CN101437827B

CN101437827B - Process for producing optically active chromene oxide compound

Info

Publication number: CN101437827B
Application number: CN2007800165479A
Authority: CN
Inventors: 近藤章一; 猿桥康一郎; 渡边久幸; 香月勗
Original assignee: Nissan Chemical Corp
Current assignee: Nissan Chemical Corp
Priority date: 2006-03-10
Filing date: 2007-03-09
Publication date: 2012-08-29
Anticipated expiration: 2027-03-09
Also published as: CN101437827A; UA94449C2; ZA200808177B

Abstract

To provide an efficient process for producing an optically active chromene oxide compound which is an important intermediate for a benzopyran compound effective in the treatment of arrhythmia. [MEANS FOR SOLVING PROBLEMS] The process for producing an optically active chromene oxide compound comprises using an optically active titanium complex represented by, e.g., the formula (1) or (2) as a catalyst to asymmetrically oxidize an optically active chromene compound with high enantioselectivity in high chemical yield.

Description

The method of manufacture of optically active chromene oxide compound

Technical field

The present invention relates to the efficient method of manufacture of conduct to the optically active chromene oxide compound of the important intermediate of the effective benzopyran compounds of ARR treatment.

Background technology

Benzopyran compounds and method of manufacture thereof as anti-arrhythmic is useful are open.That is, benzopyran compounds is after the optical activity manganese complex being carried out asymmetric Epoxidation formation optically active chromene oxide compound with chromene compounds, makes epoxy addition with amine compound, makes (with reference to patent documentation 1).

Through making chromene compounds carry out the method that asymmetric Epoxidation is made optically active chromene oxide compound, be disclosed (with reference to patent documentation 2, patent documentation 3, patent documentation 4, patent documentation 5 and patent documentation 6) with the optical activity manganese complex.In above-mentioned patent documentation, put down in writing,, used the optical activity manganese complex,, used the manufacturing example of the optically active chromene oxide compound of iodosobenzene, Youxiaolin or 30% aquae hydrogenii dioxidi as co-oxidants as catalyzer.

In the asymmetric oxidation reaction that utilizes the optical activity manganese complex to carry out; Except co-oxidants; The additive that also need be called as the 4-phenylpyridine-N-oxide compound etc. of a part, expectation utilization do not use the method for manufacture of the optically active chromene oxide compound that other method of a part carries out.

Put down in writing on the other hand; Through using asymmetrical optical activity manganese complex; Even the usage quantity of 0.01～0.2 mole of % also can be with the method (with reference to patent documentation 7) of high chemical yield and optical yield manufacturing optically active chromene oxide compound, in the document; Only put down in writing and used the example of iodosobenzene, favourable efficient method of manufacture therefore and then in industry as co-oxidants.

Reported in the optical activity titanium complex, two-μ-oxygen titanium Salalen complex compound, with aquae hydrogenii dioxidi as oxygenant, do not have in the asymmetric epoxidation reaction of heteroatomic various simple alkene, react with the high antimer selectivity.But, about heteroatomic olefin(e) compound and chromene compounds are arranged, not report example (non-patent literature 8).

Patent documentation 1: the spy opens the 2001-151767 communique

Patent documentation 2: the spy opens flat 05-301878 communique

Patent documentation 3: the spy opens flat 07-285983 communique

Patent documentation 4: the spy opens flat 08-245668 communique

Patent documentation 5:WO2005/090357A1

Patent documentation 6:WO2005/080368A2

Patent documentation 7: the spy opens flat 11-335384 communique

Non-patent literature 8:K.Matsumoto, Y.Sawada, B.Saito, K.Sakai, T.Katsuki, Angew.Chem.Int.Ed. (2005), 44,4935-4939.

Summary of the invention

The present invention provides the method for manufacture of conduct to the optically active chromene oxide compound of the important intermediate of the effective benzopyran compounds of ARR treatment.

Present inventors further investigate the method for manufacture of the optically active chromene oxide compound of the important intermediate of the effective benzopyran compounds of ARR treatment conduct; The result finds; Through utilizing the optical activity titanium complex as catalyzer; Can the high antimer selectivity and high chemical yield make optically active chromene oxide compound, thereby accomplished the present invention.

In the present invention; As the 1st scheme, be the method for manufacture of the optically active chromene oxide compound shown in formula (14), formula (15), formula (16) or the formula (17), it is characterized in that; Optical activity titanium complex shown in any one of use formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') is as catalyzer; Chromene compounds shown in formula (10), formula (11), formula (12) or the formula (13) in solvent, is carried out asymmetric Epoxidation with oxygenant

(the R in formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ¹Expression Wasserstoffatoms, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, C _6-12Aryloxy or C _6-22(this aryl can be by C for aryl _1-4Alkyl (this alkyl can be replaced arbitrarily by halogen atom), C _1-7Alkoxyl group or benzyl oxygen base replace arbitrarily, are optical activity or non-optical activity),

R ²Expression Wasserstoffatoms, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, C _6-12Aryloxy or C _6-18Aryl,

R ³Expression C _1-4Alkyl, C _6-18Aryl, perhaps, at 2 R ³Form under the situation of ring expression C together _3-5The group of divalence,

R ⁴Represent Wasserstoffatoms, halogen atom, C respectively independently _1-4Alkyl, C _1-4Alkoxyl group, nitro or cyanic acid,

M representes TiJ ¹J ²(at TiJ ¹J ²In, Ti representes titanium atom, J ¹And J ²Represent halogen atom, C respectively independently _1-4Alkoxyl group, perhaps J ¹With J ²Represent Sauerstoffatom together, perhaps J ¹With J ²Form ring together, expression is as the formula (5) of the group of divalence

(about the part-structure O-E-O in the formula, wherein, O representes Sauerstoffatom, in formula (1), as O-E-O, is represented by following formula (6); In formula (1 '),, represent by following formula (6 ') as O-E-O; In formula (2),, represent by following formula (7) as O-E-O; In formula (2 '),, represent by following formula (7 ') as O-E-O; In formula (3),, represent by following formula (8) as O-E-O; In formula (3 '),, represent by following formula (8 ') as O-E-O; In formula (4),, represent by following formula (9) as O-E-O; In formula (4 '), as O-E-O, by following formula (9 ') expression,

B representes 1～10 integer, R ¹, R ², R ³And R ⁴Same as described above));

(the R in the formula (10) ⁵, R ⁶, R ⁷And R ⁸Represent Wasserstoffatoms, cyanic acid, nitro, halogen atom, C respectively independently _1-4(this alkyl can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkyl _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4(this alkoxyl group can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkoxyl group _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4(this alkyl-carbonyl-amino can be by halogen atom, C for alkyl-carbonyl-amino _6-10Aryl (this C _6-10Aryl can be by halogen atom, hydroxyl, cyanic acid, nitro, C _1-4Alkyl or C _1-4Alkoxyl group replaces arbitrarily) replace arbitrarily), C _1-4Alkyl-carbonyl (N-C _1-4Alkyl) amino (this alkyl-carbonyl (N-alkyl) amino can be replaced arbitrarily by halogen atom), C _1-4Alkoxy carbonyl (this alkoxy carbonyl can be replaced arbitrarily by halogen atom), C _6-10(this aryl-amino-carbonyl can be by halogen atom, C for aryl-amino-carbonyl _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), C _6-10Aryl carbonyl (N-C _1-4It is alkyl) amino that (this aryl carbonyl (N-alkyl) amino can be by halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), benzyloxycarbonyl group amino, formyl radical, formamyl, C _1-4Alkyl sulphonyl, C _6-10(this alkyl sulphonyl and aryl sulfonyl can be by halogen atom, C for aryl sulfonyl _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), sulfamyl, C _1-4Alkylsulfonamido, C _6-10(this alkylsulfonamido and aryl-sulfonyl amino can be by halogen atom, C for aryl-sulfonyl amino _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), two (C _1-4Alkyl sulfonyl) (alkyl sulfonyl of this pair (alkyl sulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), two (C _6-10Arylsulfonyl) (arylsulfonyl of this pair (arylsulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), [N, N '-(C _1-4Alkyl sulfonyl) (C _6-10Arylsulfonyl)] (alkyl sulfonyl and the arylsulfonyl that are somebody's turn to do [N, N '-(alkyl sulfonyl) (arylsulfonyl)] imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace);

R in the formula (10) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily), C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily);

R in formula (11) and the formula (12) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily);

Part ring structure A in formula (11) and the formula (12) is 5,6 or 7 Yuans part-structures that ring is represented that partly form condensed ring with phenyl ring, and wherein, these 5,6 or 7 Yuans rings can be by h R ¹¹(R ¹¹Be halogen atom, hydroxyl, C _1-6(this alkyl can be by halogen atom, hydroxyl, cyanic acid, amino, nitro, C for alkyl _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino or C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-6(this alkoxyl group can be by halogen atom, hydroxyl, cyanic acid, amino, nitro, C for alkoxyl group _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino or C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), nitro, cyanic acid, formyl radical, formamido-, formamyl, sulfo group, sulfoamino-, sulfamyl, alkylsulfonyl, amino, carboxyl, C _1-6Alkylamino, two C _1-6Alkylamino, C _1-6Alkyl-carbonyl-amino, C _1-6Alkylsulfonamido, C _6-14Aryl-sulfonyl amino, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl, C _6-14Aryl sulfonyl or C _6-14Aryl carbonyl (this alkylamino, dialkyl amido, alkyl-carbonyl-amino, alkylsulfonamido, aryl-sulfonyl amino, alkyl amino-carbonyl, dialkyl amino carbonyl, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl and aryl carbonyl can be replaced arbitrarily by halogen atom); H is 1～6 integer; Be under 2～6 the situation at h, R ¹¹Can be the same or different) replace arbitrarily; Constituting atom as ring can contain 1～3 Sauerstoffatom, nitrogen-atoms or sulphur atom, the number of intra-annular unsaturated link(age) alone or in combination; The unsaturated link(age) that comprises the phenyl ring of condensation; Be 1,2 or 3, the carbon atom that constitutes ring can be carbonyl or thiocarbonyl

X in the formula (13) representes NR ²⁰(R ²⁰Expression Wasserstoffatoms or C _1-4Alkyl),

Y in the formula (13) representes Direct Bonding, SO or SO ₂,

Z in the formula (13) representes C _1-4(this alkyl can (this phenyl can be by C by 1～5 halogen atom or phenyl for alkyl _1-4Alkyl replaces arbitrarily) replace arbitrarily) or phenyl (this phenyl can be by C _1-4Alkyl replaces arbitrarily),

W in the formula (13) representes Wasserstoffatoms, hydroxyl, C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), halogen atom, C _1-4Alkyl or C _1-6Alkylsulfonamido (this alkyl and alkylsulfonamido can be replaced arbitrarily by halogen atom),

R in the formula (13) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily)),

(R in the formula ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, A, W, X, Y and Z be same as described above, ^*The absolute configuration of institute's marked carbon atoms is (R) or (S));

As the 2nd scheme; It is method of manufacture according to the described optically active chromene oxide compound of the 1st scheme; It is characterized in that, use the optical activity titanium complex shown in any one of above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') as catalyzer, with the chromene compounds shown in the above-mentioned formula (10) in solvent; Carry out asymmetric Epoxidation with oxygenant

R in the above-mentioned formula (10) ⁵And R ⁶Represent Wasserstoffatoms, cyanic acid, nitro, halogen atom, C respectively independently _1-4(this alkyl can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkyl _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4(this alkoxyl group can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkoxyl group _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4Alkyl-carbonyl-amino (this alkyl-carbonyl-amino can be replaced arbitrarily by halogen atom), C _1-4Alkyl-carbonyl (N-C _1-4Alkyl) amino (this alkyl-carbonyl (N-alkyl) amino can be replaced arbitrarily by halogen atom) C _6-10Aryl carbonyl (N-C _1-4It is alkyl) amino that (this aryl carbonyl (N-alkyl) amino can be by halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), formamyl, two (C _1-4Alkyl sulfonyl) (alkyl sulfonyl of this pair (alkyl sulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), two (C _6-10Arylsulfonyl) (arylsulfonyl of this pair (arylsulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace) or [N, N '-(C _1-4Alkyl sulfonyl) (C _6-10Arylsulfonyl)] (alkyl sulfonyl and the arylsulfonyl that are somebody's turn to do [N, N '-(alkyl sulfonyl) (arylsulfonyl)] imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace),

R in the formula (10) ⁷Expression Wasserstoffatoms, cyanic acid, nitro, two (C _1-4Alkyl sulfonyl) (alkyl sulfonyl of this pair (alkyl sulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), two (C _6-10Arylsulfonyl) (arylsulfonyl of this pair (arylsulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace) or [N, N '-(C _1-4Alkyl sulfonyl) (C _6-10Arylsulfonyl)] (alkyl sulfonyl and the arylsulfonyl that are somebody's turn to do [N, N '-(alkyl sulfonyl) (arylsulfonyl)] imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace),

R in the formula (10) ⁸Expression Wasserstoffatoms, nitro or C _1-4Alkyl (this alkyl can be replaced arbitrarily by halogen atom),

R in the formula (10) ⁹And R ¹⁰Expression C _1-6Alkyl (this alkyl can be replaced arbitrarily by halogen atom);

As the 3rd scheme, be method of manufacture according to the described optically active chromene oxide compound of the 2nd scheme, the R in the above-mentioned formula (10) ⁵And R ⁶Represent Wasserstoffatoms, nitro, fluorine atom, methoxyl group, methyl carbonylamino or methyl carbonyl (N-ethyl) amino respectively independently, the R in the formula (10) ⁷Expression Wasserstoffatoms, nitro or two (C _1-4Alkyl sulfonyl) imido grpup, the R in the formula (10) ⁸Expression Wasserstoffatoms, nitro or trifluoromethyl, the R in the formula (10) ⁹And R ¹⁰The expression methyl;

As the 4th scheme; It is method of manufacture according to the described optically active chromene oxide compound of the 1st scheme; It is characterized in that, use the optical activity titanium complex shown in any one of above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') as catalyzer, with the chromene compounds shown in above-mentioned formula (11) or the formula (12) in solvent; Carry out asymmetric Epoxidation with oxygenant

The part ring structure of A in above-mentioned formula (11) or the formula (12) is by 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), any one expression of 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)

(above-mentioned 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), the R in formula (w), formula (x), formula (ab), formula (ae), formula (af) and the formula (ag) ¹²And R ¹³Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, hydroxyl, C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by q R for heteroaryl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily), C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl oxygen base, C _1-6Alkyl-carbonyl (this alkyl-carbonyl oxygen base and alkyl-carbonyl can be replaced arbitrarily by halogen atom), C _1-6Alkyl-carbonyl-amino, C _3-8Naphthene base carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl (this naphthene base carbonyl, alkoxy carbonyl and alkyl sulphonyl can be replaced arbitrarily by halogen atom), carboxyl, C _6-14Aryl carbonyl (this aryl carbonyl can be replaced arbitrarily by halogen atom) or C _2-9The heteroaryl carbonyl replaces arbitrarily), C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by q R for heteroaryl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily), C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _3-8Naphthene base carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl, C _6-14Aryl sulfonyl, C _2-9(this aryl sulfonyl and heteroarylsulfonyl can be by q R for heteroarylsulfonyl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily), carboxyl, C _6-14Aryl carbonyl or C _2-9(this aryl carbonyl and heteroaryl carbonyl can be by q R for the heteroaryl carbonyl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily),

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), the R in formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and the formula (af) ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Represent Wasserstoffatoms, halogen atom, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, hydroxyl, C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by r R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl oxygen base, C _1-6Alkyl-carbonyl (this alkyl-carbonyl oxygen base and alkyl-carbonyl can be replaced arbitrarily by halogen atom), C _1-6Alkyl-carbonyl-amino, C _3-8Naphthene base carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl (this naphthene base carbonyl, alkoxy carbonyl and alkyl sulphonyl can be replaced arbitrarily by halogen atom), carboxyl, C _6-14Aryl carbonyl (this aryl carbonyl can be replaced arbitrarily by halogen atom) or C _2-9The heteroaryl carbonyl replaces arbitrarily), C _3-8(this naphthenic base can be by halogen atom, C for naphthenic base _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino or hydroxyl replace arbitrarily), C _1-6(this alkoxyl group can be by halogen atom, C for alkoxyl group _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), carboxyl, amino, hydroxyl, C _6-14Aryl or C _2-9(this aryl and heteroaryl can be by r R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily) replace arbitrarily), C _1-6(this thio alkoxy can be by halogen atom, C for thio alkoxy _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), carboxyl, hydroxyl, C _6-14Aryl or C _2-9(this aryl and heteroaryl can be by r R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily) replace arbitrarily), hydroxyl, C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by r R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkyl-carbonyl oxygen base, nitro, cyanic acid, formyl radical, formamido-, amino, sulfo group, C _1-6Alkylamino, two C _1-6Alkylamino, C _6-14Arylamino, C _2-9(this arylamino and heteroaryl amino can be by r R for heteroaryl amino ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkyl-carbonyl-amino, C _1-6Alkylsulfonamido, formamyl, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _6-14Aryl carbonyl, C _2-9(this aryl carbonyl and heteroaryl carbonyl can be by r R for the heteroaryl carbonyl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkoxy carbonyl, sulfamyl, C _1-6Alkyl sulphonyl, C _6-14Aryl sulfonyl, C _2-9(this aryl sulfonyl and heteroarylsulfonyl can be by r R for heteroarylsulfonyl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), carboxyl or C _2-9(this heterocyclic radical can be by halogen atom, C for heterocyclic radical _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, carboxyl or hydroxyl replace arbitrarily), C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by r R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), hydroxyl, nitro, cyanic acid, formyl radical, formamido-, amino, C _1-6Alkylamino, two C _1-6Alkylamino, C _1-6Alkyl-carbonyl-amino, C _1-6Alkylsulfonamido, formamyl, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, sulfamyl, C _1-6Alkyl sulphonyl, carboxyl or C _6-14Aryl carbonyl replaces arbitrarily),

(v), the Q in formula (w), formula (ab), formula (ac) and the formula (ad) representes O (Sauerstoffatom), S (sulphur atom), SO (sulfinyl) or SO for above-mentioned formula (c), formula (d), formula (p), formula (q), formula ₂(alkylsulfonyl));

As the 5th scheme, be method of manufacture according to the described optically active chromene oxide compound of the 4th scheme, the R in above-mentioned formula (11) or the formula (12) ⁹And R ¹⁰It is methyl;

As the 6th scheme; It is method of manufacture according to the 4th scheme or the described optically active chromene oxide compound of the 5th scheme; A in above-mentioned formula (11) or the formula (12) is by 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) expression

(in the formula, R ¹², R ¹³, R ¹⁴, R ¹⁵And R ¹⁶Identical with the record in the 4th scheme);

As the 7th scheme; It is method of manufacture according to the described optically active chromene oxide compound of the 6th scheme; A in above-mentioned formula (11) or the formula (12) representes above-mentioned 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)

Formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), the R in formula (ae) and the formula (ag) ¹²And R ¹³Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino or hydroxyl replace arbitrarily), formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), the R in formula (y) and the formula (ae) ¹⁴, R ¹⁵And R ¹⁶Represent Wasserstoffatoms, halogen atom or C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, hydroxyl, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl oxygen base, C _1-6Alkyl-carbonyl (this alkyl-carbonyl oxygen base and alkyl-carbonyl can be replaced arbitrarily by halogen atom), C _1-6Alkyl-carbonyl-amino, C _3-8Naphthene base carbonyl or C _1-6Alkoxy carbonyl replaces arbitrarily), Q representes O (Sauerstoffatom);

As the 8th scheme; It is method of manufacture according to the described optically active chromene oxide compound of the 7th scheme; A expression (a) in above-mentioned formula (11) or the formula (12), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), formula (y), formula (ae), formula (ag) or formula (ah), formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), the R in formula (ae) and the formula (ag) ¹²And R ¹³Represent Wasserstoffatoms, methyl respectively independently, formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), the R in formula (y) and the formula (ae) ¹⁴, R ¹⁵And R ¹⁶Represent Wasserstoffatoms, halogen atom or C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, hydroxyl, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl oxygen base, C _1-6Alkyl-carbonyl (this alkyl-carbonyl oxygen base and alkyl-carbonyl can be replaced arbitrarily by halogen atom), C _1-6Alkyl-carbonyl-amino, C _3-8Naphthene base carbonyl or C _1-6Alkoxy carbonyl replaces arbitrarily), Q representes O (Sauerstoffatom);

As the 9th scheme; It is method of manufacture according to the described optically active chromene oxide compound of the 1st scheme; It is characterized in that, use the optical activity titanium complex shown in any one of above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') as catalyzer, with the chromene compounds shown in the above-mentioned formula (13) in solvent; Carry out asymmetric Epoxidation with oxygenant, the R in the above-mentioned formula (13) ⁹And R ¹⁰All represent methyl;

As the 10th scheme, be method of manufacture according to the described optically active chromene oxide compound of the 9th scheme, the W in the above-mentioned formula (13) representes Wasserstoffatoms, hydroxyl, methoxyl group, chlorine atom, bromine atoms, methyl, ethyl or methylsulfonyl amido;

As the 11st scheme, be that the Y in the above-mentioned formula (13) representes SO according to the method for manufacture of the 9th scheme or the described optically active chromene oxide compound of the 10th scheme ₂(alkylsulfonyl), Z representes C _1-4Alkyl;

As the 12nd scheme, be method of manufacture according to the described optically active chromene oxide compound of the 10th scheme, the Y in the above-mentioned formula (13) representes Direct Bonding, Z representes C _1-4Alkyl;

As the 13rd scheme, be method of manufacture according to the described optically active chromene oxide compound of the 1st scheme, the R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ¹Expression C _6-22(this aryl can be by C for aryl _1-4Alkyl (this alkyl can be replaced arbitrarily by halogen atom) C _1-7Alkoxyl group or benzyl oxygen base replace arbitrarily, are optical activity or non-optical activity),

M representes TiJ ¹J ²(at TiJ ¹J ²In, Ti representes titanium atom, J ¹And J ²Represent halogen atom, C respectively independently _1-4Alkoxyl group, J ¹With J ²Represent Sauerstoffatom together, perhaps, J ¹With J ²Form ring together, (about the part-structure O-E-O in the formula, wherein, O is a Sauerstoffatom, in formula (1), as O-E-O, is represented by above-mentioned formula (6) as the above-mentioned formula (5) of the group of divalence in expression; In formula (1 '),, represent by above-mentioned formula (6 ') as O-E-O; In formula (2),, represent by above-mentioned formula (7) as O-E-O; In formula (2 '),, represent by above-mentioned formula (7 ') as O-E-O; In formula (3),, represent by above-mentioned formula (8) as O-E-O; In formula (3 '),, represent by above-mentioned formula (8 ') as O-E-O; In formula (4),, represent by above-mentioned formula (9) as O-E-O; In formula (4 '), as O-E-O, by above-mentioned formula (9 ') expression, b is 1～10 integer, R ¹, R ², R ³And R ⁴Same as described above));

As the 14th scheme, be method of manufacture according to the described optically active chromene oxide compound of the 13rd scheme, the R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ¹(this phenyl can be by C for the expression phenyl _1-4Alkyl (this alkyl can be replaced arbitrarily by halogen atom), benzyl oxygen base or C _1-7Alkoxyl group replaces arbitrarily) or naphthyl (this naphthyl can be by C _1-4Alkyl (this alkyl can be replaced arbitrarily by halogen atom), C _1-7Alkoxyl group or phenyl replace arbitrarily),

R ²The expression Wasserstoffatoms,

R ³Represent 2 R ³Form the C of ring together _3-5The group of divalence,

R ⁴The expression Wasserstoffatoms,

M representes TiJ ¹J ²(at TiJ ¹J ²In, Ti representes titanium atom, J ¹And J ²Represent halogen atom, C respectively independently _1-4Alkoxyl group, perhaps, J ¹With J ²Represent Sauerstoffatom together, perhaps, J ¹With J ²Form ring together, (about the part-structure O-E-O in the formula, wherein, O is a Sauerstoffatom, in formula (1), as O-E-O, is represented by above-mentioned formula (6) as the above-mentioned formula (5) of the group of divalence in expression; In formula (1 '),, represent by above-mentioned formula (6 ') as O-E-O; In formula (2),, represent by above-mentioned formula (7) as O-E-O; In formula (2 '),, represent by above-mentioned formula (7 ') as O-E-O; In formula (3),, represent by above-mentioned formula (8) as O-E-O; In formula (3 '),, represent by above-mentioned formula (8 ') as O-E-O; In formula (4),, represent by above-mentioned formula (9) as O-E-O; In formula (4 '), as O-E-O, by above-mentioned formula (9 ') expression, b is 1～10 integer, R ¹, R ², R ³And R ⁴Same as described above));

As the 15th scheme; It is method of manufacture according to each described optically active chromene oxide compound of the 1st scheme～the 14th scheme; The usage quantity of optical activity titanium complex is 0.001～100 mole of % with respect to the chromene compounds shown in formula (10), formula (11), formula (12) or the formula (13);

As the 16th scheme; It is method of manufacture according to each described optically active chromene oxide compound of the 1st scheme～the 14th scheme; The solvent that uses in the asymmetric epoxidation reaction is halogen series solvent, aromatic hydrocarbons series solvent, ester series solvent, ether series solvent, nitrile series solvent, pure series solvent, the mixture of perhaps above-mentioned solvent;

As the 17th scheme; Be the method for manufacture according to each described optically active chromene oxide compound of the 1st scheme～the 14th scheme, the oxygenant that uses in the asymmetric epoxidation reaction is the mixture of iodosobenzene, Youxiaolin, metachloroperbenzoic acid, Oxone (E.I.Du Pont Company's registered trademark), aquae hydrogenii dioxidi, urea-hydrogen peroxide adduct (UHP), azepine oxygen triatomic ring (oxaziridine), N-methylmorpholine oxide compound (NMO), tertbutyl peroxide (TBHP), cumene hydroperoxide (CHP) or these oxygenants;

As the 18th scheme, be method of manufacture according to the described optically active chromene oxide compound of the 17th scheme, the oxygenant that uses in the asymmetric epoxidation reaction is the mixture of aquae hydrogenii dioxidi, urea-hydrogen peroxide adduct (UHP) or these oxygenants;

As the 19th scheme, be method of manufacture according to the described optically active chromene oxide compound of the 18th scheme, the oxygenant that uses in the asymmetric epoxidation reaction is an aquae hydrogenii dioxidi, concentration is 1～100 quality %;

As the 20th scheme; It is method of manufacture according to each described optically active chromene oxide compound of the 1st scheme～the 14th scheme; The usage quantity of the oxygenant that uses in the asymmetric epoxidation reaction is 1～10 equivalent with respect to the chromene compounds shown in above-mentioned formula (10), formula (11), formula (12) or the formula (13);

As the 21st scheme, be method of manufacture according to the described optically active chromene oxide compound of the 20th scheme, the addition means of the oxygenant that uses in the asymmetric epoxidation reaction is portion-wise addition or adds continuously;

As the 22nd scheme, be method of manufacture according to the described optically active chromene oxide compound of the 21st scheme, the addition means of the oxygenant that uses in the asymmetric epoxidation reaction is continuous interpolation, its interpolation speed per hour is 0.01～40000 equivalent;

As the 23rd scheme, be method of manufacture according to the described optically active chromene oxide compound of the 21st scheme, the addition means of the oxygenant that uses in the asymmetric epoxidation reaction is a portion-wise addition, number of times is in 2～100 scope in batches;

As the 24th scheme, be method of manufacture according to each described optically active chromene oxide compound of the 1st scheme～the 23rd scheme, the temperature of reaction of asymmetric epoxidation reaction is the reflux temperature of 0 ℃～employed solvent;

As the 26th scheme, be method of manufacture according to each described optically active chromene oxide compound of the 1st scheme～the 24th scheme, the scope of the pressure in the reaction system of asymmetric epoxidation reaction is 10kPa～1100kPa.

According to the present invention, can make the optically active chromene oxide compound of conduct efficiently to the important intermediate of the effective benzopyran compounds of ARR treatment.

Embodiment

" n " just representing in this specification sheets, and " i " expression is different, and " s " representes secondary, and " t " representes uncle, and " c " representative ring, " o " are represented adjacent, and between " m " expression, it is right that " p " representes.

Below, the present invention is elaborated.In the present invention, the titanium complex that uses as chromene compounds being carried out the catalyzer of asymmetric Epoxidation with oxygenant, with following formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') expression,

M representes TiJ ¹J ²(at TiJ ¹J ²In, Ti representes titanium atom, J ¹And J ²Represent halogen atom, C respectively independently _1-4Alkoxyl group, perhaps, J ¹With J ²Represent Sauerstoffatom together, perhaps J ¹With J ²Form ring together, expression is as the formula (5) of the group of divalence

(about the part-structure O-E-O in the formula, wherein O representes Sauerstoffatom, in formula (1), as O-E-O, is represented by following formula (6); In formula (1 '),, represent by following formula (6 ') as O-E-O; In formula (2),, represent by following formula (7) as O-E-O; In formula (2 '),, represent by following formula (7 ') as O-E-O; In formula (3),, represent by following formula (8) as O-E-O; In formula (3 '),, represent by following formula (8 ') as O-E-O; In formula (4),, represent by following formula (9) as O-E-O; In formula (4 '), as O-E-O, by following formula (9 ') expression,

B is 1～10 integer, R ¹, R ², R ³And R ⁴Same as described above))).

Below, each substituting group in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') is described.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ¹Expression Wasserstoffatoms, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, C _6-12Aryloxy or C _6-22(this aryl can be by C for aryl _1-4Alkyl (this alkyl can be replaced arbitrarily by halogen atom), C _1-7Alkoxyl group or benzyl oxygen base replace arbitrarily, are optical activity or non-optical activity).

Below, to the R in formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ¹Carry out bright specifically.

As this halogen atom, can enumerate out fluorine atom, chlorine atom, bromine atoms and iodine atom,

As this C _1-4Alkyl can be enumerated out methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl and t-butyl etc.,

As this C _1-4Alkoxyl group can be enumerated out methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, c-propoxy-, n-butoxy, i-butoxy, s-butoxy, t-butoxy and c-butoxy etc.,

As this C _6-12Aryloxy can be enumerated out phenyl oxygen base, 1-naphthyl oxygen base, 2-naphthyl oxygen base, 2-xenyl oxygen base, 3-xenyl oxygen base and 4-xenyl oxygen base etc.,

As this C _6-22(this aryl can be by C for aryl _1-4Alkyl (this alkyl can be replaced arbitrarily by halogen atom), C _1-7Alkoxyl group or benzyl oxygen base replace arbitrarily; Be optical activity or non-optical activity); Can enumerate out phenyl, 2-aminomethyl phenyl, 2-trifluoromethyl, 4-aminomethyl phenyl, 2-ethylphenyl, 2-pentafluoroethyl group phenyl, 3; 5-3,5-dimethylphenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-ethoxyl phenenyl, 2-i-propoxy-phenyl, 2-benzyl oxygen base phenyl, 3; 5-Dimethoxyphenyl, 1-naphthyl, 2-naphthyl, 2-xenyl, 3-xenyl, 4-xenyl, 2-methyl isophthalic acid-naphthyl, 2-phenyl-1-naphthyl, 2-methoxyl group-1-naphthyl, 2-[3, the 5-3,5-dimethylphenyl]-1-naphthyl, 2-[4-aminomethyl phenyl]-1-naphthyl, 2-(o-xenyl)-1-naphthyl, 2-(m-xenyl)-1-naphthyl and 2-(p-xenyl)-1-naphthyl etc.In addition, above-mentioned C _6-22Aryl can be optical activity, also can be non-optical activity.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ¹Be preferably Wasserstoffatoms, fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, c-propoxy-, n-butoxy, i-butoxy, s-butoxy, t-butoxy, c-butoxy, phenyl oxygen base, 1-naphthyl oxygen base, 2-naphthyl oxygen base, phenyl, 2-aminomethyl phenyl, 2-trifluoromethyl, 4-aminomethyl phenyl, 2-ethylphenyl, 3; 5-3,5-dimethylphenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 2-ethoxyl phenenyl, 2-i-propoxy-phenyl, 2-benzyl oxygen base phenyl, 3; 5-Dimethoxyphenyl, 1-naphthyl, 2-naphthyl, 2-xenyl, 3-xenyl, 4-xenyl, 2-phenyl-1-naphthyl, 2-methoxyl group-1-naphthyl, 2-(m-xenyl)-1-naphthyl, 2-(p-xenyl)-1-naphthyl; Wherein, R ¹More preferably phenyl, 2-aminomethyl phenyl, 2-trifluoromethyl, 2-ethylphenyl, 2-p-methoxy-phenyl, 2-benzyl oxygen base phenyl, 1-naphthyl, 2-naphthyl, 2-xenyl, 2-phenyl-1-naphthyl, 2-methoxyl group-1-naphthyl, 2-(m-xenyl)-1-naphthyl, 2-(p-xenyl)-1-naphthyl (this 2-phenyl-1-naphthyl, 2-methoxyl group-1-naphthyl, 2-(m-xenyl)-1-naphthyl or 2-(p-xenyl)-1-naphthyl are optical activity or non-optical activity); Wherein, as R ¹, further be preferably phenyl, 2-aminomethyl phenyl, 2-trifluoromethyl, 2-p-methoxy-phenyl, 2-benzyl oxygen base phenyl, 2-phenyl-1-naphthyl.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ²Expression Wasserstoffatoms, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, C _6-12Aryloxy or C _6-18Aryl.

To the R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ²Specify.

As this C _1-4Alkyl can be enumerated out methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl and the tertiary butyl etc.,

As this C _6-18Aryl; Can enumerate out phenyl, 3; 5-3,5-dimethylphenyl, 4-aminomethyl phenyl, 1-naphthyl, 2-naphthyl, 2-xenyl, 2-phenyl-1-naphthyl, 2-methyl isophthalic acid-naphthyl, 2-[3, the 5-3,5-dimethylphenyl]-1-naphthyl, 2-[4-aminomethyl phenyl]-1-naphthyl and 2-methoxyl group-1-naphthyl etc.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ²Be preferably Wasserstoffatoms, fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl group, i-propyl group, n-butyl, the tertiary butyl, methoxyl group, phenyl oxygen base, 1-naphthyl oxygen base, 2-naphthyl oxygen base, phenyl, 3; 5-3,5-dimethylphenyl, 4-aminomethyl phenyl, 3; 5-Dimethoxyphenyl, 4-p-methoxy-phenyl, 1-naphthyl, 2-naphthyl, 2-xenyl, 3-xenyl, 4-xenyl, 2-methoxyl group-1-naphthyl, wherein, R ²More preferably Wasserstoffatoms, fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl group, i-propyl group, n-butyl, the tertiary butyl, methoxyl group, phenyl oxygen base, phenyl, 1-naphthyl, 2-naphthyl, 2-xenyl, wherein, R ²Further be preferably Wasserstoffatoms.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ³, expression C _1-4Alkyl, C _6-18Aryl is perhaps at 2 R ³Form under the situation of ring expression C together _3-5The group of divalence.

To the R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ³Specify.

As this C _6-18Aryl; Can enumerate out phenyl, 3; 5-3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 4-aminomethyl phenyl, 1-naphthyl, 2-xenyl, 2-phenyl-1-naphthyl, 2-methyl isophthalic acid-naphthyl, 2-[3; The 5-3,5-dimethylphenyl]-1-naphthyl, 2-[4-aminomethyl phenyl]-1-naphthyl and 2-methoxyl group-1-naphthyl etc.

At 2 R ³Forming under the situation of ring together, is C _3-5The group of divalence, can enumerate out trimethylene and tetramethylene etc.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ³Be preferably phenyl, 3,5-3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 4-aminomethyl phenyl, 2 R ³The tetramethylene of bonding, wherein, R ³2 R more preferably ³The tetramethylene of mutual bonding.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ⁴Expression Wasserstoffatoms, halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, nitro or cyanic acid.

To the R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ⁴Specify.

As this halogen radical, can enumerate out fluorine atom, chlorine atom, bromine atoms and iodine atom,

As this C _1-4Alkoxyl group can be enumerated out methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, n-butoxy, i-butoxy, s-butoxy and t-butoxy etc.

R in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') ⁴Be preferably Wasserstoffatoms, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, n-butoxy, i-butoxy, s-butoxy, t-butoxy; Wherein, as R ⁴, more preferably Wasserstoffatoms.

M in above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the formula (4 ') representes TiJ ¹J ²(at TiJ ¹J ²In, Ti representes titanium atom, J ¹And J ²Represent halogen atom, C respectively independently _1-4Alkoxyl group, perhaps J ¹With J ²Represent Sauerstoffatom together, perhaps J ¹With J ²Form ring together, expression is as the formula (5) of the group of divalence

(about the part-structure O-E-O in the formula, wherein O is a Sauerstoffatom, in formula (1), as O-E-O, with following formula (6) expression, in formula (1 '); As O-E-O, with following formula (6 ') expression, in formula (2), as O-E-O, with following formula (7) expression, in formula (2 '); As O-E-O,, in formula (3),, represent with following formula (8) as O-E-O with following formula (7 ') expression; In formula (3 '), as O-E-O, with following formula (8 ') expression, in formula (4), as O-E-O; With following formula (9) expression, in formula (4 '),, represent with following formula (9 ') as O-E-O

B is 1～10 integer, R ¹, R ², R ³And R ⁴Same as described above)).

In addition, at J ¹With J ²Represent together under the situation of Sauerstoffatom that formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') as all structures of molecule, become the oxygen titanium complex of monokaryon, at J ¹With J ²Form together under ring, the situation of expression as the formula (5) of the group of divalence; Formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 '); As all structures of molecule, become μ-oxygen titanium (b+1) nuclear complex compound as polynuclear complex.

In addition; In formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') is under the situation of above-mentioned oxygen titanium complex or μ-oxygen titanium (b+1) nuclear complex compound, and optical activity titanium complex of the present invention can be that these oxygen titanium complexs or b are the mixture that any one state μ-oxygen titanium (b+1) down of 1～10 is examined complex compound.

As preferred J ¹And J ², can enumerate out J ¹With J ²Represent Sauerstoffatom together, or J ¹With J ²Form ring together, expression is as the situation of the formula (5) of the group of divalence, and in these cases, the optical activity titanium complex is respectively the oxygen titanium complex or μ-oxygen titanium (b+1) the nuclear complex compound (b is 1～10 integer) of monokaryon.

And then; About optical activity titanium complex of the present invention; The type that is divided into the titanium Salan complex compound shown in optical activity titanium Salalen complex compound shown in above-mentioned formula (1), formula (1 '), formula (3) and the formula (3 ') or formula (2), formula (2 '), formula (4) and the formula (4 '); Below, the combination and all structures of molecule of preferred substituted described.

Optical activity titanium Salalen complex compound shown in above-mentioned formula (1), formula (1 '), formula (3) and the formula (3 ') is used J ¹With J ²Form above-mentioned formula (5) expression as the group of divalence of ring together, in formula (5), b is preferably 1.In this case, formula (1), formula (1 '), formula (3) and formula (3 ') as all structures of molecule, become the μ shown in following formula (18) and (18 ')-oxygen titanium two nuclear complex compounds.

(in the formula, O-NH-N-O in formula (1), is following formula (19); In formula (1 '), it is formula (19 '); In formula (2), be formula (20); In formula (2 '), be formula (20 '),

(R here, ¹, R ², R ³And R ⁴Same as described above), the complex compound of formula (18 ') is the enantiomer of the complex compound of formula (18).)

Combination and all structures of molecule to special preferred substituted in the above-mentioned optical activity titanium Salalen complex compound describe.Preferred especially optical activity titanium Salalen complex compound is with formula (18) and formula (18 ') expression; Part-structure O-NH-N-O in this formula is following formula (21), (21 '), (22) or formula (22 ') expression (aRS Δ; The aRS Δ)-two-μ-oxygen titanium two nuclear complex compounds and (aSR Λ, aSR Λ)-two-μ-oxygen titanium two nuclear complex compounds.

Combination as the special preferred substituted in the optical activity titanium Salan complex compound shown in above-mentioned formula (2), formula (2 '), formula (4) and the formula (4 '); Can enumerate out the oxygen titanium complex or μ-oxygen titanium (b+1) the amount body (b is 1～10 integer) of the monokaryon shown in following formula (23), (23 '), (24) or the formula (24 ')

(M in the formula representes TiJ ¹J ², J ¹With J ²Represent Sauerstoffatom together, perhaps form ring together, expression is as the above-mentioned formula (5) of the group of divalence, and in formula (5), b is 1～10 integer, and part-structure O-E-O is respectively by following formula (25), (25 '), (26) or formula (26 ') expression).

Then, the method for manufacture to the optical activity titanium complex of formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') expression describes.

About as the Salan part shown in formula (29), formula (29 '), formula (31) or the formula (31 ') of the part of the titanium Salan complex compound shown in formula (2), formula (2 '), formula (4) and the formula (4 '), can be respectively through the Salen compound shown in following formula (28), formula (28 '), formula (30) or the formula (30 ') being gone back original the manufacturing.

As reductive agent, can enumerate out Peng Qinghuana (NaBH ₄), cyaniding Peng Qinghuana (NaBH ₃CN) and lithium aluminum hydride (LiAlH ₄) etc., preferred Peng Qinghuana (NaBH ₄).

Optical activity titanium Salan complex compound shown in formula (2), formula (2 '), formula (4) and the formula (4 '); Can be through Salan part and titanium alkoxide, titanium tetrachloride or titanium tetrabromide with correspondence; After the reaction, water or water-containing solvent (in organic solvent, in quality %, contain the mixed solvent of 0.1～100% water in the organic solvent of methylene dichloride etc.; As the organic solvent that uses, can enumerate THF, methyl alcohol and i-propyl alcohol etc.) handle and make.The usage quantity of water with respect to the equivalent of above-mentioned Salan part, is preferably 1～1000 mole scope, more preferably 1～10 mole scope.

In addition, in reaction system, also can generate above-mentioned optical activity titanium Salan complex compound,, not separate, and carry out the asymmetric epoxidation reaction of chromene compounds as catalyzer.At this moment, aquae hydrogenii dioxidi can be added, also water can be added as oxygenant.

As titanium compound, preferred titanium alkoxide as this titanium alkoxide, can be enumerated out tetramethyl alcohol titanium, titanium tetraethoxide, four n-propyl alcohol titaniums, titanium tetraisopropylate, four propyl carbinol titaniums and four trimethyl carbinol titaniums etc., wherein, and more preferably titanium tetraisopropylate [Ti (Oi-Pr) ₄].The usage quantity of titanium alkoxide is with respect to above-mentioned Salan ligand 1 mole, preferred 1～2 mole scope.

Optical activity titanium Salalen complex compound shown in formula (1), formula (1 '), formula (3) and the formula (3 ') can according to non-patent literature 8 (Angew.Chem.Int.Ed. (2005), 44,4935-4939.) record method make.That is, make corresponding Salen part and titanium alcohol reactant salt, through Meerwein-Ponndrof-Verley (MPV) reduction reaction; Make the side reduction of 2 imido base keies of Salen part, form titanium complex simultaneously, after reaction finishes; Water or water-containing solvent are (in organic solvent; In quality %, contain the mixed solvent of 0.1～100% water, as the organic solvent that uses, can enumerate THF, methyl alcohol and i-propyl alcohol etc.) handle and make.

In addition, in reaction system, can also generate above-mentioned optical activity titanium Salalen complex compound,, not separate, and carry out the asymmetric epoxidation reaction of chromene compounds as catalyzer.

In addition,, can enumerate out tetramethyl alcohol titanium, titanium tetraethoxide, four n-propyl alcohol titaniums, titanium tetraisopropylate, four propyl carbinol titaniums and titanium four trimethyl carbinol titaniums etc. as this titanium alkoxide, wherein, preferred titanium tetraisopropylate [Ti (Oi-Pr) ₄].The usage quantity of titanium alkoxide, with respect to 1 mole of above-mentioned Salen part, preferred 1～2 mole scope.In addition, the usage quantity of water with respect to the equivalent of above-mentioned Salen part, is preferably 1～1000 mole scope, more preferably 1～10 mole scope.

Reaction solvent when making the optical activity titanium complex is the organic solvent of aprotic, the organic solvent of protic or the mixture of these solvents.Organic solvent as aprotic; Can enumerate out halogen series solvent, aromatic hydrocarbons series solvent, ester series solvent, ether series solvent or nitrile series solvent etc.; Specifically; Can enumerate out methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, toluene, acetate ethyl ester, THF, ether, butyronitrile, propionitrile, acetonitrile etc.As the organic solvent of protic, can enumerate out pure series solvent, specifically, can enumerate out ethanol, i-propyl alcohol or t-butanols etc.

Preferred reaction solvent is the methylene dichloride, 1 as the organic solvent of aprotic, 2-ethylene dichloride, chlorobenzene, toluene, acetate ethyl ester.

In method of manufacture of the present invention; Through use formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and the represented optical activity titanium complex of formula (4 '); Chromene compounds to as starting raw material carries out asymmetric Epoxidation, can make a side of the enantiomer of chromene oxide compound with high selectivity.Specifically, through arbitrary side of complex compound shown in the use formula (1) or the complex compound shown in the formula (1 '), a side that can optionally make two enantiomers of optically active chromene oxide compound.Through any one of complex compound shown in the use formula (2) or the complex compound shown in the formula (2 '), a side that can optionally make two enantiomers of optically active chromene oxide compound.Through any one of complex compound shown in the use formula (3) or the complex compound shown in the formula (3 '), a side that can optionally make two enantiomers of optically active chromene oxide compound.Through complex compound shown in the use formula (4) or the complex compound shown in the formula (4 ') any one, can optionally make two enantiomers of optically active chromene oxide compound.

Then, the method for manufacture to optically active chromene oxide compound of the present invention describes.It is the method for making the optically active chromene oxide compound shown in following formula (14), formula (15), formula (16) or the formula (17); Wherein, Through with the optical activity titanium complex shown in any one of the chromene compounds shown in formula (10), formula (11), formula (12) or the formula (13) and formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 '); Under nitrogen atmosphere or in atmosphere, be dissolved in the organic solvent, in this reaction soln, add oxygenant, stir; Carry out asymmetric epoxidation reaction

(the R in the formula (10) ⁵, R ⁶, R ⁷And R ⁸Represent Wasserstoffatoms, cyanic acid, nitro, halogen atom, C respectively independently _1-4(this alkyl can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkyl _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4(this alkoxyl group can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkoxyl group _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4(this alkyl-carbonyl-amino can (this phenyl can be by halogen atom, hydroxyl, cyanic acid, nitro, C by halogen atom, phenyl for alkyl-carbonyl-amino _1-4Alkyl or C _1-4Alkoxyl group replaces arbitrarily) replace arbitrarily), C _1-4Alkyl-carbonyl (N-C _1-4Alkyl) amino (this alkyl-carbonyl (N-alkyl) amino can be replaced arbitrarily by halogen atom), C _1-4Alkoxy carbonyl (this alkoxy carbonyl can be replaced arbitrarily by halogen atom), C _6-10(this aryl-amino-carbonyl can be by halogen atom, C for aryl-amino-carbonyl _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), C _6-10Aryl carbonyl (N-C _1-4It is alkyl) amino that (this aryl carbonyl (N-alkyl) amino can be by halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), benzyloxycarbonyl group amino, formyl radical, formamyl, C _1-4Alkyl sulphonyl, C _6-10(this alkyl sulphonyl and aryl sulfonyl can be by halogen atom, C for aryl sulfonyl _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), sulfamyl, C _1-4Alkylsulfonamido, C _6-10(this alkylsulfonamido and aryl-sulfonyl amino can be by halogen atom, C for aryl-sulfonyl amino _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), two (C _1-4Alkyl sulfonyl) (alkyl sulfonyl of this pair (alkyl sulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), two (C _6-10Arylsulfonyl) (arylsulfonyl of this pair (arylsulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace), [N, N '-(C _1-4Alkyl sulfonyl) (C _6-10Arylsulfonyl)] (alkyl sulfonyl and the arylsulfonyl that are somebody's turn to do [N, N '-(alkyl sulfonyl) (arylsulfonyl)] imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace),

R in the formula (10) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily), C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily),

R in formula (11) and the formula (12) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily),

Part ring structure A in formula (11) and the formula (12) representes partly to form 5,6 or 7 Yuans of the condensed ring represented part-structures of ring with phenyl ring, and (wherein, these 5,6 or 7 Yuans rings can be by h R ¹¹Replace (wherein, R arbitrarily ¹¹Be halogen atom, hydroxyl, C _1-6(this alkyl can be by halogen atom, hydroxyl, cyanic acid, amino, nitro, C for alkyl _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-6(this alkoxyl group can be by halogen atom, hydroxyl, cyanic acid, amino, nitro, C for alkoxyl group _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), nitro, cyanic acid, formyl radical, formamido-, formamyl, sulfo group, sulfoamino-, sulfamyl, alkylsulfonyl, amino, carboxyl, C _1-6Alkylamino, two C _1-6Alkylamino, C _1-6Alkyl-carbonyl-amino, C _1-6Alkylsulfonamido, C _6-14Aryl-sulfonyl amino, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl, C _6-14Aryl sulfonyl or C _6-14Aryl carbonyl (this alkylamino, dialkyl amido, alkyl-carbonyl-amino, alkylsulfonamido, aryl-sulfonyl amino, alkyl amino-carbonyl, dialkyl amino carbonyl, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl and aryl carbonyl can be replaced arbitrarily by halogen atom); H is 1～6 integer; Be under 2～6 the situation at h, R ¹¹Can be the same or different, the constituting atom as ring can contain 1～3 Sauerstoffatom, nitrogen-atoms or sulphur atom alone or in combination; The number of intra-annular unsaturated link(age) comprises the unsaturated link(age) of the phenyl ring of condensation, is 1,2 or 3; The carbon atom that constitutes ring can be carbonyl or thiocarbonyl)

X in the formula (13) representes NR ²⁰(R ²⁰Expression Wasserstoffatoms or C _1-4Alkyl), the Y in the formula (13) representes Direct Bonding, SO or SO ₂, the Z in the formula (13) representes C _1-4(this alkyl can (this phenyl can be by C by 1～5 halogen atom or phenyl for alkyl _1-4Alkyl replaces arbitrarily) replace arbitrarily) or phenyl (this phenyl can be by C _1-4Alkyl replaces arbitrarily), the W in the formula (13) representes Wasserstoffatoms, hydroxyl, C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), halogen atom, C _1-4Alkyl or C _1-6Alkylsulfonamido (this alkyl and alkylsulfonamido can be replaced arbitrarily by halogen atom),

(R in the formula ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, A, W, X, Y and Z be same as described above, ^*The absolute configuration of marked carbon atoms is (R) or (S)).

In addition, can make through the method shown in the reactions formula 1.

Reaction formula 1

Reaction formula 1 (R in the formula ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, A, W, X, Y and Z be same as described above. ^*The absolute configuration of marked carbon atoms is (R) or (S)); Be through in solvent; Chromene compounds with formula (10), formula (11), formula (12) or formula (13); Handle with oxygenant and optical activity titanium complex, by the optically active chromene oxide shown in formula (10) the manufacturing formula (14), by the optically active chromene oxide shown in formula (11) the manufacturing formula (15), by the optically active chromene oxide shown in formula (12) the manufacturing formula (16) or by the method for the optically active chromene oxide compound shown in formula (13) the manufacturing formula (17).

Chromene compounds as shown in above-mentioned formula (10), formula (11), formula (12) or the formula (13) of starting raw material of the present invention can use the general synthesis method of following chromene ring to synthesize.In addition, synthetic about the condensed ring in formula (11), the formula (12) can make through various heterocyclic compound methods shown in will be following and chromene cyclization established law appropriate combination and be used for realization.

The general synthesis method of zero chromene ring

Can be according to known method (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., the spy opens clear 56-57785 communique, spy and opens clear 56-57786 communique, spy and open that clear 58-188880 communique, spy are opened flat 2-141 communique, the spy opens the method for records such as flat 10-87650 communique and the flat 11-209366 communique of Te Kai) come synthetic.

Zero indoles, oxindoles (oxoindole)

Can be according to known method (T.Sakamoto, et al., Heterocycles,, 24,31. in 1986

M.Belley, et al., Synthesis, calendar year 2001,222.

A.D.Cross, et al., J.Chem.Soc.,, the method for record such as 2714. grades in 1961) synthetic.

Zero imidazolone

Can come synthetic according to known method (J.Kitteringham, et.al., Synthetic Commun.,, the method for 30,1937. records in 2000).

Zero quinoline

Can be according to known method (S.Imor, et al., Synthetic Commun.,, 26,2197. in 1996

Y.Kitahara, et al., Tetrahedron,, 53,6001. in 1997

A.G.Osborne, et al., J.Chem.Soc.Perkin Trans.1993,1,181.

R.T.Shuman, et al., J.Org.Chem., nineteen ninety, 55,738.

T.Sakamoto, et al., Chem.Pharm.Bull.,, 29,2485. in 1981

Y.Tsuji, et al., J.Org.Chem.,, 52,1673. in 1987

Z.Song, et al., J.Heterocyclic Chem.,, the method for record such as 30,17. grades in 1993) synthesize.

Zero quinolinone

Can be according to known method (M.R.Sabol, et al., Synthetic Commun.,, 30,427. in 2000

Z-Y.Yang, et al., Tetrahedron Lett.,, 40,4505. in 1999

H-B Sun, et al., Synthesis,, 1249. in 1997

A.Guiotto, et al., J.Heterocyclic Chem.,, 26,917. in 1989

K.Konno, et al., Heterocycles,, 24,2169. in 1986

E.Fernandez, et al., Synthesis, nineteen ninety-five, the method for record such as 1362. grades) synthesize.

Zero benzothiazole, triazole,

Can be according to known method (N.B.Ambati, et al., Synthetic Commun.,, 27,1487. in 1997

D.E.Burton, et al., J.Chem.Soc (C)., nineteen sixty-eight, the method for record such as 1268. grades) synthesize.

Zero quinoxaline, quinazolone

Can be according to known method (J.H.Liu, et al., J.Org.Chem.,, 65,3395. in 2000

J.J.Li, et al., Tetrahedron Lett.,, 40,4507. in 1999

Y.Ahmed, et al., Bull.Chem.Soc.Jpn.,, the method for record such as 60,1145. grades in 1987) synthesize.

Zero benzoxazinone

Can be according to known method (G.H.Jones, et al., J.Med.Chem.,, 30,295. in 1987

J.L.Wright, et al., J.Med.Chem.,, 43,3408. in 2000

M.Kluge, et al., J.Heterocyclic Chem., nineteen ninety-five, the method for record such as 32,395. grades) synthesize.

Zero following formula (35), the compound shown in (36) can obtain through making compound (33) and compound (34) reaction.(reference Y.Tsuji, et al., J.Org.Chem.,, 52,1673. in 1987)

Zero following formula (35), the compound shown in (36) also can obtain through compound (33) and compound (37) are reacted in the presence of acid catalyst.(reference Y.Kitahara, et al., Tetrahedron1997,53,6001., Z.Song, et al., J.Heterocyclic Chem.,, 30,17. in 1993)

Chromene compounds shown in the zero following formula (40) can be synthetic by compound (38), via using the platinum C catalyst with the compound (39) of nitroreduction as amine, then, carries out methylsulfonylization and obtain.

Each substituting group to the chromene compounds shown in above-mentioned formula (10), formula (11), formula (12) or the formula (13) specifies.

Below, each substituting group of above-mentioned formula (10) is described.R in the formula (10) ⁵, R ⁶, R ⁷And R ⁸Represent Wasserstoffatoms, cyanic acid, nitro, halogen atom, C respectively independently _1-4(this alkyl can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkyl _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4(this alkoxyl group can be by halogen atom, hydroxyl, cyanic acid, nitro, C for alkoxyl group _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-4(this alkyl-carbonyl-amino can be by halogen atom, C for alkyl-carbonyl-amino _6-10Aryl (this C _6-10Aryl can be by halogen atom, hydroxyl, cyanic acid, nitro, C _1-4Alkyl or C _1-4Alkoxyl group replaces arbitrarily) replace arbitrarily), [C _1-4Alkyl-carbonyl (N-C _1-4Alkyl) amino (this alkyl-carbonyl (N-alkyl) amino can be replaced arbitrarily by halogen atom), C _1-4Alkoxy carbonyl (this alkoxy carbonyl can be replaced arbitrarily by halogen atom), C _6-10(this aryl-amino-carbonyl can be by halogen atom, C for aryl-amino-carbonyl _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace arbitrarily), C _6-10Aryl carbonyl (N-C _1-4It is alkyl) amino that (this aryl carbonyl (N-alkyl) amino can be by halogen atom, C _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace arbitrarily), benzyloxycarbonyl group amino, formyl radical, formamyl, C _1-4Alkyl sulphonyl (this alkyl sulphonyl can be replaced arbitrarily by halogen atom), C _6-10(this aryl sulfonyl can be by halogen atom, C for aryl sulfonyl _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace arbitrarily), sulfamyl, C _1-4Alkylsulfonamido, C _6-10(this alkylsulfonamido can be by halogen atom, C with this aryl-sulfonyl amino for aryl-sulfonyl amino _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace arbitrarily), two (C _1-4Alkyl sulfonyl) (alkyl sulfonyl of this pair (alkyl sulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace arbitrarily), two (C _6-10Arylsulfonyl) (arylsulfonyl of this pair (arylsulfonyl) imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid or nitro replace arbitrarily), [N, N '-C _1-4Alkyl sulfonyl) (C _6-10Arylsulfonyl)] (arylsulfonyl and the alkyl sulfonyl that are somebody's turn to do [N, N '-(alkyl sulfonyl) (arylsulfonyl)] imido grpup can be by halogen atom, C for imido grpup _1-4Alkyl, C _1-4Alkoxyl group, cyanic acid, nitro replace arbitrarily).

Below, to the R in the formula (10) ⁵, R ⁶, R ⁷And R ⁸Each substituting group specify.

As this C _1-4Alkyl can be enumerated out methyl, trifluoromethyl, trichloromethyl, ethyl, n-propyl group, i-propyl group, c-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl and c-butyl etc., as this C _1-4Alkoxyl group can be enumerated out methoxyl group, trifluoromethoxy, trichlorine methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, c-propoxy-, n-butoxy, i-butoxy, s-butoxy, t-butoxy and c-butoxy etc., as this C _1-4Alkyl-carbonyl-amino; Can enumerate out; Methyl carbonylamino, trifluoromethyl carbonylamino, trichloromethyl carbonylamino, ethyl carbonylamino, n-propyl group carbonylamino, i-propyl group carbonylamino, c-propyl group carbonylamino, n-butyl carbonylamino, i-butyl carbonylamino, s-butyl carbonylamino, tertiary butyl carbonylamino, c-butyl carbonylamino, p-anisole ylmethyl carbonylamino, p-nitrophenyl methyl carbonylamino and p-p-methoxy-phenyl ethyl carbonylamino etc. are as this C _1-4Alkyl-carbonyl (N-C _1-4Alkyl) amino; Can enumerate out methyl carbonyl (N-methyl) amino, trifluoromethyl carbonyl (N-methyl) amino, methyl carbonyl (N-ethyl) amino, trifluoromethyl carbonyl (N-ethyl) amino, ethyl carbonyl (N-ethyl) amino, n-propyl group carbonyl (N-ethyl) amino, i-propyl group carbonyl (N-ethyl) amino, c-propyl group carbonyl (N-ethyl) amino, n-butyl carbonyl (N-ethyl) amino, i-butyl carbonyl (N-ethyl) amino, s-butyl carbonyl (N-ethyl) amino, tertiary butyl carbonyl (N-ethyl) amino and c-butyl carbonyl (N-ethyl) amino etc., as this C _1-4Alkoxy carbonyl; Can enumerate out methoxycarbonyl, trifluoromethoxy carbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, c-propoxycarbonyl, n-butoxy carbonyl, i-butoxy carbonyl, s-butoxy carbonyl, t-butoxy carbonyl and c-butoxy carbonyl etc., as this C _6-10Aryl-amino-carbonyl can be enumerated out phenylcarbonyl group amino, 1-naphthyl carbonyl amino and 2-naphthyl carbonyl amino etc., as this C _6-10Aryl carbonyl (N-C _1-4Alkyl) amino can be enumerated out phenylcarbonyl group (N-methyl) amino, phenylcarbonyl group (N-ethyl) amino, 1-naphthyl carbonyl (N-ethyl) amino and 2-naphthyl carbonyl (N-ethyl) amino etc., as this C _1-4Alkyl sulphonyl; Can enumerate out methane sulfonyl, trifluoromethane sulfonyl group, ethane alkylsulfonyl, n-propane alkylsulfonyl, i-propane alkylsulfonyl, c-propane alkylsulfonyl, n-butane alkylsulfonyl, i-butane alkylsulfonyl, s-butane alkylsulfonyl, t-butane alkylsulfonyl and c-butane alkylsulfonyl etc., as this C _6-10Aryl sulfonyl can be enumerated out benzenesulfonyl, p-fluorobenzene alkylsulfonyl, p-tosyl group, 1-naphthalene sulfonyl base and 2-naphthalene sulfonyl base etc., as this C _1-4Alkylsulfonamido; Can enumerate out methylsulfonyl amido, fluoroform sulfoamido, ethane sulphonamide base, n-propane sulfoamido, i-propane sulfoamido, c-propane sulfoamido, n-butane sulfoamido, i-butane sulfoamido, s-butane sulfoamido, t-butane sulfoamido and c-butane sulfoamido etc., as this C _6-10Aryl-sulfonyl amino can be enumerated out benzene sulfonamido, p-fluorobenzene sulfoamido, p-tolylsulfonyl amido, 1-naphthalene sulfonyl amido and 2-naphthalene sulfonyl amido etc., as this pair (C _1-4Alkyl sulfonyl) imido grpup; Can enumerate out two (sulfonyl methane) imido grpups, two (trifluoromethane sulphonyl) imido grpup, two (ethane sulphonyl) imido grpup, two (n-propane sulphonyl) imido grpup, two (i-propane sulphonyl) imido grpup, two (c-propane sulphonyl) imido grpup, two (n-butane sulphonyl) imido grpup, two (i-butane sulphonyl) imido grpup, two (s-butane sulphonyl) imido grpup, two (t-butane sulphonyl) imido grpup and two (c-butane sulphonyl) imido grpups etc., as this pair (C _6-10Arylsulfonyl) imido grpup can be enumerated out two (benzene sulfonyl) imido grpups, two (p-fluorobenzene sulphonyl) imido grpup, two (p-tolylsulfonyl) imido grpup, two (1-naphthalene sulfonyl) imido grpup and two (2-naphthalene sulfonyl) imido grpups etc., as this [N, N '-(C _1-4Alkyl sulfonyl) (C _6-10Arylsulfonyl)] imido grpup can be enumerated out [N, N '-(methane) (benzene)] imido grpup, [N; N '-(trifluoromethane) (benzene)] imido grpup, [N, N '-(trifluoromethane) (p-fluorobenzene)] imido grpup, [N, N '-(ethane) (benzene)] imido grpup, [N; N '-(methane) (p-toluene)] imido grpup, [N, N '-(trifluoromethane) (p-toluene)] imido grpup, [N, N '-(ethane) (p-toluene)] imido grpup, [N; N '-(methane) (1-naphthalene)] imido grpup, [N; N '-(trifluoromethane) (1-naphthalene)] imido grpup, [N, N '-(ethane) (1-naphthalene)] imido grpup, [N, N '-(methane) (2-naphthalene)] imido grpup, [N; N '-(trifluoromethane) (2-naphthalene)] imido grpup and [N, N '-(ethane) (2-naphthalene)] imido grpup etc.

R in the formula (10) ⁵And R ⁶Independent respectively; Preferred Wasserstoffatoms, cyanic acid, nitro, fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, c-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, c-butyl, methoxyl group, trifluoromethoxy, oxyethyl group, n-propoxy-, i-propoxy-, c-propoxy-, n-butoxy, i-butoxy, s-butoxy, t-butoxy, c-butoxy, methyl carbonylamino, trifluoromethyl carbonylamino, ethyl carbonylamino, n-propyl group carbonylamino, i-propyl group carbonylamino, c-propyl group carbonylamino, n-butyl carbonylamino, i-butyl carbonylamino, s-butyl carbonylamino, tertiary butyl carbonylamino, c-butyl carbonylamino, methyl carbonyl (N-methyl) amino, trifluoromethyl carbonyl (N-methyl) amino, methyl carbonyl (N-ethyl) amino, trifluoromethyl carbonyl (N-ethyl) amino, ethyl carbonyl (N-ethyl) amino, n-propyl group carbonyl (N-ethyl) amino, i-propyl group carbonyl (N-ethyl) amino, c-propyl group carbonyl (N-ethyl) amino, n-butyl carbonyl (N-ethyl) amino, i-butyl carbonyl (N-ethyl) amino, s-butyl carbonyl (N-ethyl) amino, tertiary butyl carbonyl (N-ethyl) amino, c-butyl carbonyl (N-ethyl) amino, methoxycarbonyl, trifluoromethoxy carbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, phenylcarbonyl group amino, 1-naphthyl carbonyl amino, 2-naphthyl carbonyl amino, phenylcarbonyl group (N-methyl) An Ji, phenylcarbonyl group (N-ethyl) An Ji, 1-naphthyl carbonyl (N-ethyl) & CAT[N N '-(methane) (benzene)] imido grpup, [N; N '-(trifluoromethane) (benzene)] imido grpup, [N; N '-(ethane) (benzene)] imido grpup, [N; N '-(methane) (p-toluene)] imido grpup, [N; N '-(trifluoromethane) (p-toluene)] imido grpup, [N; N '-(ethane) (p-toluene)] imido grpup, [N; N '-(methane) (1-naphthalene)] imido grpup, [N; N '-(trifluoromethane) (1-naphthalene)] imido grpup, [N; N '-(ethane) (1-naphthalene)] imido grpup, [N; N '-(methane) (2-naphthalene)] imido grpup, [N; N '-(trifluoromethane) (2-naphthalene)] imido grpup, [N; N '-(ethane) (2-naphthalene)] imido grpup; More preferably Wasserstoffatoms, nitro, fluorine atom, chlorine atom, methoxyl group, methyl carbonylamino, methyl carbonyl (N-ethyl) amino, two (trifluoromethane sulphonyl) imido grpup, [N; N '-(trifluoromethane) (benzene)] imido grpup, [N, N '-(trifluoromethane) (p-toluene)] imido grpup.

R in the formula (10) ⁷Preferred Wasserstoffatoms, cyanic acid, nitro, methylsulfonyl amido, fluoroform sulfoamido, ethane sulphonamide base, n-propane sulfoamido, i-propane sulfoamido, c-propane sulfoamido, n-butane sulfoamido, i-butane sulfoamido, s-butane sulfoamido, t-butane sulfoamido, c-butane sulfoamido, two (sulfonyl methane) imido grpup, two (trifluoromethane sulphonyl) imido grpup, two (ethane sulphonyl) imido grpup, two (n-propane sulphonyl) imido grpup, two (i-propane sulphonyl) imido grpup, two (c-propane sulphonyl) imido grpup, two (n-butane sulphonyl) imido grpup, two (i-butane sulphonyl) imido grpup, two (s-butane sulphonyl) imido grpup, two (t-butane sulphonyl) imido grpup, two (c-butane sulphonyl) imido grpup, two (benzene sulfonyl) imido grpup, two (p-tolylsulfonyl) imido grpup, two (1-naphthalene sulfonyl) imido grpup, two (2-naphthalene sulfonyl) imido grpup, [N; N '-(methane) (benzene)] imido grpup, [N; N '-(trifluoromethane) (benzene)] imido grpup, [N; N '-(trifluoromethane) (p-fluorobenzene)] imido grpup, [N; N '-(ethane) (benzene)] imido grpup, [N; N '-(methane) (p-toluene)] imido grpup, [N; N '-(trifluoromethane) (p-toluene)] imido grpup, [N; N '-(ethane) (p-toluene)] imido grpup, [N; N '-(methane) (1-naphthalene)] imido grpup, [N, N '-(trifluoromethane) (1-naphthalene)] imido grpup, [N, N '-(ethane) (1-naphthalene)] imido grpup, [N; N '-(methane) (2-naphthalene)] imido grpup, [N; N '-(trifluoromethane) (2-naphthalene)] imido grpup, [N, N '-(ethane) (2-naphthalene)] imido grpup, more preferably Wasserstoffatoms, nitro, two (sulfonyl methane) imido grpup, two (trifluoromethane sulphonyl) imido grpup, [N; N '-(trifluoromethane) (benzene)] imido grpup, [N, N '-(trifluoromethane) (p-toluene)] imido grpup.

R in the formula (10) ⁸Preferred Wasserstoffatoms, fluorine atom, chlorine atom, cyanic acid, nitro, methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, c-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, c-butyl, more preferably Wasserstoffatoms, fluorine atom, nitro, methyl, trifluoromethyl.

R in the formula (10) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily).

To the R in the formula (10) ⁹And R ¹⁰Each substituting group specify.As this C ^1-6Alkyl can be enumerated out methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2,2-dimethyl propyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1; 1; 2-trimethylammonium-n-propyl group, 1,2,2-trimethylammonium-n-propyl group and 3; 3-dimethyl--n-butyl etc. are as this C _6-14Aryl can be enumerated out phenyl, o-xenyl, m-xenyl, p-xenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9-phenanthryl etc.

As the R in the formula (10) ⁹And R ¹⁰, be preferably Wasserstoffatoms, methyl, trifluoromethyl, ethyl, phenyl, more preferably methyl.

Each substituting group in formula (11) and the formula (12) describes.

R in formula (11) and the formula (12) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily) or C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily).

To the R in formula (11) and the formula (12) ⁹And R ¹⁰Each substituting group specify.

As this C _1-6Alkyl can be enumerated out methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2,2-dimethyl propyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1; 1; 2-trimethylammonium-n-propyl group, 1,2,2-trimethylammonium-n-propyl group and 3; 3-dimethyl--n-butyl etc.

As this C _6-14Aryl can be enumerated out phenyl, o-xenyl, m-xenyl, p-xenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl and 9-phenanthryl etc.

R in formula (11) and the formula (12) ⁹And R ¹⁰Be preferably Wasserstoffatoms, methyl, trifluoromethyl, ethyl, phenyl, more preferably methyl.

Part ring structure A in formula (11) and the formula (12) describes.Part ring structure A representes partly to form the part-structure shown in 5,6 or 7 Yuans rings of condensed ring with phenyl ring, and (wherein, these 5,6 or 7 Yuans rings can be by h R ¹¹Replace (wherein, R arbitrarily ¹¹Be halogen atom, hydroxyl, C _1-6(this alkyl can be by halogen atom, hydroxyl, cyanic acid, amino, nitro, C for alkyl _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), C _1-6(this alkoxyl group can be by halogen atom, hydroxyl, cyanic acid, amino, nitro, C for alkoxyl group _1-4Alkoxyl group, C _1-4Alkyl-carbonyl oxygen base, C _1-4Alkyl-carbonyl-amino, C _1-4Any replacement of alkoxy carbonyl (this alkoxyl group, alkyl-carbonyl oxygen base, alkyl-carbonyl-amino and alkoxy carbonyl can be replaced arbitrarily by halogen atom)), nitro, cyanic acid, formyl radical, formamido-, formamyl, sulfo group, sulfoamino-, sulfamyl, alkylsulfonyl, amino, carboxyl, C _1-6Alkylamino, two C _1-6Alkylamino, C _1-6Alkyl-carbonyl-amino, C _1-6Alkylsulfonamido, C _6-14Aryl-sulfonyl amino, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl, C _6-14Aryl sulfonyl or C _6-14Aryl carbonyl (this alkylamino, dialkyl amido, alkyl-carbonyl-amino, alkylsulfonamido, aryl-sulfonyl amino, alkyl amino-carbonyl, dialkyl amino carbonyl, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl and aryl carbonyl can be replaced arbitrarily by halogen atom); H is 1～6 integer; Be under 2～6 the situation at h, R ¹¹Can be the same or different), the constituting atom as ring can contain 1～3 Sauerstoffatom, nitrogen-atoms or sulphur atom alone or in combination; The number of intra-annular unsaturated link(age); The unsaturated link(age) that comprises the phenyl ring of condensation is 1,2 or 3, and the carbon atom that constitutes ring can be carbonyl or thiocarbonyl).

To above-mentioned R ¹¹Specify.

As this C _1-6Alkyl; Can enumerate out methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2; 2-dimethyl propyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1; 1; 2-trimethylammonium-n-propyl group, 1,2,2-trimethylammonium-n-propyl group, 3; 3-dimethyl--n-butyl, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, trifluoromethyl carbonylamino methyl, ethyl carbonylamino methyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, trifluoromethoxy carbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl and ethoxy carbonyl ethyl etc.

As this C _1-6Alkoxyl group; Can enumerate out methoxyl group, trifluoromethoxy, oxyethyl group, n-propoxy-, i-propoxy-, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 1-amyl group oxygen base, 2-amyl group oxygen base, 3-amyl group oxygen base, i-amyl group oxygen base, neo-pentyl oxygen base, 2; 2-dimethyl-propoxy-, 1-hexyl oxygen base, 2-hexyl oxygen base, 3-hexyl oxygen base, 1-methyl-n-amyl group oxygen base, 1; 1; 2-trimethylammonium-n-propoxy-, 1; 2; 2-trimethylammonium-n-propoxy-, 3,3-dimethyl--n-butoxy, methyl ketonic oxygen ylmethoxy, ethyl ketonic oxygen ylmethoxy, methyl ketonic oxygen base oxethyl, ethyl ketonic oxygen base oxethyl, methyl carbonylamino methoxyl group, trifluoromethyl carbonylamino methoxyl group, ethyl carbonylamino methoxyl group, methyl carbonylamino oxyethyl group, ethyl carbonylamino oxyethyl group, methoxycarbonyl methoxyl group, trifluoromethoxy carbonyl methoxyl group, ethoxycarbonyl methoxy, methoxycarbonyl oxyethyl group and ethoxy carbonyl oxyethyl group etc.

As this C _1-6Alkylamino; Can enumerate out that methylamino, trifluoromethyl amino, ethylamino, n-propyl group are amino, the i-propyl group is amino, the c-propyl group is amino, the n-butyl is amino, the i-butyl is amino, the s-butyl is amino, the tertiary butyl is amino, the c-butyl is amino, the 1-amyl group is amino, the 2-amyl group is amino, the 3-amyl group is amino, the i-amyl group is amino, neo-pentyl is amino, the t-amyl group is amino, the c-amyl group is amino, the 1-hexyl is amino, the 2-hexyl is amino, the 3-hexyl is amino, the c-hexyl is amino, 1-methyl-n-amyl group is amino, 1; 1; 2-trimethylammonium-n-propyl group amino, 1,2,2-trimethylammonium-n-propyl group amino and 3; 3-dimethyl--n-butyl amino etc.

As this two C _1-6Alkylamino; Can enumerate out dimethylamino; Two-(trifluoromethyl) amino; Diethylamino; Two-n-propyl group is amino; Two-i-propyl group is amino; Two-c-propyl group is amino; Two-n-butyl is amino; Two-i-butyl is amino; Two-s-butyl is amino; Two-tertiary butyl is amino; Two-c-butyl is amino; Two-1-amyl group is amino; Two-2-amyl group is amino; Two-3-amyl group is amino; Two-i-amyl group is amino; Two-neo-pentyl is amino; Two-t-amyl group is amino; Two-c-amyl group is amino; Two-1-hexyl is amino; Two-2-hexyl is amino; Two-3-hexyl is amino; Two-c-hexyl is amino; Two-(1-methyl-n-amyl group) amino; Two-(1; 1; 2-trimethylammonium-n-propyl group) amino; Two-(1; 2; 2-trimethylammonium-n-propyl group) amino; Two-(3; 3-dimethyl--n-butyl) amino; Methyl (ethyl) amino; Methyl (n-propyl group) amino; Methyl (i-propyl group) amino; Methyl (c-propyl group) amino; Methyl (n-butyl) amino; Methyl (i-butyl) amino; Methyl (s-butyl) amino; Methyl (tertiary butyl) amino; Methyl (c-butyl) amino; Ethyl (n-propyl group) amino; Ethyl (i-propyl group) amino; Ethyl (c-propyl group) amino; Ethyl (n-butyl) amino; Ethyl (i-butyl) amino; Ethyl (s-butyl) amino; Ethyl (tertiary butyl) amino; Ethyl (c-butyl) amino; N-propyl group (i-propyl group) amino; N-propyl group (c-propyl group) amino; N-propyl group (n-butyl) amino; N-propyl group (i-butyl) amino; N-propyl group (s-butyl) amino; N-propyl group (t-butyl) amino; N-propyl group (c-butyl) amino; I-propyl group (c-propyl group) amino; I-propyl group (n-butyl) amino; I-propyl group (i-butyl) amino; I-propyl group (s-butyl) amino; I-propyl group (t-butyl) amino; I-propyl group (c-butyl) amino; C-propyl group (n-butyl) amino; C-propyl group (i-butyl) amino; C-propyl group (s-butyl) amino; C-propyl group (tertiary butyl) amino; C-propyl group (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 and the tertiary butyl (c-butyl) amino etc.

As this C _1-6Alkyl-carbonyl-amino; Can enumerate out the methyl carbonylamino; The trifluoromethyl carbonylamino; The ethyl carbonylamino; N-propyl group carbonylamino; I-propyl group carbonylamino; N-butyl carbonylamino; I-butyl carbonylamino; S-butyl carbonylamino; Tertiary butyl carbonylamino; 1-amyl group carbonylamino; 2-amyl group carbonylamino; 3-amyl group carbonylamino; I-amyl group carbonylamino; The neo-pentyl carbonylamino; T-amyl group carbonylamino; 1-hexyl carbonylamino; 2-hexyl carbonylamino and 3-hexyl carbonylamino etc.

As this C _1-6Alkylsulfonamido; Can enumerate out the methylsulfonyl amido; The fluoroform sulfoamido; The ethane sulphonamide base; N-propane sulfoamido; I-propane sulfoamido; N-butane sulfoamido; I-butane sulfoamido; S-butane sulfoamido; T-butane sulfoamido; 1-pentane sulfoamido; 2-pentane sulfoamido; 3-pentane sulfoamido; I-pentane sulfoamido; The neopentane sulfoamido; T-pentane sulfoamido; 1-hexane sulfoamido; 2-hexane sulfoamido and 3-hexane sulfoamido etc.

As this C _6-14Aryl-sulfonyl amino; Can enumerate out benzene sulfonamido, p-tolylsulfonyl amido, o-biphenyl sulfonamide base, m-biphenyl sulfonamide base, p-biphenyl sulfonamide base, 1-naphthalene sulfonyl amido, 2-naphthalene sulfonyl amido, 1-anthracene sulfoamido, 2-anthracene sulfoamido, 9-anthracene sulfoamido, the luxuriant and rich with fragrance sulfoamido of 1-, the luxuriant and rich with fragrance sulfoamido of 2-, the luxuriant and rich with fragrance sulfoamido of 3-, the luxuriant and rich with fragrance sulfoamido of 4-and the luxuriant and rich with fragrance sulfoamido of 9-etc.

As this C _1-6Alkyl amino-carbonyl; Can enumerate out the methylamino carbonyl; The trifluoromethyl aminocarboxyl; The ethylamino carbonyl; N-propyl group aminocarboxyl; I-propyl group aminocarboxyl; N-butyl aminocarboxyl; I-butyl aminocarboxyl; S-butyl aminocarboxyl; Tertiary butyl aminocarboxyl; 1-amyl group aminocarboxyl; 2-amyl group aminocarboxyl; 3-amyl group aminocarboxyl; I-amyl group aminocarboxyl; The neo-pentyl aminocarboxyl; T-amyl group aminocarboxyl; 1-hexyl aminocarboxyl; 2-hexyl aminocarboxyl and 3-hexyl aminocarboxyl etc.

As this two C _1-6Alkyl amino-carbonyl; Can enumerate out the dimethylamino carbonyl; Two (trifluoromethyl) aminocarboxyl; The diethylamino carbonyl; Two-n-propyl group aminocarboxyl; Two-i-propyl group aminocarboxyl; Two-c-propyl group aminocarboxyl; Two-n-butyl aminocarboxyl; Two-i-butyl aminocarboxyl; Two-s-butyl aminocarboxyl; Two-tertiary butyl aminocarboxyl; Two-c-butyl aminocarboxyl; Two-1-amyl group aminocarboxyl; Two-2-amyl group aminocarboxyl; Two-3-amyl group aminocarboxyl; Two-i-amyl group aminocarboxyl; Two-neo-pentyl aminocarboxyl; Two-t-amyl group aminocarboxyl; Two-c-amyl group aminocarboxyl; Two-1-hexyl aminocarboxyl; Two-2-hexyl aminocarboxyl; Two-3-hexyl aminocarboxyl; Two-c-hexyl aminocarboxyl; Two-(1-methyl-n-amyl group) aminocarboxyls; Two-(1; 1; 2-trimethylammonium-n-propyl group) aminocarboxyl; Two-(1; 2; 2-trimethylammonium-n-propyl group) aminocarboxyl; Two-(3; 3-dimethyl--n-butyl) aminocarboxyl; Methyl (ethyl) aminocarboxyl; Trifluoromethyl (ethyl) aminocarboxyl; Methyl (n-propyl group) aminocarboxyl; Methyl (i-propyl group) aminocarboxyl; Methyl (c-propyl group) aminocarboxyl; Methyl (n-butyl) aminocarboxyl; Methyl (i-butyl) aminocarboxyl; Methyl (s-butyl) aminocarboxyl; Methyl (t-butyl) aminocarboxyl; Methyl (c-butyl) aminocarboxyl; Ethyl (n-propyl group) aminocarboxyl; Ethyl (i-propyl group) aminocarboxyl; Ethyl (c-propyl group) aminocarboxyl; Ethyl (n-butyl) aminocarboxyl; Ethyl (i-butyl) aminocarboxyl; Ethyl (s-butyl) aminocarboxyl; Ethyl (t-butyl) aminocarboxyl; Ethyl (c-butyl) aminocarboxyl; N-propyl group (i-propyl group) aminocarboxyl; N-propyl group (c-propyl group) aminocarboxyl; N-propyl group (n-butyl) aminocarboxyl; N-propyl group (i-butyl) aminocarboxyl; N-propyl group (s-butyl) aminocarboxyl; N-propyl group (t-butyl) aminocarboxyl; N-propyl group (c-butyl) aminocarboxyl; I-propyl group (c-propyl group) aminocarboxyl; I-propyl group (n-butyl) aminocarboxyl; I-propyl group (i-butyl) aminocarboxyl; I-propyl group (s-butyl) aminocarboxyl; I-propyl group (t-butyl) aminocarboxyl; I-propyl group (c-butyl) aminocarboxyl; C-propyl group (n-butyl) aminocarboxyl; C-propyl group (i-butyl) aminocarboxyl; C-propyl group (s-butyl) aminocarboxyl; C-propyl group (t-butyl) aminocarboxyl; C-propyl group (c-butyl) aminocarboxyl; N-butyl (i-butyl) aminocarboxyl; N-butyl (s-butyl) aminocarboxyl; N-butyl (t-butyl) aminocarboxyl; N-butyl (c-butyl) aminocarboxyl; I-butyl (s-butyl) aminocarboxyl; I-butyl (t-butyl) aminocarboxyl; I-butyl (c-butyl) aminocarboxyl; S-butyl (t-butyl) aminocarboxyl; S-butyl (c-butyl) aminocarboxyl and the tertiary butyl (c-butyl) aminocarboxyl etc.

As this C _1-6Alkyl-carbonyl; Can enumerate out methyl carbonyl, trifluoromethyl carbonyl, ethyl carbonyl, n-propyl group carbonyl, i-propyl group carbonyl, n-butyl carbonyl, i-butyl carbonyl, s-butyl carbonyl, tertiary butyl carbonyl, 1-amyl group carbonyl, 2-amyl group carbonyl, 3-amyl group carbonyl, i-amyl group carbonyl, neo-pentyl carbonyl, t-amyl group carbonyl, 1-hexyl carbonyl, 2-hexyl carbonyl and 3-hexyl carbonyl etc.

As this C _1-6Alkoxy carbonyl; Can enumerate out methoxycarbonyl, trifluoromethoxy carbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxy carbonyl, i-butoxy carbonyl, s-butoxy carbonyl, t-butoxy carbonyl, 1-amyl group oxygen base carbonyl, 2-amyl group oxygen base carbonyl, 3-amyl group oxygen base carbonyl, i-amyl group oxygen base carbonyl, neo-pentyl oxygen base carbonyl, t-amyl group oxygen base carbonyl, 1-hexyl oxygen base carbonyl, 2-hexyl oxygen base carbonyl and 3-hexyl oxygen base carbonyl etc.

As this C _1-6Alkyl sulphonyl can be enumerated out methane sulfonyl, trifluoromethane sulfonyl group, ethane alkylsulfonyl, n-propane alkylsulfonyl and n-butane alkylsulfonyl etc.,

As this C _6-14Aryl sulfonyl; Can enumerate out benzenesulfonyl, p-fluorobenzene alkylsulfonyl, p-tosyl group, o-biphenyl sulfonyl, m-biphenyl sulfonyl, p-biphenyl sulfonyl, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base, 1-anthracene alkylsulfonyl, 2-anthracene alkylsulfonyl, 9-anthracene alkylsulfonyl, the luxuriant and rich with fragrance alkylsulfonyl of 1-, the luxuriant and rich with fragrance alkylsulfonyl of 2-, the luxuriant and rich with fragrance alkylsulfonyl of 3-, the luxuriant and rich with fragrance alkylsulfonyl of 4-and the luxuriant and rich with fragrance alkylsulfonyl of 9-etc.

As this C _6-14Aryl carbonyl can be enumerated out phenylcarbonyl group, p-fluorophenyl carbonyl, o-xenyl carbonyl, m-xenyl carbonyl, p-xenyl carbonyl, 1-naphthyl carbonyl, 2-naphthyl carbonyl, 1-anthryl carbonyl, 2-anthryl carbonyl, 9-anthryl carbonyl, 1-phenanthryl carbonyl, 2-phenanthryl carbonyl, 3-phenanthryl carbonyl, 4-phenanthryl carbonyl and 9-phenanthryl carbonyl etc.

About above-mentioned R ¹¹, preferred atom and substituting group are specified.

R ¹¹Be preferably fluorine atom, chlorine atom, bromine atoms, methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, n-amyl group, i-amyl group, 3; 3-dimethyl--n-butyl, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, trifluoromethyl carbonylamino methyl, ethyl carbonylamino methyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, trifluoromethoxy carbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl, ethoxy carbonyl ethyl, methoxyl group, trifluoromethoxy, oxyethyl group, n-propoxy-, i-propoxy-, 3,3-dimethyl--n-butoxy, methyl ketonic oxygen ylmethoxy, ethyl ketonic oxygen ylmethoxy, methyl ketonic oxygen base oxethyl, ethyl ketonic oxygen base oxethyl, methyl carbonylamino methoxyl group, trifluoromethyl carbonylamino methoxyl group, ethyl carbonylamino methoxyl group, methyl carbonylamino oxyethyl group, ethyl carbonylamino oxyethyl group, methoxycarbonyl methoxyl group, trifluoromethoxy carbonyl methoxyl group, ethoxycarbonyl methoxy, methoxycarbonyl oxyethyl group, ethoxy carbonyl oxyethyl group, methylamino, trifluoromethyl amino, ethylamino, n-propyl group amino, i-propyl group amino, n-butyl amino, dimethylamino, two-(trifluoromethyl) amino, diethylamino, two-n-propyl group amino, two-i-propyl group amino, two-n-butyl amino, methyl carbonylamino, trifluoromethyl carbonylamino, ethyl carbonylamino, n-propyl group carbonylamino, i-propyl group carbonylamino, n-butyl carbonylamino, methylsulfonyl amido, fluoroform sulfoamido, ethane sulphonamide base, n-propane sulfoamido, i-propane sulfoamido, n-butane sulfoamido, benzene sulfonamido, p-tolylsulfonyl amido, methylamino carbonyl, trifluoromethyl aminocarboxyl, ethylamino carbonyl, n-propyl group aminocarboxyl, i-propyl group aminocarboxyl, n-butyl aminocarboxyl, dimethylamino carbonyl, two (trifluoromethyl) aminocarboxyl, diethylamino carbonyl, two-n-propyl group aminocarboxyl, two-i-propyl group aminocarboxyl, two-c-propyl group aminocarboxyl, two-n-butyl aminocarboxyl, methyl (ethyl) aminocarboxyl, trifluoromethyl (ethyl) aminocarboxyl, methyl carbonyl, trifluoromethyl carbonyl, ethyl carbonyl, n-propyl group carbonyl, i-propyl group carbonyl, n-butyl carbonyl, methoxycarbonyl, trifluoromethoxy carbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxy carbonyl, i-butoxy carbonyl, s-butoxy carbonyl, t-butoxy carbonyl, methane sulfonyl, trifluoromethane sulfonyl group, ethane alkylsulfonyl, benzenesulfonyl, o-biphenyl sulfonyl, m-biphenyl sulfonyl, p-biphenyl sulfonyl, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base, phenylcarbonyl group, o-xenyl carbonyl, m-xenyl carbonyl, p-xenyl carbonyl, 1-naphthyl carbonyl, 2-naphthyl carbonyl, hydroxyl, nitro, cyanic acid, formyl radical, formamido-, formamyl, sulfoamino-, sulfamyl, amino, carboxyl.

To the part ring structure A in above-mentioned formula (11) and the formula (12) by 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)

Above-mentioned 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), the R in formula (w), formula (x), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae), formula (af), formula (ag) and the formula (ah) under the situation of expression ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Each substituting group describe.

At first, to above-mentioned 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), the R in formula (w), formula (x), formula (ab), formula (ae), formula (af) and the formula (ag) ¹²And R ¹³Describe.

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), the R in formula (w), formula (x), formula (ab), formula (ae), formula (af) and the formula (ag) ¹²And R ¹³Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, hydroxyl, C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by q R for heteroaryl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily), C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl oxygen base, C _1-6Alkyl-carbonyl (this alkyl-carbonyl oxygen base and alkyl-carbonyl can be replaced arbitrarily by halogen atom), C _1-6Alkyl-carbonyl-amino, C _3-8Naphthene base carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl (this naphthene base carbonyl, alkoxy carbonyl and alkyl sulphonyl can be replaced arbitrarily by halogen atom), carboxyl, C _6-14Aryl carbonyl (this aryl carbonyl can be replaced arbitrarily by halogen atom) or C _2-9The heteroaryl carbonyl replaces arbitrarily), C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by q R for heteroaryl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily), C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _3-8Naphthene base carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl, C _6-14Aryl sulfonyl, C _2-9(this aryl sulfonyl and heteroarylsulfonyl can be by q R for heteroarylsulfonyl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily), carboxyl, C _6-14Aryl carbonyl or C _2-9(this aryl carbonyl and heteroaryl carbonyl can be by q R for the heteroaryl carbonyl ¹⁸(R ¹⁸Expression and R ¹¹Identical implication, q representes 1～3 integer, is under 2 or 3 the situation at q, R ¹⁸Can be the same or different) replace arbitrarily).

To above-mentioned 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), the R in formula (w), formula (x), formula (ab), formula (ae), formula (af) and the formula (ag) ¹²And R ¹³Each substituting group specify.

As this C _1-6Alkyl; Can enumerate out methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, n-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2; 2-dimethyl propyl, n-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1; 1; 2-trimethylammonium-n-propyl group, 1,2,2-trimethylammonium-n-propyl group, 3; 3-dimethyl--n-butyl, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, trifluoromethyl carbonylamino methyl, ethyl carbonylamino methyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl and ethoxy carbonyl ethyl etc.

As this C _2-9Heteroaryl comprises the C of 5～7 Yuans rings that can contain 1～3 Sauerstoffatom, nitrogen-atoms, sulphur atom alone or in combination _2-6Monocyclic type heteroaromatic base and constituting atom number are 8～10 C _5-9Condensation two ring type heterocyclic radicals.

C as these 5～7 Yuans rings _2-6The monocyclic type heteroaromatic base can be enumerated out 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 1-pyrryl, 2-pyrryl, 3-pyrryl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 2-1,3; 4-oxadiazole base, 2-1,3,4-thiadiazolyl group, 3-1; 2,4-oxadiazole base, 5-1,2; 4-oxadiazole base, 3-1,2,4-thiadiazolyl group, 5-1; 2,4-thiadiazolyl group, 3-1,2; 5-oxadiazole base and 3-1; 2,5-thiadiazolyl group etc. are this C of 8～10 as the constituting atom number _5-9Condensation two ring type heterocyclic radicals; Can enumerate out 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl, 1-isobenzofuran-base, 4-isobenzofuran-base, 5-isobenzofuran-base, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-isobenzo-thienyl, 4-isobenzo-thienyl, 5-isobenzo-thienyl, 2-chromenyl (chromenyl), 3-chromenyl, 4-chromenyl, 5-chromenyl, 6-chromenyl, 7-chromenyl, 8-chromenyl, 1-pyrrocoline base (Indolizinyl), 2-pyrrocoline base, 3-pyrrocoline base, 5-pyrrocoline base, 6-pyrrocoline base, 7-pyrrocoline base, 8-pyrrocoline base, 1-pseudoindoyl, 2-pseudoindoyl, 4-pseudoindoyl, 5-pseudoindoyl, 1-indyl, 2-indyl, 3-indyl, 4-indyl, 5-indyl, 6-indyl, 7-indyl, 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl, 1-purine radicals, 2-purine radicals, 3-purine radicals, 6-purine radicals, 7-purine radicals, 8-purine radicals, 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-quinazolyl, 4-quinazolyl, 5-quinazolyl, 6-quinazolyl, 7-quinazolyl, 8-quinazolyl, 3-cinnolines base, 4-cinnolines base, 5-cinnolines base, 6-cinnolines base, 7-cinnolines base, 8-cinnolines base, 2-pteridine radicals, 4-pteridine radicals, 6-pteridine radicals and 7-pteridine radicals etc.

As this C _1-6Alkyl amino-carbonyl; Can enumerate out methylamino carbonyl, ethylamino carbonyl, n-propyl group aminocarboxyl, i-propyl group aminocarboxyl, n-butyl aminocarboxyl, i-butyl aminocarboxyl, s-butyl aminocarboxyl, tertiary butyl aminocarboxyl, 1-amyl group aminocarboxyl, 2-amyl group aminocarboxyl, 3-amyl group aminocarboxyl, i-amyl group aminocarboxyl, neo-pentyl aminocarboxyl, t-amyl group aminocarboxyl, 1-hexyl aminocarboxyl, 2-hexyl aminocarboxyl and 3-hexyl aminocarboxyl etc.

As this two C _1-6Alkyl amino-carbonyl; Can enumerate out the dimethylamino carbonyl; The diethylamino carbonyl; Two-n-propyl group aminocarboxyl; Two-i-propyl group aminocarboxyl; Two-c-propyl group aminocarboxyl; Two-n-butyl aminocarboxyl; Two-i-butyl aminocarboxyl; Two-s-butyl aminocarboxyl; Two-tertiary butyl aminocarboxyl; Two-c-butyl aminocarboxyl; Two-1-amyl group aminocarboxyl; Two-2-amyl group aminocarboxyl; Two-3-amyl group aminocarboxyl; Two-i-amyl group aminocarboxyl; Two-neo-pentyl aminocarboxyl; Two-t-amyl group aminocarboxyl; Two-c-amyl group aminocarboxyl; Two-1-hexyl aminocarboxyl; Two-2-hexyl aminocarboxyl; Two-3-hexyl aminocarboxyl; Two-c-hexyl aminocarboxyl; Two-(1-methyl-n-amyl group) aminocarboxyls; Two-(1; 1; 2-trimethylammonium-n-propyl group) aminocarboxyl; Two-(1; 2; 2-trimethylammonium-n-propyl group) aminocarboxyl; Two-(3; 3-dimethyl--n-butyl) aminocarboxyl; Methyl (ethyl) aminocarboxyl; Methyl (n-propyl group) aminocarboxyl; Methyl (i-propyl group) aminocarboxyl; Methyl (c-propyl group) aminocarboxyl; Methyl (n-butyl) aminocarboxyl; Methyl (i-butyl) aminocarboxyl; Methyl (s-butyl) aminocarboxyl; Methyl (t-butyl) aminocarboxyl; Methyl (c-butyl) aminocarboxyl; Ethyl (n-propyl group) aminocarboxyl; Ethyl (i-propyl group) aminocarboxyl; Ethyl (c-propyl group) aminocarboxyl; Ethyl (n-butyl) aminocarboxyl; Ethyl (i-butyl) aminocarboxyl; Ethyl (s-butyl) aminocarboxyl; Ethyl (t-butyl) aminocarboxyl; Ethyl (c-butyl) aminocarboxyl; N-propyl group (i-propyl group) aminocarboxyl; N-propyl group (c-propyl group) aminocarboxyl; N-propyl group (n-butyl) aminocarboxyl; N-propyl group (i-butyl) aminocarboxyl; N-propyl group (s-butyl) aminocarboxyl; N-propyl group (t-butyl) aminocarboxyl; N-propyl group (c-butyl) aminocarboxyl; I-propyl group (c-propyl group) aminocarboxyl; I-propyl group (n-butyl) aminocarboxyl; I-propyl group (i-butyl) aminocarboxyl; I-propyl group (s-butyl) aminocarboxyl; I-propyl group (t-butyl) aminocarboxyl; I-propyl group (c-butyl) aminocarboxyl; C-propyl group (n-butyl) aminocarboxyl; C-propyl group (i-butyl) aminocarboxyl; C-propyl group (s-butyl) aminocarboxyl; C-propyl group (t-butyl) aminocarboxyl; C-propyl group (c-butyl) aminocarboxyl; N-butyl (i-butyl) aminocarboxyl; N-butyl (s-butyl) aminocarboxyl; N-butyl (t-butyl) aminocarboxyl; N-butyl (c-butyl) aminocarboxyl; I-butyl (s-butyl) aminocarboxyl; I-butyl (t-butyl) aminocarboxyl; I-butyl (c-butyl) aminocarboxyl; S-butyl (t-butyl) aminocarboxyl; S-butyl (c-butyl) aminocarboxyl and the tertiary butyl (c-butyl) aminocarboxyl etc.

As this C _1-6Alkyl-carbonyl; Can enumerate out methyl carbonyl, ethyl carbonyl, n-propyl group carbonyl, i-propyl group carbonyl, n-butyl carbonyl, i-butyl carbonyl, s-butyl carbonyl, tertiary butyl carbonyl, 1-amyl group carbonyl, 2-amyl group carbonyl, 3-amyl group carbonyl, i-amyl group carbonyl, neo-pentyl carbonyl, t-amyl group carbonyl, 1-hexyl carbonyl, 2-hexyl carbonyl and 3-hexyl carbonyl

As this C _3-8Naphthene base carbonyl; Can enumerate out c-propyl group carbonyl, c-butyl carbonyl, 1-methyl-c-propyl group carbonyl, 2-methyl-c-propyl group carbonyl, c-amyl group carbonyl, 1-methyl-c-butyl carbonyl, 2-methyl-c-butyl carbonyl, 3-methyl-c-butyl carbonyl, 1; 2-dimethyl--c-propyl group carbonyl, 2; 3-dimethyl--c-propyl group carbonyl, 1-ethyl-c-propyl group carbonyl, 2-ethyl-c-propyl group carbonyl, c-hexyl carbonyl, c-heptyl carbonyl, c-octyl group carbonyl, 1-methyl-c-hexyl carbonyl, 2-methyl-c-hexyl carbonyl, 3-methyl-c-hexyl carbonyl, 1; 2-dimethyl--c-hexyl carbonyl, 2,3-dimethyl--c-propyl group carbonyl, 1-ethyl-c-propyl group carbonyl, 1-methyl-c-amyl group carbonyl, 2-methyl-c-amyl group carbonyl, 3-methyl-c-amyl group carbonyl, 1-ethyl-c-butyl carbonyl, 2-ethyl-c-butyl carbonyl, 3-ethyl-c-butyl carbonyl, 1,2-dimethyl--c-butyl carbonyl, 1; 3-dimethyl--c-butyl carbonyl, 2; 2-dimethyl--c-butyl carbonyl, 2,3-dimethyl--c-butyl carbonyl, 2,4-dimethyl--c-butyl carbonyl, 3; 3-dimethyl--c-butyl carbonyl, 1-n-propyl group-c-propyl group carbonyl, 2-n-propyl group-c-propyl group carbonyl, 1-i-propyl group-c-propyl group carbonyl, 2-i-propyl group-c-propyl group carbonyl, 1; 2,2-trimethylammonium-c-propyl group carbonyl, 1,2; 3-trimethylammonium-c-propyl group carbonyl, 2; 2,3-trimethylammonium-c-propyl group carbonyl, 1-ethyl-2-methyl-c-propyl group carbonyl, 2-ethyl-1-methyl-c-propyl group carbonyl, 2-ethyl-2-methyl-c-propyl group carbonyl and 2-ethyl-3-methyl-c-propyl group carbonyl etc.

As this C _1-6Alkoxy carbonyl; Can enumerate out methoxycarbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxy carbonyl, i-butoxy carbonyl, s-butoxy carbonyl, t-butoxy carbonyl, 1-amyl group oxygen base carbonyl, 2-amyl group oxygen base carbonyl, 3-amyl group oxygen base carbonyl, i-amyl group oxygen base carbonyl, neo-pentyl oxygen base carbonyl, t-amyl group oxygen base carbonyl, 1-hexyl oxygen base carbonyl, 2-hexyl oxygen base carbonyl and 3-hexyl oxygen base carbonyl etc.

As this C _1-6Alkyl sulphonyl can be enumerated out methane sulfonyl, trifluoromethane sulfonyl group and ethane alkylsulfonyl,

As this C _6-14Aryl sulfonyl can be enumerated out benzenesulfonyl, o-biphenyl sulfonyl, m-biphenyl sulfonyl, p-biphenyl sulfonyl, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base, 1-anthracene alkylsulfonyl, 2-anthracene alkylsulfonyl, 9-anthracene alkylsulfonyl, the luxuriant and rich with fragrance alkylsulfonyl of 1-, the luxuriant and rich with fragrance alkylsulfonyl of 2-, the luxuriant and rich with fragrance alkylsulfonyl of 3-, the luxuriant and rich with fragrance alkylsulfonyl of 4-and the luxuriant and rich with fragrance alkylsulfonyl of 9-etc.

As this C _2-9Heteroarylsulfonyl comprises the C of 5～7 Yuans rings that can contain 1～3 Sauerstoffatom, nitrogen-atoms, sulphur atom alone or in combination _2-6Monocyclic type heteroaromatic alkylsulfonyl and constituting atom number are 8～10 C _5-9Condensation two ring type heterocycle alkylsulfonyls.

C as these 5～7 Yuans rings _2-6The monocyclic type heteroaromatic alkylsulfonyl; Can enumerate out 2-thienyl sulphonyl base, 3-thienyl sulphonyl base, 2-furyl alkylsulfonyl, 3-furyl alkylsulfonyl, 2-pyranyl alkylsulfonyl, 3-pyranyl alkylsulfonyl, 4-pyranyl alkylsulfonyl, 1-pyrryl alkylsulfonyl, 2-pyrryl alkylsulfonyl, 3-pyrryl alkylsulfonyl, 1-imidazolyl alkylsulfonyl, 2-imidazolyl alkylsulfonyl, 4-imidazolyl alkylsulfonyl, 1-pyrazolyl alkylsulfonyl, 3-pyrazolyl alkylsulfonyl, 4-pyrazolyl alkylsulfonyl, 2-thiazolyl alkylsulfonyl, 4-thiazolyl alkylsulfonyl, 5-thiazolyl alkylsulfonyl, 3-isothiazolyl alkylsulfonyl, 4-isothiazolyl alkylsulfonyl, 5-isothiazolyl alkylsulfonyl, 2-oxazolyl alkylsulfonyl, 4-oxazolyl alkylsulfonyl, 5-oxazolyl alkylsulfonyl, 3-isoxazolyl alkylsulfonyl, 4-isoxazolyl alkylsulfonyl, 5-isoxazolyl alkylsulfonyl, 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, 2-pyrazinyl alkylsulfonyl, 2-pyrimidyl alkylsulfonyl, 4-pyrimidyl alkylsulfonyl, 5-pyrimidyl alkylsulfonyl, 3-pyridazinyl alkylsulfonyl, 4-pyridazinyl alkylsulfonyl, 2-1; 3; 4-oxadiazole base alkylsulfonyl, 2-1,3,4-thiadiazolyl group alkylsulfonyl, 3-1; 2; 4-oxadiazole base alkylsulfonyl, 5-1,2,4-oxadiazole base alkylsulfonyl, 3-1; 2; 4-thiadiazolyl group alkylsulfonyl, 5-1,2,4-thiadiazolyl group alkylsulfonyl, 3-1; 2; 5-oxadiazole base alkylsulfonyl and 3-1,2,5-thiadiazolyl group alkylsulfonyl etc.

As the constituting atom number this C of 8～10 _5-9Condensation two ring type heterocycle alkylsulfonyls; Can enumerate out 2-benzofuryl alkylsulfonyl, 3-benzofuryl alkylsulfonyl, 4-benzofuryl alkylsulfonyl, 5-benzofuryl alkylsulfonyl, 6-benzofuryl alkylsulfonyl, 7-benzofuryl alkylsulfonyl, 1-isobenzofuran-base alkylsulfonyl, 4-isobenzofuran-base alkylsulfonyl, 5-isobenzofuran-base alkylsulfonyl, 2-benzothienyl alkylsulfonyl, 3-benzothienyl alkylsulfonyl, 4-benzothienyl alkylsulfonyl, 5-benzothienyl alkylsulfonyl, 6-benzothienyl alkylsulfonyl, 7-benzothienyl alkylsulfonyl, 1-isobenzo-thienyl alkylsulfonyl, 4-isobenzo-thienyl alkylsulfonyl, 5-isobenzo-thienyl alkylsulfonyl, 2-chromenyl alkylsulfonyl, 3-chromenyl alkylsulfonyl, 4-chromenyl alkylsulfonyl, 5-chromenyl alkylsulfonyl, 6-chromenyl alkylsulfonyl, 7-chromenyl alkylsulfonyl, 8-chromenyl alkylsulfonyl, 1-pyrrocoline base alkylsulfonyl, 2-pyrrocoline base alkylsulfonyl, 3-pyrrocoline base alkylsulfonyl, 5-pyrrocoline base alkylsulfonyl, 6-pyrrocoline base alkylsulfonyl, 7-pyrrocoline base alkylsulfonyl, 8-pyrrocoline base alkylsulfonyl, 1-pseudoindoyl alkylsulfonyl, 2-pseudoindoyl alkylsulfonyl, 4-pseudoindoyl alkylsulfonyl, 5-pseudoindoyl alkylsulfonyl, 1-indyl alkylsulfonyl, 2-indyl alkylsulfonyl, 3-indyl alkylsulfonyl, 4-indyl alkylsulfonyl, 5-indyl alkylsulfonyl, 6-indyl alkylsulfonyl, 7-indyl alkylsulfonyl, 1-indazolyl alkylsulfonyl, 2-indazolyl alkylsulfonyl, 3-indazolyl alkylsulfonyl, 4-indazolyl alkylsulfonyl, 5-indazolyl alkylsulfonyl, 6-indazolyl alkylsulfonyl, 7-indazolyl alkylsulfonyl, 1-purine radicals alkylsulfonyl, 2-purine radicals alkylsulfonyl, 3-purine radicals alkylsulfonyl, 6-purine radicals alkylsulfonyl, 7-purine radicals alkylsulfonyl, 8-purine radicals alkylsulfonyl, 2-quinolyl alkylsulfonyl, 3-quinolyl alkylsulfonyl, 4-quinolyl alkylsulfonyl, 5-quinolyl alkylsulfonyl, 6-quinolyl alkylsulfonyl, 7-quinolyl alkylsulfonyl, 8-quinolyl alkylsulfonyl, 1-isoquinolyl alkylsulfonyl, 3-isoquinolyl alkylsulfonyl, 4-isoquinolyl alkylsulfonyl, 5-isoquinolyl alkylsulfonyl, 6-isoquinolyl alkylsulfonyl, 7-isoquinolyl alkylsulfonyl, 8-isoquinolyl alkylsulfonyl, 1-phthalazinyl alkylsulfonyl, 5-phthalazinyl alkylsulfonyl, 6-phthalazinyl alkylsulfonyl, 1-2,7-naphthyridinyl alkylsulfonyl, 3-2; 7-naphthyridinyl alkylsulfonyl, 4-2; 7-naphthyridinyl alkylsulfonyl, 1-2; 6-naphthyridinyl alkylsulfonyl, 3-2; 6-naphthyridinyl alkylsulfonyl, 4-2; 6-naphthyridinyl alkylsulfonyl, 2-1; 8-naphthyridinyl alkylsulfonyl, 3-1; 8-naphthyridinyl alkylsulfonyl, 4-1; 8-naphthyridinyl alkylsulfonyl, 2-1,7-naphthyridinyl alkylsulfonyl, 3-1,7-naphthyridinyl alkylsulfonyl, 4-1; 7-naphthyridinyl alkylsulfonyl, 5-1; 7-naphthyridinyl alkylsulfonyl, 6-1,7-naphthyridinyl alkylsulfonyl, 8-1,7-naphthyridinyl alkylsulfonyl, 2-1; 6-naphthyridinyl alkylsulfonyl, 3-1; 6-naphthyridinyl alkylsulfonyl, 4-1,6-naphthyridinyl alkylsulfonyl, 5-1,6-naphthyridinyl alkylsulfonyl, 7-1; 6-naphthyridinyl alkylsulfonyl, 8-1; 6-naphthyridinyl alkylsulfonyl, 2-1,5-naphthyridinyl alkylsulfonyl, 3-1,5-naphthyridinyl alkylsulfonyl, 4-1; 5-naphthyridinyl alkylsulfonyl, 6-1; 5-naphthyridinyl alkylsulfonyl, 7-1,5-naphthyridinyl alkylsulfonyl, 8-1,5-naphthyridinyl alkylsulfonyl, 2-quinoxalinyl alkylsulfonyl, 5-quinoxalinyl alkylsulfonyl, 6-quinoxalinyl alkylsulfonyl, 2-quinazolyl alkylsulfonyl, 4-quinazolyl alkylsulfonyl, 5-quinazolyl alkylsulfonyl, 6-quinazolyl alkylsulfonyl, 7-quinazolyl alkylsulfonyl, 8-quinazolyl alkylsulfonyl, 3-cinnolines base alkylsulfonyl, 4-cinnolines base alkylsulfonyl, 5-cinnolines base alkylsulfonyl, 6-cinnolines base alkylsulfonyl, 7-cinnolines base alkylsulfonyl, 8-cinnolines base alkylsulfonyl, 2-pteridine radicals alkylsulfonyl, 4-pteridine radicals alkylsulfonyl, 6-pteridine radicals alkylsulfonyl and 7-pteridine radicals alkylsulfonyl etc.

As this C _6-14Aryl carbonyl can be enumerated out phenylcarbonyl group, o-xenyl carbonyl, m-xenyl carbonyl, p-xenyl carbonyl, 1-naphthyl carbonyl, 2-naphthyl carbonyl, 1-anthryl carbonyl, 2-anthryl carbonyl, 9-anthryl carbonyl, 1-phenanthryl carbonyl, 2-phenanthryl carbonyl, 3-phenanthryl carbonyl, 4-phenanthryl carbonyl and 9-phenanthryl carbonyl etc.

As this C _2-9The heteroaryl carbonyl comprises the C of 5～7 Yuans rings that can contain 1～3 Sauerstoffatom, nitrogen-atoms, sulphur atom alone or in combination _2-6Monocyclic type heteroaromatic carbonyl and constituting atom number are 8～10 C _5-9Condensation two ring type heterocycle carbonyls.

C as these 5～7 Yuans rings _2-6The monocyclic type heteroaromatic carbonyl; Can enumerate out 2-thienyl carbonyl, 3-thienyl carbonyl, 2-furyl carbonyl, 3-furyl carbonyl, 2-pyranyl carbonyl, 3-pyranyl carbonyl, 4-pyranyl carbonyl, 1-pyrryl carbonyl, 2-pyrryl carbonyl, 3-pyrryl carbonyl, 1-imidazolyl carbonyl, 2-imidazolyl carbonyl, 4-imidazolyl carbonyl, 1-pyrazolyl carbonyl, 3-pyrazolyl carbonyl, 4-pyrazolyl carbonyl, 2-thiazolyl carbonyl, 4-thiazolyl carbonyl, 5-thiazolyl carbonyl, 3-isothiazolyl carbonyl, 4-isothiazolyl carbonyl, 5-isothiazolyl carbonyl, 2-oxazolyl carbonyl, 4-oxazolyl carbonyl, 5-oxazolyl carbonyl, 3-isoxazolyl carbonyl, 4-isoxazolyl carbonyl, 5-isoxazolyl carbonyl, 2-pyridyl carbonyl, 3-pyridyl carbonyl, 4-pyridyl carbonyl, 2-pyrazinyl carbonyl, 2-pyrimidyl carbonyl, 4-pyrimidyl carbonyl, 5-pyrimidyl carbonyl, 3-pyridazinyl carbonyl, 4-pyridazinyl carbonyl, 2-1,3,4-oxadiazole base carbonyl, 2-1; 3; 4-thiadiazolyl group carbonyl, 3-1,2,4-oxadiazole base carbonyl, 5-1; 2; 4-oxadiazole base carbonyl, 3-1,2,4-thiadiazolyl group carbonyl, 5-1; 2; 4-thiadiazolyl group carbonyl, 3-1,2,5-oxadiazole base carbonyl and 3-1; 2,5-thiadiazolyl group carbonyl etc.

As the constituting atom number this C of 8～10 _5-9Condensation two ring type heterocycle carbonyls; Can enumerate out 2-benzofuryl carbonyl, 3-benzofuryl carbonyl, 4-benzofuryl carbonyl, 5-benzofuryl carbonyl, 6-benzofuryl carbonyl, 7-benzofuryl carbonyl, 1-isobenzofuran-base carbonyl, 4-isobenzofuran-base carbonyl, 5-isobenzofuran-base carbonyl, 2-benzothienyl carbonyl, 3-benzothienyl carbonyl, 4-benzothienyl carbonyl, 5-benzothienyl carbonyl, 6-benzothienyl carbonyl, 7-benzothienyl carbonyl, 1-isobenzo-thienyl carbonyl, 4-isobenzo-thienyl carbonyl, 5-isobenzo-thienyl carbonyl, 2-chromenyl carbonyl, 3-chromenyl carbonyl, 4-chromenyl carbonyl, 5-chromenyl carbonyl, 6-chromenyl carbonyl, 7-chromenyl carbonyl, 8-chromenyl carbonyl, 1-pyrrocoline base carbonyl, 2-pyrrocoline base carbonyl, 3-pyrrocoline base carbonyl, 5-pyrrocoline base carbonyl, 6-pyrrocoline base carbonyl, 7-pyrrocoline base carbonyl, 8-pyrrocoline base carbonyl, 1-pseudoindoyl carbonyl, 2-pseudoindoyl carbonyl, 4-pseudoindoyl carbonyl, 5-pseudoindoyl carbonyl, 1-indole carbonyl, 2-indole carbonyl, 3-indole carbonyl, 4-indole carbonyl, 5-indole carbonyl, 6-indole carbonyl, 7-indole carbonyl, 1-indazolyl carbonyl, 2-indazolyl carbonyl, 3-indazolyl carbonyl, 4-indazolyl carbonyl, 5-indazolyl carbonyl, 6-indazolyl carbonyl, 7-indazolyl carbonyl, 1-purine radicals carbonyl, 2-purine radicals carbonyl, 3-purine radicals carbonyl, 6-purine radicals carbonyl, 7-purine radicals carbonyl, 8-purine radicals carbonyl, 2-quinolyl carbonyl, 3-quinolyl carbonyl, 4-quinolyl carbonyl, 5-quinolyl carbonyl, 6-quinolyl carbonyl, 7-quinolyl carbonyl, 8-quinolyl carbonyl, 1-isoquinolyl carbonyl, 3-isoquinolyl carbonyl, 4-isoquinolyl carbonyl, 5-isoquinolyl carbonyl, 6-isoquinolyl carbonyl, 7-isoquinolyl carbonyl, 8-isoquinolyl carbonyl, 1-phthalazinyl carbonyl, 5-phthalazinyl carbonyl, 6-phthalazinyl carbonyl, 1-2; 7-naphthyridinyl carbonyl, 3-2; 7-naphthyridinyl carbonyl, 4-2; 7-naphthyridinyl carbonyl, 1-2; 6-naphthyridinyl carbonyl, 3-2; 6-naphthyridinyl carbonyl, 4-2; 6-naphthyridinyl carbonyl, 2-1; 8-naphthyridinyl carbonyl, 3-1,8-naphthyridinyl carbonyl, 4-1,8-naphthyridinyl carbonyl, 2-1; 7-naphthyridinyl carbonyl, 3-1; 7-naphthyridinyl carbonyl, 4-1,7-naphthyridinyl carbonyl, 5-1,7-naphthyridinyl carbonyl, 6-1; 7-naphthyridinyl carbonyl, 8-1; 7-naphthyridinyl carbonyl, 2-1,6-naphthyridinyl carbonyl, 3-1,6-naphthyridinyl carbonyl, 4-1; 6-naphthyridinyl carbonyl, 5-1; 6-naphthyridinyl carbonyl, 7-1,6-naphthyridinyl carbonyl, 8-1,6-naphthyridinyl carbonyl, 2-1; 5-naphthyridinyl carbonyl, 3-1; 5-naphthyridinyl carbonyl, 4-1,5-naphthyridinyl carbonyl, 6-1,5-naphthyridinyl carbonyl, 7-1; 5-naphthyridinyl carbonyl, 8-1,5-naphthyridinyl carbonyl, 2-quinoxalinyl carbonyl, 5-quinoxalinyl carbonyl, 6-quinoxalinyl carbonyl, 2-quinazolyl carbonyl, 4-quinazolyl carbonyl, 5-quinazolyl carbonyl, 6-quinazolyl carbonyl, 7-quinazolyl carbonyl, 8-quinazolyl carbonyl, 3-cinnolines base carbonyl, 4-cinnolines base carbonyl, 5-cinnolines base carbonyl, 6-cinnolines base carbonyl, 7-cinnolines base carbonyl, 8-cinnolines base carbonyl, 2-pteridine radicals carbonyl, 4-pteridine radicals carbonyl, 6-pteridine radicals carbonyl and 7-pteridine radicals carbonyl etc.

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), the R in formula (w), formula (x), formula (ab), formula (ae), formula (af) and the formula (ag) ¹²And R ¹³, be preferably Wasserstoffatoms, methyl, ethyl, n-propyl group, i-propyl group, n-butyl, n-amyl group, i-amyl group, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, ethyl carbonylamino ethyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl, ethoxy carbonyl ethyl, phenyl, o-xenyl, m-xenyl, p-xenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, methylamino carbonyl, ethylamino carbonyl, n-propyl group aminocarboxyl, i-propyl group aminocarboxyl, n-butyl aminocarboxyl, dimethylamino carbonyl, diethylamino carbonyl, two-n-propyl group aminocarboxyl, two-i-propyl group aminocarboxyl, two-c-propyl group aminocarboxyl, two-n-butyl aminocarboxyl, methyl carbonyl, ethyl carbonyl, n-propyl group carbonyl, i-propyl group carbonyl, n-butyl carbonyl, c-amyl group carbonyl, c-hexyl carbonyl, methoxycarbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxy carbonyl, i-butoxy carbonyl, s-butoxy carbonyl, t-butoxy carbonyl, methane sulfonyl, trifluoromethane sulfonyl group, benzenesulfonyl, o-biphenyl sulfonyl, m-biphenyl sulfonyl, p-biphenyl sulfonyl, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base, 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, phenylcarbonyl group, o-xenyl carbonyl, m-xenyl carbonyl, p-xenyl carbonyl, 1-naphthyl carbonyl, 2-naphthyl carbonyl, 2-pyridyl carbonyl, 3-pyridyl carbonyl, 4-pyridyl carbonyl.More preferably Wasserstoffatoms, methyl.

Then, to 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), the R in formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and the formula (af) ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Describe.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), the R in formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and the formula (af) ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Represent Wasserstoffatoms, halogen atom, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, hydroxyl, C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl oxygen base, C _1-6Alkyl-carbonyl (this alkyl-carbonyl oxygen base and alkyl-carbonyl can be replaced arbitrarily by halogen atom), C _1-6Alkyl-carbonyl-amino, C _3-8Naphthene base carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkyl sulphonyl (this naphthene base carbonyl, alkoxy carbonyl and alkyl sulphonyl can be replaced arbitrarily by halogen atom), carboxyl, C _6-14Aryl carbonyl (this aryl carbonyl can be replaced arbitrarily by halogen atom) or C _2-9The heteroaryl carbonyl replaces arbitrarily), C _3-8(this naphthenic base can be by halogen atom, C for naphthenic base _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino or hydroxyl replace arbitrarily), C _1-6(this alkoxyl group can be by halogen atom, C for alkoxyl group _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), carboxyl, amino, hydroxyl, C _6-14Aryl or C _2-9(this aryl and heteroaryl can be by R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily) replace arbitrarily), C _1-6(this thio alkoxy can be by halogen atom, C for thio alkoxy _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), carboxyl, hydroxyl, C _6-14Aryl or C _2-9(this aryl and heteroaryl can be by R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily) replace arbitrarily), hydroxyl, C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkyl-carbonyl oxygen base, nitro, cyanic acid, formyl radical, formamido-, amino, sulfo group, C _1-6Alkylamino, two C _1-6Alkylamino, C _6-14Arylamino, C _2-9(this arylamino and heteroaryl amino can be by R for heteroaryl amino ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkyl-carbonyl-amino, C _1-6Alkylsulfonamido, formamyl, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _6-14Aryl carbonyl, C _2-9(this aryl carbonyl and heteroaryl carbonyl can be by R for the heteroaryl carbonyl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), C _1-6Alkoxy carbonyl, sulfamyl, C _1-6Alkyl sulphonyl, C _6-14Aryl sulfonyl, C _2-9(this aryl sulfonyl and heteroarylsulfonyl can be by R for heteroarylsulfonyl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), carboxyl or C _2-9(this heterocyclic radical can be by halogen atom, C for heterocyclic radical _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, carboxyl or hydroxyl replace arbitrarily), C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), C _6-14Aryl, C _2-9(this aryl and heteroaryl can be by R for heteroaryl ¹⁹(R ¹⁹Expression and R ¹¹Identical implication, r representes the implication identical with q) replace arbitrarily), hydroxyl, nitro, cyanic acid, formyl radical, formamido-, amino, C _1-6Alkylamino, two C _1-6Alkylamino, C _1-6Alkyl-carbonyl-amino, C _1-6Alkylsulfonamido, formamyl, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, sulfamyl, C _1-6Alkyl sulphonyl, carboxyl or C _6-14Aryl carbonyl replaces arbitrarily).

To 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), the R in formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and the formula (af) ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Each atom and each substituting group specify.As this halogen atom, can enumerate out fluorine atom, chlorine atom, bromine atoms and iodine atom, as this C _1-6Alkyl; Can enumerate out methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, n-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2; 2-dimethyl propyl, n-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1; 1; 2-trimethylammonium-n-propyl group, 1,2,2-trimethylammonium-n-propyl group and 3; 3-dimethyl--n-butyl, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, ethyl carbonylamino methyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl and ethoxy carbonyl ethyl etc.

As C _3-8Naphthenic base can be enumerated out c-propyl group, c-butyl, 1-methyl-c-propyl group, 2-methyl-c-propyl group, c-amyl group, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl--c-propyl group, 2; 3-dimethyl--c-propyl group, 1-ethyl-c-propyl group, 2-ethyl-c-propyl group, c-hexyl, c-heptyl, c-octyl group, 1-methyl-c-hexyl, 2-methyl-c-hexyl, 3-methyl-c-hexyl, 1; 2-dimethyl--c-hexyl, 2,3-dimethyl--c-propyl group, 1-ethyl-c-propyl group, 1-methyl-c-amyl group, 2-methyl-c-amyl group, 3-methyl-c-amyl group, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3-ethyl-c-butyl, 1,2-dimethyl--c-butyl, 1; 3-dimethyl--c-butyl, 2; 2-dimethyl--c-butyl, 2,3-dimethyl--c-butyl, 2,4-dimethyl--c-butyl, 3; 3-dimethyl--c-butyl, 1-n-propyl group-c-propyl group, 2-n-propyl group-c-propyl group, 1-i-propyl group-c-propyl group, 2-i-propyl group-c-propyl group, 1; 2,2-trimethylammonium-c-propyl group, 1,2; 3-trimethylammonium-c-propyl group, 2; 2,3-trimethylammonium-c-propyl group, 1-ethyl-2-methyl-c-propyl group, 2-ethyl-1-methyl-c-propyl group, 2-ethyl-2-methyl-c-propyl group and 2-ethyl-3-methyl-c-propyl group etc.

As this C _1-6Alkoxyl group can be enumerated out methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, n-butoxy, i-butoxy, s-butoxy, t-butoxy, 1-amyl group oxygen base, 2-amyl group oxygen base, 3-amyl group oxygen base, i-amyl group oxygen base, neo-pentyl oxygen base, 2,2-dimethyl-propoxy-, 1-hexyl oxygen base, 2-hexyl oxygen base, 3-hexyl oxygen base, 1-methyl-n-amyl group oxygen base, 1; 1; 2-trimethylammonium-n-propoxy-, 1,2,2-trimethylammonium-n-propoxy-and 3; 3-dimethyl--n-butoxy etc.

As C _1-6Thio alkoxy; Can enumerate out methyl sulphur, ethyl sulphur, n-propylthio, i-propylthio, c-propylthio, n-butyl sulphur, i-butyl sulphur, s-butyl sulphur, t-butyl sulphur, n-amyl group sulphur, i-amyl group sulphur, neo-pentyl sulphur, t-amyl group sulphur, n-hexyl sulphur and c-hexyl sulphur etc.

C as these 5～7 Yuans rings _2-6The monocyclic type heteroaromatic base can be enumerated out 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 1-pyrryl, 2-pyrryl, 3-pyrryl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 2-1,3; 4-oxadiazole base, 2-1,3,4-thiadiazolyl group, 3-1; 2,4-oxadiazole base, 5-1,2; 4-oxadiazole base, 3-1,2,4-thiadiazolyl group, 5-1; 2; 4-thiadiazolyl group, 3-1,2,5-oxadiazole base and 3-1; 2,5-thiadiazolyl group etc.

As the constituting atom number this C of 8～10 _5-9Condensation two ring type heterocyclic radicals; Can enumerate out 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl, 1-isobenzofuran-base, 4-isobenzofuran-base, 5-isobenzofuran-base, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-isobenzo-thienyl, 4-isobenzo-thienyl, 5-isobenzo-thienyl, 2-chromenyl, 3-chromenyl, 4-chromenyl, 5-chromenyl, 6-chromenyl, 7-chromenyl, 8-chromenyl, 1-pyrrocoline base, 2-pyrrocoline base, 3-pyrrocoline base, 5-pyrrocoline base, 6-pyrrocoline base, 7-pyrrocoline base, 8-pyrrocoline base, 1-pseudoindoyl, 2-pseudoindoyl, 4-pseudoindoyl, 5-pseudoindoyl, 1-indyl, 2-indyl, 3-indyl, 4-indyl, 5-indyl, 6-indyl, 7-indyl, 1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl, 1-purine radicals, 2-purine radicals, 3-purine radicals, 6-purine radicals, 7-purine radicals, 8-purine radicals, 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-quinazolyl, 4-quinazolyl, 5-quinazolyl, 6-quinazolyl, 7-quinazolyl, 8-quinazolyl, 3-cinnolines base, 4-cinnolines base, 5-cinnolines base, 6-cinnolines base, 7-cinnolines base, 8-cinnolines base, 2-pteridine radicals, 4-pteridine radicals, 6-pteridine radicals and 7-pteridine radicals etc.

As this C _1-6The alkyl-carbonyl oxygen base; Can enumerate out methyl ketonic oxygen base, ethyl ketonic oxygen base, n-propyl group ketonic oxygen base, i-propyl group ketonic oxygen base, n-butyl ketonic oxygen base, i-butyl ketonic oxygen base, s-butyl ketonic oxygen base, tertiary butyl ketonic oxygen base, 1-amyl group ketonic oxygen base, 2-amyl group ketonic oxygen base, 3-amyl group ketonic oxygen base, i-amyl group ketonic oxygen base, neo-pentyl ketonic oxygen base, t-amyl group ketonic oxygen base, 1-hexyl ketonic oxygen base, 2-hexyl ketonic oxygen base, 3-hexyl ketonic oxygen base, 1-methyl-n-amyl group ketonic oxygen base, 1; 1; 2-trimethylammonium-n-propyl group ketonic oxygen base, 1; 2; 2-trimethylammonium-n-propyl group ketonic oxygen base and 3,3-dimethyl--n-butyl ketonic oxygen base etc.

As this C _1-6Alkylamino; Can enumerate out that methylamino, ethylamino, n-propyl group are amino, the i-propyl group is amino, the c-propyl group is amino, the n-butyl is amino, the i-butyl is amino, the s-butyl is amino, the tertiary butyl is amino, the c-butyl is amino, the 1-amyl group is amino, the 2-amyl group is amino, the 3-amyl group is amino, the i-amyl group is amino, neo-pentyl is amino, the t-amyl group is amino, the c-amyl group is amino, the 1-hexyl is amino, the 2-hexyl is amino, the 3-hexyl is amino, the c-hexyl is amino, 1-methyl-n-amyl group is amino, 1; 1; 2-trimethylammonium-n-propyl group amino, 1,2,2-trimethylammonium-n-propyl group amino and 3; 3-dimethyl--n-butyl amino etc.

As this two C _1-6Alkylamino; Can enumerate out dimethylamino; Diethylamino; Two-n-propyl group is amino; Two-i-propyl group is amino; Two-c-propyl group is amino; Two-n-butyl is amino; Two-i-butyl is amino; Two-s-butyl is amino; Two-tertiary butyl is amino; Two-c-butyl is amino; Two-1-amyl group is amino; Two-2-amyl group is amino; Two-3-amyl group is amino; Two-i-amyl group is amino; Two-neo-pentyl is amino; Two-t-amyl group is amino; Two-c-amyl group is amino; Two-1-hexyl is amino; Two-2-hexyl is amino; Two-3-hexyl is amino; Two-c-hexyl is amino; Two-(1-methyl-n-amyl group) amino; Two-(1; 1; 2-trimethylammonium-n-propyl group) amino; Two-(1; 2; 2-trimethylammonium-n-propyl group) amino; Two-(3; 3-dimethyl--n-butyl) amino; Methyl (ethyl) amino; Methyl (n-propyl group) amino; Methyl (i-propyl group) amino; Methyl (c-propyl group) amino; Methyl (n-butyl) amino; Methyl (i-butyl) amino; Methyl (s-butyl) amino; Methyl (t-butyl) amino; Methyl (c-butyl) amino; Ethyl (n-propyl group) amino; Ethyl (i-propyl group) amino; Ethyl (c-propyl group) amino; Ethyl (n-butyl) amino; Ethyl (i-butyl) amino; Ethyl (s-butyl) amino; Ethyl (t-butyl) amino; Ethyl (c-butyl) amino; N-propyl group (i-propyl group) amino; N-propyl group (c-propyl group) amino; N-propyl group (n-butyl) amino; N-propyl group (i-butyl) amino; N-propyl group (s-butyl) amino; N-propyl group (t-butyl) amino; N-propyl group (c-butyl) amino; I-propyl group (c-propyl group) amino; I-propyl group (n-butyl) amino; I-propyl group (i-butyl) amino; I-propyl group (s-butyl) amino; I-propyl group (t-butyl) amino; I-propyl group (c-butyl) amino; C-propyl group (n-butyl) amino; C-propyl group (i-butyl) amino; C-propyl group (s-butyl) amino; C-propyl group (t-butyl) amino; C-propyl group (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 and the tertiary butyl (c-butyl) amino etc.

As this C _6-14Arylamino; Can enumerate out phenyl amino, o-xenyl amino, m-xenyl amino, p-xenyl amino, 1-naphthyl amino, 2-naphthyl amino, 1-anthryl amino, 2-anthryl amino, 9-anthryl amino, 1-phenanthryl amino, 2-phenanthryl amino, 3-phenanthryl amino, 4-phenanthryl amino and 9-phenanthryl amino

As this C _2-9Heteroaryl amino comprises the C of 5～7 Yuans rings that can contain 1～3 Sauerstoffatom, nitrogen-atoms, sulphur atom alone or in combination _2-6Monocyclic type heteroaromatic cyanic acid and constituting atom number are 8～10 C _5-9Condensation two ring type heterocyclic amino group.

This C as 5～7 Yuans rings _2-6Monocyclic type heteroaromatic is amino; Can enumerate out 2-thienyl amino, 3-thienyl amino, 2-furyl amino, 3-furyl amino, 2-pyranyl amino, 3-pyranyl amino, 4-pyranyl amino, 1-pyrryl amino, 2-pyrryl amino, 3-pyrryl amino, 1-imidazolyl amino, 2-imidazolyl amino, 4-imidazolyl amino, 1-pyrazolyl amino, 3-pyrazolyl amino, 4-pyrazolyl amino, 2-thiazolyl amino, 4-thiazolyl amino, 5-thiazolyl amino, 3-isothiazolyl amino, 4-isothiazolyl amino, 5-isothiazolyl amino, 2-oxazolyl amino, 4-oxazolyl amino, 5-oxazolyl amino, 3-isoxazolyl amino, 4-isoxazolyl amino, 5-isoxazolyl amino, 2-pyridinylamino, 3-pyridinylamino, 4-pyridinylamino, 2-pyrazinyl amino, 2-pyrimidinyl-amino, 4-pyrimidinyl-amino, 5-pyrimidinyl-amino, 3-pyridazinyl amino, amino, the 2-1 of 4-pyridazinyl, 3,4-oxadiazole base is amino, 2-1; 3; The 4-thiadiazolyl group is amino, 3-1, and 2,4-oxadiazole base is amino, 5-1; 2; 4-oxadiazole base is amino, 3-1, and 2, the 4-thiadiazolyl group is amino, 5-1; 2; The 4-thiadiazolyl group is amino, 3-1, and 2,5-oxadiazole base amino and 3-1; 2,5-thiadiazolyl group amino etc.

As the constituting atom number this C of 8～10 _5-9Condensation two ring type heterocyclic amino group; Can enumerate out 2-benzofuryl amino, 3-benzofuryl amino, 4-benzofuryl amino, 5-benzofuryl amino, 6-benzofuryl amino, 7-benzofuryl amino, 1-isobenzofuran-base amino, 4-isobenzofuran-base amino, 5-isobenzofuran-base amino, 2-benzothienyl amino, 3-benzothienyl amino, 4-benzothienyl amino, 5-benzothienyl amino, 6-benzothienyl amino, 7-benzothienyl amino, 1-isobenzo-thienyl amino, 4-isobenzo-thienyl amino, 5-isobenzo-thienyl amino, 2-chromenyl amino, 3-chromenyl amino, 4-chromenyl amino, 5-chromenyl amino, 6-chromenyl amino, 7-chromenyl amino, 8-chromenyl amino, 1-pyrrocoline base amino, 2-pyrrocoline base amino, 3-pyrrocoline base amino, 5-pyrrocoline base amino, 6-pyrrocoline base amino, 7-pyrrocoline base amino, 8-pyrrocoline base amino, 1-pseudoindoyl amino, 2-pseudoindoyl amino, 4-pseudoindoyl amino, 5-pseudoindoyl amino, 1-indyl amino, 2-indyl amino, 3-indyl amino, 4-indyl amino, 5-indyl amino, 6-indyl amino, 7-indyl amino, 1-indazolyl amino, 2-indazolyl amino, 3-indazolyl amino, 4-indazolyl amino, 5-indazolyl amino, 6-indazolyl amino, 7-indazolyl amino, 1-purine radicals amino, 2-purine radicals amino, 3-purine radicals amino, 6-purine radicals amino, 7-purine radicals amino, 8-purine radicals amino, 2-quinolyl amino, 3-quinolyl amino, 4-quinolyl amino, 5-quinolyl amino, 6-quinolyl An Ji, 7-quinolyl An Ji, 8-quinolyl An Ji, 1-isoquinolyl An Ji, 3-isoquinolyl An Ji, 4-isoquinolyl An Ji, 5-isoquinolyl An Ji, 6-isoquinolyl An Ji, 7-isoquinolyl An Ji, 8-isoquinolyl An Ji, 1-phthalazinyl An Ji, 5-phthalazinyl An Ji, 6-phthalazinyl An Ji, 1-2, An Ji, the 3-2 of 7-naphthyridinyl; The 7-naphthyridinyl is amino, 4-2; The 7-naphthyridinyl is amino, 1-2; The 6-naphthyridinyl is amino, 3-2; The 6-naphthyridinyl is amino, 4-2; The 6-naphthyridinyl is amino, 2-1; The 8-naphthyridinyl is amino, 3-1; The 8-naphthyridinyl is amino, 4-1; The 8-naphthyridinyl is amino, 2-1, and the 7-naphthyridinyl is amino, 3-1, and the 7-naphthyridinyl is amino, 4-1; The 7-naphthyridinyl is amino, 5-1; The 7-naphthyridinyl is amino, 6-1, and the 7-naphthyridinyl is amino, 8-1, and the 7-naphthyridinyl is amino, 2-1; The 6-naphthyridinyl is amino, 3-1; The 6-naphthyridinyl is amino, 4-1, and the 6-naphthyridinyl is amino, 5-1, and the 6-naphthyridinyl is amino, 7-1; The 6-naphthyridinyl is amino, 8-1; The 6-naphthyridinyl is amino, 2-1, and the 5-naphthyridinyl is amino, 3-1, and the 5-naphthyridinyl is amino, 4-1; The 5-naphthyridinyl is amino, 6-1; 5-naphthyridinyl amino, 7-1,5-naphthyridinyl amino, 8-1,5-naphthyridinyl amino, 2-quinoxalinyl amino, 5-quinoxalinyl amino, 6-quinoxalinyl amino, 2-quinazolyl amino, 4-quinazolyl amino, 5-quinazolyl amino, 6-quinazolyl amino, 7-quinazolyl amino, 8-quinazolyl amino, 3-cinnolines base amino, 4-cinnolines base amino, 5-cinnolines base amino, 6-cinnolines base amino, 7-cinnolines base amino, 8-cinnolines base amino, 2-pteridine radicals amino, 4-pteridine radicals amino, 6-pteridine radicals amino and 7-pteridine radicals amino etc.

As this C _1-6Alkyl-carbonyl-amino; Can enumerate out methyl carbonylamino, ethyl carbonylamino, n-propyl group carbonylamino, i-propyl group carbonylamino, n-butyl carbonylamino, i-butyl carbonylamino, s-butyl carbonylamino, tertiary butyl carbonylamino, 1-amyl group carbonylamino, 2-amyl group carbonylamino, 3-amyl group carbonylamino, i-amyl group carbonylamino, neo-pentyl carbonylamino, t-amyl group carbonylamino, 1-hexyl carbonylamino, 2-hexyl carbonylamino and 3-hexyl carbonylamino etc.

As this C _1-6Alkylsulfonamido; Can enumerate out methylsulfonyl amido, ethane sulphonamide base, n-propane sulfoamido, i-propane sulfoamido, n-butane sulfoamido, i-butane sulfoamido, s-butane sulfoamido, t-butane sulfoamido, 1-pentane sulfoamido, 2-pentane sulfoamido, 3-pentane sulfoamido, i-pentane sulfoamido, neopentane sulfoamido, t-pentane sulfoamido, 1-hexane sulfoamido, 2-hexane sulfoamido and 3-hexane sulfoamido etc.

As this C _1-6Alkyl-carbonyl; Can enumerate out methyl carbonyl, ethyl carbonyl, n-propyl group carbonyl, i-propyl group carbonyl, n-butyl carbonyl, i-butyl carbonyl, s-butyl carbonyl, tertiary butyl carbonyl, 1-amyl group carbonyl, 2-amyl group carbonyl, 3-amyl group carbonyl, i-amyl group carbonyl, neo-pentyl carbonyl, t-amyl group carbonyl, 1-hexyl carbonyl, 2-hexyl carbonyl and 3-hexyl carbonyl etc.

This C as 5～7 Yuans rings _2-6The monocyclic type heteroaromatic carbonyl; Can enumerate out 2-thienyl carbonyl, 3-thienyl carbonyl, 2-furyl carbonyl, 3-furyl carbonyl, 2-pyranyl carbonyl, 3-pyranyl carbonyl, 4-pyranyl carbonyl, 1-pyrryl carbonyl, 2-pyrryl carbonyl, 3-pyrryl carbonyl, 1-imidazolyl carbonyl, 2-imidazolyl carbonyl, 4-imidazolyl carbonyl, 1-pyrazolyl carbonyl, 3-pyrazolyl carbonyl, 4-pyrazolyl carbonyl, 2-thiazolyl carbonyl, 4-thiazolyl carbonyl, 5-thiazolyl carbonyl, 3-isothiazolyl carbonyl, 4-isothiazolyl carbonyl, 5-isothiazolyl carbonyl, 2-oxazolyl carbonyl, 4-oxazolyl carbonyl, 5-oxazolyl carbonyl, 3-isoxazolyl carbonyl, 4-isoxazolyl carbonyl, 5-isoxazolyl carbonyl, 2-pyridyl carbonyl, 3-pyridyl carbonyl, 4-pyridyl carbonyl, 2-pyrazinyl carbonyl, 2-pyrimidyl carbonyl, 4-pyrimidyl carbonyl, 5-pyrimidyl carbonyl, 3-pyridazinyl carbonyl, 4-pyridazinyl carbonyl, 2-1,3,4-oxadiazole base carbonyl, 2-1; 3; 4-thiadiazolyl group carbonyl, 3-1,2,4-oxadiazole base carbonyl, 5-1; 2; 4-oxadiazole base carbonyl, 3-1,2,4-thiadiazolyl group carbonyl, 5-1; 2; 4-thiadiazolyl group carbonyl, 3-1,2,5-oxadiazole base carbonyl and 3-1; 2,5-thiadiazolyl group carbonyl etc.

As this C _1-6Alkyl sulphonyl can be enumerated out methane sulfonyl, trifluoromethane sulfonyl group and ethane alkylsulfonyl.As this C _6-14Aryl sulfonyl can be enumerated out benzenesulfonyl, o-biphenyl sulfonyl, m-biphenyl sulfonyl, p-biphenyl sulfonyl, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base, 1-anthracene alkylsulfonyl, 2-anthracene alkylsulfonyl, 9-anthracene alkylsulfonyl, the luxuriant and rich with fragrance alkylsulfonyl of 1-, the luxuriant and rich with fragrance alkylsulfonyl of 2-, the luxuriant and rich with fragrance alkylsulfonyl of 3-, the luxuriant and rich with fragrance alkylsulfonyl of 4-and the luxuriant and rich with fragrance alkylsulfonyl of 9-etc.

This C as 5～7 Yuans rings _2-6The monocyclic type heteroaromatic alkylsulfonyl; Can enumerate out 2-thienyl sulphonyl base, 3-thienyl sulphonyl base, 2-furyl alkylsulfonyl, 3-furyl alkylsulfonyl, 2-pyranyl alkylsulfonyl, 3-pyranyl alkylsulfonyl, 4-pyranyl alkylsulfonyl, 1-pyrryl alkylsulfonyl, 2-pyrryl alkylsulfonyl, 3-pyrryl alkylsulfonyl, 1-imidazolyl alkylsulfonyl, 2-imidazolyl alkylsulfonyl, 4-imidazolyl alkylsulfonyl, 1-pyrazolyl alkylsulfonyl, 3-pyrazolyl alkylsulfonyl, 4-pyrazolyl alkylsulfonyl, 2-thiazolyl alkylsulfonyl, 4-thiazolyl alkylsulfonyl, 5-thiazolyl alkylsulfonyl, 3-isothiazolyl alkylsulfonyl, 4-isothiazolyl alkylsulfonyl, 5-isothiazolyl alkylsulfonyl, 2-oxazolyl alkylsulfonyl, 4-oxazolyl alkylsulfonyl, 5-oxazolyl alkylsulfonyl, 3-isoxazolyl alkylsulfonyl, 4-isoxazolyl alkylsulfonyl, 5-isoxazolyl alkylsulfonyl, 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, 2-pyrazinyl alkylsulfonyl, 2-pyrimidyl alkylsulfonyl, 4-pyrimidyl alkylsulfonyl, 5-pyrimidyl alkylsulfonyl, 3-pyridazinyl alkylsulfonyl, 4-pyridazinyl alkylsulfonyl, 2-1; 3; 4-oxadiazole base alkylsulfonyl, 2-1,3,4-thiadiazolyl group alkylsulfonyl, 3-1; 2; 4-oxadiazole base alkylsulfonyl, 5-1,2,4-oxadiazole base alkylsulfonyl, 3-1; 2; 4-thiadiazolyl group alkylsulfonyl, 5-1,2,4-thiadiazolyl group alkylsulfonyl, 3-1; 2; 5-oxadiazole base alkylsulfonyl and 3-1,2,5-thiadiazolyl group alkylsulfonyl etc.

As the constituting atom number this C of 8～10 _5-9Condensation two ring type heterocycle alkylsulfonyls; Can enumerate out 2-benzofuryl alkylsulfonyl, 3-benzofuryl alkylsulfonyl, 4-benzofuryl alkylsulfonyl, 5-benzofuryl alkylsulfonyl, 6-benzofuryl alkylsulfonyl, 7-benzofuryl alkylsulfonyl, 1-isobenzofuran-base alkylsulfonyl, 4-isobenzofuran-base alkylsulfonyl, 5-isobenzofuran-base alkylsulfonyl, 2-benzothienyl alkylsulfonyl, 3-benzothienyl alkylsulfonyl, 4-benzothienyl alkylsulfonyl, 5-benzothienyl alkylsulfonyl, 6-benzothienyl alkylsulfonyl, 7-benzothienyl alkylsulfonyl, 1-isobenzo-thienyl alkylsulfonyl, 4-isobenzo-thienyl alkylsulfonyl, 5-isobenzo-thienyl alkylsulfonyl, 2-chromenyl alkylsulfonyl, 3-chromenyl alkylsulfonyl, 4-chromenyl alkylsulfonyl, 5-chromenyl alkylsulfonyl, 6-chromenyl alkylsulfonyl, 7-chromenyl alkylsulfonyl, 8-chromenyl alkylsulfonyl, 1-pyrrocoline base alkylsulfonyl, 2-pyrrocoline base alkylsulfonyl, 3-pyrrocoline base alkylsulfonyl, 5-pyrrocoline base alkylsulfonyl, 6-pyrrocoline base alkylsulfonyl, 7-pyrrocoline base alkylsulfonyl, 8-pyrrocoline base alkylsulfonyl, 1-pseudoindoyl alkylsulfonyl, 2-pseudoindoyl alkylsulfonyl, 4-pseudoindoyl alkylsulfonyl, 5-pseudoindoyl alkylsulfonyl, 1-indyl alkylsulfonyl, 2-indyl alkylsulfonyl, 3-indyl alkylsulfonyl, 4-indyl alkylsulfonyl, 5-indyl alkylsulfonyl, 6-indyl alkylsulfonyl, 7-indyl alkylsulfonyl, 1-indazolyl alkylsulfonyl, 2-indazolyl alkylsulfonyl, 3-indazolyl alkylsulfonyl, 4-indazolyl alkylsulfonyl, 5-indazolyl alkylsulfonyl, 6-indazolyl alkylsulfonyl, 7-indazolyl alkylsulfonyl, 1-purine radicals alkylsulfonyl, 2-purine radicals alkylsulfonyl, 3-purine radicals alkylsulfonyl, 6-purine radicals alkylsulfonyl, 7-purine radicals alkylsulfonyl, 8-purine radicals alkylsulfonyl, 2-quinolyl alkylsulfonyl, 3-quinolyl alkylsulfonyl, 4-quinolyl alkylsulfonyl, 5-quinolyl alkylsulfonyl, 6-quinolyl alkylsulfonyl, 7-quinolyl alkylsulfonyl, 8-quinolyl alkylsulfonyl, 1-isoquinolyl alkylsulfonyl, 3-isoquinolyl alkylsulfonyl, 4-isoquinolyl alkylsulfonyl, 5-isoquinolyl alkylsulfonyl, 6-isoquinolyl alkylsulfonyl, 7-isoquinolyl alkylsulfonyl, 8-isoquinolyl alkylsulfonyl, 1-phthalazinyl alkylsulfonyl, 5-phthalazinyl alkylsulfonyl, 6-phthalazinyl alkylsulfonyl, 1-2; 7-naphthyridinyl alkylsulfonyl, 3-2; 7-naphthyridinyl alkylsulfonyl, 4-2; 7-naphthyridinyl alkylsulfonyl, 1-2; 6-naphthyridinyl alkylsulfonyl, 3-2; 6-naphthyridinyl alkylsulfonyl, 4-2; 6-naphthyridinyl alkylsulfonyl, 2-1; 8-naphthyridinyl alkylsulfonyl, 3-1,8-naphthyridinyl alkylsulfonyl, 4-1,8-naphthyridinyl alkylsulfonyl, 2-1; 7-naphthyridinyl alkylsulfonyl, 3-1; 7-naphthyridinyl alkylsulfonyl, 4-1,7-naphthyridinyl alkylsulfonyl, 5-1,7-naphthyridinyl alkylsulfonyl, 6-1; 7-naphthyridinyl alkylsulfonyl, 8-1; 7-naphthyridinyl alkylsulfonyl, 2-1,6-naphthyridinyl alkylsulfonyl, 3-1,6-naphthyridinyl alkylsulfonyl, 4-1; 6-naphthyridinyl alkylsulfonyl, 5-1; 6-naphthyridinyl alkylsulfonyl, 7-1,6-naphthyridinyl alkylsulfonyl, 8-1,6-naphthyridinyl alkylsulfonyl, 2-1; 5-naphthyridinyl alkylsulfonyl, 3-1; 5-naphthyridinyl alkylsulfonyl, 4-1,5-naphthyridinyl alkylsulfonyl, 6-1,5-naphthyridinyl alkylsulfonyl, 7-1; 5-naphthyridinyl alkylsulfonyl, 8-1,5-naphthyridinyl alkylsulfonyl, 2-quinoxalinyl alkylsulfonyl, 5-quinoxalinyl alkylsulfonyl, 6-quinoxalinyl alkylsulfonyl, 2-quinazolyl alkylsulfonyl, 4-quinazolyl alkylsulfonyl, 5-quinazolyl alkylsulfonyl, 6-quinazolyl alkylsulfonyl, 7-quinazolyl alkylsulfonyl, 8-quinazolyl alkylsulfonyl, 3-cinnolines base alkylsulfonyl, 4-cinnolines base alkylsulfonyl, 5-cinnolines base alkylsulfonyl, 6-cinnolines base alkylsulfonyl, 7-cinnolines base alkylsulfonyl, 8-cinnolines base alkylsulfonyl, 2-pteridine radicals alkylsulfonyl, 4-pteridine radicals alkylsulfonyl, 6-pteridine radicals alkylsulfonyl and 7-pteridine radicals alkylsulfonyl etc.

As this C _2-9Heterocyclic radical can be enumerated out the atom of from nitrogen-atoms, Sauerstoffatom and sulphur atom, freely selecting and the monocycle of 2～9 carbon atoms and the heterocyclic radical of the ring two ring property that contract that contain more than 1, and specifically, can enumerate out following radicals etc.

and

Put down in writing in each ring structure in the following formula-(expression bonding), can be taken on the chemical structure can substituted position arbitrarily, does not represent specific replacement position.

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), the R in formula (w), formula (y), formula (z), formula (aa), formula (ab), formula (ac), formula (ad), formula (ae) and the formula (af) ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Independent respectively; Preferred Wasserstoffatoms, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl group, i-propyl group, n-butyl, n-amyl group, i-amyl group, 3,3-dimethyl--n-butyl, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, ethyl carbonylamino methyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl, ethoxy carbonyl ethyl, c-propyl group, c-amyl group, c-hexyl methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, methyl sulfenyl, ethyl sulfenyl, phenyl, o-xenyl, m-xenyl, p-xenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, methyl ketonic oxygen base, ethyl ketonic oxygen base, n-propyl group ketonic oxygen base, i-propyl group ketonic oxygen base, n-butyl ketonic oxygen base, tertiary butyl ketonic oxygen base, methylamino, ethylamino, n-propyl group amino, i-propyl group amino, n-butyl amino, dimethylamino, diethylamino, two-n-propyl group amino, two-i-propyl group amino, two-n-butyl amino, phenyl amino, o-xenyl amino, m-xenyl amino, p-xenyl amino, 1-naphthyl amino, 2-naphthyl amino, 2-pyridinylamino, 3-pyridinylamino, 4-pyridinylamino, methyl carbonylamino, ethyl carbonylamino, n-propyl group carbonylamino, i-propyl group carbonylamino, n-butyl carbonylamino, methylsulfonyl amido, ethane sulphonamide base, n-propane sulfoamido, i-propane sulfoamido, n-butane sulfoamido, methylamino carbonyl, ethylamino carbonyl, n-propyl group aminocarboxyl, i-propyl group aminocarboxyl, n-butyl aminocarboxyl, dimethylamino carbonyl, diethylamino carbonyl, two-n-propyl group aminocarboxyl, two-i-propyl group aminocarboxyl, two-c-propyl group aminocarboxyl, two-n-butyl aminocarboxyl, methyl carbonyl, ethyl carbonyl, n-propyl group carbonyl, i-propyl group carbonyl, n-butyl carbonyl, phenylcarbonyl group, o-xenyl carbonyl, m-xenyl carbonyl, p-xenyl carbonyl, 1-naphthyl carbonyl, 2-naphthyl carbonyl, 2-pyridyl carbonyl, 3-pyridyl carbonyl, 4-pyridyl carbonyl, methoxycarbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxy carbonyl, i-butoxy carbonyl, s-butoxy carbonyl, t-butoxy carbonyl, methane sulfonyl, trifluoromethane sulfonyl group, benzenesulfonyl, o-biphenyl sulfonyl, m-biphenyl sulfonyl, p-biphenyl sulfonyl, 1-naphthalene sulfonyl base, 2-naphthalene sulfonyl base, 2-pyridyl sulfonyl, 3-pyridyl sulfonyl, 4-pyridyl sulfonyl, amino, cyanic acid, formamyl, carboxyl,

Above-mentioned formula (c), formula (d), formula (p), formula (q), formula (v), the Q in formula (w), formula (ab), formula (ac) and the formula (ad), expression O (Sauerstoffatom), S (sulphur atom), SO (sulfinyl) or SO ₂(alkylsulfonyl).(v), Q is preferably O (Sauerstoffatom) in formula (w), formula (ab), formula (ac) and the formula (ad) for formula (c), formula (d), formula (p), formula (q), formula.

Below, be formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), the formula (a) under the situation of formula (y), formula (ae), formula (ag) or formula (ah), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), the R in formula (y), formula (ae), formula (ag) or the formula (ah) to the part ring structure A in above-mentioned formula (11) or the formula (12) ¹², R ¹³, R ¹⁴, R ¹⁵And R ¹⁶Describe.

Part ring structure to the A in above-mentioned formula (11) or the formula (12) is formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), the formula (a) under the situation of formula (y), formula (ae), formula (ag) or formula (ah), formula (b), formula (i), formula (k), formula (p), formula (v), the R in formula (ae) and the formula (ag) ¹²And R ¹³Describe.

Formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), the R in formula (ae) and the formula (ag) ¹²And R ¹³Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino or hydroxyl replace arbitrarily).

To formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), the R in formula (ae) and the formula (ag) ¹²And R ¹³Each substituting group specify.

As this C _1-6Alkyl; Can enumerate out methyl, trifluoromethyl, methoxymethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, n-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2,2-dimethyl propyl, n-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1,1; 2-trimethylammonium-n-propyl group, 1; 2,2-trimethylammonium-n-propyl group and 3,3-dimethyl--n-butyl etc.

Formula (a), formula (b), formula (i), formula (k), formula (p), formula (v), the R in formula (ae) and the formula (ag) ¹²And R ¹³Independent respectively, be preferably Wasserstoffatoms, methyl, trifluoromethyl, methoxymethyl, ethyl, n-propyl group, i-propyl group, n-butyl, n-amyl group, i-amyl group, amino, hydroxyl, more preferably Wasserstoffatoms, methyl.

Part ring structure to the A in above-mentioned formula (11) or the formula (12) is formula (a), formula (b), formula (i), formula (k), formula (o), formula (p), formula (s), formula (v), the formula (a) under the situation of formula (y), formula (ae), formula (ag) or formula (ah), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), the R in formula (y) and the formula (ae) ¹⁴, R ¹⁵And R ¹⁶Describe.Formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), the R in formula (y) and the formula (ae) ¹⁴, R ¹⁵And R ¹⁶Represent Wasserstoffatoms, halogen atom or C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), amino, hydroxyl, C _1-6Alkyl amino-carbonyl, two C _1-6Alkyl amino-carbonyl, C _1-6Alkyl-carbonyl oxygen base, C _1-6Alkyl-carbonyl (this alkyl-carbonyl oxygen base and alkyl-carbonyl can be replaced arbitrarily by halogen atom), C _1-6Alkyl-carbonyl-amino, C _3-8Naphthene base carbonyl or C _1-6Alkoxy carbonyl replaces arbitrarily).

To formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), the R in formula (y) and the formula (ae) ¹⁴, R ¹⁵And R ¹⁶Each atom and each substituting group specify.As this halogen atom, can enumerate out fluorine atom, chlorine atom, bromine atoms and iodine atom,

As this C _1-6Alkyl; Can enumerate out methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, n-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2; 2-dimethyl propyl, n-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1; 1; 2-trimethylammonium-n-propyl group, 1; 2,2-trimethylammonium-n-propyl group and 3,3-dimethyl--n-butyl, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, ethyl carbonylamino methyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl, trifluoromethoxy carbonyl methyl and ethoxy carbonyl ethyl etc.As this C _1-6Alkyl-carbonyl-amino; Can enumerate out the methyl carbonylamino; The trifluoromethyl carbonylamino; The ethyl carbonylamino; N-propyl group carbonylamino; I-propyl group carbonylamino; N-butyl carbonylamino; I-butyl carbonylamino; S-butyl carbonylamino; T-butyl carbonylamino; 1-amyl group carbonylamino; 2-amyl group carbonylamino; 3-amyl group carbonylamino; I-amyl group carbonylamino; The neo-pentyl carbonylamino; T-amyl group carbonylamino; 1-hexyl carbonylamino; 2-hexyl carbonylamino and 3-hexyl carbonylamino etc.

As this C _1-6Alkoxy carbonyl can be enumerated out methoxycarbonyl, ethoxy carbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxy carbonyl, i-butoxy carbonyl, s-butoxy carbonyl, t-butoxy carbonyl, 1-amyl group oxygen base carbonyl, 2-amyl group oxygen base carbonyl, 3-amyl group oxygen base carbonyl, i-amyl group oxygen base carbonyl, neo-pentyl oxygen base carbonyl, t-amyl group oxygen base carbonyl, 1-hexyl oxygen base carbonyl, 2-hexyl oxygen base carbonyl and 3-hexyl oxygen base carbonyl etc.

Formula (a), formula (b), formula (k), formula (o), formula (p), formula (s), formula (v), the R in formula (y) and the formula (ae) ¹⁴, R ¹⁵And R ¹⁶Independent respectively; Preferred Wasserstoffatoms, fluorine atom, chlorine atom, bromine atoms, methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, n-amyl group, i-amyl group, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl ketonic oxygen base ethyl, ethyl ketonic oxygen base ethyl, methyl carbonylamino methyl, ethyl carbonylamino ethyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, ethoxy carbonyl methyl, methoxycarbonyl ethyl, trifluoromethoxy carbonyl methyl, ethoxy carbonyl ethyl, more preferably Wasserstoffatoms, fluorine atom, chlorine atom, methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, methyl ketonic oxygen ylmethyl, ethyl ketonic oxygen ylmethyl, methyl carbonylamino ethyl, ethyl carbonylamino ethyl, methoxycarbonyl methyl, trifluoromethoxy carbonyl methyl.

The part ring structure of A in above-mentioned formula (11) or the formula (12) is that (v), (Q v) means O (Sauerstoffatom), S (sulphur atom), SO (sulfinyl) or SO for above-mentioned formula (p) or formula for above-mentioned formula (p) and formula ₂(alkylsulfonyl).(Q v) is preferably O (Sauerstoffatom) for formula (p) or formula.

To the R in the above-mentioned formula (13) ⁹, R ¹⁰, W, X, Y and Z describe.

R in the formula (13) ⁹And R ¹⁰Represent Wasserstoffatoms, C respectively independently _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily), C _6-14(this aryl can be by halogen atom, hydroxyl, nitro, cyanic acid, C for aryl _1-6(this alkyl can be by halogen atom, C for alkyl _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) or hydroxyl replace arbitrarily), C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom) replaces arbitrarily).

To the R in the formula (13) ⁹And R ¹⁰Each substituting group specify.

As this C _1-6Alkyl can be enumerated out methyl, trifluoromethyl, methoxymethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl, the tertiary butyl, 1-amyl group, 2-amyl group, 3-amyl group, i-amyl group, neo-pentyl, 2,2-dimethyl propyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-methyl-n-amyl group, 1; 1; 2-trimethylammonium-n-propyl group, 1,2,2-trimethylammonium-n-propyl group and 3; 3-dimethyl--n-butyl etc.

R in the formula (13) ⁹And R ¹⁰Preferable methyl, trifluoromethyl, ethyl, more preferably methyl.

W in the formula (13) representes Wasserstoffatoms, hydroxyl, C _1-6Alkoxyl group (this alkoxyl group can be replaced arbitrarily by halogen atom), halogen atom, C _1-4Alkyl or C _1-6Alkylsulfonamido (this alkyl and alkylsulfonamido can be replaced arbitrarily by halogen atom).

Each atom to the W in the formula (13) specifies with each substituting group.

As this C _1-4Alkyl can be enumerated out methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl and the tertiary butyl etc.,

As this C _1-6Alkylsulfonamido can be enumerated out methylsulfonyl amido, fluoroform sulfoamido, ethane sulphonamide base, n-propane sulfoamido, i-propane sulfoamido, n-butane sulfoamido, i-butane sulfoamido, s-butane sulfoamido, t-butane sulfoamido, 1-pentane sulfoamido, 2-pentane sulfoamido, 3-pentane sulfoamido, i-pentane sulfoamido, neopentane sulfoamido, t-pentane sulfoamido, 1-hexane sulfoamido, 2-hexane sulfoamido and 3-hexane sulfoamido etc.

W in the formula (13) is preferably Wasserstoffatoms, hydroxyl, fluorine atom, chlorine atom, bromine atoms, methyl, trifluoromethyl, ethyl, methoxyl group, oxyethyl group, n-propoxy-, i-propoxy-, methylsulfonyl amido, fluoroform sulfoamido, ethane sulphonamide base, n-propane sulfoamido, i-propane sulfoamido, n-butane sulfoamido, more preferably Wasserstoffatoms, hydroxyl, fluorine atom, methyl, trifluoromethyl, ethyl, methoxyl group, methylsulfonyl amido, fluoroform sulfoamido.

X in the formula (13) representes NR ²⁰, N representes nitrogen-atoms,

R ²⁰Expression Wasserstoffatoms or C _1-4Alkyl.

To the R among the X of formula (13) ²⁰Each substituting group specify.

As this C _1-4Alkyl can be enumerated out methyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl and the tertiary butyl etc.

R among the X of formula (13) ²⁰Be preferably Wasserstoffatoms, methyl, ethyl.

Y in the formula (13) is Direct Bonding, SO (sulfinyl) or SO ₂(alkylsulfonyl) is preferably Direct Bonding and SO ₂

Z in the formula (13) representes C _1-4Alkyl (this C _1-4Alkyl can (this phenyl can be by C by 1～5 halogen atom or phenyl _1-4Alkyl replaces arbitrarily) replace arbitrarily) or phenyl (this phenyl can be by C _1-4Alkyl replaces arbitrarily).

Each substituting group to the Z in the formula (13) specifies.

As this C _1-4Alkyl can be enumerated out methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, n-butyl, i-butyl, s-butyl and the tertiary butyl etc.

Z in the formula (13) is preferably methyl, trifluoromethyl, ethyl, n-propyl group, i-propyl group, phenyl.

When using the optical activity titanium complex shown in any one of above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') as catalyzer; The usage quantity of this optical activity titanium complex; With respect to the chromene compounds shown in formula (10), formula (11), formula (12) or the formula (13); In the scope of 0.001～100 mole of %, preferably in the scope of 0.01～20 mole of %, more preferably in the scope of 0.3～5 mole of %.

When using the optical activity titanium complex shown in any one of above-mentioned formula (1), formula (1 '), formula (2), formula (2 '), formula (3), formula (3 '), formula (4) and formula (4 ') as catalyzer; The solvent that uses in the asymmetric epoxidation reaction; Organic solvent as aprotic; Being halogen series solvent, aromatic hydrocarbons series solvent, ester series solvent, ether series solvent or nitrile series solvent, as the organic solvent of protic, is pure series solvent.As the halogen series solvent, can enumerate out methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene etc.; As the aromatic hydrocarbons series solvent, can enumerate out benzene, toluene etc., as the ester series solvent; Acetate ethyl ester etc. can be enumerated out,, THF, ether etc. can be enumerated out as the ether series solvent; As the nitrile series solvent, can enumerate out butyronitrile, propionitrile, acetonitrile etc.As pure series solvent, can enumerate out methyl alcohol, ethanol, i-propyl alcohol etc., and then can also enumerate out the mixture of above-mentioned solvent.In addition, when using the aqueous solution (aquae hydrogenii dioxidi) of hydrogen peroxide in this reaction, through mixing with the organic solvent that is not dissolved in water, organic phase is also separated with water sometimes, still such 2 be mutually solvent also can be used as reaction solvent of the present invention.Preferred solvent is the methylene dichloride, 1 as the organic solvent of aprotic, the mixture of 2-ethylene dichloride, chlorobenzene, toluene, acetate ethyl ester or these solvents.

As manufacturing operation, as long as in organic solvent, add chromene compounds, optical activity titanium complex, oxygenant, reaction is just carried out.As the interpolation order, preferably in the solution that contains organic solvent, chromene compounds, optical activity titanium complex, add oxygenant.

As the concrete example of the oxygenant that uses in the reaction, can enumerate out the mixture of iodosobenzene, Youxiaolin, metachloroperbenzoic acid, Oxone (E.I.Du Pont Company's registered trademark), aquae hydrogenii dioxidi, urea-hydrogen peroxide adduct (UHP), azepine oxygen triatomic ring (oxaziridine), N-methylmorpholine oxide compound (NMO), tertbutyl peroxide (TBHP), cumene hydroperoxide (CHP) and these oxygenants.Wherein, the mixture of preferred aquae hydrogenii dioxidi, urea-hydrogen peroxide adduct (UHP) and these oxygenants.Oxygenant is the concentration under the situation of aquae hydrogenii dioxidi, can enumerate out the scope of 1～100% (weight %), is preferably the scope of 5～60% (weight %).

As the usage quantity of the oxygenant that uses in the reaction,, can enumerate out 1～10 normal scope, preferred 1～3 normal scope with respect to the chromene compounds shown in formula (10), formula (11), formula (12) or the formula (13).

As the addition means of oxygenant, except adding in the lump, can also enumerate out portion-wise addition and add continuously.

Under the situation of adding continuously, interpolation speed is the scope that sharply do not rise of the interior temperature in reaction solvent system preferably, specifically, and preferred 0.01～40000 normal scope per hour, more preferably 0.05～0.3 normal scope per hour.In addition, portion-wise addition is the method for the oxygenant that uses being divided p (p for integer) arbitrarily interpolation.Five equilibrium can be in batches, also non-five equilibrium, the scope of p preferred 2～100 can be.

Temperature of reaction can be enumerated out-78 ℃～solvent refluxing temperature, the scope of perhaps employed solvent melting temperature～solvent refluxing temperature, preferred-20～50 ℃ scope, more preferably 0～35 ℃ scope.

Pressure in the reaction system can be enumerated out the scope of 10kPa～1100kPa, preferred 15kPa～200kPa.Through pressurization, react under the high temperature of solvent refluxing temperature that can be when being higher than normal pressure.

In the process of reacting, can append the optical activity titanium complex of interpolation as catalyzer, shorten the reaction times.In addition, can append the interpolation oxygenant, shorten the reaction times.

After reaction finishes, carry out distillation procedure, silica gel column chromatography, separatory extracting operation, recrystallization operation or combination aforesaid operations, carry out separation and purification, obtain the active chromene oxide compound of objective optics.

The optical purity of the optically active chromene oxide compound that is obtained can be passed through optical activity efficient liquid phase chromatographic analysis, optical activity gas chromatographic analysis or angle-of-rotation measuring etc., analyzes.

Explain in more detail through embodiment below, but the invention is not restricted to this.

In addition, in the optically active chromene oxide compound among the embodiment, also there is the compound of the absolute configuration of not distinguishing asymmetric carbon.About these compounds, asymmetric carbon among the figure and the absolute configuration souvenir in the compound name have asterisk (*), and the record of presentation graphs and compound name is the absolute configuration souvenir of supposition.

Optical activity titanium Salalen complex compound (A) is synthetic with (C) (B)

The optical activity titanium Salalen complex compound (A) that uses among the embodiment (B) with (C), according to non-patent literature 8 (Angew.Chem.Int.Ed. (2005), 44,4935-4939.) record the method manufacturing.

Following such acquisition of optical activity titanium Salan complex compound (D) shown in the following formula.

Salan part (42 ')

In the methylene dichloride reaction solvent of Salan part (42 '), under nitrogen atmosphere,,, add 1.1 moles titanium tetraisopropylate [Ti (Oi-Pr) with respect to 1 mole of Salan part (42 ') at 25～28 ℃ ₄], stirred 5 hours, add water at 25～28 ℃ then, stirring reaction solution is 12 hours then.Then, heat up in a steamer the dereaction solvent, it is biological to obtain thick one-tenth, and it is carried out the recrystallization operation with methylene dichloride, obtains optical activity titanium complex (D).

The yellowish white solid

MS(CSI)＝1082，2163

Optical activity titanium Salan complex compound (E) and (F) also obtains with method of manufacture same as described above.

Embodiment 1

(3S, 4S)-6-ethanamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl--7-nitro-2H-1-chromene (compound (I)) synthetic

At 28 ℃, in the dichloromethane solution (3mL) of optical activity titanium Salalen complex compound (B) (38mg, 0.021mmol) (is 1.0 moles of % with respect to matrix), add 6-ethanamide-2,2-dimethyl--7-nitro-2H-1-chromene (0.54g, 2.1mmol).Stirring reaction solution on one side, on one side with 10 hours 28 ℃ of interpolation 7.5% aquae hydrogenii dioxidis (1.4g, 3.1mmol).With interpolation time opening of 7.5% aquae hydrogenii dioxidi as the reaction time opening, the reaction beginning after 14 hours 28 ℃ add 7.5% aquae hydrogenii dioxidis (0.1g, 0.2mmol), and then 28 ℃ continue to stir 19 hours that calculate from the reaction time opening till.After reaction finishes; In reaction solution, add methylene dichloride (6mL) and zero(ppm) water (6mL), with the organic phase separatory, and then will be from the organic phase merging of water extraction with methylene dichloride (6mL); With column chromatography spissated thick resultant is made with extra care; Obtain the compound (I) (0.49g, yield 86% is more than the optical purity 99.9%ee) of yellow powder shape.

Analysis condition: chromatographic column name CHIRALPAK OJ-RH; Elutriant acetonitrile/methanol/0.01M sodium chloride aqueous solution=1/3/5 (v/v/v), flow 1.5mL/min, 40 ℃ of column temperatures; The resultant of this reaction of RT: 15.9 minutes (3S; 4S), enantiomer: (3R 4R), measured wavelength 242nm. in 11.7 minutes

¹H-NMR(CDCl ₃)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)

Embodiment 2

(3R, 4R)-6-ethanamide-3,4-epoxy-3,4-dihydro-2,2-dimethyl--7-nitro-2H-1-chromene (compound (II)) synthetic

In the dichloromethane solution (3mL) of optical activity titanium Salan complex compound (E) (25.6mg, 0.021mmol) (, being 1.0 moles of %), add 6-ethanamide-2 at 30 ℃ with respect to matrix, and 2-dimethyl--7-nitro-2H-1-chromene (537.4mg, 2.1mmol).Stirring reaction solution on one side, on one side with 1 second 30 ℃ of interpolation 30% aquae hydrogenii dioxidis (302.7mg, 2.7mmol).Then, continue to stir 7 hours at 30 ℃.After reaction finishes; Methylene dichloride and zero(ppm) water are added in the reaction solution, organic phase is carried out separatory, and then will merge with the organic phase of methylene dichloride from the water extraction; Make with extra care with column chromatography concentrating the thick resultant that obtains; Obtain yellow powder shape compound (II) (0.53g, yield 93% is more than the optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALPAK OJ-RH; Elutriant acetonitrile/methanol/0.01M sodium chloride aqueous solution=1/3/5 (v/v/v), flow 1.5mL/min, 40 ℃ of column temperatures; The resultant of this reaction of RT: 13.4 minutes (3R; 4R), enantiomer: (3S 4S), measured wavelength 242nm. in 17.5 minutes

¹H-NMR(CDCl ₃)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)

Embodiment 3

(3S, 4S)-3,4-epoxy-3,4-dihydro-2,2-dimethyl--6-nitro-2H-1-chromene (compound (III)) synthetic

25 ℃ to optical activity titanium Salalen complex compound (B) (73mg 0.041mmol) adds 2 in the dichloromethane solution (8mL) of (with respect to matrix, being 2.0 moles of %), 2-dimethyl--6-nitro-2H-1-chromene (0.41g, 2.0mmol).Stirring reaction solution on one side, on one side with 2 seconds 25 ℃ of interpolation 30% aquae hydrogenii dioxidis (0.24g, 2.1mmol).The interpolation time opening of 30% aquae hydrogenii dioxidi is as the reaction time opening, the time opening begin to calculate from reaction 25 ℃ of stirrings 27 hours.Reaction finishes the back, in reaction solution, adds methylene dichloride (6mL) and zero(ppm) water (6mL); Organic phase is carried out separatory; And then will use methylene dichloride (6ml) to merge from the organic phase that water extracts, and spissated thick resultant is made with extra care with column chromatography, obtain white yellow powder shape compound (III) (0.43g; Yield 97% is more than the optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALCEL OD-H, elutriant n-hexane/i-propyl alcohol=9/1 (v/v), flow 1.0mL/min; 40 ℃ of column temperatures, the resultant of this reaction of RT: 9.6 minutes (3S, 4S), enantiomer: 8.4 minutes (3R; 4R), measure wavelength 300nm.

¹H-NMR(CDCl ₃)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)

Embodiment 4

(4.9mg 0.0080mmol) adds titanium tetraisopropylate [Ti (Oi-Pr) in the dichloromethane solution (0.3mL) of (with respect to matrix, being 4.0 moles of %) to the Salan part shown in the formula (43 ') at 20 ℃ ₄] (2.3mg, 0.0080mmol).After 1 hour, in above-mentioned solution, add 2 20 ℃ of stirrings, and 2-dimethyl--6-nitro-2H-1-chromene (41mg, 0.20mmol).With 30% aquae hydrogenii dioxidi (0.034g 0.30mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, make the 1st time 20 ℃ of interpolations on one side, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, after calculate from the reaction time opening 20 ℃ of stirrings 24 hours, with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (III) is more than 99%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress, elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v), flow: 1.0mL/min; 40 ℃ of column temperatures; The resultant of this reaction of RT: 15.8 minutes (3S, 4S), enantiomer: 12.6 minutes (3R; 4R), measure wavelength: 330nm.

Embodiment 5

(3R, 4R)-3,4-epoxy-3,4-dihydro-2,2-dimethyl--6-nitro-2H-1-chromene (compound (IV)) synthetic

To optical activity titanium Salan complex compound (E) (48mg 0.040mmol) in the dichloromethane solution (6mL) of (with respect to matrix, being 2.0 moles of %), adds 2 at 20 ℃, 2-dimethyl--6-nitro-2H-1-chromene (0.41g, 2.0mmol).With 30% aquae hydrogenii dioxidi (0.24g 2.1mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, make the 1st time 20 ℃ of interpolations on one side, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.The interpolation time of the 1st time 30% aquae hydrogenii dioxidi is as the reaction time opening; After calculate from the reaction time opening 20 ℃ of stirrings 24 hours; In reaction solution, add methylene dichloride (5mL) and zero(ppm) water (5mL), organic phase is carried out separatory, and then will use methylene dichloride (5mL, 3mL) to merge from the organic phase that 2 extractions of aqueous phase obtain; Spissated thick resultant is made with extra care with column chromatography; Obtain white yellow powder shape compound (IV) (0.41g, yield 94% is more than the optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress, elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v), flow: 1.0mL/min; 40 ℃ of column temperatures; The resultant of this reaction of RT: 12.6 minutes (3R, 4R), enantiomer: 15.8 minutes (3S; 4S), measure wavelength: 330nm.

¹H-NMR(CDCl ₃)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)

Embodiment 6

In the dichloromethane solution (8mL) of optical activity titanium Salalen complex compound (A) (73mg, 0.041mmol) (, being 2.0 moles of %) with respect to matrix, add 2 at 25 ℃, 2-dimethyl--6-nitro-2H-1-chromene (0.41g, 2.0mmol).Stirring reaction solution on one side, on one side with 2 seconds 25 ℃ of interpolation 30% aquae hydrogenii dioxidis (0.24g, 2.1mmol).Continue to stir at 25 ℃ then, with interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, the reaction beginning is after 8 hours, with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (IV) is more than 99%, and optical purity is 96%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v), flow: 1.0mL/min, 40 ℃ of column temperatures; The resultant of this reaction of RT: 5.2 minutes (3R; 4R), enantiomer: (3S 4S), measured wavelength: 330nm. in 6.1 minutes

Embodiment 7

(3S ^*, 4S ^*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl--7-nitro-6-methoxyl group-2H-1-chromene is (in the compound (V) ^*Synthesizing expression relative configuration)

be

perhaps

In the dichloromethane solution (8mL) of optical activity titanium Salalen complex compound (B) (71mg, 0.040mmol) (, being 2.0 moles of %) with respect to matrix, add 2 at 25 ℃, 2-dimethyl--7-nitro-6-methoxyl group-2H-1-chromene (0.47g, 2.0mmol).Stirring reaction solution on one side, on one side with 2 seconds 25 ℃ of interpolation 30% aquae hydrogenii dioxidis (0.24g, 2.1mmol).With interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, reaction beginning back continues to stir 19 hours at 25 ℃.Reaction finishes the back, in reaction solution, adds methylene dichloride (3mL) and zero(ppm) water (3mL); Organic phase is carried out separatory; And then will use methylene dichloride (3mL) to merge from the organic phase that the aqueous phase extraction obtains, and spissated thick resultant is made with extra care with column chromatography, obtain yellow oily compound (V) (0.50g; Yield 99% is more than the optical purity 99.9%ee).Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.8mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 12.1 minutes; Enantiomer: 11.3 minutes, measure wavelength: 225nm.

¹H-NMR(CDCl ₃)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)

Embodiment 8

(14mg 0.020mmol) in the dichloromethane solution (0.9mL) of (with respect to matrix, being 4.0 moles of %), adds titanium tetraisopropylate [Ti (Oi-Pr) at 20 ℃ to the Salan part shown in the formula (41 ') ₄] (5.7mg, 0.020mmol).After 1 hour, add 2 20 ℃ of stirrings, and 2-dimethyl--7-nitro-6-methoxyl group-2H-1-chromene (0.118g, 0.50mmol).With 30% aquae hydrogenii dioxidi (0.085g 0.75mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, reaction beginning back 20 ℃ stir 24 hours after, with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (V) is more than 99%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.5mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 18.3 minutes; Enantiomer: 17.5 minutes, measure wavelength: 225nm.

Embodiment 9

(3R ^*, 4R ^*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl--7-nitro-6-methoxyl group-2H-1-chromene (compound (V ') in ^*Synthesizing expression relative configuration)

To optical activity titanium Salan complex compound (E) (48mg 0.040mmol) in the dichloromethane solution (7mL) of (with respect to matrix, being 2.0 moles of %), adds 2 at 25 ℃, 2-dimethyl--7-nitro-6-methoxyl group-2H-1-chromene (0.47g, 2.0mmol).With 30% aquae hydrogenii dioxidi (0.24g 2.1mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.The interpolation time of the 1st time 30% aquae hydrogenii dioxidi,, added methylene dichloride (5mL) and zero(ppm) water (5mL) in the reaction solution to after 24 hours 20 ℃ of stirrings reaction beginning back as the reaction time opening; Organic phase is carried out separatory; And then will use methylene dichloride (5mL, 3mL) to merge from the organic phase that 2 extractions of water obtain, spissated thick resultant is made with extra care with column chromatography, acquisition yellow oily compound (V ') (0.48g; Yield 96% is more than the optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.5mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 17.5 minutes; Enantiomer: 18.3 minutes, measure wavelength: 225nm.

¹H-NMR(CDCl ₃)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)

Embodiment 10

To optical activity titanium Salalen complex compound (A) (71mg 0.040mmol) in the dichloromethane solution (8mL) of (with respect to matrix, being 2.0 moles of %), adds 2 at 25 ℃, 2-dimethyl--7-nitro-6-methoxyl group-2H-1-chromene (0.47g, 2.0mmol).Stirring reaction solution on one side, on one side with 2 seconds 25 ℃ of interpolation 30% aquae hydrogenii dioxidis (0.24g, 2.1mmol).With interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, the reaction beginning is after 18 hours, with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (V ') is more than 99%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.8mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 11.3 minutes; Enantiomer: 12.1 minutes, measure wavelength: 225nm.

Embodiment 11

(3S ^*, 4S ^*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl--7-nitro-2H-1-chromene (compound (VI) in * represent relative configuration) synthetic

be

perhaps

To optical activity titanium Salalen complex compound (B) (36mg 0.020mmol) in the dichloromethane solution (4mL) of (with respect to matrix, being 2.0 moles of %), adds 2 at 25 ℃, 2-dimethyl--7-nitro-2H-1-chromene (0.21g, 1.0mmol).Stirring reaction solution on one side, on one side with add for 2 seconds 30% aquae hydrogenii dioxidi (0.12g, 1.1mmol).With interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, stirred 27 hours at 25 ℃ reaction beginning back.After reaction finishes; Methylene dichloride (2mL) and zero(ppm) water (2mL) are added in the reaction solution, organic phase is carried out separatory, and then will use methylene dichloride (2mL) to merge from the organic phase that the aqueous phase extraction obtains; Spissated thick resultant is made with extra care with column chromatography; Obtain yellow powder shape compound (VI) (0.43g, yield 99%, optical purity 99.4%ee).

Analysis condition: chromatographic column name CHIRALPAK AD-RH, elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v), flow: 1.0mL/min; 40 ℃ of column temperatures; The resultant of this reaction of RT: 9.2 minutes, enantiomer: 4.9 minutes, measure wavelength: 220nm.

¹H-NMR(CDCl ₃)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)

Embodiment 12

To optical activity titanium Salan complex compound (F) (48mg 0.040mmol) in the dichloromethane solution (6mL) of (with respect to matrix, being 2.0 moles of %), adds 2 at 25 ℃, 2-dimethyl--7-nitro-2H-1-chromene (0.41g, 2.0mmol).With 30% aquae hydrogenii dioxidi (0.25g 2.2mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, stirred 24 hours at 20 ℃ reaction beginning back.Reaction finishes the back, methylene dichloride (5mL) and zero(ppm) water (5mL) is added in the reaction solution; Organic phase is carried out separatory; And then will use methylene dichloride (5mL, 3mL) to merge from the organic phase that 2 extractions of water obtain, and spissated thick resultant is made with extra care with column chromatography, obtain yellow crystal compound (VI) (0.44g; Yield 98%, optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 1.0mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 25.2 minutes; Enantiomer: 13.9 minutes, measure wavelength: 220nm.

¹H-NMR(CDCl ₃)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)

Embodiment 13

(3R ^*, 4R ^*)-3,4-epoxy-3,4-dihydro-2, * representes relative configuration in the 2-dimethyl--7-nitro-2H-1-chromene (compound (VI ')) synthetic

To optical activity titanium Salalen complex compound (A) (36mg 0.020mmol) in the dichloromethane solution (4mL) of (with respect to matrix, being 2.0 moles of %), adds 2 at 25 ℃, 2-dimethyl--7-nitro-2H-1-chromene (0.21g, 1.0mmol).Stirring reaction solution on one side, on one side with 2 seconds 25 ℃ of interpolation 30% aquae hydrogenii dioxidis (0.12g, 1.1mmol).Continue to stir at 25 ℃ then, with interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, the reaction beginning after 24 hours with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (VI ') is more than 99%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH, elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v), flow: 1.0mL/min; 40 ℃ of column temperatures; The resultant of this reaction of RT: 4.9 minutes, enantiomer: 9.2 minutes, measure wavelength: 220nm.

Embodiment 14

To optical activity titanium Salan complex compound (E) (24mg 0.020mmol) in the dichloromethane solution (3mL) of (with respect to matrix, being 2.0 moles of %), adds 2 at 20 ℃, 2-dimethyl--7-nitro-2H-1-chromene (0.205g, 1.0mmol).With 30% aquae hydrogenii dioxidi (0.12g 1.1mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.The interpolation time of the 1st time 30% aquae hydrogenii dioxidi, the reaction beginning 20 ℃ of stirrings, was taken a sample reaction solution, with HPLC analytical reaction transformation efficiency after 24 hours then as the reaction time opening.Transformation efficiency to compound (VI ') is more than 99%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 1.0mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 13.9 minutes; Enantiomer: 25.2 minutes, measure wavelength: 220nm.

Embodiment 15

(3S ^*, 4S ^*)-3,4-epoxy-6-fluoro-3,4-dihydro-2,2-dimethyl--8-nitro-2H-1-chromene (compound (VII) in * represent relative configuration) synthetic

be

perhaps

To optical activity titanium Salalen complex compound (B) (37mg 0.021mmol) in the dichloromethane solution (4mL) of (with respect to matrix, being 2.0 moles of %), adds 6-fluoro-2 at 25 ℃, 2-dimethyl--8-nitro-2H-1-chromene (0.23g, 1.0mmol).Stirring reaction solution on one side, on one side with 2 seconds 25 ℃ of interpolation 30% aquae hydrogenii dioxidis (0.12g, 1.1mmol).With interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, stirred 29 hours at 25 ℃ reaction beginning back.Reaction finishes the back, methylene dichloride (2mL) and zero(ppm) water (2mL) is added in the reaction solution; Organic phase is carried out separatory; And then will use methylene dichloride (2mL) to merge from the organic phase that the aqueous phase extraction obtains, and spissated thick resultant is made with extra care with column chromatography, obtain yellow powder shape compound (VII) (0.23g; Yield 94% is more than the optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.5mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 17.4 minutes; Enantiomer: 18.1 minutes, measure wavelength: 220nm.

¹H-NMR(CDCl ₃)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)

Embodiment 16

(3S ^*, 4S ^*)-3,4-epoxy-6-fluoro-2,2-dimethyl--8-nitro-2H-1-chromene (compound (VII) in * represent relative configuration) synthetic

(43mg 0.080mmol) in the dichloromethane solution (1.7mL) of (with respect to matrix, being 4.0 moles of %), adds titanium tetraisopropylate [Ti (Oi-Pr) at 25 ℃ to the Salan part shown in the formula (44 ') ₄] (11mg, 0.040mmol).After 1 hour, add 6-fluoro-2 20 ℃ of stirrings, and 2-dimethyl--8-nitro-2H-1-chromene (0.446g, 2.0mmol).With 30% aquae hydrogenii dioxidi (0.25g 2.2mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, stirred 40 hours at 20 ℃ reaction beginning back.After reaction finishes; Methylene dichloride (5mL) and zero(ppm) water (5mL) are added in the reaction solution, organic phase is carried out separatory, and then will use methylene dichloride (5mL, 3mL) to merge from the organic phase that 2 extractions of water obtain; Spissated thick resultant is made with extra care with column chromatography; Obtain yellow oily compound (VII) (optical purity is more than the 99.9%ee for 0.43g, yield 90%).

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.5mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 16.8 minutes; Enantiomer: 17.3 minutes, measure wavelength: 220nm.

¹H-NMR(CDCl ₃)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)

Embodiment 17

(3R ^*, 4R ^*)-3,4-epoxy-6-fluoro-3,4-dihydro-2, * representes relative configuration in the 2-dimethyl--8-nitro-2H-1-chromene (compound (VII ')) synthetic

To optical activity titanium Salalen complex compound (A) (37mg 0.021mmol) in the dichloromethane solution (4mL) of (with respect to matrix, being 2.0 moles of %), adds 6-fluoro-2 at 25 ℃, 2-dimethyl--8-nitro-2H-1-chromene (0.23g, 1.0mmol).On one side stirring reaction solution used for 2 seconds on one side, 25 ℃ of interpolation 30% aquae hydrogenii dioxidis (0.12g, 1.1mmol).With interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, the reaction beginning is after 3 hours, with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (VII ') is 76%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAKAD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.5mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 18.1 minutes; Enantiomer: 17.4 minutes, measure wavelength: 220nm.

Embodiment 18

To optical activity titanium Salan complex compound (E) (24mg 0.020mmol) in the dichloromethane solution (3mL) of (with respect to matrix, being 2.0 moles of %), adds 6-fluoro-2 at 20 ℃, 2-dimethyl--8-nitro-2H-1-chromene (0.23g, 1.0mmol).With 30% aquae hydrogenii dioxidi (0.12g 1.1mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, 20 ℃ stir 24 hours after, with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (VII ') is 96%, and optical purity is more than the 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 0.5mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 17.3 minutes; Enantiomer: 16.8 minutes, measure wavelength: 220nm.

Embodiment 19

(3R ^*, 4R ^*)-(3,4-epoxy-2,2,9-trimethylammonium-3,4-dihydro-2H-pyrans be [2,3-g] quinoline-7-yl also)-methyl acetic acid ester (compound (VIII ') in * represent relative configuration) synthetic

be perhaps

In the dichloromethane solution (3mL) of optical activity titanium Salalen complex compound (A) (71mg, 0.040mmol) (, being 1.9 moles of %), add (2 at 28 ℃ with respect to matrix; 2; 9-trimethylammonium-2H-pyrans is [2,3-g] quinoline-7-yl also)-the methyl acetic acid ester (0.61g, 2.1mmol).Stirring reaction solution on one side, on one side with 10 hours 28 ℃ of interpolation 7.5% aquae hydrogenii dioxidis (1.4g, 3.1mmol).With interpolation time opening of 7.5% aquae hydrogenii dioxidi as the reaction time opening, the reaction beginning after 12 hours 28 ℃ append add 7.5% aquae hydrogenii dioxidi (0.1g, 0.2mmol).Continued to stir 14 hours that calculate from the reaction time opening at 28 ℃ then.Reaction finishes the back, in reaction solution, adds methylene dichloride (6mL) and zero(ppm) water (6mL); Organic phase is carried out separatory; And then will use methylene dichloride (6ml) to merge from the organic phase that water extracts, spissated thick resultant is made with extra care with column chromatography, acquisition yellow oily compound (VIII ') (0.65g; Yield 99% is more than the optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALPAK AD-RH, elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v), flow: 1.0mL/min; 40 ℃ of column temperatures; The resultant of this reaction of RT: 3.9 minutes, enantiomer: 9.3 minutes, measure wavelength: 254nm.

¹H-NMR(CDCl ₃)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)

Embodiment 20

(3R ^*, 4R ^*)-(3,4-epoxy-2,2,9-trimethylammonium-3,4-dihydro-2H-pyrans be [2,3-g] quinoline-7-yl also)-methyl acetic acid ester (compound (VIII)) synthetic

In the dichloromethane solution (1.2mL) of optical activity titanium Salan complex compound (D) (6.2mg, 0.006mmol) (, being 5.0 moles of %), add (2 at 28 ℃ with respect to matrix; 2; 9-trimethylammonium-2H-pyrans is [2,3-g] quinoline-7-yl also)-methyl acetic acid ester (34.2mg, 0.12mmol), Yi Bian stir this reaction soln; On one side with 1 second 28 ℃ of interpolation 30% aquae hydrogenii dioxidis (8.5mg, 0.075mmol).With interpolation time opening of 30% aquae hydrogenii dioxidi as the reaction time opening, the reaction beginning is after 20 minutes, with 1 second 28 ℃ of interpolation 30% aquae hydrogenii dioxidis (8.5mg, 0.075mmol).Then, continue to stir, after 3 hours reaction solution is taken a sample, with HPLC analytical reaction transformation efficiency at 28 ℃.Transformation efficiency to compound (VIII) is 80%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH, elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v), flow: 1.0mL/min; 40 ℃ of column temperatures; The resultant of this reaction of RT: 10.2 minutes, enantiomer: 4.1 minutes, measure wavelength: 254nm.

Embodiment 21

(48mg is 0.040mmol) in the dichloromethane solution (4mL) of (with respect to matrix, being 2.0 moles of %) to optical activity titanium Salan complex compound (E); 20 ℃ of interpolations (2,2,9-trimethylammonium-2H-pyrans also [2; 3-g] quinoline-7-yl)-the methyl acetic acid ester (0.595g, 2.0mmol).With 30% aquae hydrogenii dioxidi (0.34g 3.0mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.The interpolation time of the 1st time 30% aquae hydrogenii dioxidi continued to stir 24 hours that calculate from the reaction time opening at 20 ℃ as the reaction time opening then.Reaction finishes the back, methylene dichloride (5mL) and zero(ppm) water (5mL) is added in reaction solution; Organic phase is carried out separatory; And then will use methylene dichloride (5mL, 3mL) to merge from the organic phase that 2 extractions of water obtain, spissated thick resultant is made with extra care with column chromatography, acquisition yellow powder shape compound (VIII ') (0.61g; Yield 97%, optical purity 99.3%ee).

Analysis condition: chromatographic column name CHIRALPAKAD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 1.0mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 11.2 minutes; Enantiomer: 26.6 minutes, measure wavelength: 320nm.

¹H-NMR(CDCl ₃)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)

Embodiment 22

(3S ^*, 4S ^*)-7-chloro-3,4-epoxy-2,2,9-trimethylammonium-3,4-dihydro-2H-pyrans be synthesizing of [2,3-g] quinoline (* representing relative configuration in the compound (IX)) also

be perhaps

In the dichloromethane solution (2mL) of optical activity titanium Salan complex compound (F) (120mg, 0.10mmol) (, being 10 moles of %) with respect to matrix, add 7-chloro-2,2 at 20 ℃, 9-trimethylammonium-2H-pyrans also [2,3-g] quinoline (0.26g, 1.0mmol).With 30% aquae hydrogenii dioxidi (0.17g 1.5mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, reaction beginning back continues to stir 26 hours at 20 ℃.Reaction finishes the back, methylene dichloride (5mL) and zero(ppm) water (5mL) is added in the reaction solution; Organic phase is carried out separatory; And then will use methylene dichloride (5mL, 3mL) to merge from the organic phase that 2 extractions of aqueous phase obtain, and spissated thick resultant is made with extra care with column chromatography, obtain pale yellow powder compound (IX) (0.21g; Yield 77% is more than the optical purity 99.9%ee).

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 1.0mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 42.1 minutes; Enantiomer: 21.7 minutes, measure wavelength: 220nm.

¹H-NMR(CDCl ₃)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)

Embodiment 23

(3R ^*, 4R ^*)-7-chloro-3,4-epoxy-2,2,9-trimethylammonium-3,4-dihydro-2H-pyrans also in [2,3-g] quinoline (compound (IX ') * represent relative configuration) synthetic

(27mg 0.050mmol) in the dichloromethane solution (0.5mL) of (with respect to matrix, being 10 moles of %), adds titanium tetraisopropylate [Ti (Oi-Pr) at 20 ℃ to the Salan part shown in the formula (44) ₄] (2.8mg, 0.010mmol).20 ℃ stir 1 hour after, add 7-chloro-2,2,9-trimethylammonium-2H-pyrans also [2,3-g] quinoline (0.130g, 0.50mmol) and methylene dichloride (1mL).With 30% aquae hydrogenii dioxidi (0.085g 0.75mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.The interpolation time of the 1st time 30% aquae hydrogenii dioxidi, stirred 45 hours at 20 ℃ reaction beginning back as the reaction time opening, then with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (IX ') is more than 99%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=6/4 (v/v); Flow: 1.0mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 21.7 minutes; Enantiomer: 42.1 minutes, measure wavelength: 220nm.

Embodiment 24

(3S ^*, 4S ^*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl--7-bismethane sulfonamido-6-methoxyl group-2H-1-chromene (compound (X) in * represent relative configuration) synthetic

be

perhaps

To optical activity titanium Salan complex compound (F) (12mg, 0.010mmol) (with respect to matrix; Be 2.0 moles of %) dichloromethane solution (1mL) in; Add 2 at 20 ℃, and 2-dimethyl--7-bismethane sulfonamido-6-methoxyl group-2H-1-chromene (0.18g, 0.50mmol).With 30% aquae hydrogenii dioxidi (0.085g 0.75mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, stirred 30 hours at 20 ℃ reaction beginning back, then methylene dichloride (2mL) and zero(ppm) water (2mL) is added in the reaction solution; Organic phase is carried out separatory; And then will use methylene dichloride (2mL, 1mL) to merge from the organic phase that 2 extractions of water obtain, and spissated thick resultant is made with extra care with column chromatography, obtain white powder compound (X) (0.18g; Yield 97.5%, optical purity 99%).

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=3/7 (v/v); Flow: 1.0mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 19.8 minutes; Enantiomer: 18.6 minutes, measure wavelength: 320nm.

¹H-NMR(CDCl ₃)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)

Embodiment 25

(3R ^*, 4R ^*)-3,4-epoxy-3,4-dihydro-2,2-dimethyl--7-bismethane sulfonamido-6-methoxyl group-2H-1-chromene (compound (X ') in ^*Synthesizing expression relative configuration)

To optical activity titanium Salan complex compound (E) (12mg, 0.010mmol) (with respect to matrix; Be 2.0 moles of %) dichloromethane solution (1mL) in; Add 2 at 20 ℃, and 2-dimethyl--7-bismethane sulfonamido-6-methoxyl group-2H-1-chromene (72mg, 0.20mmol).With 30% aquae hydrogenii dioxidi (0.034g 0.30mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.With interpolation time of the 1st time 30% aquae hydrogenii dioxidi as the reaction time opening, stirred 48 hours at 20 ℃ reaction beginning back, then with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (X ') is 99%, and optical purity is 99%ee.

Analysis condition: chromatographic column name CHIRALPAK AD-RH carries out 3 and connects dress; Elutriant: acetonitrile/20mM (pH8) phosphoric acid buffer=3/7 (v/v); Flow: 1.0mL/min, 40 ℃ of column temperatures, the resultant of this reaction of RT: 18.5 minutes; Enantiomer: 20.0 minutes, measure wavelength: 320nm.

Embodiment 26

To optical activity titanium Salalen complex compound (C) (16mg, 0.010mmol) (with respect to matrix; Be 2.0 moles of %) dichloromethane solution (0.5mL) in; Add 2 at 20 ℃, and 2-dimethyl--7-bismethane sulfonamido-6-methoxyl group-2H-1-chromene (72mg, 0.20mmol).With 30% aquae hydrogenii dioxidi (0.034g 0.30mmol) is divided into 3 five equilibriums, on one side stirring reaction solution, carry out the 1st time at 20 ℃ on one side and add, make and after 30 minutes, add for the 2nd time, make and after 1 hour, add for the 3rd time.The interpolation time of the 1st time 30% aquae hydrogenii dioxidi, stirred 24 hours at 20 ℃ reaction beginning back as the reaction time opening, then with the reaction solution sampling, with HPLC analytical reaction transformation efficiency.Transformation efficiency to compound (X) is 83%, and optical purity is 99%ee.

The industry utilizability

According to the present invention; Can not use the lock out operation that is used for target compound is carried out optical segmentation; Obtain to have the optically active chromene oxide compound of the high-optical-purity more than the 99%ee with the high yield more than 90%, can be fully with the important intermediate of the effective benzopyran compounds of ARR treatment of opposing.Therefore, the present invention is useful in industry.

Claims

1. the method for manufacture of the optically active chromene oxide compound shown in formula (14) or the formula (15); It is characterized in that; Optical activity titanium complex shown in any one of use formula (2) and formula (2 ') is as catalyzer; Chromene compounds shown in formula (10) or the formula (11) in the halogen series solvent, is carried out asymmetric Epoxidation with aquae hydrogenii dioxidi

R in formula (2) and the formula (2 ') ¹The expression phenyl,

This phenyl can be by C _1-4Alkyl, C _1-7Alkoxyl group or benzyl oxygen base replace this C arbitrarily _1-4Alkyl can be replaced arbitrarily by halogen atom,

R ²The expression Wasserstoffatoms,

At 2 R ³Form under the situation of ring R together ³Expression C ₄The group of divalence,

R ⁴Represent Wasserstoffatoms respectively independently,

M representes TiJ ¹J ², at TiJ ¹J ²In, Ti representes titanium atom, J ¹With J ²Form ring together, represent formula (5) as the group of divalence,

About the part-structure O-E-O in the formula, wherein, O representes Sauerstoffatom, in formula (2), as O-E-O, is represented by following formula (7); In formula (2 '),, represent by following formula (7 ') as O-E-O;

B representes 1, R ¹, R ², R ³And R ⁴Same as described above;

R in the formula (10) ⁵, R ⁶, R ⁷And R ⁸Expression independently respectively

Wasserstoffatoms;

Nitro;

Halogen atom;

C _1-4Alkoxyl group;

C _1-4Alkyl-carbonyl-amino; Or

Two (C _1-4Alkyl sulfonyl) imido grpup;

R in the formula (10) ⁹And R ¹⁰Represent C respectively independently _1-6Alkyl;

R in the formula (11) ⁹And R ¹⁰Represent C respectively independently _1-6Alkyl;

Part ring structure A in the formula (11) is represented by formula (s)

In the formula (s), R ¹⁴, R ¹⁵And R ¹⁶Expression independently respectively

Wasserstoffatoms;

Halogen atom; Or

C _1-6Alkyl, this alkyl can be by C _1-6The alkyl-carbonyl oxygen base replaces arbitrarily;

R in the formula ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰Same as described above with A, the absolute configuration of the carbon atom of * institute souvenir is (R) or (S).

2. the method for manufacture of optically active chromene oxide compound according to claim 1; It is characterized in that; Use the optical activity titanium complex shown in any one of above-mentioned formula (2) and formula (2 ') as catalyzer; Chromene compounds shown in the above-mentioned formula (10) in the halogen series solvent, is carried out asymmetric Epoxidation with aquae hydrogenii dioxidi

R in the above-mentioned formula (10) ⁵And R ⁶Expression independently respectively

Wasserstoffatoms;

Nitro;

Halogen atom;

C _1-4Alkoxyl group; Or

C _1-4Alkyl-carbonyl-amino,

R in the formula (10) ⁷Expression

Wasserstoffatoms;

Nitro; Or

Two (C _1-4Alkyl sulfonyl) imido grpup,

R in the formula (10) ⁸Expression Wasserstoffatoms or nitro,

R in the formula (10) ⁹And R ¹⁰Expression C _1-6Alkyl.

3. the method for manufacture of optically active chromene oxide compound according to claim 2, the R in the above-mentioned formula (10) ⁵And R ⁶Represent Wasserstoffatoms, nitro, fluorine atom, methoxyl group or methyl carbonylamino respectively independently, the R in the formula (10) ⁷Expression Wasserstoffatoms, nitro or two (C _1-4Alkyl sulfonyl) imido grpup, the R in the formula (10) ⁸Expression Wasserstoffatoms or nitro, the R in the formula (10) ⁹And R ¹⁰The expression methyl.