DESCRIPTION
TITLE OF THE INVENTION: METHOD FOR PRODUCING OPTICALLY ACTIVE
5-HYDROXY-3-KETOESTER
5
TECHNICAL FIELD
[0001] The present invention relates to a method for producing an optically
active 5-hydroxy-3-ketoester compound that is useful as a pl~armaceuticali ntermediate
10 using 1,3-bis-(trialkylsi1oxy)-I -alkoxy-buta-l,3-diene. The present invention further
relates to a novel pharmaceutical intermediate compound having a crystalline form that is
obtained by the method described above.
BACKGROUND ART
15
[0002] As a method for synthesizing an optically active 5-hydroxy-3-ketoester
compound, an asymnlehic aldol reaction in which
1,3-bis-(trimethylsiloxy)-l-methoxy-buta-l,3-diene and an aldehyde are reacted in the
presence of an optically active binaphthol-titanium complex under a low temperature
20 condition has been reported (Non-Patent Document 1 and Non-Patent Document2).
Subsequently, a reaction example in which high yield and high stereoselectivity are
achieved by the same asymmetric aldol reaction in the presence of
N,N,N',N'-tetramethyletl~ylenediamine under a room temperature condition has been
reported. However, in this report, a reactive substrate is limited to cinnamaldehyde.
25 Furthermore, when an amine other than N,N,N1,N'-tetramethylethylenediaminies used,
the stereoselectivity decreases, and in particular, when a pyridine is used, the
stereoselectivity largely decreases won-Patent Document 3).
[0003] Among the optically active 5-hydroxy-3-ketoester compounds described
above, isopropyl
-5-l1ydroxy-3-oxohept-6-e1loate is a compound that has not been known. Therefore, a
method for synthesizing the compound and a crystal of the conlpound are also unknown
(for compounds of similar structure, see Patent Documents 1 to 6).
5
Prior Art Documents
Patent Documents
[0004] Patent Document 1: International Publication WO 20061106526
Patent Docutnent 2: International Publication WO 20081096257
10 Patent Document 3: International Publication WO 20081065410
Patent Document 4: International Publication WO 200710071 19
Patent Document 5: International Publication WO 200710171 17
Patent Document 6: International Publication WO 2006/100689
Non-Patent Documents
15 [0005] Non-Patent Document 1: Tetrahedron: Asymtnetry, 2000, vol. 11, pp.
2255 to 2258
Non-Patent Document 2: Tetrahedron: Asymmetry, 2001, vol. 12, pp. 959 to 963
Non-Patent Document 3: Tetrahedron: Asymmetry, 2010, vol. 21, pp. 156 to 158
20 SUMMARY OF THE INVENTION
Problem to be Solved by the Invention
[0006] It is an object of the present invention to provide a method for producing
an optically active 5-hydroxy-3-ketoester compound in high yield with high
25 stereoselectivity. It is another object of the present invention to provide a novel
pharmaceutical intermediate compound obtained by the method described above.
Means for Solving the Problems
[0007] The inventors of the present invention have intensively shtdied the
problems described above, and as a result, the inventors have found that the
3
aforementioned asymmetric aldol reaction is carried out in tlie presence of an optically
active binaphthol-titanium complex together with a substituted nitrogen-containing 5 or
6-membered aromatic lieterocyclic compound to obtain an optically active
5-hydroxy-3-ketoester compound in high yield with high stereoselectivity.
5 In addition, the inventors have showri that isopropyl
(S,E)-7-[4-(4-fluorophe1iyl)-6-isopropyl-2-@-niethyl1nethylsulfona1nido)pyrimidin-5-yl]
-5-hydroxy-3-oxoliept-6-e1ioate can be synthesized as a novel coliipound by the
production method. Among esters of
(S,E)-7-[4-(4-fl~1oropl1enyl)-6-isopropyl-2--methylnetliylsulfonamido)pyri1nidin-5-yl]
10 -5-hydroxy-3-oxohept-6-enoic acid, a methyl ester, an ethyl ester, and a t-butyl ester
thereof have been known. However, an isopropyl ester thereof has not been known.
Tlie esters are production intermediates of rosuvastatiii calcium known as an HMG-CoA
reductase inhibitor. Therefore, it is desirable that tlie esters be obtained with high purity.
However, the properties of already existing esters are confirmed to be oils, and therefore
15 there is a problem that the esters are unlikely to be purified industrially. The inventors
have tried crystallization of the novel isopropyl ester as a pharmaceutical intermediate
having properties that allow industrial purification. The inventors have intensively
studied furthel; and as a result, succeeded the crystallization of tlie ester for the first time.
Thus, the present invention has been accomplislied.
20 [0008] Specifically, the present invention is characterized as follows:
(I) A method for producing an optically active 5-hydroxy-3-ketoester compound of
Formula (4):
(wherein R~ is a CL.a~lk yl group, a C34 cycloalkyl group, a C6.14 a171 group, or a C7.16
25 aralkyl group, R' is a hydrogen atom, a C Ial~kyl group, a C3.6 cycloalkyl group, a C6.14
aryl group, or a C7.16 aralkyl group, R~ is an optionally substituted c1.6 alkyl group, an
4
optionally substituted C3.6 cycloalkyl group, an optionally substituted C6.14 aryl group, an
optionally substituted C7.16 aralkyl group, or an optionally substituted 5 to 10-meinbered
heterocyclic group, and n is an integer of 0 or I), characterized by cotnprising a step of
reacting a 1,3-diene compound of Formula (2):
R~~sXJJ~R~~
OR' (2)
R8
5
(wherein R5 and R6 are each independently a C1.6 alkyl group, a C3.6 cycloalkyl group, or
a C7.16 aralkyl group, and R7 and R* are defined the same as in Formula (4)) with an
aldehyde of Formula (3):
10 (wherein R9 and n are defined the same as in Formula (4)) in the presence of an optically
active binaphthol-titanium complex that is prepared from an optically active
1,l'-bi-2-naphthol compound of Formula (1):
(wherein R', R2, R', and R4 are each independently a hydrogen atom, a halogen atom, a
15 nitro group, a cyano group, a trialkylsilylethynyl group, an optionally substituted C1.6
alkyl group, an optionally substituted C3.6 cycloalkyl group, an optionally substituted CI-4
alkoxy group, an optionally substituted Q4 cycloalkoxy group, an optionally substituted
C1.6 alkenyl group, an optionally substituted C6.14 aryl group, an optionally substituted
C7-16 aralkyl group, or an optionally substituted 5 to 10-membered Iietesocyclic group)
5
and a tetravalent titaniunl compound while a substituted nitrogen-containing 5 to
6-membered aromatic heterocyclic compound is allowed to coexist.
(11) The method according to (I), wherein
R', R2, R', and R4 are each a hydrogen atom,
5 R5 and R6 are methyl group,
R7 is a c1.6 alkyl group,
Rs is a hydrogen atom,
R9 is an optionally substituted C6.14 aryl group or an optionally substituted 5 to
10-membered heterocyclic group, and
10 nis 1.
(111) The method according to (I) or (II), wherein R~ is a C6.L4a ty1 group, or a 5 to
10-membered heteroaryl group (the C6.14 aryl group and the 5 to 10-membered heteroaryl
group are not substituted or substituted by one substituent or two or more identical or
different substituents selected from the substituent group A), the substituent group A
15 includes a phenyl group, a phenyl group substituted by one or more halogen atoms, a C14
alkyl group, a C3.6 cycloalkyl group, and a C1.6 alkyl(C1.6 alkylsulfonyl)amino group.
(IV) The method according to (III), wherein R9 is a
4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-ygl roup, a
2-cyclopropyl-4-(4-fluoropheny1)quinolin-3 group, or phenyl group.
20 (V) The method according to any one of (I) to (IV), wherein the substituted
nitrogen-containing 5 to 6-membered aromatic l~eterocyclicc ompound is pyrrole,
imidazole, 1,2,3-triazole, or 1,2,4-triazole (the pyrrole, imidazole, 1,2,3-triazole, and
1,2,4-triazole are substituted by one or more substituents selected fsom the group
consisting of a C1.6 alkyl group, a C3.6 cycloalkyl group, a C Ial~kox y group, a C34
25 cycloalkoxy group, and a di-'21.6 alkylan~inog roup).
(VI) The method according to (V), wherein the substituted nitrogen-containing 5 to
6-membered aromatic heterocyclic compound is 1-metl~ylimidazole.
(VII) The method according to any one of (I) to (IV), wherein the substituted
nitrogen-containing 5 to 6-membered aromatic heterocyclic compound is pyridine,
6
pyridazine, pyrimidine, pyrazine, 1,2,3-triaziae, 1,2,4-triazine, or 1,3,5-triazine (the
pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazinie, 1,2,4-triazine, and
1,3,5-triazine are substituted by one or more substituents selected fro111 the group
consisting of a CL.a~lk yl group, a C3.6 cycloalkyl group, a c1.4a lkoxy group, a C34
5 cycloalkoxy group, and a Cl.6 alkylatnino group).
(VIII) The method according to (VII), wherein the suibstitutted nitrogen-containing 5
to 6-membered aromatic heterocyclic compound is 4-metl~oxypyridineo r
N,N-dimetliyl-4-aminopyridit~e.
(IX) Isopropyl
10 (S,E)-7-[4-(4-fluoropIienyl)-6-isoproppl-2-~-metliyl1netliylsulfonamido)pyrimidin-5-yl]
-5-liydroxy-3-oxohept-6-enoate of Formula (5).
F
(X) A crystal of the isopropyl
(S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-~-methylmethylsulfonamido)pyrimidin-5-ylJ
15 -5-hydroxy-3-oxohept-6-enoate according to (IX) having characteristic peaks at 28 =
4.5f0.2", 8.9&0.2", 11.6f0.2O, 15.5+0.2O, 18.0+0.2", 18.5+0.2", 19.5+0.2", 19.9+0.2",
21.4+_0.2', 22.1+_0.2", 22.8+_0.2", and 23.439.2" by powder X-ray diffraction
measurement using Cu-Ka as a radiation source.
(XI) A crystal of the isopropyl
20 (S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-~-metliylmetliylsu1fonamido)pyrimidin-5-ylJ
-5-hydroxy-3-oxohept-6-enoate according to (IX) having characteristic peaks at 28 = 4.5',
8.9", 11.6", 15.S0, 18.0°, 18.S0, 19S0, 19.9", 21.4",22.1°, 22.8", and 23.4" by powder
X-ray diffraction measurement using Cu-Ka as a radiation source.
Effects of the Invention
[0009] The present invention can provide a method for producing an optically
active 5-hydroxy-3-ketoester coil~poundin high yield with high stereoselectivity. The
5 present invention can firtl~eprr ovide a novel production intermediate compound having a
crystalline folm.
BRIEF DESCRIPTION OF THE DRAWINGS
10 [0010] [FIG. 11 FIG 1 shows a powdel X-ray diffraction pattern of crystal of
isopropyl
(S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-~-methylmethylsulfonamido)pyrimidin-5-yl]
-5-hydroxy-3-oxohept-6-enoate of the present invention. In FIG. 1, a vertical axis
represents a diffraction intensity (count), which means the number of counts of X-ray
15 photons. A horizontal axis represents a diffraction angle 20 (").
MODES FOR CARRYING OUT THE INVENTION
[0011] Hereinafter, the present invention will be further described in detail.
20 Tenns used herein will be described.
In the present specificaiton, "nu means normal, "i" means iso, "s" means secondary,
"t" means tertiary, and "c" means cyclo.
[0012] A c1.6 alkyl group means an alkyl gronp having a carbon atom number
of I to 6, that is, a linear or branched alkyl group having 1 to 6 carbon atoms. Specific
25 examples thereof include methyl group, ethyl gronp, n-propyl group, i-propyl group,
n-butyl gronp, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 2-methylbutyl
group, 3-methylbutyl group, n-hexyl gronp, 2-methylpentyl group, 3-methylpentyl group,
4-methylpentyl group, 2-ethylbutyl group, and 3-ethylbutyl group.
[0013] A C3-6 cycloalkyl group means a cycloalkyl group having a carbon atom
8
uu~llbero f 3 to 6, that is, a cyclic alkyl group having 3 to 6 carbon atoms. Specific
examples thereof include c-propyl group, c-butyl group, c-pentyl group, and c-hexyl
group.
[0014] A c1.4 alkoxy group means an alkoxy group having a carbon atom
5 nuniber of 1 to 4, that is, a substituent in which a linear or branched alkyl group having 1
to 4 carbon atoms is bonded to an oxygen atom. Specific examples thereof include
niethoxy group, ethoxy group, n-propoxy group, i-propoxy group, 11-butoxy group,
i-butoxy group, s-butoxy group, and t-butoxy group.
[0015] A '23.4 cycloalkoxy group means c-propoxy group or c-butoxy group.
10 [0016] A C2.6 alkenyl group means an alkenyl group having a carbon atotn
number of 2 to 6, that is, a linear or branched alkenyl group having 2 to 6 carbon atoms
and a double bond. Specific examples thereof include ethenyl group, 1-propenyl group,
2-propenyl group, 1-butenyl group, 2-butenyl group, and 3-butenyl group.
[0017] A C6.14 aryl group means an aryl group having a carbon atom number of
15 6 to 14, that is, an aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific
examples thereof include phenyl group, 1-naphtlryl group, 2-naphthyl group,
1-anthracenyl group, 2-anthracenyl group, 9-anthracenyl group, and biphenyl group.
[0018] A C6.14 aryloxy group means a group in which one "C6.14 aryl group"
described above is bonded to an oxygen atom. Specific examples thereof include
20 phenoxy group, 1-naphthyloxy group, and 2-naphthyloxy group.
[0019] A C7.16 aralkyl group means an aralkyl group having a carbon atom
number of 7 to 16, that is, an alkyl group that has an aromatic hydrocarbon as a
substituent and has 7 to 16 carbon atoms in the whole substituent. Specific examples
thereof include phenylmethyl group (benzyl group), 1-phenylethyl group, 2-phenylethyl
25 group, 1-phenylpropyl group, 2-plienylpropyl group, 3-plienylpropyl group,
naphthalea-1-ylmethyl group, naphthalen-2-ylniethyl group, naphthalen-1-ylethyl group,
naplithalen-2-ylethyl group, antluacen-1-yln~ethylg roup, anthracen-2-ylmethyl group,
and anthracen-9-ylmethyl group.
[0020] A 5 to 10-membered heterocyclic group means a monocyclic or
9
fused-ring heterocyclic group in which the nu~imber of atoms constituting the ring is 5 to
10 and the atoms constituting the ring contain a heteroatom selected from the group
consisting of a nitrogen atom, an oxygen atom, and a sulfi~ar tom or two to four identical
or different heteroatoms. The heterocyclic group may be saturated, partially unsaturated,
5 or unsaturated. Specific examples thereof include pyrrolidinyl group, tetrahydrofury1
group, tetrahydrothienyl group, piperidyl group, tetrahydropyranyl group,
tetral~ydrothiopyranylg roup, pyrrole group, fury1 group, thienyl group, pyridyl group,
pyritnidinyl group, pyridazinyl group, azepanyl group, oxepanyl group, thiepanyl group,
azepinyl group, oxepinyl group, thiepinyl group, imidazolyl group, pyrazolyl group,
10 oxazolyl group, thiazolyl group, imidazolynyl group, pyrazinyl group, morpl~olinygl roup,
thiadinyl group, indolyl group, isoindolyl group, benzin~idazolylg roup, purinyl group,
quinolyl group, isoquinolyl group, quinoxalinyl group, cimiolinyl group, pteridinyl group,
chromenyl group, and isochromenyl group.
[0021] A 5 to 10-membered heteroaryl group particularly tneans an unsaturated
15 5 to 10-membered heterocyclic group among the 5 to 10-membered heterocyclic groups
described above.
[0022] A m ~ n o - Ca~lk.y~la mino group means a group in which one hydrogen
atom in an amino group is substituted by one "C1.6 alkyl group" described above.
Specific examples thereof include methylamino group, ethylamino group, n-propylamino
20 group, i-propylamino group, n-butylamino group, i-butylamino group, t-butylamino
group, n-pentylamino group, and n-hexylamino group.
[0023] A di-C1.6 alkylamino group means a group in which two hydrogen atoms
in an amino group are substituted by two identical or different "C1.6 alkyl groups"
described above. Specific examples thereof include dimethylamino group, diethylamino
25 group, di-n-propylamino group, di-i-propylamino group, di-n-butylamino group,
di-i-butylamino group, di-t-butylamino group, di-n-pentylamino group, di-n-hexylamino
group, N-ethyl-N-methylamino group, N-methyl-N-11-propylamino group,
N-isopropyl-N-methylamino group, N-n-butyl-N-methylamino group,
N-i-butyl-N-methylamino group, N-t-butyl-N-methylamino group,
10
N-methyl-N-n-pentylamino group, N-11-hexyl-N-methylaniino group,
N-ethyl-N-n-propylamino group, N-ethyl-N-i-propylamino group,
N-n-butyl-N-ethylamino group, N-ethyl-N-i-butylamino group, N-t-butyl-N-ethyla~ni~lo
group, N-ethyl-N-n-pentylamilio group, and N-ethyl-N-n-hexylamino group.
5 [0024] A C1.4 alkoxycarbonyl group means a group in which one "Cl.4 alkoxy
group" described above is bonded to a carbobonyl group. Specific exanlples thereof
include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group,
i-propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, and
t-butoxycarbonyl group.
10 [0025] A C1.6 alkylsulfonyl group means a group in which one "Cl.6 alkyl
group" described above is bonded to a sulfonyl group. Specific examples thereof
include metl~ylsulfonygl roup, ethylsulfonyl group, n-propylsulfonyl group,
i-propylsulfonyl group, n-butylsulfo~~ygrl oup, i-butylsulfonyl group, t-butylsulfonyl
group, n-pentylsulfonyl group, and n-hexylsulfonyl group.
15 [0026] A C1.6 alkylsulfonylamino group means a group in which one hydrogen
atom in an amino group is substituted by one "c1.6a lkylsulfonyl group" described above.
Specific examples thereof include methylsulfonylamino group, etl~ylsulfonylaminog roup,
n-propylsulfonylamino group, i-propylsulfonylamino group, 11-butylsulfonylamino group,
i-butylsulfonylamino group, t-butylsulfo~~ylamingor oup, u-pentylsulfonylamino group,
20 and n-hexylsulfonylamino group.
[0027] A bis(C~.a~lk ylsulfonyl)amino group means a group in which two
hydrogen atoms in an amino group are substituted by two identical or different "CI.6
alkylsulfonyl groups" described above. Specific examples thereof include
bis(methylsulfonyl)atnino group, bis(ethylsulfonyl)a~ninog roup,
25 bis(n-propylsulfonyl)amino group, bis(i-propylsulfonyl)amino group,
bis(n-butylsulfonyl)amino group, bis(i-butylsulfonyl)amino group,
bis(t-butylsulfonyl)amino group, bis(n-pentylsulfonyl)amino group,
bis(n-hexylsulfonyl)amino group, N-ethylsutfonyl-N-mlethylsulfonylaminog roup,
N-n~ethylsulfonyl-N-n-propylsulfonylamingor oup,
11
N-i-propylsulfonyl-N-metliylsulfonylatlingor oup,
N-n-butylsulfonyl-N-methylsulfo~iylami~gioro up,
N-i-butylsulfonyl-N-n~ethylsulfonyla~nignroo up,
N-t-butylsulfonyl-N-methylsulfonylami~io group,
5 N-methylsulfonyl-N-n-pentylsulfonylanii~io group,
N-n-hexylsulfonyl-N-methylsulfonylaniino group,
N-ethylsulfouyl-N-n-propylsulfonylamino group,
N-ethylsulfonyl-N-i-propylsulfonylaniino group,
N-n-butylsulfonyl-N-ethylsulfonylamino group, N-ethylsulfonyl-N-i-butylsulfonylamino
10 group, N-t-butylsulfonyl-N-ethylsulfonylamino group,
N-ethylsulfonyl-N-n-pentylsulfonyla~nignroo up, and
N-ethylsulfonyl-N-n-hexylsulfonylamino group.
[0028] A C1.6 alkyl(Cl.6 alkylsulfotiyl)amino group, that is, an alkyl group
having a carbon atom number of 1 to 6 -(alkylsulfonyl having a carbon atom number of 1
15 to 6)amino group means a group in which two hydrogen atoms in an amino group are
substituted by one ''CI.~al kyl group" described above and one "CI.~al kylsulfonyl group"
described above. Specific examples thereof include N-methyl-N-methylsulfonylamino
group, N-ethyl-N-ethylsulfonylamino group, N-n-propyl-N-n-propylsulfonylamino group,
N-i-propyl-N-i-propylsulfonyla~ninog roup, N-n-butyl-N-n-butylsulfonylamingor oup,
20 N-i-butyl-N-i-butylsulfonylamino group, N-t-butyl-N-t-butylsulfonylamino group,
N-n-pentyl-N-n-pentylsulfonylamino group, N-n-hexyl-N-n-hexylsulfonyla~ningoro up,
N-ethyl-N-methylsulfonylamino group, N-methyl-N-n-propylsulfonylamino group,
N-i-propyl-N-methylsulfonylamino group, N-n-propyl-N-methylsulfonylamino group,
N-n-butyl-N-metl~ylsulfonylamignroo up, N-t-butyl-N-methylsulfonylamino group,
25 N-methyl-N-n-pentylsulfonylamino group, N-n-liexyl-N-metl~ylsulfonylaminog roup,
N-ethyl-N-n-propylsulfonylamino group, N-ethyl-N-i-propylsulfonylamino group,
N-n-butyl-N-etliylsulfo~~ylamingor oup, N-ethyl-N-i-butylsulfonylamino group,
N-t-butyl-N-ethylsulfonylamino group, N-etliyl-N-11-pentylsulfonylamig~r~oou p, and
N-ethyl-N-n-hexylsulfonylamino group.
12
[0029] A halogen atom means a fluorine atom, a chlorine atom, a bromine atom,
or an iodine atom.
[0030] "Optionally substituted" means unsubstituted or substituted by any
number of optional substitutions.
5 "Substituted" means substituted by any number of optional substitutions.
The "optional substituents" described above are not particularly limited as long as
the substituents do not adversely affect a reaction according to the present invention.
Examples of the optional substituents include a C1.6 alkyl group, a C3.6 cycloalkyl group,
a C2-6 alkenyl group, a C6-14 alyl group, a C6.14 aryloxy group, a C7.i6 aralkyl group, a 5 to
10 10-membered heterocyclic group, a hydroxyl group, a CIA alkoxy group, a CX4
cycloalkoxy group, an acetoxy group, a benzoyloxy group, an amino group, a mon~-C~.~
alkylamino group, a CE-6a lkylsulfonylamino group, a N-acetylamino group, a di-C~.~
alkylamino group, a bis(Ci.6 alkylsulfonyl)amino group, a C1.6 aikyl(Cl.6
alkylsulfony1)amino group, a N,N-diacetylamino group, a halogen atom, a CIA
15 alkoxycarbonyl group, a phenoxycarbonyl group, a N-methylcarbamoyl group, a
N-phenylcarbamoyl group, a cyano group, a nitro group, and a carboxy group.
Additional examples thereof include phenyl groups substituted by the aforementioned
substituents.
[0031] A 5 to 6-membered nitrogen-containing aromatic heterocyclic compound
20 means a monocyelie aromatic heteroaromatic compound in which the number of atoms
constituting the ring is 5 to 6 and the atoms constituting the ring contain 1 to 4 nitrogen
atoms. Specific examples thereof include pyrrole, pyrazole, imidazole, triazole,
tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiazole, isothiazole,
oxazole, isoxazole, oxadiazole, and thiadiazole.
25 [0032] Next, preferable structures and preferable reaction conditions in the
present invention will be described.
[0033] A 1,l'-bi-2-naphthol compound that is optically active binaphthol used in
the method of the present invention is represented by Formula (1). In Formula (I), R',
R2, R3, and R~ are each independently a hydrogen atom, a halogen atom, a nitro group, a
13
cyano group, a trialkylsilylethynyl group, an optionally substituted CI.6 alkyl group, an
optionally substituted C3.6 cycloalkyl group, an optionally substituted C1.4 alkoxy group,
an optionally substituted C34 cycloalkoxy group, an optionally substituted C2.6 alkenyl
group, an optionally substituted C6.14 aryl group, or an optionally substituted 5 to
5 10-membered heterocyclic group, and are each preferably a hydrogen atom.
[0034] The tetravale~t~itta nium compound in the present invention is not
particularly limited as long as the reaction according to the present invention can be
achieved.
A counterpart of titanium of the tetravalent titanium compound (hereinafter referred
10 to as titanium substituent) may be an organic substance or an inorgauic substance.
Specific examples of the titanium substituent include a halogen atom, an alkoxy group, or
an oxygen atom. The halogen atom is preferably a chlorine atom, and the alkoxy group
is preferably a c1.4 alkoxy group or a C3.4 cycloalkoxy group, and niore preferably an
isopropoxy group.
15 The tetravalent titanium compound is preferably halogenated titanium,
dihalogenated dialkoxytitanium, or tetralkoxytitaniurn, more preferably titanium
tetrachloride, dichloro-Cl4 alkoxytitanium, dibromo-C14 alkoxytitanium, or tetra-C14
alkoxytitanium, further preferably tetra-CI.4 alkoxytitanium, and particularly preferably
tetraisopropoxytitanium.
20 [0035] The tetravalent titanium compound is preferably used in an amount of
0.5 molar equivalents to 2.0 molar equivalents, and more preferably 0.8 molar
equivalents to 1.2 molar equivalents, relative to the optically active binaplithol.
[0036] An optically active binaphthol-titanium complex used in the method of
the present invention is prepared, for example, in accordance with the method described
25 in Patent Document 2. Specifically, the optically active binaphthol and titanium
tetraisopropoxide are reacted in an organic solvent such as tetrahydrofuran and toluene.
At that time, the optically active binaphthol-titanium complex is prepared by a method of
allowing n~oleculars ieves to coexist, or a method of adding water, The optically active
binaphthol-titanium complex can be used in a concentrated and isolated form or in a
14
solution form as it is in the next step. The optically active binaphthol-titanium con~plex
is preferably used in an atnount of 0.1% by mole to 50% by mole, and more preferably
0.5% by mole to 10% by mole, relative to an aldehyde.
[0037] A 1,3-diene conlpound used in the method of the present invention is
5 represented by Formula (2). In Formula (2), RS and R~ are each independently a C1.6
alkyl group, a C3.6 cycloalkyl group, or a C7.16 aralkyl group, each preferably
independently a Cl.6 alkyl group, and each more preferably a methyl group. R~ is a CI.6
alkyl group, a C3-6 cycloalkyl group, a C6.14 aryl group, or a C7.16 aralkyl group,
preferably a C1.6 alkyl group, and more preferably a methyl group, an ethyl group, a
10 n-propyl group, an i-propyl group, or a t-butyl group. R8 is a hydrogen atom, a C1.6,
alkyl group, a C3.6 cycloalkyl group, a C6.14 aryl group, or a C7.16 aralkyl group, and
preferably a hydrogen atom.
[0038] This 1,3-diene compound is prepared, for example, in accordance with a
method by Brownbridge et al. (Canadian Journal of Chemistry, 1983, vol. 61 (4), pp. 688
15 to 693). The 1,3-diene compound is used in an amount of 1.0 molar equivalent or more,
preferably 1.0 molar equivalent to 3.0 molar equivalents, and more preferably 1.1 molar
equivalents to 2.0 molar equivalents, relative to the aldehyde.
[0039] The aldehyde used in the method of the present invention is represented
by Formula (3). In Formula (3), R~ is preferably a C6.14 aryl group or a 5 to
20 10-membered heteroaryl group (the C6.14 aryl group and the 5 to 10-membered heteroaryl
group are not substituted or are substituted by one substituent or two or more identical or
different substituents selected from the substituent group A). The substituent group A
includes phenyl group, phenyl group substituted by a halogen atom, a alkyl group, a
C3.6 cycloalkyl group, and a c1.6 alkyl(Cl.6 alky1sulfonyl)amino group, and is preferably a
25 phenyl group, a pyrimidinyl group, or a quinolyl group (the phenyl group, the
pyrimidinyl group, and the quinolyl group are not substituted or are substituted by one
substituent or two or more identical or different substituents selected from the substituent
group A). The substituent group A niore preferably includes a phenyl group, a phenyl
group substituted by one or more halogen atoms, a C1.6 alkyl group, a 4 . 6 cycloalkyl
15
group, and a C1.6 alkyl(C1.6 alkylsulfonyl)amino group, and is more preferabty a
4-(4-flnoropl1enyl)-6-isopropyl-2-~-1nethj~1metI1y1s~1fonamido)pyrin1idig11ro-u5-py, la
2-cyclopropyl-4-(4-fluorophenyl)quiuoli11-3-yg1r oup, or a phenyl group.
n is an integer of 0 or 1, and preferably 1.
5 [0040] A substituted nitrogen-containing 5 to 6-ntembered aromatic heterocyclic
comnpound is preferably substituted pyrrole, substituted imidazole, substituted
1,2,3-triazole, or substituted 1,2,4-triazole. Apreferable substitaent in the compound is
one or more substituents selected from the group consisti~~ogf a C1.6 alkyl group, a C3.6
cycloalkyl group, a C1.4 alkoxy group, a C3.4 cycloalkoxy group, and a Cl.6 alkylamino
10 group. The co~npoundis more preferably pyrrole substituted by a CI.a~lk yl group,
imidazole substituted by a C1.6 alkyl group, 1,2,3-triazole substituted by a CI.6 alkyl
group, or 1,2,4-triazole substituted by a C1.6 alkyl group, further preferably
1- methylpyrrole, 1- methyli~nidazole1 -methyl-1 H - 1,2,3-triazole,
2-methyl-2H-l,2,3-triazolel,- rnetl1yl-lH-l,2,4-triazoleo,r 4-methyl-413-l,2,4-triazole,
15 and particularly preferably 1-methylimidazole.
[0041] Furthel; the substituted nitrogen-containing 5 to 6-membered aromatic
heterocyclic compound is preferably substituted pyridine, substituted pyridazine,
substituted pyrimidine, substituted pyrazine, substituted 1,2,3-triazine, substituted
1,2,4-triazine, or substituted 1,3,5-triazine. A preferable substituent in the compound is
20 one or more substituents selected from the group consisting of a C1.6 alkyl group, a C3.6
cycloalkyl group, a Ct-4 alkoxy group, a C3.4 cycloalkoxy group, and a Cl.6 alkyla~nino
group. The compound is more preferably pyridine substituted by a C1.4 alkyl group, or
pyridine substituted by a C1.6 alkylamino group, and further preferably
4-methoxypyridine or N,N-dimetl~yl-4-aminopyridine.
25 [0042] The nitrogen-containing 5 to 6-membered aromatic heterocyclic
compounds may be used singly or as a mixture of a plurality of these.
[0043] The reaction in the method of the present invention is preferably carried
out in the presence of a solvent. The solvent used is not particularly limited as long as it
does not inhibit the reaction. Preferred examples of the solvent include aliphatic
16
hydrocarbons (hexane, heptane, etc.), aromatic hydrocarbons (benzene, toluene, xylene,
etc.), ethers (diethyl ethel; diisopropyl ether, tetrahydrofuran, 1,4-dioxane, t-butyl methyl
ether, etc.), halogenated aliphatic hydrocarbons (methylene chloride, chloroform,
dichloroetl~anee, tc.), and nitriles (acetonitrile, propionitrile, etc.). Aromatic
5 hydrocarbons and ethers are more preferred, toluene and tetrahydrofuran are further
preferred, and tetrahydrofi~ranis particula~lyp referred.
[0044] The solvents may be used alone or as a mixture of a plurality of the
solvents. In general, the amount of the solvent to be used depends on whether or not a
substrate is crystalline, whether or not the viscosity is high, or the like. Tlierefore, the
10 amount of the solvent to be used can be optionally determined according to the substrate,
and is not limited as long as the substrate can be partially dissolved. In terms of effects
of stirring efficiency and volume efficiency, the substrate concentration of aldehyde is
generally 1% by weight to 80% by weight, preferably 3% by weight to 50% by weight,
and more preferably 5% by weight to 20% by weight.
15 [0045] The reaction can be carried out at any temperature of -78°C to the
boiling point of a reaction medium. From the viewpoints of reaction operation and the
industrial point of view, the temperature is generally -40°C or higher and 60°C or lower,
preferably -20°C or higher and 40°C or lower, and more preferably -5OC or higher and
40°C or lower.
20 [0046] With respect to a reaction pattern, a mixture of the aldehyde, the
1,3-diene conlpound, the substituted nitrogen-containing 5 to 6-membered aromatic
heterocyclic compound, and the solvent may be added to the optically active
binaphthol-titanium complex that has been prepared in advance, or the aldehyde, the
optically active hinaphthol, the tetravalent titanium conlpound, the substituted
25 nitrogen-containing 5 to 6-membered aromatic heterocyclic compound, and the 1,3-diene
compound may be added in sequence. The addition order and method are not limited as
long as they do not affect the reaction.
[0047] After completion of the reaction, an acid aqueous solution containing
trifluoroacetic acid and sulfuric acid and the like is added to reaction solution and stirred
17
to inactive a cornplex in the solution. A trialkylsilyl group is removed, and an alkaline
solution such as an aqueous sodium carbonate solution is then added. The target
conlpound is extracted by separation. The obtained organic phase is subjected to a
purification operation such as column chromatography and crystallization. Thus, the
5 target conlpound can be obtained.
[0048] Next, isopropyl
(S,E)-7-[4-(4-fluoropl~enyl)-6-isopropyl-2-~-1nethylmetl1ylst~lfo~1amido)pyri1~1idin-5-yl]
-5-hydroxy-3-oxohept-6-enoate of Formula (5) that is the novel compound of the present
invention will be described. The conlpound of Formula (5) can be produced by a
10 reaction of
(E)-N-[4-(4-fluo1~opl1enyl)-6-isopropyl-5-(3-oxoprop-l-en--yll )pyrimidin-2-yl]-N-metha
nesulfoneamide with 1,3-bis-(trimetlrylsiloxy)-l-isopropoxybnta-l,3-diene in the method
of the present invention.
[0049] As described above, as esters of
15 (S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-~-methylmetl~ylsulfonamido)pyrimidin-5-yl]
-5-l1ydroxy-3-oxohept-6-enoiacc id, a nlethyl estel; an ethyl ester, and a t-butyl ester
thereof have been known. Hereinafter, the respective esters will be described as
references.
(1) Methyl ester
20 CAS NO. 912337-61-2 (5S, 6E), 890028-67-8 (6E)
Property: yellow oil
Source: International Publication WO 2006f106526
(2) Ethyl ester
CAS NO. 901765-36-4 (5S, 6E)
25 Property: oil
Source: International Publication WO 20081096257, International Publication WO
20081065410, and International Publication WO 2007/007119 (Patent Document 2,
Patent Document 3, and Patent Document 4)
(3) t-butyl ester
18
CAS NO. 910867-13-9 (5S, 6E), 947262-23-9 (6E)
Property: oil (Patent Document 2), brown oil (Patent Document 5), or orange oil (Patent
Document 6)
Source: International Publication WO 20081096257, International Publication WO
5 200710171 17, and International Publication WO 20061100689
[0050] For a crystallization operation of the compouttd of Forniula (5), an
alcohol solvent, an ester solvent, or an aromatic ltydrocarbon solvent is used.
[0051] The alcohol solvent to be used is an alcohol having 1 to 4 carbobon atoms
such as methanol, ethanol, n-propanol, i-propanol, n-butanol, s-butanol, t-butanol and the
10 like and preferably i-propanol.
LO0521 Tlte ester solvent to be used is a foimate ester (methyl formate, ethyl
formate, and n-propyl formate), or acetate ester (methyl acetate, etl~yal cetate, n-propyl
acetate, i-propyl acetate, n-butyl acetate, i-butyl acetate, and t-butyl acetate), and
preferably ethyl acetate.
15 [0053] The aromatic hydrocarbon solvent to be used is an aromatic hydrocarbon
having 6 to 8 carbon atoms (benzene, toluene, and xylene), and preferably toluene.
[0054] These solvents may be used as a mixture with other solvents at any
mixing ratio.
[0055] These solvents may be used for crystallization in an amount of 1 part by
20 weight to 100 parts by weight, preferably 2 parts by weight to 20 parts by weight, and
more preferably 5 parts by weight to 15 parts by weight, relative to 1 g of the target
con~poundo f Formula (5).
[0056] The crystallization is catried out by any one of a method of cooling after
heating and dissolving, a method of concentrating after dissolving, and a method of
25 adding low-soluble solvent (poor solvent) after dissolving, or a combination of these.
[0057] The crystallization temperature falls within a range of -20°C to 60°C,
and preferably -lO°C to 50°C unless otherwise stated.
[0058] For the crystallization, a seed crystal can be used. Tlte seed crystal can
be obtained by a method known by those skilled in the art, the ntetltod in which a wall of
19
a container containing a solution of the target compound is rubbed with a spatula.
[0059] Characteristics of a crystal, particularly a difference fro~nan other
crystalline form (crystal polymorphism) can be analyzed by powder X-ray diffraction
measurement. Aposition of peak (peak value) obtained by the powder X-ray diffraction
5 measurement is represented by 28. The unit of 28 is degree ("). The peak value may
vary depending on measurement conditions. In a case where a crystalline form of a
sample is identified by comparing the measured peak of the sample with the peak value
of a standard substance, when the crystalline forms are identical, the peak value of the
sample and the peak value of the standard substance are generally equal within a
10 difference of 0.2" (see The Japanese Pharmacopoeia 16th edition). Therefore, a peak
value according to the compound of the present invention allows a difference within
about +0.2", and is identified. Accordingly, when the peak value according to the
compound of the present invention is compared with the measured peak value of the
target sample, a peak having a difference within about k0.2" is regarded as identical
15 diffraction peak. Thus, the identification can be carried out. However, the peak value
may be affected by measurement devices and measurement conditions. Therefore, a
difference of crystalline form can be finally confirmed by comprehensive analysis of the
measurement condition, the peak value, the diffraction pattern, and the like.
[Examples]
20 [0060] Hereinafter, the present invention will be described specifically with
reference to Examples, but the scope of the present invention is not limited to these
Examples.
[0061] A structure of a product was confirmed by 'H-NMR in ECP-300
manufactured by JEOL Ltd. Hereinaftel; 'H-NMR data described is represented by a
25 chemical shift 6 (unit: ppm) (division pattern, integrated value) of signal using
tetramethylsilane as an internal standard substance. In a described division pattern, "s"
means singlet, "d" means doublet, "t" means triplet, "septet" means septet, "dd" means
double doublet, "n~m" eans multiplet, "J" means coupling constant, and "CDCI3 " means
deuterated chloroform.
20
[0062] Powder X-ray diffraction was measured by X'PestPRO (radiation source:
Cu-Ka, wavelength: 1.54060 (lo-'' 111)) manufactured by PANalytical B.V. Differential
scanning calori~netryw as measured by DSCl ~nanufacturedb y Mettler-Toledo
International Inc.
5 [0063] Reference Example 1
Preparation of (S)-(-)-binaphthol-titanium co~nplexs olution
4.41 g of toluene was added to 0.7570 g (2.65 mmol) of (S)-(-)-1,l'-bi-2-naphthol
and mixed at O°C to 10°C. To the mixed liquid, a mixed solution of 0.7571 g (2.65
mmol) of titanium tetraisopropoxide, 0.0477 g (2.65 mmol) of water, and 2.28 g of
10 tetrahydrofuran was added dropwise, and 1.12 g of tetrahydrofuran was further added.
The resultant mixture was stirred for 20 minutes to obtain an (S)-(-)-binaphthol-titanium
complex solution.
[0064] Example 1
Synthesis of isopropyl
15 (S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-~-n~etl~ylmethylsulfonamido)pyrimidin-5-yl]
-5-hydroxy-3-oxohept-6-enoate using N,N-dimethyl-4-aminopyridine
10.00 g (26.49 mmol) of
methanesulfoneamide and 48.03 g of tetrahydrofi~ranw ere mixed and stisred at room
20 temperature for 10 minutes. To this solution, 1.83 g (0.53 mmol) of the
(S)-(-)-binaphthol-titanium complex solution prepared in accordance with the nlethod of
Reference Example 1 was added, and the mixture was washed with 2.01 g of
tetrahydrofuran. In addition, 1.30 g (1 0.60 mmol) of N,N-dimethyl-4-amitiopyridine
and 17.61 g (45.04 mmol) of 1,3-bis-(trimetl~ylsiloxy)-I-isopropoxybuta-l,3-dienwe ere
25 added, and the resultant solution was stirred at room temperature for 22 hours.
Subsequently, 30.01 g of tetrahydrofuran was added to this solution, 7.83 g (39.74 mmol)
of aqueous solution of 50% sulfuric acid was then added dropwise, and the resultant
solution was sti~~aetd s oon1 temperature for 1 hour. To the solution, 25.30 g (23.85
mmol) of aqueous solution of 10% sodium carbonate was further added, and the resultant
2 1
solution was stirred at room temperature for 30 minutes, and separated to obtain an
organic phase. The obtained organic phase was washed with 29.53 g of 20% salt
solutio~a~n,d separated to obtain 100.00 g of organic phase. The organic phase was
concentrated under reduced pressure to obtain 30.30 g of solution. To the solution,
5 100.13 g of ethyl acetate was added, and the resultant solution was concentrated again
under reduced pressure to obtain 26.07 g of solution. Then 19.99 g of n-heptane was
added. An insoluble substance was collected by filtration through CeliteB, and washed
with a mixed solution of 2.00 g of ethyl acetate and 2.01 g of 11-heptane. To the
combined solution of the filtrate and the washing liquid, 20.05 g of ethyl acetate and
10 20.08 g of n-heptane were added, the resultant solution was heated to 50°C, stirred for 5
minutes, cooled to 2S°C, and stirred for 120 minutes. To this solution, 40.00 g of
n-heptane was further added dropwise over 60 minutes, and the resultant mixture was
stirred in an ice bath for 16,hours. A solid deposited during stirring in the ice bath was
collected by filtration, washed with a mixed solution of 3.80 g of ethyl acetate and 8.27 g
15 of n-heptane, and dried at 50°C under reduced pressure to obtain 11.52 g (22.09 mmol) of
isopropyl
(S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-~-methyImethylsulfonamido)pyrimidin-5-yl]
-5-hydroxy-3-oxohept-6-enoate as a pale yellow solid. The isolated yield was 83.4%,
and the optical purity was 99.46%~.
20 'H-NMR (CDC13)
6 ppm: 1.25-1.27 (m, 12H), 2.64-2.66 (m, 2H), 2.91 (d, lH, J=4.1 Hz), 3.32-3.38 (m, lH),
3.41 (s, 2H), 3.51 (s, 3H), 3.57 (s, 3H), 4.61-4.68 (m, lH), 5.06 (septet, lH, J=6.1 Hz),
5.44 (dd, lH, J=5.1, 16.2 Hz), 6.67 (dd, IH, J=1.7, 16.0 Hz), 7.15-7.60 (m, 2H),
7.60-7.67 (m, 2H)
25 [0065] The optical purity was calculated as an enantiomeric excess (%ee) by
high performance liquid chromatography analysis using a colum~flo r separation of
optical isomer.
Column: CHIRALPAK IA (manufactured by DAICEL CORPORATION)
Eluent: n-hexane/methanol/diethylamine=970/30/3V NN
LL
Eluent flow rate: 1.0 mL/min
Detection wavelength: 245 nni
[0066] The powder X-ray diffraction of crystal obtained in Example 1 was
measured, and the following characteristic peaks and particularly characteristics peaks are
5 confirmed.
(Characteristic peaks)
28=4.5", 8.9", 11.6", 15S0, 18.0°, 18.5", 19S0, 19.9°,21.40,22.10,22.2830.,4 "
(Particularly characteristic peaks)
28=4.S0, 15.S0, 18.0°, 18.5°,21.40,22.10,22.80
10 A powder X-ray diffraction pattern obtained in the measurement is shown in FIG. 1.
[0067] In Exarnples 2 and 3, a reaction yield was calculated by quantitative
analysis using high performance liquid chromatography with tlie compound obtained in
Example 1 used as a standard substance and diethyl phthalate used as an internal standard
substance.
15 Column: L-column ODs (manufactured by Chen~icalEs valuation and Research Institute,
Japan)
Eluent: aqueous solution of methanol-0.01 M ammonium acetate, 65:35
Eluent flow rate: 0.4 mL/min
Detection wavelength: 250 nm
20 [0068] Example 2
Synthesis of isopropyl
(S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-~-methylmethylsulfonamido)pyrimidin-5-yl]
-5-hydroxy-3-oxohept-6-enoate using 4-methoxypyridine
The title compound was obtained by the same operation as in Example 1 except that
25 the used amount of
(E)-N-[4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-l -en-1-y1)pyrimidin-2-yl]-N-nietha
nesulfoneamide was changed to 5.00 g (13.2 mmol) and 0.58 g (5.30 mmol) of
4-metlioxypyridine was used instead of N,N-dimethyl-4-aminopyridine. As other
reagents, the same reagents as those in Example 1 were used (provided that the molar
23
equivalents of the other used reagents were the same as the amounts relative to the
amount of aldehyde in Exanlple 1). The quantitative yield was 92.1%, and the optical
purity was 99.75%ee.
[0069] Example 3
5 Synthesis of isopropyl
-5-hydroxy-3-oxohept-6-enoate using N-~nethylin~idazole
The title con~poundw as obtaitled by the same operation as in Example 1 except that
the used amount of
10 (E)-N-[4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-l-en-l-yl)pyrin~idin-2-yl]-N-n~ethyl
methanesulfoneamide was changed to 5.00 g (13.2 rnmol) and 0.44 g (5.30 mmol) of
N-methylimidazole was used instead of N,N-dimethyl-4-aminopyridine. As other
reagents, the same reagents as those in Example 1 were used (provided that the molar
equivalents of the other used reagents were the same as the amoulrts relative to the
15 amount of aldehyde in Example 1). The quantitative yield was 88.2%, and the optical
purity was 99.13%ee.
[0070] In Examples 4 and 5, a reaction yield was calculated by quantitative
analysis using high performance liquid chromatography with isopropyl
(S,E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-5-hydroxy-3-oxol~ept-6-enoate
20 obtained by a method described in International Publicatiou WO 20031042180 used as a
standard substance and diethyl phthalate used as an internal standard substance.
Column: L-column ODs (manufactured by Chemicals Evaluation and Research Institute,
Japan)
Eluent: aqueous solution of methanol-0.01 M ammonium acetate, 75:25, VN
25 Eluent flow rate: 0.4 mL/min
Detection wavelength: 250 mn
[0071] The optical purity was calculated as an enantiomeric excess (%ee) by
high performance liquid chromatography analysis using a column for separation of
optical isomer.
24
Column: CHIRALPAK AD-H (manufactured by DAICEL CORPORATION)
Eluent: n-l1exane/ethanol/diethylamine=950/50/5,V NN
Eluent flow rate: 0.5 n~L/min
Detection wavelength: 245 nm
5 [0072] Example 4
Synthesis of isopropyl
(S,E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-5-hydroxy-3-oxoI1ept-6-e11oate
using N,N-dimethyl-4-aminopyridine
5.00 g (15.75 mmol) of
10 (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]acrylaldehyde and 24.00 g of
tetrahydrofuran were mixed and stirred at room temperature for 10 minutes. To this
solution, 1.09 g (0.32 mmol) of the (S)-(-)-binaplrthol-titanium complex solution
prepared in accordance with the method of Reference Example 1 was then added, and the
resultant mixture was washed with 1.00 g of tetrahydrofuran. 0.77 g (6.30 mmol) of
15 N,N-dimethyl-4-aminopyridinean d 10.47 g (26.78 mmol) of
1,3-bis-(~imethylsiloxy)-l-isopropoxybuta-1,3-dienwe ere added, and the resultant
mixture was stirred at room temperature for 22 hours. Subsequently, 15.02 g of
tetrahydrofuran was added, 4.64 g (23.63 mmol) of aqueous solution of 50% sulfuric acid
was then added dropwise, and the resultant mixture was stirred at room temperature for 1
20 hour. To the resultant mixture, 15.03 g (14.18 mmol) of aqueous solution of 10%
sodium carbonate was further added, and the resultant mixture was stirred at room
temperature for 30 minutes, and separated to obtain an organic phase. The quantitative
yield was 97.5%, and the optical purity was 99.29%~~.
[0073] Example 5
25 Synthesis of isopropyl
using N-n~ethylimidazole
The title compound was obtained by the same operation as in Example 4 except that
0.51 g (6.30 mmol) of N-methylimidazole was used instead of
25
N,N-din1ethyl-4-aminopyridinue sed in Example 4. As other reagents, the same
reagents as those in Example 4 were used. The quantitative yield was 96.2%, and the
optical purity was 99.28%ee.
100741 Example 6
5 Synthesis of isopropyl (S,E)-5-l1ydroxy-3-0~0-7-phenylhept-6-euoautsei ng
N,N-dimethyl-4-amiuopyridine
To a mixed solution of 3.00 g (22.70 nnnol) of cinnamaldehyde and 14.40 g of
tetrahydrofuran, 1.61 g (equivalent to 0.45 n~mol)o f the (S)-(-)-binapl~thol-titanium
complex solution prepared in accordance with the method of Reference Exarnple 1 was
10 added, and the resultant mixture was washed with 0.60 g of tetrahydrofuran. 1.10 g
(9.08 mmol) of N,N-dimethyl-4-aminopyridinean d 10.23 g (equivalent to 38.59 mmol)
of 1,3-bis-(trimethylsiloxy)-l-isopropoxybuta-l,3-dienwe ere added, and the resultant
mixture was stirred at roonl temperature for 22 hours. Subsequently, 9.00 g of
tetrahydrofuran was added, 6.68 g (34.05 rnmol) of aqueous solution of 50% sulfuric acid
15 was then added dropwise, and the resultant mixture was stirred at room temperature for 1
hour. To the resultant mixture, 21.65 g (20.43 n~mol)o f aqueous solution of 10%
sodium carbonate was further added, and the resultant mixture was stirred at room
temperature for 30 minutes, and separated to obtain 39.55 g of organic phase. The
resultant organic phase was concentrated under reduced pressure, and then purified by
20 silica gel column chromatography (hexanelethyl acetate = 70130) to obtain isopropyl
(S,E)-5-hydroxy-3-0~0-7-phenyll1ept-6-enoate.T he isolated yield was 96.9%, and the
optical purity was 95.43%ee.
'H-NMR (CDC13)
6 ppm:1.26 (d, 6H, J=6.1 Hz), 2.77-2.95 (m, 2H), 3.48 (s, 2H), 4.72-4.85 (m, lH),
25 4.98-5.14(m, lH),6.20(dd, IH, J=6.1, 15.7Hz),6.65 (dd, lH, J=1.0, 15.7Hz),
7.18-7.42 (m, 5H)
[0075] The optical purity was calculated as an enantiomeric excess (%ee) by
high performance liquid chromatography analysis using a column for separation of
optical isomer.
26
Column: CHIRALPAK AD (manufactured by DAICEL CORPORATION)
Eluent: n-I~exane/ethanol/diethylamine=950/50V, N, containing 0.01% of trifluoroacetic
acid
Eluent flow rate: 1.0 mL/min
5 Detection wavelengtli: 254 nnl
[0076] Exanlple 7
Synthesis of isopropyl (S,E)-5-l1ydroxy-3-oxo-7-pl1enyll1ept-6-enoatues ing
N-metl~ylin~idamle
The title compouild was obtained by the same operation as in Example 6 except that
10 0.75 g (9.08 mmol) of N-metl~ylimidazolew as used instead of
N,N-dimethyl-4-aminopyridineu sed in Example 6. As other reagents, the same
reagents as those in Example 6 were used. The isolated yield was 95.5%, and the
optical purity was 93.85%ee.
15 INDUSTRIAL APPLICABILITY
[0077] The present invention is useful in that an optically active
5-hydroxy-3-ketoester compound useful as a phalmaceutical intermediate can be
produced in lugh yield with high stereoselectivity. The present invention is further
20 useful in that a novel production intermediate compound having a crystalline form can be
provided.

CLAIMS
1. A method for producing an optically active 5-hydroxy-3-ketoester compound of
Formula (4):
(wherein, R7 is a C1.6 alkyl group, a C3.6 cycloalkyl group, a C6.14 aryl group, or a C7.,6
aralkyl group, R8 is a l~ydrogena tom, a C1.6 alkyl group, a C3.6 cycloalkyl group, a C6-14
aryl group, or a C7.16 aralkyl group, R~ is an optionally substituted C1.6 alkyl gronp, an
optionally substituted C3.6 cycloalkyl group, an optionally substituted C6.14 acyl group, an
10 optionally substituted C7-16 aralkyl group, or an optionally substituted 5 to 10-membered
heterocyclic group, and n is an integer of 0 or I), characterized by comprising a step of
reacting a 1,3-diene compound of Formula (2):
(wherein R' and R6 are each independently a CI.6 alkyl group, a C3.6 cycloalkyl group, or
15 a c7-1ar~al kyl group, and R7 and R* are defined the same as in Formula (4)) with an
aldehyde of Formula (3):
(wherein R9 and n are defined the same as in Fornlula (4)) in the presence of an optically
active binaphthol-titanium complex that is prepared from at1 optically active
20 1,l'-bi-2-naphthol compound of Formula (1):
(wherein R', R2, R ~a,nd R4 are each independently a hydrogen atom, a halogen atom, a
nitro group, a cyano group, a trialkylsilyletllyn~g~rlo up, an optionally substituted CI.6
alkyl group, an optionally substituted C3.6 cycloalkyl group, an optionally substituted C14
5 alkoxy group, an optionally substituted C34 cycloalkoxy group, an optionally substituted
C1.6 alkenyl group, an optionally substituted C6.14 aryl group, an optionally substituted
C7-16a ralkyl group, or an optionally substituted 5 to 10-membered heterocyclic group)
and a tetravalent titanium compound while a substituted nitrogen-containing 5 to
6-membered aromatic heterocyclic compound is allowed to coexist.
10
2. The method according to claim 1, wherein
R', R ~R,3 , and R4 are each a hydrogen atom,
RS and R6 are methyl group,
R7 is a C1.6 alkyl group,
15 R' is a hydrogen atom,
R9 is an optionally substituted C6.14 aryl group or an optionally substituted 5 to
10-membered heterocyclic group, and
n is 1.
20 3. The method according to claim 1 or 2, wherein R~ is a C6.14 aryl group, or a 5 to
10-membered heteroaryl group(the C6.14 aryl group and 5 to 10-membered heteroaryl
group are not substituted or substituted by one substituent or two or more identical or
different substituents selected from the substituent group A), the substituent group A
includes a phenyl group, a phenyl group substituted by one or more halogen atoms, a c1.6
29
alkyl group, a C3.6 cycloalkyl group, and a C1.6 alkyl(Cl.6 alkylsulfonyl)a~~~ginroou p.
4. The method according to claim 3, wherein R~ is a
4-(4-fluoropl1enyl)-6-isopropyl-2-~-met11yl11ethylsulfonamido)pyri11idi1g-ro5u-pyl, a
5 2-cyclopropyl-4-(4-fluoropl1eny)quinolin-3-ylg roup, or a phenyl group.
5. The method according to any one of claims 1 to 4, wherein the substituted
nitrogen-containing 5 to 6-membered aromatic heterocyclic compound is pyrrole,
imidazole, 1,2,3-triazole, or 1,2,4-triazole (the pyrrole, imidazole, 1,2,3-triazole, and
10 1,2,4-triazole are substituted by one or more substituents selected from the group
consisting of a C1.6 alkyl group, a C3.6 cycloalkyl group, a C14 alkoxy group, a C3.4
cycloalkoxy group, and a (21.6 alkylamino group).
6. The method according to claim 5, wherein the substituted nitrogen-containing 5
15 to 6-membered aromatic heterocyclic compound is 1-methylimidazole.
7. The method according to any one of claims 1 to 4, wherein the substituted
nitrogen-containing 5 to 6-membered aromatic heterocyclic compound is pyridine,
pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, or 1,3,5-triazine (the
20 pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, and
1,3,5-triazine are substituted by one or more substituents selected fiom tlie group
consisting of a Ci.6 alkyl group, a C3.6 cycloalkyl group, a C14 alkoxy group, a C34
cycloalkoxy group, and a C1.6 alkylamino group).
25 8. The method according to claim 7, wherein the substituted nitrogen-containing 5
to 6-membered aromatic heterocyclic compound is 4-methoxypyridine or
9. Isopropyl
5 10. A crystal of the isopropyl
(S,E)-7-[4-(4-fluorophenyl)-6-isop~opyl-2-@-1netl~yIn1ethyls~1lfonamido)pyrimidin-5-yl]
-5-llydroxy-3-oxollept-6-enoaatcec ording to claim 9 having characteristic peaks at 20 =
4.5+0.2",8 .9+0.2",1 1.6+0.2",1 5.5f0.2",1 8.0+0.2O,1 8.5+0.2",1 9.5+0.2",1 9.9t0.2",
21.4&0.2",2 2.1&0.2", 22.8*0.2", and 23.4_+0.2"b y powder X-ray diffraction
10 measurement using Ca-Ka as a radiation source.
11. A c~ystaol f the isopropyl
(S,E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-@-methy1n1ethylsu~fonamido)pyrimidin-5-yl]
-5-hydroxy-3-oxohept-6-enoate according to the claim 9 having characteristic peaks at 20
15 =4.S0,8 .9", 11.6', 15.5", 18.0°, 18.S0,1 9.S0,1 9.9°,21.40,22.10,22.80,and23.40b y
powder X-ray diffraction measuremeut using Cu-Ka as a radiation source.