-1.76 (m, 3H),
1.72-1.70 (m, 1H), 1.34-1.27 (m,2H), 1.25-1.18 (m, 1H), 1.10-1.03 (m,2H)
LC-MS (ESI +) m/z: 501 (M+NH4+)
[0069] Example 6: Synthesis of compound (17)
20 ^ ^ A ^ - s ^ N, vo
K^J on K^J OH o
(16) (18)
o o
<19)
15 [0074] To the solution of 3.06 g of the compound (16) synthesized in accordance
with the method described in Patent Document 1 in 63 g of toluene, 1.88 g of phthalic
anhydride and 1.70 g of N,N-diisopropylethylamine were added. After completion of
the addition, the reaction mixture was refluxed for 2 hours and thereafter 0.13 g of
phthalic anhydride and 0.56 g of N,N-diisopropylethylamine were added. After
20 completion of the addition, the reaction mixture was continuously stirred for 1 hour and
thereafter concentrated under reduced pressure. To the concentrated reaction liquid, 50
mL of ethyl acetate and 10 mL of 1 moI/L hydrochloric acid aqueous solution were added
and the resultant mixture was separated. The obtained organic phase was washed with
50 g of 10% by mass sodium hydrogen carbonate aqueous solution. Thereafter, the
36
organic phase was dehydrated and dried by adding 50 g of 15% by mass sodium chloride
aqueous solution and then 10 g of sodium sulfate in this order. Thereafter, the solvent
was distilled away under reduced pressure to give 5.2 g of the compound (18) being the
target product as a yellow oily substance.
5 [0075] Purification of compound (18)
The crude product of the compound (18) obtained by the method described above
was purified by column chromatography in accordance with the following conditions.
3.76 g of the compound (18) whose area percentage obtained by the LC measurement
was increased to 99% was obtained.
10 Silica gel used: BW300SP, manufactured by Fuji Silysia Chemical Ltd., 50 g
Solvent composition: n-hexane/ethyl acetate = 2/1
[0076] To the solution of 3.37 g of the compound (18) obtained by the
purification method described above in 33 g of toluene, 0.13 g of
N-hydroxy-2-azaadamantane [AZADOL (registered trademark), sold by Wako Pure
15 Chemical Industries, Ltd.], 18.3 g of 5% by mass sodium hydrogen carbonate aqueous
solution, and 9.2 g of 14% by mass sodium hypochlorite aqueous solution were added.
After completion of the addition, the reaction mixture was stirred at about 5°C for 1 hour.
After completion of the stirring, the disappearance of the starting material in the reaction
mixture was ascertained by LC. Thereafter, 40 g of 10% by mass sodium thiosulfate
20 aqueous solution and 13 g of 1 mol/L hydrochloric acid aqueous solution were added
dropwise at about 10°C. After completion of the dropwise addition, the reaction liquid
was stirred at room temperature for 30 minutes and then extracted with toluene (20 g).
After combining the obtained organic phases, the resultant organic phase was washed
with 40 g of 10% by mass sodium hydrogen carbonate aqueous solution. Thereafter, the
25 organic phase was dehydrated and dried by adding 50 g of 10% by mass sodium chloride
aqueous solution and then 10 g of magnesium sulfate in this order. Thereafter, the
solvent was distilled away under reduced pressure to give 2.57 g of the crude product of
the compound (19) being the target product as a white crystal.
Analysis conditions of LC at the time of ascertainment of starting material
37
disappearance: LC-1
[0077] Purification of compound (19)
The crude product of the compound (19) obtained by the method described above
was purified by column chromatography in accordance with the following conditions.
5 1.1 g of the compound (19) whose area percentage obtained by the LC measurement was
increased from 85% to 95% was obtained as yellow oily substance. In this case, the
yield from the compound (16) was 24%.
Column used: Hi-Flash Column, 40 urn, 60 A, 120 g
Solvent composition: n-hexane/ethyl acetate = 5/1 (flow rate 60 mL/min)
10 [0078] 'H-NMR of compound (19) (500 MHz, ppm, in CDCI3) 8: 7.85 (m, 2H),
7.72 (m, 2H), 7.49 (d-like, J = 7.8 Hz, 1H) 7.45 (s-like, 1H), 7.33 (dd, J = 7.8, 8. 1 Hz,
1H), 7.09 (d-like, J - 8. 1 Hz, 1H), 4. 14 (t, J = 7.5 Hz, 2H), 3.78 (d, J = 6. 6 Hz, 2H),
3.41 (t, J = 7.5 Hz, 2H), 1.87-1. 85 (m, 2H), 1.83-1. 74 (m, 3H), 1.71-1. 68 (m, 1H),
1.33-1. 26 (m,2H), 1.24-1. 17 (m, 1H), 1.08-1. 02(m,2H)
15 LC-MS (ES +) m/z: 392 (M+H)
[0079] Example 8: Synthesis of compound (20)
(11)
[0080] To the solution of 2.99 g of the compound (11) synthesized in accordance
with the method described in Example 1 in 21 g of dichloromethane, 12.01 g of
20 trifluoroacetic acid was added. After completion of the addition, the reaction mixture
was stirred at 45°C for 30 minutes. After completion of the stirring, the disappearance
of the compound (11) being the starting material in the reaction mixture was ascertained
by LC. After ascertaining the disappearance of the starting material, the reaction
mixture was cooled to 10°C to 15°C. Thereafter, 20 g of 5% sodium hydrogen
25 carbonate aqueous solution was added and the mixture was separated. The obtained
aqueous phase was extracted two times with 20 g and 15 g of methylene chloride. After
combining the obtained organic phases, the resultant organic phase was dehydrated and
38
dried by adding 10 g of magnesium sulfate. Thereafter, the solvent was distilled away
under reduced pressure to give the crude product of the compound (20) being the target
product as a brown oily substance.
Analysis conditions of LC at the time of ascertainment of starting material
5 disappearance: LC-1
[0081] Purification of compound (20)
The crude product of the compound (20) obtained by the method described above
was purified by column chromatography in accordance with the following conditions.
1.1 g of the compound (20) whose area percentage obtained by the LC measurement is
10 increased to 95% was obtained.
Silica gel used; Hi-Flash Column, 40 urn, 60 A, 120 g
Solvent composition: n-hexane/ethyl acetate = 9/1 (flow rate 60 mL/min)
[0082] 'H-NMR of compound (20) (500 MHz, ppm, in CDCi3) 8: 8. 21 (bs, 3H),
7.44 (d, J = 7.8 Hz, IH), 7.39 (s-iike, IH), 7.31 (dd, J - 7.8,7.8 Hz, IH), 7.09 (d-like, J =
15 7.8 Hz, IH), 3.74 (d, J - 6.6 Hz, 2H), 3.39 (m, 2H), 3.36 (m, 2H), 1.85-1. 83 (m, 2H),
1.79-1. 74 (m, 3H), 1.71-1. 68 (m, IH), 1.32-1. 25 (m, 2H), 1.23-1. 15 (m, IH), 1.07-1.
00 (m, 2H)
LC-MS (ES +) m/z: 262 (M+H)
[0083] Example 9: Synthesis of compound (24)
20
[0084] To the solution of 17.7 g of the compound (21) synthesized in accordance
with the method described in Patent Document 1 in 177.1 g of dichloromethane, 13.10 g
of diazabicycloundecene and 11.01 g of tert-butyldimethylsilyl chloride (TBS-C1) were
added. After completion of the addition, the reaction mixture was stirred at room
39
temperature for 1 hour. After completion of the stirring, the disappearance of the
starting material in the reaction mixture was ascertained by LC. After ascertaining the
disappearance of the starting material, 50 mL of water was added to the reaction liquid
and the resultant mixture was separated. The obtained organic phase was washed with
5 50 mL of water. Thereafter, the organic phase was dehydrated and dried by adding 50
mL of 20% by mass salt solution and then 20 g of magnesium sulfate in this order.
Thereafter, the solvent was distilled away under reduced pressure to give 28 g of the
crude product of the compound (22).
To the solution of 25.0 g of the obtained crude product of the compound (22) in 250
10 g of toluene, 1.00 g of N-hydroxy-2-azaadamantane [AZADOL (registered trademark),
sold by Wako Pure Chemical Industries, Ltd.], 143 g of 5% by mass sodium hydrogen
carbonate aqueous solution, and 71.2 g of 14% by mass sodium hypochlorite aqueous
solution were added. After completion of the addition, the reaction mixture was stirred
at about room temperature for 3 hours. After completion of the stirring, the
15 disappearance of the starting material in the reaction mixture was ascertained by LC.
Thereafter, 50 g of 10% by mass sodium thiosulfate aqueous solution and 100 g of 3
mol/L hydrochloric acid aqueous solution were added dropwise at about 20°C. After
completion of the dropwise addition, the reaction liquid was stirred at room temperature
for 30 minutes and then separated. The obtained aqueous phase was extracted with 100
20 g of toluene. After combining the obtained organic phases, the resultant organic phase
was washed with 50 g of 10% by mass sodium hydrogen carbonate aqueous solution.
Thereafter, the solvent was distilled away under reduced pressure to give 24.1 g of the
crude product of the compound (23).
Analysis conditions of LC at the time of ascertainment of starting material
25 disappearance: LC-1
[0085] The crude product of the compound (23) was purified by column
chromatography in accordance with the following conditions.
Column used: Hi-Flash Column, 40 iim, 60 A, 120 g
Gradient composition: n-hexane/ethyl acetate = 96/4 -» 80/20 (flow rate 70
40
mL/min)
[0086] The solution of 6.4 g of the obtained compound (23) by the purification
method described above in 64 g of tetrahydrofuran was cooled to 0°C to 5°C. To the
solution, 20 mL of tetrahydrofuran solution (1 M) of tetrabutylammonium fluoride was
5 added dropwise. After completion of the dropwise addition, the reaction mixture was
stirred at 0°C to 5°C for 1 hour. After completion of the stirring, the disappearance of
the starting material in the reaction mixture was ascertained by LC under the LC-1
conditions. Thereafter, 12.8 g of ethyl acetate and 12.8 g of water were added to the
reaction liquid and the resultant mixture was separated. The aqueous phase after the
10 liquid separation was extracted with ethyl acetate (12.8 g). After combining the
obtained organic phases, the solvent was distilled away under reduced pressure to give
4.0 g of the crude product of the compound (24).
[0087] The crude product of the compound (24) obtained by the method
described above was purified by column chromatography in accordance with the
15 following conditions to give 4.6 g of the compound (24). The yield from the compound
(21) [three stages of TBS group formation, oxidation, and TBS group removal] was 26%
and the area percentage of the compound (24) obtained by the LC measurement was
99%.
Silica gel used: Hi-Flash Column, 40 um, 60 A, 120 g
20 Gradient composition: n-hexane/ethyl acetate = 4/1 (flow rate 30 mL/min)
[0088] 'H-NMR of compound (23) (500 MHz, ppm, in CDC13) 8: 7.54 (d, J = 7.8
Hz, 1H), 7.41 (s-like, 1H), 7.32 (dd, J - 7.8, 7.8 Hz, 1H), 7.05 (d-like, J = 7.8 Hz, 1H),
5.15 (brs, 1H), 3.54 (q, J - 5.4 Hz, 2H), 3.17 (t, J = 5.4,2H), 1.43 (s, 9H)> LOO (s, 9H), 0.
22 (s, 6H) LC-MS(ES-)m/z:378 (M-H)
25 'H-NMR of compound (24) (500 MHz, ppm, in CDCI3) 5: 9. 76 (s, 1H), 7.38 (d, J =
7.8 Hz, 1H), 7.32 (dd, J = 7.8,7.8 Hz, 1H), 7.28 (s-like, 1H), 7.02 (d, 1H, J - 7.8 Hz), 6.
80 (t, J - 5.4 Hz, 1H), 3.25 (q, J - 5.4,2H), 3.08 (t, J = 5.4, 2H), 1.36 (s, 9H)
LC-MS (ES +) m/z: 266 (M+H)
[0089] Example 10: Synthesis of compound (29)
41
OH OH OH
(25) C20) (27)
Tflr:o^Ji--Ir---N>iC0CF- — ^ X X ^ N ^ O C F,
o o
(2B) (29)
[0090] To the solution of 5.83 g of the compound (25) synthesized in accordance
with the method described in Patent Document 1 in 100 g of dichloromethane, 6.09 g
triethylamine was added and the reaction mixture was cooled to 5°C. After cooling,
5 7.01 g of trifluoroacetic anhydride was added dropwise at a temperature in a range of 3°C
to 23°C. After completion of the dropwise addition, the reaction mixture was stirred at
about 20°C for 3 hours. After completion of the reaction, 50 g of 20% by mass
ammonium chloride aqueous solution was added to the reaction liquid and the resultant
mixture was extracted with dichloromethane (50 g). After combining the obtained
10 organic phases, the resultant organic phase was dehydrated and dried by adding 50 g of
20% by mass salt solution and then 10 g of magnesium sulfate in this order. Thereafter,
the solvent was distilled away under reduced pressure to give 5.6 g of the crude product
of the compound (26) as a brown oily substance.
[0091] To the solution of 2.00 g of the obtained compound (26) in 20 g of
15 dichloromethane, 1.50 g of diazabicycloundecene and 1.26 g of tert-butyldimethylsilyl
chloride were added. After completion of the addition, the reaction mixture was stirred
at room temperature for 1 hour. After completion of the stirring, the disappearance of
the starting material was ascertained under the LC-1 analysis conditions, 4 mL of water
was added to the reaction liquid and the resultant mixture was separated. The obtained
20 organic phase was washed with 4 mL of water. Thereafter, the organic phase was
dehydrated and dried by adding 4 mL of 20% by mass salt solution and then 5 g of
magnesium sulfate in this order. Thereafter, the solvent was distilled away under
reduced pressure to give 2.7 g of the crude product of the compound (27).
[0092] To the solution of 2.9 g of the crude product of the compound (27) in 29.2
25 g of toluene, 120 mg of N-hydroxy-2-azaadamantane [AZADOL (registered trademark),
42
sold by Wako Pure Chemical Industries, Ltd.], 16.78 g of 5% by mass sodium hydrogen
carbonate aqueous solution, and 8.35 g of 14% by mass sodium hypochlorite aqueous
solution were added. After completion of the addition, the reaction mixture was stirred
at about room temperature for 1 hour. After completion of the stirring, the
5 disappearance of the starting material in the reaction mixture was ascertained by LC.
Thereafter, 15 g of 10% by mass sodium thiosulfate aqueous solution and 30 g of 3 mol/L
hydrochloric acid aqueous solution were added at about 20°C, followed by extracting the
resultant mixture with 10 g of toluene. The obtained organic phase was washed with 10
g of 10% by mass sodium hydrogen carbonate aqueous solution. The solvent of the
10 obtained organic phase was distilled away under reduced pressure to give 2.8 g of the
crude product of the compound (28).
[0093] The solution of 2.5 g of the compound (28) in 25 g of tetrahydrofuran was
cooled to 0°C to 5°C. To the solution, 9.0 mL of tetrahydrofuran solution (1 M) of
tetrabutyiammonium fluoride was added dropwise and the resultant mixture was stirred at
15 0°C to 5°C for 1 hour. After completion of the stirring, the disappearance of the starting
material was ascertained by LC. Thereafter, 5.0 g of ethyl acetate and 5.0 g of water
were added to the reaction mixture and the resultant mixture was separated. The
aqueous phase after the liquid separation was extracted with 5.0 g of ethyl acetate.
After combining the obtained organic phases, the solvent was distilled away under
20 reduced pressure to give 3.0 g of the crude product of the compound (29).
Analysis conditions of LC at the time of ascertainment of starting material
disappearance: LC-1
[0094] The obtained crude product of the compound (29) was purified by column
chromatography in accordance with the following conditions to give 2.1 g of the
25 compound (29). The yield from the compound (25) was 41% and the area percentage
obtained by the LC measurement was 95%.
Silica gel used; Hi-Flash Column, 40 urn, 60 A, 50 g
Gradient composition: n-hexane/ethyl acetate - 1/1 (flow rate 30 mL/min)
'H-NMR of the compound (29) (500 MHz, ppm, in DMSO) 8: 9.79 (s, 1H), 9.43 (bss
43
1H), 7.41 (d, J - 7.8 Hz, 1H), 7.33 (dd, J = 7.8, 7.8 Hz, 1H), 7.31 (s-like, 1H), 7.03 (d, J =
7.8 Hz, 1H), 3.52 (q, 6.3 Hz, 2H), 3.25 (t, J - 6.3 Hz, 2H)
[0095] Example 11: Synthesis of compound (33)
- Q. AP
TBSCT ^y - -^
OH O OH O
(30) (31)
6 o o o
(32) (33)
5 [0096] To the solution of 1.90 g of the compound (30) synthesized in accordance
with the method described in Patent Document 1 in 19.0 g of dichloromethane, 1.27 g of
diazabicycloundecene and 1.05 g of teit-butyldimethylsilyl chloride were added and the
resultant reaction mixture was stirred at room temperature for 1 hour. After completion
of the stirring, the disappearance of the starting material was ascertained under the LC-1
10 conditions, and 4 mL of water was added to the reaction mixture, followed by separating
the resultant mixture. The obtained organic phase was washed with 4 mL of water.
Thereafter, the organic phase was dehydrated and dried by adding 4 mL of 20% by mass
salt solution and then 5 g of magnesium sulfate in this order. Thereafter, the solvent was
distilled away under reduced pressure to give 2.5 g of the crude product of the compound
15 (31).
[0097] To the solution of 2.5 g of the obtained crude product of the compound
(31) in 27.1 g of toluene, 100 mg of N-hydroxy-2-azaadamantane [AZADOL (registered
trademark), sold by Wako Pure Chemical Industries, Ltd.], 14.3 g of 5% by mass sodium
hydrogen carbonate aqueous solution, and 7.13 g of 14% by mass sodium hypochlorite
20 aqueous solution were added. After completion of the addition, the reaction mixture
was stirred at about room temperature for 1 hour. After completion of the stirring, the
disappearance of the starting material in the reaction mixture was ascertained by LC
under the LC-1 conditions. Thereafter, 15 g of 10% by mass sodium thiosulfate aqueous
solution and 30 g of 3 mol/L hydrochloric acid aqueous solution were added dropwise at
J
44
about 20°C. After completion of the dropwise addition, the resultant mixture was
separated and the aqueous phase was extracted with 10 g of toluene. After combining
the obtained organic phases, the resultant organic phase was washed with 10 g of 10% by
mass sodium hydrogen carbonate aqueous solution. The solvent of the obtained organic
5 phase was distilled away under reduced pressure to give 2.5 g of the crude product of the
compound (32).
[0098] The solution of 2.5 g of the compound (32) in 25 g of tetrahydrofuran was
cooled to 0°C to 5°C. To the reaction liquid, 8 mL of tetrahydrofuran solution
(concentration 1 M) of tetrabutylammonium fluoride was added dropwise and the
10 resultant mixture was stirred at 0°C to 5°C for 1 hour. After completion of the reaction,
5.0 g of ethyl acetate and 5.0 g of water were added to the reaction liquid and the
resultant mixture was separated. The aqueous phase after the liquid separation was
extracted with 5.0 g of ethyl acetate. The solvent of the obtained organic phase was
distilled away under reduced pressure to give 3.0 g of the crude product of the compound
15 (33).
[0099] The obtained crude product of the compound (33) was purified by column
chromatography in accordance with the following conditions to give 2.0 g of the
compound (33). The yield from the compound (30) [three stages of TBS group
formation, oxidation, and TBS group removal] was 80% and the area percentage of the
20 compound (33) obtained by the LC measurement was 95%.
Silica gel used: Hi-Flash Column, 40 urn, 60 A, 50 g
Gradient composition: n-hexane/ethyl acetate ~ 1/1 (flow rate 100 mL/min)
lH-NMR of compound (33) (500 MHz, ppm, in DMSO) 5: 9. 78 (s, 1H), 7.87-7.85
(m, 2H), 7.85-7.82 (m, 2H), 7.38 (d, J - 7.8 Hz, 1H), 7.30 (dd, J = 7.8,7.8 Hz, 1H), 7.28
25 (s-Iike, 1H), 7.01 (d, J - 7.8 Hz, 1H), 3.91 (t, J = 7.2 Hz, 2H), 3.37 (t, J - 7.2 Hz, 2H)
LC-MS (ES +) m/z: 296 (M+H)
[0100] Example 12: Synthesis of compound (38)
£ ) y * H O^
45
HO' "^ Y H0 T "CN T,iS0'" "Y CN
O OH OH
(34) (35) (36)
L !l . . I: 1 ^
TBSO'' "^ 'Y' ^CN HO'" ""^ Y CN
O 0
(37) (38)
[0101] Into a reaction flask, 213 g of potassium tert-butoxide and 1097 g of
tetrahydrofuran were charged and the resultant mixture was stirred at -50°C for 1 hour.
After completion of the stirring, 70 g of acetonitrile was added to the reaction mixture at
5 -40°C to -50°C and the resultant mixture was stirred for 10 minutes. After completion
of the stirring, the solution in which 86 g of 3-hydroxy benzaldehyde (34) was dissolved
into 86 g of tetrahydrofuran was added dropwise to the reaction mixture at -30°C to
-50°C, and the reaction liquid was stirred for 10 minutes. After completion of the
stirring, the temperature of the reaction liquid was raised to 0°C and stirred for 1 hour.
10 After completion of the stirring, 200 g of water was added to the reaction liquid and
thereafter the solvent was distilled away under reduced pressure. 500 mL of ethyl
acetate was added to the obtained residue and extraction operation was repeated two
times. After combining the obtained organic phases, the combined organic phase was
washed with 500 g of water. Thereafter, the organic phase was washed and dried by
15 adding 400 mLof 20% by mass salt solution and then 30 g of magnesium sulfate in this
order. Thereafter, the solvent was distilled away under reduced pressure to give 121 g
of the crude product of the compound (35).
[0102] To the solution of 6.0 g of the obtained crude product of compound (35) in
50.0 g of N,N-dimethylformamide, 6.1 g of diazabicycloundecene was added and the
20 resultant reaction mixture was stirred at room temperature. After completion of the
stirring, 5.1 g of tert-butyldimethylsilyl chloride was added to the reaction mixture and
the resultant reaction mixture was stirred at room temperature for 1 hour. After
completion of the stirring, 4.6 g of diazabicycloundecene and 3.0 g of
tert-butyldimethylsilyl chloride were added to the reaction mixture and the resultant
25 reaction mixture was continuously stirred for 15 hours. After completion of the stirring,
46
the solvent of the reaction liquid was distilled away under reduced pressure. Thereafter
50 mL of water and 100 mL of ethyl acetate were added and the resultant mixture was
separated. The aqueous phase after the liquid separation was extracted with 30 L of
ethyl acetate. After combining the obtained organic phases, the combined organic phase
5 was washed with 50 mL of water. Thereafter, the organic phase was washed and dried
by adding 50 mL of 20% by mass salt solution and then 10 g of magnesium sulfate in this
order. Thereafter, the solvent was distilled away under reduced pressure to give 7.5 g of
the crude product of the compound (36).
[0103] To the solution of 8.5 g of the obtained crude product of the compound
10 (36) in 97.0 g of acetonitrile, 0.38 g of water, 1.2 g of potassium
2-iodo-5-methylbenzenesulfonate, and 20.2 g of OXONE (registered trademark,
potassium monopersulfate compound salt) were added and the resultant reacting mixture
was stirred at 80°C for 6 hours. After completion of the stirring, 100 mL of 20% by
mass sodium thiosulfate aqueous solution was added to the reaction mixture and the
15 resultant mixture was extracted with toluene (100 mL x 2). After combining the
obtained organic phases, the combined organic phase was washed and dried by adding
100 mL of 20% by mass salt solution and then 10 g of magnesium sulfate in this order.
Thereafter, the solvent was distilled away under reduced pressure to give 8.9 g of the
crude product of the compound (37).
20 [0 i 04] To the solution of 1.2 g of the obtained crude product of the compound
(37) in 12.0 g of tetrahydrofuran, 4.8 g of 1 mol/L tetrahydrofuran solution of
tetra-normal-butyl ammonium fluoride was added and the resultant reaction mixture was
stirred at room temperature for 1 hour. After completion of the stirring, 10 mL of water
and 10 mL of ethyl acetate were added to the reaction mixture and the resultant mixture
25 was separated. The aqueous phase after the liquid separation was extracted with ethyl
acetate (10 mL). After combining the obtained organic phases, the solvent was distilled
away under reduced pressure to give 1.1 g of the crude product of the compound (38).
[0105] The obtained crude product of the compound (38) was purified by column
chromatography in accordance with the following conditions to give 0.3 g of the
47
compound (38). The area percentage of the compound (38) obtained by the LC
measurement was 100%.
Silica gel used: Hi-Flash Column, 40 pm, 60 A, 15 g
Gradient composition: n-hexane/ethyl acetate = 6/3 (flow rate 10 mL/min)
5 'H-NMR of compound (37) (500 MHz, ppm, in DMSO) 8: 7.48 (d, J = 7.8 Hz, IH),
7.38 (s-like, IH), 7.38 (dd, J - 7.8, 7.8 Hz, IH), 7.13 (d-like, J = 7.8 Hz, IH), 4.05 (s, 2H),
1.00 (s,9H), 0.23 (s,6H)
LC-MS (ES +) m/z: 276 (M+H)
lH-NMR of compound (38) (500 MHz, ppm, in DMSO) 8: 9. 92 (s, IH), 7.38 (d, J -
10 7.8 Hz, IH), 7.35 (dd, J = 7.8, 7.8 Hz, IH), 7.28 (s, IH), 7.09 (d-like, J = 7.8 Hz, IH), 4.
7 (s, 2H)
LC-MS (ES -) m/z: 160 (M-H)
[0106] Example 13: Synthesis of compound (39)
o o
(24) (39)
15 [0107] To the solution of 0.3 g of the compound (24) in 3.6 g of dichloromethane,
0.2 g of pyridine and 0.2 g of benzoyl chloride were added and the resultant reaction
mixture was stirred at room temperature for 5 hours. After completion of the stirring,
10 mL of 20% by mass ammonium chloride aqueous solution and 10 mL of ethyl acetate
were added to the reaction mixture and the resultant mixture was separated. The
20 aqueous phase after the liquid separation was extracted with ethyl acetate (10 mL x 2).
After combining the obtained organic phases, the resultant organic phase was washed
with 10 mL of water. Thereafter, the organic phase was dehydrated and dried by adding
10 mL of 15% by mass salt solution and then 2.1 g of magnesium sulfate in this order.
Thereafter, the solvent was distilled away under reduced pressure to give 0.5 g of the
25 crude product of the compound (39).
[0108] The obtained crude product of the compound (39) was purified by column
chromatography in accordance with the following conditions to give 0.4 g of the
.NHQoc
48
compound (39). The area percentage of the compound (39) obtained by the LC
measurement was 100%.
Silica gel used: Hi-Flash Column, 40 urn, 60 A, 15 g
Gradient composition: n-hexane/ethyl acetate - 100/0 (flow rate 15 mL/min)
5 *H-NMR of compound (23) (500 MHz, ppm, in CDC13) 8: 8. 21 (d, J = 7.8 Hz, 2H),
7.87 (d, J = 7.8 Hz, IH), 7.81 (s-Iike, IH), 7.66 (t, IH, J = 7.8 Hz), 7.55 (dd, J - 7.8 Hz,
IH), 7.53 (dd, J = 7.8, 7.8 Hz, 2H), 7.46 (d, J - 7.8, IH), 5.14 (brs, IH), 3.56 (q, J - 5.4,
2H), 3.22 (t, J = 5.4, 2H), 1.43 (s, 9H)
LC-MS (ES+) m/z: 370 (M+H)
10 [0109] Example 14: Synthesis of compound (40)
o o
(24) (40)
[0110] To the solution of 0.3 g of the compound (24) in 3.0 g of
N.N-dimethyiformamide, 0.3 g of potassium carbonate and 0.3 g of benzyl chloride were
added and the obtained reaction mixture was stirred at 60°C for 5 hours. After
15 completion of the stirring, the reaction mixture was cooled to 0°C. Thereafter, 20 mL of
20% by mass ammonium chloride aqueous solution and 10 mL of ethyl acetate were
added and the resultant mixture was separated. The aqueous phase after the liquid
separation was extracted with ethyl acetate (10 mL x 2). After combining the obtained
organic phases, the combined organic phase was washed with 10 mL of water.
20 Thereafter, the organic phase was dehydrated and dried by adding 10 mL of 15% by mass
salt solution and then 5.0 g of magnesium sulfate in this order. Thereafter, the solvent
was distilled away under reduced pressure to give 0.5 g of the crude product of the
compound (40).
[0111] The obtained crude product of the compound (40) was purified by column
25 chromatography in accordance with the following conditions to give 0.3 g of the
compound (40). The area percentage of the compound (40) obtained by the LC
measurement was 100%,
49
Silica gel used: Hi-Flash Column, 40 pm, 60 A, 15 g
Gradient composition: n-hexane/ethyl acetate = 90/10 -» 4/1 (flow rate 15 mL/min)
'H-NMR of compound (40) (500 MHz, ppm, in CDC13) 6: 7.57 (s-like, IH), 7.55 (d,
J = 7.8 Hz, IH), 7.44 (d, J = 7.8 Hz, 2H), 7.40 (dd, J = 7.8, 7.8 Hz, 2H), 7.38 (dd, J - 7.8,
7.8 Hz, IH), 7.34 (t, J - 7.8 Hz, IH), 7.19 (d, J = 7.8, IH), 5.12 (bis, IH), 5.12 (s, 2H),
3.54 (q, J - 6. 0, 2H), 3.18 (t, J = 6. 0,2H), 1.43 (s, 9H)
LC-MS (ES+) m/z: 356 (M+H)
[0112] Example 15: Synthesis of compound (41)
o o
<24) (41)
10 [0113] To the solution of 0.5 g of the compound (24) in 8.5 g of dichloromethane,
0.5 g of diisopropylethylamine and 0.2 g of methoxymethyl chloride were added and the
resultant reaction mixture was stirred at room temperature for 5 hours. After completion
of the stirring, the reaction mixture was cooled to 0°C. Thereafter, 20 mL of 20% by
mass ammonium chloride aqueous solution and 30 mL of ethyl acetate were added and
15 the resultant mixture was separated. The obtained organic phase was washed with 20
mL of water. Thereafter, the organic phase was dehydrated and dried by adding 20 mL
of 15% by mass salt solution. Thereafter, the solvent was distilled away under reduced
pressure to give 0.7 g of the crude product of the compound (41).
[0114] The obtained crude product of the compound (40) was purified by column
20 chromatography in accordance with the following conditions to give 0.4 g of the
compound (41). The area percentage of the compound (41) obtained by the LC
measurement was 100%.
Silica gel used: Hi-Flash Column, 40 pm, 60 A, 15 g
Gradient composition: n-hexane/ethyl acetate = 100/0 -> 4/1 (flow rate 15 mL/min)
25 'H-NMR of compound (41) (500 MHz, ppm, in CDC13) 8: 7.62 (s-like, IH), 7.59 (d,
J - 7.8 Hz, IH), 7.38 (dd, J = 7.8,7.8 Hz, IH), 7.25 (d, IH, J = 7.8 Hz), 5.22 (s, 2H), 5.18
(brs, IH), 3.54 (q, J - 5.4,2H), 3.48 (s, 3H), 3.19 (t, J - 5.4,2H), 1.42 (s, 9H)
50
LC-MS (ES+) m/z: 327 (M+NH4)
[0115] Example 16: Asymmetric reduction reaction using catalyst (4), that is,
(S)-RUCY-XylBINAP as catalyst
(3) O (8> °H
5 [0116] To the solution of 100 mg of the ketone (3) in ethanol [5 times in mass
relative to ketone (3) was used] and 2-propanol [5 times in mass relative to ketone (3)
was used], potassium tert-butoxide [0.2 times in mole relative to ketone (3) was used] and
catalyst (4), that is, (S>RUCY (registered trademark)-XylBINAP (sold by TAKASAGO
INTERNATIONAL CORPORATION) [0.01 times in mole relative to ketone (3) was
10 used] were added. After completion of the addition, the inside of the vessel of the
reaction solution was purged with hydrogen gas, and thereafter the reaction solution was
reacted under a hydrogen pressure of 0.5 MPa at a reaction temperature of 25°.
After ascertaining the disappearance of the starting material by LC analysis, the
reaction liquid was diluted with acetonitrile using a 25 mL measuring flask. The
15 quantitative analysis of the acetonitrile diluted solution was carried out to determine the
yield of the compound (8). As the standard substance used in the quantitative analysis
of the compound (8), the compound obtained by purifying the racemic form of the
compound (8) obtained at the time of synthesizing the compound (3) was used.
Analysis condition of LC at the time of ascertainment of starting material
20 disappearance: LC-1
Conditions at the time of quantitative analysis: LC-1
[0117] The starting materials to be used, the yields of the reduction reaction, and
the optical purities of the compound (8) being the product are listed in the following
table.
[0118J in the above table, the reactions were not progressed and the starting
materials were recovered in Examples 16-4 to 16-10. In the columns of Yield of
Example 16-11 to 16-13, reaction conversion rates are listed.
The reaction conversion rate was calculated based on [LC area value of compound
5 (8)]/[Sum of LC area values of compounds (8) and (3)] x 100%.
[0119] The optical purities of the reaction products in Example 16-1 to 16-3 were
obtained by deriving each reaction product into the compound (1) in accordance with the
methods described below and thereafter calculating the optical purities in accordance
with the analytical conditions described in Example 2.
10 Example 16-1:5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 1 g of methanol, 0.11 g of potassium carbonate, and 0.26
g of water were added to the obtained residue, followed by stirring the resultant mixture
at room temperature. After completion of the stirring, the reaction liquid was
concentrated under reduced pressure and the obtained residue was used for the analysis of
15 the optical purity.
Example 16-2: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 1 g of ethanol and 0.10 g of hydrazine monohydrate were
added to the obtained residue, followed by stirring the resultant mixture at 80°C for 1
hour. After completion of the stirring, the reaction liquid was concentrated under
20 reduced pressure and the obtained residue was used for the analysis of the optical purity.
Example 16-3: 10 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 0.5 g of dimethylformamide and 0.25 g of morpholine
52
were added to the obtained residue, followed by stirring the resultant mixture at room
temperature for 0.5 hour. After completion of the stirring, the reaction liquid was
concentrated under reduced pressure and the obtained residue was used for the analysis of
the optical purity.
5 [0120] The optical purities of the reaction products in Example 16-11 to 16-13
were obtained by deriving each reaction product into the compound [(R)-21] in
accordance with the methods described below and thereafter calculating the optical
purities in accordance with the analytical conditions of LC-3.
[35]
Example 19-13:5 mL of the acetonitrile diluted solution used for the quantitative
10 analysis was concentrated, and 1.0 g of tetrahydrofuran and 50 mg of
tetrabutylammonium fluoride were added to the obtained residue, followed by stirring the
resultant mixture at room temperature for 7 hours. After completion of the stirring, the
reaction liquid was concentrated under reduced pressure and the obtained residue was
used for the analysis of the optical purity.
15 [0136] Example 20: Asymmetric reduction reaction using catalyst (7), that is,
(S)-5,5-diphenyl-2-methyl-3,4-propano-l,3,2-oxazaborolidine as catalyst
[0137] To the solution of
(S)-5,5-diphenyl-2-methyl-3,4-propano-l,3,2-oxazaborolidine [0.3 times in mole relative
20 to ketone (3) was used] in methylene chloride [10 times in mass relative to ketone (3) was
used], Borane-dimethylsulfide complex [1.5 times in mole relative to ketone (3) was
used] was added, and thereafter the reaction liquid was cooled to -50°C. After
completion of the cooling, the solution of 100 mg of the ketone (3) in methylene chloride
[10 times in mass relative to ketone (3) was used] was added dropwise to the reaction
25 liquid and the resultant reaction liquid was reacted at -50°C for 2 hours.
59
After ascertaining the disappearance of the starting material by LC analysis, the
reaction liquid was diluted with acetonitrile using a 25 mL measuring flask. The
quantitative analysis of the acetonitrile diluted solution was carried out to calculate the
yield of the compound (8). As the standard substance used in the quantitative analysis
5 of the compound (8), the compound obtained by purifying the racemic form of the
compound (8) obtained at the time of synthesizing the compound (3) was used.
Analysis conditions of LC at the time of ascertainment of starting material
disappearance: LC-1
Conditions at the time of quantitative analysis: LC-1
10 [0138] The starting materials to be used, the yields of the reduction reaction, and
the optical purities of the compound (8) being the product are listed in the following
table.
[0139] In the above table, reaction conversion rates are listed in the columns of
15 Yield of Examples 20-10 to 20-15.
The reaction conversion rate was calculated based on [LC area value of compound
(8)]/[Sum of LC area values of compounds (8) and (3)]* 100%
[0140] The optical purities of the reaction products in Example 20-1,20-3,20-6,
20-7, and 20-9 were obtained by concentrating 5 mL of the acetonitrile diluted solution
60
used for the quantitative analysis, analyzing the obtained residue in accordance with the
analysis conditions described in Example 2, and calculating.
[0141] The optical purities of the reaction products in Example 20-2, 20-4, and
20-5 were obtained by deriving each reaction product into the compound (1) in
5 accordance with the methods described below and thereafter calculating the optical
purities in accordance with the analytical conditions described in Example 2.
Example 20-2: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 2.0 g of methanol, 0.1 g of potassium carbonate, and 0.5 g
of water were added to the obtained residue, followed by stirring the resultant mixture at
10 room temperature for 0.5 hour. After completion of the stirring, the reaction liquid was
concentrated under reduced pressure and the obtained residue was used for the analysis of
the optical purity.
Example 20-4: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 2.0 g of ethanol and 0.10 g of hydrazine monohydrate
15 were added to the obtained residue, followed by stirring the resultant mixture at 80°C for
80 minutes. After completion of the stirring, the reaction liquid was concentrated under
reduced pressure and the resultant residue was used for the analysis of the optical purity.
Example 20-5: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 0.5 g of N,N-dimethylformamide and 0.25 g of
20 morpholine were added to the obtained residue, followed by stirring the resultant mixture
at room temperature for 70 minutes. After completion of the stirring, the reaction liquid
was concentrated under reduced pressure and the resultant residue was used for the
analysis of the optical purity.
[0142] The optical purities of the reaction product in Example 20-8 was obtained
25 by deriving the reaction product into the compound [(R)-25] in accordance with the
methods described below and thereafter calculating the optical purities in accordance
with the analytical conditions of LC-2.
Example 20-8: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 3.0 g of ethanol and 0.1 g of hydrazine monohydrate were
3
61
added to the obtained residue, followed by stirring the resultant mixture at 80°C for 1
hour. After completion of the stirring, the reaction liquid was concentrated under
reduced pressure and the obtained residue was used for the analysis of the optical purity.
[0143] The optical purity of the reaction products in Example 20-10 was obtained
5 by concentrating 5 mL of the acetonitrile diluted solution used for the quantitative
analysis, and calculating the optical purities of the obtained residue in accordance with
the analytical conditions of LC-4.
[0144] The optical purities of the reaction products in Examples 20-11, 20-12,
20-13, and 20-14 were obtained by deriving each reaction product into the compound
10 [(R)-21] in accordance with the methods described below and thereafter calculating the
optical purities in accordance with the analytical conditions of LC-3.
Example 20-11:10 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 0.5 g of tetrahydrofuran and 0.1 g (1 mol/1) of
tetrahydrofiuan solution of tetra-normal-butyl ammonium fluoride were added to the
15 obtained residue, followed by stirring the resultant mixture at room temperature for 2
hours. After completion of the stirring, the reaction liquid was concentrated under
reduced pressure and the obtained residue was used for the analysis of the optical purity.
Example 20-12: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 0.5 g of ethanol and 10 mg of 10% by mass palladium
20 carbon were added to the obtained residue, followed by stirring the reaction mixture
under hydrogen atmosphere at room temperature for 6 hours. After completion of the
stirring, the palladium carbon was separated by filtration and the obtained filtrate was
concentrated under reduced pressure, followed by using the obtained residue for the
analysis of the optical purity.
25 Example 20-13: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 0.5 g of methanol and 0.1 g of 1% by mass sodium
hydroxide aqueous solution were added to the obtained residue, followed by stirring the
resultant mixture at room temperature for 2 hours. After completion of the stirring, the
reaction liquid was concentrated under reduced pressure and the obtained residue was
q
62
used for the analysis of the optical purity.
Example 20-14: 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 0.5 g of methanol and 50 mg of hydrochloric acid (1 M)
were added to the obtained residue, followed by stirring the resultant mixture at room
5 temperature for 2 hours. After completion of the stirring, the reaction liquid was
concentrated under reduced pressure and the obtained residue was used for the analysis of
the optical purity.
[0145] The optical purities of the reaction products in Example 20-15 were
obtained by deriving each reaction product into the compound [(R)-35] in accordance
10 with the methods described below and thereafter calculating the optical purities in
accordance with the analytical conditions of LC-4.
Example 20-15; 5 mL of the acetonitrile diluted solution used for the quantitative
analysis was concentrated, and 1.0 g of tetrahydrofuran and 50 mg (1 mol/1) of
tetrahydrofuran solution of tetra-normal-butyl ammonium fluoride were added to the
15 obtained residue, followed by stirring the resultant mixture at room temperature for 7
hours. After completion of the stirring, the reaction liquid was concentrated under
reduced pressure and the obtained residue was used for the analysis of the optical purity.
INDUSTRIAL APPLICABILITY
20
[0146] The present invention is useful for the method for industrially producing
the optically active alcohol compounds as the intermediates of the medical products.

CLAIMS
1. A method for producing an optically active alcohol compound of Formula (8):
R10A5>Y^R2
(8) OH
5 [in the formula, R1 is a hydrogen atom, Cj.6 alkyl, (Ci^) alkyl optionally substituted with
R3, -C(0)R8, or -Si(RI2a)(R12b)R12; and
R2 is cyano or -CH2N(R5)R4;
R3 is Ci_6 alkoxy, phenyl, or C3-8 cycloalkyl;
R4 is a hydrogen atom, -C(0)R6, or -C(0)OR7;
10 R5 is a hydrogen atom or C^ alkyl, or R5 optionally forms a 5- to 7-membered ring
together with a nitrogen atom to which R4 and R5 are bonded by forming a C4-6 alkylene
chain together with R4, and in this case the alkylene chain is optionally substituted with
one or more selected from the group consisting of C 1.6 alkyl, (Ci^) alkyl optionally
substituted with Y, phenyl, and an oxo group, or the alkylene chain optionally forms
15 phenyl together with carbon atoms to which two substituents each bond when the two
substituents exist at adjacent positions on the alkylene chain;
R6 is C1-6 alkyl, (Ci-e) alkyl optionally substituted with a halogen atom, or phenyl;
R7isCi.6alkylor-CH2R13;
R8 is a hydrogen atom, Ci_6 alkyl, (C|^) alkyl optionally substituted with a halogen
20 atom, phenyl, or phenyl substituted with (Z)p;
R12, Ri2a, and RI2b each are independently Ci.6 alkyl or phenyl;
Ri3 is phenyl or 9-fluorenyl;
Y is a halogen atom;
Z is a halogen atom or Ci-g alkoxy; and
25 p is an integer of 1,2, 3, 4, or 5];
the method characterized by comprising the step of:
reacting a compound of Formula (3):
64
^ ^
R10" R<
(3) 6
(in the formula, R and R are the same meaning as Formula (8));
with a reducing agent in the presence of an optically active ruthenium catalyst selected
from the group consisting of a compound of Formula (4):
X)CH3
H3CC) (4)
(in the formula, Ar is 3,5-dimethylphenyl), a compound of Formula (5):
OCH,
(in the formula, Ar is 3,5-dimethylphenyl), and a compound of Formula (6):
ci (6)
10 (in the formula, Ts is paratoluenesuifonyl) or an optically active oxazaborolidine
compound of Formula (7),
r4
6 5
2. The method for producing the optically active alcohol compound according to
claim 1, wherein R1 is a hydrogen atom, (Cj.g) alkyl optionally substituted with R3,
5 -C(0)R8-, or -Si(Rl2a)(Ri2b)R12.
3. The method for producing the optically active alcohol compound according to
claim 2, wherein the reaction is carried out in the presence of the optically active
ruthenium catalyst of Formula (4).
10
4. The method for producing the optically active alcohol compound according to
claim 3, wherein
R2 is -CH2N(R5)R4;
R4 is -C(0)R6 or -C(0)OR7;
15 R is Ci.6 alkyl or (Ci-e) alkyl optionally substituted with a halogen atom; and
R is a hydrogen atom, Ci-g alkyl, or (Ci-6) alkyl optionally substituted with a
halogen atom.
5. The method for producing the optically active alcohol compound according to
20 claim 4, wherein
R1 is (Ci-6) alkyl optionally substituted with R3, or -*Si(RI2a)(Rl2b)R12;
R is phenyl, or C3.8 cycloalkyl;
is a hydrogen atom, or R5 optionally forms a 5-membered ring together with a
nitrogen atom to which R4 and R5 are bonded by forming a C4 alkylene chain together
25 with R4, and in this case the alkylene chain is optionally substituted with an oxo group, or
66
the alkyiene chain optionally forms phenyl together with carbon atoms to which two
substituents each bond when the two substituents exist at adjacent positions on the
alkyiene chain;
R6 is (Cj.6) alkyl optionally substituted with a halogen atom; and
5 R13 is 9-fluorenyl.
6. The method for producing the optically active alcohol compound according to
claim 5, wherein
1 1
R is (Ci-s) alkyl optionally substituted with R ;
10 R3 is C3.8 cycloalkyl;
R4 is a -C(0)OR7;
R5 is a hydrogen atom; and
R7 is d.6 alkyl.
15 7. The method for producing the optically active alcohol compound according to
any one of claims 3 to 6, wherein the reducing agent is hydrogen gas.
8. The method for producing the optically active alcohol compound according to
claim 2, wherein the reaction is carried out in the presence of the optically active
20 ruthenium catalyst of Formula (6).
9. The method for producing the optically active alcohol compound according to
claim 8, wherein R6 is Cj-6 alkyl or (C|-e) alkyl optionally substituted with a halogen
atom.
25
10. The method for producing the optically active alcohol compound according to
claim 9, wherein
R1 is a hydrogen atom, (Gj.6)alkyl optionally substituted with R3, -C(0)R8, or
-Si(R,2a)(R12b)R12;
67
R5 is a hydrogen atom, or R5 optionally forms a 5-membered ring together with a
nitrogen atom to which R and R5 are bonded by forming a C4 alkylene chain together
with R4, and in this case the alkylene chain is optionally substituted with an oxo group, or
the alkylene chain optionally forms phenyl together with carbon atoms to which two
5 substituents each bond when the two substituents exist at adjacent positions on the
alkylene chain;
R6 is (Ci.g) alkyl optionally substituted with a halogen atom;
R7 is Ci.6 alky!;
R8 is phenyl; and
10 R13 is 9-fluorenyl.
11. The method for producing the optically active alcohol compound according to
claim 10, wherein
R is Ci_6 alkyl optionally substituted with R ;
15 R2 is cyano; and
R3 is C3.g cycloalkyl.
12. The method for producing the optically active alcohol compound according to
any one of claims 8 to 11, wherein the reducing agent is formic acid.
20
13. A compound of Formula (3'):
(in the formula, R is Q alkyl substituted with R ;
R is cyano; and
25 _R3 is cyclohexyl).
14. A method for producing a compound of Formula (3"):
68
(3") o
(in the formula, R1 is a cyciohexylmethyl group; and
R2 is -CH2NHC(0)0(C4H9-t) or -CH2NHCOCF3);
the method characterized by comprising the step of:
reacting an alcohol compound of Formula (44):
OH
(44)
(in the formula, R and R are the same meaning as Formula (3")) with an oxidizin
agent in the presence of N-hydroxy-2-azaadamantane of Formula (43):