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HK1128288B - Process for producing optically active chromene oxide compound - Google Patents

Process for producing optically active chromene oxide compound Download PDF

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Publication number
HK1128288B
HK1128288B HK09106017.7A HK09106017A HK1128288B HK 1128288 B HK1128288 B HK 1128288B HK 09106017 A HK09106017 A HK 09106017A HK 1128288 B HK1128288 B HK 1128288B
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HK
Hong Kong
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group
formula
butyl
propyl
atom
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HK09106017.7A
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Chinese (zh)
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HK1128288A1 (en
Inventor
Shoichi Kondo
Kowichiro Saruhashi
Hisayuki Watanabe
Tsutomu Katsuki
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Nissan Chemical Industries, Ltd.
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Application filed by Nissan Chemical Industries, Ltd. filed Critical Nissan Chemical Industries, Ltd.
Priority claimed from PCT/JP2007/054730 external-priority patent/WO2007105658A1/en
Publication of HK1128288A1 publication Critical patent/HK1128288A1/en
Publication of HK1128288B publication Critical patent/HK1128288B/en

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Description

Method for producing optically active chromene oxide compound
Technical Field
The present invention relates to an efficient process for producing an optically active chromene oxide compound which is an important intermediate of a benzopyran compound effective for the treatment of arrhythmia.
Background
Benzopyran compounds useful as antiarrhythmic agents and processes for producing the same have been disclosed. That is, the benzopyran compound is produced by asymmetrically epoxidizing an optically active manganese complex with a chromene compound to form an optically active chromene oxide compound, and then opening the ring of the epoxy with an amine compound (see patent document 1).
A method for producing an optically active chromene oxide compound by subjecting a chromene compound to asymmetric epoxidation with an optically active manganese complex has been disclosed (see patent document 2, patent document 3, patent document 4, patent document 5, and patent document 6). The above patent documents describe examples of producing optically active chromene oxide compounds using an optically active manganese complex as a catalyst and iodosobenzene, sodium hypochlorite or 30% hydrogen peroxide water as a co-oxidant.
In the asymmetric oxidation reaction using the optically active manganese complex, an additive such as 4-phenylpyridine-N-oxide called an axial ligand is required in addition to the co-oxidant, and a method for producing an optically active chromene oxide compound by another method without using an axial ligand is desired.
On the other hand, there is described a method for producing an optically active chromene oxide compound in a high chemical yield and optical yield even in an amount of 0.01 to 0.2 mol% by using an asymmetric optically active manganese complex (see patent document 7), and this document describes only an example in which iodosobenzene is used as a co-oxidant, and therefore, further, there is described an industrially advantageous and efficient production method.
It has been reported that among the optically active titanium complexes, the di-mu-oxytitanium Salalen complex reacts with high enantioselectivity in an asymmetric epoxidation reaction of various simple olefins having no heteroatom using hydrogen peroxide water as an oxidizing agent. However, there is no report on an olefin compound and a chromene compound having a heteroatom (non-patent document 8).
Patent document 1: japanese laid-open patent publication No. 2001-151767
Patent document 2: japanese unexamined patent publication Hei 05-301878
Patent document 3: japanese unexamined patent publication Hei 07-285983
Patent document 4: japanese unexamined patent publication Hei 08-245668
Patent document 5: WO2005/090357A1
Patent document 6: WO2005/080368A2
Patent document 7: japanese unexamined patent publication No. 11-335384
Non-patent document 8: matsumoto, Y.Sawada, B.Saito, K.Sakai, T.Katsuki, Angew.chem.int.Ed. (2005), 44, 4935-.
Disclosure of Invention
Disclosed is a method for producing an optically active chromene oxide compound which is an important intermediate for a benzopyran compound that is effective for the treatment of arrhythmia.
The present inventors have conducted intensive studies on a process for producing an optically active chromene oxide compound which is an important intermediate for a benzopyran compound effective for the treatment of arrhythmia, and as a result, have found that an optically active chromene oxide compound can be produced with high enantioselectivity and high chemical yield by using an optically active titanium complex as a catalyst, thereby completing the present invention.
In the present invention, as the 1 st aspect, there is provided a process for producing an optically active chromene oxide compound represented by the formula (14), the formula (15), the formula (16) or the formula (17), which comprises subjecting a chromene compound represented by the formula (10), the formula (11), the formula (12) or the formula (13) to asymmetric epoxidation with an oxidizing agent in a solvent using an optically active titanium complex represented by any one of the formulae (1), (1 '), the formula (2), (2'), the formula (3 '), the formula (4) and the formula (4') as a catalyst,
r in (formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4'))1Represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C6-12Aryloxy or C6-22Aryl (the aryl group may be substituted by C)1-4Alkyl (the alkyl may be optionally substituted with halogen atom), C1-7Alkoxy or benzyloxy are optionally substituted, optically active or non-optically active),
R2represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C6-12Aryloxy or C6-18An aryl group, a heteroaryl group,
R3is represented by C1-4Alkyl radical, C6-18Aryl, or, at 2R3When they form a ring together, they represent C3-5The divalent group of (a) is,
R4each independently represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group, a nitro group or a cyano group,
m represents TiJ1J2(at TiJ)1J2In which Ti represents a titanium atom, J1And J2Each independently represents a halogen atom or C1-4Alkoxy, or J1And J2Together represent an oxygen atom, or J1And J2Together form a ring, represent formula (5) as a divalent group
(partial structure O-E-O in the formula (1), wherein O represents an oxygen atom, as O-E-O, represented by the following formula (6), as O-E-O, represented by the following formula (6 '), as O-E-O, represented by the following formula (7 '), as O-E-O, represented by the following formula (8 '), as O-E-O, represented by the following formula (4), as O-E-O, represented by the following formula (9), as O-E-O, represented by the following formula (9'),
b represents an integer of 1 to 10, R1、R2、R3And R4The same as above));
r in (formula (10)5、R6、R7And R8Each independently represents a hydrogen atom, a cyano group, a nitro group, a halogen atom, C1-4Alkyl (the alkyl may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkoxy (the alkoxy may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkylcarbonylamino (the alkylcarbonylamino group may be substituted with a halogen atom, C)6-10Aryl radical (the radical C)6-10Aryl radicals optionally substituted by halogen atoms, hydroxy, cyano, nitro, C1-4Alkyl, or C1-4Alkoxy optionally substituted) C1-4Alkylcarbonyl (N-C)1-4Alkyl) amino (the alkylcarbonyl (N-alkyl) amino group may be optionally substituted with a halogen atom), C1-4Alkoxycarbonyl group (the alkoxycarbonyl group may be optionally substituted by a halogen atom), C6-10Arylcarbonylamino (the arylcarbonylamino can be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), C6-10Aryl carbonyl (N-C)1-4Alkyl) amino (the arylcarbonyl (N-alkyl) amino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), benzylcarbonylamino, formyl, carbamoyl, C1-4Alkylsulfonyl radical, C6-10Arylsulfonyl (the alkylsulfonyl and arylsulfonyl groups may be substituted by halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), sulfamoyl, C1-4Alkylsulfonamide group, C6-10Arylsulfonamide group (the alkylsulfonamide group and the arylsulfonamide group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), bis (C)1-4Alkylsulfonyl) imino group (the alkylsulfonyl group of the bis (alkylsulfonyl) imino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), bis (C)6-10Arylsulfonyl) imino group (the arylsulfonyl group of the bis (arylsulfonyl) imino group may be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substitution), [ N, N' - (C)1-4Alkylsulfonyl) (C6-10Aryl sulfonyl radical]Imino group (the [ N, N' - (alkylsulfonyl) (arylsulfonyl group)]The alkyl-and aryl-sulphonyl radicals of the imino group may be substituted by halogen atoms, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted);
r in the formula (10)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy), C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom);
r in the formulae (11) and (12)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom);
the partial ring structure A in the formulae (11) and (12) is a partial structure represented by a 5-, 6-or 7-membered ring forming a condensed ring with the benzene ring moiety, wherein the 5-, 6-or 7-membered ring may be substituted with h R11(R11Is a halogen atom, a hydroxyl group, C1-6Alkyl (the alkyl may be substituted by halogen atom, hydroxy, cyano, amino, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, or C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-6Alkoxy (the alkoxy may be substituted by halogen atom, hydroxy, cyano, amino, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, or C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), nitro, cyano, formyl, carboxamido, carbamoyl, sulfo, sulfonamido, sulfamoyl, sulfonyl, amino, carboxyl, C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkylcarbonylamino, C1-6Alkylsulfonamide group, C6-14Arylsulfonamide group, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl radical, C6-14Arylsulfonyl, or C6-14Arylcarbonyl (the alkylamino, dialkylamino)The group, alkylcarbonylamino group, alkylsulfonamido group, arylsulfonamido group, alkylaminocarbonyl group, dialkylaminocarbonyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylsulfonyl group, arylsulfonyl group, and arylcarbonyl group may be optionally substituted with a halogen atom), h is an integer of 1 to 6, and in the case where h is 2 to 6, R is11May be the same or different), may contain 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms, alone or in combination, the number of unsaturated bonds in the ring, including the unsaturated bond of the condensed benzene ring, is 1, 2 or 3, and the carbon atom constituting the ring may be a carbonyl group or a thiocarbonyl group,
x in formula (13) represents NR20(R20Represents a hydrogen atom or C1-4An alkyl group),
y in formula (13) represents a direct bond, SO or SO2，
Z in the formula (13) represents C1-4An alkyl group (the alkyl group may be substituted with 1 to 5 halogen atoms or a phenyl group (the phenyl group may be substituted with C)1-4Alkyl optionally substituted) or phenyl (which phenyl may be C substituted)1-4Alkyl groups are optionally substituted),
w in formula (13) represents a hydrogen atom, a hydroxyl group, C1-6Alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), halogen atom, C1-4Alkyl or C1-6An alkylsulfonamide group (the alkyl group and the alkylsulfonamide group may be optionally substituted with a halogen atom),
r in the formula (13)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy group (the alkoxy group may be optionally substituted with a halogen atom)),
(in the formula, R5、R6、R7、R8、R9、R10A, W, X, Y and Z are the same as described above,＊the absolute configuration of the carbon atom labeled is (R) or (S));
the 2 nd aspect is the process for producing an optically active chromene oxide compound according to the 1 st aspect, characterized in that an optically active titanium complex represented by any one of the above formulae (1), (1 '), (2), (2'), (3), (3 '), formula (4) and (4') is used as a catalyst, and a chromene compound represented by the above formula (10) is asymmetrically epoxidized with an oxidizing agent in a solvent,
r in the above formula (10)5And R6Each independently represents a hydrogen atom, a cyano group, a nitro group, a halogen atom, C1-4Alkyl (the alkyl may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkoxy (the alkoxy may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkylcarbonylamino (the alkylcarbonylamino group may be optionally substituted with a halogen atom), C1-4Alkylcarbonyl (N-C)1-4Alkyl) amino (the alkylcarbonyl (N-alkyl) amino group may be optionally substituted with a halogen atom) C6-10Aryl carbonyl (N-C)1-4Alkyl) amino (the arylcarbonyl (N-alkyl) amino group may be substituted with a halogen atom,C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), carbamoyl, bis (C)1-4Alkylsulfonyl) imino group (the alkylsulfonyl group of the bis (alkylsulfonyl) imino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), bis (C)6-10Arylsulfonyl) imino group (the arylsulfonyl group of the bis (arylsulfonyl) imino group may be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted) or [ N, N' - (C)1-4Alkylsulfonyl) (C6-10Aryl sulfonyl radical]Imino group (the [ N, N' - (alkylsulfonyl) (arylsulfonyl group)]The alkyl-and aryl-sulphonyl radicals of the imino group may be substituted by halogen atoms, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted),
r in the formula (10)7Represents a hydrogen atom, a cyano group, a nitro group, a bis (C)1-4Alkylsulfonyl) imino group (the alkylsulfonyl group of the bis (alkylsulfonyl) imino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), bis (C)6-10Arylsulfonyl) imino group (the arylsulfonyl group of the bis (arylsulfonyl) imino group may be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted) or [ N, N' - (C)1-4Alkylsulfonyl) (C6-10Aryl sulfonyl radical]Imino group (the [ N, N' - (alkylsulfonyl) (arylsulfonyl group)]The alkyl-and aryl-sulphonyl radicals of the imino group may be substituted by halogen atoms, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted),
r in the formula (10)8Represents a hydrogen atom, a nitro group or C1-4An alkyl group (the alkyl group may be optionally substituted with a halogen atom),
r in the formula (10)9And R10Is represented by C1-6An alkyl group (the alkyl group may be optionally substituted with a halogen atom);
as the 3 rd aspect, there is provided the process for producing an optically active chromene oxide compound according to the 2 nd aspect, wherein R is represented by the formula (10)5And R6Are respectively independentAnd (b) represents a hydrogen atom, a nitro group, a fluorine atom, a methoxy group, a methylcarbonylamino group or a methylcarbonyl (N-ethyl) amino group, R in the formula (10)7Represents a hydrogen atom, a nitro group or a bis (C)1-4Alkylsulfonyl) imino group, R in the formula (10)8Represents a hydrogen atom, a nitro group or a trifluoromethyl group, R in the formula (10)9And R10Represents a methyl group;
the 4 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to the 1 st aspect, characterized by using an optically active titanium complex represented by any one of the above formulae (1), (1 '), (2), (2'), (3), (3 '), formula (4) and (4') as a catalyst, subjecting a chromene compound represented by the above formula (11) or (12) to asymmetric epoxidation with an oxidizing agent in a solvent,
the partial ring structure of A in the above formula (11) or formula (12) is represented by any one of formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), formula(s), formula (t), formula (u), formula (v), formula (w), formula (x), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae), formula (af), formula (ag) and formula (ah),
r in the above formula (a), formula (b), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), formula (p), formula (q), formula (v), formula (w), formula (x), formula (ab), formula (ae), formula (af) and formula (ag)12And R13Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino, hydroxy, C6-14Aryl radical, C2-9Heteroaryl (both aryl and heteroaryl may be substituted by q R18(R18Is represented by the formula11In the same sense, q represents an integer of 1 to 3In case q is 2 or 3, R18May be the same or different)) optionally substituted with C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonyl (the alkylcarbonyloxy and alkylcarbonyl may be optionally substituted with a halogen atom), C1-6Alkylcarbonylamino, C3-8Cycloalkyl carbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl (the cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group may be optionally substituted by a halogen atom), carboxyl group, C6-14Arylcarbonyl (the arylcarbonyl group may be optionally substituted with a halogen atom) or C2-9Optionally substituted heteroarylcarbonyl), C6-14Aryl radical, C2-9Heteroaryl (both aryl and heteroaryl may be substituted by q R18(R18Is represented by the formula11The same meaning, q represents an integer of 1 to 3, and R is R when q is 2 or 318May be the same or different)) optionally substituted with C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C3-8Cycloalkyl carbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl radical, C6-14Arylsulfonyl radical, C2-9Heteroarylsulfonyl (both the arylsulfonyl and heteroarylsulfonyl can be substituted by q R18(R18Is represented by the formula11The same meaning, q represents an integer of 1 to 3, and R is R when q is 2 or 318The same or different) optionally substituted), carboxyl group, C6-14Aryl carbonyl or C2-9Heteroarylcarbonyl (both arylcarbonyl and heteroarylcarbonyl can be substituted by q R18(R18Is represented by the formula11The same meaning, q represents an integer of 1 to 3, and R is R when q is 2 or 318May be the same or different) optionally substituted),
the above-mentioned formula (a), formula (b), formula (c), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), formula(s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and formula (af)R14、R15、R16And R17Each independently represents a hydrogen atom, a halogen atom, C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino, hydroxy, C6-14Aryl radical, C2-9Heteroaryl (the aryl and heteroaryl can be substituted by R R19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonyl (the alkylcarbonyloxy and alkylcarbonyl may be optionally substituted with a halogen atom), C1-6Alkylcarbonylamino, C3-8Cycloalkyl carbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl (the cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group may be optionally substituted by a halogen atom), carboxyl group, C6-14Arylcarbonyl (the arylcarbonyl group may be optionally substituted with a halogen atom) or C2-9Optionally substituted heteroarylcarbonyl), C3-8Cycloalkyl (which may be interrupted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom), amino or hydroxy), C1-6Alkoxy (the alkoxy may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by halogen atom), carboxyl, amino, hydroxyl, C6-14Aryl or C2-9Heteroaryl (the aryl and heteroaryl can be substituted by R R19(R19Is represented by the formula11The same meaning, r represents the same meaning as q) optionally substituted), C1-6Thioalkoxy (the thioalkoxy group may be substituted by a halogen atom, C)1-6Alkoxy (the alkoxy may be optionally substituted by halogen atom), carboxyl, hydroxyl, C6-14Aryl or C2-9Heteroaryl (the aryl and heteroaryl can be substituted by R R19(R19Is represented by the formula11The same meaning as that of q), r represents the same meaning as that of q), optionally substituted), hydroxyl group, C6-14Aryl radical, C2-9Heteroaryl (the aryl and heteroaryl can be substituted by R R19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkylcarbonyloxy, nitro, cyano, formyl, carboxamido, amino, sulfo, C1-6Alkylamino, di-C1-6Alkylamino radical, C6-14Arylamino, C2-9Heteroarylamino (both the arylamino and heteroarylamino groups can be substituted by R R19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkylcarbonylamino, C1-6Alkylsulfonamide group, carbamoyl group, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C6-14Aryl carbonyl group, C2-9Heteroarylcarbonyl (both arylcarbonyl and heteroarylcarbonyl can be substituted by R R19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkoxycarbonyl, sulfamoyl, C1-6Alkylsulfonyl radical, C6-14Arylsulfonyl radical, C2-9Heteroarylsulfonyl (both the arylsulfonyl and heteroarylsulfonyl can be substituted by R R19(R19Is represented by the formula11Same as q, r represents the same as q)), carboxyl group or C2-9Heterocyclic group (the heterocyclic group may be substituted by halogen atom, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom), amino, carboxyl or hydroxyl), C1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), C6-14Aryl radical, C2-9Heteroaryl (the aryl and heteroaryl can be substituted by R R19(R19Is represented by the formula11The same as q, r represents the same as q)), hydroxy, nitro, cyano, formyl, carboxamide, amino, C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkylcarbonylamino, C1-6Alkylsulfonamide group, carbamoyl group, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, sulfamoyl, C1-6Alkylsulfonyl, carboxyl or C6-14The arylcarbonyl group is optionally substituted),
q in the above formula (c), formula (d), formula (p), formula (Q), formula (v), formula (w), formula (ab), formula (ac) and formula (ad) represents O (oxygen atom), S (sulfur atom), SO (sulfinyl group) or SO (sulfinyl group)2(sulfonyl));
as the 5 th aspect, there is provided the process for producing an optically active chromene oxide compound according to the 4 th aspect, wherein R is represented by the above formula (11) or formula (12)9And R10Is methyl;
the 6 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to the 4 th or 5 th aspect, wherein A in the formula (11) or (12) is represented by the following formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula(s), formula (v), formula (y), formula (ae), formula (ag) or formula (ah),
(in the formula, R12、R13、R14、R15And R16The same as described in claim 4);
the 7 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to the 6 th aspect, wherein A in the formula (11) or the formula (12) is represented by the formula (a), the formula (b), the formula (i), the formula (k), the formula (o), the formula (p), the formula(s), the formula (v), the formula (y), the formula (ae), the formula (ag) or the formula (ah),
r in the formula (a), the formula (b), the formula (i), the formula (k), the formula (p), the formula (v), the formula (ae) and the formula (ag)12And R13Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino or hydroxy), formula (a), formula (b), formula (k), formula (o), formula (p), formula(s), formula (v),R in the formulae (y) and (ae)14、R15And R16Each independently represents a hydrogen atom, a halogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino, hydroxy, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonyl (the alkylcarbonyloxy and alkylcarbonyl may be optionally substituted with a halogen atom), C1-6Alkylcarbonylamino, C3-8Cycloalkyl carbonyl or C1-6Alkoxycarbonyl optionally substituted), Q represents O (oxygen atom);
the 8 th aspect of the present invention is the process according to the 7 th aspect of the present invention, wherein A in the formula (11) or the formula (12) represents R in the formula (a), the formula (b), the formula (i), the formula (k), the formula (o), the formula (p), the formula(s), the formula (v), the formula (y), the formula (ae), the formula (ag) or the formula (ah), the formula (a), the formula (b), the formula (i), the formula (k), the formula (p), the formula (v), the formula (ae) or the formula (ag)12And R13Each independently represents a hydrogen atom, a methyl group, R in the formula (a), the formula (b), the formula (k), the formula (o), the formula (p), the formula(s), the formula (v), the formula (y) and the formula (ae)14、R15And R16Each independently represents a hydrogen atom, a halogen atom, or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino, hydroxy, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonyl (the alkylcarbonyloxy and alkylcarbonyl may be optionally substituted with a halogen atom), C1-6Alkylcarbonylamino, C3-8Cycloalkyl carbonyl or C1-6Alkoxycarbonyl optionally substituted), Q represents O (oxygen atom);
the 9 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to the 1 st aspect, wherein the optically active compound represented by any one of the above-mentioned formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4') is usedAn asymmetric epoxidation method comprising using an oxidizing agent to asymmetrically epoxidize a chromene compound represented by the above formula (13) in a solvent using an acidic titanium complex as a catalyst, wherein R in the above formula (13)9And R10Both represent a methyl group;
as the 10 th aspect, there is provided the process for producing an optically active chromene oxide compound according to the 9 th aspect, wherein W in the formula (13) represents a hydrogen atom, a hydroxyl group, a methoxy group, a chlorine atom, a bromine atom, a methyl group, an ethyl group or a methanesulfonamide group;
the 11 th aspect is the process according to the 9 th or 10 th aspect, wherein Y in the formula (13) represents SO2(sulfonyl), Z represents C1-4An alkyl group;
as the 12 th aspect, there is provided the process for producing an optically active chromene oxide compound according to the 10 th aspect, wherein Y in the above formula (13) represents a direct bond, and Z represents C1-4An alkyl group;
the 13 th aspect of the present invention is the process for producing the optically active chromene oxide compound according to the 1 st aspect, wherein R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4') is R1Is represented by C6-22Aryl (the aryl group may be substituted by C)1-4Alkyl (the alkyl may be optionally substituted with halogen atom) C1-7Alkoxy or benzyloxy is optionally substituted, optically active or non-optically active),
R2represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C6-12Aryloxy or C6-18An aryl group, a heteroaryl group,
R3is represented by C1-4Alkyl radical, C6-18Aryl, or, at 2R3When they form a ring together, they represent C3-5The divalent group of (a) is,
R4each independently represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, nitro, or cyanoThe base group is a group of a compound,
m represents TiJ1J2(at TiJ)1J2In which Ti represents a titanium atom, J1And J2Each independently represents a halogen atom or C1-4Alkoxy radical, J1And J2Together represent an oxygen atom, or, J1And J2Form a ring together, and represent the above formula (5) (represented by the above formula (6) as a partial structure of O-E-O in formula (1) wherein O is an oxygen atom, and represented by the above formula (6) as O-E-O in formula (1 '); represented by the above formula (6') as O-E-O in formula (2) as O-E-O, represented by the above formula (7); represented by the above formula (7 ') as O-E-O in formula (2'); represented by the above formula (7 ') as O-E-O in formula (3), represented by the above formula (8) as O-E-O in formula (3'), represented by the above formula (8 ') as O-E-O; represented by the above formula (9) as O-E-O in formula (4'), O-E-O is represented by the formula (9'), b is an integer of 1 to 10, R1、R2、R3And R4The same as above));
the 14 th aspect is the process according to the 13 th aspect for producing an optically active chromene oxide compound, wherein R in the formulae (1), (1 '), formula (2), (2'), formula (3), (3 '), formula (4) and (4') is R1Represents phenyl (which phenyl may be substituted by C)1-4Alkyl (the alkyl may be optionally substituted with a halogen atom), benzyloxy, or C1-7Alkoxy optionally substituted) or naphthyl (which naphthyl may be C-substituted)1-4Alkyl (the alkyl may be optionally substituted with halogen atom), C1-7Alkoxy or phenyl optionally substituted),
R2represents a hydrogen atom, and is represented by,
R3represents 2R3Together form C of a ring3-5The divalent group of (a) is,
R4represents a hydrogen atom, and is represented by,
m represents TiJ1J2(at TiJ)1J2In the formula, Ti represents a titanium atom，J1And J2Each independently represents a halogen atom or C1-4Alkoxy, or, J1And J2Together represent an oxygen atom, or, J1And J2Form a ring together, and represent the above formula (5) (represented by the above formula (6) as a partial structure of O-E-O in formula (1) wherein O is an oxygen atom, and represented by the above formula (6) as O-E-O in formula (1 '); represented by the above formula (6') as O-E-O in formula (2) as O-E-O, represented by the above formula (7); represented by the above formula (7 ') as O-E-O in formula (2'); represented by the above formula (7 ') as O-E-O in formula (3), represented by the above formula (8) as O-E-O in formula (3'), represented by the above formula (8 ') as O-E-O; represented by the above formula (9) as O-E-O in formula (4'), O-E-O is represented by the formula (9'), b is an integer of 1 to 10, R1、R2、R3And R4The same as above));
the 15 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to any one of the 1 st to 14 th aspects, wherein the optically active titanium complex is used in an amount of 0.001 to 100 mol% based on the chromene compound represented by formula (10), formula (11), formula (12) or formula (13);
the 16 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to any one of the 1 st to 14 th aspects, wherein the solvent used in the asymmetric epoxidation reaction is a halogen-based solvent, an aromatic hydrocarbon-based solvent, an ester-based solvent, an ether-based solvent, a nitrile-based solvent, an alcohol-based solvent, or a mixture of the above solvents;
as the 17 th aspect, there is provided the process for producing an optically active chromene oxide compound according to any one of the 1 st to 14 th aspects, wherein the oxidizing agent used in the asymmetric epoxidation reaction is iodosobenzene, sodium hypochlorite, m-chloroperoxybenzoic acid, Oxone (registered trademark of dupont), hydrogen peroxide water, urea-hydrogen peroxide adduct (UHP), an azaoxy tricyclic ring (oxaziridine), N-methylmorpholine oxide (NMO), tert-butyl hydrogen peroxide (TBHP), Cumene Hydrogen Peroxide (CHP), or a mixture of these oxidizing agents;
as the 18 th aspect, there is the process for producing an optically active chromene oxide compound according to the 17 th aspect, wherein the oxidizing agent used in the asymmetric epoxidation reaction is hydrogen peroxide water, urea-hydrogen peroxide adduct (UHP) or a mixture of these oxidizing agents;
the 19 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to the 18 th aspect, wherein the oxidizing agent used in the asymmetric epoxidation reaction is hydrogen peroxide water, and the concentration thereof is 1 to 100% by mass;
the 20 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to any one of the 1 st to 14 th aspects, wherein the amount of the oxidizing agent used in the asymmetric epoxidation reaction is 1 to 10 equivalents relative to the chromene compound represented by the above formula (10), formula (11), formula (12) or formula (13);
the 21 st aspect is the method for producing an optically active chromene oxide compound according to the 20 th aspect, wherein the oxidizing agent used in the asymmetric epoxidation reaction is added in a batch or continuous manner;
the 22 nd embodiment is the process for producing an optically active chromene oxide compound according to the 21 st embodiment, wherein the oxidizing agent used in the asymmetric epoxidation reaction is continuously added at a rate of 0.01 to 40000 equivalents per hour;
the 23 rd aspect is the method for producing an optically active chromene oxide compound according to the 21 st aspect, wherein the oxidizing agent used in the asymmetric epoxidation reaction is added in portions, the number of portions being in the range of 2 to 100;
the 24 th aspect of the present invention is the process for producing an optically active chromene oxide compound according to any one of the 1 st to 23 th aspects, wherein the reaction temperature of the asymmetric epoxidation reaction is from 0 ℃ to the reflux temperature of the solvent used;
the 26 th aspect is the process for producing an optically active chromene oxide compound according to any one of the 1 st to 24 th aspects, wherein the pressure in the reaction system of the asymmetric epoxidation reaction is in the range of 10kPa to 1100 kPa.
According to the present invention, an optically active chromene oxide compound which is an important intermediate of a benzopyran compound effective for the treatment of arrhythmia can be efficiently produced.
Detailed Description
In the present specification, "n" represents a positive number, "i" represents a negative number, "s" represents a secondary number, "t" represents a tertiary number, "c" represents a ring, "o" represents a neighboring number, "m" represents a space, and "p" represents a pair.
The present invention will be described in detail below. In the present invention, the titanium complex used as a catalyst for the asymmetric epoxidation of a chromene compound with an oxidizing agent is represented by the following formulae (1), (1 '), formulae (2), (2'), formulae (3), (3 '), formulae (4) and (4'),
r in (formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4'))1Represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C6-12Aryloxy or C6-22Aryl (the aryl group may be substituted by C)1-4Alkyl (the alkyl may be optionally substituted with halogen atom), C1-7Alkoxy or benzyloxy, optionally substituted, is optically active or non-optically active),
R2represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C6-12Aryloxy or C6-18An aryl group, a heteroaryl group,
R3is represented by C1-4Alkyl radical, C6-18Aryl, or, at 2R3When they form a ring together, they represent C3-5The divalent group of (a) is,
R4each independently represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4An alkoxy group, a nitro group or a cyano group,
m represents TiJ1J2(at TiJ)1J2In which Ti represents a titanium atom, J1And J2Each independently represents a halogen atom or C1-4Alkoxy, or, J1And J2Together represent an oxygen atom, or J1And J2Together form a ring, represent formula (5) as a divalent group
(regarding the partial structure O-E-O in the formula, wherein O represents an oxygen atom, in the formula (1), as O-E-O, represented by the following formula (6), in the formula (1 '), as O-E-O, represented by the following formula (6 '), in the formula (2), as O-E-O, represented by the following formula (7), in the formula (2 '), as O-E-O, represented by the following formula (7 '), in the formula (3), as O-E-O, represented by the following formula (8), in the formula (3 '), as O-E-O, represented by the following formula (8 '), in the formula (4), as O-E-O, represented by the following formula (9), in the formula (4 '), as O-E-O, represented by the following formula (9'),
b is an integer of 1 to 10, R1、R2、R3And R4The same as described above)).
The substituents in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4') will be described below.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')1Represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical, C6-12Aryloxy or C6-22Aryl (the aryl group may be substituted by C)1-4Alkyl (the alkyl may be optionally substituted with halogen atom), C1-7Alkoxy or benzyloxy optionally substituted, optically active or non-optically active).
Next, R in the formulae (1), (1 '), (2), (2'), (3), (3 '), formula (4) and (4') is shown1The detailed description is made.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
as the C1-4Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl,
as the C1-4Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and c-butoxy,
as the C6-12Examples of the aryloxy group include a phenoxy group, a 1-naphthyloxy group, a 2-biphenyloxy group, a 3-biphenyloxy group and a 4-biphenyloxy group,
as the C6-22Aryl (the aryl group may be substituted by C)1-4Alkyl (the alkyl may be optionally substituted with halogen atom), C1-7Alkoxy or benzyloxy optionally substituted and optically active or non-optically active), there may be mentioned phenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 4-methylphenyl, 2-ethylphenyl, 2-pentafluoroethylphenyl, 3, 5-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 2-i-propoxyphenyl, 2-benzyloxyphenyl, 3, 5-dimethoxyphenyl, 1-naphthylphenyl2-naphthyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-methyl-1-naphthyl, 2-phenyl-1-naphthyl, 2-methoxy-1-naphthyl, 2- [3, 5-dimethylphenyl]-1-naphthyl, 2- [ 4-methylphenyl [ ]]-1-naphthyl, 2- (o-biphenyl) -1-naphthyl, 2- (m-biphenyl) -1-naphthyl, and 2- (p-biphenyl) -1-naphthyl, and the like. In addition, the above-mentioned C6-22The aryl group may be optically active or non-optically active.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')1Preferably, it is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a t-butyl group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a c-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, a c-butoxy group, a phenyloxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, a phenyl group, a 2-methylphenyl group, a 2-trifluoromethylphenyl group, a 4-methylphenyl group, a 2-ethylphenyl group, a 3, 5-dimethylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, 2-i-propoxyphenyl group, 2-benzyloxyphenyl group, 3, 5-dimethoxyphenyl group, 1-naphthyl group, 2-biphenyl group, 3-biphenyl group, 4-biphenyl group, 2-phenyl-1-naphthyl group, 2-methoxy-1-naphthyl group, 2- (m-biphenyl) -1-naphthyl group, 2- (p-biphenyl) -1-naphthyl group, wherein R is1More preferably phenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-ethylphenyl, 2-methoxyphenyl, 2-benzyloxyphenyl, 1-naphthyl, 2-biphenyl, 2-phenyl-1-naphthyl, 2-methoxy-1-naphthyl, 2- (m-biphenyl) -1-naphthyl, 2- (p-biphenyl) -1-naphthyl (the 2-phenyl-1-naphthyl, 2-methoxy-1-naphthyl, 2- (m-biphenyl) -1-naphthyl or 2- (p-biphenyl) -1-naphthyl is optically active or optically inactive), wherein R is defined as R.1More preferred are phenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 2-benzyloxyphenyl and 2-phenyl-1-naphthyl.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')2Represents a hydrogen atom or a halogen atom、C1-4Alkyl radical, C1-4Alkoxy radical, C6-12Aryloxy or C6-18And (4) an aryl group.
For R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')2The description will be specifically made.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
as the C1-4Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl,
as the C1-4Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy and c-butoxy,
as the C6-12Examples of the aryloxy group include a phenoxy group, a 1-naphthyloxy group, a 2-biphenyloxy group, a 3-biphenyloxy group and a 4-biphenyloxy group,
as the C6-18Examples of the aryl group include a phenyl group, a 3, 5-dimethylphenyl group, a 4-methylphenyl group, a 1-naphthyl group, a 2-biphenyl group, a 2-phenyl-1-naphthyl group, a 2-methyl-1-naphthyl group and a 2- [3, 5-dimethylphenyl group]-1-naphthyl, 2- [ 4-methylphenyl [ ]]-1-naphthyl and 2-methoxy-1-naphthyl and the like.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')2Preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a t-butyl group, a methoxy group, a phenyloxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, a phenyl group, a 3, 5-dimethylphenyl group, a 4-methylphenyl group, a 3, 5-dimethoxyphenyl group, a 4-methoxyphenyl group, a 1-naphthyl group, a 2-biphenyl group, a 3-biphenyl group, a 4-biphenyl group, a 2-methoxy-1-naphthyl group, wherein R is2More preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromogenIodine atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, methoxy group, phenoxy group, phenyl group, 1-naphthyl group, 2-biphenyl group, wherein R is2Further preferably a hydrogen atom.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')3Is represented by C1-4Alkyl radical, C6-18Aryl, or at 2R3When they form a ring together, they represent C3-5A divalent group of (a).
For R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')3The description will be specifically made.
As the C1-4Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl,
as the C6-18Examples of the aryl group include a phenyl group, a 3, 5-dimethylphenyl group, a2, 4, 6-trimethylphenyl group, a 4-methylphenyl group, a 1-naphthyl group, a 2-biphenyl group, a 2-phenyl-1-naphthyl group, a 2-methyl-1-naphthyl group and a 2- [3, 5-dimethylphenyl group]-1-naphthyl, 2- [ 4-methylphenyl [ ]]-1-naphthyl and 2-methoxy-1-naphthyl and the like,
at 2R3When they form a ring together, is C3-5Examples of the divalent group of (2) include a trimethylene group and a tetramethylene group.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')3Preferably phenyl, 3, 5-dimethylphenyl, 2, 4, 6-trimethylphenyl, 4-methylphenyl, 2R3Bonded tetramethylene radical, wherein R3More preferably 2R3An intercoupled tetramethylene group.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')4Represents a hydrogen atom, a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, nitro or cyano.
For R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')4The description will be specifically made.
Examples of the halogen group include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
as the C1-4Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl,
as the C1-4Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.
R in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4')4Preferably a hydrogen atom, fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, wherein R is a group4More preferably a hydrogen atom.
M in the above formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4') represents TiJ1J2(at TiJ)1J2In which Ti represents a titanium atom, J1And J2Each independently represents a halogen atom or C1-4Alkoxy, or J1And J2Together represent an oxygen atom, or J1And J2Together form a ring, represent formula (5) as a divalent group
(partial structure O-E-O in the formula (1) wherein O is an oxygen atom, as O-E-O, represented by the following formula (6), as O-E-O, represented by the following formula (6 '), in the formula (1') wherein O-E-O, represented by the following formula (6 '), in the formula (2) wherein O-E-O, represented by the following formula (7), as O-E-O, represented by the following formula (7'), in the formula (2 '), as O-E-O, represented by the following formula (8), in the formula (3'), as O-E-O, represented by the following formula (8 '), in the formula (4) wherein O-E-O, represented by the following formula (9), and in the formula (4') wherein O-E-O, represented by the following formula (9'),
b is an integer of 1 to 10, R1、R2、R3And R4The same as described above)).
In addition, in J1And J2When the compounds (A) and (B) together represent an oxygen atom, the compound represented by formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) or formula (4') is a mononuclear oxytitanium complex represented by the general molecular structure, and is represented by J1And J2When formula (5) which is a divalent group is formed together with a ring, formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4') become a μ -oxytitanium (b +1) nuclear complex which is a polynuclear complex as the structure of the whole molecule.
When the formulas (1), (1 '), (2), (2'), (3), (3 '), and (4') are the above-mentioned oxytitanium complexes or μ -oxytitanium (b +1) nuclear complexes, the optically active titanium complex of the present invention may be a mixture of these oxytitanium complexes or μ -oxytitanium (b +1) nuclear complexes in which b is any one of 1 to 10.
As preferred J1And J2Examples thereof include J1And J2Together represent an oxygen atom, or J1And J2Form a ring together, and represent the case of formula (5) as a divalent group, in which case the optically active titanium complex is a mononuclear titanyl complex or μ -titanyl (b +1)A nuclear complex (b is an integer of 1 to 10).
Further, the optically active titanium complex of the present invention is classified into the types of optically active titanium Salalen complexes represented by the above formulae (1), (1 '), (3) and (3') or titanium Salan complexes represented by the formulae (2), (2 '), (4) and (4'), and preferred combinations of substituents and the structure of the whole molecule will be described below.
An optically active titanium Salalen complex represented by the above formula (1), formula (1 '), formula (3) or formula (3') is prepared by using J1And J2The divalent group which forms a ring together is represented by the formula (5), and in the formula (5), b is preferably 1. In this case, the formula (1), the formula (1 '), the formula (3) and the formula (3 ') are μ -oxytitanium dinuclear complexes represented by the following formulae (18) and (18 ') as the structure of the whole molecule.
(wherein O-NH-N-O in the formula (1) is represented by the following formula (19); in the formula (1 ') is represented by the formula (19'); in the formula (2) is represented by the formula (20); in the formula (2 ') is represented by the formula (20'),
(Here, R is1、R2、R3And R4As above), the complex of formula (18') is an enantiomer of the complex of formula (18). )
The combination of particularly preferable substituents in the above optically active titanium Salalen complex and the structure of the whole molecule will be described. Particularly preferred optically active titanium Salalen complexes are represented by the formulae (18) and (18 '), in which the partial structure O-NH-N-O is a (aRS. DELTA., aRS. DELTA) -di-. mu. -oxytitanium dinuclear complex represented by the following formulae (21), (21 '), (22) or (22 '), and a (aSR. lambda., aSR. lambda) -di-. mu. -oxytitanium dinuclear complex.
Particularly preferred combinations of substituents in the optically active titanium Salan complex represented by the above formulae (2), (2 '), (4) and (4') include mononuclear titanyl complexes represented by the following formulae (23), (23 '), (24) or (24'), and μ -titanyl (b +1) isomers (b is an integer of 1 to 10),
(wherein M represents TiJ1J2，J1And J2The above formula (5) which represents an oxygen atom or forms a ring together and is a divalent group, wherein b is an integer of 1 to 10 in the formula (5), and the partial structure O-E-O is represented by the following formula (25), (25 '), (26) or (26') respectively.
Next, a method for producing an optically active titanium complex represented by formula (1), formula (1 '), formula (2'), formula (3 '), formula (4), and formula (4') will be described.
The Salan ligand represented by formula (29), formula (29 '), formula (31) or formula (31') which is a ligand of the titanium Salan complex represented by formula (2), (2 '), formula (4) or formula (4') can be produced by reducing a Salen compound represented by formula (28), (28 '), formula (30) or formula (30'), respectively.
As the reducing agent, sodium borohydride (NaBH) may be mentioned4) Sodium cyanoborohydride (NaBH)3CN) and lithium aluminum hydride (LiAlH)4) Etc., preferably sodium borohydride (NaBH)4)。
The optically active titanium Salan complex represented by the formula (2), (2 '), formula (4) or formula (4') can be produced by reacting the corresponding Salan ligand with a titanium alkoxide, titanium tetrachloride or titanium tetrabromide in an organic solvent such as methylene chloride, and then treating with water or a water-containing solvent (a mixed solvent containing 0.1 to 100% by mass of water in the organic solvent, and examples of the organic solvent used include THF, methanol, i-propanol and the like). The amount of water used is preferably in the range of 1 to 1000 moles, more preferably 1 to 10 moles, based on the equivalent of the Salan ligand.
In addition, the optically active titanium Salan complex can be produced in the reaction system, and the asymmetric epoxidation reaction of the chromene compound can be carried out without separation as a catalyst. In this case, hydrogen peroxide water used as an oxidizing agent may be added, or water may be added.
The titanium compound is preferably a titanium alkoxide, and examples of the titanium alkoxide include titanium tetramethoxide, titanium tetraethoxide, titanium tetra-n-propoxide, titanium tetraisopropoxide, titanium tetra-n-butoxide, titanium tetra-t-butoxide, etc., and among them, titanium tetraisopropoxide [ Ti (Oi-Pr) is more preferable4]. The amount of the titanium alkoxide used is preferably in the range of 1 to 2 moles based on1 mole of the Salan ligand.
The optically active titanium Salalen complexes represented by the formulae (1), (1 '), (3) and (3') can be produced by the method described in non-patent document 8(Angew. chem. int. Ed. (2005), 44, 4935-. Specifically, the corresponding Salen ligand is reacted with a titanium alkoxide, one of 2 imino bonds of the Salen ligand is reduced by a Meerwein-ponnduf-verley (mpv) reduction reaction to form a titanium complex, and after the reaction is completed, the reaction product is treated with water or a water-containing solvent (a mixed solvent containing 0.1 to 100% by mass of water in an organic solvent, and examples of the organic solvent used include THF, methanol, and i-propanol).
Further, the optically active titanium Salalen complex can be produced in the reaction system, and the asymmetric epoxidation reaction of the chromene compound can be carried out without separation as a catalyst.
Examples of the titanium alkoxide include titanium tetramethoxide, titanium tetraethoxide, titanium tetra-n-propoxide, titanium tetraisopropoxide, titanium tetra-n-butoxide, titanium tetra-t-butoxide, and titanium tetraisopropoxide [ Ti (Oi-Pr)4]. The amount of the titanium alkoxide used is preferably in the range of 1 to 2 moles based on1 mole of the Salen ligand. The amount of water used is preferably in the range of 1 to 1000 moles, more preferably 1 to 10 moles, based on the equivalent of the Salen ligand.
The reaction solvent for producing the optically active titanium complex is an aprotic organic solvent, a protic organic solvent, or a mixture of these solvents. Examples of the aprotic organic solvent include halogen-based solvents, aromatic hydrocarbon-based solvents, ester-based solvents, ether-based solvents, and nitrile-based solvents, and specifically include dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, toluene, ethyl acetate, tetrahydrofuran, diethyl ether, butyronitrile, propionitrile, and acetonitrile. The protic organic solvent may be an alcohol solvent, specifically ethanol, i-propanol, t-butanol, or the like.
Preferred reaction solvents are dichloromethane, 1, 2-dichloroethane, chlorobenzene, toluene, ethyl acetate as aprotic organic solvents.
In the production method of the present invention, by using the optically active titanium complexes represented by formula (1), formula (1 '), formula (2'), formula (3 '), formula (4) and formula (4'), the chromene compound as a starting material is subjected to asymmetric epoxidation, and one of enantiomers of the chromene oxide compound can be produced with high selectivity. Specifically, one of the two enantiomers of the optically active chromene oxide compound can be selectively produced by using either one of the complex represented by the formula (1) or the complex represented by the formula (1'). By using either the complex represented by the formula (2) or the complex represented by the formula (2'), one of the two enantiomers of the optically active chromene oxide compound can be selectively produced. By using either the complex represented by the formula (3) or the complex represented by the formula (3'), one of the two enantiomers of the optically active chromene oxide compound can be selectively produced. By using either the complex represented by formula (4) or the complex represented by formula (4'), two enantiomers of the optically active chromene oxide compound can be selectively produced.
Next, a method for producing the optically active chromene oxide compound of the present invention will be described. A process for producing an optically active chromene oxide compound represented by the following formula (14), formula (15), formula (16) or formula (17), which comprises dissolving an optically active titanium complex represented by any one of the formulae (1), (1 '), formula (2), (2'), formula (3), (3 '), formula (4) and formula (4') in an organic solvent under a nitrogen atmosphere or in the atmosphere, adding an oxidizing agent to the reaction solution, stirring the solution to carry out an asymmetric epoxidation reaction,
r in (formula (10)5、R6、R7And R8Each independently represents a hydrogen atom, a cyano group, a nitro group, a halogen atom, C1-4Alkyl (the alkyl may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkoxy (the alkoxy may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkyl carbonyl oxygenBase, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkylcarbonylamino (the alkylcarbonylamino group may be substituted with halogen atom, phenyl (the phenyl group may be substituted with halogen atom, hydroxy, cyano, nitro, C)1-4Alkyl, or C1-4Alkoxy optionally substituted) C1-4Alkylcarbonyl (N-C)1-4Alkyl) amino (the alkylcarbonyl (N-alkyl) amino group may be optionally substituted with a halogen atom), C1-4Alkoxycarbonyl group (the alkoxycarbonyl group may be optionally substituted by a halogen atom), C6-10Arylcarbonylamino (the arylcarbonylamino can be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), C6-10Aryl carbonyl (N-C)1-4Alkyl) amino (the arylcarbonyl (N-alkyl) amino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), benzylcarbonylamino, formyl, carbamoyl, C1-4Alkylsulfonyl radical, C6-10Arylsulfonyl (the alkylsulfonyl and arylsulfonyl groups may be substituted by halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), sulfamoyl, C1-4Alkylsulfonamide group, C6-10Arylsulfonamide group (the alkylsulfonamide group and the arylsulfonamide group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), bis (C)1-4Alkylsulfonyl) imino group (the alkylsulfonyl group of the bis (alkylsulfonyl) imino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted), bis (C)6-10Arylsulfonyl) imino group (the arylsulfonyl group of the bis (arylsulfonyl) imino group may be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substitution), [ N, N' - (C)1-4Alkylsulfonyl) (C6-10Aryl sulfonyl radical]Imino group (the [ N, N' - (alkylsulfonyl) (arylsulfonyl group)]The alkyl-and aryl-sulphonyl radicals of the imino group may be substituted by halogen atoms, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro substituted),
r in the formula (10)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy), C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom),
r in the formulae (11) and (12)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom),
the partial ring structure A in the formulae (11) and (12) represents a partial structure represented by a 5-, 6-or 7-membered ring forming a condensed ring with the benzene ring moiety (wherein the 5-, 6-or 7-membered ring may be substituted with h R' s11Optionally substituted (wherein, R11Is a halogen atom, a hydroxyl group, C1-6Alkyl (the alkyl may be substituted by halogen atom, hydroxy, cyano, amino, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-6Alkoxy (the alkoxy may be substituted by halogen atom, hydroxy, cyano, amino, nitro, C)1-4Alkoxy radical, C1-4Alkyl radicalCarbonyloxy radical, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), nitro, cyano, formyl, carboxamido, carbamoyl, sulfo, sulfonamido, sulfamoyl, sulfonyl, amino, carboxyl, C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkylcarbonylamino, C1-6Alkylsulfonamide group, C6-14Arylsulfonamide group, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl radical, C6-14Arylsulfonyl, or C6-14An arylcarbonyl group (the alkylamino group, dialkylamino group, alkylcarbonylamino group, alkylsulfonamido group, arylsulfonamido group, alkylaminocarbonyl group, dialkylaminocarbonyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylsulfonyl group, arylsulfonyl group and arylcarbonyl group may be optionally substituted with a halogen atom), h is an integer of 1 to 6, and in the case where h is 2 to 6, R is an integer of 2 to 611May be the same or different, and may contain, as ring-constituting atoms, 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms, alone or in combination, the number of unsaturated bonds in the ring, including the unsaturated bond of the condensed benzene ring, being 1, 2 or 3, and the carbon atom constituting the ring may be a carbonyl group or thiocarbonyl group),
x in formula (13) represents NR20(R20Represents a hydrogen atom or C1-4Alkyl), Y in formula (13) represents a direct bond, SO or SO2Z in the formula (13) represents C1-4An alkyl group (the alkyl group may be substituted with 1 to 5 halogen atoms or a phenyl group (the phenyl group may be substituted with C)1-4Alkyl optionally substituted) or phenyl (which phenyl may be C substituted)1-4Alkyl group optionally substituted), W in formula (13) represents a hydrogen atom, a hydroxyl group, C1-6Alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), halogen atom, C1-4Alkyl or C1-6An alkylsulfonamide group (the alkyl group and the alkylsulfonamide group may be optionally substituted with a halogen atom),
r in the formula (13)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy group (the alkoxy group may be optionally substituted with a halogen atom)),
(in the formula, R5、R6、R7、R8、R9、R10A, W, X, Y and Z are the same as described above,＊the absolute configuration of the carbon atom of the label is (R) or (S)).
The compound can be produced by a method shown in the following reaction formula 1.
Reaction scheme 1
Reaction formula 1 (wherein R5、R6、R7、R8、R9、R10A, W, X, Y and Z are the same as described above.＊The absolute configuration of the carbon atom of the label is (R) or (S)), by treating a chromene compound of formula (10), formula (11), formula (12) or formula (13) with an oxidizing agent and an optically active titanium complex in a solvent to produce an optically active chromene oxide represented by formula (14) from formula (10), an optically active chromene oxide represented by formula (15) from formula (11), an optically active chromene oxide represented by formula (16) from formula (12) or an optically active chromene oxide represented by formula (17) from formula (13)A method for preparing an alkene oxide compound.
The chromene compound represented by the above formula (10), formula (11), formula (12) or formula (13) which is a starting material of the present invention can be synthesized by using the following general synthesis method of a benzopyran ring. The synthesis of the condensed rings in the formulae (11) and (12) can be achieved by appropriately combining the synthesis methods of various heterocycles shown below with the benzopyran ring synthesis method.
General benzopyran Ring Synthesis
Can be synthesized by a known method (methods described in J.M. Evans, et al., J.Med.chem.1984, 27, 1127., J.Med.chem.1986, 29, 2194., J.T.North, et al., J.Org.chem.1995, 60, 3397, Japanese patent laid-open No. 56-57785, Japanese patent laid-open No. 56-57786, Japanese patent laid-open No. 58-188880, Japanese patent laid-open No. 2-141, Japanese patent laid-open No. 10-87650, and Japanese patent laid-open No. 11-209366).
O indole, O indole (oxindole)
Known methods can be followed (t.sakamoto, et al, Heterocycles, 1986, 24, 31.
Belley, et al, Synthesis, 2001, 222.
Cross, et al, j.chem.soc., 1961, 2714, et al).
O imidazolinone
Can be synthesized according to known methods (methods described in j. kitteringham, et al, Synthetic Commun, 2000, 30, 1937).
Quinoline ring
Known methods can be followed (s.imor, et al., Synthetic Commun., 1996, 26, 2197.
Y. kitahara, et al, Tetrahedron, 1997, 53, 6001.
Osborne, et al, j. chem. soc. perkin trans, 1993, 1, 181.
R.t. shuman, et al, j.org.chem., 1990, 55, 738.
T.sakamoto, et al, chem.pharm.bull, 1981, 29, 2485.
Y.tsuji, et al, j.org.chem., 1987, 52, 1673.
Z. song, et al, j.heterocyclic chem., 1993, 30, 17, et al).
Quinolinones
The method may be according to known methods (m.r. sabol, et al, Synthetic commun, 2000, 30, 427.
Yang, et al, Tetrahedron lett, 1999, 40, 4505.
H-B Sun, et al, Synthesis, 1997, 1249.
Guiotto, et al, j.heterocyclic chem., 1989, 26, 917.
K.konno, et al, Heterocycles, 1986, 24, 2169.
E.fernandez, et al, Synthesis, 1995, 1362 et al).
O-benzothiazole, triazole, and,
Known methods can be used (n.b. ambati, et al, Synthetic commun, 1997, 27, 1487).
D.e. burton, et al, j.chem.soc (C), 1968, 1268, et al).
Quinoxaline, quinazolinone
The method can be according to known methods (j.h.liu, et al., j.org.chem., 2000, 65, 3395.
Li, et al, Tetrahedron lett, 1999, 40, 4507.
Y. ahmed, et al, bull. chem.soc. jpn., 1987, 60, 1145, et al).
Benzoxazinone
Known methods can be followed (g.h.jones, et al., j.med.chem., 1987, 30, 295).
J.l.wright, et al., j.med.chem., 2000, 43, 3408.
M. kluge, et al, j.heterocylic chem., 1995, 32, 395, et al).
The compounds represented by the following formulae (35) and (36) can be obtained by reacting the compound (33) with the compound (34). (references Y.Tsuji, et al, J.org.chem., 1987, 52, 1673.)
The compounds represented by the following formulae (35) and (36) can also be obtained by reacting the compound (33) with the compound (37) in the presence of an acid catalyst. (ref. Y.Kitahara, et al, Tetrahedron1997, 53, 6001, Z.Song, et al, J.Heterocyclic chem., 1993, 30, 17.)
The chromene compound represented by the following formula (40) can be synthesized from the compound (38) through the reduction of a nitro group to the amine compound (39) with a platinum-carbon catalyst, and then, can be obtained by mesylation.
The substituents of the chromene compound represented by the above formula (10), formula (11), formula (12) or formula (13) will be specifically described.
Next, each substituent of the above formula (10) will be described. R in the formula (10)5、R6、R7And R8Each independently represents a hydrogen atom, a cyano group, a nitro group, a halogen atom, C1-4Alkyl (the alkyl may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkoxy (the alkoxy may be substituted by halogen atom, hydroxy, cyano, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), C1-4Alkylcarbonylamino (the alkylcarbonylamino group may be substituted with a halogen atom, C)6-10Aryl radical (the radical C)6-10Aryl radicals optionally substituted by halogen atoms, hydroxy, cyano, nitro, C1-4Alkyl, or C1-4Alkoxy is optionally substituted) and (C)1-4Alkylcarbonyl (N-C)1-4Alkyl) amino (the alkylcarbonyl (N-alkyl) amino group may be optionally substituted with a halogen atom), C1-4Alkoxycarbonyl group (the alkoxycarbonyl group may be optionally substituted by a halogen atom), C6-10Arylcarbonylamino (the arylcarbonylamino can be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro optionally substituted), C6-10Aryl carbonyl (N-C)1-4Alkyl) amino (the arylcarbonyl (N-alkyl) amino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro optionally substituted), benzylcarbonylamino, formyl, carbamoyl, C1-4Alkylsulfonyl (said alkylsulfonyl group may be optionally substituted with a halogen atom), C6-10Aryl sulfonyl radicalRadical (the arylsulfonyl radical may be interrupted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro optionally substituted), sulfamoyl, C1-4Alkylsulfonamide group, C6-10Arylsulfonamide group (the alkylsulfonamide group and the arylsulfonamide group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro optionally substituted), bis (C)1-4Alkylsulfonyl) imino group (the alkylsulfonyl group of the bis (alkylsulfonyl) imino group may be substituted with a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro optionally substituted), bis (C)6-10Arylsulfonyl) imino group (the arylsulfonyl group of the bis (arylsulfonyl) imino group may be substituted by a halogen atom, C1-4Alkyl radical, C1-4Alkoxy, cyano or nitro being optionally substituted), [ N, N' -C1-4Alkylsulfonyl) (C6-10Aryl sulfonyl radical]Imino group (the [ N, N' - (alkylsulfonyl) (arylsulfonyl group)]The aryl-and alkyl-sulphonyl radicals of the imino group may be substituted by halogen atoms, C1-4Alkyl radical, C1-4Alkoxy, cyano, nitro are optionally substituted).
Next, for R in the formula (10)5、R6、R7And R8The respective substituents of (A) are specifically described.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
as the C1-4Examples of the alkyl group include methyl, trifluoromethyl, trichloromethyl, ethyl, n-propyl, i-propyl, C-propyl, n-butyl, i-butyl, s-butyl, t-butyl and C-butyl, and C is1-4Examples of the alkoxy group include a methoxy group, a trifluoromethoxy group, a trichloromethoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a C-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group and a C-butoxy group, and C represents1-4Alkylcarbonylamino groups include methylcarbonylamino, trifluoromethylcarbonylamino, trichloromethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, c-propylcarbonylamino and n-butylcarbonylArylamino, i-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, C-butylcarbonylamino, p-methoxyphenylmethylcarbonylamino, p-nitrophenylmethylcarbonylamino, p-methoxyphenylethylcarbonylamino and the like as C1-4Alkylcarbonyl (N-C)1-4Examples of the alkyl) amino group include a methylcarbonyl (N-methyl) amino group, a trifluoromethylcarbonyl (N-methyl) amino group, a methylcarbonyl (N-ethyl) amino group, a trifluoromethylcarbonyl (N-ethyl) amino group, an ethylcarbonyl (N-ethyl) amino group, an N-propylcarbonyl (N-ethyl) amino group, an i-propylcarbonyl (N-ethyl) amino group, a C-propylcarbonyl (N-ethyl) amino group, an N-butylcarbonyl (N-ethyl) amino group, an i-butylcarbonyl (N-ethyl) amino group, an s-butylcarbonyl (N-ethyl) amino group, a tert-butylcarbonyl (N-ethyl) amino group and a C-butylcarbonyl (N-ethyl) amino group, and the C-carbonyl (N-ethyl) amino group1-4Examples of the alkoxycarbonyl group include a methoxycarbonyl group, a trifluoromethoxy carbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, a C-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, an s-butoxycarbonyl group, a t-butoxycarbonyl group, and a C-butoxycarbonyl group, and the C6-10Examples of the arylcarbonylamino group include phenylcarbonylamino group, 1-naphthylcarbonylamino group and 2-naphthylcarbonylamino group, and C6-10Aryl carbonyl (N-C)1-4Alkyl) amino, there may be mentioned phenylcarbonyl (N-methyl) amino, phenylcarbonyl (N-ethyl) amino, 1-naphthylcarbonyl (N-ethyl) amino and 2-naphthylcarbonyl (N-ethyl) amino, as C1-4Examples of the alkylsulfonyl group include methanesulfonyl group, trifluoromethanesulfonyl group, ethanesulfonyl group, n-propanesulfonyl group, i-propanesulfonyl group, C-propanesulfonyl group, n-butanesulfonyl group, i-butanesulfonyl group, s-butanesulfonyl group, t-butanesulfonyl group and C-butanesulfonyl group6-10Examples of the arylsulfonyl group include a benzenesulfonyl group, a p-fluorobenzenesulfonyl group, a p-toluenesulfonyl group, a 1-naphthalenesulfonyl group and a 2-naphthalenesulfonyl group, and the like1-4Examples of the alkylsulfonamide group include a methanesulfonamide group, a trifluoromethanesulfonamide group, an ethanesulfonamide group, an n-propanesulfonamide group, an i-propanesulfonamide group, a c-propanesulfonamide group, an n-butanesulfonamide group, an i-butanesulfonamide group, and an s-butanesulfonamide groupC is an amide group, a t-butanesulfonamide group, a C-butanesulfonamide group, or the like6-10Examples of the arylsulfonamide group include a benzenesulfonamide group, a p-fluorobenzenesulfonamide group, a p-toluenesulfonamide group, a 1-naphthalenesulfonamide group, and a 2-naphthalenesulfonamide group1-4Examples of the alkylsulfonyl) imino group include a bis (methanesulfonyl) imino group, a bis (trifluoromethanesulfonyl) imino group, a bis (ethanesulfonyl) imino group, a bis (n-propanesulfonyl) imino group, a bis (i-propanesulfonyl) imino group, a bis (C-propanesulfonyl) imino group, a bis (n-butanesulfonyl) imino group, a bis (i-butanesulfonyl) imino group, a bis (s-butanesulfonyl) imino group, a bis (t-butanesulfonyl) imino group and a bis (C-butanesulfonyl) imino group, and the bis (C-butanesulfonyl) imino group is the above-mentioned bis (C)6-10Examples of the arylsulfonyl) imino group include a bis (phenylsulfonyl) imino group, a bis (p-fluorophenylsulfonyl) imino group, a bis (p-toluenesulfonyl) imino group, a bis (1-naphthalenesulfonyl) imino group and a bis (2-naphthalenesulfonyl) imino group1-4Alkylsulfonyl) (C6-10Aryl sulfonyl radical]Examples of the imino group include [ N, N' - (methane) (benzene)]Imino, [ N, N' - (trifluoromethane) (benzene)]Imino, [ N, N' - (trifluoromethane) (p-fluorobenzene)]Imino, [ N, N' - (ethane) (benzene)]Imino, [ N, N' - (methane) (p-toluene)]Imino, [ N, N' - (trifluoromethane) (p-toluene)]Imino, [ N, N' - (ethane) (p-toluene)]Imino, [ N, N' - (methane) (1-naphthalene)]Imino, [ N, N' - (trifluoromethane) (1-naphthalene)]Imino, [ N, N' - (ethane) (1-naphthalene)]Imino, [ N, N' - (methane) (2-naphthalene)]Imino, [ N, N' - (trifluoromethane) (2-naphthalene)]Imino and [ N, N' - (ethane) (2-naphthalene)]Imino groups, and the like.
R in the formula (10)5And R6Independently of each other, preferably a hydrogen atom, cyano group, nitro group, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, trifluoromethyl group, ethyl group, n-propyl group, i-propyl group, c-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, c-butyl group, methoxy group, trifluoromethoxy group, ethoxy group, n-propoxy group, i-propoxy group, c-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, c-butoxy group, methylcarbonylamino group, trifluoromethylcarbonylamino group, ethylcarbonylamino group, n-propylcarbonylamino groupArylamino, i-propylcarbonylamino, c-propylcarbonylamino, N-butylcarbonylamino, i-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, c-butylcarbonylamino, methylcarbonyl (N-methyl) amino, trifluoromethylcarbonyl (N-methyl) amino, methylcarbonyl (N-ethyl) amino, trifluoromethylcarbonyl (N-ethyl) amino, ethylcarbonyl (N-ethyl) amino, N-propylcarbonyl (N-ethyl) amino, i-propylcarbonyl (N-ethyl) amino, c-propylcarbonyl (N-ethyl) amino, N-butylcarbonyl (N-ethyl) amino, i-butylcarbonyl (N-ethyl) amino, s-butylcarbonyl (N-ethyl) amino, N-butylcarbonylamino, t-butyl, T-butylcarbonyl (N-ethyl) amino, c-butylcarbonyl (N-ethyl) amino, methoxycarbonyl, trifluoromethoxy-carbonyl, ethoxycarbonyl, N-propoxycarbonyl, i-propoxycarbonyl, phenylcarbonylamino, 1-naphthylcarbonylamino, 2-naphthylcarbonylamino, phenylcarbonyl (N-methyl) amino, phenylcarbonyl (N-ethyl) amino, 1-naphthylcarbonyl (N-ethyl) amino, 2-naphthylcarbonyl (N-ethyl) amino, benzylcarbonylamino, formyl, carbamoyl, methanesulfonamido, trifluoromethanesulfonylamino, ethanesulfonamide, N-propanesulfonamide, i-propanesulfonamide, c-propanesulfonamide, N-butanesulfonamide, i-butanesulfonamide, N-butanesulfonamide, etc, s-butanesulfonamido group, t-butanesulfonamido group, c-butanesulfonamido group, bis (methanesulfonyl) imide group, bis (trifluoromethanesulfonyl) imide group, bis (ethanesulfonyl) imide group, bis (n-propanesulfonyl) imide group, bis (i-propanesulfonyl) imide group, bis (c-propanesulfonyl) imide group, bis (n-butanesulfonyl) imide group, bis (i-butanesulfonyl) imino, bis (s-butanesulfonyl) imino, bis (t-butanesulfonyl) imino, bis (c-butanesulfonyl) imino, bis (phenylsulfonyl) imino, bis (p-toluenesulfonyl) imino, bis (1-naphthalenesulfonyl) imino, bis (2-naphthalenesulfonyl) imino, [ N, N' - (methane) (benzene).]Imino, [ N, N' - (trifluoromethane) (benzene)]Imino, [ N, N' - (ethane) (benzene)]Imino, [ N, N' - (methane) (p-toluene)]Imino, [ N, N' - (trifluoromethane) (p-toluene)]Imino, [ N, N' - (ethane) (p-toluene)]Imino, [ N, N' - (methane) (1-naphthalene)]Imino, [ N, N' - (trifluoromethane) (1-naphthalene)]Imino, [ N, N' - (ethane) (1-naphthalene)]Imino, [ N, N' - (methane) (2-naphthalene)]Imine(s)Base, [ N, N' - (trifluoromethane) (2-naphthalene)]Imino, [ N, N' - (ethane) (2-naphthalene)]More preferably a hydrogen atom, nitro group, fluorine atom, chlorine atom, methoxy group, methylcarbonylamino group, methylcarbonyl (N-ethyl) amino group, bis (trifluoromethanesulfonyl) imino group, [ N, N' - (trifluoromethane) (benzene)]Imino, [ N, N' - (trifluoromethane) (p-toluene)]And (3) imino.
R in the formula (10)7Preferably a hydrogen atom, a cyano group, a nitro group, a methanesulfonamide group, a trifluoromethanesulfonamide group, an ethanesulfonamide group, an n-propanesulfonamide group, an i-propanesulfonamide group, a c-propanesulfonamide group, an n-butanesulfonamide group, an i-butanesulfonamide group, an s-butanesulfonamide group, a t-butanesulfonamide group, a c-butanesulfonamide group, a bis (methanesulfonyl) imide group, a bis (trifluoromethanesulfonyl) imide group, a bis (ethanesulfonyl) imide group, a bis (n-propanesulfonyl) imide group, a bis (i-propanesulfonyl) imide group, a bis (c-propanesulfonyl) imide group, a bis (n-butanesulfonyl) imide group, a bis (i-butanesulfonyl) imide group, a bis (s-butanesulfonyl) imide group, a bis (t-butanesulfonyl) imide group, a bis (s-butanesulfonyl) imide group, a bis (, Bis (c-butanesulfonyl) imide, bis (phenylsulfonyl) imide, bis (p-toluenesulfonyl) imide, bis (1-naphthalenesulfonyl) imide, bis (2-naphthalenesulfonyl) imide, [ N, N' - (methane) (benzene)]Imino, [ N, N' - (trifluoromethane) (benzene)]Imino, [ N, N' - (trifluoromethane) (p-fluorobenzene)]Imino, [ N, N' - (ethane) (benzene)]Imino, [ N, N' - (methane) (p-toluene)]Imino, [ N, N' - (trifluoromethane) (p-toluene)]Imino, [ N, N' - (ethane) (p-toluene)]Imino, [ N, N' - (methane) (1-naphthalene)]Imino, [ N, N' - (trifluoromethane) (1-naphthalene)]Imino, [ N, N' - (ethane) (1-naphthalene)]Imino, [ N, N' - (methane) (2-naphthalene)]Imino, [ N, N' - (trifluoromethane) (2-naphthalene)]Imino, [ N, N' - (ethane) (2-naphthalene)]More preferred examples of the imino group include a hydrogen atom, a nitro group, a bis (methanesulfonyl) imino group, a bis (trifluoromethanesulfonyl) imino group, [ N, N' - (trifluoromethane) (benzene)]Imino, [ N, N' - (trifluoromethane) (p-toluene)]And (3) imino.
R in the formula (10)8Preferably a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a nitro group, a methyl group, a trifluoromethyl group, an ethyl group, an n-propyl groupI-propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, more preferably a hydrogen atom, fluorine atom, nitro group, methyl group, trifluoromethyl group.
R in the formula (10)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom).
For R in formula (10)9And R10The respective substituents of (A) are specifically described. As the C1-6Examples of the alkyl group include a methyl group, a trifluoromethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a tert-butyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, an i-pentyl group, a neopentyl group, a2, 2-dimethylpropyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 1-methyl-n-pentyl group, a1, 1, 2-trimethyl-n-propyl group, a1, 2, 2-trimethyl-n-propyl group and a 3, 3-dimethyl-n-butyl group, and the C is the C6-14Examples of the aryl group include phenyl, o-biphenyl, m-biphenyl, p-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9-phenanthryl.
As R in formula (10)9And R10The hydrogen atom, methyl group, trifluoromethyl group, ethyl group, and phenyl group are preferable, and methyl group is more preferable.
The substituents in the formulae (11) and (12) will be described.
R in the formulae (11) and (12)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom)) Or optionally substituted by hydroxy) or C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy) or C1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom).
For R in formula (11) and formula (12)9And R10The respective substituents of (A) are specifically described.
As the C1-6Examples of the alkyl group include methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2, 2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1, 2-trimethyl-n-propyl, 1, 2, 2-trimethyl-n-propyl and 3, 3-dimethyl-n-butyl,
as the C6-14Examples of the aryl group include phenyl, o-biphenyl, m-biphenyl, p-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9-phenanthryl.
R in the formulae (11) and (12)9And R10Preferably a hydrogen atom, methyl group, trifluoromethyl group, ethyl group, or phenyl group, and more preferably a methyl group.
The partial ring structure a in formula (11) and formula (12) will be explained. The partial ring structure A represents a partial structure represented by a 5-, 6-or 7-membered ring forming a condensed ring with the benzene ring moiety (wherein the 5-, 6-or 7-membered ring may be substituted with h R11Optionally substituted (wherein, R11Is a halogen atom, a hydroxyl group, C1-6Alkyl (the alkyl may be substituted by halogen atom, hydroxy, cyano, amino, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom)Generation), C1-6Alkoxy (the alkoxy may be substituted by halogen atom, hydroxy, cyano, amino, nitro, C)1-4Alkoxy radical, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkoxycarbonyl (the alkoxy, alkylcarbonyloxy, alkylcarbonylamino and alkoxycarbonyl may be optionally substituted by a halogen atom), nitro, cyano, formyl, carboxamido, carbamoyl, sulfo, sulfonamido, sulfamoyl, sulfonyl, amino, carboxyl, C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkylcarbonylamino, C1-6Alkylsulfonamide group, C6-14Arylsulfonamide group, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl radical, C6-14Arylsulfonyl, or C6-14An arylcarbonyl group (the alkylamino group, dialkylamino group, alkylcarbonylamino group, alkylsulfonamido group, arylsulfonamido group, alkylaminocarbonyl group, dialkylaminocarbonyl group, alkylcarbonyl group, alkoxycarbonyl group, alkylsulfonyl group, arylsulfonyl group and arylcarbonyl group may be optionally substituted with a halogen atom), h is an integer of 1 to 6, and in the case where h is 2 to 6, R is11The same or different) may be used, and the number of unsaturated bonds in the ring, including the unsaturated bond of the condensed benzene ring, may be 1, 2 or 3, and the carbon atom constituting the ring may be a carbonyl group or a thiocarbonyl group).
For the above R11The description will be specifically made.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
as the C1-6Examples of the alkyl group include methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexylHexyl, 1-methyl-n-pentyl, 1, 2-trimethyl-n-propyl, 1, 2, 2-trimethyl-n-propyl, 3-dimethyl-n-butyl, methylcarbonyloxymethyl, ethylcarbonyloxymethyl, methylcarbonyloxyethyl, ethylcarbonyloxyethyl, methylcarbonylaminomethyl, trifluoromethylcarbonylaminomethyl, ethylcarbonylaminomethyl, methylcarbonylaminoethyl, ethylcarbonylaminoethyl, methoxycarbonylmethyl, trifluoromethoxy-carbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl and the like,
as the C1-6Alkoxy includes methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, i-pentyloxy, neopentyloxy, 2, 2-dimethylpropoxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-methyl-n-pentyloxy, 1, 2-trimethyl-n-propoxy, 1, 2, 2-trimethyl-n-propoxy, 3-dimethyl-n-butoxy, methylcarbonyloxymethoxy, ethylcarbonyloxymethoxy, methylcarbonyloxyethoxy, n-butoxy, n-propyloxy, n-butyloxy, Ethylcarbonyloxyethoxy, methylcarbonylaminomethoxy, trifluoromethylcarbonylaminomethoxy, ethylcarbonylaminomethoxy, methylcarbonylaminoethoxy, ethylcarbonylaminoethoxy, methoxycarbonylmethoxy, trifluoromethoxycarbonylmethoxy, ethoxycarbonylmethoxy, methoxycarbonylethoxy and ethoxycarbonylethoxy and the like,
as the C1-6Alkylamino groups, there may be mentioned methylamino, trifluoromethylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino, i-butylamino, s-butylamino, t-butylamino, c-butylamino, 1-pentylamino, 2-pentylamino, 3-pentylamino, i-pentylamino, neopentylamino, t-pentylamino, c-pentylamino, 1-hexylamino, 2-hexylamino, 3-hexylamino, c-hexylamino, 1-methyl-n-pentylamino, 1, 2-trimethyl-n-propylamino, 1, 2, 2-trimethyl-n-propylamino and 3, 3-dimethyl-n-butylAmino group, etc.,
as the di-C1-6As the alkylamino group, there may be mentioned dimethylamino group, di- (trifluoromethyl) amino group, diethylamino group, di-n-propylamino group, di-i-propylamino group, di-c-propylamino group, di-n-butylamino group, di-i-butylamino group, di-s-butylamino group, di-tert-butylamino group, di-c-butylamino group, di-1-pentylamino group, di-2-pentylamino group, di-3-pentylamino group, di-i-pentylamino group, di-neopentylamino group, di-t-pentylamino group, di-c-pentylamino group, di-1-hexylamino group, di-2-hexylamino group, di-3-hexylamino group, di-s-n-propylamino group, di-i-butylamino group, di-s-butylamino group, di, Di-c-hexylamino, di- (1-methyl-n-pentyl) amino, di- (1, 1, 2-trimethyl-n-propyl) amino, di- (1, 2, 2-trimethyl-n-propyl) amino, di- (3, 3-dimethyl-n-butyl) amino, methyl (ethyl) amino, methyl (n-propyl) amino, methyl (i-propyl) amino, methyl (c-propyl) amino, methyl (n-butyl) amino, methyl (i-butyl) amino, methyl (s-butyl) amino, methyl (t-butyl) amino, methyl (c-butyl) amino, ethyl (n-propyl) amino, ethyl (i-propyl) amino, methyl (i-butyl) amino, methyl (ethyl) amino, methyl (n-propyl) amino, methyl (i-butyl), Ethyl (c-propyl) amino, ethyl (n-butyl) amino, ethyl (i-butyl) amino, ethyl (s-butyl) amino, ethyl (tert-butyl) amino, ethyl (c-butyl) amino, n-propyl (i-propyl) amino, n-propyl (c-propyl) amino, n-propyl (n-butyl) amino, n-propyl (i-butyl) amino, n-propyl (s-butyl) amino, n-propyl (t-butyl) amino, n-propyl (c-butyl) amino, i-propyl (c-propyl) amino, i-propyl (n-butyl) amino, i-propyl (i-butyl) amino, i-propyl (s-butyl) amino, ethyl (i-butyl) amino, ethyl (s-butyl) amino, n-propyl (n-, i-propyl (t-butyl) amino, i-propyl (c-butyl) amino, c-propyl (n-butyl) amino, c-propyl (i-butyl) amino, c-propyl (s-butyl) amino, c-propyl (t-butyl) amino, c-propyl (c-butyl) amino, n-butyl (i-butyl) amino, n-butyl (s-butyl) amino, n-butyl (t-butyl) amino, n-butyl (c-butyl) amino, i-butyl (s-butyl) amino, i-butyl (t-butyl) amino, i-butyl (c-butyl) amino, s-butyl (t-butyl) amino, s-butyl (c-butyl) amino, t-butyl (c-butyl) amino and the like,
as the C1-6Alkylcarbonylamino group, there may be mentionedMethylcarbonylamino, trifluoromethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, 1-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, i-pentylcarbonylamino, neopentylcarbonylamino, t-pentylcarbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino, and 3-hexylcarbonylamino, etc.,
as the C1-6Examples of the alkylsulfonamide group include a methanesulfonamide group, a trifluoromethanesulfonamide group, an ethanesulfonamide group, an n-propanesulfonamide group, an i-propanesulfonamide group, an n-butanesulfonamide group, an i-butanesulfonamide group, an s-butanesulfonamide group, a t-butanesulfonamide group, a 1-pentanesulfonamide group, a 2-pentanesulfonamide group, a 3-pentanesulfonamide group, an i-pentanesulfonamide group, a neopentanesulfonamide group, a t-pentanesulfonamide group, a 1-hexanesulfonamide group, a 2-hexanesulfonamide group and a 3-hexanesulfonamide group,
as the C6-14Examples of the arylsulfonamide group include a benzenesulfonamide group, a p-toluenesulfonamide group, an o-biphenylsulfonamide group, an m-biphenylsulfonamide group, a p-biphenylsulfonamide group, a 1-naphthalenesulfonamide group, a 2-naphthalenesulfonamide group, a 1-anthracenesulfonamide group, a 2-anthracenesulfonamide group, a 9-anthracenesulfonamide group, a 1-phenanthrenesulfonamide group, a 2-phenanthrenesulfonamide group, a 3-phenanthrenesulfonamide group, a 4-phenanthrenesulfonamide group and a 9-phenanthrenesulfonamide group,
as the C1-6As the alkylaminocarbonyl group, there may be mentioned methylaminocarbonyl group, trifluoromethylaminocarbonyl group, ethylaminocarbonyl group, n-propylaminocarbonyl group, i-propylaminocarbonyl group, n-butylaminocarbonyl group, i-butylaminocarbonyl group, s-butylaminocarbonyl group, t-butylaminocarbonyl group, 1-pentylaminocarbonyl group, 2-pentylaminocarbonyl group, 3-pentylaminocarbonyl group, i-pentylaminocarbonyl group, neopentylaminocarbonyl group, t-pentylaminocarbonyl group, 1-hexylaminocarbonyl group, 2-hexylaminocarbonyl group, 3-hexylaminocarbonyl group and the like,
as the di-C1-6Alkylaminocarbonyl group, which may be mentioned is dimethylaminoCarbonyl, bis (trifluoromethyl) aminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl, di-n-butylaminocarbonyl, di-i-butylaminocarbonyl, di-s-butylaminocarbonyl, di-t-butylaminocarbonyl, di-c-butylaminocarbonyl, di-1-pentylaminocarbonyl, di-2-pentylaminocarbonyl, di-3-pentylaminocarbonyl, di-i-pentylaminocarbonyl, di-neopentylaminocarbonyl, di-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl, di-1-hexylaminocarbonyl, di-n-propylaminocarbonyl, di-n-butylaminocarbonyl, di-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl, di-1-hexylaminocarbonyl, di-n, Di-2-hexylaminocarbonyl, di-3-hexylaminocarbonyl, di-c-hexylaminocarbonyl, di- (1-methyl-n-pentyl) aminocarbonyl, di- (1, 1, 2-trimethyl-n-propyl) aminocarbonyl, di- (1, 2, 2-trimethyl-n-propyl) aminocarbonyl, di- (3, 3-dimethyl-n-butyl) aminocarbonyl, methyl (ethyl) aminocarbonyl, trifluoromethyl (ethyl) aminocarbonyl, methyl (n-propyl) aminocarbonyl, methyl (i-propyl) aminocarbonyl, methyl (c-propyl) aminocarbonyl, methyl (n-butyl) aminocarbonyl, methyl (i-butyl) aminocarbo, Methyl (s-butyl) aminocarbonyl, methyl (t-butyl) aminocarbonyl, methyl (c-butyl) aminocarbonyl, ethyl (n-propyl) aminocarbonyl, ethyl (i-propyl) aminocarbonyl, ethyl (c-propyl) aminocarbonyl, ethyl (n-butyl) aminocarbonyl, ethyl (i-butyl) aminocarbonyl, ethyl (s-butyl) aminocarbonyl, ethyl (t-butyl) aminocarbonyl, ethyl (c-butyl) aminocarbonyl, n-propyl (i-propyl) aminocarbonyl, n-propyl (c-propyl) aminocarbonyl, n-propyl (n-butyl) aminocarbonyl, n-propyl (i-butyl) aminocarbonyl, n-propyl (s-butyl) aminocarbonyl, n-butyl (i-butyl, n-propyl (t-butyl) aminocarbonyl, n-propyl (c-butyl) aminocarbonyl, i-propyl (c-propyl) aminocarbonyl, i-propyl (n-butyl) aminocarbonyl, i-propyl (i-butyl) aminocarbonyl, i-propyl (s-butyl) aminocarbonyl, i-propyl (t-butyl) aminocarbonyl, i-propyl (c-butyl) aminocarbonyl, c-propyl (n-butyl) aminocarbonyl, c-propyl (i-butyl) aminocarbonyl, c-propyl (s-butyl) aminocarbonyl, c-propyl (t-butyl) aminocarbonyl, c-propyl (c-butyl) aminocarbonyl, n-butyl (i-butyl) aminocarbonyl, n-butyl (s-butyl) aminocarbonyl, n-butyl (t-butyl) aminocarbonyl, n-butyl (c-butyl) aminocarbonyl, iButyl (s-butyl) aminocarbonyl, i-butyl (t-butyl) aminocarbonyl, i-butyl (c-butyl) aminocarbonyl, s-butyl (t-butyl) aminocarbonyl, s-butyl (c-butyl) aminocarbonyl, t-butyl (c-butyl) aminocarbonyl and the like,
as the C1-6Examples of the alkylcarbonyl group include methylcarbonyl, trifluoromethylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl, and 3-hexylcarbonyl,
as the C1-6Examples of the alkoxycarbonyl group include a methoxycarbonyl group, a trifluoromethoxy carbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, an s-butoxycarbonyl group, a t-butoxycarbonyl group, a 1-pentyloxycarbonyl group, a 2-pentyloxycarbonyl group, a 3-pentyloxycarbonyl group, an i-pentyloxycarbonyl group, a neopentyloxycarbonyl group, a t-pentyloxycarbonyl group, a 1-hexyloxycarbonyl group, a 2-hexyloxycarbonyl group, and a 3-hexyloxycarbonyl group,
as the C1-6Examples of the alkylsulfonyl group include methanesulfonyl group, trifluoromethanesulfonyl group, ethanesulfonyl group, n-propanesulfonyl group, n-butanesulfonyl group and the like,
as the C6-14Examples of the arylsulfonyl group include benzenesulfonyl, p-fluorobenzenesulfonyl, p-toluenesulfonyl, o-biphenylsulfonyl, m-biphenylsulfonyl, p-biphenylsulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, 1-anthracenesulfonyl, 2-anthracenesulfonyl, 9-anthracenesulfonyl, 1-phenanthrenesulfonyl, 2-phenanthrenesulfonyl, 3-phenanthrenesulfonyl, 4-phenanthrenesulfonyl and 9-phenanthrenesulfonyl,
as the C6-14Examples of the arylcarbonyl group include phenylcarbonyl group, p-fluorophenylcarbonyl group, o-biphenylcarbonyl group, m-biphenylcarbonyl group, p-biphenylcarbonyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group, 1-anthrylcarbonyl group, 2-anthrylcarbonyl group, 9-anthrylcarbonyl group and 1-phenanthryl groupCarbonyl, 2-phenanthrylcarbonyl, 3-phenanthrylcarbonyl, 4-phenanthrylcarbonyl, 9-phenanthrylcarbonyl and the like.
With respect to R mentioned above11Preferred atoms and substituents are specifically described.
R11Preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a trifluoromethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an n-pentyl group, an i-pentyl group, a 3, 3-dimethyl-n-butyl group, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, a methylcarbonyloxyethyl group, an ethylcarbonyloxyethyl group, a methylcarbonylaminomethyl group, a trifluoromethylcarbonylaminomethyl group, an ethylcarbonylaminomethyl group, a methylcarbonylaminoethyl group, a methoxycarbonylmethyl group, a trifluoromethoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a methoxy group, a trifluoromethoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a 3, 3-dimethyl-n-butoxy group, a methylcarbonyloxymethoxymethoxy group, a, Ethylcarbonyloxymethoxy, methylcarbonyloxyethoxy, ethylcarbonyloxyethoxy, methylcarbonylaminomethoxy, trifluoromethylcarbonylaminomethoxy, ethylcarbonylaminomethoxy, methylcarbonylaminoethoxy, ethylcarbonylaminoethoxy, methoxycarbonylmethoxy, trifluoromethoxy-carbonylmethoxy, ethoxycarbonylmethoxy, methoxycarbonylethoxy, ethoxycarbonylethoxy, methylamino, trifluoromethylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, dimethylamino, di- (trifluoromethyl) amino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, methylcarbonylamino, trifluoromethylcarbonylamino, ethylcarbonylamino, t-butylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-butylcarbonylamino, methanesulfonamido, trifluoromethanesulfonylamino, ethanesulfonamide, n-propanesulfonamide, i-propanesulfonamide, n-butanesulfonamide, benzenesulfonamide, p-toluenesulfonylamino, methylaminocarbonyl, trifluoromethylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl, n-butylaminocarbonyl, dimethylaminocarbonyl, bis (N-butylcarbonylamino)Trifluoromethyl) aminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl, di-n-butylaminocarbonyl, methyl (ethyl) aminocarbonyl, trifluoromethyl (ethyl) aminocarbonyl, methylcarbonyl, trifluoromethylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, methoxycarbonyl, trifluoromethoxy-carbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, o-biphenylsulfonyl, amino-n-propylaminocarbonyl, methoxycarbonyl, trifluoromethanesulfonyl, ethanesulfonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-, m-biphenylsulfonyl, p-biphenylsulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, phenylcarbonyl, o-biphenylcarbonyl, m-biphenylcarbonyl, p-biphenylcarbonyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl, hydroxyl, nitro, cyano, formyl, carboxamido, carbamoyl, sulfonamido, sulfamoyl, amino, carboxyl.
The partial ring structure A in the above formula (11) and formula (12) is represented by the following formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), formula(s), formula (t), formula (u), formula (v), formula (w), formula (x), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae), formula (af), formula (ag) and formula (ah)
R in the above formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m), formula (n), formula (o), formula (p), formula (q), formula (R), formula(s), formula (t), formula (u), formula (v), formula (w), formula (x), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae), formula (af), formula (ag) and formula (ah) in the case of expression12、R13、R14、R15、R16And R17The respective substituents of (A) are illustrated.
First, R in the above formulae (a), (b), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (p), (q), (v), (w), (x), (ab), (ae), (af) and (ag)12And R13The description is given.
R in the formulae (a), (b), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (p), (q), (v), (w), (x), (ab), (ae), (af) and (ag)12And R13Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino, hydroxy, C6-14Aryl radical, C2-9Heteroaryl (both aryl and heteroaryl may be substituted by q R18(R18Is represented by the formula11The same meaning, q represents an integer of 1 to 3, and R is R when q is 2 or 318May be the same or different)) optionally substituted with C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonyl (the alkylcarbonyloxy and alkylcarbonyl may be optionally substituted with a halogen atom), C1-6Alkylcarbonylamino, C3-8Cycloalkyl carbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl (the cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group may be optionally substituted by a halogen atom), carboxyl group, C6-14Arylcarbonyl (the arylcarbonyl group may be optionally substituted with a halogen atom) or C2-9Optionally substituted heteroarylcarbonyl), C6-14Aryl radical, C2-9Heteroaryl (both aryl and heteroaryl may be substituted by q R18(R18Is represented by the formula11The same meaning, q represents an integer of 1 to 3, and R is R when q is 2 or 318May be the same or different)) optionally substituted with C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C3-8Cycloalkyl carbonyl group, C1-6Alkoxycarbonyl radicalsBase, C1-6Alkylsulfonyl radical, C6-14Arylsulfonyl radical, C2-9Heteroarylsulfonyl (both the arylsulfonyl and heteroarylsulfonyl can be substituted by q R18(R18Is represented by the formula11The same meaning, q represents an integer of 1 to 3, and R is R when q is 2 or 318The same or different) optionally substituted), carboxyl group, C6-14Aryl carbonyl or C2-9Heteroarylcarbonyl (both arylcarbonyl and heteroarylcarbonyl can be substituted by q R18(R18Is represented by the formula11The same meaning, q represents an integer of 1 to 3, and R is R when q is 2 or 318The same or different) may be substituted arbitrarily).
R in the above formulae (a), (b), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (p), (q), (v), (w), (x), (ab), (ae), (af) and (ag)12And R13The respective substituents of (A) are specifically described.
As the C1-6Examples of the alkyl group include a methyl group, a trifluoromethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a tert-butyl group, an n-pentyl group, a 2-pentyl group, a 3-pentyl group, an i-pentyl group, a neopentyl group, a2, 2-dimethylpropyl group, an n-hexyl group, a 2-hexyl group, a 3-hexyl group, a 1-methyl-n-pentyl group, a1, 1, 2-trimethyl-n-propyl group, a1, 2, 2-trimethyl-n-propyl group, a 3, 3-dimethyl-n-butyl group, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, a methylcarbonyloxyethyl group, an ethylcarbonyloxyethyl group, a methylcarbonylaminomethyl group, a trifluoromethylcarbonylaminomethyl group, an ethyl, Methylcarbonylaminoethyl, ethylcarbonylaminoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl and ethoxycarbonylethyl, and the like,
as the C6-14Examples of the aryl group include phenyl, o-biphenyl, m-biphenyl, p-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9-phenanthryl.
As the C2-9Heteroaryl group including C of 5 to 7-membered ring containing 1 to 3 oxygen atom, nitrogen atom, sulfur atom alone or in combination2-6Monocyclic heterocyclic group and C having 8 to 10 constituent atoms5-9Condensed bicyclic heterocyclic group.
C as the 5-to 7-membered ring2-6Examples of the monocyclic heterocyclic group include a 2-thienyl group, a 3-thienyl group, a 2-furyl group, a 3-furyl group, a 2-pyranyl group, a 3-pyranyl group, a 4-pyranyl group, a 1-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a 4-imidazolyl group, a 1-pyrazolyl group, a 3-pyrazolyl group, a 4-pyrazolyl group, a 2-thiazolyl group, a 5-thiazolyl group, a 3-isothiazolyl group, a 4-isothiazolyl group, a 5-isothiazolyl group, a 2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, a 3-isoxazolyl group, a 4-isoxazolyl group, a 5-isoxazolyl group, a 2-pyridyl group, a 3-pyridyl, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1, 3, 4-oxadiazolyl group, 2-1, 3, 4-thiadiazolyl group, 3-1, 2, 4-oxadiazolyl group, 5-1, 2, 4-oxadiazolyl group, 3-1, 2, 4-thiadiazolyl group, 5-1, 2, 4-thiadiazolyl group, 3-1, 2, 5-oxadiazolyl group, 3-1, 2, 5-thiadiazolyl group, and the like, wherein the constituent C having 8 to 10 atoms is5-9Examples of the condensed bicyclic heterocyclic group include a 2-benzofuranyl group, a 3-benzofuranyl group, a 4-benzofuranyl group, a 5-benzofuranyl group, a 6-benzofuranyl group, a 7-benzofuranyl group, a 1-isobenzofuranyl group, a 4-isobenzofuranyl group, a 5-isobenzofuranyl group, a 2-benzothienyl group, a 3-benzothienyl group, a 4-benzothienyl group, a 5-benzothienyl group, a 6-benzothienyl group, a 7-benzothienyl group, a 1-isobenzothiophenyl group, a 4-isobenzothiophenyl group, a 5-isobenzothiophenyl group, a 2-chromenyl group (chromenyl), a 3-chromenyl group, a 4-chromenyl group, a 5-chromenyl group, a 6-chromenyl group, a 7-chromenyl group, an 8-chromenyl group, a 5-chromenyl group, a 6-, 1-Indolizinyl, 2-Indolizinyl, 3-Indolizinyl, 5-Indolizinyl, 6-Indolizinyl, 7-Indolizinyl, 8-Indolizinyl, 1-isoindolyl, 2-isoindolyl, 4-isoindolyl, 5-isoindolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-indazolyl, 2-indazolylA group, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl, 1-purinyl, 2-purinyl, 3-purinyl, 6-purinyl, 7-purinyl, 8-purinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl, 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl, 1-2, 7-naphthyridinyl, 3-2, 7-naphthyridinyl, 4-2, 7-naphthyridinyl, 1-2, 6-naphthyridinyl, 3-2, 6-naphthyridinyl, 4-2, 6-naphthyridinyl, 2-1, 8-naphthyridinyl, 3-1, 8-naphthyridinyl, 4-1, 8-naphthyridinyl, 2-1, 7-naphthyridinyl, 3-1, 7-naphthyridinyl, 4-1, 7-naphthyridinyl, 5-1, 7-naphthyridinyl, 6-1, 7-naphthyridinyl, 8-1, 7-naphthyridinyl, 2-1, 6-naphthyridinyl, 3-1, 6-naphthyridinyl, 4-1, 6-naphthyridinyl, 5-1, 6-naphthyridinyl, 7-1, 6-naphthyridinyl, 8-1, 6-naphthyridinyl, 2-1, 5-naphthyridinyl, 3-1, 5-naphthyridinyl, 4-1, 5-naphthyridinyl, 6-1, 5-naphthyridinyl, 7-1, 5-naphthyridinyl, 8-1, 5-naphthyridinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl and the like.
As the C1-6As the alkylaminocarbonyl group, there may be mentioned methylaminocarbonyl group, ethylaminocarbonyl group, n-propylaminocarbonyl group, i-propylaminocarbonyl group, n-butylaminocarbonyl group, i-butylaminocarbonyl group, s-butylaminocarbonyl group, t-butylaminocarbonyl group, 1-pentylaminocarbonyl group, 2-pentylaminocarbonyl group, 3-pentylaminocarbonyl group, i-pentylaminocarbonyl group, neopentylaminocarbonyl group, t-pentylaminocarbonyl group, 1-hexylaminocarbonyl group, 2-hexylaminocarbonyl group, 3-hexylaminocarbonyl group and the like,
as the di-C1-6Examples of the alkylaminocarbonyl group include dimethylaminocarbonyl group, diethylaminocarbonyl group, di-n-propylaminocarbonyl group, di-i-propylaminocarbonyl group, di-c-propylaminocarbonyl group, di-n-butylaminocarbonyl group, and di-i-butylaminocarbonyl groupAlkylaminocarbonyl, di-s-butylaminocarbonyl, di-tert-butylaminocarbonyl, di-c-butylaminocarbonyl, di-1-pentylaminocarbonyl, di-2-pentylaminocarbonyl, di-3-pentylaminocarbonyl, di-i-pentylaminocarbonyl, di-neopentylaminocarbonyl, di-t-pentylaminocarbonyl, di-c-pentylaminocarbonyl, di-1-hexylaminocarbonyl, di-2-hexylaminocarbonyl, di-3-hexylaminocarbonyl, di-c-hexylaminocarbonyl, di- (1-methyl-n-pentyl) aminocarbonyl, di- (1, 1, 2-trimethyl-n-propyl) aminocarbonyl, di-n-pentyl-pentylaminocarbonyl, di-, Bis- (1, 2, 2-trimethyl-n-propyl) aminocarbonyl, bis- (3, 3-dimethyl-n-butyl) aminocarbonyl, methyl (ethyl) aminocarbonyl, methyl (n-propyl) aminocarbonyl, methyl (i-propyl) aminocarbonyl, methyl (c-propyl) aminocarbonyl, methyl (n-butyl) aminocarbonyl, methyl (i-butyl) aminocarbonyl, methyl (s-butyl) aminocarbonyl, methyl (t-butyl) aminocarbonyl, methyl (c-butyl) aminocarbonyl, ethyl (n-propyl) aminocarbonyl, ethyl (i-propyl) aminocarbonyl, ethyl (c-propyl) aminocarbonyl, ethyl (n-butyl) aminocarbonyl, ethyl (i-butyl) aminocarbonyl, methyl (n-propyl) aminocarbonyl, methyl (n-butyl), Ethyl (s-butyl) aminocarbonyl, ethyl (t-butyl) aminocarbonyl, ethyl (c-butyl) aminocarbonyl, n-propyl (i-propyl) aminocarbonyl, n-propyl (c-propyl) aminocarbonyl, n-propyl (n-butyl) aminocarbonyl, n-propyl (i-butyl) aminocarbonyl, n-propyl (s-butyl) aminocarbonyl, n-propyl (t-butyl) aminocarbonyl, n-propyl (c-butyl) aminocarbonyl, i-propyl (c-propyl) aminocarbonyl, i-propyl (n-butyl) aminocarbonyl, i-propyl (i-butyl) aminocarbonyl, i-propyl (s-butyl) aminocarbonyl, i-propyl (t-butyl) aminocarbonyl, i-propyl (c-butyl) aminocarbonyl, c-propyl (n-butyl) aminocarbonyl, c-propyl (i-butyl) aminocarbonyl, c-propyl (s-butyl) aminocarbonyl, c-propyl (t-butyl) aminocarbonyl, c-propyl (c-butyl) aminocarbonyl, n-butyl (i-butyl) aminocarbonyl, n-butyl (s-butyl) aminocarbonyl, n-butyl (t-butyl) aminocarbonyl, n-butyl (c-butyl) aminocarbonyl, i-butyl (s-butyl) aminocarbonyl, i-butyl (t-butyl) aminocarbonyl, i-butyl (c-butyl) aminocarbonyl, s-butyl (t-butyl) aminocarbonyl, s-butyl (c-butyl) aminocarbonyl, t-butyl (c-butyl) aminocarbonyl and the like,
as the C1-6Examples of the alkylcarbonyl group include a methylcarbonyl group, ethylcarbonyl group, n-propylcarbonyl group, i-propylcarbonyl group, n-butylcarbonyl group, i-butylcarbonyl group, s-butylcarbonyl group, t-butylcarbonyl group, 1-pentylcarbonyl group, 2-pentylcarbonyl group, 3-pentylcarbonyl group, i-pentylcarbonyl group, neopentylcarbonyl group, t-pentylcarbonyl group, 1-hexylcarbonyl group, 2-hexylcarbonyl group and 3-hexylcarbonyl group,
as the C3-8Cycloalkylcarbonyl groups include c-propylcarbonyl, c-butylcarbonyl, 1-methyl-c-propylcarbonyl, 2-methyl-c-propylcarbonyl, c-pentylcarbonyl, 1-methyl-c-butylcarbonyl, 2-methyl-c-butylcarbonyl, 3-methyl-c-butylcarbonyl, 1, 2-dimethyl-c-propylcarbonyl, 2, 3-dimethyl-c-propylcarbonyl, 1-ethyl-c-propylcarbonyl, 2-ethyl-c-propylcarbonyl, c-hexylcarbonyl, c-heptylcarbonyl, c-octylcarbonyl, 1-methyl-c-hexylcarbonyl, 2-methyl-c-hexylcarbonyl, 3-methyl-c-hexylcarbonyl, 1, 2-dimethyl-c-hexylcarbonyl, 2, 3-dimethyl-c-propylcarbonyl, 1-ethyl-c-propylcarbonyl, 1-methyl-c-pentylcarbonyl, 2-methyl-c-pentylcarbonyl, 3-methyl-c-pentylcarbonyl, 1-ethyl-c-butylcarbonyl, 2-ethyl-c-butylcarbonyl, 3-ethyl-c-butylcarbonyl, 1, 2-dimethyl-c-butylcarbonyl, 1, 3-dimethyl-c-butylcarbonyl, 2-dimethyl-c-butylcarbonyl, 2, 3-dimethyl-c-butylcarbonyl, 2, 4-dimethyl-c-butylcarbonyl, 3-dimethyl-c-butylcarbonyl, 1-n-propyl-c-propylcarbonyl, 2-n-propyl-c-propylcarbonyl, 1-i-propyl-c-propylcarbonyl, 2-i-propyl-c-propylcarbonyl, 1, 2, 2-trimethyl-c-propylcarbonyl, 1, 2, 3-trimethyl-c-propylcarbonyl, 2, 2, 3-trimethyl-c-propylcarbonyl, 1-ethyl-2-methyl-c-propylcarbonyl, 2-ethyl-1-methyl-c-propylcarbonyl, 2-ethyl-2-methyl-c-propylcarbonyl and 2-ethyl- 3-methyl-c-propylcarbonyl group, etc.,
as the C1-6Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, an s-butoxycarbonyl group, a t-butoxycarbonyl group, a 1-pentyloxycarbonyl group, and a 2-pentyloxycarbonyl group3-pentyloxycarbonyl group, i-pentyloxycarbonyl group, neopentyloxycarbonyl group, t-pentyloxycarbonyl group, 1-hexyloxycarbonyl group, 2-hexyloxycarbonyl group, 3-hexyloxycarbonyl group and the like,
as the C1-6Alkylsulfonyl groups, there may be mentioned methanesulfonyl group, trifluoromethanesulfonyl group and ethanesulfonyl group,
as the C6-14Examples of the arylsulfonyl group include a benzenesulfonyl group, an o-biphenylsulfonyl group, an m-biphenylsulfonyl group, a p-biphenylsulfonyl group, a 1-naphthalenesulfonyl group, a 2-naphthalenesulfonyl group, a 1-anthracenesulfonyl group, a 2-anthracenesulfonyl group, a 9-anthracenesulfonyl group, a 1-phenanthrenesulfonyl group, a 2-phenanthrenesulfonyl group, a 3-phenanthrenesulfonyl group, a 4-phenanthrenesulfonyl group and a 9-phenanthrenesulfonyl group.
As the C2-9Heteroarylsulfonyl group including C of 5 to 7 membered ring containing 1 to 3 oxygen atom, nitrogen atom, sulfur atom alone or in combination2-6Monocyclic heterocyclic sulfonyl group and C having 8 to 10 constituent atoms5-9Condensed bicyclic heterocyclic sulfonyl.
C as the 5-to 7-membered ring2-6Examples of the monocyclic heterocyclic sulfonyl group include a 2-thienylsulfonyl group, a 3-thienylsulfonyl group, a 2-furylsulfonyl group, a 3-furylsulfonyl group, a 2-pyranylsulfonyl group, a 3-pyranylsulfonyl group, a 4-pyranylsulfonyl group, a 1-pyrrolylsulfonyl group, a 2-pyrrolylsulfonyl group, a 3-pyrrolylsulfonyl group, a 1-imidazolylsulfonyl group, a 2-imidazolylsulfonyl group, a 4-imidazolylsulfonyl group, a 1-pyrazolylsulfonyl group, a 3-pyrazolylsulfonyl group, a 4-pyrazolylsulfonyl group, a 2-thiazolylsulfonyl group, a 4-thiazolylsulfonyl group, a 5-thiazolylsulfonyl group, a 3-isothiazolylsulfonyl group, a 4-isothiazolylsulfonyl group, a 5-isothiazolylsulfonyl, 2-oxazolylsulfonyl, 4-oxazolylsulfonyl, 5-oxazolylsulfonyl, 3-isoxazolylsulfonyl, 4-isoxazolylsulfonyl, 5-isoxazolylsulfonyl, 2-pyridylsulfonyl, 3-pyridylsulfonyl, 4-pyridylsulfonyl, 2-pyrazinylsulfonyl, 2-pyrimidylsulfonyl, 4-pyrimidylsulfonyl, 5-pyrimidylsulfonyl, 3-pyridazinylsulfonyl, 4-pyridazinylsulfonyl, 2-1, 3, 4-oxadiazolylSulfonyl, 2-1, 3, 4-thiadiazolylsulfonyl, 3-1, 2, 4-oxadiazoylsulfonyl, 5-1, 2, 4-oxadiazoylsulfonyl, 3-1, 2, 4-thiadiazolylsulfonyl, 5-1, 2, 4-thiadiazolylsulfonyl, 3-1, 2, 5-oxadiazoylsulfonyl, 3-1, 2, 5-thiadiazolylsulfonyl and the like.
C as the constituent atom number of 8 to 105-9Condensed bicyclic heterocyclic sulfonyl groups include 2-benzofuranylsulfonyl, 3-benzofuranylsulfonyl, 4-benzofuranylsulfonyl, 5-benzofuranylsulfonyl, 6-benzofuranylsulfonyl, 7-benzofuranylsulfonyl, 1-isobenzofuranylsulfonyl, 4-isobenzofuranylsulfonyl, 5-isobenzofuranylsulfonyl, 2-benzothienylsulfonyl, 3-benzothienylsulfonyl, 4-benzothienylsulfonyl, 5-benzothienylsulfonyl, 6-benzothienylsulfonyl, 7-benzothienylsulfonyl, 1-isobenzothiophenylsulfonyl, 4-isobenzothiophenylsulfonyl, 5-isobenzothiophenylsulfonyl, 2-chromenylsulfonyl, and the like, 3-chromenylsulfonyl, 4-chromenylsulfonyl, 5-chromenylsulfonyl, 6-chromenylsulfonyl, 7-chromenylsulfonyl, 8-chromenylsulfonyl, 1-indolizinylsulfonyl, 2-indolizinylsulfonyl, 3-indolizinylsulfonyl, 5-indolizinylsulfonyl, 6-indolizinylsulfonyl, 7-indolizinylsulfonyl, 8-indolizinylsulfonyl, 1-isoindolylsulfonyl, 2-isoindolylsulfonyl, 4-isoindolylsulfonyl, 5-isoindolylsulfonyl, 1-indolsulfonyl, 2-indolsulfonyl, 3-indolsulfonyl, 4-indolsulfonyl, 5-indolsulfonyl, 6-indolsulfonyl, 7-Indolylsulfonyl, 1-indazolylsulfonyl, 2-indazolylsulfonyl, 3-indazolylsulfonyl, 4-indazolylsulfonyl, 5-indazolylsulfonyl, 6-indazolylsulfonyl, 7-indazolylsulfonyl, 1-purinylsulfonyl, 2-purinylsulfonyl, 3-purinylsulfonyl, 6-purinylsulfonyl, 7-purinylsulfonyl, 8-purinylsulfonyl, 2-quinolylsulfonyl, 3-quinolylsulfonyl, 4-quinolylsulfonyl, 5-quinolylsulfonyl, 6-quinolylsulfonyl, 7-quinolylsulfonyl, 8-quinolylsulfonyl, 1-isoquinolylsulfonylAcyl group, 3-isoquinolylsulfonyl group, 4-isoquinolylsulfonyl group, 5-isoquinolylsulfonyl group, 6-isoquinolylsulfonyl group, 7-isoquinolylsulfonyl group, 8-isoquinolylsulfonyl group, 1-phthalazinylsulfonyl group, 5-phthalazinylsulfonyl group, 6-phthalazinylsulfonyl group, 1-2, 7-naphthyridinylsulfonyl group, 3-2, 7-naphthyridinylsulfonyl group, 4-2, 7-naphthyridinylsulfonyl group, 1-2, 6-naphthyridinylsulfonyl group, 3-2, 6-naphthyridinylsulfonyl group, 4-2, 6-naphthyridinylsulfonyl group, 2-1, 8-naphthyridinylsulfonyl group, 3-1, 8-naphthyridinylsulfonyl group, 4-1, 8-naphthyridinylsulfonyl group, 2-1, 7-naphthyridinylsulfonyl, 3-1, 7-naphthyridinylsulfonyl, 4-1, 7-naphthyridinylsulfonyl, 5-1, 7-naphthyridinylsulfonyl, 6-1, 7-naphthyridinylsulfonyl, 8-1, 7-naphthyridinylsulfonyl, 2-1, 6-naphthyridinylsulfonyl, 3-1, 6-naphthyridinylsulfonyl, 4-1, 6-naphthyridinylsulfonyl, 5-1, 6-naphthyridinylsulfonyl, 7-1, 6-naphthyridinylsulfonyl, 8-1, 6-naphthyridinylsulfonyl, 2-1, 5-naphthyridinylsulfonyl, 3-1, 5-naphthyridinylsulfonyl, 4-1, 5-naphthyridinylsulfonyl, 6-1, 5-naphthyridinylsulfonyl, 7-1, 5-naphthyridinylsulfonyl, 8-1, 5-naphthyridinylsulfonyl, 2-quinoxalinylsulfonyl, 5-quinoxalinylsulfonyl, 6-quinoxalinylsulfonyl, 2-quinoxalinylsulfonyl, 4-quinoxalinylsulfonyl, 5-quinoxalinylsulfonyl, 6-quinoxalinylsulfonyl, 7-quinoxalinylsulfonyl, 8-quinazolinylsulfonyl, 3-cinnolinylsulfonyl, 4-cinnolinylsulfonyl, 5-cinnolinylsulfonyl, 6-cinnolinylsulfonyl, 7-cinnolinylsulfonyl, 8-cinnolinylsulfonyl, 2-pteridinylsulfonyl, 4-pteridinylsulfonyl, 6-pteridinylsulfonyl and 7-pteridinylsulfonyl and the like.
As the C6-14Examples of the arylcarbonyl group include phenylcarbonyl group, o-biphenylcarbonyl group, m-biphenylcarbonyl group, p-biphenylcarbonyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group, 1-anthrylcarbonyl group, 2-anthrylcarbonyl group, 9-anthrylcarbonyl group, 1-phenanthrylcarbonyl group, 2-phenanthrylcarbonyl group, 3-phenanthrylcarbonyl group, 4-phenanthrylcarbonyl group, and 9-phenanthrylcarbonyl group.
As the C2-9Heteroarylcarbonyl group including C of 5 to 7-membered ring containing 1 to 3 oxygen atoms, nitrogen atoms, sulfur atoms either alone or in combination2-6Monocyclic heterocyclic carbonyl group and C having 8 to 10 constituent atoms5-9Condensed bicyclic heterocyclic carbonyl.
C as the 5-to 7-membered ring2-6Examples of the monocyclic heterocyclic carbonyl group include a 2-thienylcarbonyl group, a 3-thienylcarbonyl group, a 2-furylcarbonyl group, a 3-furylcarbonyl group, a 2-pyranylcarbonyl group, a 3-pyranylcarbonyl group, a 4-pyranylcarbonyl group, a 1-pyrrolylcarbonyl group, a 2-pyrrolylcarbonyl group, a 3-pyrrolylcarbonyl group, a 1-imidazolylcarbonyl group, a 2-imidazolylcarbonyl group, a 4-imidazolylcarbonyl group, a 1-pyrazolylcarbonyl group, a 3-pyrazolylcarbonyl group, a 4-pyrazolylcarbonyl group, a 2-thiazolylcarbonyl group, a 5-thiazolylcarbonyl group, a 3-isothiazolylcarbonyl group, a 4-isothiazolylcarbonyl group, a 5-isothiazolylcarbonyl group, a 2-oxazolylcarbonyl group, 3-isoxazolylcarbonyl, 4-isoxazolylcarbonyl, 5-isoxazolylcarbonyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, 2-pyrazinylcarbonyl, 2-pyrimidylcarbonyl, 4-pyrimidylcarbonyl, 5-pyrimidylcarbonyl, 3-pyridazinylcarbonyl, 4-pyridazinylcarbonyl, 2-1, 3, 4-oxadiazoylcarbonyl, 2-1, 3, 4-thiadiazolylcarbonyl, 3-1, 2, 4-oxadiazoylcarbonyl, 5-1, 2, 4-oxadiazoylcarbonyl, 3-1, 2, 4-thiadiazolylcarbonyl, 5-1, 2, 4-thiadiazolylcarbonyl, 3-1, 2, 5-oxadiazoylcarbonyl and 3-1, 2, 5-thiadiazolylcarbonyl and the like.
C as the constituent atom number of 8 to 105-9Examples of the condensed bicyclic heterocyclic carbonyl group include a 2-benzofuranylcarbonyl group, a 3-benzofuranylcarbonyl group, a 4-benzofuranylcarbonyl group, a 5-benzofuranylcarbonyl group, a 6-benzofuranylcarbonyl group, a 7-benzofuranylcarbonyl group, a 1-isobenzofuranylcarbonyl group, a 4-isobenzofuranylcarbonyl group, a 5-isobenzofuranylcarbonyl group, a 2-benzothiophenylcarbonyl group, a 3-benzothiophenylcarbonyl group, a 4-benzothiophenylcarbonyl group, a 5-benzothiophenylcarbonyl group, a 6-benzothiophenylcarbonyl group, a 7-benzothiophenylcarbonyl group, a 1-isobenzothiophenylcarbonyl group, a 4-isobenzothiophenylcarbonyl group, a 5-isobenzothiophenylcarbonyl group, a 2-chromenylcarbonyl group, a 3-chromenylcarbonyl group, 4-chromenylcarbonyl, 5-chromenylcarbonyl, 6-chromenylcarbonyl, 7-chromenylcarbonyl, 8-chromenylcarbonyl, 1-indolizinylCarbonyl, 2-indolizinylcarbonyl, 3-indolizinylcarbonyl, 5-indolizinylcarbonyl, 6-indolizinylcarbonyl, 7-indolizinylcarbonyl, 8-indolizinylcarbonyl, 1-isoindolylcarbonyl, 2-isoindolylcarbonyl, 4-isoindolylcarbonyl, 5-isoindolylcarbonyl, 1-indoylcarbonyl, 2-indoylcarbonyl, 3-indoylcarbonyl, 4-indoylcarbonyl, 5-indoylcarbonyl, 6-indoylcarbonyl, 7-indoylcarbonyl, 1-indazolylcarbonyl, 2-indazolylcarbonyl, 3-indazolylcarbonyl, 4-indazolylcarbonyl, 5-indazolylcarbonyl, 6-indazolylcarbonyl, 7-indazolylcarbonyl, 1-purinylcarbonyl, 2-purinylcarbonyl, 3-purinylcarbonyl, 6-purinylcarbonyl, 7-purinylcarbonyl, 8-purinylcarbonyl, 2-quinolylcarbonyl, 3-quinolylcarbonyl, 4-quinolylcarbonyl, 5-quinolylcarbonyl, 6-quinolylcarbonyl, 7-quinolylcarbonyl, 8-quinolylcarbonyl, 1-isoquinolylcarbonyl, 3-isoquinolylcarbonyl, 4-isoquinolylcarbonyl, 5-isoquinolylcarbonyl, 6-isoquinolylcarbonyl, 7-isoquinolylcarbonyl, 8-isoquinolylcarbonyl, 1-phthalazinylcarbonyl, 5-phthalazinylcarbonyl, 6-phthalazinylcarbonyl, 1-2, 7-naphthyridinylcarbonyl, 3-2, 7-naphthyridinylcarbonyl, 4-2, 7-naphthyridinylcarbonyl, 1-2, 6-naphthyridinylcarbonyl, 3-2, 6-naphthyridinylcarbonyl, 4-2, 6-naphthyridinylcarbonyl, 2-1, 8-naphthyridinylcarbonyl, 3-1, 8-naphthyridinylcarbonyl, 4-1, 8-naphthyridinylcarbonyl, 2-1, 7-naphthyridinylcarbonyl, 3-1, 7-naphthyridinylcarbonyl, 4-1, 7-naphthyridinylcarbonyl, 5-1, 7-naphthyridinylcarbonyl, 6-1, 7-naphthyridinylcarbonyl, 8-1, 7-naphthyridinylcarbonyl, 2-1, 6-naphthyridinylcarbonyl, 3-1, 6-naphthyridinylcarbonyl, 4-1, 6-naphthyridinylcarbonyl, 5-1, 6-naphthyridinylcarbonyl, 7-1, 6-naphthyridinylcarbonyl, 8-1, 6-naphthyridinylcarbonyl, 2-1, 5-naphthyridinylcarbonyl, 3-1, 5-naphthyridinylcarbonyl, 4-1, 5-naphthyridinylcarbonyl, 6-1, 5-naphthyridinylcarbonyl, 7-1, 5-naphthyridinylcarbonyl, 8-1, 5-naphthyridinylcarbonyl, 2-quinoxalylcarbonyl, 5-quinoxalylcarbonyl, 6-quinoxalylcarbonyl, 2-quinazolinylcarbonyl, 4-quinazolinylcarbonyl, 5-quinazolinylcarbonyl, 6-quinazolinylcarbonyl, 7-quinazolinylcarbonyl, 8-quinazolinylcarbonyl, 3-cinnolinylcarbonyl, 4-cinnolinylcarbonyl, 5-cinnolinylcarbonyl group, 6-cinnolinylcarbonyl group, 7-cinnolinylcarbonyl group, 8-cinnolinylcarbonyl group, 2-pteridinylcarbonyl group,4-pteridinylcarbonyl, 6-pteridinylcarbonyl, 7-pteridinylcarbonyl and the like.
R in the formulae (a), (b), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (p), (q), (v), (w), (x), (ab), (ae), (af) and (ag)12And R13Preferably a hydrogen atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, n-pentyl group, i-pentyl group, methylcarbonyloxymethyl group, ethylcarbonyloxymethyl group, methylcarbonyloxyethyl group, ethylcarbonyloxyethyl group, methylcarbonylaminomethyl group, ethylcarbonylaminoethyl group, methylcarbonylaminoethyl group, ethylcarbonylaminoethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group, phenyl group, o-biphenyl group, m-biphenyl group, p-biphenyl group, 1-naphthyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, methylaminocarbonyl group, ethylaminocarbonyl group, n-propylaminocarbonyl group, i-propylaminocarbonyl group, n-butylaminocarbonyl group, n-pentyl group, methyl carbonyloxymethyl group, Dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl, di-n-butylaminocarbonyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, c-pentylcarbonyl, c-hexylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, o-biphenylsulfonyl, m-biphenylsulfonyl, p-biphenylsulfonyl, 1-naphthalenesulfonyl, N-naphthylsulfonyl, N-propylcarbonyl, N-ethylcarbonyl, n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 2-naphthylsulfonyl, 2-pyridylsulfonyl, 3-pyridylsulfonyl, 4-pyridylsulfonyl, phenylcarbonyl, o-biphenylcarbonyl, m-biphenylcarbonyl, p-biphenylcarbonyl, 1-naphthylcarbonyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl. More preferably a hydrogen atom or a methyl group.
Then, the above-mentioned formula (a), formula (b), formula (c), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (r), formula(s), formula (p) are subjected toR in (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and formula (af)14，R15，R16And R17The description is given. R in formula (a), formula (b), formula (c), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (R), formula(s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and formula (af)14，R15，R16And R17Each independently represents a hydrogen atom, a halogen atom, C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino, hydroxy, C6-14Aryl radical, C2-9Heteroaryl (both aryl and heteroaryl may be substituted by R)19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonyl (the alkylcarbonyloxy and alkylcarbonyl may be optionally substituted with a halogen atom), C1-6Alkylcarbonylamino, C3-8Cycloalkyl carbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylsulfonyl (the cycloalkylcarbonyl group, alkoxycarbonyl group and alkylsulfonyl group may be optionally substituted by a halogen atom), carboxyl group, C6-14Arylcarbonyl (the arylcarbonyl group may be optionally substituted with a halogen atom) or C2-9Optionally substituted heteroarylcarbonyl), C3-8Cycloalkyl (which may be interrupted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom), amino or hydroxy), C1-6Alkoxy (the alkoxy may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by halogen atom), carboxyl, amino, hydroxyl, C6-14Aryl or C2-9Heteroaryl (both aryl and heteroaryl may be substituted by R)19(R19Is represented by the formula11The same meaning, r represents the same meaning as q) optionally substituted), C1-6Thioalkoxy radical(the thioalkoxy group may be substituted by a halogen atom, C1-6Alkoxy (the alkoxy may be optionally substituted by halogen atom), carboxyl, hydroxyl, C6-14Aryl or C2-9Heteroaryl (both aryl and heteroaryl may be substituted by R)19(R19Is represented by the formula11The same meaning as that of q), r represents the same meaning as that of q), optionally substituted), hydroxyl group, C6-14Aryl radical, C2-9Heteroaryl (both aryl and heteroaryl may be substituted by R)19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkylcarbonyloxy, nitro, cyano, formyl, carboxamido, amino, sulfo, C1-6Alkylamino, di-C1-6Alkylamino radical, C6-14Arylamino, C2-9Heteroarylamino (both the arylamino and heteroarylamino may be substituted by R)19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkylcarbonylamino, C1-6Alkylsulfonamide group, carbamoyl group, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C6-14Aryl carbonyl group, C2-9Heteroarylcarbonyl (both arylcarbonyl and heteroarylcarbonyl can be substituted by R)19(R19Is represented by the formula11The same meaning, r represents the same meaning as q), C)1-6Alkoxycarbonyl, sulfamoyl, C1-6Alkylsulfonyl radical, C6-14Arylsulfonyl radical, C2-9Heteroarylsulfonyl (both the arylsulfonyl and heteroarylsulfonyl can be substituted by R)19(R19Is represented by the formula11Same as q, r represents the same as q)), carboxyl group or C2-9Heterocyclic group (the heterocyclic group may be substituted by halogen atom, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom), amino, carboxyl or hydroxyl), C1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), C6-14Aryl radical, C2-9Heteroaryl (both the aryl and heteroaryl can beTo be R19(R19Is represented by the formula11The same as q, r represents the same as q)), hydroxy, nitro, cyano, formyl, carboxamide, amino, C1-6Alkylamino, di-C1-6Alkylamino radical, C1-6Alkylcarbonylamino, C1-6Alkylsulfonamide group, carbamoyl group, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl, sulfamoyl, C1-6Alkylsulfonyl, carboxyl or C6-14Arylcarbonyl optionally substituted).
For R in formula (a), formula (b), formula (c), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (R), formula(s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and formula (af)14，R15，R16And R17The respective atoms and the respective substituents of (A) are specifically described. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and C is1-6Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2, 2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1, 2-trimethyl-n-propyl, 1, 2, 2-trimethyl-n-propyl and 3, 3-dimethyl-n-butyl, methylcarbonyloxymethyl, ethylcarbonyloxymethyl, methylcarbonyloxyethyl, ethylcarbonyloxyethyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, methylcarbonylaminoethyl, n-propyl, n-butyl, n-pentyl, 2-pentyl, 3-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1, 2, 2-trimethyl-n-, Ethylcarbonylaminoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl and ethoxycarbonylethyl and the like,
as C3-8Examples of cycloalkyl include c-propyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1, 2-dimethyl-c-propyl, 2, 3-dimethyl-c-Propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, c-hexyl, c-heptyl, c-octyl, 1-methyl-c-hexyl, 2-methyl-c-hexyl, 3-methyl-c-hexyl, 1, 2-dimethyl-c-hexyl, 2, 3-dimethyl-c-propyl, 1-ethyl-c-propyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3-ethyl-c-butyl, 1, 2-dimethyl-c-butyl, n-propyl, n-butyl, 1, 3-dimethyl-c-butyl, 2, 2-dimethyl-c-butyl, 2, 3-dimethyl-c-butyl, 2, 4-dimethyl-c-butyl, 3-dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl-c-propyl, 2-i-propyl-c-propyl, 1, 2, 2-trimethyl-c-propyl, 1, 2, 3-trimethyl-c-propyl, 2, 2, 3-trimethyl-c-propyl, 1-ethyl-2-methyl-c-propyl, methyl-n-propyl, ethyl-n-propyl, n-propyl-c-propyl, n, 2-ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl, 2-ethyl-3-methyl-c-propyl, and the like,
as the C1-6Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, an i-pentyloxy group, a neopentyloxy group, a2, 2-dimethylpropoxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 1-methyl-n-pentyloxy group, a1, 1, 2-trimethyl-n-propoxy group, a1, 2, 2-trimethyl-n-propoxy group and a 3, 3-dimethyl-n-butoxy group,
as C1-6Examples of the thioalkoxy group include methylthio, ethylthio, n-propylthio, i-propylthio, c-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, n-pentylthio, i-pentylthio, neopentylthio, t-pentylthio, n-hexylthio and c-hexylthio,
as the C6-14Examples of the aryl group include phenyl, o-biphenyl, m-biphenyl, p-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9-phenanthryl.
As the C2-9Heteroaryl groups including those containing 1 to 3 oxygen atoms, nitrogen atoms, either alone or in combinationC of 5-to 7-membered ring of sulfur atom2-6A monocyclic heterocyclic group and C having 8 to 10 constituent atoms5-9Condensed bicyclic heterocyclic group.
C as the 5-to 7-membered ring2-6Examples of the monocyclic heterocyclic group include a 2-thienyl group, a 3-thienyl group, a 2-furyl group, a 3-furyl group, a 2-pyranyl group, a 3-pyranyl group, a 4-pyranyl group, a 1-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, a 1-imidazolyl group, a 2-imidazolyl group, a 4-imidazolyl group, a 1-pyrazolyl group, a 3-pyrazolyl group, a 4-pyrazolyl group, a 2-thiazolyl group, a 5-thiazolyl group, a 3-isothiazolyl group, a 4-isothiazolyl group, a 5-isothiazolyl group, a 2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, a 3-isoxazolyl group, a 4-isoxazolyl group, a 5-isoxazolyl group, a 2-pyridyl group, a 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-1, 3, 4-oxadiazolyl, 2-1, 3, 4-thiadiazolyl, 3-1, 2, 4-oxadiazolyl, 5-1, 2, 4-oxadiazolyl, 3-1, 2, 4-thiadiazolyl, 5-1, 2, 4-thiadiazolyl, 3-1, 2, 5-oxadiazolyl, and 3-1, 2, 5-thiadiazolyl, and the like.
C as the constituent atom number of 8 to 105-9Examples of the condensed bicyclic heterocyclic group include a 2-benzofuranyl group, a 3-benzofuranyl group, a 4-benzofuranyl group, a 5-benzofuranyl group, a 6-benzofuranyl group, a 7-benzofuranyl group, a 1-isobenzofuranyl group, a 4-isobenzofuranyl group, a 5-isobenzofuranyl group, a 2-benzothienyl group, a 3-benzothienyl group, a 4-benzothienyl group, a 5-benzothienyl group, a 6-benzothienyl group, a 7-benzothienyl group, a 1-isobenzothiophenyl group, a 4-isobenzothiophenyl group, a 5-isobenzothiophenyl group, a 2-chromenyl group, a 3-chromenyl group, a 4-chromenyl group, a 5-chromenyl group, a 6-chromenyl group, a 7-chromenyl group, an 8-chromenyl group, a 1-indolizinyl group, a, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl, 6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 2-isoindolyl, 4-isoindolyl, 5-isoindolyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl, 1-purinyl, 2-indolizinylPurinyl group, 3-purinyl group, 6-purinyl group, 7-purinyl group, 8-purinyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 1-2, 7-naphthyridinyl group, 3-2, 7-naphthyridinyl group, 4-2, 7-naphthyridinyl group, 1-2, 6-naphthyridinyl group, 3-2, 6-naphthyridinyl group, 4-2, 6-naphthyridinyl group, 2-1, 8-naphthyridinyl group, 3-1, 8-naphthyridinyl group, 4-1, 8-naphthyridinyl group, 2-1, 7-naphthyridinyl group, 3-1, 7-naphthyridinyl group, 4-1, 7-naphthyridinyl group, 5-1, 7-naphthyridinyl group, 6-1, 7-naphthyridinyl group, 8-1, 7-naphthyridinyl group, 2-1, 6-naphthyridinyl group, 3-1, 6-naphthyridinyl group, 4-1, 6-naphthyridinyl group, 5-1, 6-naphthyridinyl group, 7-1, 6-naphthyridinyl group, 8-1, 6-naphthyridinyl group, 2-1, 5-naphthyridinyl group, 3-1, 5-naphthyridinyl group, 4-1, 5-naphthyridinyl group, 6-1, 5-naphthyridinyl, 7-1, 5-naphthyridinyl, 8-1, 5-naphthyridinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl and 7-pteridinyl, and the like.
As the C1-6Alkylcarbonyloxy, there may be mentioned, for example, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy, i-butylcarbonyloxy, s-butylcarbonyloxy, t-butylcarbonyloxy, 1-pentylcarbonyloxy, 2-pentylcarbonyloxy, 3-pentylcarbonyloxy, i-pentylcarbonyloxy, neopentylcarbonyloxy, t-pentylcarbonyloxy, 1-hexylcarbonyloxy, 2-hexylcarbonyloxy, 3-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy, 1, 2-trimethyl-n-propylcarbonyloxy, 1, 2, 2-trimethyl-n-propylcarbonyloxy and 3, 3-dimethyl-n-butylcarbonyloxy, etc.,
as the C1-6As the alkylamino group, there may be mentioned methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino, i-butylaminoA group such as s-butylamino, t-butylamino, c-butylamino, 1-pentylamino, 2-pentylamino, 3-pentylamino, i-pentylamino, neopentylamino, t-pentylamino, c-pentylamino, 1-hexylamino, 2-hexylamino, 3-hexylamino, c-hexylamino, 1-methyl-n-pentylamino, 1, 2-trimethyl-n-propylamino, 1, 2, 2-trimethyl-n-propylamino, and 3, 3-dimethyl-n-butylamino,
as the di-C1-6As the alkylamino group, there may be mentioned dimethylamino group, diethylamino group, di-n-propylamino group, di-i-propylamino group, di-c-propylamino group, di-n-butylamino group, di-i-butylamino group, di-s-butylamino group, di-t-butylamino group, di-c-butylamino group, di-1-pentylamino group, di-2-pentylamino group, di-3-pentylamino group, di-i-pentylamino group, di-neopentylamino group, di-t-pentylamino group, di-c-pentylamino group, di-1-hexylamino group, di-2-hexylamino group, di-3-hexylamino group, di-c-hexylamino group, di-n-propylamino group, di-i-butylamino group, di-t-pentylamino group, di-, Bis- (1-methyl-n-pentyl) amino, bis- (1, 1, 2-trimethyl-n-propyl) amino, bis- (1, 2, 2-trimethyl-n-propyl) amino, bis- (3, 3-dimethyl-n-butyl) amino, methyl (ethyl) amino, methyl (n-propyl) amino, methyl (i-propyl) amino, methyl (c-propyl) amino, methyl (n-butyl) amino, methyl (i-butyl) amino, methyl (s-butyl) amino, methyl (t-butyl) amino, methyl (c-butyl) amino, ethyl (n-propyl) amino, ethyl (i-propyl) amino, ethyl (c-propyl) amino, Ethyl (n-butyl) amino, ethyl (i-butyl) amino, ethyl (s-butyl) amino, ethyl (t-butyl) amino, ethyl (c-butyl) amino, n-propyl (i-propyl) amino, n-propyl (c-propyl) amino, n-propyl (n-butyl) amino, n-propyl (i-butyl) amino, n-propyl (s-butyl) amino, n-propyl (t-butyl) amino, n-propyl (c-butyl) amino, i-propyl (c-propyl) amino, i-propyl (n-butyl) amino, i-propyl (i-butyl) amino, i-propyl (s-butyl) amino, i-propyl (t-butyl) amino, i-propyl (c-butyl) amino, c-propyl (n-butyl) amino, c-propyl (i-butyl) amino, c-propyl (s-butyl) amino, c-propyl (t-butyl) amino, c-propyl (c-butyl) amino, n-butyl (i-butyl) amino, n-butyl (s-butyl) aminoN-butyl (t-butyl) amino, n-butyl (c-butyl) amino, i-butyl (s-butyl) amino, i-butyl (t-butyl) amino, i-butyl (c-butyl) amino, s-butyl (t-butyl) amino, s-butyl (c-butyl) amino and tert-butyl (c-butyl) amino, and the like,
as the C6-14Arylamino groups, which may be mentioned phenylamino, o-biphenylamino, m-biphenylamino, p-biphenylamino, 1-naphthylamino, 2-naphthylamino, 1-anthrylamino, 2-anthrylamino, 9-anthrylamino, 1-phenanthrylamino, 2-phenanthrylamino, 3-phenanthrylamino, 4-phenanthrylamino and 9-phenanthrylamino,
as the C2-9Heteroarylamino group including C of 5 to 7-membered ring containing 1 to 3 oxygen atoms, nitrogen atoms, sulfur atoms either singly or in combination2-6Monocyclic heterocyclic cyano group and C having 8 to 10 constituent atoms5-9Condensed bicyclic heterocyclic amino.
The C as a 5-to 7-membered ring2-6Monocyclic heterocyclic amino groups include 2-thienylamino, 3-thienylamino, 2-furylamino, 3-furylamino, 2-pyranylamino, 3-pyranylamino, 4-pyranylamino, 1-pyrrolylamino, 2-pyrrolylamino, 3-pyrrolylamino, 1-imidazolylamino, 2-imidazolylamino, 4-imidazolylamino, 1-pyrazolylamino, 3-pyrazolylamino, 4-pyrazolylamino, 2-thiazolylamino, 4-thiazolylamino, 5-thiazolylamino, 3-isothiazolylamino, 4-isothiazolylamino, 5-isothiazolylamino, 2-oxazolylamino, 4-oxazolylamino, 5-oxazolylamino, 2-pyrrolylamino, 3-pyrrolylamino, 1-imidazolylamino, 4-pyrazolylamino, 4-thiazolylamino, 5-thiazolylamino, 3-isoxazolylamino, 4-isoxazolylamino, 5-isoxazolylamino, 2-pyridylamino, 3-pyridylamino, 4-pyridylamino, 2-pyrazinylamino, 2-pyrimidylamino, 4-pyrimidylamino, 5-pyrimidylamino, 3-pyridazinylamino, 4-pyridazinylamino, 2-1, 3, 4-oxadiazoylamino, 2-1, 3, 4-thiadiazolylamino, 3-1, 2, 4-oxadiazoylamino, 5-1, 2, 4-oxadiazoylamino, 3-1, 2, 4-oxadiazoylamino, 5-1, 2, 4-thiadiazolylamino, 3-1, 2, 5-oxadiazoylamino and 3-1, 2, 5-thiadiazolylamino and the like.
C as the constituent atom number of 8 to 105-9Examples of the condensed bicyclic heterocyclic amino group include a 2-benzofuranylamino group, a 3-benzofuranylamino group, a 4-benzofuranylamino group, a 5-benzofuranylamino group, a 6-benzofuranylamino group, a 7-benzofuranylamino group, a 1-isobenzofuranylamino group, a 4-isobenzofuranylamino group, a 5-isobenzofuranylamino group, a 2-benzothienylamino group, a 3-benzothienylamino group, a 4-benzothienylamino group, a 5-benzothienylamino group, a 6-benzothienylamino group, a 7-benzothienylamino group, a 1-isobenzothiophenylamino group, a 4-isobenzothiophenylamino group, a 5-isobenzothiophenylamino group, a 2-chromenylamino group, a 3-chromenylamino group, a, 4-chromenylamino, 5-chromenylamino, 6-chromenylamino, 7-chromenylamino, 8-chromenylamino, 1-indolinylamino, 2-indolinylamino, 3-indolinylamino, 5-indolinylamino, 6-indolizinamino, 7-indolizinamino, 8-indolizinamino, 1-isoindolylamino, 2-isoindolylamino, 4-isoindolylamino, 5-isoindolylamino, 1-indolylamino, 2-indolylamino, 3-indolylamino, 4-indolylamino, 5-indolylamino, 6-indolylamino, 7-indolylamino, 1-indazolylamino, 2-indazolylamino, 3-indazolylamino, 4-indazolylamino, 5-indazolylamino, 6-indazolylamino, 7-indazolylamino, 1-purinylamino, 2-purinylamino, 3-purinylamino, 6-purinylamino, 7-purinylamino, 8-purinylamino, 2-quinolylamino, 3-quinolylamino, 4-quinolylamino, 5-quinolylamino, 6-quinolylamino, 7-quinolylamino, 8-quinolylamino, 1-isoquinolylamino, 3-isoquinolylamino, 4-isoquinolylamino, 5-isoquinolylamino, 6-isoquinolylamino, 7-isoquinolylamino, 8-isoquinolylamino, 5-isoquinolylamino, 6-isoquinolylamino, 8-isoquinolylamino, 5-indazolylamino, 7-purinylamino, 6-purinylamino, 7-purinylamino, 2-purinylamino, 7-purinylamino, 4, 1-phthalazinylamino, 5-phthalazinylamino, 6-phthalazinylamino, 1-2, 7-naphthyridinylamino, 3-2, 7-naphthyridinylamino, 4-2, 7-naphthyridinylamino, 1-2, 6-naphthyridinylamino, 3-2, 6-naphthyridinylamino, 4-2, 6-naphthyridinylamino, 2-1, 8-naphthyridinylamino, 3-1, 8-naphthyridinylamino, 4-1, 8-naphthyridinylamino, 2-1, 7-naphthyridinylamino3-1, 7-naphthyridinylamino, 4-1, 7-naphthyridinylamino, 5-1, 7-naphthyridinylamino, 6-1, 7-naphthyridinylamino, 8-1, 7-naphthyridinylamino, 2-1, 6-naphthyridinylamino, 3-1, 6-naphthyridinylamino, 4-1, 6-naphthyridinylamino, 5-1, 6-naphthyridinylamino, 7-1, 6-naphthyridinylamino, 8-1, 6-naphthyridinylamino, 2-1, 5-naphthyridinylamino, 3-1, 5-naphthyridinylamino, 4-1, 5-naphthyridinylamino, 6-1, 5-naphthyridinylamino, 7-1, 5-naphthyridinylamino, 8-1, 5-naphthyridinylamino, 2-quinazolinylamino, 5-quinazolinylamino, 6-quinazolinylamino, 2-quinazolinylamino, 4-quinazolinylamino, 5-quinazolinylamino, 6-quinazolinylamino, 7-quinazolinylamino, 8-quinazolinylamino, 3-cinnolinylamino, 4-cinnolinylamino, 5-cinnolinylamino, 6-cinnolinylamino, 7-cinnolinylamino, 8-cinnolinylamino, 2-pteridinylamino, 4-piperidinylamino, 6-pteridinylamino and 7-pteridinylamino and the like.
As the C1-6Alkylcarbonylamino groups include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, 1-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, i-pentylcarbonylamino, neopentylcarbonylamino, t-pentylcarbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino and 3-hexylcarbonylamino,
as the C1-6Examples of the alkylsulfonamide group include a methanesulfonamide group, an ethanesulfonamide group, an n-propanesulfonamide group, an i-propanesulfonamide group, an n-butanesulfonamide group, an i-butanesulfonamide group, an s-butanesulfonamide group, a t-butanesulfonamide group, a 1-pentanesulfonamide group, a 2-pentanesulfonamide group, a 3-pentanesulfonamide group, an i-pentanesulfonamide group, a neopentanesulfonamide group, a t-pentanesulfonamide group, a 1-hexanesulfonamide group, a 2-hexanesulfonamide group, and a 3-hexanesulfonamide group,
as the C1-6Examples of the alkylaminocarbonyl group include methylaminocarbonyl group, ethylaminocarbonyl group, and n-propylaminocarbonyl groupI-propylaminocarbonyl group, n-butylaminocarbonyl group, i-butylaminocarbonyl group, s-butylaminocarbonyl group, t-butylaminocarbonyl group, 1-pentylaminocarbonyl group, 2-pentylaminocarbonyl group, 3-pentylaminocarbonyl group, i-pentylaminocarbonyl group, neopentylaminocarbonyl group, t-pentylaminocarbonyl group, 1-hexylaminocarbonyl group, 2-hexylaminocarbonyl group, 3-hexylaminocarbonyl group and the like,
as the di-C1-6As the alkylaminocarbonyl group, there may be mentioned dimethylaminocarbonyl group, diethylaminocarbonyl group, di-n-propylaminocarbonyl group, di-i-propylaminocarbonyl group, di-c-propylaminocarbonyl group, di-n-butylaminocarbonyl group, di-i-butylaminocarbonyl group, di-s-butylaminocarbonyl group, di-t-butylaminocarbonyl group, di-c-butylaminocarbonyl group, di-1-pentylaminocarbonyl group, di-2-pentylaminocarbonyl group, di-3-pentylaminocarbonyl group, di-i-pentylaminocarbonyl group, di-neopentylaminocarbonyl group, di-t-pentylaminocarbonyl group, di-c-pentylaminocarbonyl group, di-1-hexylaminocarbonyl group, di-n-propylaminocarbonyl group, di-n-butylaminocarbonyl group, di-t-pentylaminocarbonyl group, di-2-hexylaminocarbonyl, di-3-hexylaminocarbonyl, di-c-hexylaminocarbonyl, di- (1-methyl-n-pentyl) aminocarbonyl, di- (1, 1, 2-trimethyl-n-propyl) aminocarbonyl, di- (1, 2, 2-trimethyl-n-propyl) aminocarbonyl, di- (3, 3-dimethyl-n-butyl) aminocarbonyl, methyl (ethyl) aminocarbonyl, methyl (n-propyl) aminocarbonyl, methyl (i-propyl) aminocarbonyl, methyl (c-propyl) aminocarbonyl, methyl (n-butyl) aminocarbonyl, methyl (i-butyl) aminocarbonyl, methyl (s-butyl) aminocarbonyl, methyl (n-butyl), Methyl (t-butyl) aminocarbonyl, methyl (c-butyl) aminocarbonyl, ethyl (n-propyl) aminocarbonyl, ethyl (i-propyl) aminocarbonyl, ethyl (c-propyl) aminocarbonyl, ethyl (n-butyl) aminocarbonyl, ethyl (i-butyl) aminocarbonyl, ethyl (s-butyl) aminocarbonyl, ethyl (t-butyl) aminocarbonyl, ethyl (c-butyl) aminocarbonyl, n-propyl (i-propyl) aminocarbonyl, n-propyl (c-propyl) aminocarbonyl, n-propyl (n-butyl) aminocarbonyl, n-propyl (i-butyl) aminocarbonyl, n-propyl (s-butyl) aminocarbonyl, n-propyl (t-butyl) aminocarbonyl, n-butyl (n-butyl) aminocarbonyl, n-propyl (c-butyl) aminocarbonyl, i-propyl (c-propyl) aminocarbonyl, i-propyl (n-butyl) aminocarbonyl, i-propyl (i-butyl) aminocarbonyl,i-propyl (s-butyl) aminocarbonyl, i-propyl (t-butyl) aminocarbonyl, i-propyl (c-butyl) aminocarbonyl, c-propyl (n-butyl) aminocarbonyl, c-propyl (i-butyl) aminocarbonyl, c-propyl (s-butyl) aminocarbonyl, c-propyl (t-butyl) aminocarbonyl, c-propyl (c-butyl) aminocarbonyl, n-butyl (i-butyl) aminocarbonyl, n-butyl (s-butyl) aminocarbonyl, n-butyl (t-butyl) aminocarbonyl, n-butyl (c-butyl) aminocarbonyl, i-butyl (s-butyl) aminocarbonyl, i-butyl (t-butyl) aminocarbonyl, i-butyl (c-butyl) aminocarbonyl, s-butyl (t-butyl) aminocarbonyl, s-butyl (c-butyl) aminocarbonyl, t-butyl (c-butyl) aminocarbonyl and the like,
as the C1-6Examples of the alkylcarbonyl group include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, i-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl, and 3-hexylcarbonyl,
as the C6-14Examples of the arylcarbonyl group include phenylcarbonyl group, o-biphenylcarbonyl group, m-biphenylcarbonyl group, p-biphenylcarbonyl group, 1-naphthylcarbonyl group, 2-naphthylcarbonyl group, 1-anthrylcarbonyl group, 2-anthrylcarbonyl group, 9-anthrylcarbonyl group, 1-phenanthrylcarbonyl group, 2-phenanthrylcarbonyl group, 3-phenanthrylcarbonyl group, 4-phenanthrylcarbonyl group, and 9-phenanthrylcarbonyl group.
As the C2-9Heteroarylcarbonyl group including C of 5 to 7-membered ring containing 1 to 3 oxygen atoms, nitrogen atoms, sulfur atoms either alone or in combination2-6Monocyclic heterocyclic carbonyl group and C having 8 to 10 constituent atoms5-9Condensed bicyclic heterocyclic carbonyl.
The C as a 5-to 7-membered ring2-6Examples of the monocyclic heterocyclic carbonyl group include a 2-thienylcarbonyl group, a 3-thienylcarbonyl group, a 2-furylcarbonyl group, a 3-furylcarbonyl group, a 2-pyranylcarbonyl group, a 3-pyranylcarbonyl group, a 4-pyranylcarbonyl group, a 1-pyrrolylcarbonyl group, a 2-pyrrolylcarbonyl group, a 3-pyrrolylcarbonyl group, a 1-imidazolyl carbonyl group, a 2-imidazolyl carbonyl group, and a 4-imidazolyl carbonyl groupA group, 1-pyrazolylcarbonyl group, 3-pyrazolylcarbonyl group, 4-pyrazolylcarbonyl group, 2-thiazolylcarbonyl group, 4-thiazolylcarbonyl group, 5-thiazolylcarbonyl group, 3-isothiazolylcarbonyl group, 4-isothiazolylcarbonyl group, 5-isothiazolylcarbonyl group, 2-oxazolylcarbonyl group, 4-oxazolylcarbonyl group, 5-oxazolylcarbonyl group, 3-isoxazolylcarbonyl group, 4-isoxazolylcarbonyl group, 5-isoxazolylcarbonyl group, 2-pyridylcarbonyl group, 3-pyridylcarbonyl group, 4-pyridylcarbonyl group, 2-pyrazinylcarbonyl group, 4-pyrimidylcarbonyl group, 5-pyrimidylcarbonyl group, 3-pyridazinylcarbonyl group, 4-pyridazinylcarbonyl group, 2-1, 3, 4-oxadiazoylcarbonyl group, 2-1, 3, 4-thiadiazolylcarbonyl, 3-1, 2, 4-oxadiazolyl carbonyl, 5-1, 2, 4-oxadiazolyl carbonyl, 3-1, 2, 4-thiadiazolylcarbonyl, 5-1, 2, 4-thiadiazolylcarbonyl, 3-1, 2, 5-oxadiazolyl carbonyl, 3-1, 2, 5-thiadiazolylcarbonyl, and the like.
C as the constituent atom number of 8 to 105-9Examples of the condensed bicyclic heterocyclic carbonyl group include a 2-benzofuranylcarbonyl group, a 3-benzofuranylcarbonyl group, a 4-benzofuranylcarbonyl group, a 5-benzofuranylcarbonyl group, a 6-benzofuranylcarbonyl group, a 7-benzofuranylcarbonyl group, a 1-isobenzofuranylcarbonyl group, a 4-isobenzofuranylcarbonyl group, a 5-isobenzofuranylcarbonyl group, a 2-benzothiophenylcarbonyl group, a 3-benzothiophenylcarbonyl group, a 4-benzothiophenylcarbonyl group, a 5-benzothiophenylcarbonyl group, a 6-benzothiophenylcarbonyl group, a 7-benzothiophenylcarbonyl group, a 1-isobenzothiophenylcarbonyl group, a 4-isobenzothiophenylcarbonyl group, a 5-isobenzothiophenylcarbonyl group, a 2-chromenylcarbonyl group, a 3-chromenylcarbonyl group, 4-chromenylcarbonyl, 5-chromenylcarbonyl, 6-chromenylcarbonyl, 7-chromenylcarbonyl, 8-chromenylcarbonyl, 1-indolinylcarbonyl, 2-indolinylcarbonyl, 3-indolinylcarbonyl, 5-indolinylcarbonyl, 6-indolinylcarbonyl, 7-indolinylcarbonyl, 8-indolinylcarbonyl, 1-isoindolylcarbonyl, 2-isoindolylcarbonyl, 4-isoindolylcarbonyl, 5-isoindolylcarbonyl, 1-indolylcarbonyl, 2-indolylcarbonyl, 3-indolylcarbonyl, 4-indolylcarbonyl, 5-indolylcarbonyl, 6-indolylcarbonyl, 7-indolylcarbonyl, 1-indazolylcarbonyl, 2-indazolylcarbonyl, 3-indazolylcarbonyl, 4-indazolylcarbonyl, 5-indazolylcarbonyl, 6-indazolylcarbonylOxazolylcarbonyl, 7-indazolylcarbonyl, 1-purinylcarbonyl, 2-purinylcarbonyl, 3-purinylcarbonyl, 6-purinylcarbonyl, 7-purinylcarbonyl, 8-purinylcarbonyl, 2-quinolylcarbonyl, 3-quinolylcarbonyl, 4-quinolylcarbonyl, 5-quinolylcarbonyl, 6-quinolylcarbonyl, 7-quinolylcarbonyl, 8-quinolylcarbonyl, 1-isoquinolylcarbonyl, 3-isoquinolylcarbonyl, 4-isoquinolylcarbonyl, 5-isoquinolylcarbonyl, 6-isoquinolylcarbonyl, 7-isoquinolylcarbonyl, 8-isoquinolylcarbonyl, 1-phthalazinylcarbonyl, 5-phthalazinylcarbonyl, 6-phthalazinylcarbonyl, 1-2, 7-naphthyridinylcarbonyl group, 3-2, 7-naphthyridinylcarbonyl group, 4-2, 7-naphthyridinylcarbonyl group, 1-2, 6-naphthyridinylcarbonyl group, 3-2, 6-naphthyridinylcarbonyl group, 4-2, 6-naphthyridinylcarbonyl group, 2-1, 8-naphthyridinylcarbonyl group, 3-1, 8-naphthyridinylcarbonyl group, 2-1, 7-naphthyridinylcarbonyl group, 3-1, 7-naphthyridinylcarbonyl group, 4-1, 7-naphthyridinylcarbonyl group, 5-1, 7-naphthyridinylcarbonyl group, 6-1, 7-naphthyridinylcarbonyl group, 8-1, 7-naphthyridinylcarbonyl group, 2-1, 6-naphthyridinylcarbonyl group, 3-1, 6-naphthyridinylcarbonyl group, 4-1, 6-naphthyridinylcarbonyl, 5-1, 6-naphthyridinylcarbonyl, 7-1, 6-naphthyridinylcarbonyl, 8-1, 6-naphthyridinylcarbonyl, 2-1, 5-naphthyridinylcarbonyl, 3-1, 5-naphthyridinylcarbonyl, 4-1, 5-naphthyridinylcarbonyl, 6-1, 5-naphthyridinylcarbonyl, 7-1, 5-naphthyridinylcarbonyl, 8-1, 5-naphthyridinylcarbonyl, 2-quinoxalylcarbonyl, 5-quinoxalylcarbonyl, 6-quinoxalylcarbonyl, 2-quinazolinylcarbonyl, 4-quinazolinylcarbonyl, 5-quinazolinylcarbonyl, 6-quinazolinylcarbonyl, 7-quinazolinylcarbonyl, 8-quinoxalylcarbonyl, 3-cinnolinylcarbonyl, 4-cinnolinylcarbonyl, 5-cinnolinylcarbonyl, 6-cinnolinylcarbonyl, 7-cinnolinylcarbonyl, 8-cinnolinylcarbonyl, 2-pteridinylcarbonyl, 4-pteridinylcarbonyl, 6-pteridinylcarbonyl, 7-pteridinylcarbonyl and the like.
As the C1-6Alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl, 1-hexyloxyAlkylcarbonyl, 2-hexyloxycarbonyl, 3-hexyloxycarbonyl and the like,
as the C1-6As the alkylsulfonyl group, methanesulfonyl, trifluoromethanesulfonyl and ethanesulfonyl groups can be mentioned. As the C6-14Examples of the arylsulfonyl group include a benzenesulfonyl group, an o-biphenylsulfonyl group, an m-biphenylsulfonyl group, a p-biphenylsulfonyl group, a 1-naphthalenesulfonyl group, a 2-naphthalenesulfonyl group, a 1-anthracenesulfonyl group, a 2-anthracenesulfonyl group, a 9-anthracenesulfonyl group, a 1-phenanthrenesulfonyl group, a 2-phenanthrenesulfonyl group, a 3-phenanthrenesulfonyl group, a 4-phenanthrenesulfonyl group and a 9-phenanthrenesulfonyl group.
As the C2-9Heteroarylsulfonyl group including C of 5 to 7 membered ring containing 1 to 3 oxygen atom, nitrogen atom, sulfur atom alone or in combination2-6Monocyclic heterocyclic sulfonyl group and C having 8 to 10 constituent atoms5-9Condensed bicyclic heterocyclic sulfonyl.
The C as a 5-to 7-membered ring2-6Examples of the monocyclic heterocyclic sulfonyl group include a 2-thienylsulfonyl group, a 3-thienylsulfonyl group, a 2-furylsulfonyl group, a 3-furylsulfonyl group, a 2-pyranylsulfonyl group, a 3-pyranylsulfonyl group, a 4-pyranylsulfonyl group, a 1-pyrrolylsulfonyl group, a 2-pyrrolylsulfonyl group, a 3-pyrrolylsulfonyl group, a 1-imidazolylsulfonyl group, a 2-imidazolylsulfonyl group, a 4-imidazolylsulfonyl group, a 1-pyrazolylsulfonyl group, a 3-pyrazolylsulfonyl group, a 4-pyrazolylsulfonyl group, a 2-thiazolylsulfonyl group, a 4-thiazolylsulfonyl group, a 5-thiazolylsulfonyl group, a 3-isothiazolylsulfonyl group, a 4-isothiazolylsulfonyl group, a 5-isothiazolylsulfonyl, 2-oxazolylsulfonyl, 4-oxazolylsulfonyl, 5-oxazolylsulfonyl, 3-isoxazolylsulfonyl, 4-isoxazolylsulfonyl, 5-isoxazolylsulfonyl, 2-pyridylsulfonyl, 3-pyridylsulfonyl, 4-pyridylsulfonyl, 2-pyrazinylsulfonyl, 2-pyrimidylsulfonyl, 4-pyrimidylsulfonyl, 5-pyrimidylsulfonyl, 3-pyridazinylsulfonyl, 4-pyridazinylsulfonyl, 2-1, 3, 4-oxadiazoylsulfonyl, 2-1, 3, 4-thiadiazolylsulfonyl, 3-1, 2, 4-oxadiazoylsulfonyl, 5-1, 2, 4-oxadiazoylsulfonyl, 3-1, 2, 4-thiadiazolylsulfonyl, 3-isoxazolylsulfonyl, 4-isoxazolylsulfonyl, 3-pyridazolylsulfonyl, 5-1,2,4Thiadiazolylsulfonyl, 3-1, 2, 5-oxadiazoylsulfonyl, 3-1, 2, 5-thiadiazolylsulfonyl and the like.
C as the constituent atom number of 8 to 105-9Condensed bicyclic heterocyclic sulfonyl groups include 2-benzofuranylsulfonyl, 3-benzofuranylsulfonyl, 4-benzofuranylsulfonyl, 5-benzofuranylsulfonyl, 6-benzofuranylsulfonyl, 7-benzofuranylsulfonyl, 1-isobenzofuranylsulfonyl, 4-isobenzofuranylsulfonyl, 5-isobenzofuranylsulfonyl, 2-benzothienylsulfonyl, 3-benzothienylsulfonyl, 4-benzothienylsulfonyl, 5-benzothienylsulfonyl, 6-benzothienylsulfonyl, 7-benzothienylsulfonyl, 1-isobenzothiophenylsulfonyl, 4-isobenzothiophenylsulfonyl, 5-isobenzothiophenylsulfonyl, 2-chromenylsulfonyl, and the like, 3-chromenylsulfonyl, 4-chromenylsulfonyl, 5-chromenylsulfonyl, 6-chromenylsulfonyl, 7-chromenylsulfonyl, 8-chromenylsulfonyl, 1-indolizinylsulfonyl, 2-indolizinylsulfonyl, 3-indolizinylsulfonyl, 5-indolizinylsulfonyl, 6-indolizinylsulfonyl, 7-indolizinylsulfonyl, 8-indolizinylsulfonyl, 1-isoindolylsulfonyl, 2-isoindolylsulfonyl, 4-isoindolylsulfonyl, 5-isoindolylsulfonyl, 1-indolsulfonyl, 2-indolsulfonyl, 3-indolsulfonyl, 4-indolsulfonyl, 5-indolsulfonyl, 6-indolsulfonyl, 7-indolsulfonyl, 1-indazolylsulfonyl, 2-indazolylsulfonyl, 3-indazolylsulfonyl, 4-indazolylsulfonyl, 5-indazolylsulfonyl, 6-indazolylsulfonyl, 7-indazolylsulfonyl, 1-purinylsulfonyl, 2-purinylsulfonyl, 3-purinylsulfonyl, 6-purinylsulfonyl, 7-purinylsulfonyl, 8-purinylsulfonyl, 2-quinolinylsulfonyl, 3-quinolinylsulfonyl, 4-quinolinylsulfonyl, 5-quinolinylsulfonyl, 6-quinolinylsulfonyl, 7-quinolinylsulfonyl, 8-quinolinylsulfonyl, 1-isoquinolylsulfonyl, 3-isoquinolylsulfonyl, 4-isoquinolylsulfonyl, 2-indazolylsulfonyl, 2-purinylsulfonyl, 3-purinylsulfonyl, 4-purinylsulfonyl, 2-purinylsulfonyl, 3-quinolinylsulfonyl, 6, 5-isoquinolylsulfonyl, 6-isoquinolylsulfonyl, 7-isoquinolylsulfonyl, 8-isoquinolylsulfonyl, 1-Phthalazinylsulfonyl, 5-phthalazinylsulfonyl, 6-phthalazinylsulfonyl, 1-2, 7-naphthyridinylsulfonyl, 3-2, 7-naphthyridinylsulfonyl, 4-2, 7-naphthyridinylsulfonyl, 1-2, 6-naphthyridinylsulfonyl, 3-2, 6-naphthyridinylsulfonyl, 4-2, 6-naphthyridinylsulfonyl, 2-1, 8-naphthyridinylsulfonyl, 3-1, 8-naphthyridinylsulfonyl, 4-1, 8-naphthyridinylsulfonyl, 2-1, 7-naphthyridinylsulfonyl, 3-1, 7-naphthyridinylsulfonyl, 4-1, 7-naphthyridinylsulfonyl, 5-1, 7-naphthyridinylsulfonyl, 6-1, 7-naphthyridinylsulfonyl, 8-1, 7-naphthyridinylsulfonyl, 2-1, 6-naphthyridinylsulfonyl, 3-1, 6-naphthyridinylsulfonyl, 4-1, 6-naphthyridinylsulfonyl, 5-1, 6-naphthyridinylsulfonyl, 7-1, 6-naphthyridinylsulfonyl, 8-1, 6-naphthyridinylsulfonyl, 2-1, 5-naphthyridinylsulfonyl, 3-1, 5-naphthyridinylsulfonyl, 4-1, 5-naphthyridinylsulfonyl, 6-1, 5-naphthyridinylsulfonyl, 7-1, 5-naphthyridinylsulfonyl, 8-1, 5-naphthyridinylsulfonyl, 2-quinoxalinylsulfonyl, 5-quinoxalinylsulfonyl, 6-quinoxalinylsulfonyl, 2-quinazolinylsulfonyl, 4-quinazolinylsulfonyl, 5-quinazolinylsulfonyl, 6-quinazolinylsulfonyl, 7-quinazolinylsulfonyl, 8-quinazolinylsulfonyl, 3-cinnolinylsulfonyl, 4-cinnolinylsulfonyl, 5-cinnolinylsulfonyl, 6-cinnolinylsulfonyl, 7-cinnolinylsulfonyl, 8-cinnolinylsulfonyl, 2-pteridinylsulfonyl, 4-pteridinylsulfonyl, 6-pteridinylsulfonyl and 7-pteridinylsulfonyl and the like.
As the C2-9Examples of the heterocyclic group include monocyclic and condensed bicyclic heterocyclic groups containing 1 or more atoms freely selected from nitrogen atoms, oxygen atoms and sulfur atoms and 2 to 9 carbon atoms, and specifically include the following groups.
And
the- (representing a bond) in each ring structure in the above formula may be at any position that can be substituted in the chemical structure, and does not represent a specific substitution site.
R in formula (a), formula (b), formula (c), formula (d), formula (f), formula (g), formula (h), formula (j), formula (k), formula (m), formula (n), formula (o), formula (p), formula (q), formula (R), formula(s), formula (t), formula (u), formula (v), formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and formula (af)14，R15，R16And R17Independently of one another, it is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an n-pentyl group, an i-pentyl group, a 3, 3-dimethyl-n-butyl group, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, a methylcarbonyloxyethyl group, an ethylcarbonyloxyethyl group, a methylcarbonylaminomethyl group, an ethylcarbonylaminomethyl group, a methylcarbonylaminoethyl group, an ethylcarbonylaminoethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a c-propyl group, a c-pentyl group, a c-hexylmethoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a methylthio group, an ethylthio group, a, p-biphenylyl, 1-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, i-propylcarbonyloxy, n-butylcarbonyloxy, t-butylcarbonyloxy, methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, phenylamino, o-biphenylamino, m-biphenylamino, p-biphenylamino, 1-naphthylamino, 2-pyridylamino, 3-pyridylamino, 2-pyridylamino, methyl-ethyl-methyl-ethyl-amino, n-propylamino, di-n-propylamino, 4-pyridylamino, methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-butylcarbonylamino, methanesulfonamido, ethanesulfonamide, n-propanesulfonamide, i-propanesulfonamide, n-butanesulfonamide, methylaminoCarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl, n-butylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, di-i-propylaminocarbonyl, di-c-propylaminocarbonyl, di-n-butylaminocarbonyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl, phenylcarbonyl, o-biphenylcarbonyl, m-biphenylcarbonyl, p-biphenylcarbonyl, 1-naphthylcarbonyl, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, N-propylaminocarbonyl, N-butylaminocarbonyl, di-n-propylaminocarbonyl, di-n-butylaminocarbonyl, N-propylaminocarbonyl, n, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, o-biphenylsulfonyl, m-biphenylsulfonyl, p-biphenylsulfonyl, 1-naphthalenesulfonyl, 2-pyridylsulfonyl, 3-pyridylsulfonyl, 4-pyridylsulfonyl, amino, cyano, carbamoyl, carboxyl, beta-butenylsulfonyl, beta-buten,
The- (representing a bond) in each ring structure in the above formula may be at any position that can be substituted in the chemical structure, and does not represent a specific substitution site.
Q in the above formula (c), formula (d), formula (p), formula (Q), formula (v), formula (w), formula (ab), formula (ac) and formula (ad) represents O (oxygen atom), S (sulfur atom), SO (sulfinyl group) or SO (sulfinyl group)2(sulfonyl group). In the formulae (c), (d), (p), (Q), (v), (w), (ab), (ac) and (ad), Q is preferably O (oxygen atom).
In the following, R in the formula (a), (b), (i), (k), (o), (p),(s), (v), (ae), (ag) or (ah) in the case where the partial ring structure A in the formula (11) or (12) is the formula (a), (b), (i), (k), (o), (e), (v), (y), (ae), (ag) or (ah) is12、R13、R14、R15And R16The description is given.
R in formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (ae), formula (ag) or formula (ah) in the case where the partial ring structure of A in formula (11) or formula (12) is formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), formula (ae) or formula (ah)12And R13The description is given.
R in the formula (a), the formula (b), the formula (i), the formula (k), the formula (p), the formula (v), the formula (ae) and the formula (ag)12And R13Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6An alkoxy group (the alkoxy group may be optionally substituted with a halogen atom), an amino group or a hydroxyl group).
R in the formulae (a), (b), (i), (k), (p), (v), (ae) and (ag)12And R13The respective substituents of (A) are specifically described.
As the C1-6Examples of the alkyl group include a methyl group, a trifluoromethyl group, a methoxymethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a tert-butyl group, an n-pentyl group, a 2-pentyl group, a 3-pentyl group, an i-pentyl group, a neopentyl group, a2, 2-dimethylpropyl group, an n-hexyl group, a 2-hexyl group, a 3-hexyl group, a 1-methyl-n-pentyl group, a1, 1, 2-trimethyl-n-propyl group, a1, 2, 2-trimethyl-n-propyl group, and a 3, 3-dimethyl-n-butyl group.
R in the formula (a), the formula (b), the formula (i), the formula (k), the formula (p), the formula (v), the formula (ae) and the formula (ag)12And R13Each independently is preferably a hydrogen atom, methyl group, trifluoromethyl group, methoxymethyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, n-pentyl group, i-pentyl group, amino group or hydroxyl group, more preferably a hydrogen atom or methyl group.
To the above formula (11) Or R in the formula (a), the formula (b), the formula (k), the formula (o), the formula (p), the formula(s), the formula (v), the formula (y), the formula (ae), the formula (ag) or the formula (ah) in the case where the partial ring structure of A in the formula (12) is R in the formula (a), the formula (b), the formula (k), the formula (o), the formula (p), the formula(s), the formula (v), the formula (y) and the formula (ae)14、R15And R16The description is given. R in the formula (a), the formula (b), the formula (k), the formula (o), the formula (p), the formula(s), the formula (v), the formula (y) and the formula (ae)14、R15And R16Each independently represents a hydrogen atom, a halogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted by a halogen atom), amino, hydroxy, C1-6Alkylaminocarbonyl, di-C1-6Alkylaminocarbonyl radical, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonyl (the alkylcarbonyloxy and alkylcarbonyl may be optionally substituted with a halogen atom), C1-6Alkylcarbonylamino, C3-8Cycloalkyl carbonyl or C1-6Alkoxycarbonyl optionally substituted).
R in the formulae (a), (b), (k), (o), (p),(s), (v), (y) and (ae)14、R15And R16The respective atoms and the respective substituents of (A) are specifically described. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
as the C1-6Examples of the alkyl group include a methyl group, a trifluoromethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a tert-butyl group, an n-pentyl group, a 2-pentyl group, a 3-pentyl group, an i-pentyl group, a neopentyl group, a2, 2-dimethylpropyl group, an n-hexyl group, a 2-hexyl group, a 3-hexyl group, a 1-methyl-n-pentyl group, a1, 1, 2-trimethyl-n-propyl group, a1, 2, 2-trimethyl-n-propyl group and a 3, 3-dimethyl-n-butyl group, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, a methylcarbonyloxyethyl group, an ethylcarbonyloxyethyl group, a methylcarbonylaminomethyl group, an ethylcarbonylaminomethyl group, a, Ethylcarbonylaminoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, trifluoromethoxycarbonylmethyl and ethoxyCarbonylethyl, and the like. As the C1-6Alkylcarbonylamino groups include methylcarbonylamino, trifluoromethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, i-propylcarbonylamino, n-butylcarbonylamino, i-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, 1-pentylcarbonylamino, 2-pentylcarbonylamino, 3-pentylcarbonylamino, i-pentylcarbonylamino, neopentylcarbonylamino, t-pentylcarbonylamino, 1-hexylcarbonylamino, 2-hexylcarbonylamino and 3-hexylcarbonylamino groups,
as the C3-8Cycloalkylcarbonyl groups include c-propylcarbonyl, c-butylcarbonyl, 1-methyl-c-propylcarbonyl, 2-methyl-c-propylcarbonyl, c-pentylcarbonyl, 1-methyl-c-butylcarbonyl, 2-methyl-c-butylcarbonyl, 3-methyl-c-butylcarbonyl, 1, 2-dimethyl-c-propylcarbonyl, 2, 3-dimethyl-c-propylcarbonyl, 1-ethyl-c-propylcarbonyl, 2-ethyl-c-propylcarbonyl, c-hexylcarbonyl, c-heptylcarbonyl, c-octylcarbonyl, 1-methyl-c-hexylcarbonyl, 2-methyl-c-hexylcarbonyl, 3-methyl-c-hexylcarbonyl, 1, 2-dimethyl-c-hexylcarbonyl, 2, 3-dimethyl-c-propylcarbonyl, 1-ethyl-c-propylcarbonyl, 1-methyl-c-pentylcarbonyl, 2-methyl-c-pentylcarbonyl, 3-methyl-c-pentylcarbonyl, 1-ethyl-c-butylcarbonyl, 2-ethyl-c-butylcarbonyl, 3-ethyl-c-butylcarbonyl, 1, 2-dimethyl-c-butylcarbonyl, 1, 3-dimethyl-c-butylcarbonyl, 2-dimethyl-c-butylcarbonyl, 2, 3-dimethyl-c-butylcarbonyl, 2, 4-dimethyl-c-butylcarbonyl, 3-dimethyl-c-butylcarbonyl, 1-n-propyl-c-propylcarbonyl, 2-n-propyl-c-propylcarbonyl, 1-i-propyl-c-propylcarbonyl, 2-i-propyl-c-propylcarbonyl, 1, 2, 2-trimethyl-c-propylcarbonyl, 1, 2, 3-trimethyl-c-propylcarbonyl, 2, 2, 3-trimethyl-c-propylcarbonyl, 1-ethyl-2-methyl-c-propylcarbonyl, 2-ethyl-1-methyl-c-propylcarbonyl, 2-ethyl-2-methyl-c-propylcarbonyl and 2-ethyl- 3-methyl-c-propylcarbonyl group, etc.,
as the C1-6Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group and an n-butoxycarbonyl groupAlkylcarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, 1-pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxycarbonyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t-pentyloxycarbonyl, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl, 3-hexyloxycarbonyl and the like.
R in the formula (a), the formula (b), the formula (k), the formula (o), the formula (p), the formula(s), the formula (v), the formula (y) and the formula (ae)14、R15And R16Independently of each other, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a trifluoromethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an n-pentyl group, an i-pentyl group, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, a methylcarbonyloxyethyl group, an ethylcarbonyloxyethyl group, a methylcarbonylaminomethyl group, an ethylcarbonylaminoethyl group, a methylcarbonylaminoethyl group, an ethylcarbonylaminoethyl group, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a methoxycarbonylethyl group, a trifluoromethoxy carbonylmethyl group, an ethoxycarbonylethyl group are preferred, and a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, an ethyl group, an n-propyl group, an i-propyl group, a methylcarbonyloxymethyl group, an ethylcarbonyloxymethyl group, a methylcarbonyl, Methoxycarbonylmethyl, trifluoromethoxycarbonylmethyl.
The partial ring structure of A in the formula (11) or (12) is represented by the formula (p) or (v), wherein Q in the formula (p) or (v) represents O (oxygen atom), S (sulfur atom), SO (sulfinyl group) or SO (sulfinyl group)2(sulfonyl group). Q in the formula (p) or the formula (v) is preferably O (oxygen atom).
For R in the above formula (13)9、R10W, X, Y and Z.
R in the formula (13)9And R10Each independently represents a hydrogen atom or C1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy), C6-14Aryl (which may be substituted by halogen atoms, hydroxy, nitro, cyano, C)1-6Alkyl (the alkyl may be substituted by halogen atoms, C)1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom) or hydroxy), C1-6Alkoxy (the alkoxy may be optionally substituted with a halogen atom).
For R in formula (13)9And R10The respective substituents of (A) are specifically described.
As the C1-6Examples of the alkyl group include methyl, trifluoromethyl, methoxymethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, i-pentyl, neopentyl, 2, 2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-pentyl, 1, 2-trimethyl-n-propyl, 1, 2, 2-trimethyl-n-propyl, and 3, 3-dimethyl-n-butyl,
as the C6-14Examples of the aryl group include phenyl, o-biphenyl, m-biphenyl, p-biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9-phenanthryl.
R in the formula (13)9And R10Methyl, trifluoromethyl and ethyl are preferred, and methyl is more preferred.
W in formula (13) represents a hydrogen atom, a hydroxyl group, C1-6Alkoxy group (the alkoxy group may be optionally substituted by a halogen atom), halogen atom, C1-4Alkyl or C1-6An alkylsulfonamide group (the alkyl group and the alkylsulfonamide group may be optionally substituted with a halogen atom).
Each atom and each substituent of W in formula (13) will be specifically described.
As the C1-6Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3-pentyloxy group, an i-pentyloxy group, a neopentyloxy group, a2, 2-dimethylpropoxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group1-methyl-n-pentyloxy, 1, 2-trimethyl-n-propoxy, 1, 2, 2-trimethyl-n-propoxy, 3-dimethyl-n-butoxy and the like,
examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom,
as the C1-4Examples of the alkyl group include methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl,
as the C1-6Examples of the alkylsulfonamide group include a methanesulfonamide group, a trifluoromethanesulfonamide group, an ethanesulfonamide group, an n-propanesulfonamide group, an i-propanesulfonamide group, an n-butanesulfonamide group, an i-butanesulfonamide group, an s-butanesulfonamide group, a t-butanesulfonamide group, a 1-pentanesulfonamide group, a 2-pentanesulfonamide group, a 3-pentanesulfonamide group, an i-pentanesulfonamide group, a neopentanesulfonamide group, a t-pentanesulfonamide group, a 1-hexanesulfonamide group, a 2-hexanesulfonamide group and a 3-hexanesulfonamide group.
W in formula (13) is preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a trifluoromethyl group, an ethyl group, a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, a methanesulfonamide group, a trifluoromethanesulfonamide group, an ethanesulfonamide group, an n-propanesulfonamide group, an i-propanesulfonamide group, an n-butanesulfonamide group, more preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, a trifluoromethyl group, an ethyl group, a methoxy group, a methanesulfonamide group, a trifluoromethanesulfonamide group.
X in formula (13) represents NR20N represents a nitrogen atom, and N represents a nitrogen atom,
R20represents a hydrogen atom or C1-4An alkyl group.
R in X of formula (13)20The respective substituents of (A) are specifically described.
As the C1-4Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
R in X of formula (13)20Preferably a hydrogen atom, methyl group or ethyl group.
Y in formula (13) is a direct bond, SO (sulfinyl) or SO2(sulfonyl), preferably direct bonding and SO2。
Z in the formula (13) represents C1-4Alkyl (the C)1-4The alkyl group may be substituted with 1 to 5 halogen atoms or phenyl (the phenyl group may be substituted with C)1-4Alkyl optionally substituted) or phenyl (which phenyl may be C substituted)1-4Alkyl optionally substituted).
The substituents of Z in the formula (13) will be specifically described.
As the C1-4Examples of the alkyl group include methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
Z in formula (13) is preferably methyl, trifluoromethyl, ethyl, n-propyl, i-propyl, or phenyl.
When the optically active titanium complex represented by any one of the above formulae (1), (1 '), (2), (2'), (3), (3 '), (4) and (4') is used as a catalyst, the amount of the optically active titanium complex to be used is in the range of 0.001 to 100 mol%, preferably 0.01 to 20 mol%, more preferably 0.3 to 5 mol% relative to the chromene compound represented by the formula (10), (11), (12) or (13).
When the optically active titanium complex represented by any one of the above formulae (1), (1 '), (2), (2'), (3), (3 '), and (4') is used as a catalyst, the solvent used in the asymmetric epoxidation reaction is a halogen-based solvent, an aromatic hydrocarbon-based solvent, an ester-based solvent, an ether-based solvent, or a nitrile-based solvent as an aprotic organic solvent, and an alcohol-based solvent as a protic organic solvent. Examples of the halogen-based solvent include dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, etc., examples of the aromatic hydrocarbon-based solvent include benzene, toluene, etc., examples of the ester-based solvent include ethyl acetate, etc., examples of the ether-based solvent include tetrahydrofuran, diethyl ether, etc., and examples of the nitrile-based solvent include butyronitrile, propionitrile, acetonitrile, etc. Examples of the alcohol solvent include methanol, ethanol, and i-propanol, and further, a mixture of the above solvents may be mentioned. When an aqueous solution of hydrogen peroxide (hydrogen peroxide solution) is used in the reaction, the organic solvent and the aqueous phase may be separated from each other by mixing with an organic solvent insoluble in water, but such a 2-phase solvent can also be used as the reaction solvent of the present invention. Preferred solvents are dichloromethane, 1, 2-dichloroethane, chlorobenzene, toluene, ethyl acetate or mixtures of these solvents as aprotic organic solvents.
The production operation is carried out by adding a chromene compound, an optically active titanium complex, and an oxidizing agent to an organic solvent. In the order of addition, it is preferable to add an oxidizing agent to a solution containing an organic solvent, a chromene compound, and an optically active titanium complex.
Specific examples of the oxidizing agent used in the reaction include iodosobenzene, sodium hypochlorite, m-chloroperoxybenzoic acid, Oxone (registered trademark of dupont), hydrogen peroxide water, urea-hydrogen peroxide adduct (UHP), oxaziridine (oxaziridine), N-methylmorpholine oxide (NMO), tert-butyl hydroperoxide (TBHP), Cumene Hydroperoxide (CHP), and mixtures of these oxidizing agents. Among them, hydrogen peroxide water, urea-hydrogen peroxide adduct (UHP) and a mixture of these oxidizing agents are preferable. The concentration of the oxidizing agent in the case of hydrogen peroxide water is in the range of 1 to 100% (wt%), preferably 5 to 60% (wt%).
The amount of the oxidizing agent used in the reaction is in the range of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to the chromene compound represented by formula (10), formula (11), formula (12) or formula (13).
As a method of adding the oxidizing agent, in addition to the collective addition, a batch addition and a continuous addition may be cited.
In the case of continuous addition, the addition rate is preferably within a range in which the internal temperature in the reaction solvent system does not increase rapidly, specifically, preferably within a range of 0.01 to 40000 equivalents per hour, and more preferably within a range of 0.05 to 0.3 equivalents per hour. The addition in portions is a method of adding the oxidizing agent to the reaction mixture p times (p is an arbitrary integer). The batches may be divided equally or unequally, and p is preferably in the range of 2 to 100.
The reaction temperature may be-78 ℃ to the solvent reflux temperature, or the melting point temperature of the solvent to be used may be in the range of-20 ℃ to 50 ℃ and more preferably in the range of 0 ℃ to 35 ℃.
The pressure in the reaction system may be in the range of 10kPa to 1100kPa, preferably 15kPa to 200 kPa. The reaction can be carried out at a temperature higher than the reflux temperature of the solvent at normal pressure by applying pressure.
In the course of the reaction, an optically active titanium complex as a catalyst can be added additionally to shorten the reaction time. In addition, an oxidizing agent can be added to shorten the reaction time.
After the reaction is completed, the target optically active chromene oxide compound is obtained by performing separation and purification through distillation, silica gel column chromatography, liquid separation and extraction, recrystallization, or a combination thereof.
The optical purity of the obtained optically active chromene oxide compound can be analyzed by optically active high performance liquid chromatography, optically active gas chromatography, optical rotation measurement, or the like.
The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
In addition, in the optically active chromene oxide compounds in the examples, there are also compounds in which the absolute configuration of asymmetric carbon is not known. In the figures, the absolute configuration notation in the asymmetric carbon and compound names is provided with an asterisk (, v), and the notation in the figures and compound names is a hypothetical absolute configuration notation.
Synthesis of optically active titanium Salalen complexes (A) (B) and (C)
The optically active titanium Salalen complexes (A) (B) and (C) used in the examples were prepared according to the method described in non-patent document 8(Angew. chem. int. Ed. (2005), 44, 4935-.
The optically active titanium Salan complex (D) represented by the following formula is obtained as follows.
Salan ligand (42')
Adding 1.1 moles of titanium tetraisopropoxide [ Ti (Oi-Pr) to 1 mole of the Salan ligand (42 ') in a dichloromethane reaction solvent of the Salan ligand (42') under a nitrogen atmosphere at 25 to 28 DEG C4]Stirring for 5 hours, adding water at 25-28 ℃, and stirring the reaction solution for 12 hours. Then, the reaction solvent was distilled off to obtain a crude product, which was subjected to a recrystallization operation with methylene chloride to obtain an optically active titanium complex (D).
Pale yellow white solid
MS(CSI)＝1082，2163
The optically active titanium Salan complexes (E) and (F) were also obtained by the same production method as described above.
Example 1
Synthesis of (3S, 4S) -6-acetamide-3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-2H-1-benzopyran (Compound (I))
To a solution of optically active titanium Salalen complex (B) (38mg, 0.021mmol) (1.0 mol% relative to the substrate) in methylene chloride (3mL) at 28 ℃ was added 6-acetamide-2, 2-dimethyl-7-nitro-2H-1-benzopyran (0.54g, 2.1 mmol). While the reaction solution was stirred, 7.5% hydrogen peroxide water (1.4g, 3.1mmol) was added at 28 ℃ over 10 hours. The reaction initiation time was defined as the time at which the addition of 7.5% hydrogen peroxide solution was initiated, and 14 hours after the initiation of the reaction, 7.5% hydrogen peroxide solution (0.1g, 0.2mmol) was added at 28 ℃ and stirring was continued at 28 ℃ for 19 hours from the time at which the reaction was initiated. After completion of the reaction, methylene chloride (6mL) and distilled water (6mL) were added to the reaction mixture, the organic phase was separated, the organic phases extracted from the aqueous phase were combined with methylene chloride (6mL), and the concentrated crude product was purified by column chromatography to obtain compound (I) as a yellow powder (0.49g, yield 86%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALPAK OJ-RH, eluent acetonitrile/methanol/0.01M aqueous sodium chloride solution 1/3/5(v/v/v), flow rate 1.5mL/min, column temperature 40 ℃, retention time the reaction product: 15.9 min (3S, 4S), enantiomer: 11.7 min (3R, 4R), the wavelength 242nm was determined.
1H-NMR(CDCl3)δ；1.27(s，3H)，1.59(s，3H)，2.28(s，3H)，3.55(d，J＝4.1Hz，1H)，3.97(d，J＝4.1Hz，1H)，7.64(s，1H)，8.79(s，1H)，10.10(br，1H)
Example 2
Synthesis of (3R, 4R) -6-acetamide-3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-2H-1-benzopyran (Compound (II))
To a solution of optically active titanium Salan complex (E) (25.6mg, 0.021mmol) (1.0 mol% relative to the substrate) in methylene chloride (3mL) at 30 ℃ was added 6-acetamide-2, 2-dimethyl-7-nitro-2H-1-benzopyran (537.4mg, 2.1 mmol). While the reaction solution was stirred, 30% aqueous hydrogen peroxide (302.7mg, 2.7mmol) was added at 30 ℃ over 1 second. Then, stirring was continued at 30 ℃ for 7 hours. After completion of the reaction, methylene chloride and distilled water were added to the reaction mixture, the organic phase was separated, and the organic phases extracted from the aqueous phase with methylene chloride were combined, and the crude product obtained by concentration was purified by column chromatography to obtain compound (II) as a yellow powder (0.53g, yield 93%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALPAK OJ-RH, eluent acetonitrile/methanol/0.01M aqueous sodium chloride solution 1/3/5(v/v/v), flow rate 1.5mL/min, column temperature 40 ℃, retention time the reaction product: 13.4 min (3R, 4R), enantiomer: 17.5 min (3S, 4S), the wavelength 242nm is determined.
1H-NMR(CDCl3)δ；1.27(s，3H)，1.59(s，3H)，2.28(s，3H)，3.55(d，J＝4.2Hz，1H)，3.97(d，J＝4.5Hz，1H)，7.63(s，1H)，8.79(s，1H)，10.09(br，1H)
Example 3
Synthesis of (3S, 4S) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-6-nitro-2H-1-benzopyran (Compound (III))
To a solution of optically active titanium Salalen complex (B) (73mg, 0.041mmol) (2.0 mol% relative to the substrate) in dichloromethane (8mL) was added 2, 2-dimethyl-6-nitro-2H-1-benzopyran (0.41g, 2.0mmol) at 25 ℃. While the reaction solution was stirred, 30% aqueous hydrogen peroxide (0.24g, 2.1mmol) was added at 25 ℃ over 2 seconds. The start time of addition of 30% hydrogen peroxide water was taken as the reaction start time, and 27 hours calculated from the reaction start time was stirred at 25 ℃. After completion of the reaction, methylene chloride (6mL) and distilled water (6mL) were added to the reaction mixture to separate the organic phases, and the organic phases extracted from the aqueous phase with methylene chloride (6mL) were combined, and the concentrated crude product was purified by column chromatography to obtain compound (III) as a white yellow powder (0.43g, yield 97%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALCEL OD-H, eluent n-hexane/i-propanol 9/1(v/v), flow rate 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 9.6 min (3S, 4S), enantiomer: 8.4 min (3R, 4R), the wavelength was determined at 300nm.
1H-NMR(CDCl3)δ；1.33(s，3H)，1.63(s，3H)，3.57(d，J＝4.4Hz，1H)，4.00(d，J＝4.4Hz，1H)，6.89(d，J＝9.1Hz，1H)，8.15(dd，J＝9.1，2.8Hz，1H)，8.31(d，J＝2.8Hz，1H)
Example 4
Synthesis of (3S, 4S) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-6-nitro-2H-1-benzopyran (Compound (III))
To formula (43 ') at 20℃') To a solution of the Salan ligand (4.9mg, 0.0080mmol) (4.0 mol% relative to the substrate) in methylene chloride (0.3mL) was added titanium tetraisopropoxide [ Ti (Oi-Pr)4](2.3mg, 0.0080 mmol). After stirring at 20 ℃ for 1 hour, 2-dimethyl-6-nitro-2H-1-benzopyran (41mg, 0.20mmol) was added to the above solution. 30% hydrogen peroxide water (0.034g, 0.30mmol) was divided into 3 portions, and the reaction solution was added at 20 ℃ for the 1 st time, 30 minutes for the 2 nd time, and 1 hour for the 3 rd time while stirring the reaction solution. The reaction was started by adding 30% hydrogen peroxide solution at the 1 st time, and after stirring at 20 ℃ for 24 hours calculated from the reaction start time, the reaction solution was sampled and analyzed for the reaction conversion by HPLC. The conversion into the compound (III) was 99% or more, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 15.8 min (3S, 4S), enantiomer: 12.6 min (3R, 4R), measurement wavelength: 330nm.
Example 5
Synthesis of (3R, 4R) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-6-nitro-2H-1-benzopyran (Compound (IV))
To a solution of optically active titanium Salan complex (E) (48mg, 0.040mmol) (2.0 mol% relative to the substrate) in methylene chloride (6mL) was added 2, 2-dimethyl-6-nitro-2H-1-benzopyran (0.41g, 2.0mmol) at 20 ℃. 30% hydrogen peroxide water (0.24g, 2.1mmol) was divided into 3 portions, and the reaction solution was added at 20 ℃ for the 1 st time, 30 minutes for the 2 nd time, and 1 hour for the 3 rd time while stirring. The 1 st addition of 30% hydrogen peroxide water was performed as a reaction start time, and after stirring at 20 ℃ for 24 hours calculated from the reaction start time, methylene chloride (5mL) and distilled water (5mL) were added to the reaction solution to separate the organic phase, and the organic phases obtained by 2 extractions from the aqueous phase with methylene chloride (5mL, 3mL) were combined, and the concentrated crude product was purified by column chromatography to obtain a white yellow powdery compound (IV) (0.41g, yield 94%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 12.6 min (3R, 4R), enantiomer: 15.8 min (3S, 4S), measurement wavelength: 330nm.
1H-NMR(CDCl3)δ；1.33(s，3H)，1.62(s，3H)，3.58(d，J＝4.4Hz，1H)，4.00(d，J＝4.4Hz，1H)，6.89(d，J＝8.6Hz，1H)，8.14(dd，J＝8.6，3.0Hz，1H)，8.30(d，J＝3.0Hz，1H)
Example 6
Synthesis of (3R, 4R) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-6-nitro-2H-1-benzopyran (Compound (IV))
To a solution of the optically active titanium Salalen complex (A) (73mg, 0.041mmol) (2.0 mol% relative to the substrate) in dichloromethane (8mL) was added 2, 2-dimethyl-6-nitro-2H-1-benzopyran (0.41g, 2.0mmol) at 25 ℃. While the reaction solution was stirred, 30% aqueous hydrogen peroxide (0.24g, 2.1mmol) was added at 25 ℃ over 2 seconds. Then, the stirring was continued at 25 ℃ and the reaction was started by adding 30% hydrogen peroxide water for 8 hours, and the reaction solution was sampled and analyzed for the reaction conversion by HPLC. The conversion into the compound (IV) was 99% or more, and the optical purity was 96% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 5.2 min (3R, 4R), enantiomer: 6.1 min (3S, 4S), measurement wavelength: 330nm.
Example 7
(3S＊，4S＊) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V))＊Representing a relative configuration) of the corresponding compounds
Or
To a dichloromethane solution (8mL) of optically active titanium Salalen complex (B) (71mg, 0.040mmol) (2.0 mol% based on the substrate) was added 2, 2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (0.47g, 2.0mmol) at 25 ℃. While the reaction solution was stirred, 30% aqueous hydrogen peroxide (0.24g, 2.1mmol) was added at 25 ℃ over 2 seconds. The reaction was started by the addition of 30% hydrogen peroxide solution, and the stirring was continued at 25 ℃ for 19 hours after the start of the reaction. After completion of the reaction, methylene chloride (3mL) and distilled water (3mL) were added to the reaction mixture, the organic phase was separated, the organic phases obtained by extraction from the aqueous phase with methylene chloride (3mL) were combined, and the concentrated crude product was purified by column chromatography to obtain compound (V) as a yellow oil (0.50g, yield 99%, optical purity 99.9% ee or more). Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.8mL/min, column temperature 40 ℃, retention time of the reaction product: 12.1 min, enantiomer: 11.3 minutes, measurement wavelength: 225nm.
1H-NMR(CDCl3)δ；1.26(s，3H)，1.59(s，3H)，3.53(d，J＝4.4Hz，1H)，3.90(d，J＝4.4Hz，1H)，3.95(s，3H)，7.08(s，1H)，7.33(s，1H)
Example 8
(3S＊，4S＊) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethylIn the group-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V))＊Representing a relative configuration) of the corresponding compounds
To a solution (0.9mL) of Salan ligand (14mg, 0.020mmol) (4.0 mol% relative to the substrate) represented by formula (41') in methylene chloride was added titanium tetraisopropoxide [ Ti (Oi-Pr)4](5.7mg, 0.020 mmol). After stirring for 1 hour at 20 ℃ 2, 2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (0.118g, 0.50mmol) was added. 30% hydrogen peroxide water (0.085g, 0.75mmol) was divided into 3 portions, and the 1 st addition was made at 20 ℃ while stirring the reaction solution, the 2 nd addition was made after 30 minutes, and the 3 rd addition was made after 1 hour. The time of addition of the 1 st 30% hydrogen peroxide solution was defined as the reaction initiation time, and after the reaction was initiated and stirred at 20 ℃ for 24 hours, the reaction solution was sampled and analyzed for reaction conversion by HPLC. The conversion into the compound (V) was 99% or more, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.5mL/min, column temperature 40 ℃, retention time of the reaction product: 18.3 min, enantiomer: 17.5 minutes, measurement wavelength: 225nm.
Example 9
(3R＊，4R＊) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V'))＊Representing a relative configuration) of the corresponding compounds
To a dichloromethane solution (7mL) of optically active titanium Salan complex (E) (48mg, 0.040mmol) (2.0 mol% relative to the substrate) was added 2, 2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (0.47g, 2.0mmol) at 25 ℃. 30% hydrogen peroxide water (0.24g, 2.1mmol) was divided into 3 portions, and the 1 st addition was performed at 20 ℃ while stirring the reaction solution, so that the 2 nd addition was performed after 30 minutes, and the 3 rd addition was performed after 1 hour. The time for which the 1 st 30% hydrogen peroxide solution was added was taken as the reaction initiation time, and after the reaction was started and stirred at 20 ℃ for 24 hours, methylene chloride (5mL) and distilled water (5mL) were added to the reaction solution, and the organic phase was separated, and the organic phases obtained by 2 extractions from the aqueous phase with methylene chloride (5mL, 3mL) were combined, and the concentrated crude product was purified by column chromatography to obtain a yellow oily compound (V') (0.48g, yield 96%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.5mL/min, column temperature 40 ℃, retention time of the reaction product: 17.5 min, enantiomer: 18.3 min, measurement wavelength: 225nm.
1H-NMR(CDCl3)δ；1.26(s，3H)，1.58(s，3H)，3.54(d，J＝4.5Hz，1H)，3.91(d，J＝4.5Hz，1H)，3.95(s，3H)，7.09(s，1H)，7.32(s，1H)
Example 10
(3R＊，4R＊) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (Compound (V'))＊Representing a relative configuration) of the corresponding compounds
To a solution of optically active titanium Salalen complex (A) (71mg, 0.040mmol) (2.0 mol% relative to the substrate) in methylene chloride (8mL) was added 2, 2-dimethyl-7-nitro-6-methoxy-2H-1-benzopyran (0.47g, 2.0mmol) at 25 ℃. While the reaction solution was stirred, 30% aqueous hydrogen peroxide (0.24g, 2.1mmol) was added at 25 ℃ over 2 seconds. The reaction start time was defined as the time at which the addition of 30% hydrogen peroxide solution started, and 18 hours after the start of the reaction, the reaction solution was sampled and analyzed for the reaction conversion by HPLC. The conversion into the compound (V') was 99% or more, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.8mL/min, column temperature 40 ℃, retention time of the reaction product: 11.3 min, enantiomer: 12.1 min, measurement wavelength: 225nm.
Example 11
(3S＊，4S＊) Synthesis of (E) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-2H-1-benzopyran (formula (VI) wherein R represents the relative configuration)
Or
To a solution of optically active titanium Salalen complex (B) (36mg, 0.020mmol) (2.0 mol% relative to the substrate) in dichloromethane (4mL) was added 2, 2-dimethyl-7-nitro-2H-1-benzopyran (0.21g, 1.0mmol) at 25 ℃. While the reaction solution was stirred, 30% hydrogen peroxide water (0.12g, 1.1mmol) was added thereto over 2 seconds. The reaction was started by the addition of 30% hydrogen peroxide solution and stirred at 25 ℃ for 27 hours after the start of the reaction. After completion of the reaction, methylene chloride (2mL) and distilled water (2mL) were added to the reaction mixture, the organic phase was separated, the organic phases obtained by extraction from the aqueous phase with methylene chloride (2mL) were combined, and the concentrated crude product was purified by column chromatography to obtain compound (VI) as a yellow powder (0.43g, yield 99%, optical purity 99.4% ee).
Analysis conditions were as follows: column name CHIRALPAK AD-RH, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 9.2 min, enantiomer: 4.9 minutes, measurement wavelength: 220nm.
1H-NMR(CDCl3)δ；1.29(s，3H)，1.62(s，3H)，3.58(d，J＝4.4Hz，1H)，3.97(d，J＝4.4Hz，1H)，7.50(d，J＝8.3Hz，1H)，7.67(dd，J＝8.3，2.2Hz，1H)，7.80(d，J＝2.2Hz，1H)
Example 12
(3S＊，4S＊) Synthesis of (E) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-2H-1-benzopyran (formula (VI) wherein R represents the relative configuration)
To a dichloromethane solution (6mL) of optically active titanium Salan complex (F) (48mg, 0.040mmol) (2.0 mol% relative to the substrate) was added 2, 2-dimethyl-7-nitro-2H-1-benzopyran (0.41g, 2.0mmol) at 25 ℃. 30% hydrogen peroxide water (0.25g, 2.2mmol) was divided into 3 portions, and the 1 st addition was performed at 20 ℃ while stirring the reaction solution, so that the 2 nd addition was performed after 30 minutes, and the 3 rd addition was performed after 1 hour. The time for which the 1 st 30% hydrogen peroxide solution was added was defined as the reaction initiation time, and the mixture was stirred at 20 ℃ for 24 hours after the initiation of the reaction. After completion of the reaction, methylene chloride (5mL) and distilled water (5mL) were added to the reaction mixture, the organic phase was separated, the organic phases obtained by 2 extractions from the aqueous phase with methylene chloride (5mL, 3mL) were combined, and the concentrated crude product was purified by column chromatography to obtain yellow crystalline compound (VI) (0.44g, yield 98%, optical purity 99.9% ee).
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 25.2 min, enantiomer: 13.9 minutes, measurement wavelength: 220nm.
1H-NMR(CDCl3)δ；1.29(s，3H)，1.61(s，3H)，3.60(d，J＝4.5Hz，1H)，3.99(d，J＝4.5Hz，1H)，7.52(d，J＝8.3Hz，1H)，7.62(d，J＝2.1Hz，1H)，7.70(dd，J＝8.3，2.1Hz，1H)
Example 13
(3R＊，4R＊) 3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-2H-1-benzopyran (formula (VI') wherein R representsRelative configuration) synthesis
To a solution of optically active titanium Salalen complex (A) (36mg, 0.020mmol) (2.0 mol% relative to the substrate) in dichloromethane (4mL) was added 2, 2-dimethyl-7-nitro-2H-1-benzopyran (0.21g, 1.0mmol) at 25 ℃. While the reaction solution was stirred, 30% aqueous hydrogen peroxide (0.12g, 1.1mmol) was added thereto at 25 ℃ over 2 seconds. Then, stirring was continued at 25 ℃ and the reaction was started by adding 30% hydrogen peroxide water, and the reaction mixture was sampled 24 hours after the start of the reaction, and the reaction conversion rate was analyzed by HPLC. The conversion into the compound (VI') was 99% or more, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 4.9 min, enantiomer: 9.2 min, measurement wavelength: 220nm.
Example 14
(3R＊，4R＊) Synthesis of (E) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-nitro-2H-1-benzopyran (formula (VI') wherein R represents the relative configuration)
To a solution of optically active titanium Salan complex (E) (24mg, 0.020mmol) (2.0 mol% relative to the substrate) in methylene chloride (3mL) was added 2, 2-dimethyl-7-nitro-2H-1-benzopyran (0.205g, 1.0mmol) at 20 ℃. 30% hydrogen peroxide water (0.12g, 1.1mmol) was divided into 3 portions, and the 1 st addition was performed at 20 ℃ while stirring the reaction solution, so that the 2 nd addition was performed after 30 minutes, and the 3 rd addition was performed after 1 hour. The time of addition of the 1 st 30% hydrogen peroxide solution was defined as the reaction initiation time, and after 24 hours from the initiation of the reaction, the reaction solution was stirred at 20 ℃ and then sampled, and the reaction conversion rate was analyzed by HPLC. The conversion into the compound (VI') was 99% or more, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 13.9 min, enantiomer: 25.2 minutes, measurement wavelength: 220nm.
Example 15
(3S＊，4S＊) Synthesis of (E) -3, 4-epoxy-6-fluoro-3, 4-dihydro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (formula (VII) wherein R represents the relative configuration)
Or
To a solution of optically active titanium Salalen complex (B) (37mg, 0.021mmol) (2.0 mol% relative to the substrate) in methylene chloride (4mL) was added 6-fluoro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (0.23g, 1.0mmol) at 25 ℃. While the reaction solution was stirred, 30% aqueous hydrogen peroxide (0.12g, 1.1mmol) was added thereto at 25 ℃ over 2 seconds. The reaction was started by the addition of 30% hydrogen peroxide solution, and the mixture was stirred at 25 ℃ for 29 hours after the start of the reaction. After completion of the reaction, methylene chloride (2mL) and distilled water (2mL) were added to the reaction mixture, the organic phase was separated, the organic phases obtained by extraction from the aqueous phase with methylene chloride (2mL) were combined, and the concentrated crude product was purified by column chromatography to obtain compound (VII) as a yellow powder (0.23g, yield 94%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.5mL/min, column temperature 40 ℃, retention time of the reaction product: 17.4 min, enantiomer: 18.1 min, measurement wavelength: 220nm.
1H-NMR(CDCl3)δ；1.33(s，3H)，1.64(s，3H)，3.57(d，J＝4.4Hz，1H)，3.94(d，J＝4.4Hz，1H)，7.35(dd，J＝4.4，7.1Hz，1H)，7.56(dd，J＝4.4，7.9Hz，1H)
Example 16
(3S＊，4S＊) Synthesis of (E) -3, 4-epoxy-6-fluoro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (formula (VII) wherein R represents the relative configuration)
To a dichloromethane solution (1.7mL) of Salan ligand (43mg, 0.080mmol) (4.0 mol% relative to the substrate) represented by formula (44'), titanium tetraisopropoxide [ Ti (Oi-Pr) was added at 25 ℃4](11mg, 0.040 mmol). After stirring for 1 hour at 20 ℃ 6-fluoro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (0.446g, 2.0mmol) was added. 30% hydrogen peroxide water (0.25g, 2.2mmol) was divided into 3 portions, and the 1 st addition was performed at 20 ℃ while stirring the reaction solution, so that the 2 nd addition was performed after 30 minutes, and the 3 rd addition was performed after 1 hour. The time for which the 1 st 30% hydrogen peroxide solution was added was defined as the reaction initiation time, and the mixture was stirred at 20 ℃ for 40 hours after the initiation of the reaction. After completion of the reaction, dichloromethane (5mL) and distilled water (5mL) were added to the reaction solution, the organic phase was separated, the organic phases obtained by 2 extractions from the aqueous phase with dichloromethane (5mL, 3mL) were combined, and the concentrated crude product was purified by column chromatography to obtain compound (VII) as a yellow oil (0.43g, yield 90%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.5mL/min, column temperature 40 ℃, retention time of the reaction product: 16.8 min, enantiomer: 17.3 min, measurement wavelength: 220nm.
1H-NMR(CDCl3)δ；1.33(s，3H)，1.63(s，3H)，3.60(d，J＝4.5Hz，1H)，3.98(d，J＝4.5Hz，1H)，7.38(dd，J＝3.0，7.4Hz，1H)，7.54(dd，J＝3.0，7.4Hz，1H)
Example 17
(3R＊，4R＊) Synthesis of (E) -3, 4-epoxy-6-fluoro-3, 4-dihydro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (formula (VII') wherein R represents the relative configuration)
To a solution of optically active titanium Salalen complex (A) (37mg, 0.021mmol) (2.0 mol% relative to the substrate) in methylene chloride (4mL) was added 6-fluoro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (0.23g, 1.0mmol) at 25 ℃. While the reaction solution was stirred, 30% aqueous hydrogen peroxide (0.12g, 1.1mmol) was added thereto at 25 ℃ over 2 seconds. The reaction start time was defined as the time at which the addition of 30% hydrogen peroxide solution started, and 3 hours after the start of the reaction, the reaction solution was sampled and analyzed for the reaction conversion by HPLC. The conversion into the compound (VII') was 76%, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAKAD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.5mL/min, column temperature 40 ℃, retention time of the reaction product: 18.1 min, enantiomer: 17.4 min, measurement wavelength: 220nm.
Example 18
(3R＊，4R＊) Synthesis of (E) -3, 4-epoxy-6-fluoro-3, 4-dihydro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (formula (VII') wherein R represents the relative configuration)
To a solution of optically active titanium Salan complex (E) (24mg, 0.020mmol) (2.0 mol% relative to the substrate) in methylene chloride (3mL) was added 6-fluoro-2, 2-dimethyl-8-nitro-2H-1-benzopyran (0.23g, 1.0mmol) at 20 ℃. 30% hydrogen peroxide water (0.12g, 1.1mmol) was divided into 3 portions, and the 1 st addition was performed at 20 ℃ while stirring the reaction solution, so that the 2 nd addition was performed after 30 minutes, and the 3 rd addition was performed after 1 hour. The reaction was started by adding 30% hydrogen peroxide solution at the 1 st time, and after stirring at 20 ℃ for 24 hours, the reaction solution was sampled and analyzed for the reaction conversion by HPLC. The conversion into the compound (VII') was 96%, and the optical purity was 99% ee or more.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 0.5mL/min, column temperature 40 ℃, retention time of the reaction product: 17.3 min, enantiomer: 16.8 minutes, measurement wavelength: 220nm.
Example 19
(3R＊，4R＊) - (3, 4-epoxy-2, 2, 9-trimethyl-3, 4-dihydro-2H-pyrano [2, 3-g)]Synthesis of quinolin-7-yl-methyl-acetic acid esters (compounds (VIII') in which r represents the relative configuration)
Or
To a solution of optically active titanium Salalen complex (A) (71mg, 0.040mmol) (1.9 mol% relative to the substrate) in dichloromethane (3mL) was added (2, 2, 9-trimethyl-2H-pyrano [2, 3-g ] quinolin-7-yl) -methyl acetate (0.61g, 2.1mmol) at 28 ℃. While the reaction solution was stirred, 7.5% hydrogen peroxide water (1.4g, 3.1mmol) was added at 28 ℃ over 10 hours. The reaction initiation time was defined as the time at which the addition of 7.5% hydrogen peroxide solution was initiated, and after 12 hours from the initiation of the reaction, 7.5% hydrogen peroxide solution (0.1g, 0.2mmol) was additionally added at 28 ℃. Stirring was then continued at 28 ℃ for 14 hours calculated from the reaction start time. After completion of the reaction, methylene chloride (6mL) and distilled water (6mL) were added to the reaction mixture to separate the organic phases, and the organic phases extracted from the aqueous phase with methylene chloride (6mL) were combined, and the concentrated crude product was purified by column chromatography to obtain a yellow oily compound (VIII') (0.65g, yield 99%, optical purity 99.9% ee or more).
Analysis conditions were as follows: column name CHIRALPAK AD-RH, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 3.9 min, enantiomer: 9.3 min, measurement wavelength: 254nm.
1H-NMR(CDCl3)δ；1.30(s，3H)，1.65(s，3H)，2.19(s，3H)，2.62(d，J＝0.8Hz，3H)，3.61(d，J＝4.4Hz，1H)，4.15(d，J＝4.4Hz，1H)，5.30(s，2H)，7.26(s，1H)，7.32(s，1H)，8.10(s，1H)
Example 20
(3R＊，4R＊) - (3, 4-epoxy-2, 2, 9-trimethyl-3, 4-dihydro-2H-pyrano [2, 3-g)]Synthesis of quinolin-7-yl-methyl acetate (Compound (VIII))
To a dichloromethane solution (1.2mL) of optically active titanium Salan complex (D) (6.2mg, 0.006mmol) (5.0 mol% based on the substrate) was added (2, 2, 9-trimethyl-2H-pyrano [2, 3-g ] quinolin-7-yl) -methyl acetate (34.2mg, 0.12mmol) at 28 ℃, and 30% aqueous hydrogen peroxide (8.5mg, 0.075mmol) was added at 28 ℃ over 1 second while stirring the reaction solution. The reaction initiation time was defined as the initiation time of the addition of 30% hydrogen peroxide solution, and 20 minutes after the initiation of the reaction, 30% hydrogen peroxide solution (8.5mg, 0.075mmol) was added at 28 ℃ over 1 second. Then, stirring was continued at 28 ℃ and after 3 hours, the reaction solution was sampled and analyzed for the conversion by HPLC. The conversion into the compound (VIII) was 80%, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 10.2 min, enantiomer: 4.1 min, measurement wavelength: 254nm.
Example 21
(3R＊，4R＊) - (3, 4-epoxy-2, 2, 9-trimethyl-3, 4-dihydro-2H-pyrano [2, 3-g)]Synthesis of quinolin-7-yl-methyl-acetic acid esters (compounds (VIII') in which r represents the relative configuration)
To a solution of optically active titanium Salan complex (E) (48mg, 0.040mmol) (2.0 mol% based on the substrate) in methylene chloride (4mL) was added (2, 2, 9-trimethyl-2H-pyrano [2, 3-g ] quinolin-7-yl) -methyl acetate (0.595g, 2.0mmol) at 20 ℃. 30% hydrogen peroxide water (0.34g, 3.0mmol) was divided into 3 portions, and the 1 st addition was performed at 20 ℃ while stirring the reaction solution, the 2 nd addition was performed after 30 minutes, and the 3 rd addition was performed after 1 hour. The 1 st addition time of 30% hydrogen peroxide water was taken as a reaction start time, and then stirring was continued at 20 ℃ for 24 hours calculated from the reaction start time. After completion of the reaction, methylene chloride (5mL) and distilled water (5mL) were added to the reaction mixture, the organic phase was separated, the organic phases obtained by 2 extractions from the aqueous phase with methylene chloride (5mL, 3mL) were combined, and the concentrated crude product was purified by column chromatography to obtain yellow powdery compound (VIII') (0.61g, yield 97%, optical purity 99.3% ee).
Analysis conditions were as follows: column name CHIRALPAKAD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 11.2 min, enantiomer: 26.6 minutes, measurement wavelength: 320nm.
1H-NMR(CDCl3)δ；1.30(s，3H)，1.65(s，3H)，2.19(s，d，J＝1.9Hz，3H)，2.60(s，3H)，3.60(dd，J＝4.5Hz，1.9Hz，1H)，4.14(d，J＝4.5Hz，1H)，5.30(s，2H)，7.25(s，1H)，7.31(s，1H)，8.10(s，1H)
Example 22
(3S＊，4S＊) -7-chloro-3, 4-epoxy-2, 2, 9-trimethyl-3, 4-dihydro-2H-pyrano [2, 3-g]Synthesis of quinoline (Compound (IX) < CHEM > represents a relative configuration)
Or
To a solution of optically active titanium Salan complex (F) (120mg, 0.10mmol) (10 mol% relative to the substrate) in methylene chloride (2mL) was added 7-chloro-2, 2, 9-trimethyl-2H-pyrano [2, 3-g ] quinoline (0.26g, 1.0mmol) at 20 ℃. 30% hydrogen peroxide water (0.17g, 1.5mmol) was divided into 3 portions, and the 1 st addition was performed at 20 ℃ while stirring the reaction solution, so that the 2 nd addition was performed after 30 minutes, and the 3 rd addition was performed after 1 hour. The time of addition of the 1 st 30% hydrogen peroxide solution was defined as the reaction start time, and stirring was continued at 20 ℃ for 26 hours after the start of the reaction. After completion of the reaction, methylene chloride (5mL) and distilled water (5mL) were added to the reaction mixture, the organic phase was separated, the organic phases obtained by 2 extractions from the aqueous phase with methylene chloride (5mL, 3mL) were combined, and the concentrated crude product was purified by column chromatography to obtain compound (IX) (0.21g, yield 77%, optical purity 99.9% ee or more) as a pale yellow powder.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 42.1 min, enantiomer: 21.7 minutes, measurement wavelength: 220nm.
1H-NMR(CDCl3)δ；1.30(s，3H)，1.64(s，3H)，2.56(s，3H)，3.61(d，J＝4.2Hz，1H)，4.13(d，J＝4.2Hz，1H)，7.15(s，1H)，7.27(s，1H)，8.00(s，1H)
Example 23
(3R＊，4R＊) -7-chloro-3, 4-epoxy-2, 2, 9-trimethyl-3, 4-dihydro-2H-pyrano [2, 3-g]Synthesis of quinoline (Compound (IX'), wherein R represents a relative configuration)
Is shown by formula (44)To a solution of the Salan ligand (27mg, 0.050mmol) (10 mol% relative to the substrate) in methylene chloride (0.5mL) was added titanium tetraisopropoxide [ Ti (Oi-Pr) at 20 deg.C4](2.8mg, 0.010 mmol). After stirring at 20 ℃ for 1 hour, 7-chloro-2, 2, 9-trimethyl-2H-pyrano [2, 3-g ] was added]Quinoline (0.130g, 0.50mmol) and dichloromethane (1 mL). 30% hydrogen peroxide water (0.085g, 0.75mmol) was divided into 3 portions, and the 1 st addition was made at 20 ℃ while stirring the reaction solution, the 2 nd addition was made after 30 minutes, and the 3 rd addition was made after 1 hour. The time of addition of the 1 st 30% hydrogen peroxide solution was defined as the reaction initiation time, and after the initiation of the reaction, the reaction solution was stirred at 20 ℃ for 45 hours, after which the reaction solution was sampled and analyzed for the reaction conversion by HPLC. The conversion into the compound (IX') was 99% or more, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 6/4(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 21.7 min, enantiomer: 42.1 min, measurement wavelength: 220nm.
Example 24
(3S＊，4S＊) Synthesis of (E) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-dimethanesulphonylamino-6-methoxy-2H-1-benzopyran (in the compound (X) the symbols represent the relative configuration)
Or
To a solution of optically active titanium Salan complex (F) (12mg, 0.010mmol) (2.0 mol% relative to the substrate) in methylene chloride (1mL) was added 2, 2-dimethyl-7-dimethanesulfonylamino-6-methoxy-2H-1-benzopyran (0.18g, 0.50mmol) at 20 ℃. 30% hydrogen peroxide water (0.085g, 0.75mmol) was divided into 3 portions, and the 1 st addition was made at 20 ℃ while stirring the reaction solution, the 2 nd addition was made after 30 minutes, and the 3 rd addition was made after 1 hour. After the reaction was started by stirring at 20 ℃ for 30 hours with the time of addition of the 1 st 30% hydrogen peroxide solution as the reaction start time, dichloromethane (2mL) and distilled water (2mL) were added to the reaction solution to separate the organic phase, the organic phases obtained by 2 extractions from the aqueous phase with dichloromethane (2mL, 1mL) were combined, and the concentrated crude product was purified by column chromatography to obtain a white powdery compound (X) (0.18g, yield 97.5%, optical purity 99%).
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 3/7(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 19.8 min, enantiomer: 18.6 min, measurement wavelength: 320nm.
1H-NMR(CDCl3)δ；1.26(s，3H)，1.55(s，3H)，3.35(s，3H)，3.42(s，3H)，3.49(d，J＝4.5Hz，1H)，3.88(s，3H)，3.88(d，J＝4.5Hz，1H)，6.77(s，1H)，7.00(s，1H)
Example 25
(3R＊，4R＊) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-dimethanesulfonylamino-6-methoxy-2H-1-benzopyran (Compound (X'))*Representing a relative configuration) of the corresponding compounds
To a solution of optically active titanium Salan complex (E) (12mg, 0.010mmol) (2.0 mol% relative to the substrate) in methylene chloride (1mL) was added 2, 2-dimethyl-7-dimethanesulfonylamino-6-methoxy-2H-1-benzopyran (72mg, 0.20mmol) at 20 ℃. 30% hydrogen peroxide water (0.034g, 0.30mmol) was divided into 3 portions, and the 1 st addition was made at 20 ℃ while stirring the reaction solution, the 2 nd addition was made after 30 minutes, and the 3 rd addition was made after 1 hour. The reaction was started by adding 30% hydrogen peroxide solution at the 1 st time, and after the reaction was started, the reaction mixture was stirred at 20 ℃ for 48 hours, and then the reaction mixture was sampled and analyzed for the conversion by HPLC. The conversion into the compound (X') was 99%, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 3/7(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 18.5 min, enantiomer: 20.0 min, measurement wavelength: 320nm.
Example 26
(3S＊，4S＊) Synthesis of (E) -3, 4-epoxy-3, 4-dihydro-2, 2-dimethyl-7-dimethanesulfonylamino-6-methoxy-2H-1-benzopyran (compound (X): relative configuration)
To a solution of optically active titanium Salalen complex (C) (16mg, 0.010mmol) (2.0 mol% relative to the substrate) in methylene chloride (0.5mL) was added 2, 2-dimethyl-7-dimethanesulfonamido-6-methoxy-2H-1-benzopyran (72mg, 0.20mmol) at 20 ℃. 30% hydrogen peroxide water (0.034g, 0.30mmol) was divided into 3 portions, and the 1 st addition was made at 20 ℃ while stirring the reaction solution, the 2 nd addition was made after 30 minutes, and the 3 rd addition was made after 1 hour. The time of addition of the 1 st 30% hydrogen peroxide solution was defined as the reaction initiation time, and after the reaction was initiated, the reaction solution was stirred at 20 ℃ for 24 hours, and then sampled, and the reaction conversion rate was analyzed by HPLC. The conversion into the compound (X) was 83%, and the optical purity was 99% ee.
Analysis conditions were as follows: column name CHIRALPAK AD-RH 3-ligation, eluent: acetonitrile/20 mM (pH8) phosphate buffer 3/7(v/v), flow rate: 1.0mL/min, column temperature 40 ℃, retention time of the reaction product: 19.8 min, enantiomer: 18.6 min, measurement wavelength: 320nm.
Industrial applicability
According to the present invention, an optically active chromene oxide compound having a high optical purity of 99% ee or more can be obtained in a high yield of 90% or more without using a separation procedure for optically separating a target substance, and can be sufficiently used as an important intermediate of a benzopyran compound effective for the treatment of arrhythmia. Therefore, the present invention is industrially useful.

Claims (3)

1. A process for producing an optically active chromene oxide compound represented by formula (14) or formula (15), which comprises subjecting a chromene compound represented by formula (10) or formula (11) to asymmetric epoxidation with hydrogen peroxide water in a halogen-based solvent using an optically active titanium complex represented by either formula (2) or formula (2') as a catalyst,
r in the formulae (2) and (2')1Represents a phenyl group, and is represented by,
the phenyl group may be substituted by C1-4Alkyl radical, C1-7Alkoxy or benzyloxy being optionally substituted, the C1-4The alkyl group may be optionally substituted with a halogen atom,
R2represents a hydrogen atom, and is represented by,
at 2R3When they form a ring together, R3Is represented by C4The divalent group of (a) is,
R4each independently represents a hydrogen atom, and each independently represents a hydrogen atom,
m represents TiJ1J2At TiJ1J2In which Ti represents a titanium atom, J1And J2Form a ring together, represent formula (5) as a divalent group,
regarding the partial structure O-E-O in the formula, O represents an oxygen atom, and in the formula (2), O-E-O is represented by the following formula (7); in the formula (2 '), the O-E-O is represented by the following formula (7');
b represents 1, R1、R2、R3And R4The same as above;
r in the formula (10)5、R6、R7And R8Each independently represent
A hydrogen atom;
a nitro group;
a halogen atom;
C1-4an alkoxy group;
C1-4an alkylcarbonylamino group; or
Bis (C)1-4Alkylsulfonyl) imino;
r in the formula (10)9And R10Each independently represents C1-6An alkyl group;
r in the formula (11)9And R10Each independently represents C1-6An alkyl group;
the partial ring structure A in the formula (11) is represented by the formula(s)
In the formula(s), R14、R15And R16Each independently represent
A hydrogen atom;
a halogen atom; or
C1-6Alkyl, which may be substituted by C1-6Alkylcarbonyloxy optionally substituted;
in the formula R5、R6、R7、R8、R9、R10And A is the same as above, and the absolute configuration of the carbon atom represented by (A) is (R) or (S).
2. The method for producing an optically active chromene oxide compound according to claim 1, wherein the optically active titanium complex represented by any one of the formulae (2) and (2') is used as a catalyst, and the chromene compound represented by the formula (10) is subjected to asymmetric epoxidation with hydrogen peroxide water in a halogen-based solvent,
r in the above formula (10)5And R6Each independently represent
A hydrogen atom;
a nitro group;
a halogen atom;
C1-4an alkoxy group; or
C1-4An alkylcarbonylamino group, a carbonyl amino group,
r in the formula (10)7To represent
A hydrogen atom;
a nitro group; or
Bis (C)1-4Alkyl sulfonyl) imide group(s),
r in the formula (10)8Represents a hydrogen atom or a nitro group,
r in the formula (10)9And R10Is represented by C1-6An alkyl group.
3. The process for producing an optically active chromene oxide compound according to claim 2, wherein R in the formula (10)5And R6Each independently represents a hydrogen atom, a nitro group, a fluorine atom, a methoxy group or a methylcarbonylamino group, R in the formula (10)7Represents a hydrogen atom, a nitro group or a bis (C)1-4Alkylsulfonyl) imino group, R in the formula (10)8Represents a hydrogen atom or a nitro group, R in the formula (10)9And R10Represents a methyl group.
HK09106017.7A 2006-03-10 2007-03-09 Process for producing optically active chromene oxide compound HK1128288B (en)

Applications Claiming Priority (5)

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JP2006066818 2006-03-10
JP066818/2006 2006-03-10
JP084285/2006 2006-03-24
JP2006084285 2006-03-24
PCT/JP2007/054730 WO2007105658A1 (en) 2006-03-10 2007-03-09 Process for producing optically active chromene oxide compound

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HK1128288A1 HK1128288A1 (en) 2009-10-23
HK1128288B true HK1128288B (en) 2013-01-25

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