JPH0645618B2 - Process for producing 2-alkoxypyrazine 4-oxide derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a 2-alkoxypyrazine 4-oxide derivative.

DISCLOSURE OF THE INVENTION According to the present invention, the general formula [Wherein R ¹ is (In the formula, R ⁶ has a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a phenyl lower alkoxycarbonyl group, a carboxy group, a benzoyl group or a lower alkyl group on the phenyl ring. A certain phenylsulfonyl group is shown.
-A- is a single bond, Alternatively, it represents a lower alkylene group. R ⁵ is a hydrogen atom, a cyano group, a phenyl lower alkoxy group, a carboxy group, a phenyl group, a lower alkoxycarbonyl group, a lower alkyl group,
A lower alkoxy group, a hydroxyl group or a halogen atom,
Indicates 1 or 2. ) Is shown. R ² represents a hydrogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group. R ³ is a hydrogen atom, an oxo group, a halogen atom, a lower alkoxy group, a lower alkanoyloxy group, a lower alkyl group, a benzoyloxy group, a lower alkoxycarbonyloxy group,
A silyloxy group having 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl group, a group consisting of a halogen atom, a lower alkyl group, a nitro group, an amino group and a lower alkoxy group as a substituent on the phenyl ring. A phenyl lower alkoxy group or a hydroxyl group which may have a group selected from R ⁴ is a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl lower alkyl group which may have a group selected from the group consisting of a hydroxyl group and a phenyl lower alkoxy group on the phenyl ring as a substituent, a cycloalkyl group, a cycloalkyl group. A lower alkyl group, an indolyl lower alkyl group or a lower alkenylene group is shown. R ⁷ represents a lower alkyl group. The 1,2-position bond of the pyrazine skeleton represents a single bond or a double bond. ] The 2-alkoxypyrazine 4-oxide derivative represented by [In the formula, R ¹ , R ² , R ³ , R ⁴ and the 1,2-position bond of the pyrazine skeleton are the same as above. ] It is manufactured by alkylating the 2-hydroxypyrazine 4-oxide derivative represented by these.

The compounds represented by the general formulas (1) and (2) have, for example, an inhibitory effect on superoxide (O ₂ ⁻ ) released by stimulation from guinea pig macrophages, an antiproteinuria effect on Masugi nephritis, and the like, Diseases and cases related to the above superoxide radical,
For example, it is useful in various clinical fields as a preventive and therapeutic agent for autoimmune diseases such as rheumatism, arteriosclerosis, ischemic heart disease, ischemic brain injury, liver failure, renal failure, etc., and as a preventive and therapeutic agent for nephritis. .

Each group represented by the general formulas (1) and (2) is
More specifically, they are as follows.

Examples of the lower alkylene group include methylene, ethylene, trimethylene, tetramethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, pentamethylene and hexamethylene groups. Examples thereof include linear or branched alkylene groups having 1 to 6 carbon atoms.

Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl groups.

As the phenyl lower alkyl group, for example, benzyl, 2
-Phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2
-Phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl and the like are exemplified by phenylalkyl groups in which the alkyl portion is a linear or branched alkyl group having 1 to 6 carbon atoms. it can.

Examples of the lower alkanoyl group include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, and hexanoyl groups, which may be linear or branched alkanoyl groups having 1 to 6 carbon atoms.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Examples thereof include linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms such as tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups.

As the phenyl lower alkoxycarbonyl group, for example, benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 1,1-dimethyl-2-phenylethoxycarbonyl, 5 A phenylalkoxycarbonyl group in which the alkoxy moiety such as -phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, 2-methyl-3-phenylpropoxycarbonyl group is a linear or branched alkoxy group having 1 to 6 carbon atoms; It can be illustrated.

Examples of the phenylsulfonyl group which may have a lower alkyl group on the phenyl ring include 4-methylphenylsulfonyl, 3-ethylphenylsulfonyl, 2-propylphenylsulfonyl, 4-n-butylphenylsulfonyl and 3-pentylphenylsulfonyl. , 2-hexylphenylsulfonyl, etc. have 1 to 6 carbon atoms on the phenyl ring.
Examples of the phenylsulfonyl group which may have a linear or branched alkyl group of

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups.

Examples of the lower alkanoyloxy group include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, te.
Examples thereof include linear or branched alkanoyloxy groups having 1 to 6 carbon atoms such as rt-butylcarbonyloxy and hexanoyloxy groups.

Examples of the phenyl lower alkoxy group include phenylmethoxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy,
1,1-dimethyl-2-phenylethoxy, 4-phenylpentyloxy, 6-phenylhexyloxy, 2-
Examples thereof include a phenylalkoxy group in which an alkoxy moiety such as a methyl-3-phenylpropoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms.

Examples of the lower alkenylene group include vinylene, 2-propenylene, 2-butenylene, 2-pentenylene and 3-
Examples thereof include linear or branched alkenylene groups having 2 to 6 carbon atoms such as pentenylene, 1-methyl-2-butenylene, 2-hexenylene and 4-hexenylene groups.

Examples of the halogen atom include chlorine atom, bromine atom, iodine atom and fluorine atom.

Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and other cycloalkyl groups having 3 to 8 carbon atoms.

Examples of the cycloalkyl lower alkyl group include cyclopropylmethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 3-cyclohexylpropyl, 4-cycloheptylbutyl, 6-cyclooctylhexyl, 5
-Alkyl moiety such as cyclopropylpentyl, 1,1-dimethyl-2-cyclopropylethyl, 2-methyl-3-cyclohexylpropyl, cyclohexylmethyl group is a linear or branched alkyl group having 1 to 6 carbon atoms. An example is a cycloalkylalkyl group having 3 to 8 carbon atoms.

Examples of the indolyl lower alkyl group include (3-indolyl) methyl, (1-indolyl) methyl, and 2- (2
-Indolyl) ethyl, 1- (4-indolyl) ethyl, 3- (5-indolyl) propyl, 4- (6-indolyl) butyl, 6- (7-indolyl) hexyl, 5
-(3-Indolyl) pentyl, 1,1-dimethyl-2
-(2-Indolyl) ethyl, 2-methyl-3- (3-
Indolyl) The number of carbon atoms in the alkyl moiety such as propyl is 1
The indolylalkyl group which is a linear or branched alkyl group of ~ 6 can be illustrated.

Examples of the phenyl lower alkyl group which may have a group selected from the group consisting of a hydroxyl group and a phenyl lower alkoxy group on the phenyl ring include, in addition to the unsubstituted phenyl lower alkyl group exemplified above, 4-hydroxybenzyl, 2- (3-hydroxyphenyl) ethyl, 1- (2
-Hydroxyphenyl) ethyl, 3- (2,4-dihydroxyphenyl) propyl, 4- (3,4-dihydroxyphenyl) butyl, 1,1-dimethyl-2- (2,2
3,4-trihydroxyphenyl) ethyl, 5- (4-
Hydroxyphenyl) pentyl, 6- (3-hydroxyphenyl) hexyl, 2-methyl-3- (2-hydroxyphenyl) propyl, 4-benzyloxybenzyl,
2- [3-[(2-phenylethoxy) phenyl] ethyl, 1- [2-[(1-phenylethoxy) phenyl]
Ethyl, 3- (2,4-dibenzyloxyphenyl) propyl, 4- (3,4-dibenzyloxyphenyl) butyl, 1,1-dimethyl-2- (2,3,4-tribenzyloxyphenyl) Ethyl, 5- [4-[(3-phenylpropoxy) phenyl] pentyl, 6- [3-
[(4-phenylbutoxy) phenyl] hexyl, 2-
On the phenyl ring such as methyl-3- [2- (5-phenylpentyl) phenyl] propyl and 4- (6-phenylexyloxy) benzyl group, a hydroxyl group and an alkoxy moiety are directly substituted with 1 to 6 carbon atoms as a substituent. A phenylalkyl group which has 1 to 3 phenylalkoxy groups which are chain or branched alkoxy groups and whose alkyl part is a linear or branched alkyl group having 1 to 6 carbon atoms can be exemplified.

Examples of the phenyl lower alkoxy group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a nitro group, an amino group and a lower alkoxy group on the phenyl ring include, for example, benzyloxy, 2- Phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1,1-dimethyl-2-
Phenylethoxy, 5-phenylpentyloxy, 6-
Phenylhexyloxy, 2-methyl-3-phenylpropoxy, 2-chlorobenzyloxy, 2- (3-chlorophenyl) ethoxy, 1- (4-chlorophenyl) ethoxy, 3- (2-fluorophenyl) propoxy, 4
-(3-Fluorophenyl) butoxy, 1,1-dimethyl-2- (4-fluorophenyl) ethoxy, 5- (2
-Bromophenyl) pentyloxy, 6- (3-bromophenyl) hexyloxy, 2-methyl-3- (4-bromophenyl) propoxy, 3-iodobenzyloxy, 2- (4-iodophenyl) ethoxy, 1- (3,
5-dichlorophenyl) ethoxy, 2- (3,4-dichlorophenyl) ethoxy, 3- (2,6-dichlorophenyl) propoxy, 4- (3,4-dichlorophenyl)
Butoxy, 1,1-dimethyl-2- (3,4-difluorophenyl) ethoxy, 5- (3,5-dibromophenyl) pentyloxy, 6- (3,4,5-trichlorophenyl) hexyloxy, 4 -Methylbenzyloxy,
2- (2-methylphenyl) ethoxy, 1- (3-methylphenyl) ethoxy, 3- (3-ethylphenyl) propoxy, 4- (2-ethylphenyl) butoxy, 5-
(4-Ethylphenyl) pentyloxy, 6- (3-isopropylphenyl) hexyloxy, 2-methyl-3
-(4-hexylphenyl) propoxy, 2- (3,4
-Dimethylphenyl) ethoxy, 2- (2,5-dimethylphenyl) ethoxy, 2- (3,4,5-trimethylphenyl) ethoxy, 4-methoxybenzyloxy,
3,4-dimethoxybenzyloxy, 3,4,5-trimethoxybenzyloxy, 1- (3-methoxyphenyl) ethoxy, 2- (2-methoxyphenyl) ethoxy, 3- (2-ethoxyphenyl) propoxy, 4 −
(4-ethoxyphenyl) butoxy, 5- (3-ethoxyphenyl) pentyloxy, 6- (4-isopropoxyphenyl) hexyloxy, 1,1-dimethyl-2-
(4-hexyloxyphenyl) ethoxy, 2-methyl-3- (3,4-dimethoxyphenyl) propoxy, 2
-(3,4-dimethoxyphenyl) ethoxy, 2-
(3,4-diethoxyphenyl) ethoxy, 2- (3,
4,5-trimethoxyphenyl) ethoxy, 1- (2,
5-dimethoxyphenyl) ethoxy, (2-chloro-4
-Methoxy) benzyloxy, 2-aminobenzyloxy, 1- (3-aminophenyl) ethoxy, 1- (4-
Aminophenyl) propoxy, 1- (2,3-diaminophenyl) butoxy, 1- (2,3,4-triaminophenyl) pentyloxy, 1- (2,4-diaminophenyl) hexyloxy, 2-nitrobenzyl Oxy, 1
-(3-Nitrophenyl) ethoxy, 1- (4-nitrophenyl) propoxy, 1- (2,4-dinitrophenyl) butoxy, 1- (2,4,6-trinitrophenyl) pentyloxy, 1- ( 2-chloro-4-nitrophenyl) hexyloxy, (3-methyl-4-amino)
A halogen atom as a substituent on a phenyl ring such as a benzyloxy group, a linear or branched alkyl group having 1 to 6 carbon atoms, a nitro group, an amino group and a linear or branched chain having 1 to 6 carbon atoms. Examples thereof include a phenylalkoxy group which is a linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety which may have 1 to 3 groups selected from the group consisting of alkoxy groups.

Examples of the lower alkoxycarbonyloxy group include methoxycarbonyloxy, ethoxycarbonyloxy,
Propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy,
A linear or branched alkoxycarbonyloxy group having 1 to 6 carbon atoms such as a hexyloxycarbonyloxy group can be exemplified.

Examples of the silyloxy group having 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl group include trimethylsilyloxy, triethylsilyloxy, tripropylsilyloxy, tributylsilyloxy, tert-butyldimethylsilyloxy, tert-butyl. Examples thereof include a trialkylsilyloxy group in which the alkyl moiety of diphenylsilyloxy, tripentylsilyloxy, trihexylsilyloxy, dimethylethylsilyloxy group and the like is a linear or branched alkyl group having 1 to 6 carbon atoms.

In the present invention, the 2-hydroxypyrazine 4-oxide derivative represented by the general formula (2), which is used as a starting material, can be produced by various methods. For example, it can be easily produced according to the method shown below.

[Reaction formula-1] [Wherein, R ² , R ⁴ , R ⁵ and R ⁶ are the same as defined above.
X represents a halogen atom. R ⁸ represents a lower alkyl group or a phenyl lower alkyl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group and a cyano group on the phenyl ring. B'represents a single bond or a lower alkylene group. R ⁹ is a hydroxyl group, a phenyl lower alkoxy group which may have a group selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group and an amino group on the phenyl ring as a substituent, tetrahydropyranyloxy A silyloxy group or a lower alkoxy lower alkoxy group having 1 to 3 groups selected from the group consisting of a group, a lower alkyl group and a phenyl group. Here, as the phenyl lower alkoxy group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group and an amino group on the phenyl ring, benzyloxy, 2 -Phenylethoxy,
1-phenylethoxy, 3-phenylpropoxy, 4-
Phenylbutoxy, 1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy, 6-phenylhexyloxy, 2-methyl-3-phenylpropoxy,
2-chlorobenzyloxy, 2- (3-chlorophenyl) ethoxy, 1- (4-chlorophenyl) ethoxy,
3- (2-fluorophenyl) propoxy, 4- (3-
Fluorophenyl) butoxy, 1,1-dimethyl-2-
(4-fluorophenyl) ethoxy, 5- (2-bromophenyl) pentyloxy, 6- (3-bromophenyl) hexyloxy, 2-methyl-3- (4-bromophenyl) propoxy, 3-iodobenzyloxy, 2-
(4-iodophenyl) ethoxy, 1- (3,5-dichlorophenyl) ethoxy, 2- (3,4-dichlorophenyl) ethoxy, 3- (2,6-dichlorophenyl) propoxy, 4- (3,4-dichlorophenyl) Butoxy, 1,1-dimethyl-2- (3,4-difluorophenyl) ethoxy, 5- (3,5-dibromophenyl) pentyloxy, 6- (3,4,5-trichlorophenyl) hexyloxy, 4 -Methylbenzyloxy, 2-
(2-methylphenyl) ethoxy, 1- (3-methylphenyl) ethoxy, 3- (3-ethylphenyl) propoxy, 4- (2-ethylphenyl) butoxy, 5- (4
-Ethylphenyl) pentyloxy, 6- (3-isopropylphenyl) hexyloxy, 2-methyl-3-
(4-hexylphenyl) propoxy, 2- (3,4-
Dimethylphenyl) ethoxy, 2- (2,5-dimethylphenyl) ethoxy, 2- (3,4,5-trimethylphenyl) ethoxy, 4-methoxybenzyloxy, 3,
4-dimethoxybenzyloxy, 3,4,5-trimethoxybenzyloxy, 1- (3-methoxyphenyl) ethoxy, 2- (2-methoxyphenyl) ethoxy, 3-
(2-ethoxyphenyl) propoxy, 4- (4-ethoxyphenyl) butoxy, 5- (3-ethoxyphenyl) pentyloxy, 6- (4-isopropoxyphenyl) hexyloxy, 1,1-dimethyl-2- ( 4-hexyloxyphenyl) ethoxy, 2-methyl-3-
(3,4-dimethoxyphenyl) propoxy, 2-
(3,4-dimethoxyphenyl) ethoxy, 2- (3,
4-diethoxyphenyl) ethoxy, 2- (3,4,5)
-Trimethoxyphenyl) ethoxy, 1- (2,5-dimethoxyphenyl) ethoxy, (2-chloro-4-methoxy) benzyloxy, 2-aminobenzyloxy, 1
-(3-aminophenyl) ethoxy, 1- (4-aminophenyl) propoxy, 1- (2,3-diaminophenyl) butoxy, 1- (2,3,4-triaminophenyl) pentyloxy, 1- ( 2,4-diaminophenyl) hexyloxy, 2-nitrobenzyloxy, 1-
(3-Nitrophenyl) ethoxy, 1- (4-nitrophenyl) propoxy, 1- (2,4-dinitrophenyl) butoxy, 1- (2,4,6-trinitrophenyl) pentyloxy, 1- (2 -Chloro-4-nitrophenyl) hexyloxy, (3-methyl-4-amino)
A halogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, a nitro group, an amino group and a straight chain having 1 to 6 carbon atoms as a substituent on the phenyl ring such as benzyloxy, trityloxy, and diphenylmethoxy group. A linear or branched alkoxy group having 1 to 6 carbon atoms in the alkoxy moiety which may have 1 to 3 groups selected from the group consisting of a chain or branched alkoxy group, wherein the phenyl group is Examples thereof include phenylalkoxy groups having 1 to 3 substituents. Among these, especially benzyloxy, 1-phenylethoxy, 1- (4-chlorophenyl) ethoxy, 1- (3,5-dichlorophenyl) ethoxy, 1- (3-methylphenyl) ethoxy,
1- (3-methoxyphenyl) ethoxy, 1- (2,5
A phenyl lower alkoxy group in which 1 to 3 of the above-mentioned substituted or unsubstituted phenyl groups are substituted at the 1-position of the alkyl moiety such as -dimethoxyphenyl) ethoxy, trityloxy and diphenylmethoxy groups is preferable.

Examples of the silyloxy group having 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl group include trimethylsilyloxy, triethylsilyloxy, tripropylsilyloxy, tributylsilyloxy, tert-butyldimethylsilyloxy, tert-butyl. Examples thereof include a trialkylsilyloxy group in which the alkyl moiety of diphenylsilyloxy, tripentylsilyloxy, trihexylsilyloxy, dimethylethylsilyloxy group and the like is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the lower alkoxy lower alkoxy group include methoxymethoxy, 2-methoxyethoxy, 1-ethoxyethoxy, 3-propoxypropoxy, 4-butoxybutoxy, 5-pentyloxypentyloxy, 6-hexyloxyhexyloxy, 1,1- Examples thereof include an alkoxyalkoxy group in which the alkoxy moiety such as dimethyl-2-methoxyethoxy and 2-methyl-3-methoxypropoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms. Of these, 1-lower alkoxy and lower alkoxy groups such as methoxymethoxy and 1-ethoxyethoxy groups are particularly preferable.

Examples of the phenyl lower alkyl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group and a cyano group on the phenyl ring include benzyl, 2-phenylethyl, 1 -Phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-
3-phenylpropyl, 2-chlorobenzyl, 2- (3
-Chlorophenyl) ethyl, 1- (4-chlorophenyl) ethyl, 3- (2-fluorophenyl) propyl,
4- (3-fluorophenyl) butyl, 1,1-dimethyl-2- (4-fluorophenyl) ethyl, 5- (2-
Bromophenyl) pentyl, 6- (3-bromophenyl) hexyl, 2-methyl-3- (4-bromophenyl) propyl, 3-iodobenzyl, 2- (4-iodophenyl) ethyl, 1- (3,5 -Dichlorophenyl)
Ethyl, 2- (3,4-dichlorophenyl) ethyl, 3
-(2,6-dichlorophenyl) propyl, 4- (3,
4-dichlorophenyl) butyl, 1,1-dimethyl-2
-(3,4-difluorophenyl) ethyl, 5- (3,3
5-dibromophenyl) pentyl, 6- (3,4,5-
Trichlorophenyl) hexyl, 4-methylbenzyl,
2- (2-methylphenyl) ethyl, 1- (3-methylphenyl) ethyl, 3- (3-ethylphenyl) propyl, 4- (2-ethylphenyl) butyl, 5- (4-ethylphenyl) pentyl, 6- (3-isopropylphenyl) hexyl, 2-methyl-3- (4-hexylphenyl) propyl, 2- (3,4-dimethylphenyl) ethyl, 2- (2,5-dimethylphenyl) ethyl, 2-
(3,4,5-Trimethylphenyl) ethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4
5-trimethoxybenzyl, 1- (3-methoxyphenyl) ethyl, 2- (2-methoxyphenyl) ethyl, 3
-(2-ethoxyphenyl) propyl, 4- (4-ethoxyphenyl) butyl, 5- (3-ethoxyphenyl)
Pentyl, 6- (4-isopropoxyphenyl) hexyl, 1,1-dimethyl-2- (4-hexyloxyphenyl) ethyl, 2-methyl-3- (3,4-dimethoxyphenyl) propyl, 2- (3 , 4-dimethoxyphenyl) ethyl, 2- (3,4-diethoxyphenyl) ethyl, 2- (3,4,5-trimethoxyphenyl) ethyl, 1- (2,5-dimethoxyphenyl) ethyl, (2
-Chloro-4-methoxy) benzyl, 2-aminobenzyl, 1- (3-cyanophenyl) ethyl, 1- (4-cyanophenyl) propyl, 1- (2,3-dicyanophenyl) butyl, 1- (2 , 3,4-Tricyanophenyl) pentyl, 1- (2,4-dicyanophenyl) hexyl, 2-nitrobenzyl, 1- (3-nitrophenyl) ethyl, 1- (4-nitrophenyl) propyl, 1
-(2,4-dinitrophenyl) butyl, 1- (2,
4,6-trinitrophenyl) pentyl, 1- (2-chloro-4-nitrophenyl) hexyl, (3-methyl-
4-cyano) benzyl, trityl, diphenylmethyl group and the like on the phenyl ring as a substituent, a halogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a nitro group, a cyano group and 1 to 6 carbon atoms A straight or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl moiety, which may have 1 to 3 groups selected from the group consisting of A phenylalkyl group in which 1 to 3 groups are substituted can be exemplified. Among these, especially benzyl,
1-phenylethyl, 1- (4-chlorophenyl) ethyl, 1- (3,5-dichlorophenyl) ethyl, 1-
(3-Methylphenyl) ethyl, 1- (3-methoxyphenyl) ethyl, 1- (2,5-dimethoxyphenyl)
A phenyl lower alkyl group in which 1 to 3 of the above-mentioned substituted or unsubstituted phenyl groups are substituted at the 1-position of the alkyl moiety of ethyl, trityl, diphenylmethyl group and the like is preferable.

Reaction of Compound (3) with Compound (6) and Compound (3)
The reaction of the compound (4) with the compound (4) is carried out according to a usual amide bond formation reaction. The amide bond formation reaction is carried out by various known methods, for example, (a) mixed acid anhydride method, for example, carboxylic acid (6) or compound (4) is reacted with a halocarboxylic acid alkyl ester to obtain a mixed acid anhydride, and an amine Method of reacting (3); (b) Active ester method, for example, carboxylic acid (6) or (4) with p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-
A method of preparing an active ester such as hydroxybenzotriazole ester and reacting this with an amine (3);
Carbodiimide method, that is, a method of condensing amine (3) with carboxylic acid (6) or (4) in the presence of an activator such as dicyclohexylcarbodiimide, carbonyldiimidazole; (d) Other method, for example, carboxylic acid (6 )
Alternatively, a method in which (4) is converted into a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and the amine (3) is reacted with the carboxylic acid (6) or (4) and an ester of a lower alcohol with the amine (3) Can be carried out under high pressure and high temperature, a method of reacting an acid halide of carboxylic acid (6) or (4), that is, a carboxylic acid halide with amine (3), and the like. Further, carboxylic acid (6) or (4)
Is activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and is reacted with an amine (3), and the carboxylic acid (6) or (4) is treated with phosgene or chloroformic acid trichloromethyl ester to give N-. It is also possible to use a method of reacting the carboxyamino acid anhydride with the amine (3) and the like. Furthermore, the carboxylic acid (6) or (4) is activated with an acetylene compound such as trimethylsilylethoxyacetylene,
It can also be carried out by a method of reacting this with an amine (3).

In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is obtained by an ordinary Schotten-Baumann reaction, and this is generally reacted with an amine (3) without isolation to give a compound of the general formula The compound of (7) or (5) is produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, a compound commonly used in the Schotten-Baumann reaction is used, and for example, triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-
Dimethylaminopyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU),
1,4-diazabicyclo [2,2,2] octane (DA
Examples thereof include organic bases such as BCO) and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like. The reaction is carried out at about -20 to 100 ° C, preferably 0 to 50 ° C for about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (3) is performed at about −20 to 150 ° C.
It is preferably carried out at 10 to 50 ° C. for about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. The mixed acid anhydride is generally a solvent commonly used in this kind of mixed acid anhydride method, specifically, methylene chloride, chloroform, dichloroethane, and other halogenated hydrocarbons, benzene, toluene, xylene, and other aromatic hydrocarbons. Ethers such as diethyl ether, dioxane, diisopropyl ether, tetridrofuran, dimethoxyethane, esters such as methyl acetate and ethyl acetate, 1,1,3,3-tetramethylurea, N, N-dimethylformamide, It is carried out in a suitable solvent or mixed solvent such as an aprotic polar solvent such as dimethylsulfoxide and hexamethylphosphoric triamide, or in the absence thereof. Examples of the halocarboxylic acid alkyl ester used in the production of the above mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The alkyl halocarboxylate is usually used in at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the amine (3). The amount of the carboxylic acid (6) or (4) used is usually at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the amine (3).

The active ester method shown in (b) above is carried out in the presence or absence of a basic compound in a suitable solvent that does not affect the reaction, for example, in the case of using N-hydroxysuccinimide ester. Be done. A condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, etc. may be added to the reaction system of the reaction. Here, as the basic compound, any of the basic compounds used in the Schotten-Baumann reaction can be used, and in addition to them, sodium acetate, sodium benzoate, sodium formate, potassium acetate, lithium benzoate, cesium acetate. Carboxylic acid alkali metal salts such as
It is also possible to use an alkali metal halide such as potassium fluoride or cesium fluoride. As the solvent, specifically, methylene chloride, chloroform, halogenated hydrocarbons such as dichloroethane, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, Esters such as methyl acetate and ethyl acetate, N,
Examples thereof include aprotic polar solvents such as N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like, or a solvent mixture thereof. The reaction is 0
˜150 ° C., preferably 10˜100 ° C., and completed in 5˜30 hours. The ratio of the amine (3) and the N-hydroxysuccinimide ester used is usually at least equimolar, preferably equimolar to 2 times the molar amount of the compound (6) or (4).

In addition, amine (3) and carboxylic acid (6) or (4),
Triphenylphosphine, triphenylphosphine-
Phosphorus such as 2,2′-dipyridyl disulfide, diethyl chlorophosphate, diphenylphosphinyl chloride, phenyl, N-phenylphosphoramide chloride, diethyl cyanophosphate, and bis (2-oxo-3-oxazolidinyl) phosphinic chloride The compound (5) or (7) can also be obtained by reacting the compound in the presence of a condensing agent.

As the basic compound used here, known compounds can be widely used, and examples thereof include sodium hydroxide and potassium hydroxide in addition to the basic compound used in the Schotten-Baumann reaction. Examples of the solvent include, in addition to the solvent used in the mixed acid anhydride method, for example, pyridine, acetone, acetonitrile and the like, or a mixed solvent of two or more of the above solvents.

The reaction is usually about -20 to 150 ° C, preferably 0 to
The reaction is carried out at about 100 ° C., and the reaction is generally completed in about 5 minutes to 30 hours. The amount of the condensing agent and the carboxylic acid (6) or (4) to be used is, with respect to the amine (3),
At least about equimolar, preferably about equimolar to 2 times the molar.

The compound (5) can also be obtained by reacting the amine (3) with the carboxylic acid (6) or (4) in the presence of a condensing agent.
Alternatively, (7) can be obtained. The reaction is carried out in a suitable solvent in the presence or absence of a catalyst. Examples of the solvent used here include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, acetonitrile, dimethylformamide and the like. Examples of the catalyst used include organic bases such as dimethylaminopyridine and 4-piperidinopyridine, salts such as pyridinium tosylate, camphorsulfonic acid, and mercury oxide. Examples of the condensing agent include acetylene compounds such as trimethylsilylethoxyacetylene. The condensing agent is usually equimolar to 1 with respect to the amine (3).
It is preferable to use a 0-fold molar amount, preferably a 2- to 6-fold molar amount. The carboxylic acid (6) or (4) is the amine (3)
On the other hand, it is usually at least about equimolar, preferably equimolar to 2 times the molar amount. The reaction is usually 0 to 1
The reaction is carried out at about 50 ° C., preferably room temperature to about 100 ° C., and the reaction is generally completed in about 1 to 10 hours.

The reaction for converting the compound (5) to the compound (8) is carried out by reducing the compound (5) when R ⁹ is a phenyl lower alkoxy group. This reduction reaction can be carried out, for example, by catalytic hydrogenation in the presence of a catalyst in a suitable solvent. As the solvent used, for example, water, acetic acid, alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, ethyl acetate, acetic acid. Esters such as methyl,
An aprotic polar solvent such as dimethylformamide or a mixed solvent thereof may be used. Examples of the catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like. The amount of the catalyst used is generally about 0.02 to 1 times the amount of the compound (5). The reaction temperature is generally around -20 to 100 ° C, preferably 0 to
At about 80 ° C., hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 20 hours.

When R ⁹ is a tetrahydropyranyloxy group or a tri-lower alkylsilyloxy group, the reaction for converting the compound (5) into the compound (8) is carried out by hydrolyzing the compound (5). This hydrolysis is carried out in the presence of acid in a suitable solvent or without solvent. As the solvent, any of those that do not affect the reaction can be used, for example, water, dichloromethane, halogenated hydrocarbons such as chloroform, lower alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone, Examples thereof include ethers such as dioxane, tetrahydrofuran, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether, fatty acids such as formic acid and acetic acid, and mixed solvents thereof. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, and organic acids such as formic acid, trifluoroacetic acid, acetic acid and aromatic sulfonic acid. The amount of the acid used is not particularly limited and can be appropriately selected from a wide range, but is usually about 1 to 10 mol, preferably about 1 to 2 mol with respect to the compound (5). The reaction normally proceeds at about 0 to 200 ° C., preferably room temperature to about 150 ° C.,
The reaction is usually completed in about 0.5 to 15 hours. See also R ⁹
Is a tri-lower alkylsilyloxy group, tetra-
The reaction may be carried out using a fluorine compound such as n-butylammonium fluoride, hydrogen fluoride or cesium fluoride.

When R ⁹ is a lower alkoxy lower alkoxy group, the reaction for converting the compound (5) to the compound (8) is carried out by converting the compound (5) into a mineral acid such as hydrobromic acid or hydrochloric acid or p-toluenesulfonic acid or the like. Organic acids and water, methanol, ethanol,
0 to 150 in a mixture with a solvent such as isopropanol
C., preferably at room temperature to 120.degree. C., or by hydrolysis. The latter hydrolysis is carried out in the presence of acid in a suitable solvent. As the solvent, for example, water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, polar solvents such as acetonitrile, a mixture thereof. A solvent etc. can be mentioned. Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, fatty acids such as formic acid and acetic acid, Lewis acids such as boron trifluoride, aluminum chloride and boron tribromide, sodium iodide and potassium iodide. And the mixture of the above Lewis acid and iodide. The reaction is usually 0 to
It proceeds suitably at 150 ° C., preferably room temperature to 100 ° C., and generally ends in about 0.5 to 15 hours.

The reaction for converting the compound (8) into the compound (9) is carried out by hydrolyzing the compound (8) in the presence of a basic compound. Examples of the basic compound used here include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide and the like. The amount of such a basic compound is usually about 1 to 15 mol, preferably about 1 to 10 mol, relative to the compound (8). As the solvent used, water, methanol, ethanol, alcohols such as isopropanol, tetrahydrofuran, dioxane, ethers such as dimethoxyethane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like and mixed solvents thereof and the like. It can be illustrated. The above reaction normally proceeds suitably at about 0 to 200 ° C, preferably at room temperature to about 150 ° C, and is generally completed in about 0.5 to 15 hours.

When R ⁸ of the compound (8) is a phenyl lower alkyl group, the compound (8) can also be reduced under the same conditions as in the reduction reaction for leading the compound (5) to the compound (8). You can lead to 9).

In the above method, the compound (9) or (8) obtained above is first converted to the compound (2a).

The reaction conditions similar to the reaction of the compound (3) and the compound (4) in the reaction formula-1 can be adopted for this reduction reaction. In particular, a method using a phosphorus compound such as triphenylphosphine-2,2′-dipyridyl disulfide or an acetylene compound such as trimethylsilylethoxyacetylene, and the above-mentioned (b) N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. A method using an active ester is preferable, and the basic compound used here is an alkali metal carboxylic acid salt,
Particularly preferred are alkali metal halide salts and the like.

Further, the compound (9) can increase the purity and stability of the compound (9) by forming a salt with an organic amine such as DBU, DBN or diisopropylethylamine, or an alkali metal salt such as sodium or potassium. This is advantageous for the next reaction.

[Reaction formula-2] [In the formula, R ² , R ³ , ⁴ , R ⁵ , R ⁶ and the bond at the 1- and 2-positions of the pyrazine ring are the same as described above. The reaction for obtaining the compound (2c) from the compound (2b) is carried out in a solvent in the presence of an oxidizing agent. Examples of the oxidizing agent include DDQ, selenium compounds such as selenium dioxide, cerium compounds such as cerium ammonium nitrate, and examples of the solvent include ethers such as THF, diethyl ether, dioxane, and the like.
The reaction is usually about 0 to 100 ° C, preferably room temperature to 70 ° C.
It is carried out at a temperature of about 0 ° C, and usually finishes in about 1 to 7 hours.

[Reaction Formula-3] [In the formula, R ² , R ³ , R ⁴ , R ⁵ , and the bond at the 1- and 2-positions of the pyrazine ring are the same as described above. B represents a lower alkylene group. X ¹ is hydrogen base paper, an alkali metal such as lithium or potassium, MgX ³ (X ³ represents a halogen atom), Sn
R ⁹ (R ⁹ represents a lower alkyl group) or ZnX ³ (X
³ is the same as above). X ² represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. Here, as the lower alkanesulfonyloxy group, specifically, methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulonyloxy, hexanesulfonyl. Examples thereof include an oxy group, and specific examples of the arylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy. And substituted or unsubstituted arylsulfonyloxy groups such as 3-chlorophenylsulfonyloxy and α-naphthylphenylsulfonyloxy groups, and aralkylsulfonyloxy groups. Specific examples of the Si group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4
Examples thereof include substituted or unsubstituted aralkylsulfonyloxy groups such as -methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy groups. Further, preferable examples of X ¹ include alkali metals such as lithium, sodium and potassium, ZnX ^{3 and the} like.

The above reaction can usually be carried out in a suitable solvent. Examples of the solvent used here include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, dioxane and diethylene glycol dimethyl ether. Examples thereof include dimethylsulfoxide, dimethylformamide and the like, or mixed solvents such as the above. The reaction is usually -30
~ 150 ° C, preferably around 0-100 ° C, 1
It ends in about 0 minutes to 50 hours. The amount of the compound (10) used is at least equimolar, preferably equimolar to 5 times the molar amount of the compound (11).

[Reaction Formula-4] [In the formula, R ² , R ³ , R ⁴ , X ² , B, and the bond at the 1- and 2-positions of the pyrazine ring are the same as described above. In the above reaction formula-4, the compound (11) in which X ² represents a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group is the compound (12) and the compound represented by the general formula R ¹⁰ -X ³ (13) [ In the formula, R ¹⁰ represents a lower alkanesulfonyl group, an arylsulfonyl group or an aralkylsulfonyl group. X ³ is the same as above. ] It manufactures by making it react with the compound represented.

The reaction between the compound of general formula (12) and the compound of general formula (13) is generally carried out in a suitable inert solvent in the presence or absence of a basic compound. As the inert solvent used, for example, aromatic hydrocarbons such as benzene, toluene, xylene, chloroform, dichloromethane, halogenated hydrocarbons such as carbon tetrachloride, tetrahydrofuran, dioxane, ethers such as diethylene glycol dimethyl ether, acetic acid, Examples thereof include ethyl acetate, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide and the like. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium and sodium amide. Metal alkoxides such as sodium methylate and sodium ethylate, pyridine,
Ethyl-diisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4,4
3,0] Nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU), 1,4-
Diazabicyclo "2,2,2] octane (DABCO)
Examples thereof include organic bases and the like. General formula (12)
The ratio of the compound of formula (1) to the compound of general formula (13) is not particularly limited and may be appropriately selected within a wide range.
The latter is usually used in an amount of at least about equimolar to the former, preferably about equimolar to 1.5 times. The reaction is generally about -78 to 100 ° C, preferably -30.
It is carried out at about 70 ° C, and the reaction is usually completed in about 30 minutes to 3 hours.

The ^{compound X 2} is a halogen atom (11), ^{X 2}
To a compound (11) in which is a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, a tetra-alkylammonium halide such as tetra-n-butylammonium iodide, tetra-n-butylammonium bromide, etc. It can also be obtained by reacting an alkali metal halide such as sodium or an alkali metal halide with a halogenating agent such as a phase transfer catalyst such as 18-crown-6 in a suitable solvent.

As the solvent used here, any of the solvents used in the reaction between the compound (12) and the compound (13) can be exemplified. The amount of the halogenating agent used is at least equimolar, preferably equimolar to the starting material.
It is preferable that the amount is about twice the molar amount. The reaction is usually 0 to 1
It is carried out at 00 ° C, preferably 0 to 70 ° C, and is generally completed in about 10 minutes to 5 hours.

In the above, the starting material pyrazine derivative (12)
Can be produced, for example, by the method described below.

[Reaction Formula-5] [In the formula, R ² , R ³ , R ⁴ and the bond at the 1st and 2nd positions of the pyrazine ring are the same as defined above. R ¹¹ is a lower alkyl group, a lower alkanoyl group, a succinimyl group, a lower alkoxycarbonyl group, a thiazolidinyl group which may have a thio group as a substituent, a methyleneiminium group having a lower alkyl group as a substituent or a group —SR ¹² ( R ¹² is a pyridyl group,
A thiazolidinyl group, a lower alkyl group, a cycloalkyl group, a phenyl group or a phenyl lower alkyl group). The reaction for converting the compound (14) into the compound (15) is carried out according to a usual hydrolysis reaction. This hydrolysis reaction
More specifically, for example, in the presence of a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid, acetic acid, an organic acid such as aromatic sulfonic acid, or the like, or sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide. In the presence of a basic compound such as, water, alcohols such as methanol, ethanol and isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, dioxane, ethers such as ethylene glycol dimethyl ether, solvents such as acetic acid or a mixed solvent thereof. It can be done inside. The reaction is usually 0
The process proceeds at about 200 ° C., preferably at room temperature to about 150 ° C., and generally ends in about 0.5 to 15 hours.

For the reduction reaction of compound (14) and compound (15), a reduction method using a hydrogenating / reducing agent is preferably used. Examples of the hydride reducing agent used here include lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, diborane, lithium borohydride, calcium borohydride and the like, and the amount thereof is usually used. The amount is at least equimolar, preferably equimolar to 5 times the molar amount of the compound (14) or the compound (15).

As the solvent used, for example, water, methanol, ethanol, lower alcohols such as isopropyl alcohol, tetrahydrofuran, dioxane, diethyl ether, ethers such as diglyme, dichloromethane, chloroform, halogenated hydrocarbons such as carbon tetrachloride, Acetonitrile, dimethylformamide or the like, or a mixed solvent thereof or the like can be illustrated. The reaction is usually performed at about -60 to 70 ° C, preferably at about -30 to 50 ° C, and at about 1
It will be completed in about 0 minutes to 20 hours. When lithium aluminum hydride or diborane is used as the reducing agent,
It is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme. When diisobutylaluminum hydride is used, aromatic hydrocarbons such as benzene, toluene and xylene can be used in addition to the above ether solvents.

[Reaction Formula-6] [In the formula, R ² , R ³ , R ⁴ , R ⁵ , and the bond at the 1- and 2-positions of the pyrazine ring are the same as described above. The reaction for converting the compound (12a) to the compound (16) is carried out in a suitable solvent in the presence of an oxidizing agent. Examples of the solvent used here include water, formic acid, acetic acid, organic acids such as trifluoroacetic acid, alcohols such as methanol and ethanol, halogenated hydrocarbons such as chloroform and dichloromethane, tetrahydrofuran, diethyl ether, and the like.
Examples thereof include ethers such as dioxane, dimethylsulfoxide, dimethylformamide, and mixed solvents such as the above. Examples of the oxidizing agent used include pyridinium chlorochromate, pyridinium chromate salts such as pyridinium dichlorochromate, dimethyl sulfoxide-oxalyl chloride, dichromic acid, sodium dichromate, dichromate salts such as potassium dichromate, Examples thereof include permanganates such as permanganate, potassium permanganate, and sodium permanganate. The oxidizing agent is usually used in an amount of at least an equimolar amount, preferably an equimolar to 2-fold molar amount with respect to the starting material. The above reaction is usually performed at about 0 to 100 ° C, preferably about 0 to 70 ° C, and is completed in about 1 to 7 hours.

The reaction between compound (16) and compound (17) is generally performed in an inert solvent in the presence of a basic compound. Examples of the inert solvent used include benzene, toluene, aromatic hydrocarbons such as xylene, tetrahydrofuran, dioxane, ethers such as diethylene glycol dimethyl ether, lower alcohols such as methanol, ethanol, isopropyl alcohol, acetic acid, ethyl acetate, etc. Acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide and the like can be mentioned. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium and sodium amide. Metal alkoxides such as sodium methylate and sodium ethylate, pyridine, ethyl-diisopropylamine,
Dimethylaminopyridine, triethylamine, 1,5-
Diazabicyclo [4,3,0] nonene-5 (DBN),
1,8-diazabicyclo [5,4,0] undecene-7
(DBU), 1,4-diazabicyclo “2,2,2] octane (DABCO), and other organic bases, etc. Proportion of Compound of General Formula (16) and Compound of General Formula (17) Used Is not particularly limited and may be appropriately determined in a wide range, but usually the latter is at least an equimolar amount, preferably an equimolar to 5-fold molar amount with respect to the former. It is usually carried out at about 0 to 200 ° C, preferably about 0 to 170 ° C, and generally 30 minutes to
It will be finished in about 30 hours.

The oxidation reaction of the compound (2e) is carried out by the above-mentioned compound (12
It is carried out under the same conditions as the reaction for converting a) to compound (16). In the reaction, DDQ can be used as the oxidizing agent in addition to the above.

For the reduction reaction of compound (2f), a reduction method using a hydrogenation reducing agent is preferably used. Examples of the hydrogenation reducing agent used here include sodium borohydride, lithium borohydride, tetrabutylammonium borohydride, calcium borohydride and the like. The amount used is at least an equimolar amount, preferably an equimolar amount to 15-fold molar amount, relative to the raw material compound. This reduction reaction is usually carried out in a suitable solvent, for example, lower alcohols such as water, methanol, ethanol and isopropyl alcohol, tetrahydrofuran, diethyl ether, diisopropyl ether, ethers such as diglyme and mixed solvents such as Usually -60 to 15
It is completed at about 0 ° C., preferably in the vicinity of −30 to 100 ° C., generally in about 10 minutes to 5 hours.

The alkylation reaction of the compound (2) obtained above is carried out in the presence of an alkylating agent in a suitable solvent. Examples of the solvent used here include methanol, ethanol,
Lower alcohols such as propanol, ethers such as dioxane, tetrahydrofuran, diethyl ether, ethylene glycol monomethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, acetonitrile, nitromethane, acetone, methyl acetate, ethyl acetate, etc. Examples thereof include esters and mixed solvents thereof. As the alkylating agent, for example, R ¹² —N═N—NH—R ₁₃ (18) [wherein R ¹² is a lower alkyl group, a lower alkoxy group, a nitro group or a halogen atom as a substituent on the phenyl ring] And a phenyl group which may have 1 to 3 groups selected from the group consisting of an amino group which may have a lower alkyl group. R ¹³ represents a lower alkyl group. ] The triazene derivative represented by these can be mentioned.
1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a nitro group, a halogen atom and an amino group which may have a lower alkyl group as a substituent on the phenyl ring represented by R ^12. As the phenyl group which may have, for example, phenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-
Bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3,5-dibromophenyl, 3,4,5-Trichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 2,6-dimethylphenyl , 3-isopropylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 2,5-dimethylphenyl, 3,4,5-trimethylphenyl, 2
-Methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-hexyloxyphenyl, 2,4-dimethoxyphenyl, 3, 6-dimethoxyphenyl, 3,4-
Dimethoxyphenyl, 2,5-dimethoxyphenyl,
3,4,5-trimethoxyphenyl, 2-chloro-4-
Methoxyphenyl, 2-methyl-4-methoxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 2,4,6
-Trinitrophenyl, 2-chloro-4-nitrophenyl, 2-methyl-4-chlorophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2,
3-diaminophenyl, 2,3,4-triaminophenyl, 2-methylaminophenyl, 3-ethylaminophenyl, 4-propylaminophenyl, 2-isopropylaminophenyl, 3-butylaminophenyl, 4-tert
-Butylaminophenyl, 2-pentylaminophenyl, 3-hexylaminophenyl, 4-dimethylaminophenyl, 2-diethylaminophenyl, 3-dipropylaminophenyl, 4-dibutylaminophenyl, 2-
Dipentylaminophenyl, 3-dihexylaminophenyl, 4- (N-methyl-N-ethylamino) phenyl, 2 (N-ethyl-N-propylamino) phenyl,
3- (N-methyl-N-butylamino) phenyl, 4-
(N-Methyl-N-hexylamino) phenyl group such as phenyl ring has a straight-chain or branched alkyl group having 1 to 6 carbon atoms as a substituent, a straight-chain or branched chain group having 1 to 6 carbon atoms 1 to 3 groups selected from the group consisting of an alkoxy group, a nitro group, a halogen atom and an amino group which may have 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms. There is a phenyl group. Among these, 2-methoxyphenyl, 4-chloro-2-methylphenyl, 2-
Methylphenyl, 4-methylphenyl, 4-chlorophenyl groups and the like are particularly preferable.

The amount of the alkylating agent used is at least equimolar, preferably equimolar to the compound of the general formula (2).
It is preferable that the amount is about twice the molar amount. The above reaction is usually -2
The reaction proceeds suitably at 0 to 100 ° C., preferably around -20 to 50 ° C., and the reaction is generally completed in about 1 to 20 hours.

When the alkylation reaction is carried out using the above-mentioned alkylating agent of the present invention, the target compound is obtained at a position of 5-position of the pyrazine skeleton with a good yield and a high purity on an industrial scale with a simple operation and good selectivity. be able to.

Each target compound thus obtained can be easily isolated and purified from the reaction mixture by a conventional separation means. Examples of such separation means include solvent extraction method,
The dilution method, recrystallization method, column chromatography, preparative thin layer chromatography and the like can be exemplified.

Examples Reference examples and examples are given below.

Reference Example 1 6 kg of L-tryptophan methyl ester hydrochloride was added to dimethylformamide 4 together with 3280 m of triethylamine.
Add to 8 and stir for 30 minutes. Then at 10 ° C or below,
3035 g of 1-hydroxybenzotriazole and 2-
3760 g of oxime oxoisocaproate is added.
After stirring for another hour, dicyclohexylcarbodiimide 5
345 g of dimethylformamide 12 solution is added dropwise at 10 ° C or lower. After dropping, at the same temperature for 1 hour, and at room temperature,
Stir for 3 hours. Saturated aqueous sodium hydrogen carbonate 60 and ethyl acetate 60 are added to the reaction mixture, the organic layer is separated, the insoluble material is removed, and the organic layer is dried over magnesium sulfate. The solvent was distilled off and the obtained residue was recrystallized from methanol to obtain 7750 g of N (α-hydroxyimino) -isocaproyl-L-triprofan methyl ester.

^{mp116~118 ℃ 1 H-NMR (CDC} 3) δ: 0.89 (6H, d, J = 6.8Hz), 1.9~2.1 (1H, m), 2.51 (2H, d, J = 7.2 Hz), 3.28 (2H, d, J = 5.6 Hz), 3.65 (3H, s), 4.9 to 5.0 (1H, m), 6.92 (1H, d, J = 2.2 Hz, 7.06 to 7.20 (2H, m), 7.27 to 7.55 (2H, m), 8.12 (1H, br.s), 8.29 (1H , Br.s) Reference Example 2 N- (α-hydroxyimino) -isocaproyl-L-
7530 g of tryptophan methyl ester is dissolved in methanol 53, a solution of sodium hydroxide 1125 g in water 53 is added at 10 ° C. or lower, and the mixture is stirred at room temperature for 2 hours and at 50-60 ° C. for 1 hour. Methanol was distilled off, acidified with hydrochloric acid, and the precipitated crystals were recrystallized from ethyl acetate-dichloromethane to give 5810 g of N- (α-hydroxyimino) -isocaproyl-L-.
Get tryptophan.

mp 97-98 ° C. ¹ H-NMR (CMSO-d ₆ ) δ: 0.78 (6H, d, J = 6.8 Hz), 1.8-2.0 (1H, m), 2.32 (2H, d, J = 7.4 Hz), 3.21 (2H, d, J = 6.2 Hz), 4.5 to 4.6 (1 H, m), 6.90 to 7.06 (3 H, m), 7.30 (1H, d, J = 7.8Hz), 7.46 (1H, d, J = 7.2Hz), 7.62 (1H, d, J = 7.8Hz), 10.8 (1H , D, J = 1 Hz), 11.6 (1H, s), 12.7 to 13.0 (1H, br.s) Reference Example 3 (6S, Z) -1-acetyl-3- (1-benzyl) Oxycarbonylindol-3-yl) -methylidene-6
-Isobutylpiperazine-2,5-dione (Compound A)
Synthesis of N-benzyloxycarbonyl-indole-3-carbaldehyde (4.5 g) in anhydrous THF (100 m
) Was added dropwise with a 1.6 mol n-hexane solution (12.7 m) of n-BuLi at -78 ° C with stirring. Then, after stirring for another 30 minutes at the same temperature, (3S) -1,4
An anhydrous THF solution (30 m) of -diacetyl-3-isobutyl-2,5-diketopiperazine (5.0 g) was added dropwise. After the dropping was completed, the temperature was raised to −60 ° C. over 30 minutes, water was added, and the mixture was extracted with CH ₂ C ₂ . This was washed with saturated brine, dried over MgSO ₄ , and the solvent-distilled yellow oil (9 g) was dissolved in benzene (100 m).
2 m was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 3: 1) to obtain the desired product (5.5 g, 66%). Pale yellow prism crystal. mp
95-97 ° C Reference Example 4 Synthesis of (6S, Z) -3- (1-benzyloxycarbonylindol-3-yl) -methylidene-6-isobutylpiperazine-2,5-dione (Compound B) Compound A (4 80 g of 1N hydrochloric acid was added to a methanol solution (400 m) of 0.0 g) and the mixture was refluxed for 2 hours. After cooling with ice, crude crystals (3.3 g, 91%) were collected. Colorless needles. mp 255-257 ° C (ethyl acetate-
Recrystallized from n-hexane).

Reference Example 5 (3S, Z) -6- (1-Benzyloxycarbonylindol-3-yl) -methylidene-3-isobutyl-
5-methoxy-1,2,3,6-tetridro (1H)
Pyrazin-2-one (Compound C) Compound B (9.5 g) was dried over CH ₂ C ₂ (500 m
), CH ₃ OTf (12.5 m) was added, and the mixture was refluxed (bath temperature: 50 to 60 ° C.) for 36 hours with stirring. After allowing to cool, it was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The obtained residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate =
5: 1 → 3: 1 → CH ₂ C ₂ : methanol = 3: 1)
Compound C (7.0 g, 71%) and its dimethyl compound, Compound D (0.3 g, 3%) were obtained.
Further, 1.8 g (18%) of the compound B as a starting material was recovered.

Physical properties of compound (C) Colorless needle crystals. mp129-131 ° C (ethyl acetate-n-
Hexane).

3- (1-benzyloxycarbonylindole-3-
Physical properties of (yl) -methyl-6-isobutyl-2,5-dimethoxypyrazine (Compound D) colorless needle crystals (recrystallized from ethyl acetate-n-hexane). ¹ H-NMR (250 MHz, CDC ₃ ) δ: 0.91 (6 H, d, J = 6.5 Hz), 2.03 to 2.23 (1 H, m), 2.54 (2 H, d, J =) 7Hz), 3.81 (3H, s), 3.91 (3H, s), 4.07 (2H, s), 5.43 (2H, s), 7.19 to 7.50 (7H, m) ), 7.52 (1H, s), 7.74 (1H, d, J = 8Hz), 8.15 (1H, br.d, J = 8Hz) Reference Example 6 6- (1-benzyloxycarbonylindole) -3-
Yl) -methyl-3-isobutyl-4-methoxy-1,
2-Dihydro (1H) pyrazin-2-one (Compound E)
Synthesis of compound C (4.5 g) was dissolved in 200 m of THF, and D
10 drops of BU was added, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in CH ₂ C ₂ to give 1N-HC
, Saturated saline, saturated NaHCO ₃ aqueous solution, saturated saline in that order, and dried over MgSO ₄ . The crude crystal (E) after the solvent was distilled off was recrystallized from ethyl acetate-n-hexane, and 4.
0 g (89%) was obtained as colorless prism crystals. mp14
9-151 ° C.

Reference Example 7 Synthesis of 6- (indol-3-yl) -methyl-3-isobutyl-4-methoxy-1,2-dihydro (1H) pyrazin-2-one (Compound F) Compound E (0.62 g) It was dissolved in 20 m of dioxane, 10% Pd-C (0.20 g) was added, and the mixture was stirred under a H ₂ gas atmosphere at room temperature and atmospheric pressure for 1 hour.

After removing the catalyst, the liquid was refluxed for 1 hour. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (n-
Purification with hexane: ethyl acetate = 4: 1) yielded 0.34 g (79%) of the desired product F. Recrystallized from ethyl acetate-n-hexane. Colorless needles. mp172-173 ° C.

Reference Example 8 N- (α-hydroxyimino) -isocaproyl-L-
500 g of tryptophan and 191 g of N-hydroxysuccinimide are dissolved in 7.5 of dioxane, and 374 g of dicyclohexylcarbodiimide is added to 2.5 of dioxane.
The solution is added dropwise below 20 ° C. After stirring for 1 hour, the dicyclohexylurea formed is removed. Sodium acetate (124 g) is added to the obtained solution, and the mixture is reacted at room temperature for 2-3 hours. Water was added to the reaction solution, the precipitated crystals were collected, washed thoroughly with water, and then dissolved in dimethylformamide to prepare equimolar 1,8
-Diazabicyclo [5,4,0] undecene-7 (DB
U) is added and the precipitated crystals are washed with dichloromethane and 351 g of 5-hydroxy-6- (indol-3-yl) methyl-3-isobutyl-1,2-dihydropyrazin-2-one 4 -Oxide DBU salt is obtained. mp 160 to 170 ° C. (decomposition) ¹ H-NMR (CD ₃ OD / CDC ₃ = 1/1) δ: 0.92 (6 H, d, J = 8 Hz), 1.6 to 1.85 (6 H, br, s), 1.9 to 2.05 (2H, m), 2.28 (1H, m), 2.6 to 2.7 (2H, m), 2.77 (2H, d, J = 9Hz). , 3.3 to 3.4 (2H, m), 3.4 to 3.55 (4H, m), 4.18 (2H, s), 6.98 to 7.2 (2H, m), 7 .18 (1H, s), 7.39 (1H, d, J = 10Hz), 7.60 (1H, d, J = 10Hz), using the appropriate starting materials, in the same manner as in Reference Example 8 Got

5-hydroxy-6- (indol-3-yl) methyl-3-isobutyl-1,2-dihydropyrazine-2-
On 4-oxide Light brown powder ¹ H-NMR (200 MHz, CDC ₃ -CD ₃ OD =
1: 1) δ: 0.92 (6H, d, J = 6.5Hz) 2.15-2.39 (1H, m) 2.76 (2H, d, J = 7Hz) 4.13 (2H, s) 6.99 (1H, t, J = 7.5Hz) 7.11 (1H, t, J = 7.5Hz) 7.14 (1H, s) 7.36 (1H, d, J = 7. 5 Hz) 7.61 (1 H, d, J = 7.5 Hz) 3-tert-butoxycarbonyloxy-6-hydroxy-5- (indol-3-yl) methyl-2-isobutylpyrazine 1-oxide Light brown solid ¹ 1 H-NMR (500 MHz, CDC ₃ ) δ: 0.85 (6H, d, J = 6.5Hz) 1.56 (9H, s) 2.10-2.25 (1H, m) 2.70 (2H , D, J = 7 Hz) 4.19 (2H, s) 6.93-7.18 (4H, m) 7.72 (1H, d, J = 7.5Hz) 8.11 (1H , Brs) IR ν _max (CHC ₃ ): 1755, 1605, 1535, 1500, 1255, 1155,
1130 cm ^-1 6-[(1-tert-butoxycarbonyl) indol-3-yl] methyl-5-hydroxy-3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide yellow solid ¹ H-NMR ( _{500MHz, CDC 3 -CD 3 OD =} 1
0: 1) δ: 0.83 (6H, d, J = 6Hz) 1.65 (9H, s) 2.05-2.17 (1H, m) 2.70 (2H, d, J = 7. 5Hz) 4.07 (2H, s) 7.11 (1H, t, J = 8Hz) 7.26 (1H, t, J = 8Hz) 7.51 (1H, s) 7.57 (1H, d, J = 8 Hz) 8.06 (1H, d, J = 8 Hz) 3-benzyloxy-5-[(1-tert-butoxycarbonyl) indol-3-yl] methyl-6-hydroxy-2-isobutylpyrazine 1- Oxide pale yellow solid ¹ H-NMR (500 MHz, CDC ₃ ) δ: 0.89 (6 H, d, J = 6 Hz) 1.64 (9 H, s) 2.15-2.26 (1 H, m) 2. 82 (2H, d, J = 7Hz) 4.24 (2H, s) 4.92 (1H, brs) 5.19 (2H, s) 7.15-7.4 (7H, m) 7.71 (1H , d, J = 7Hz) 8.06 (1H, d, J = 8Hz) IR ν max (CHC 3): 1720cm -1 3- cyclohexylmethyl-5-hydroxy-6 −
(Indol-3-yl) -methyl-1,2-dihydropyrazin-2-one 4-oxide Yellow powder ¹ H-NMR (250 MHz, DMSO-D ₆ ) δ: 0.95-1.25 (5H, m ), 1.46-1.90 (6H, m), 2.64 (2H, d, J = 7Hz), 4.01 (2H, s), 6.96 (1H, t, J = 7.5Hz). ), 7.06 (1H, t, J = 7.0Hz), 7.19 (1H, d, J = 2.5Hz), 7.34 (1H, d, J = 8.0Hz), 7.60. (1H, d, J = 7.5Hz), 10.88 (1H, s), 5-hydroxy-6- (indol-3-yl) -methyl-3-methyl-1,2-dihydropyrazine-2- one 4-oxide yellow powder ^{1 H-NMR (250MHz, DMSO} -d 6) δ: 2.23 (3H, s), 4.01 (2H, ), 6.96 (1H, t, J = 7.5 Hz), 7.07 (1H, t, J = 7.5 Hz), 7.19 (1H, s), 7.34 (1H, d, J) = 8 Hz), 7.61 (1H, d, J = 7.5 Hz), 10.88 (1H, s), 3-sec-butyl-5-hydroxy-6- (indol-3-yl) -methyl- 1,2-dihydropyrazine-
2-one 4-oxide yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 0.76 (3H, t, J = 7.5Hz), 1.25 (3H, d, J = 7Hz), 5.4-1.73 (1H, m), 1.70-2.02 (1H, m), 3.41-3.55 (1H, m), 4.01 (2H, s), 6. 97 (1H, t, J = 7Hz), 7.07 (1H, t, J = 7Hz), 7.19 (1H, d, J = 2.5Hz), 7.34 (1H, d, J = 8) 0.0Hz), 7.60 (1H, d, J = 8Hz) 10.88 (1H, s) 3-benzyl-5-hydroxy-6- (indole-
3-yl) -methyl-1,2-dihydropyrazine-2-
On 4-oxide Yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 4.02 (2H, s), 4.07 (2H, s), 6.96 (1H, t, J = 7. 5 Hz), 7.07 (1 H, t, J = 7.5 Hz), 7.16-7.30 (6 H, m), 7.34 (1 H, d, J = 8.0 Hz), 7.60 ( 1H, d, J = 7.5Hz), 10.87 (1H, s), 5-hydroxy-6- (indol-3-yl) -methyl-3- (2-phenyl) -ethyl-1,2- Dihydropyrazin-2-one 4-oxide yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 2.77-2.90 (2H, m), 2.96-3.10 (2H, m). , 4.02 (2H, s), 6.97 (1H, t, J = 7Hz), 7.07 (1H, t, J = 7Hz), 7.14- .32 (6H, m), 7.34 (1H, d, J = 8Hz), 7.34 (1H, d, J = 8Hz), 7.60 (1H, d, J = 7.5Hz), 10 .88 (1H, s) 3,6-di (indol-3-yl) -methyl-5-
Hydroxy-1,2-dihydropyrazin-2-one 4
-Oxide Yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 3.99 (2H, s), 4.15 (2H, s), 6.94 (2H, t, J = 7.5Hz) , 7.01-7.10 (2H, m), 7.14-7.21 (2H, m), 7.37-7.46 (2H, m), 7.57 (1H, d, J = 7.5 Hz), 7.73 (1H, d, J = 7.5 Hz), 10.86 (2H, s), 3- (4-benzyloxy) -benzyl-5-hydroxy-6- (indole-3) -Yl) -methyl-1,2
-Dihydropyrazin-2-one 4-oxide yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 3.99 (2H, s), 4.00 (2H, s), 5.04 (2H, s), 6.95 (1H, t, J = 7Hz), 6.98 (2H, d, J = 8.5Hz), 7.05 (1H, t, J = 7Hz), 7.15-7. 25 (3H, m), 7.30-7.50 (6H, m), 7.60 (1H, d, J = 7.5Hz), 10.85 (1H, s) 3-cyclohexyl-5-hydroxy -6- (Indol-3-yl) -methyl-1,2-dihydropyrazin-2-one 4-oxide ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 0.95-1.40 (3H, m), 1.40-1.86 (5H, m), 1.95-2.20 (2H, m), 3.23-3. 8 (1H, m), 4.00 (2H, s), 6.97 (1H, t, J = 7.5Hz), 7.07 (1H, t, J = 7.5Hz), 7.20 ( 1H, d, J = 2.0Hz), 7.34 (1H, d, J = 7.5Hz), 7.63 (1H, d, J = 7.5Hz), 10.88 (1H, s) 5 -Hydroxy-6- (indol-3-yl) -methyl-3-isobutyl-1,2-dihydropyrazine-2
-On 4-oxide yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 1.28 (6 H, d, J = 7 Hz), 3.57-3.77 (1 H, m), 4.00. (2H, s), 6.98 (1H, t, J = 7.5Hz), 7.08 (1H, t, J = 8Hz), 7.20 (1H, d, J = 2Hz), 7.35. (1H, d, J = 8Hz), 7.64 (1H, d, J = 7.5Hz), 3-tert-butyldimethylsilyloxy-2-cyclohexylmethyl-6-hydroxy-5- (indole-
3-yl) -methylpyrazin-1-one 4-oxide brown oil ¹ H-NMR (250 MHz, CDC ₃ ) δ: 0.10 (6H, s), 0.91 (9H, s), 1.1 -2.0 (11H, m), 2.72 (2H, d, J = 7Hz), 4.00 (2H, s), 6.88-7.27 (4H, m), 7.44 (1H) , D, J = 8 Hz), 7.58 (1H, brs) 3-tert-butyldimethylsilyloxy-2,5-di (indol-3-yl) -methyl-6-hydroxypyrazine 1-oxide brown oil ¹ H-NMR (250 MHz, CDC ₃ ) δ: 0.13 (6H, s), 0.84 (9H, s), 4.01 (4H, brs) 6.80-7.20 (10H, m) , 7.66 (2H, brs) 5-hydroxy-6- [1- (indol-3-yl)- Ethyl] -3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide pale yellow needle crystals mp165-167 ° C ¹ H-NMR (250 MHz, CDC ₃ ): δ 0.98 (3H, d, J = 6.5 Hz), 0.99 (3H, d, J = 6.5Hz), 1.77 (3H, d, J = 7.5Hz), 2.17-2.38 (1H, m), 2 0.83 (2H, d, J = 7.5Hz), 4.76 (1H, q, J = 7.5Hz), 7.09 (1H, t, J = 7.5Hz), 7.20 (1H, 1H, t, J = 7.5 Hz), 7.33 (1 H, d, J = 2 Hz), 7.36 (1 H, d, J = 8 Hz), 7.53 (1 H, d, J = 8 Hz), 8. 13 (1H, s) 5-Hydroxy-6- [2- (indol-3-yl) -ethyl] -3-isobutyl-1,2-dihydropyrazin-2-one 4-o Xide yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 0.90 (6 H, d, J = 7 Hz), 2.13 (1 H, sept, J = 7 Hz), 2.65 (2 H, d). , J = 7 Hz), 2.8-3.1 (4 H, m), 3.97 (1 H, t, J = 7 Hz), 7.07 (1 H, t, J = 7 Hz), 7.13 (1 H , D, J = 2 Hz), 7.34 (1H, d, J = 7 Hz), 7.52 (1H, d, J = 7 Hz), 10.80 (1H, br) Example 1 6- (indole- 3-yl) methyl-5-methoxy-
Synthesis of DMF complex of 3-isobutyl-1,2-dihydropyrazin-2-one 4-oxide 6- (Indol-3-yl) methyl-5-hydroxy-3-isobutyl-1,2-dihydropyrazine-2- On 4-oxide 1 g dichloromethane (40 m)-
Suspended in methanol (2m) then 1-methyl-3
0.79 g of-(2-methoxyphenyl) triazene is added, and the mixture is stirred at room temperature for 2 to 5 hours. After reaction, mix 5
% Hydrochloric acid, saturated multi-layered water, and then washed several times with water, and dried with Glauber's salt. The residue obtained by distilling off the solvent is dissolved in a mixed solution of dimethylformamide (DMF) -ethyl acetate, and left standing to obtain 047 g of the above target compound.

mp. 230 ° C (decomposition) ¹ H-NMR (250 MHz, CDC ₃ -CD ₃ OD =
1: 1): δ 0.95 (6H, d, J = 6.8Hz), 2.12-2.32 (1H, m), 2.76 (2H, d, J = 7.2Hz), 2 .89, 3.00, 3.89 (each 3H, s), 4.08 (2H, s) 7.02-7.20 (3H, m), 7.40 (1H, d, J = 8Hz) , 7.60 (1H, d, J = 7.6Hz), 7.97 (1H, brs), 10.3 (1H, brs) The DMF complex of the target compound obtained above is recrystallized with ethanol. Thus, 0.34 g of the above target compound
Got

Light yellow prism mp. 225 ° C. Example 2 Synthesis of 6- (indol-3-yl) methyl-3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one 4-oxide DMF complex 1-methyl-3- (2- The target compound is obtained in the yield shown in Table 1 in the same manner as in Example 1 except that various triazene derivatives shown in Table 1 below are used in place of 0.79 g of methoxyphenyl) triazene.

The following compounds are obtained in the same manner as in Examples 1 and 2 using appropriate starting materials.

3-chloro-5- (indol-3-yl) -methyl
-2-isobutyl-6-methoxypyrazine 1-oxy
De colorless needle crystal (recrystallized from ethanol) mp 137-139 ° C. 3-chloro-2-isobutyl-5-[(1-methoxy
Carbonyl) -indol-3-yl] -methyl-6-
Methoxypyrazine 1-oxide colorless needle crystals (recrystallized from ethanol) mp 146-147 ° C. 3-chloro-5- (2-chloroindole-3-i)
) -Methyl-2-isobutyl-6-methoxypyrazine
1-oxide light brown oil ¹ H-NMR (200MHz, CDC _Three ) Δ: 0.97 (6H, d, J = 6.5Hz), 2.14 to 2.40 (1H, m), 2.90 (2H, d, J = 7Hz), 3.88 (3H, 3H, s), 4.21 (2H, s), 7.10 (1H, dt, J = 6.5Hz, 2Hz), 7.17 (1H, dt, J = 6.5Hz, 1.5Hz), 7. 25 (1H, dd, J = 6.5Hz, 2Hz), 7.63 (1H, dd, J = 6.5Hz, 1.5Hz), 8.28 (1H, brs) 6- (Indol-3-yl) ) -Methyl-3-isobu
Tyl-5-methoxy-1-methyl-1,2-dihydropyr
Lazin-2-one 4-oxide yellow powder ¹ H-NMR (200MHz, CDC _Three ) Δ: 0.98 (6H, d, J = 6.5Hz), 2.21 to 2.41 (1H, m), 2.90 (2H, d, J = 7.5Hz), 3.43 ( 3H, s), 3.99 (3H, s), 4.21 (2H, s), 6.85 (1H, d, J = 2.5Hz), 7.17 (1H, t, J = 8Hz) , 7.25 (1H, t, J = 8Hz), 7.41 (1H, d, J = 8Hz), 7.62 (1H, d, J = 8Hz), 8.65 (1H, brs) 3- (Indol-3-yl) -methyl-6-isobu
Cyl-2,5-dimethoxypyrazine 1-oxide colorless needle crystals (recrystallized from ethyl acetate-n-hexane),
mp 177-179 ° C ¹ H-NMR (200MHz, CDC _Three ) Δ: 0.91 (6H, d, J = 6.5Hz), 2.10 to 2.30 (1H, m), 2.74 (2H, d, J = 7.5Hz), 3.94 ( 3H, s), 3.95 (3H, s), 4.18 (2H, s), 7.10 to 7.25 (3H, m), 7.35 (1H, d, J = 7.5Hz) , 7.85 (1H, d, J = 7.5 Hz), 8.06 (1H, brs) 3-benzyloxy-5- (3-indolylmethyl)
-2-isobutyl-6-methoxypyrazine 1-oxy
Domp 139.6 to 141.9 ° C. White prism shape (from diethyl ether-n-hexane)
Recrystallization) 3-benzyloxy-5- (3-indolylmethyl)
-2-isobutyl-6-methoxypyrazine 1-oxy
Domp 139.6 to 141.9 ° C. White prismatic form 3-benzyloxy-5- (3-indolylmethyl)
-2-isobutyl-6-methoxypyrazine 1-oxy
Domp 139.6 to 141.9 ° C. White prismatic 3- (2-chlorobenzyloxy) -5- (3-yne
(Drill methyl) -2-isobutyl-6-methoxypyrazy
1-oxide pale yellow oily NMR (CDC _Three ) Δ: 0.92 (6H, d, J = 6.5Hz), 2.22 (1H, m), 2.80 (2H, d, J = 7.0Hz), 4.18 (2H, s). 5.49 (2H, s) 7.07 to 7.76 (8H, m), 7.78 (1H, d, J = 8.0Hz), 8.19 (1H, brs) 3-tert-butoxy Carbonyloxy-5- (India
Ol-3-yl) methyl-2-isobutyl-6-methoxy
Cypyrazine 1-oxide light brown solid ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.94 (6H, d, J = 6.5Hz) 1.55 (9H, s) 2.10 to 2.33 (1H, m) 2.71 (2H, d, J = 7Hz) 3 .89 (3H, s) 4.23 (2H, s) 7.08 (1H, d, J = 2.5Hz) 7.10-7.23 (2H, m) 7.33 (1H, d, J) = 9 Hz) 7.73 (1H, t, J = 7.5 Hz) 8.12 (1H, brs) IR ν _max (CHC _Three ): 1770 cm _-1 3-benzyloxy-5-[(1-tert-butoxyca
Lubonyl) indol-3-yl] methyl-2-isobu
Chill-6-methoxypyrazine 1-oxide light brown solid ¹ H-NMR (500MHz, CDC _Three ) Δ: 0.92 (6H, d, J = 6.5Hz) 1.66 (9H, s) 2.17-2.27 (1H, m) 2.79 (2H, d, J = 7.5Hz) ) 3.99 (3H, s) 4.10 (2H, s) 5.31 (2H, s) 7.21 (1H, t, J = 8Hz) 7.26-7.52 (6H, m) 7 .48 (1H, s) 7.66 (1H, d, J = 8Hz) 8.10 (1H, t, J = 8Hz) IR ν _max (CHC _Three ): 1725 cm _-1 3-benzyloxy-5-[(1-methoxycarbonyl
Le) indol-3-yl] methyl-2-isobutyl-
6-methoxypyrazine 1-oxide ¹ H-NMR (500MHz, CDC _Three ) Δ: 0.92 (6H, d, J = 7Hz) 1.56 (9H, s) 2.15-2.27 (1H, m) 2.79 (2H, d, J = 7.5Hz) 3 .98 (3H, s) 4.03 (3H, s) 4.10 (2H, s) 5.32 (2H, s) 7.23 (1H, t, J = 8Hz) 7.32 (5H, s) ) 7.33 (1H, t, J = 8Hz) 7.46 (1H, s) 7.66 (1H, d, J = 8Hz) 8.16 (1H, d, J = 8Hz) IR ν _max (CHC _Three ): 1730 cm _-1 3-benzyloxy-5- (indol-3-yl)
Methyl-2-isobutyl-6-methoxypyrazine 1-
Oxide white solid mp 140-142 ° C ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.92 (6H, d, J = 6.5Hz) 2.12-2.32 (1H, m) 2.78 (2H, d, J = 7Hz) 3.93 (3H, s) 4 .18 (2H, s) 5.37 (2H, s) 7.05 (1H, d, J = 2Hz) 7.13 (1H, t, J = 8Hz) 7.19 (1H, t, J = 8Hz) ) 7.35 (5H, s) 7.36 (1H, d, J = 8Hz) 7.76 (1H, d, J = 8Hz) 8.06 (1H, brs) MS spectrum; m / z: 418 ( 13%), 417 (M ⁺ , 31%),
401 (22%), 400 (51%), 358 (10
%), 193 (100%) 3-benzyloxy-5- (indol-3-yl)
-Methyl-2-isobutyl-6-methoxypyrazine 1
-Oxide colorless prismatic crystals mp 139.6 to 141.9 ° C (diethyl ether-n
-Recrystallized from hexane) 3-Ethyl-6- (indol-3-yl) -methyl
-5-methoxy-1,2-dihydropyrazin-2-one
4-oxide colorless prism (recrystallized from methanol) mp202-204 ° C (decomposition) ¹ H-NMR (250 MHz, DMSO-d ₆ ) Δ: 1.03 (3H, t, J = 7.5Hz), 2.71 (2H, q, J = 7.5Hz), 3.80 (3H, s), 3.93 (2H, s). , 7.01 (1H, t, J = 7.5 Hz), 7.09 (1H, t, J = 7.5 Hz), 7.28 (1H, d, J = 2 Hz), 7.36 (1H, 1H, d, J = 8 Hz), 7.61 (1H, d, J = 7.5 Hz), 10.97 (1H, s), 12.00 (1H, brs) 6- (indol-3-yl) -methyl -5-Metoki
Ci-3-methyl-1,2-dihydropyrazin-2-one
4-Oxide pale yellow prismatic crystal (recrystallized from methanol) ¹ H-NMR (250 MHz, DMSO-d ₆ ) Δ: 2.16 (3H, s), 3.79 (3H, s), 3.93 (2H, s), 7.00 (1H, t, J = 7.5Hz), 7.09 (1H) , T, J = 7.5 Hz), 7.27 (1H, s), 7.36 (1H, d, J = 8 Hz), 7.60 (1H, d, J = 7.5 Hz), 10.97 (1H, s), 11.97 (1H, brs) 3-sec-Butyl-6- (indol-3-yl)-
Methyl-5-methoxy-1,2-dihydropyrazine-2
-On 4-oxide pale yellow prismatic crystal (recrystallized from methanol) mp 218.5-219.5 ° C (decomposition) ¹ H-NMR (250 MHz, DMSO-d ₆ ) Δ: 0.75 (3H, t, J = 7.5Hz), 1.21 (3H, d, J = 7.0Hz), 1.53-1.73 (1H, m), 1.80- 2.01 (1H, m), 3.45-3.62 (1H, m), 3.79 (3H, s), 3.92 (2H, s), 7.00 (1H, t, J = 7.5 Hz), 7.09 (1 H, t, J = 7.5 Hz), 7.28 (1 H, s), 7.36 (1 H, d, J = 7.5 Hz), 7.61 (1 H, d, J = 7.5 Hz), 10.98 (1H, s), 11.90 (1H, brs) 3-benzyl-6- (indol-3-yl) -methyl
Lu-5-methoxy-1,2-dihydropyrazin-2-o
4-Oxide Pale yellow prismatic crystal (recrystallized from methanol) mp222-222.5 ° C (decomposition) ¹ H-NMR (250 MHz, DMSO-d ₆ ) Δ: 3.78 (3H, s), 3.95 (2H, s), 4.03 (2H, s), 7.00 (1H, t, J = 7.5Hz), 7.09 (1H) , T, J = 7.5 Hz), 7.15-7.35 (6 H, m), 7.36 (1 H, d, J = 8 Hz), 7.60 (1 H, d, J = 8 Hz), 10 .99 (1H, s), 12.12 (1H, brs) 6- (indol-3-yl) -methyl-5-methoxy
Ci-3- (2-phenyl) -ethyl-1,2-dihydro
Pyrazin-2-one 4-oxide pale yellow prismatic crystal (recrystallized from methanol) mp 231.5 to 232 ° C (decomposition) ¹ H-NMR (250 MHz, DMSO-d ₆ ) Δ: 2.74-2.88 (2H, m), 2.90-3.08 (2H, m), 3.79 (3H, s), 3.94 (2H, s), 7.02. (1H, t, J = 7Hz), 7.10 (1H, t, J = 7Hz), 7.14-7.32 (6H, m), 7.37 (1H, d, J = 8Hz), 7 .60 (1H, d, J = 7.5 Hz), 11.00 (1H, s), 12.03 (1H, brs) 3-cyclohexylmethyl-6- (indole-3-)
Iyl) methyl-5-methoxy-1,2-dihydropyrazy
N-2-one 4-oxide yellow prismatic crystal mp 200.5-201 ° C (decomposition) ¹ H-NMR (250 MHz, DMSO-d ₆ ) Delta: 0.90-1.30 (5H, m), 1.45-1.71 (5H, m), 1.71-1.90 (1H, m), 2.63 (2H, d,). J = 7Hz), 3.79 (3H, s), 3.93 (2H, s), 7.00 (1H, t, J = 7.5Hz), 7.10 (1H, t, J = 7. 5Hz), 7.28 (1H, d, J = 2.0Hz), 7.37 (1H, d, J = 8.0Hz), 7.60 (1H, d, J = 7.5Hz), 10. 97 (1H, s), 11.95 (1H, brs) 3,6-di (indol-3-yl) -methyl-5-
Methoxy-1,2-dihydropyrazin-2-one 4-
Oxide ¹ H-NMR (250 MHz, DMSO-d ₆ ) Delta: 3.78 (3H, s), 3.92 (2H, s), 4.10 (2H, s), 6.90-7.15 (4H, m), 7.15-7.40. (6H, m), 7.57 (1H, d, J = 7.5Hz), 7.74 (1H, d, J = 7.5Hz), 10.85 (1H, s), 10.97 (1H , S), 11.98 (2H, brs) 3-cyclohexyl-6- (indol-3-yl)
-Methyl-5-methoxy-1,2-dihydropyrazine-
2-one 4-oxide ¹ H-NMR (250 MHz, DMSO-d ₆ ) Δ: 0.98-1.90 (8H, m), 2.03-2.30 (2H, m), 3.30-3.60 (1H, m), 3.80 (3H, s). , 3.90 (2H, s), 7.01 (1H, t, J = 7.5Hz), 7.09 (1H, t, J = 7.5Hz), 7.30 (1H, s), 7 .36 (1H, d, J = 7.5 Hz), 7.62 (1H, d, J = 7.5 Hz), 11.00 (1H, s), 11.93 (1H, brs) 3- (4) -Benzyloxy) -benzyl-6- (yne
Dol-3-yl) -methyl-5-methoxy-1,2-
Dihydropyrazin-2-one 4-oxide yellow powder ¹ H-NMR (250MHz, CDC _Three ) Δ: 4.01 (3H, s), 4.05 (2H, s), 4.11 (2H, s), 4.99 (2H, s), 6.83 (2H, d, J = 8) .5 Hz), 6.97 (1 H, t, J = 8 Hz), 7.09 (1 H, t, J = 8 Hz), 7.07-7.47 (9 H, m), 7.60 (1 H, d). , J = 8.5 Hz), 8.03 (1H, brs) IR (KBr): 1680 cm ^-1 Elemental analysis (C ₂₈ H ₂₅ N _Three O _Four As) 3- (4-hydroxy) -benzyl-6- (indole
Lu-3-yl) -methyl-5-methoxy-1,2-dihi
Dropyrazin-2-one 4-oxide pale yellow powder ¹ H-NMR (250 MHz, DMSO-d ₆ ) Δ: 3.73 (3H, s), 3.87 (2H, s), 3.89 (2H, s), 6.59 (2H, d, J = 8.5Hz), 6.96 (1H) , T, J = 8 Hz), 7.05 (1H, t, J = 8 Hz), 7.06 (2H, d, J = 8.5 Hz), 7.22 (1H, d, J = 2.5 Hz) , 7.32 (1H, d, J = 8Hz), 7.57 (1H, d, J = 8Hz), 9.22 (1H, brs), 10.93 (1H, brs) IR (KBr): 1680cm ^-1 Elemental analysis (C ₂₁ H ₁₉ N _Three O _Four As) 5-Ethoxy-6- (indol-3-yl) -meth
Ru-3-isobutyl 1,2-dihydropyrazin-2-o
4-Oxide yellow prismatic crystal (recrystallized from methanol) mp192-193 ° C. 6- [1- (indol-3-yl) -ethyl] -3
-Isobutyl-5-methoxy-1,2-dihydropyrazy
N-2-one 4-oxide colorless needle crystal (recrystallized from methanol) mp 238 to 240 ° C. 6- [2- (indol-3-yl) -ethyl] -3
-Isobutyl-5-methoxy-1,2-dihydropyrazy
N-2-one 4-oxide yellow powder mp 222-224 ° C. 3-benzyloxy-5-[(5-fluoro) -yne
Dol-3-yl] -methyl-2-isobutyl-6-me
Toxypyrazine 1-oxide colorless needle crystals (diethyl ether
Re-crystallized from ether-n-hexane) mp 140-141 ° C. 3-benzyloxy-5-[(5-chloro) -indo
-3-L] -yl] -methyl-2-isobutyl-6-meth
Xypyrazine 1-oxide colorless prismatic crystals
Recrystallized from luether-n-hexane) mp135 to 135.5 ° C. 3-benzyloxy-5-[(5-bromo) -indo
-3-l] -yl] -methyl-2-isobutyl-6-meth
Xypyrazine 1-oxide colorless needle crystals (diethyl ether
Recrystallized from ter-n-hexane) mp124-125 ° C. 3-benzyloxy-2-isobutyl-6-methoxy
-5-[(2-methyl) -indol-3-yl] -me
Cylpyrazine 1-oxide Pale yellow prismatic crystal
Recrystallized from Nol) mp164.5-165.5 ° C. 3-benzyloxy-2-isobutyl-6-methoxy
-5-[(5-methyl) -indol-3-yl] -me
Cylpyrazine 1-oxide colorless needle crystals (diethyl ether
Recrystallized from ter-n-hexane) mp128-129 ° C 3-benzyloxy-2-isobutyl-6-methoxy
-5-[(7-methyl) -indol-3-yl] -me
Cylpyrazine 1-oxide colorless needle crystals (diethyl ether
Recrystallized from ter-n-hexane) mp 121.5 to 123.5 ° C. 3-benzyloxy-2-isobutyl-6-methoxy
-5-[(2-phenyl) -indol-3-yl]-
Methylpyrazine 1-oxide Pale yellow prismatic crystal (d
Recrystallized from tanol) mp 180-182 ° C 3-benzyloxy-2-isobutyl-6-methoxy
-5-[(5-methoxy) -indol-3-yl]-
Methylpyrazine 1-oxide colorless needle crystals (methyl chloride
Re-crystallized from hexane-n-hexane) mp118-119 ° C 3-benzyloxy-5-[(2-benzyloxy)
-Indol-3-yl] -methyl-2-isobutyl-
6-methoxypyrazine 1-oxide colorless needle crystal (recrystallized from methylene chloride-n-hexane) mp93-94.5 ° C 3-benzyloxy-2-isobutyl-6-methoxy
-5-[(5-methoxy-2-methyl) -indole-
3-yl] -methylpyrazine 1-oxide colorless needle crystal (recrystallized from methylene chloride-n-hexane) recrystallized from methylene-n-hexane mp137 to 138.5 ° C 3-benzyloxy-5-[(5 , 6-dimethoxy)
-Indol-3-yl] -methyl-2-isobutyl-
6-methoxypyrazine 1-oxide pale yellow needle-like crystals (recrystallized from ethyl acetate) mp 151-153 ° C. 3-benzyloxy-5-[(4-ethoxycarbonyl
) -Indol-3-yl] -methyl-2-isobutyi
Le-6-methoxypyrazine 1-oxide white powder (recrystallized from methylene chloride-n-hexane) mp 142-142.5 ° C. 6-[(5-fluoro) -indol-3-yl]-
Methyl-3-isobutyl-5-methoxy-1,2-dihi
Dropyrazin-2-one 4-oxide pale yellow prismatic crystals (recrystallized from ethanol) mp209-210 ° C 6-[(5-chloro) -indol-3-yl] -me
Cyl-3-isobutyl-5-methoxy-1,2-dihydr
Lopyrazin-2-one 4-oxide light yellow prismatic crystal (recrystallized from ethanol) mp200-203.5 ° C 6-[(5-bromo) -indol-3-yl] -me
Cyl-3-isobutyl-5-methoxy-1,2-dihydr
Lopyrazin-2-one 4-oxide Pale yellow prismatic crystal (recrystallized from ethanol) mp 199.5-203.5 ° C. 3-isobutyl-5-methoxy-6-[(2-methyl
) -Indol-3-yl] -methyl-1,2-dihi
Dropyrazin-2-one 4-oxide light yellow prismatic crystals (recrystallized from ethanol) mp218 to 219.5 ° C. 3-isobutyl-5-methoxy-6-[(5-methyl)
) -Indol-3-yl] -methyl-1,2-dihi
Dropyrazin-2-one 4-oxide pale yellow prismatic crystal (recrystallized from ethanol) mp 195.5-197 ° C. 3-isobutyl-5-methoxy-6-[(7-methyi)
) -Indol-3-yl] -methyl-1,2-dihi
Dropyrazin-2-one 4-oxide pale yellow prismatic crystal (recrystallized from ethanol) mp200-201 ° C 3-isobutyl-5-methoxy-6-[(2-phenyl
) -Indol-3-yl] -methyl-1,2-dihi
Dropyrazin-2-one 4-oxide light yellow needle crystals (recrystallized from ethanol) mp194-195.5 ° C. 3-isobutyl-5-methoxy-6-[(5-methoxy
Ci) -Indol-3-yl] -methyl-1,2-dihi
Dropyrazin-2-one 4-oxide pale yellow needle crystals (recrystallized from ethanol) mp209-210 ° C 6-[(5-hydroxy) -indol-3-yl]
-Methyl-3-isobutyl-5-methoxy-1,2-di
Hydropyrazin-2-one 4-oxide colorless needle crystals (recrystallized from ethanol) mp 207.5-208 ° C. 3-isobutyl-5-methoxy-6-[(5-methoxy)
Ci-2-methyl) -indol-3-yl] -methyl-
1,2-Dihydropyrazin-2-one 4-oxide pale yellow powder (recrystallized from ethanol) mp 190-191 ° C. 6-[(5,6-dimethoxy) -indole-3-y
] -Methyl-3-isobutyl-5-methoxy-1,2
-Dihydropyrazin-2-one 4-oxide pale yellow prismatic crystals (recrystallized from ethanol) mp204 ° C (decomposition) 6-[(4-ethoxycarbonyl) -indole-3
-Yl] -methyl-3-isobutyl-5-methoxy-
1,2-Dihydropyrazin-2-one 4-oxide pale yellow needle crystals (regenerated from methylene chloride-diethyl ether)
Crystal) mp 147.5-149 ° C. 6-[(4-carboxy) -indol-3-yl]
-Methyl-3-isobutyl-5-methoxy-1,2-di
Hydropyrazin-2-one 4-oxide Pale yellow needle crystals (reconstituted from methylene chloride-n-hexane)
Crystal) mp 160.5 to 163.5 ° C. 3-benzyloxy-5- (indol-1-yl)
-Methyl-2-isobutyl-6-methoxypyrazine 1
-Oxide colorless oil ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.91 (6H, d, J = 7Hz), 2.18 (1H, sept, J = 7Hz), 2.77 (2H, d, J = 7Hz), 3.90 (3H, s). , 5.28 (2H, s), 5.31 (2H, s), 6.53 (1H, d, J = 3Hz), 7.10 (1H, t, J = 7Hz), 7.18 (1H) , T, J = 7 Hz), 7.23 (1H, d, J = 3 Hz), 7.31 (5H, m), 7.48 (1H, d, J = 7 Hz), 7.62 (1H, d) , J = 7 Hz), 3-benzyloxy-5-[(5-cyano) -indo
1-yl] -methyl-2-isobutyl-6-meth
Xypyrazine 1-oxide colorless needle crystals (diethyl ether
Recrystallized from ter-n-hexane) mp 97-99 ° C. 3-benzyloxy-2-isobutyl-6-methoxy
-5- (Oxyndol-3-yl) -methylpyrazy
1-oxide white powder ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.90 (3H, d, J = 7Hz), 0.91 (3H, d, J = 7Hz), 2.21 (1H, sept, J = 7Hz), 2.79 (2H, d, 7Hz). J = 7 Hz), 3.32 (1 H, dd, J = 16 Hz, 7 Hz), 3.53 (1 H, dd, J = 16 Hz, 5 Hz), 3.97 (3 H, s), 4.00 (1 H, brt, J = 6 Hz), 5.18 (2H, ABq, J = 13 Hz), 6.78 (1H, d, J = 7 Hz), 6.86 (1H, t, J = 7 Hz), 6.91 ( 1H, d, J = 7Hz), 7.16 (1H, t, J = 7Hz), 7.33 (5H, m), 7.59 (1H, brs) 6-[(5-cyano) -indole- 1-yl] -me
Cyl-3-isobutyl-5-methoxy-1,2-dihydr
Lopyrazin-2-one 4-oxide colorless needle crystals (recrystallized from ethanol) mp 205-207 ° C. 6- (indol-1-yl] -methyl-3-isobu
Cyl-5-methoxy-1,2-dihydropyrazine-2-
On 4-oxide Light yellow needle crystals (recrystallized from ethanol) mp179.5-180.5 ° C 3-isobutyl-5-methoxy-6- (oxyindo)
-3-l) yl-methyl-1,2-dihydropyrazine
2-one 4-oxide white powder (recrystallized from ethanol) mp 200-201.5 ° C. 3-benzyloxy-5- (indol-3-yl)
-Methyl-2-isobutyl-6-isopropoxypyrazy
N-Oxide colorless prismatic crystals (from diethyl ether-n-hexane
Re-crystallization) mp 106-107 ° C. 3-benzyloxy-6-n-butoxy-5- (yne
Dole-3-yl) -methyl-2-isobutylpyrazine
1-oxide pale yellow oil ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.93 (6H, d, J = 7Hz), 1.01 (3H, t, J = 7Hz), 1.54 (2H, sex, J = 7Hz), 1.88 (2H, qui, J = 7 Hz), 2.23 (1H, sept, J = 7 Hz), 2.79 (2H, d, J = 7 Hz), 4.37 (2H, t, J = 7 Hz), 4.45 (2H, s), 5.37 (2H, s), 7.3-7.5 (5H, m) 6- (indol-3-yl) -methyl-3-isobu
Cyl-5-isopropoxy-1,2-dihydropyrazine
2-one 4-oxide pale yellow prismatic crystal (recrystallized from ethanol) mp182-183 ° C 5-n-butoxy-6- (indol-3-yl)-
Methyl-3-isobutyl-1,2-dihydropyrazine-
2-one 4-oxide pale yellow needle crystal (recrystallized from ethanol) mp185-187 ° C 3-benzyloxy-5- [1-hydroxy-1-
(Indol-3-yl)]-methyl-2-isobutyl
-6-Methoxypyrazine 1-oxide colorless needle crystal (recrystallized from ethanol) mp 161.5-163.5 ° C 3-benzyloxy-5- (indole-3-yl)
-Carbonyl-2-isobutyl-6-methoxypyrazine
1-oxide Pale yellow needle crystals (reproduced from methylene chloride-diethyl ether)
Crystal) mp 166.5 to 167.5 ° C. 6- (indol-3-yl) -carbonyl-3-y
Sobutyl-5-methoxy-1,2-dihydropyrazine-
2-one 4-oxide / ethanol adduct Yellow needle crystals (recrystallized from ethanol) mp 176 to 178.5 ° C. 6- [1-hydroxy-1- (indole-3-a)
)]-Methyl-3-isobutyl-5-methoxy-1,
2-dihydropyrazin-2-one 4-oxide pale yellow oil ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.81 (3H, d, J = 7Hz), 0.82 (3H, d, J = 7Hz), 2.07 (1H, sept, J = 7Hz), 2.59 (2H, d, 7Hz) J = 7Hz), 3.64 (3H, s), 6.19 (1H, s), 6.93 (1H, d, J = 7Hz), 7.06 (1H, t, J = 7Hz), 7 .16 (1H, t, J = 7Hz), 7.28 (1H, d, J = 7Hz), 7.62 (1H, d, J = 7Hz), 8.68 (1H, brs) 3-acetoxy- 5- (Indol-3-yl) -me
Cyl-2-isobutyl-6-methoxypyrazine 1-o
Xide colorless needle crystal (reconstituted from diethyl ether-n-hexane)
Crystal) mp 105-106 ° C. 3-benzyloxy-2-isobutyl-5-[(1-
Methyl)-(indol-3-yl)]-methyl-6-
Methoxypyrazine 1-oxide colorless needle crystals (recrystallized from ethyl acetate-n-hexane) mp83-84.5 ° C 5-[(1-benzyl) -indol-3-yl]-
Methyl-3-benzyloxy-2-isobutyl-6-me
Toxipyrazine 1-oxide yellow oil ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.92 (6H, d, J = 6.5Hz), 2.12-2.31 (1H, m), 2.78 (2H, d, J = 7Hz), 3.88 (3H, s), 4.17 (2H, s), 5.26 (2H, s), 5.35 (2H, s), 6.98 (1H, s), 7.05-7.13 (3H, m) ), 7.17 (1H, dt, J = 7.5Hz, 1Hz), 7.23-7.40 (9H, m), 7.76 (1H, d, J = 7.5Hz) 3-benzyloxy -5-[(1-ethyl) -india
-3-l] -yl] -methyl-2-isobutyl-6-meth
Xypyrazine 1-oxide yellow oil ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.92 (6H, d, J = 6.5Hz), 1.42 (3H, t, J = 7.5Hz), 2.11-2.30 (1H, m), 2.78 ( 2H, d, J = 7Hz), 3.93 (3H, s), 4.11 (2H, q, J = 7.5Hz), 4.16 (2H, s), 5.38 (2H, s) , 6.97 (1H, s), 7.08 (1H, dt, J = 7.5Hz, 1Hz), 7.20 (1H, dt, J = 7.5Hz, 1Hz), 7.30-7. 43 (6H, m), 7.75 (1H, d, J = 7.5Hz) 3-benzyloxy-2-isobutyl-5-[(1-
Isobutyl) -indol-3-yl] -methyl-6-
Methoxypyrazine 1-oxide yellow oil ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.90 (6H, d, J = 6.5Hz), 0.92 (6H, d, J = 6.5Hz), 2.07-2.30 (2H, m), 2.78 ( 2H, d, J = 7Hz), 3.84 (2H, d, J = 7.5Hz), 3.93 (3H, s), 4.16 (2H, s), 5.37 (2H, s) , 6.94 (1H, s), 7.07 (1H, t, J = 7Hz), 7.18 (1H, t, J = 7Hz), 7.29 (1H, d, J = 7.5Hz) , 7.32-7.43 (5H, m), 7.75 (1H, d, J = 7.5Hz) 5-[(1-acetyl) -indol-3-yl]-
Methyl-3-benzyloxy-2-isobutyl-6-me
Toxipyrazine 1-oxide pale yellow oil ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.92 (6H, d, J = 6.5Hz), 2.13-2.31 (1H, m), 2.57 (3H, s), 2.80 (2H, d, J =). 7 Hz), 4.00 (2H, s), 4.11 (2H, s), 5.31 (2H, s), 7.13-7.33 (7H, m), 7.36 (1H, t) , J = 7.5 Hz), 7.66 (1 H, d, J = 7.5 Hz), 8.42 (1 H, d, J = 7.5 Hz) 3-isobutyl-6-[(1-methyl)- Indole
-3-yl] -methyl-5-methoxy-1,2-dihydride
Lopyrazin-2-one 4-oxide pale yellow needle crystals (recrystallized from ethanol) mp186-187 ° C 6-[(1-benzyl) -indol-3-yl]-
Methyl-3-isobutyl-5-methoxy-1,2-dihi
Synthesis of doropyrazin-2-one 4-oxide colorless needle crystals (recrystallized from ethanol) mp195-196 ° C 6-[(1-ethyl) -indol-3-yl] -me
Cyl-3-isobutyl-5-methoxy-1,2-dihydr
Synthesis of lopyrazin-2-one 4-oxide colorless needle crystal (recrystallized from ethanol) mp165-166 ° C 3-isobutyl-6-[(1-isobutyl) -india
Ol-3-yl] -methyl-5-methoxy-1,2-di
Synthesis of hydropyrazin-2-one 4-oxide colorless needle crystals (recrystallized from ethanol) mp 152-153 ° C 6-[(1-acetyl) -indol-3-yl]-
Methyl-3-isobutyl-5-methoxy-1,2-dihi
Synthesis of doropyrazin-2-one 4-oxide Pale yellow prismatic crystals (recrystallized from ethanol) mp219-220 ° C 3-[(1-tert-butoxycarbonyl) -indole
Lu-3-yl] -methyl-6-isobutyl-2-methoxy
Cypyrazine 1-oxide ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.94 (6H, d, J = 6.5Hz), 1.65 (9H, s), 2.03-2.20 (1H, m), 2.54 (2H, d, J =) 7 Hz), 3.98 (2H, s), 4.20 (2H, S), 7.2-7.3 (2H, m), 7.43 (1H, s), 7.66 (1H, d) , J = 7.5 Hz), 7.83 (1 H, s), 8.12 (1 H, brd, J = 7.5 Hz) 3-[(1-tert-butoxycarbonyl) -indole
Lu-3-yl] -methyl-6-isobutyl-2-methoxy
Ci-5-methylpyrazine 1-oxide ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.97 (6H, d, J = 6.5Hz), 1.65 (9H, s), 2.17-2.37 (1H, m), 2.52 (3H, s), 2 0.78 (2H, d, J = 7 Hz), 3.97 (3H, s), 4.16 (2H, s), 7.2-7.3 (2H, m), 7.45 (1H, s) ), 7.69 (1H, d, J = 7Hz), 8.10 (1H, brd, J = 8.5Hz) 3-[(1-tert-butoxycarbonyl) -indole
Lu-3-yl] -methyl-5-isobutyl-2-methoxy
Ci-6-methylpyrazine 1-oxide ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.97 (6H, d, J = 6.5Hz), 1.65 (9H, s), 2.06-2.23 (1H, m), 2.44 (3H, s), 2 .67 (2H, d, J = 7 Hz), 3.97 (3H, s), 4.18 (2H, s), 7.2-7.3 (2H, m), 7.42 (1H, s) ), 7.69 (1H, d, J = 7Hz), 8.10 (1H, brd, J = 8Hz) 3- (indol-3-yl) -methyl-6-isobu
Tyl-2-methoxypyrazine 1-oxide brown powder (diethyl ether-diisopropyl ether
More recrystallized) mp126-130 ° C ¹ H-NMR (250MHz, CDC _Three ) Δ: 0.95 (6H, d, J = 6.5Hz), 2.03-2.23 (1H, m), 2.53 (2H, d, J = 7Hz), 3.90 (3H, 3H, s), 4.28 (2H, s), 7.1-7.2 (3H, m), 7.34 (1H, d, J = 8Hz), 7.73 (1H, d, J = 8Hz) , 7.80 (1H, s), 8.10 (1H, brs) 3- (indol-3-yl) -methyl-6-isobu
Cyl-2-methoxy-5-methylpyrazine 1-oxy
De brown powder (from diisopropyl ether-n-hexane)
Recrystallization) mp 148 ° C (decomposition) 3- (indol-3-yl) -methyl-5-isobu
Cyl-2-methoxy-6-methylpyrazine 1-oxy
De light brown prismatic crystals (diisopropyl ether-n-
Recrystallized from xane) mp 107-108 ° C

Claims (1)

[Claims] 1. A general formula [Wherein R ¹ is (In the formula, R ⁶ has a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a phenyl lower alkoxycarbonyl group, a carboxy group, a benzoyl group or a lower alkyl group on the phenyl ring. A certain phenylsulfonyl group is shown.
-A- is a single bond, Alternatively, it represents a lower alkylene group. R ⁵ is a hydrogen atom, a cyano group, a phenyl lower alkoxy group, a carboxy group, a phenyl group, a lower alkoxycarbonyl group, a lower alkyl group,
A lower alkoxy group, a hydroxyl group or a halogen atom,
Indicates 1 or 2. ) Is shown. R ² represents a hydrogen atom, a lower alkyl group, a hydroxyl group or a lower alkoxy group. R ³ is a hydrogen atom, an oxo group, a halogen atom, a lower alkoxy group, a lower alkanoyloxy group, a lower alkyl group, a benzoyloxy group, a lower alkoxycarbonyloxy group,
A silyloxy group having 1 to 3 groups selected from the group consisting of a lower alkyl group and a phenyl group, a group consisting of a halogen atom, a lower alkyl group, a nitro group, an amino group and a lower alkoxy group as a substituent on the phenyl ring. A phenyl lower alkoxy group or a hydroxyl group which may have a group selected from R ⁴ is a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl lower alkyl group which may have a group selected from the group consisting of a hydroxyl group and a phenyl lower alkoxy group on the phenyl ring as a substituent, a cycloalkyl group, a cycloalkyl group. A lower alkyl group, an indolyl lower alkyl group or a lower alkenylene group is shown. The 1,2-position bond of the pyrazine skeleton represents a single bond or a double bond. ] The 2-hydroxypyrazine 4-oxide derivative represented by [In the formula, R ¹ , R ² , R ³ , R ⁴ and the 1,2-position bond of the pyrazine skeleton are the same as above. R ⁷ represents a lower alkyl group. ] 2-Alkoxypyrazine characterized by obtaining a 4-alkoxypyrazine 4-oxide derivative represented by
Process for producing 4-oxide derivative.