JP2001199906A - Method for producing optically active cyclic enaminone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for carrying out the optical resolution of an enaminone derivative without unstabilize the structure because the optical resolution of the enaminone derivative by an optically active acid has hardly been reported and sufficient study has been not carried out. SOLUTION: This method for producing the optically active cyclic enaminone derivative is characterized in that one carbonyl group of the diketone of a cyclic 1,3-diketone derivative having a symmetry plane is aminated to provide a chiral cyclic enaminone derivative, and subjecting the resultant mixture of optical isomers of the cyclic enaminone derivative to the optical resolution to provide the objective optically active enaminone derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active cyclic enaminone derivative which is a synthetic raw material for producing a medicine, a pesticide and the like.

[0002]

2. Description of the Related Art When a desired drug or pesticide is to be synthesized in a stereoselective manner, it is theoretically necessary to carry out isomer separation at a stage close to the final step, because the yield of isomer separation is theoretically 50%.
% Or less, there is much waste. Therefore, it is preferable in terms of synthetic design that an optically active intermediate is obtained at an early stage of the production process, and the final target compound is reached while maintaining this stereostructure. In addition, as a method for optically resolving a chiral compound having an amino group, a method is known in which an optically active acid is added to form a salt to isolate the compound.

[0003]

SUMMARY OF THE INVENTION An enaminone derivative is
It is a compound useful as a synthetic raw material for producing pharmaceuticals, agricultural chemicals, and the like. The same applies to the case where a pharmaceutical or a pesticide is produced stereoselectively using this enaminone derivative as a raw material compound for synthesis. Can be avoided, and the manufacturing cost can be significantly reduced. However, enaminone derivatives tend to undergo amino group substitution and exchange under acidic conditions due to their enaminone partial structure, and are more unstable than ordinary organic bases such as alkylamines, monoarylamines, heterocyclic bases and alkaloids. It is. For these reasons, there have been few reports that the enaminone derivative could be optically resolved with an optically active acid, and at present, no sufficient study has been made.

[0004]

In view of the above situation, the present inventors have studied a method of optically resolving an enaminone derivative without destabilizing its structure. An optical isomer mixture (a racemic mixture, which does not mean "conglomerate", but merely a (±) -isomer and a mixture thereof which does not define such a state of presence) is treated with a specific optically active acid. It has been newly found that optical resolution can be achieved with good yield. Further, when a cyclic 1,3-diketone derivative having a symmetric plane is used as a precursor of the intended optically active cyclic enaminone derivative, the objective compound can be obtained from a mixture of an optical isomer of a chiral cyclic enaminone derivative obtained using the compound as a raw material. After one of the optical isomers is separated, the other optical isomer is again converted into a cyclic 1, having a symmetric plane as a raw material.
It has been found that it can be returned to a 3-diketone derivative. By combining these methods, it was confirmed that the cyclic 1,3-diketone derivative having a symmetry plane as a raw material can be converted into one of the desired optically active forms of the cyclic enaminone derivative without waste. Thus, the present invention has been completed.

That is, the present invention provides (1) a method for producing an optically active cyclic enaminone derivative, which comprises optically resolving a mixture of optical isomers of a cyclic enaminonone derivative using a highly acidic optical resolving agent; 2) An optical activity characterized by aminating one carbonyl group of a diketone of a cyclic 1,3-diketone derivative having a plane of symmetry and optically resolving a mixture of optical isomers of a chiral cyclic enaminone derivative obtained thereby. A method for producing a cyclic enaminone derivative, (3) using a cyclic 1,3-diketone derivative having a symmetry plane as a raw material, aminating one of the carbonyl groups of the diketone of the derivative, and obtaining an optical isomer of a chiral cyclic enaminone derivative obtained thereby. The body mixture is optically resolved to obtain one optically active cyclic enaminone derivative and then the other optically active cyclic enaminone derivative. A process for producing an optically active cyclic enaminone derivative, comprising recovering a cyclic 1,3-diketone derivative having a symmetry plane as a raw material by hydrolyzing a naminone derivative; (4) a cyclic 1,3 having a symmetry plane -The process according to (2) or (3), wherein the diketone derivative is a 5- to 7-membered ring, (5) a cyclic 1,
The 3-diketone derivative has the following formula (I):

Embedded image And a partial structure (A) in the formula (I):

Embedded image Is the following formulas (A-1) to (A-3):

Embedded image [Wherein, R ⁰ to R ¹⁰ each independently represent a hydrogen atom or a substituent (provided that R ¹ and R ² are not the same,
R ³ and R ⁴ and R ⁵ and R ⁶ are not simultaneously the same, and R ⁷ and R ⁸ and R ⁹ and R ¹⁰ are not simultaneously the same.)] 2)
Or (6) the production method according to (3), wherein the partial structure (A) is represented by the following formula (A-1):

Embedded image [Wherein R ¹ and R ² are as defined above], (7) wherein the partial structure (A) is represented by the following formula (A-2):

Embedded image [Wherein, R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above]
A process according to (5) is, (8) the partial structure (A) wherein R ³ and R ⁴ of the compound represented by the formula (A-2)
Are each independently a hydrogen atom or an optionally substituted 5- or 6-membered aromatic homo- or heterocyclic group, and R ⁵
And R ⁶ are each independently a hydrogen atom, a halogen, an optionally substituted linear or branched aliphatic hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group (However, R ³ and R ^4, and R ⁵ and R ⁶ are not necessarily the same at the same time), (9) wherein the partial structure (A) is represented by the formula (A- R ³ and R ^{4 of the} compound represented by 2)
Are each independently a hydrogen atom or an optionally substituted 5- or 6-membered aromatic homo or heterocyclic group (provided that R ³ and R ⁴ are not the same), and R ⁵ and R ⁶ are hydrogen atoms (7) wherein the partial structure (A) is represented by the following formula (A-3):

Embedded image (Wherein R ⁷ to R ¹⁰ are as defined above), (11) wherein the optical resolution is carried out with an optically resolving agent having high acidity. (12) The method according to (1) or (11), wherein the optical resolution agent is an optically active sulfonic acid derivative or a sulfamic acid derivative. (13) The production method according to (1) or (11), wherein the optical resolution agent is an optically active phosphoric acid derivative, (14) the following formula:

Embedded image [Wherein, R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted 5- or 6-membered aromatic homo- or heterocyclic ring (however, R ³ and R ⁴ are not the same)]
An optically active cyclic enaminone derivative represented by the formula (15):
(±) -3-Amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1-one,
(-)-4- (mono or dichloro or methoxyphenyl) -2-hydroxy-5,5-dimethyl-1,
(-)-3-amino-characterized by optical resolution using 3,2-dioxaphospholinan-2-oxide
Method for producing 5- (5-fluoro-2-methylphenyl) -2-cyclohexen-1-one, and (16)
(±) -3-Amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1-one,
(-)-4- (mono or dichloro or methoxyphenyl) -2-hydroxy-5,5-dimethyl-1,
(-)-3-Amino-5- (5) obtained by optical resolution using 3,2-dioxaphosphorinane-2-oxide
-Fluoro-2-methylphenyl) -2-cyclohexen-1-one and (-)-7- (5-fluoro-) obtained by reacting 1,1-dimethoxy-3-butanone
(5E, 7) characterized by reacting 2-methylphenyl) -4-methyl-7,8-dihydroquinolin-5 (6H) -one with aminoguanidine or a salt thereof.
S)-[7- (5-Fluoro-2-methylphenyl)-
4-methyl-7,8-dihydro-5 (6H) -quinolinylideneamino] guanidine or a salt thereof.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the term "cyclic 1,3-diketone derivative having a plane of symmetry" refers to the cyclic 1,3-diketone derivative.
-Means a compound having a surface such that when the diketone derivative is bisected, the divided portions are mirror images of each other. Among them, preferred compounds to which the production method of the present invention can be applied include the following formula (I):

Embedded image And a partial structure (A) in the formula (I):

Embedded image Is the following formulas (A-1) to (A-3):

Embedded image [Wherein R ⁰ to R ¹⁰ are as defined above].

Further, the “substituent” in R ⁰ to R ¹⁰
As a halogen atom, an optionally substituted linear or branched aliphatic hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, and an optionally substituted A good amino group, an optionally substituted imidoyl group, an optionally substituted amidino group,
Nitro group, cyano group, carboxyl group which may be esterified or amidated, sulfonyl group which may be substituted, acyl group derived from carboxylic acid, acyl group derived from sulfonic acid, acyl group derived from sulfinic acid, substitution And an optionally substituted aromatic or non-aromatic homocyclic group, and an optionally substituted aromatic or non-aromatic heterocyclic group.

The "halogen atom" here includes, for example, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine and the like.

Examples of the "linear or branched aliphatic hydrocarbon group" include an alkyl group, an alkenyl group and an alkynyl group. As the alkyl group,
For example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-
Methylpropyl, n-hexyl, isohexyl, 1,1
-Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl , Nonyl and the like, and a C _1-10 alkyl group and the like, and preferably a lower (C _1-6 ) alkyl. As the alkenyl group,
For example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- Pentenyl, 4-methyl-3
-Pentenyl, 1-hexenyl, 2-hexenyl, 3-
C such as hexenyl, 4-hexenyl and 5-hexenyl
_2-6 alkenyl group and the like. Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-
Examples thereof include _C2-6 alkynyl groups such as pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

These "straight or branched fats"
"A group hydrocarbon group" further includes, for example, a halogen atom;
(C_1-6) Alkoxy group, C_3-6Cycloalkyloxy group,
An optionally substituted hydroxy such as an aryloxy group
Group; lower (C_1-6) Alkylthio group, C_3-6Cycloalkyl
Optionally substituted mel such as thio group, arylthio group, etc.
Capto group; lower (C_1-6) Alkyl, lower (C_1-6) Alkoki
Si, C_3-6Cycloalkyl, hydroxy, carbamoy
Phenyl, phenyl-lower (C_1-6) Alkyl, lower
(C_1-6) Alkanoyl, C_3-6Cycloalkyl-carboni
Benzoyl, phenyl-C_2-6Alkanoyl, lower
(C_1-6) Alkoxy-carbonyl, phenoxycarboni
Phenyl-C_1-6Alkoxy-carbonyl, lower (C
_1-6) Alkylsulfinyl, C_3-6Cycloalkylsul
Finyl, phenylsulfinyl, lower (C_1-6) Archi
Rusulfonyl, C_3-6Cycloalkylsulfonyl, lower
(C_1-6) Alkoxysulfonyl and phenylsulfonyl
One or two selected from the same or different
An optionally substituted amino group or two of the substituents
Substituted with a cyclic amino group, etc.
Amino group; lower (C_{1 -6}) Alkyl, lower (C_1-6A)
Lucoxy, C_3-6Substituted with cycloalkyl, aryl, etc.
An imidoyl group or an amidino group which may be substituted; a nitro group;
Cyano group; lower alkoxycarbonyl group, aryloxy
D. Such as carbonyl and aralkyloxycarbonyl groups
Carboxyl group which may be stealized; lower alkyl
, Cycloalkyl, aryl, aralkyl, described below
Aromatic or non-aromatic homocyclic group, aromatic or non-aromatic
One or two members selected from aromatic heterocyclic groups,
N-monosubstitution or N,
N-disubstituted carbamoyl group; lower (C_1-6) Alkylsul
Honyl, C_3-6Cycloalkylsulfonyl, phenyl-
C _1-6Alkylsulfonyl, lower (C_1-6) Alkoxysul
Honyl, C_3-6Cycloalkyloxysulfonyl,
Nil-C_1-6Alkoxysulfonyl, sulfamoyl,
Low (C_1-6) Alkylaminosulfonyl, C_3-6Cycloa
Alkylaminosulfonyl, phenyl-C_1-6Alkyria
Minosulfonyl, cyclic aminosulfonyl, nitroxy C
_1-6Alkylaminosulfonyl, anilinosulfonyl, etc.
Optionally substituted sulfonyl group; lower (C_1-6A)
Alkyl-carbonyl (alkanoyl), C_3-6Cycloa
Derived from carboxylic acids such as alkyl-carbonyl, benzoyl, etc.
Acyl group; lower (C_1-6) Alkylsulfonyl, C_3-6Shiku
Sulfo such as low alkylsulfonyl and phenylsulfonyl
Acyl groups derived from acid; lower (C_1-6) Alkylsulfini
Le, C_3-6Cycloalkyl sulfinyl, phenyl sulf
Acyl groups derived from sulfinic acid such as finyl; cycloal
Kill group, cycloalkenyl group, cycloalkanedienyl
Or unsaturated alicyclic hydrocarbon group such as a group; an aryl group
Monocyclic or fused polycyclic aromatic hydrocarbon groups such as
6-membered aromatic monocyclic heterocyclic group, and 8- to 12-membered aromatic
1 to 3 identical members selected from group-fused heterocyclic groups, etc.
Or a different substituent at a substitutable position.
You may.

The "optionally substituted hydroxy group" includes not only a free hydroxy group but also a lower (C _1-6 ) alkoxy group (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sebutoxy, etc.).
c-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc., C _3-6 cycloalkyloxy group (cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.), aryloxy group (phenyloxy, naphthyloxy) Etc.).

These substituted hydroxy groups further include, for example, a halogen atom; an alkyl group, an alkenyl group,
A linear or branched aliphatic hydrocarbon group such as an alkynyl group; an optionally substituted hydroxy such as a lower (C _1-6 ) alkoxy group, a C _3-6 cycloalkyloxy group, an aryloxy group; An optionally substituted mercapto group such as a lower (C _1-6 ) alkylthio group, a C _3-6 cycloalkylthio group, an arylthio group; a lower (C _1-6 ) alkyl,
_1-6 ) alkoxy, C _3-6 cycloalkyl, hydroxy,
Carbamoyl, phenyl, phenyl - lower (C _1-6) alkyl, lower (C _1-6) alkanoyl, C _3-6 cycloalkyl - carbonyl, benzoyl, phenyl -C _{2 -6} alkanoyl, lower (C _1-6) Alkoxy-carbonyl, phenoxycarbonyl, phenyl-C _1-6 alkoxy-carbonyl, lower (C _1-6 ) alkylsulfinyl, C _3-6 cycloalkylsulfinyl, phenylsulfinyl, lower (C
_1-6 ) an amino group which may be substituted with 1 or 2 same or different ones selected from alkylsulfonyl, C _3-6 cycloalkylsulfonyl, lower (C _1-6 ) alkoxysulfonyl, phenylsulfonyl and the like, or An optionally substituted amino group such as a cyclic amino group in which two of the substituents are combined with a nitrogen atom; lower (C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, C _3-6 cycloalkyl An imidoyl group or an amidino group which may be substituted with alkyl, aryl and the like;
A nitro group; a cyano group; a carboxyl group which may be esterified such as a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group;
One or two selected from lower alkyl, cycloalkyl, aryl, aralkyl, aromatic or non-aromatic homocyclic groups, and aromatic or non-aromatic heterocyclic groups described below may be the same or different and may be substituted. An N-monosubstituted or N, N-disubstituted carbamoyl group; lower (C _1-6 ) alkylsulfonyl, C _3-6 cycloalkylsulfonyl,
Phenyl-C _1-6 alkylsulfonyl, lower (C _1-6 ) alkoxysulfonyl, C _3-6 cycloalkyloxysulfonyl, phenyl-C _1-6 alkoxysulfonyl, sulfamoyl, lower (C _1-6 ) alkylaminosulfonyl, C
_3-6 cycloalkyl-aminosulfonyl, phenyl -C _1-6
Optionally substituted sulfonyl groups such as alkylaminosulfonyl, cyclic aminosulfonyl, nitroxy C _1-6 alkylaminosulfonyl, anilinosulfonyl and the like; lower
(C _1-6 ) alkyl-carbonyl (alkanoyl), C _3-6
Acyl groups derived from carboxylic acids such as cycloalkyl-carbonyl and benzoyl; lower (C _1-6 ) alkylsulfonyl,
Acyl group derived from sulfinic acid lower (C _1-6) alkylsulfinyl, C _3-6 cycloalkylsulfinyl, phenylsulfinyl, etc., C _3-6 cycloalkyl sulfonyl, acyl group derived from sulfonic acids such as phenylsulfonyl;
A saturated or unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group and a cycloalkanedienyl group;
A monocyclic or condensed polycyclic aromatic hydrocarbon group such as an aryl group; a 5- or 6-membered aromatic monocyclic heterocyclic group;
1 to 3 selected from a 12-membered aromatic condensed heterocyclic group, etc.
And the same or different substituents may be substituted at substitutable positions.

The "optionally substituted mercapto group" includes not only a free mercapto group but also a lower (C _1-6 ) alkylthio group (methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio,
Pentylthio, hexylthio, etc.), a C _3-6 cycloalkylthio group (cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.), an arylthio group (phenylthio, naphthylthio, etc.) and the like.

These substituted mercapto groups further include, for example, a halogen atom; an alkyl group, an alkenyl group,
A linear or branched aliphatic hydrocarbon group such as an alkynyl group; an optionally substituted hydroxy such as a lower (C _1-6 ) alkoxy group, a C _3-6 cycloalkyloxy group, an aryloxy group; An optionally substituted mercapto group such as a lower (C _1-6 ) alkylthio group, a C _3-6 cycloalkylthio group, an arylthio group; a lower (C _1-6 ) alkyl,
_1-6 ) alkoxy, C _3-6 cycloalkyl, hydroxy,
Carbamoyl, phenyl, phenyl - lower (C _1-6) alkyl, lower (C _1-6) alkanoyl, C _3-6 cycloalkyl - carbonyl, benzoyl, phenyl -C _{2 -6} alkanoyl, lower (C _1-6) Alkoxy-carbonyl, phenoxycarbonyl, phenyl-C _1-6 alkoxy-carbonyl, lower (C _1-6 ) alkylsulfinyl, C _3-6 cycloalkylsulfinyl, phenylsulfinyl, lower (C
_1-6 ) an amino group which may be substituted with 1 or 2 same or different ones selected from alkylsulfonyl, C _3-6 cycloalkylsulfonyl, lower (C _1-6 ) alkoxysulfonyl, phenylsulfonyl and the like, or An optionally substituted amino group such as a cyclic amino group in which two of the substituents are combined with a nitrogen atom; lower (C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, C _3-6 cycloalkyl An imidoyl group or an amidino group which may be substituted with alkyl, aryl and the like;
A nitro group; a cyano group; a carboxyl group which may be esterified such as a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group;
One or two selected from lower alkyl, cycloalkyl, aryl, aralkyl, aromatic or non-aromatic homocyclic groups, and aromatic or non-aromatic heterocyclic groups described below may be the same or different and may be substituted. An N-monosubstituted or N, N-disubstituted carbamoyl group; lower (C _1-6 ) alkylsulfonyl, C _3-6 cycloalkylsulfonyl,
Phenyl-C _1-6 alkylsulfonyl, lower (C _1-6 ) alkoxysulfonyl, C _3-6 cycloalkyloxysulfonyl, phenyl-C _1-6 alkoxysulfonyl, sulfamoyl, lower (C _1-6 ) alkylaminosulfonyl, C
_3-6 cycloalkyl-aminosulfonyl, phenyl -C _1-6
Optionally substituted sulfonyl groups such as alkylaminosulfonyl, cyclic aminosulfonyl, nitroxy C _1-6 alkylaminosulfonyl, anilinosulfonyl and the like; lower
(C _1-6 ) alkyl-carbonyl (alkanoyl), C _3-6
Acyl groups derived from carboxylic acids such as cycloalkyl-carbonyl and benzoyl; lower (C _1-6 ) alkylsulfonyl,
C _3-6 cycloalkyl sulfonyl, acyl group derived from sulfonic acids such as phenylsulfonyl; lower (C _1-6) alkylsulfinyl, C _3-6 cycloalkylsulfinyl, acyl group derived from sulfinic acid, such as phenylsulfonyl; cycloalkyl A saturated or unsaturated alicyclic hydrocarbon group such as a group, a cycloalkenyl group or a cycloalkanedienyl group; a monocyclic or condensed polycyclic aromatic hydrocarbon group such as an aryl group;
5- to 6-membered aromatic monocyclic heterocyclic group, and 8 to 12
And 1 to 3 identical or different substituents selected from a membered aromatic condensed heterocyclic group and the like, and may be substituted at substitutable positions.

As the "optionally substituted amino group"
Means not only a free amino group but also a lower (C
_1-6) Alkyl (methyl, ethyl, propyl, isopropyl
Butyl, isobutyl, sec-butyl, tert-butyl
, Pentyl, hexyl, etc.), lower grade (C_1-6) Alkoxy
(Methoxy, ethoxy, propoxy, isopropoxy,
Butoxy, isobutoxy, sec-butoxy, tert-butoxy
Xy, pentyloxy, hexyloxy, etc.), C_3-6Shi
Chloroalkyl (cyclopropyl, cyclobutyl, cyclo
Pentyl, cyclohexyl, etc.), hydroxy, carbamo
Yl, phenyl, phenyl-lower (C_1-6) Alkyl
Benzyl, phenethyl, 3-phenylpropyl, 4-fe
Low-grade (C_1-6) Alkanoyl (holmi
Acetyl, propionyl, butyryl, isobutylyl
Le, valeryl, pivaloyl, etc.), C_3-6Cycloalkyl
-Carbonyl (cyclopropylcarbonyl, cyclobutyl
Carbonyl, cyclopentylcarbonyl, cyclohexyl
Silcarbonyl, etc.), benzoyl, phenyl-C_2-6A
Lucanoyl (phenylacetyl, phenylpropionyl
Etc.), low grade (C_1-6) Alkoxy-carbonyl (methoxy
Carbonyl, ethoxycarbonyl, propoxycarbonyl
, Isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, tert-butoxycarbonyl,
Pentyloxycarbonyl, hexyloxycarbonyl
Etc.), phenoxycarbonyl, phenyl-C _1-6Arco
Xy-carbonyl (benzyloxycarbonyl, phenyl
Ethoxycarbonyl, etc.), lower (C_1-6) Alkylsulf
Ynyl (methylsulfinyl, ethylsulfinyl,
Ropirsulfinyl, isopropylsulfinyl, butyral
Rusulfinyl, isobutylsulfinyl, sec-butyl
Rusulfinyl, tert-butylsulfinyl, pentyl
Sulfinyl, hexylsulfinyl, etc.), C_3-6Shiku
Loalkylsulfinyl (cyclopropylsulfinyl
, Cyclobutylsulfinyl, cyclopentylsulfur
Phenyl, cyclohexylsulfinyl, etc.), phenyls
Rufinil, lower (C_1-6) Alkylsulfonyl (methyl
Sulfonyl, ethylsulfonyl, propylsulfonyl,
Isopropylsulfonyl, butylsulfonyl, isobutyl
Rusulfonyl, tert-butylsulfonyl, sec-butyl
Sulfonyl, pentylsulfonyl, hexylsulfonyl
Etc.), C_3-6Cycloalkylsulfonyl (cyclopropyl
Rusulfonyl, cyclobutylsulfonyl, cyclopent
Rusulfonyl, cyclohexylsulfonyl, etc.), lower
(C_1-6) Alkoxysulfonyl (methoxysulfonyl,
Ethoxysulfonyl, propoxysulfonyl, isopro
Poxysulfonyl, butoxysulfonyl, isobutoxy
Sulfonyl, sec-butoxysulfonyl, tert-butoxy
Disulfonyl, pentyloxysulfonyl, hexylo
Xylsulfonyl, etc.) and phenylsulfonyl, etc.
One or two identical or different substituents
And an optionally substituted amino group. 2 of such a substituent
When the individual forms a cyclic amino group together with the nitrogen atom
Such cyclic amino groups include, for example,
Loridino, piperidino, morpholino, thiomorpholino, etc.
Is mentioned.

These substituted amino groups are furthermore exemplified by
For example, halogen atom; alkyl group, alkenyl group, and alkyl
Linear or branched aliphatic hydrocarbon such as a nyl group
Group; lower (C_1-6) Alkoxy group, C_3-6Cycloalkyl
Optionally substituted xy group, aryloxy group, etc.
Droxy group; lower (C_1-6) Alkylthio group, C_3-6Cyclo
Even if it is substituted by alkylthio group, arylthio group, etc.
Good mercapto group; lower (C_1-6) Alkyl, lower (C_1-6)
Alkoxy, C_3-6Cycloalkyl, hydroxy, cal
Bamoyl, phenyl, phenyl-lower (C_1-6) Archi
Low, low grade (C_1-6) Alkanoyl, C_3-6Cycloalkyl-
Carbonyl, benzoyl, phenyl-C_2-6Arcanoy
Low, low grade (C_1-6) Alkoxy-carbonyl, phenoxy
Carbonyl, phenyl-C_1-6Alkoxy-carboni
Low, low grade (C_1-6) Alkylsulfinyl, C _3-6Cycloa
Rukylsulfinyl, phenylsulfinyl, lower (C
_1-6) Alkylsulfonyl, C_3-6Cycloalkyl sulfo
Nil, lower (C_1-6) Alkoxysulfonyl and phenyl
One or two members selected from the group consisting of sulfonyl and the like, or
An amino group or a substituent which may be substituted differently
Of a cyclic amino group, etc. in which two of the above are combined with a nitrogen atom
Optionally substituted amino group; lower (C_1-6) Alkyl, low
Grade (C_1-6) Alkoxy, C_3-6Cycloalkyl, aryl
An imidoyl group or an amidino group which may be substituted with the like;
Nitro group; cyano group; lower alkoxycarbonyl group;
Reeloxycarbonyl group, aralkyloxycarbonyl
An optionally esterified carboxyl group such as
Lower alkyl, cycloalkyl, aryl, aralkyl
, Aromatic or non-aromatic homocyclic groups described below, aromatic
Or one or two selected from non-aromatic heterocyclic groups
N-mono units which may be substituted the same or different
Substituted or N, N-disubstituted carbamoyl groups; lower (C_1-6A)
Rukylsulfonyl, C_3-6Cycloalkylsulfonyl,
Phenyl-C_1-6Alkylsulfonyl, lower (C_1-6) Al
Coxysulfonyl, C_3-6Cycloalkyloxy sulfo
Nil, phenyl-C_1-6Alkoxysulfonyl, sulf
Amoyl, low grade (C_1-6) Alkylaminosulfonyl, C
_3-6Cycloalkylaminosulfonyl, phenyl-C_1-6
Alkylaminosulfonyl, cyclic aminosulfonyl,
Troxy C_1-6Alkylaminosulfonyl, anilinos
An optionally substituted sulfonyl group such as rufonyl; lower
(C_1-6) Alkyl-carbonyl (alkanoyl), C_3-6
Carboxyls such as cycloalkyl-carbonyl and benzoyl
Acyl groups derived from acids; lower (C_1-6) Alkylsulfonyl,
C_3-6Cycloalkylsulfonyl, phenylsulfonyl, etc.
Acyl group derived from sulfonic acid of the formula (C)_1-6) Alkyls
Rufinil, C_3-6Cycloalkylsulfinyl, Fe
Acyl groups derived from sulfinic acid such as nylsulfinyl;
Chloroalkyl group, cycloalkenyl group, cycloalkane
A saturated or unsaturated alicyclic hydrocarbon group such as a dienyl group;
A monocyclic or fused polycyclic aromatic hydrocarbon group such as a reel group;
5- to 6-membered aromatic monocyclic heterocyclic group, and 8 to 12
1 to 3 members selected from membered aromatic condensed heterocyclic groups, etc.
Substitute at the substitutable position with the same or different substituent
It may be.

Examples of the substituent in the “optionally substituted imidoyl group” and the “optionally substituted amidino group” include lower (C _1-6 ) alkyl (methyl, ethyl, propyl, isopropyl, butyl, Isobutyl,
sec-butyl, tert-butyl, pentyl, hexyl, etc.), lower (C _1-6 ) alkoxy (methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc., _C3-6 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aryl (phenyl, naphthyl, etc.) And the like.

These substituted imidoyl groups and
The substituted amidino group further includes, for example, a halogen atom;
Linear groups such as alkyl, alkenyl, and alkynyl groups
Or branched aliphatic hydrocarbon group; lower (C_1-6Arco
Xy group, C_3-6Cycloalkyloxy group, aryloxy
A substituted or unsubstituted hydroxy group such as a cyclo group;_1
-6) Alkylthio group, C_3-6Cycloalkylthio group, ant
Mercapto group which may be substituted, such as
Grade (C_1-6) Alkyl, lower (C_1-6) Alkoxy, C _3-6Shi
Chloroalkyl, hydroxy, carbamoyl, phenyl,
Phenyl-lower (C _1-6) Alkyl, lower (C_1-6) Alkano
Il, C_3-6Cycloalkyl-carbonyl, benzoyl,
Phenyl-C_2-6Alkanoyl, lower (C_1-6) Alkoxy
-Carbonyl, phenoxycarbonyl, phenyl-C
_1-6Alkoxy-carbonyl, lower (C _1-6) Alkylsul
Finil, C_3-6Cycloalkylsulfinyl, phenyl
Rusulfinyl, lower (C_1-6) Alkylsulfonyl, C
_3-6Cycloalkylsulfonyl, lower (C_1-6) Alkoxy
One selected from sulfonyl, phenylsulfonyl, etc.
Two or more substituents may be the same or different
An amino group or two of the substituents together with a nitrogen atom
Optionally substituted amino groups such as cyclic amino groups; low
Grade (C_1-6) Alkyl, lower (C_1-6) Alkoxy, C_3-6Shi
Imi which may be substituted with chloroalkyl, aryl, etc.
Doyl or amidino group; nitro group; cyano group; lower alkyl
Oxycarbonyl group, aryloxycarbonyl group,
Esterified such as aralkyloxycarbonyl groups
Good carboxyl group; lower alkyl, cycloalkyl
, Aryl, aralkyl, aromatic or non-
From aromatic homocyclic groups, aromatic or non-aromatic heterocyclic groups
1 or 2 selected groups are the same or different and are substituted
Optionally substituted N-monosubstituted or N, N-disubstituted carba
Moyl group; lower (C_1-6) Alkylsulfonyl, C_3-6Shiku
Loalkylsulfonyl, phenyl-C_1-6Alkylsul
Honyl, low grade (C_1-6) Alkoxysulfonyl, C_{3- 6}Shiku
Loalkyloxysulfonyl, phenyl-C_1-6Arco
Xisulfonyl, sulfamoyl, lower (C_1-6) Archi
Luminosulfonyl, C_3-6Cycloalkylaminosul
Honyl, phenyl-C_1-6Alkylaminosulfonyl,
Cyclic aminosulfonyl, nitroxy C_1-6Alkylam
Substituted with nosulfonyl, anilinosulfonyl, etc.
A lower sulfonyl group; lower (C_1-6) Alkyl-carboni
Le (alkanoyl), C_3-6Cycloalkyl-carboni
Acyl groups derived from carboxylic acids such as benzoyl and benzoyl; lower
(C_1-6) Alkylsulfonyl, C_3-6Cycloalkylsul
Acids derived from sulfonic acids such as phonyl and phenylsulfonyl
Group; lower (C_1-6) Alkylsulfinyl, C_3-6Cyclo
Sulfol such as alkylsulfinyl and phenylsulfinyl
Acyl group derived from finic acid; cycloalkyl group, cycloa
Saturated or unsaturated alkenyl groups, cycloalkanedienyl groups, etc.
Saturated alicyclic hydrocarbon group; monocyclic or condensed such as aryl group
Polycyclic aromatic hydrocarbon group; 5- or 6-membered aromatic monocyclic ring
Formula heterocyclic group, 8- to 12-membered fused aromatic heterocyclic group, etc.
1 to 3 identical or different substitutions selected from
Group may be substituted at a substitutable position.

The "carboxyl group which may be esterified" of the "carboxyl group which may be esterified or amidated" includes, in addition to a free carboxyl group, for example, a lower alkoxycarbonyl group, an aryloxycarbonyl group, And aralkyloxycarbonyl groups. Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyl C _1-6 alkoxycarbonyl groups such as oxycarbonyl, hexyloxycarbonyl, etc., for example, C _3-6 cycloalkoxycarbonyl such as cyclopropoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, eg, benzyloxycarbonyl, phenyloxy Phenyl-C _1-6 alkoxycarbonyl such as carbonyl, for example, 2-nitroxyethoxycarbonyl, Examples include nitroxy-C _1-6 alkoxycarbonyl such as 3-nitroxypropoxycarbonyl, and among others, C such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl.
_1-3 alkoxycarbonyl groups and the like are preferred. As the aryloxycarbonyl group, for example, a C _7-12 aryloxycarbonyl group such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like are preferable. Examples of the aralkyloxycarbonyl group include C _7-10 aralkyloxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl (eg, C _6-10 aryl-C _1-4 alkoxycarbonyl).
Is preferred.

These esterified carboxyl groups
Further represents, for example, a halogen atom; an alkyl group, an alkenyl
Straight-chain or branched-chain fats such as
Group hydrocarbon group; lower (C_1-6) Alkoxy group, C_3-6Cyclo
Substituted with an alkyloxy group, an aryloxy group, etc.
A hydroxy group; lower (C_1-6) Alkylthio group,
C_3-6Substitution of cycloalkylthio group, arylthio group, etc.
Optionally substituted mercapto groups; lower (C_1-6) Archi
Low, low grade (C_1-6) Alkoxy, C_3-6Cycloalkyl, ar
Droxy, carbamoyl, phenyl, phenyl-lower
(C_1-6) Alkyl, lower (C_1-6) Alkanoyl, C_3-6Shi
Chloroalkyl-carbonyl, benzoyl, phenyl-C
_2-6Alkanoyl, lower (C_1-6) Alkoxy-carboni
Phenoxycarbonyl, phenyl-C_1-6Alkoki
C-carbonyl, lower (C_1-6) Alkylsulfinyl,
C_3-6Cycloalkylsulfinyl, phenylsulfi
Nil, lower (C_1-6) Alkylsulfonyl, C_3-6Cycloa
Rukylsulfonyl, lower (C_1-6) Alkoxysulfonyl
And one or two selected from phenylsulfonyl and the like
An amino group which may be substituted the same or different,
Or a cyclic amine having two substituents together with a nitrogen atom
An amino group which may be substituted, such as_1-6)
Alkyl, lower (C_1-6) Alkoxy, C_3-6Cycloalkyl
Imidoyl group which may be substituted with
Amidino group; nitro group; cyano group; lower alkoxycar
Bonyl group, aryloxycarbonyl group, aralkylo
An optionally esterified carbonyl such as a xycarbonyl group
Boxyl group; lower alkyl, cycloalkyl, aryl
Aralkyl, aromatic or non-aromatic allotropes described below
1 selected from a cyclic group, an aromatic or non-aromatic heterocyclic group
Or two or more may be the same or different
A N-monosubstituted or N, N-disubstituted carbamoyl group;
Low (C _1-6) Alkylsulfonyl, C_3-6Cycloalkyl
Sulfonyl, phenyl-C_1-6Alkylsulfonyl, low
Grade (C_1-6) Alkoxysulfonyl, C_3-6Cycloalkyl
Oxysulfonyl, phenyl-C_1-6Alkoxy sulfo
Nil, sulfamoyl, lower (C_1-6) Alkylaminos
Ruphonyl, C_3-6Cycloalkylaminosulfonyl,
Enyl-C_1-6Alkylaminosulfonyl, cyclic amino
Sulfonyl, nitroxy C_1-6Alkylaminosulfoni
And optionally substituted sulfo such as anilinosulfonyl
Honyl group; lower (C_1-6) Alkyl-carbonyl (alka
Noil), C_3-6Cycloalkyl-carbonyl, benzo
Acyl groups derived from carboxylic acids such as yl; lower (C_1-6) Al
Killsulfonyl, C_3-6Cycloalkylsulfonyl, Fe
Acyl groups derived from sulfonic acids such as nylsulfonyl; lower
(C_1-6) Alkylsulfinyl, C_3-6Cycloalkyls
Sulfinic acids such as rufinyl and phenylsulfinyl
Conventional acyl group; cycloalkyl group, cycloalkenyl
Or unsaturated fatty acids such as a cycloalkanedienyl group
Cyclic hydrocarbon group; monocyclic or condensed polycyclic such as aryl group
Aromatic hydrocarbon group; 5- or 6-membered aromatic monocyclic heterocycle
Selected from an aromatic condensed heterocyclic group having 8 to 12 members
With one to three identical or different substituents
It may be substituted at a replaceable position.

The "amidated carboxyl group" includes not only a carbamoyl group but also an N-monosubstituted carbamoyl group and an N, N-disubstituted carbamoyl group. The N-monosubstituted carbamoyl group means a carbamoyl group having one substituent on a nitrogen atom, such as a lower alkyl group (for example, methyl,
A C _1-6 alkyl group such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., a cycloalkyl group (eg, C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) ), aryl groups (e.g. phenyl, 1-naphthyl, 2-C _{6- 10} aryl naphthyl, etc.), an aralkyl group (e.g. benzyl, C _7-10 aralkyl phenethyl, preferably phenyl -C _1-4 alkyl or the like ) And the later-described heterocyclic groups. Preferred N
Mono-lower (C _1-6 ) alkylcarbamoyl
Examples include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, tert-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl and the like.

The N, N-disubstituted carbamoyl group means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is the aforementioned “N-monosubstituted carbamoyl group”. And the other examples thereof include, for example, lower alkyl groups (for example, methyl, ethyl, propyl, isopropyl, butyl,
C _1-6 alkyl groups such as t-butyl, pentyl, hexyl, etc., C _3-6 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl groups (eg, benzyl, phenethyl, etc.) And preferably a phenyl-C _1-4 alkyl group). In some cases, two substituents may form a cyclic amino group together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl group include 1-azetidinylcarbonyl and 1-pyrrolidinyl. Carbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and a lower alkyl group at the 4-position (for example, methyl, ethyl, propyl, isopropyl, butyl, t
A C _1-6 alkyl group such as butyl, pentyl, hexyl and the like; an aralkyl group (such as a C _7-10 aralkyl group such as benzyl and phenethyl); an aryl group (such as phenyl, 1-naphthyl and 2-naphthyl). And a 3- to 8-membered (preferably 5 to 6-membered) cyclic amino-carbonyl such as 1-piperazinylcarbonyl which may have a C _6-10 aryl group. Preferred N, N-di-lower
(C _1-6 ) alkylcarbamoyl includes, for example, N, N-
Preferred C _3-6 cycloalkylcarbamoyl such as dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl and N, N-dibutylcarbamoyl include, for example, cyclopropylcarbamoyl,
Cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl or the like, preferable phenyl -C _1-6 alkylcarbamoyl, for example benzylcarbamoyl, phenethylcarbamoyl, etc., as preferable nitroxy C _1-6 alkylaminocarbonyl,
Preferred cyclic aminocarbonyl such as 2-nitroxyethylcarbamoyl and 3-nitroxypropylcarbamoyl include, for example, morpholinocarbonyl, piperidinocarbonyl, pyrrolidinocarbonyl, thiomorpholinocarbonyl and the like. In addition, anilinocarbonyl and the like can also be exemplified.

These amidated carboxyl groups
Further represents, for example, a halogen atom; an alkyl group, an alkenyl
Straight-chain or branched-chain fats such as
Group hydrocarbon group; lower (C_1-6) Alkoxy group, C_3-6Cyclo
Substituted with an alkyloxy group, an aryloxy group, etc.
A hydroxy group; lower (C_1-6) Alkylthio group,
C_3-6Substitution of cycloalkylthio group, arylthio group, etc.
Optionally substituted mercapto groups; lower (C_1-6) Archi
Low, low grade (C_1-6) Alkoxy, C_3-6Cycloalkyl, ar
Droxy, carbamoyl, phenyl, phenyl-lower
(C_1-6) Alkyl, lower (C_1-6) Alkanoyl, C_3-6Shi
Chloroalkyl-carbonyl, benzoyl, phenyl-C
_2-6Alkanoyl, lower (C_1-6) Alkoxy-carboni
Phenoxycarbonyl, phenyl-C_1-6Alkoki
C-carbonyl, lower (C_1-6) Alkylsulfinyl,
C_3-6Cycloalkylsulfinyl, phenylsulfi
Nil, lower (C _1-6) Alkylsulfonyl, C_3-6Cycloa
Rukylsulfonyl, lower (C_1-6) Alkoxysulfonyl
And one or two selected from phenylsulfonyl and the like
An amino group which may be substituted the same or different,
Or a cyclic amine having two substituents together with a nitrogen atom
An amino group which may be substituted, such as_1-6)
Alkyl, lower (C_1-6) Alkoxy, C_3-6Cycloalkyl
Imidoyl group which may be substituted with
Amidino group; nitro group; cyano group; lower alkoxycar
Bonyl group, aryloxycarbonyl group, aralkylo
An optionally esterified carbonyl such as a xycarbonyl group
Boxyl group; lower alkyl, cycloalkyl, aryl
Aralkyl, aromatic or non-aromatic allotropes described below
1 selected from a cyclic group, an aromatic or non-aromatic heterocyclic group
Or two or more may be the same or different
A N-monosubstituted or N, N-disubstituted carbamoyl group;
Low (C_{1- 6}) Alkylsulfonyl, C_3-6Cycloalkyl
Sulfonyl, phenyl-C_1-6Alkylsulfonyl, low
Grade (C_1-6) Alkoxysulfonyl, C_3-6Cycloalkyl
Oxysulfonyl, phenyl-C_1-6Alkoxy sulfo
Nil, sulfamoyl, lower (C_1-6) Alkylaminos
Ruphonyl, C_3-6Cycloalkylaminosulfonyl,
Enyl-C_1-6Alkylaminosulfonyl, cyclic amino
Sulfonyl, nitroxy C_1-6Alkylaminosulfoni
And optionally substituted sulfo such as anilinosulfonyl
Honyl group; lower (C_1-6) Alkyl-carbonyl (alka
Noil), C_3-6Cycloalkyl-carbonyl, benzo
Acyl groups derived from carboxylic acids such as yl; lower (C_1-6) Al
Killsulfonyl, C_3-6Cycloalkylsulfonyl, Fe
Acyl groups derived from sulfonic acids such as nylsulfonyl; lower
(C_1-6) Alkylsulfinyl, C_3-6Cycloalkyls
Sulfinic acids such as rufinyl and phenylsulfinyl
Conventional acyl group; cycloalkyl group, cycloalkenyl
Or unsaturated fatty acids such as a cycloalkanedienyl group
Cyclic hydrocarbon group; monocyclic or condensed polycyclic such as aryl group
Aromatic hydrocarbon group; 5- or 6-membered aromatic monocyclic heterocycle
Selected from an aromatic condensed heterocyclic group having 8 to 12 members
With one to three identical or different substituents
It may be substituted at a replaceable position.

The "optionally substituted sulfonyl group" includes, for example, lower (C _1-6 ) alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
Isobutylsulfonyl, sec-butylsulfonyl, tert
- butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), C _3-6 cycloalkylsulfonyl (e.g. cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.), phenyl -C _1-6 alkylsulfonyl (e.g. benzylsulfonyl, Phenethylsulfonyl, etc.), lower (C _1-6 ) alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl,
Isopropoxysulfonyl, butoxysulfonyl, isobutoxysulfonyl, sec-butoxysulfonyl, tert
- butoxysulfonyl, pentyloxy sulfonyl, such as hexyloxy sulfonyl), C _3-6 cycloalkyloxy alkylsulfonyl (e.g. cyclopropoxy sulfonyl,
Cyclobutyloxysulfonyl, cyclopentyloxysulfonyl, cyclohexyloxysulfonyl, etc.), phenyl-C _1-6 alkoxysulfonyl (eg, benzyloxysulfonyl, phenethyloxysulfonyl, etc.),
Sulfamoyl, lower (C _1-6 ) alkylaminosulfonyl (eg, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylaminosulfonyl, sec-butylaminosulfonyl, tert
- butyl aminosulfonyl, pentyl aminosulfonyl, hexyl aminosulfonyl, etc.), C _3-6 cycloalkyl-aminosulfonyl (e.g., cyclopropyl aminosulfonyl, cyclobutyl aminosulfonyl, cyclopentyl aminosulfonyl, cyclohexylaminosulfonyl, etc.), phenyl -C _{1- 6-} alkylaminosulfonyl (eg, benzylaminosulfonyl, phenethylaminosulfonyl, etc.), cyclic aminosulfonyl (eg, morpholinosulfonyl, piperidinosulfonyl, pyrrolidinosulfonyl, thiomorpholinosulfonyl, etc.), nitroxy C _1-6 alkylaminosulfonyl (eg, 2 -Nitroxyethylaminosulfonyl, 3-nitroxypropylaminosulfonyl, etc.), anilinosulfonyl and the like.

As the “acyl group derived from carboxylic acid”,
For example, lower (C _1-6 ) alkyl-carbonyl (alkanoyl) (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, etc.), C
_3-6 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), benzoyl and the like.

As the “acyl group derived from sulfonic acid”,
For example, lower (C _1-6 ) alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl,
Isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc., C _3-6 cycloalkylsulfonyl (eg, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.) ),
Phenylsulfonyl and the like.

The “acyl group derived from sulfinic acid” includes, for example, lower (C _1-6 ) alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert. -Butylsulfinyl, pentylsulfinyl, hexylsulfinyl and the like), C _3-6 cycloalkylsulfinyl (eg cyclopropylsulfinyl,
Cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl and the like), phenylsulfinyl and the like.

The individual “acyl groups” specifically exemplified as described above further include, for example, a halogen atom; a linear or branched aliphatic hydrocarbon group such as an alkyl group, an alkenyl group and an alkynyl group. ; lower (C _1-6) alkoxy groups, C _3-6 cycloalkyloxy group, an optionally substituted hydroxy group and an aryloxy group; a lower (C _1-6)
An optionally substituted mercapto group such as an alkylthio group, a C _3-6 cycloalkylthio group, an arylthio group;
(C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, C _3-6 cycloalkyl, hydroxy, carbamoyl, phenyl, phenyl-lower (C _1-6 ) alkyl, lower (C _1-6 ) alkanoyl, C _3-6 cycloalkyl-carbonyl, benzoyl,
Phenyl-C _2-6 alkanoyl, lower (C _1-6 ) alkoxy-carbonyl, phenoxycarbonyl, phenyl-C
_1-6 alkoxy-carbonyl, lower (C _1-6 ) alkylsulfinyl, C _3-6 cycloalkylsulfinyl, phenylsulfinyl, lower (C _1-6 ) alkylsulfonyl, C
1 to 2 amino groups selected from the group consisting of _3-6 cycloalkylsulfonyl, lower (C _1-6 ) alkoxysulfonyl, phenylsulfonyl and the like, which may be substituted identically or differently, or two of the substituents are nitrogen atoms An optionally substituted amino group such as a cyclic amino group together with a lower (C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, C _3-6 cycloalkyl, aryl or the like Nitro group; cyano group; carboxyl group which may be esterified such as lower alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group; lower alkyl, cycloalkyl, aryl, aralkyl One or two aromatic or non-aromatic homocyclic groups, aromatic or non-aromatic heterocyclic groups described below. An N-mono-substituted or N, N-disubstituted carbamoyl group which may be substituted the same or different; lower (C _1-6 ) alkylsulfonyl, C _3-6 cycloalkylsulfonyl, phenyl-C _1-6 alkylsulfonyl Lower (C _1-6 ) alkoxysulfonyl, C _3-6 cycloalkyloxysulfonyl, phenyl-C _1-6 alkoxysulfonyl, sulfamoyl, lower (C _1-6 ) alkylaminosulfonyl, C _3-6 cycloalkylaminosulfonyl Phenyl-C _1-6 alkylaminosulfonyl,
Optionally substituted sulfonyl groups such as cyclic aminosulfonyl, nitroxy C _1-6 alkylaminosulfonyl, anilinosulfonyl, etc .; lower (C _1-6 ) alkyl-carbonyl (alkanoyl), C _3-6 cycloalkyl-carbonyl, Acyl groups derived from carboxylic acids such as benzoyl; lower
(C _1-6) alkylsulfonyl, C _3-6 cycloalkylsulfonyl, acyl group derived from sulfonic acids such as phenylsulfonyl; lower (C _1-6) alkylsulfinyl, C _3-6 cycloalkylsulfinyl, such as phenylsulfinyl Acyl group derived from sulfinic acid; saturated or unsaturated alicyclic hydrocarbon group such as cycloalkyl group, cycloalkenyl group, cycloalkanedienyl group; monocyclic or condensed polycyclic aromatic hydrocarbon such as aryl group Group; at one or three identical or different substituents selected from a 5- or 6-membered aromatic monocyclic heterocyclic group, and an 8- to 12-membered fused aromatic heterocyclic group, at a substitutable position. It may be substituted.

As the "aromatic or non-aromatic homocyclic group", for example, a cycloalkyl group, a cycloalkenyl group,
Saturated or unsaturated alicyclic hydrocarbon groups such as cycloalkanedienyl groups and aryl groups such as monocyclic or condensed polycyclic aromatic hydrocarbon groups, such as cycloalkyl groups, for example, cyclopropyl, cyclobutyl, C _3-9 cycloalkyl such as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like can be mentioned. Examples of the cycloalkenyl group include 2-cyclopentene-
1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,
1-cyclobuten-1-yl, 1-cyclopentene-1
And C _3-6 cycloalkenyl groups such as -yl.
Examples of the cycloalkanedienyl group include 2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl, and 2,5-cyclohexanediene-
And C _4-6 cycloalkanedienyl groups such as 1-yl. Examples of the aryl group include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl,
And C _6-14 aryl groups such as acenaphthylenyl. Of these, 5 which may be optionally substituted
A 6-membered aromatic or non-aromatic homocyclic group,
Particularly preferred is a 5- or 6-membered aromatic homocyclic group.

The aromatic heterocyclic ring of the “aromatic or non-aromatic heterocyclic group” includes, for example, a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom as an atom (ring atom) constituting a ring system. An aromatic heterocyclic ring containing at least 1 (preferably 1 to 3, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) atoms is exemplified. Specifically, an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
5- or 6-membered aromatic monocyclic heterocyclic groups such as triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and aromatic fused heterocyclic groups (for example, benzofuranyl, Isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl,
1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, Phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5-
a ) pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,
2,4-triazolo [4,3- a ] pyridyl, 1,2,4-
8-) such as triazolo [4,3- b ] pyridazinyl
And a 12-membered fused aromatic heterocyclic group. Among these, a 5- or 6-membered aromatic or non-aromatic heterocyclic group which may be substituted is preferable, and a 5- or 6-membered aromatic heterocyclic group is particularly preferable.

As the “non-aromatic heterocyclic group”, for example,
As the atoms constituting the ring (ring atoms), at least one (preferably 1 to 4) of 1 to 3 (preferably 1 to 2) heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like. And more preferably one or two) saturated or unsaturated non-aromatic heterocycles (aliphatic heterocycles). And a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) such as phenyl, morpholinyl, thiomorpholinyl, and piperazinyl. The heterocyclic group may be a nitrogen atom constituting the ring may be oxidized, and when the ring is a nitrogen-containing aromatic heterocycle having a hydroxyl group as a substituent such as 2-oxypyridine, It may be a nitrogen-containing aromatic heterocycle having an oxo group such as α-pyridone (which is equivalent in chemical structure to a nitrogen-containing aromatic heterocycle having a hydroxyl group as a substituent), and the ring may be an oxo group. In the case of a nitrogen-containing aromatic heterocyclic ring having the above formula, the above substituent may be present on the nitrogen atom of the ring.

These "aromatic or non-aromatic homocyclic rings"
`` Group '' and `` aromatic or non-aromatic heterocyclic group ''
A halogen atom; an alkyl group, an alkenyl group,
Linear or branched aliphatic carbon such as alkynyl group
Hydrogen group; lower (C_1-6) Alkoxy group, C_3-6Cycloalkyl
May be substituted such as a ruoxy group and an aryloxy group.
Hydroxy group; lower (C_1-6) Alkylthio group, C_3-6Shi
Substituted with chloroalkylthio, arylthio, etc.
Mercapto group; lower (C_1-6) Alkyl, lower (C
_1-6) Alkoxy, C_3-6Cycloalkyl, hydroxy,
Carbamoyl, phenyl, phenyl-lower (C_1-6) Al
Kill, low grade (C_1-6) Alkanoyl, C_{3- 6}Cycloalkyl
-Carbonyl, benzoyl, phenyl-C_2-6Alkano
Il, low grade (C_1-6) Alkoxy-carbonyl, phenoxy
Cycarbonyl, phenyl-C_1-6Alkoxy-carboni
Low, low grade (C_1-6) Alkylsulfinyl, C_3-6Cycloa
Rukylsulfinyl, phenylsulfinyl, lower (C
_1-6) Alkylsulfonyl, C_{Three -6}Cycloalkyl sulfo
Nil, lower (C_1-6) Alkoxysulfonyl and phenyl
One or two members selected from the group consisting of sulfonyl and the like, or
An amino group or a substituent which may be substituted differently
Of a cyclic amino group, etc. in which two of the above are combined with a nitrogen atom
Optionally substituted amino group; lower (C_1-6) Alkyl, low
Grade (C_1-6) Alkoxy, C_3-6Cycloalkyl, aryl
An imidoyl group or an amidino group which may be substituted with the like;
Nitro group; cyano group; lower alkoxycarbonyl group;
Reeloxycarbonyl group, aralkyloxycarbonyl
An optionally esterified carboxyl group such as
Lower alkyl, cycloalkyl, aryl, aralkyl
, Aromatic or non-aromatic homocyclic groups described below, aromatic
Or one or two selected from non-aromatic heterocyclic groups
N-mono units which may be substituted the same or different
Substituted or N, N-disubstituted carbamoyl groups; lower (C_1-6A)
Rukylsulfonyl, C_{3- 6}Cycloalkylsulfonyl,
Phenyl-C_1-6Alkylsulfonyl, lower (C_1-6) Al
Coxysulfonyl, C_3-6Cycloalkyloxy sulfo
Nil, phenyl-C _1-6Alkoxysulfonyl, sulf
Amoyl, low grade (C_1-6) Alkylaminosulfonyl, C
_3-6Cycloalkylaminosulfonyl, phenyl-C_1-6
Alkylaminosulfonyl, cyclic aminosulfonyl,
Troxy C_1-6Alkylaminosulfonyl, anilinos
An optionally substituted sulfonyl group such as rufonyl; lower
(C_1-6) Alkyl-carbonyl (alkanoyl), C_3-6
Carboxyls such as cycloalkyl-carbonyl and benzoyl
Acyl groups derived from acids; lower (C_1-6) Alkylsulfonyl,
C_3-6Cycloalkylsulfonyl, phenylsulfonyl, etc.
Acyl group derived from sulfonic acid of the formula (C)_1-6) Alkyls
Rufinil, C_3-6Cycloalkylsulfinyl, Fe
Acyl groups derived from sulfinic acid such as nylsulfinyl;
Chloroalkyl group, cycloalkenyl group, cycloalkane
A saturated or unsaturated alicyclic hydrocarbon group such as a dienyl group;
A monocyclic or fused polycyclic aromatic hydrocarbon group such as a reel group;
5- to 6-membered aromatic monocyclic heterocyclic group, and 8 to 12
1 to 3 members selected from membered aromatic condensed heterocyclic groups, etc.
Substitute at the substitutable position with the same or different substituent
It may be.

The cyclic 1,3-diketone derivative having a symmetry plane used in the production method of the present invention, more specifically, R ¹ to R ⁴ , R ⁷ and R ^{8 of the} compound represented by the formula (I)
Can be selected widely from among the above-mentioned `` substituents '', but is preferably a halogen atom, a linear or branched aliphatic hydrocarbon group which may be substituted, or a substituted or unsubstituted aliphatic hydrocarbon group. Good hydroxy group, optionally substituted mercapto group, optionally substituted amino group, optionally substituted imidoyl group, optionally substituted amidino group, nitro group, cyano group, esterification or amide Carboxyl group which may be converted, sulfonyl group which may be substituted, acyl group derived from carboxylic acid, acyl group derived from sulfonic acid, acyl group derived from sulfinic acid,
An optionally substituted aromatic or non-aromatic homocyclic group, and an optionally substituted aromatic or non-aromatic heterocyclic group, more preferably a halogen atom, an optionally substituted straight chain Or branched aliphatic hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted aromatic or non-aromatic homocyclic group, and an optionally substituted aromatic or non-aromatic group And particularly preferably a lower (C <sub>1-6</sub> ) alkyl group and a 5- or 6-membered aromatic homo- or heterocyclic group which may be substituted. Specific examples of these particularly preferred are And optionally substituted methyl, ethyl, propyl, phenyl, pyrrolyl, furyl, thienyl and the like. R <sup>0</sup> , R <sup>5</sup> , R <sup>6</sup> , R <sup>9</sup> and R <sup>10</sup>
Can be selected widely from among the above-mentioned `` substituents '', but is preferably a halogen atom, a linear or branched aliphatic hydrocarbon group which may be substituted, or a substituted or unsubstituted aliphatic hydrocarbon group. Preferred are a hydroxy group and an optionally substituted mercapto group, particularly preferably a hydrogen atom.

Specific examples of the cyclic 1,3-diketone derivative having a symmetry plane particularly preferably used in the production method of the present invention are as follows. 5-phenylcyclohexane-1,3-dione; 5- (2-fluorophenyl) cyclohexane-1,3-dione; 5- (4-fluorophenyl) cyclohexane-1,3-dione;
(2,4-difluorophenyl) cyclohexane-1,
5- (2-chlorophenyl) cyclohexane-1,3-dione; 5- (2,3-dichlorophenyl) cyclohexane-1,3-dione; 5- (2,6-
Dichlorophenyl) cyclohexane-1,3-dione;
5- (2-bromophenyl) cyclohexane-1,3-
Dione; 5- (3-bromophenyl) cyclohexane-
1,3-dione; 5- (2-methylphenyl) cyclohexane-1,3-dione; 5- (2-trifluoromethylphenyl) cyclohexane-1,3-dione; 5-
(2,5-dimethylphenyl) cyclohexane-1,3
-Dione; 2- (1-hydroxyethylidene) -5-
(2-chlorophenyl) cyclohexane-1,3-dione; 5- (2-methoxyphenyl) cyclohexane-
1,3-dione; 5- (4-methoxyphenyl) cyclohexane-1,3-dione; 5- (2-furyl) cyclohexane-1,3-dione; 5- (2-thienyl) cyclohexane-1,3-dione Dione; 5- (3-thienyl) cyclohexane-1,3-dione; 5- (3-methyl-2
-Thienyl) cyclohexane-1,3-dione; 5-
(5-methyl-2-thienyl) cyclohexane-1,3
-Dione; 5- (3-chloro-2-thienyl) cyclohexane-1,3-dione; 5- (5-chloro-2-thienyl) cyclohexane-1,3-dione; 5- (2-pyridyl) cyclohexane- 1,3-dione; 5- (4-
Pyridyl) cyclohexane-1,3-dione; 5- (5
-Fluoro-2-methylphenyl) cyclohexane-
1,3-dione and the like.

The following compounds can also be preferably used in the production method of the present invention. 5- (2-chlorophenyl) -2-propionylcyclohexane-1,3
-Dione; 2- (1-hydroxyethylidene) -5-
(2-methylphenyl) cyclohexane-1,3-dione; 2-acetyl-5- (2-methoxyphenyl) cyclohexane-1,3-dione; 2-acetyl-5- (2
-Chlorophenyl) cyclohexane-1,3-dione;
4,5-dimethylcyclopentane-1,3-dione;
5,6-diphenylcycloheptane-1,3-dione and the like.

The cyclic 1,3-diketone derivative having a plane of symmetry and the chiral cyclic enaminonone derivative used in the production method of the present invention have tautomers, and any of these tautomers can be used. Are included in the scope of the present invention.

The production method of the present invention is schematically represented by the following formula:

Embedded image [Partial structure of each compound in the formula:

Embedded image Is as defined above].

That is, one of the carbonyl groups of the diketone of the cyclic 1,3-diketone derivative having a plane of symmetry of the present invention represented by the formula (I) is aminated to give a compound of the formula (II-1) or (II-2) To obtain a mixture of optical isomers of a chiral cyclic enaminone derivative represented by the following formula: Next, a desired optically active cyclic enaminone derivative is optically resolved from the optical isomer mixture to obtain an optically active isomer, for example, a compound represented by the formula (II-
1) is derived to a target drug as a raw material for synthesis. On the other hand, the remaining optically active substance represented by the formula (II-2) is recovered and subjected to a hydrolysis reaction, whereby the cyclic 1,3 having a symmetry plane represented by the formula (I) used as an initial raw material in the present invention is obtained.
-A diketone derivative can be obtained. By subjecting the obtained compound represented by the formula (I) to the above-mentioned amination reaction again, all the compounds represented by the formula (I) are converted into the desired optically active cyclic enaminonone derivative represented by the formula (II-1) Can be converted to

The amination of the present invention is described, for example, in the literature Synth
esis, vol. 11, p. 902, 1983. Specifically, a cyclic 1,3-diketone derivative having a plane of symmetry, for example, a compound represented by the formula (I) is added in an amount of about 1 to 30 equivalents, preferably about 1 to 30 equivalents.
10 equivalents of an ammonium salt (eg, ammonium formate,
Ammonium salts selected from aminating agents such as ammonium acetate, ammonium chloride, ammonium sulfate)
A solvent inert to the reaction, for example, methanol, ethanol, benzene, toluene, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide and the like, or a mixed solvent thereof, preferably A temperature of about 0 ° C. to the reflux temperature of the solvent together with an alcoholic solvent such as ethanol, preferably at room temperature to about 100 ° C.
The stirring can be performed for about 48 hours. By the above amination reaction, a mixture of optical isomers of a chiral cyclic enaminone derivative, for example, a mixture of optical isomers represented by formulas (II-1) and (II-2) can be obtained. When a cyclic 1,3-diketone derivative having a symmetry plane as a raw material, for example, a compound represented by the formula (I) has a substituent which is affected by the above amination reaction, it is usually added as necessary. The substituent can be protected by a method.

Next, the desired optically active cyclic enaminone derivative can be obtained by subjecting the obtained optical isomer mixture of the chiral cyclic enaminone derivative to the optical resolution method of the present invention. That is, an optical resolving agent, preferably an optical resolving agent having high acidity, is caused to react with the optical isomer mixture of the cyclic enaminonone derivative, and the mixture is separated as a salt with the optical resolving agent. As the optical resolving agent having a high acidity used herein, those having a dissociation constant pKa in water of about 4 or less, preferably about -10 to about 3 are used. Specifically, for example, an optically active phosphoric acid derivative, an optically active sulfamic acid derivative and an optically active sulfonic acid derivative are preferred.
As the optically active phosphoric acid derivative, for example,

Embedded image [In the formula, ring A represents a benzene ring which may have a substituent, and R ^1a and R ^2a each represent a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, Represents a C _1-4 alkoxy group or a nitro group which may be possessed, or has a C _2-6 alkylene or a substituent which R ^1a and R ^2a together may have a substituent. Represents an optionally substituted methylenedioxy, and * represents an asymmetric center. ] Or an optically active form of a salt thereof, or a compound represented by the formula

Embedded image [In the formula, the A ¹ ring and the A ² ring each represent an aromatic ring which may have a substituent. ] Or an optically active form of a salt thereof. These compounds are
JP-A-61-103886, JP-B-55-47013,
J. Org. Chem., 50, 4508 (1985) and the like, and can be easily obtained, and some compounds can be easily obtained as commercial products. Specifically, for example, 2
-Hydroxy-5,5-dimethyl-4-phenyl-1,
3,2-dioxaphospholinan-2-oxide, 4-
(2-chlorophenyl) -2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide, 4- (2,4-dichlorophenyl) -2-hydroxy-5,5-dimethyl -1,3,2-dioxaphosphorinane-2-oxide, 2-hydroxy-4- (2-methoxyphenyl) -5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide, 2-hydroxy-
4,4-dimethyl-5-phenyl-1,3,2-dioxaphosphorane-2-oxide, 2-hydroxy-5
(2-methoxyphenyl) -4,4-dimethyl-1,
3,2-dioxaphosphorane-2-oxide, 1,1 ′
-Binaphthyl-2,2'-diyl hydrogen phosphate, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, 3'-hydroxy-1,1'-binaphthyl-2,2'-diyl Hydrogen phosphate, 9,9′-biphenanthryl-10,10′-diyl hydrogen phosphate and the like.

The optically active sulfamic acid derivatives include:
For example, the expression

Embedded image [Wherein, B is a C _6-14 aryl group which may have a substituent, R ^1b is a hydrogen atom or a hydroxyl group, and R ^2b is a hydrogen atom or a hydrocarbon group which may have a substituent. Or, a carboxyl group which may be esterified, R ^3b represents a hydrogen atom or a hydrocarbon group which may have a substituent, and n represents 0 or 1. ] Or an optically active form of a salt thereof, or a compound represented by the formula

Embedded image [Wherein, the ring C is a hydrocarbon group which may have a substituent,
It shows pyrrolidine or piperidine substituted respectively by one or two substituents selected from a carboxyl group and a cyano group which may be esterified or amidated. Or an optically active form of a salt thereof. These can be easily obtained as commercial products. Also, from commercially available optically active amines, etc.,
J. Org. Chem., 23, 1133 (1958), etc., and can be easily obtained.Furthermore, after a racemic sulfamic acid is synthesized from a commercially available racemic amine or the like in the same manner, this is usually used. It can also be obtained by optical resolution according to the method. Specifically, for example, 1-phenylethylsulfamic acid, 1-phenyl-2- (p-tolyl) ethylsulfamic acid, 1- (1-naphthyl) ethylsulfamic acid, 2-phenylpyrrolidine-1-sulfonic acid, 2
-Benzylpyrrolidine-1-sulfonic acid, 3-phenylpyrrolidine-1-sulfonic acid, 2- (4-methoxyphenyl) piperidine-1-sulfonic acid and the like.

Examples of the optically active sulfonic acid derivative include camphor-10-sulfonic acid, 3-bromocamphor-8-sulfonic acid, 1-phenylethanesulfonic acid, and 1-phenylpropanesulfonic acid. The optically active sulfamic acid derivative exemplified here is
For example, it can be easily obtained according to the method described in J. Org. Chem. 23, p1133 (1958).

In the above formula, the “aromatic ring” of the “optionally substituted aromatic ring” represented by ring A ^{1 and} ring A ² includes, for example, a benzene ring, a naphthalene ring and a phenanthrene ring. Can be As the compound (Ia ′), a compound represented by the formula

Embedded image[Where A^ThreeRing, A^FourRing, A^FiveRing and A⁶Rings
A benzene ring which may have a substituent is shown. ]
Optically active form of a compound or a salt thereof is preferred. Said
Wherein A ring, A¹Ring or A⁶Ring and B are each optional
May have one or two substituents at the position
As the substituent, for example, a low
Secondary alkyl group, hydroxyl group which may have a substituent, substitution
Thiol group, nitro group,
An amino group, an acyl group, a halogen atom,
Methylenedioxy which may have a cyano group or a substituent
Group (or two adjacent substituents are bonded)
I can do it. A lower alkyl group optionally having a substituent
Are, for example, methyl, ethyl, n-propyl, iso-
Propyl, n-butyl, isobutyl, sec-butyl, ter
Linear or branched chains such as t-butyl, pentyl, hexyl, etc.
Unsubstituted C_1-6Other than these alkyl groups
Based on C_2-5Alkanoyl (eg, acetyl, propionyl
Etc.), carboxyl, C_1-4Alkoxy-carbonyl
(Eg, methoxycarbonyl, ethoxycarbonyl, buto
Xyl, etc.)
You. Examples of the hydroxyl group which may have a substituent include
In addition to a substituted hydroxyl group, for example, a lower alkoxy group (eg, methyl
Oxy, ethyloxy, n-propyloxy, isopro
Pyroxy, n-butyloxy, isobutyloxy, se
c-butyloxy, tert-butyloxy, pentyloxy
Linear or branched C such as C, hexyloxy, etc._1-6A
Alkoxyl group), lower alkanoyloxy group (eg, acetyl
C such as tyloxy and propionyloxy_1-4Arcanoy
Oxy), carbamoylo which may have a substituent
A xy group (eg, unsubstituted carbamoyloxy,
Methylcarbamoyloxy, ethylcarbamoyloxy
Si, dimethylcarbamoyloxy, diethylcarbamoy
Such as loxy, methylethylcarbamoyloxy, etc.
Is two C_1-4Carbamoylo substituted with an alkyl group
Xy) and the like. May have the substituent
As the thiol group, other than an unsubstituted thiol group, for example,
Secondary alkylthio groups (eg, methylthio, ethylthio, pro
C such as pirthio _1-4Alkylthio group), lower alkano
Ylthio group (eg, acetylthio, propionylthio, etc.
C_1-4Alkanoylthio) and the like. The substituent
The amino group which may have an unsubstituted amino group
Other than a lower alkylamino group (eg, methylamino
C such as no, ethylamino, propylamino_1-4Archi
Amino group), di-lower alkylamino group (eg, dimethyl
Di-C such as amino and diethylamino_1-4Alkylam
No), C_1-4Alkanoylamino group (eg, acetamido,
And propionamide. The acyl group
As an alkanoyl group (eg, formyl; a
C such as cetyl and propionyl_1-6Alkanoyl), a
Alkylsulfonyl group (eg, methylsulfonyl, ethyls
C such as rufonyl_1-4Alkylsulfonyl), aryl
Sulfonyl group (eg, benzenesulfonyl, p-toluene
Sulfonyl, etc.), carbamo optionally having substituent (s)
Yl group (eg, methylcarbamoyl, ethylcarbamoy
Dimethylcarbamoyl, diethylcarbamoyl, etc.
Mono- or di-C_{1- Ten}An alkyl-carbamoyl group,
For example, phenylcarbamoyl, diphenylcarbamoy
Mono- or di-C such as_6-14Aryl-carbamoy
Benzylcarbamoyl, dibenzylcarbayl
Mono- or di-C such as moils_7-16Aralkyl-cal
Bamoyl group), sulfa which may have a substituent
Moyl group (eg, methylsulfamoyl, ethylsulfa
Moyl, dimethyl sulfamoyl, diethyl sulfamo
Mono- or di-C such as il_1-10Alkylsulfamo
Yl groups such as phenylsulfamoyl, diphenyl
Mono- or di-C such as sulfamoyl_6-14Aryl
Sulfamoyl groups such as benzylsulfamoyl,
Mono- or di-C such as dibenzylsulfamoyl
_7-16Aralkylsulfamoyl group, etc.)
You. Examples of the halogen atom include fluorine, chlorine, bromine and iodine.
Urine. Methylene optionally having the substituent
Dioxy group is substituted on two adjacent carbons of the benzene ring
Examples include unsubstituted methylenedioxy
In addition to the group, the methylene group may be, for example, a halogen atom (eg,
Nitrogen, chlorine, bromine, iodine), nitro,
It may be substituted with a hydroxyl group, amino group or the like.

The ring A is preferably a benzene ring optionally having one or two substituents selected from halogen, a C _1-6 alkyl group and a C _1-6 alkoxy group. The ring A is particularly preferably an unsubstituted one or a ring having one or two chlorine atoms or a methoxy group as a substituent. The substitution position is 2-position, 4-position and 2,4-position. The substituents on the A ¹ to A ⁶ rings include a halogen atom, a hydroxyl group,
One or two members selected from a _1-6 alkoxy group, a C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl group, a C _6-14 aryl group and a C _1-6 alkoxy-carbonyl group are preferable. . B represents a C _6-14 aryl group (phenyl group, naphthyl group) which may have one or two substituents selected from nitro, halogen atom, C _1-6 alkyl group and C _1-6 alkoxy group Is preferred. Ring C is substituted with one or two substituents selected from nitro, cyano, halogen, hydroxyl, C _1-4 alkoxy, carboxyl, carbamoyl, C _1-4 alkoxy-carbonylamino and acylamino. Pyrrolidine or piperidine substituted with one or two substituents selected from a hydrocarbon group, a carboxyl group, a C _1-4 alkoxy-carbonyl group, a carbamoyl group and a cyano group, respectively, is preferable.

R^1a, R^2a, R^2b, R^3bAnd substitution of ring C
The "optionally substituted hydrocarbon group" in the group
For example, unsubstituted methyl, ethyl, propyl, etc.
C _1-4In addition to alkyl groups, these alkyl groups
Atom, nitro, cyano, C_{1 -Four}Alkanoyl (eg,
Cetyl, propionyl, etc.), carboxyl, hydroxyl,
C_1-4Alkoxy (eg, methoxy, ethoxy, propoxy
Etc.), C_1-4Alkoxy-carbonyl (eg, methoxy
Carbonyl, ethoxycarbonyl, butoxycarbonyl
Carbamoyl, C_1-4Alkoxy-carbonyl
Amino (eg, methoxycarbonylamino, ethoxycal
One or two positions selected from
And those substituted with a substituent. R^1aAnd R^2a
C optionally having a substituent represented by_1-4Alkoxy
Examples of the group include unsubstituted methyloxy and ethyloxy.
C_1-4In addition to alkoxy groups, these alkoxy groups may have C_1-4
Alkanoyl (eg, acetyl, propionyl, etc.),
Ruboxyl, hydroxyl group, C_1-4Alkoxy (eg, methoki
C, ethoxy, propoxy, etc.), C_1-4Alkoxy-ka
Rubonyl (eg, methoxycarbonyl, ethoxycarbonyl
, Butoxycarbonyl, etc.)
Or those substituted with two substituents. R
^1aAnd R^2aAs the halogen atom represented by
For example, fluorine, chlorine, bromine, iodine, etc.
No. R^1aAnd R^2aTogether have a substituent
When an alkylene group which may be present is present,
As the alkylene group which may be present, an alkylene group having 2 to 6 carbon atoms
Substituted alkylene (dimethylene, trimethylene, tetra
Methylene, pentamethylene) and their alkylenes
At any position, for example, a lower alkyl group (eg, methyl
C such as toluene, ethyl and propyl_1-4Alkyl), lower alkyl
Coxy group (eg, C such as methoxy, ethoxy, propoxy, etc.)
_1-4Alkoxy), hydroxyl, amino, nitro, halo
Gen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine
Having one or two substituents selected from
It may be something. R^1aAnd R^2aAs a preferred example of
R^1aAnd R^2aAre both methyl groups,
And when both bond to each other to show a tetramethylene group
Case. R^2b"Is esterified
Or a carboxyl group which may be
"Carbos, which may be esterified or amidated
Xyl groups ”include the above R⁰Or R^TenIn "place
And the same as those described in detail in `` Substituent group ''.
You.

When the above compound has an acidic group, for example, it may form a salt with a metal (eg, sodium, potassium, calcium, etc.) or an ammonium ion. Addition salts, such as inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide,
Phosphates, etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumarate,
Propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.) may be formed.

The optical resolution in the production method of the present invention is carried out by reacting an optical isomer mixture of a cyclic enaminone derivative with an organic solvent inert to the reaction, for example, an alcohol such as methanol, ethanol, 1-propanol, 2-propanol or 1-butanol. Nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; lactams such as N-methylpyrrolidone; ketones such as acetone and methyl ethyl ketone; Esters; carboxylic acids such as formic acid and acetic acid; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran and diisopropyl ether; halogenated hydrocarbons such as methylene chloride; aliphatic hydrocarbons such as hexane; dimethyl sulfoxide Dissolved in a solvent appropriately selected from , About 0.5 to 5 equivalents, preferably by addition of about 0.5 to 2 equivalents of the acid a high degree of optical resolution agent, a reflux temperature of from about 0 ℃ solvent, preferably about 0
Dissolve at 0 ° C. Next, after concentration as required, for example, a solvent appropriately selected from the above-mentioned solvents is added, and heating, cooling, or concentration, or an operation in which these are combined is performed to crystallize and isolate a crystalline salt. It can be done by doing.

The cooling temperature for precipitating the salt is, for example,
A range from about -20 to 20C is preferred. Further, the concentration of the organic solvent may be carried out, for example, by dissolving the optically active cyclic enaminone derivative and the optical resolving agent in the organic solvent, and then distilling off the organic solvent under reduced pressure until a part or a sufficient amount of the crystalline salt is precipitated. As a specific example of a method for crystallizing a crystalline salt, for example, a cyclic enaminone derivative and an optical resolving agent are dissolved by heating in ethanol, and then ethyl acetate is added dropwise to crystallize.

The crystalline salt of the optically active cyclic enaminone derivative and the optical resolving agent obtained by the above method can be subjected to recrystallization by a conventional method, if necessary. In addition, if desired, by treating with an alkali in a solvent inert to the reaction, a desired optically active cyclic enaminone derivative or a salt thereof can be obtained. Specifically, for example, the crystalline salt is distributed between an organic solvent such as ethyl acetate, tetrahydrofuran, and methyl ethyl ketone and an aqueous alkali solution such as sodium hydroxide to obtain a free cyclic enaminonone derivative. The resulting optically active cyclic enaminone derivative is
Further, it can be isolated as a desired salt by treating with an inorganic acid or an organic acid. As the salt, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, methanesulfonate, toluenesulfonate, 1-
Phenylethyl sulfamate and the like can be exemplified.

In the production method of the present invention, the desired optically active cyclic enaminone derivative is isolated from the mixture of optical isomers as a salt with the above-mentioned optical resolving agent, and the remaining optically active cyclic enaminone derivative is hydrolyzed. As a result, a 1,3-diketone derivative having a symmetry plane, which is a raw material compound, can be recovered. The hydrolysis treatment performed here may be performed in accordance with a usual acid hydrolysis reaction, and for example, about 0.1 to 100 equivalents, preferably about 0.1 to 50 equivalents, of an optically active cyclic enaminone derivative or a salt thereof. An inorganic or organic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, an acid selected from toluenesulfonic acid, and water, or In a mixture of water and an organic solvent soluble in water, for example, an appropriate solvent selected from alcohols such as methanol and ethanol, and ketones such as acetone at about 0 to 100 ° C. for about 0.5 The stirring can be performed almost quantitatively by stirring for ~ 48 hours.

The cyclic 1,3-diketone derivative having a symmetry plane used as a raw material in the production method of the present invention is known per se and can be easily obtained as a commercial product. It can be easily obtained by conversion by a method. More specifically, when the partial structure (A) is a compound represented by the formula (A-2), a known method, for example, J. Am. Chem. Soc., 72, 1645 (1950), etc.
And some compounds can also be easily obtained as commercial products. When the partial structure (A) is a compound represented by the formula (A-1) or (A-3), for example, 2,3-dimethylmaleic anhydride, 2,3-diphenylmaleic anhydride,
3,4,5,6-tetrahydrophthalic anhydride, 2,3
It can be easily obtained from commercially available compounds such as -bis (2,4,5-trimethyl-3-thienyl) maleic anhydride by a combination of known reactions.

The optically active cyclic enaminone derivative obtained by the production method of the present invention is useful as a synthetic raw material or a synthetic intermediate for producing an optically active drug or agricultural chemical. For example,

Embedded image The optically active cyclic enaminonone derivative represented by is produced by the same method as described in Examples 1 to 4 described below, and further, by the same method as Reference Examples 1 to 2 described below,

Embedded image Can be obtained. Also, for example,

Embedded image The optically active cyclic enaminonone derivative represented by the following formula was produced by the same method as described in Example 5 described below, and further produced by the same method as in Reference Examples 7 to 9 described below.

Embedded image Can be obtained. The compounds are useful as Na ⁺ / H ⁺ exchange inhibitors such as preventive and therapeutic agents for ischemic heart disease and preventive and therapeutic agents for heart failure (WO99 /
42442).

[0053]

The present invention will be described in more detail with reference to examples and reference examples below, but the present invention is not limited to these examples.

Example 1 (±) -3-amino-5- (2-chlorophenyl) -2
Preparation of -cyclohexenone-1-one: 5- (2-chlorophenyl) cyclohexane-1,3-dione (180
mg), ammonium acetate (300 mg) and ethanol (3 ml), and the mixture was stirred at 100 ° C. for 2 hours. Water was added to the residue obtained by concentration under reduced pressure, and the precipitated crystals were collected by filtration.
After washing with water and drying under vacuum, the title compound (1
57 mg, yield 87.6%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.2
3 (1H, dd, J = 15.8 Hz, 4.1 Hz), 2.
30-2.70 (3H, m), 3.61 (1H, m),
5.05 (1H, s), 6.60-7.20 (2H, b
r), 7.20-7.55 (4H, m). Chiral stationary phase HPLC analysis (column: Daicel CHIR)
ALCELOJ-R 150 mm length 4.6 mm inner diameter, mobile phase: water / ethanol 65/35, flow rate 0.5 ml / m
in, detection wavelength 254 nm) (R) -isomer 49.7%
(Retention time 16.7 minutes), 50.1% of (S) -isomer (retention time 19.1 minutes), complete racemization.

Example 2 (S) -3-Amino-5- (2-chlorophenyl) -2
Production of -cyclohexenon-1-one (S) -1-phenylethylsulfamate: (±) -3-amino-5- (2-chlorophenyl)-obtained in Example 1 above.
2-cyclohexenone-1-one (35.25 g) and (S) -1-phenylethylsulfamic acid (32
g) was dissolved by heating in ethanol (71 ml), and ethyl acetate (460 ml) was added dropwise over about 1.5 hours, followed by stirring for 3 hours. The precipitated crystals were collected by filtration, washed with ice-cooled ethanol: ethyl acetate = 1: 8 (140 ml), and dried in vacuo to obtain crude crystals of the title compound (23.5 g). The obtained crude crystals (23 g) were dissolved by heating in ethanol (92 ml), and ethyl acetate (23 g) was added.
0 ml) was added dropwise over about 1 hour and then stirred for 3 hours. The precipitated crystals were collected by filtration, washed with ice-cooled ethanol: ethyl acetate = 1: 8 (92 ml), and dried in vacuo to give the title compound (14 g, yield 20.8%).
I got ¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 1.5
5 (3H, d, J = 6.8 Hz), 2.28 (1H, d
d, J = 15.9 Hz, 4.0 Hz). 2.24-2.75
(3H, m), 3.63 (1H, m), 4.49 (1H,
q, J = 6.8 Hz), 5.15 (1H, s), 6.90
−7.60 (2H, br), 7.20-7.60 (4H,
m).

Example 3 (S) -3-Amino-5- (2-chlorophenyl) -2
Production of -cyclohexen-1-one: The compound obtained in Example 2 (1 g), a 1: 1 mixed solvent of ethyl acetate and methyl ethyl ketone (20 ml) and a 1N aqueous sodium hydroxide solution (20 ml) were mixed, and the mixture was stirred at room temperature. For about 1 hour. After confirming that the solid was completely dissolved, the organic layer was washed with saturated saline (20 ml) and dried over magnesium sulfate (1 g). The solvent was distilled off under reduced pressure, and the powder obtained was dried in vacuo to give the title compound (0.1%).
52 g, yield 99.2%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.2
3 (1H, dd, J = 15.8 Hz, 4.1 Hz), 2.
30-2.70 (3H, m), 3.61 (1H, m),
5.05 (1H, s), 6.60-7.20 (2H, b
r), 7.20-7.55 (4H, m). Chiral stationary phase HPLC analysis (column: Daicel CHIR)
ALCELOJ-R 150 mm length 4.6 mm inner diameter, mobile phase: water / ethanol 65/35, flow rate 0.5 ml / m
in, detection wavelength 254 nm) (S) -isomer 99.6%
(Retention time 18.8 minutes), 0.3% of (R) -isomer (retention time 17.1 minutes), optical purity 99.4% ee.

Example 4 Preparation of 5- (2-chlorophenyl) cyclohexane-1,3-dione: (R) obtained in the same manner as in Examples 1 to 3 using (R) -1-phenylethylsulfamic acid. -3-amino-5- (2-chlorophenyl) -2
-Cyclohexenone (200 mg, 99.2% ee) and 0.5 M sulfuric acid (10 ml) were mixed and stirred at 100 ° C for 2 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, and dried in vacuo to give the title compound (187 mg, yield 9).
3.1%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.3
0-2.75 (4H, m), 3.70 (1H, m), 5.
32 (1H, s), 7.15-7.60 (4H, m), 1
0.80-11.6 (1H, br).

Example 5 Preparation of (-)-3-amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1-one:
(±) -3-Amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1-one (2.8
2g), (-)-4- (2,4-dichlorophenyl)-
A mixture of 2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide (4.0 g) and acetonitrile (42.3 ml) was heated under reflux for 15 minutes. After stirring at room temperature for 2 hours, the precipitated crystals were collected by filtration and washed with acetonitrile (20 ml). This crystal was suspended in tetrahydrofuran (36 ml), and isopropyl alcohol (9.43 ml) was added dropwise under reflux with heating to dissolve. 5 ℃
After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with tetrahydrofuran-isopropyl ether (5: 1).
(-)-3-amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1-one and (-)
Diastereomeric salts with -4- (2,4-dichlorophenyl) -2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide (2.89
g, 43.5%). The diastereomer salt (2.
8g), toluene (5.6 ml), and water (28 ml), 2N NaOH (5.85 ml) was added at room temperature, and
Stir at C for 2 hours. The precipitated crystals were collected by filtration and washed with water to give the title compound (1.00 g, 36.6%). ¹ H-NMR (CDCl ₃ ) δ: 2.30 (3H, s),
2.20-2.75 (4H, m), 3.47-3.65
(1H, m), 4.75 (2Hbs), 5.35 (1
H, s), 6.80-7.03 (2H, m), 7.08
-7.19 (1H, m) Chiral stationary phase HPLC analysis (column: Daicel Chemical CHIR)
ALCEL OJ-R length 150mm inner diameter 4.6mm,
Mobile phase: 0.2 M NaClO ₄ / acetonitrile 85 /
15 was adjusted to pH 2 with HClO ₄ , flow rate: 1.0 ml /
min, detection wavelength: 254 nm) (-)-isomer (retention time 24.0 minutes), (+)-isomer (retention time 22.
2 min), optical purity 92% ee (HPLC).

Example 6 (-)-3-Amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexen-1-one and (S)-
Preparation of a salt of (-)-4- (2-chlorophenyl) -2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide 3-amino-5- (5-fluoro Racemic 50 m of -2-methylphenyl) -2-cyclohexen-1-one
g and (S)-(-)-4- (2-chlorophenyl)-
63.1 mg of 2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide was added to 0.3 ml of isopropyl alcohol and 0.6 m of acetonitrile.
and left in the refrigerator overnight. The next day, the precipitate was filtered to obtain 63 mg of a crystal. Chiral stationary phase HPLC analysis (column: CHIRALPAK AD (manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane / isopropyl alcohol / diethylamine 90: 10: 0.1, flow rate: 0.6 ml / min., Detection
As a result, the diastereomer excess was 62% de. Of these, 62 mg was recrystallized from 1 ml of tetrahydrofuran. The obtained crystals were 27.6 mg. (Yield 25%) As a result of HPLC analysis, the diastereomer excess was 98% de.

Example 7 (-)-3-Amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexen-1-one and (S)-
Preparation of a salt of (-)-2-hydroxy-4- (2-methoxyphenyl) -5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide 3-amino-5- (5- Racemic 50 m of (fluoro-2-methylphenyl) -2-cyclohexen-1-one
g and 62.1 mg of (S)-(-)-2-hydroxy-4- (2-methoxyphenyl) -5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide in isopropyl alcohol 0 .1 ml, acetonitrile 0.6
and left in the refrigerator overnight. The next day, the precipitate was filtered to obtain 66 mg of a crystal. Chiral stationary phase HPLC analysis (column: CHIRALPAK AD (manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane / isopropyl alcohol / diethylamine 90: 10: 0.1, flow rate: 0.6 ml / min., Detection
As a result, the diastereomer excess was 56% de. Of these, 65 mg was suspended in 1.5 ml of tetrahydrofuran and 0.5 ml of isopropyl alcohol and left in a refrigerator overnight. The next day, the precipitate was filtered to obtain 40.9 mg of crystals. (Yield 3
7%) As a result of HPLC analysis, the diastereomeric excess was 8
It was 6% de.

Reference Example 1 Preparation of (S)-(-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline: obtained in Example 3. Compound (12
g) was dissolved in ethanol (120 ml), toluene (360 ml), 1,1-dimethoxy-3-butanone (7.2 g) and sodium methoxide (3.7 g) were added, and the mixture was heated under reflux for 2 hours. Cool to room temperature and add water (60
ml) was added and stirred, and then the organic layer was separated. After the aqueous layer was washed with toluene (60 ml), the organic layers were combined, washed with saturated saline (50 ml), and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (130 ml), and aminoguanidine hydrochloride (3.23 g) and concentrated hydrochloric acid (8.5 m) were added.
l) was added and the mixture was refluxed for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (100 ml).
After adjusting the pH to 9 with aqueous sodium hydroxide, 2-
Extracted with butanone (165 ml, 65 ml). The organic layers were combined, washed with a saturated saline solution (65 ml), and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol (10 ml).
0 ml), and then diisopropyl ether (20 m
l) was added dropwise. After stirring at room temperature for 1 hour and under ice cooling for 1 hour, the crystals were collected by filtration, washed with ice-cooled ethanol: diisopropyl ether = 1: 4 (50 ml), and dried in vacuo to give the title compound (6). .66 g, 73.
2%). ¹ H NMR (300 MHz, CDCl ₃ ) δ: 2.60 −
2.80 (1H, m), 2.68 (3H, s), 3.05
-3.30 (2H, m), 3.50-3.70 (2H,
m), 7.05 (1H, d, J = 5.0 Hz), 7.10
−7.40 (4H, m), 8.26 (1H, d, J = 5.0
Hz).

Reference Example 2 Preparation of (S)-(-)-7- (2-chlorophenyl) -5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline dimethanesulfonate: Reference Example 1
Compound (6.5 g) obtained in
After heating and dissolving in 1) and filtering off the insoluble matter, methanesulfonic acid (3.8 g) was added, followed by stirring at room temperature for 2 hours. The precipitated crystals are collected by filtration, and ethanol: acetone = 1: 1 (50 m
After washing in l) and drying under vacuum, the title compound (7.44 g, yield 72.2%) was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.3
8 (6H, s), 2.79 (1H, dd, J = 17.4H
z, 11.7 Hz), 2.89 (3H, s) 3.05-3.
30 (2H, m). 3.45-3.80 (2H, m),
7.30-7.55 (3H, m), 7.55-7.70 (1
H, m), 7.87 (1H, d, J = 6.0 Hz), 8.
67 (1H, d, J = 6.0 Hz). Chiral stationary phase HPLC analysis (column: Shinwa Chemical ULTR)
ONES-OVM length 150mm internal diameter 4.6 mm, mobile phase: 0.02MKH ₂ PO ₄ / ethanol 77/23, flow rate 1.0 ml / min, detection wavelength 254nm) (S) -
99.5% isomer (retention time 6.2 min), below the detection limit of (R) -isomer, optical purity 100% ee.

Reference Example 3 Production of 5-fluoro-2-methylbenzaldehyde: magnesium (26.28 g), tetrahydrofuran (6
Iodine (about 1 mg) was added to the mixture of 2-bromo-4-fluorotoluene (200.4 ml) under ice cooling.
g) was added dropwise (the internal temperature was kept at 65 ° C. or lower). After completion of the dropwise addition, the mixture was stirred for 1 hour to prepare a Grignard reagent. Then, N-formylmorpholine (134.3 g) was added dropwise under ice cooling. After stirring at room temperature for 1 hour, 6N HCl (4
00 ml) and extracted with ethyl acetate. 5% extract
After washing sequentially with brine and water, the solvent was distilled off to give the title compound quantitatively as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.64 (3H, s),
7.18-7.53 (2H, m), 7.47-7.53
(1H, m), 10.25 (1H, d, J = 1.8H
z)

Reference Example 4 Production of 4- (5-fluoro-2-methylphenyl) -3-buten-2-one: sodium hydroxide (30.35
g) in water (815 ml) and acetone (543 ml)
Was added dropwise with a solution of 5-fluoro-2-methylbenzaldehyde (100 g) in acetone (136 ml) over about 2 minutes. After stirring at 30 ° C. for 20 minutes, acetone was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed successively with 5% saline and water, and the solvent was distilled off to give the title compound (12
(2.97 g, 95.3%). ¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s),
2.41 (3H, s), 6.63 (1H, d, J = 16
Hz), 6.94-7.27 (3H, m), 7.74
(1H, dd, J = 1.4, 16Hz)

Reference Example 5 Production of 5- (5-fluoro-2-methylphenyl) cyclohexane-1,3-dione: 4- (5-fluoro-2)
-Methylphenyl) -3-buten-2-one (50
g) and 20% sodium ethoxide (113.81 g) was added dropwise to a solution of diethyl malonate (53.57 g) in ethanol (100 ml) at 10 ° C. or lower. 30 at room temperature
After stirring for 2 minutes under reflux for 2 minutes, the solvent was distilled off. 2N to residue
NaOH (154 ml) was added and the mixture was stirred at 90 ° C. for 2.5 hours. Then, 2.5 MH ₂ SO ₄ was added at room temperature, further toluene (100 ml) was added, and the mixture was stirred at 70 ° C. for 30 minutes and at reflux for 1 hour. After cooling with ice, the precipitated crystals were collected by filtration to give the title compound (39.28 g, 63.6%). ¹ H-NMR (CDCl ₃ ) δ: 2.30 (3H, s),
2.27-256 (4H, m), 2.5-4.4 (1
H, b), 3.44-3.63 (1H, m), 5.55
(1H, s), 6.77-7.01 (2H, m), 7.
09-7.17 (1H, m)

Reference Example 6 Preparation of (±) -3-amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexen-1-one:
A mixture of 5- (5-fluoro-2-methylphenyl) cyclohexane-1,3-dione (34 g), ammonium acetate (35.22 g) and isopropanol (340 ml) was stirred under reflux for 2.5 hours, and the solvent was distilled off. Leave. Tetrahydrofuran (90 ml) was added to the residue, and isopropyl ether (450 ml) was added at 57 ° C. for crystallization. After stirring at 5 ° C. for 1 hour, the crystals were collected by filtration and washed with tetrahydrofuran-isopropyl ether (1: 5) to obtain the title compound (31.2 g, 92.2%). ¹ H-NMR (CDCl ₃ ) δ: 2.30 (3H, s),
2.20-2.75 (4H, m), 3.47-3.65
(1H, m), 4.75 (2Hbs), 5.35 (1
H, s), 6.80-7.03 (2H, m), 7.08
−7.19 (1H, m)

Reference Example 7 (-)-7- (5-fluoro-2-methylphenyl)-
4-methyl-7,8-dihydroquinoline-5 (6H)-
Preparation of ON: (-)-3-amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1-
On (0.95 g), 1,1-dimethoxy-3-butanone (1.15 g), toluene (9.5 ml) in a mixture of potassium carbonate (0.12 g) and 28% sodium methoxide (1.0 g). And stirred at 71-73 ° C for 2 hours. Further, 28% sodium methoxide (0.1 g) was added, and the mixture was stirred at the same temperature for 2 hours.
l) was added. The toluene layer was separated, washed with water and the solvent was distilled off to obtain the title compound (1.15 g, 98.8%). ¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s),
2.78-2.98 (2H, m), 3.24 (1H, d
d, J = 11, 16 Hz), 3.28-3.44 (1
H, m), 3.55-3.74 (1H, m), 6.82.
−7.04 (2H, m), 7.12 (1H, d, J = 5)
Hz), 7.07-7.22 (2H, m), 8.50
(1H, d, J = 5Hz)

Reference Example 8 (5E, 7S)-[7- (5-Fluoro-2-methylphenyl) -4-methyl-7,8-dihydro-5 (6H)
Preparation of -quinolinylideneamino] guanidine dihydrochloride: (-)-7- (5-fluoro-2-methylphenyl) -4-methyl-7,8-dihydroquinoline-5 (6
H) -one (1.15 g) in methanol (11.7 m
l) Aminoguanidine hydrochloride (0.72 g) was added to the solution, and the mixture was stirred at 65 ° C for 20 minutes, and concentrated hydrochloric acid (1.15 ml) was added.
And heated under reflux for 2 hours. The solvent was distilled off, and the residue was crystallized from isopropanol to give the title compound (1.68 g, 10
0%). ¹ H-NMR (DMSO-d ₆ ) δ: 2.31 (3H,
s), 2.72-3.03 (1H, m), 2.90 (3
H, s), 3.13-3.57 (4H, m), 6.93.
−7.06 (1H, m), 7.17-7.40 (2H,
m), 7.50-8.40 (4H, br), 7.85
(1H, d, J = 6 Hz), 8.65 (1H, d, J =
6Hz), 11.39 (1H, s)

Reference Example 9 (5E, 7S)-[7- (5-Fluoro-2-methylphenyl) -4-methyl-7,8-dihydro-5 (6H)
Preparation of -quinolinylideneamino] guanidine dimethanesulfonate: (5E, 7S)-[7- (5-fluoro-2-methylphenyl) -4-methyl-7,8-dihydro-5 (6H)- Quinolinylideneamino] guanidine
Dihydrochloride (1.68 g) in methanol (11.5 ml)
To the solution, 28% sodium methoxide (2.51 g) was added dropwise. After stirring for 20 minutes, water (4.1 ml) was added,
The solvent was distilled off under reduced pressure. The residue was dissolved by adding water (1.17 ml) and ethyl acetate (3.5 ml). Then, heptane (10.5 ml) was added dropwise to crystallize. The mixture was stirred at 5 ° C. for 1 hour, washed with ethyl acetate-heptane (1: 3), and washed with (5E, 7S)-[7- (5-fluoro-2-methylphenyl) -4-methyl-7,8. -Dihydro-5
(6H) -Quinolinylideneamino] guanidine (1.1
5 g, 81.7%). Methanesulfonic acid (0.71 g) was added dropwise to a solution of this compound (1.15 g) in ethanol (8.05 ml) at room temperature. After cooling to 5 ° C and stirring for 2 hours, the precipitated crystals were collected by filtration and the title compound (1.40 g,
76.5%). ¹ H-NMR (DMSO-d ₆ ) δ: 2.30 (3H,
s), 2.35 (6H, s), 2.58-2.95 (1
H, m), 2.86 (3H, s), 3.00-3.23.
(2H, m), 3.44-3.60 (2H, m), 6.
96-7.09 (1H, m), 7.20-8.40 (4
H, b), 7.81 (1H, d, J = 5 Hz), 8.6
5 (1H, d, J = 6 Hz), 10.68 (1H, s) Chiral stationary phase HPLC analysis (same conditions as in Example 1) Optical purity 1
00% ee

[0070]

Industrial Applicability According to the production method of the present invention, an optically active cyclic enaminone derivative useful as a raw material for synthesizing stereospecific drugs, agricultural chemicals, and the like can be obtained by preparing a precursor having a symmetrical plane having a symmetry plane of 1,3.
-The diketone derivative can be efficiently produced without waste.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Norio Iwano 6-18-16 Tokiwadai, Toyono-cho, Toyono-gun, Osaka (72) Inventor Isao Aoki 3-17-17 Yamatohigashi, Kawanishi-shi, Hyogo 1 (72) Invention Person Banri Adachi 4-2, Mihogaoka, Nishi-ku, Kobe-shi, Hyogo

Claims (16)

[Claims] 1. A method for producing an optically active cyclic enaminone derivative, comprising optically resolving an optical isomer mixture of a cyclic enaminonone derivative using a highly acidic optical resolving agent. 2. The method according to claim 1, wherein one of the carbonyl groups of the diketone of the cyclic 1,3-diketone derivative having a symmetry plane is aminated, and the resulting mixture of the optical isomers of the chiral cyclic enaminonone derivative is optically resolved. And a method for producing an optically active cyclic enaminone derivative. 3. A cyclic 1,3-diketone derivative having a plane of symmetry as a raw material, one of the carbonyl groups of the diketone of this derivative is aminated, and the resulting mixture of optical isomers of a chiral cyclic enaminone derivative is optically resolved. To obtain one optically active cyclic enaminone derivative,
A process for producing an optically active cyclic enaminone derivative, comprising recovering a cyclic 1,3-diketone derivative having a symmetry plane as a raw material by hydrolyzing the other optically active cyclic enaminone derivative. 4. The process according to claim 2, wherein the cyclic 1,3-diketone derivative having a symmetry plane is a 5- to 7-membered ring. 5. A cyclic 1,3-diketone derivative having a plane of symmetry is represented by the following formula (I): And a partial structure (A) in the formula (I): Is the following formula (A-1) to (A-3): [Wherein, R ⁰ to R ¹⁰ each independently represent a hydrogen atom or a substituent (provided that R ¹ and R ² are not the same,
R ³ and R ^4, and R ⁵ and R ⁶ are not the same at the same time, and R ⁷ and R ^8, and R ⁹ and R ¹⁰ are not the same at the same time.] 4. The production method according to 2 or 3. 6. The partial structure (A) having the following formula (A-1): 6. The method according to claim 5, wherein R ¹ and R ² are as defined above. 7. The partial structure (A) having the following formula (A-2): [Wherein, R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above]
The production method according to claim 5, wherein 8. A compound in which the partial structure (A) is represented by the formula (A-2), wherein R ³ and R ⁴ are each independently a hydrogen atom,
Or an optionally substituted 5- or 6-membered aromatic homo- or heterocyclic group, wherein R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, an optionally substituted linear or branched chain. Aliphatic hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted mercapto group (provided that R ³ and R ⁴ and R ⁵ and R ⁶ are not the same at the same time) The method according to claim 7. 9. A compound in which said partial structure (A) is represented by the formula (A-2), wherein R ³ and R ⁴ are each independently a hydrogen atom,
Or a 5- or 6-membered aromatic homo- or heterocyclic group which may be substituted, provided that R ³ and R ⁴ are not the same, and wherein R ⁵ and R ⁶ are hydrogen atoms. Manufacturing method. 10. The partial structure (A) has the following formula (A-3): 6. The method according to claim 5, wherein R ⁷ to R ¹⁰ are as defined above. 11. The method according to claim 2, wherein the optical resolution is performed with an optical resolution agent having a high acidity. 12. The method according to claim 1, wherein the optical resolution agent is an optically active sulfonic acid derivative or sulfamic acid derivative.
The production method according to claim 1. 13. The method according to claim 1, wherein the optical resolution agent is an optically active phosphoric acid derivative. 14. A compound represented by the following formula: [Wherein, R ³ and R ⁴ each independently represent a hydrogen atom or an optionally substituted 5- or 6-membered aromatic homo- or heterocyclic ring (however, R ³ and R ⁴ are not the same)]
An optically active cyclic enaminone derivative represented by the formula: 15. A (±) -3-amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexene-1-
Optical resolution of on with (-)-4- (mono or dichloro or methoxyphenyl) -2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide. (-)-3-amino-5- (5-fluoro-2-methylphenyl) -2
-Method for producing cyclohexen-1-one. 16. The (±) -3-amino-5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1
The -one is optically resolved using (-)-4- (mono or dichloro or methoxyphenyl) -2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide. The resulting (-)-3-amino-
5- (5-fluoro-2-methylphenyl) -2-cyclohexenone-1-one and 1,1-dimethoxy-3-
(-)-7- (5-Fluoro-2-methylphenyl) -4-methyl-7,8- obtained by reacting with butanone
Reacting dihydroquinolin-5 (6H) -one with aminoguanidine or a salt thereof,
(5E, 7S)-[7- (5-fluoro-2-methylphenyl) -4-methyl-7,8-dihydro-5 (6H)
-Quinolinylideneamino] guanidine or a salt thereof.