JPH03184975A - Production of nf-1616-904 substance - Google Patents

Abstract

PURPOSE:To enable production of the subject compound of high purity useful for autoimmune diseases, etc., in a high yield using a ready operation without using microorganisms by reducing a reaction product among a pyrazine derivative, indole and a salt thereof. CONSTITUTION:A pyrazine derivative of formula I (R<1> is phenyl lower alkyl; x is halogen, lower alkanesulfonyloxy, etc.) is reacted with indole and a salt thereof to obtain an indole derivative of formula II. The resultant indole derivative is reduced to obtain the objective NF-1616-904 substance of the formula III. By the above-mentioned reaction method, the objective substance of the formula III is obtained in an industrial scale without using the microorganism culture method and without using a complicated separation method.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing NF-1616-904 material, and more particularly to a method for producing NF-1616-904 material represented by formula U.

Prior art and its problems NF-1616-904 substance represented by the above formula (1) is a known compound (EP No. 0303250, 1989/
Sealabia minor 〇 FR-1561 was previously isolated from the soil of Iriomote Island, Okishu Prefecture (released on February 15).
(Thielavia a+1norOFR-156
1), [National Institute of Microbial Technology, Agency of Industrial Science and Technology, Ministry of International Trade and Industry,
Accession number “FERM
It was produced by hydrolyzing a substance isolated from BP-1980) as an intermediate. Since this method uses microorganisms, it is necessary to maintain constant culture conditions, and special and expensive equipment is required for mass production.
This method had the disadvantage that it was difficult to isolate the synthetic intermediate of -1616-904 in a good yield and with high purity.

Means for Solving the Problems As a result of intensive research, the inventors of the present invention have developed the NF-1616-904 substance of the above formula (1) without using microorganisms and without using complicated separation means. The present inventors have discovered a method for obtaining high yield and high purity on a large scale, and have completed the present invention.

That is, the present invention provides a compound of the general formula [wherein R1 has a group selected from the 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. Indicates a certain phenyl lower alkyl group. X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group.

] A pyrazine derivative represented by the general formula [wherein R1 is the same as above] obtained by reacting an indole or a salt thereof (3). ] This relates to a method for producing an NF-1616-904 substance represented by the formula, characterized by reducing an indole derivative represented by the following.

The NF-1616-904 substance represented by the above formula (1) has, for example, an inhibitory effect on superoxide (02-) released by stimulation from guinea pig macrophages, an antiproteinuric effect on Masugi nephritis, etc.
As a prophylactic and therapeutic agent for autoimmune diseases such as rheumatism, arteriosclerosis, ischemic heart disease, ischemic brain damage, liver failure, renal failure, etc. involving the above-mentioned superoxide radicals, and as a prophylactic and therapeutic agent for nephritis. It is useful in various clinical fields.

More specifically, each group shown in this specification is as follows.

Examples of the phenyl lower alkyl group which may have a group selected from the 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 include benzyl, 2-phenyl, ethyl,
1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1゜1-dimethyl-2-phenylethyl,
5-phenylpentyl, 6-phenylhexyl, 2-methyl3-phenylpropyl, 2-chlorobenzyl, 2-
(3-chlorophenyl)ethyl, 1-(4chlorophenyl)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-difluorophenyful)ethyl, 5-(3,5-dibromphenyl)pentyl, 6- (3,4,5 -)lichlorphenyl)hexyl, 4-methylbenzyl, 2-(2methylphenyl)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-(2,5dimethylphenyl)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-(3ethoxyphenyl)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-jethoxyphenyl)ethyl, 2-(3,4,5
-trimethoxyphenyl)ethyl, 1-(2,5-dimethoxyphenyl)ethyl, (2-chloro-4-methoxy)benzyl, 2-aminobenzyl, 1-(3-aminophenyl)ethyl, 1-(4- aminophenyl)propyl, 1-(2,3-diaminophenyl)butyl, 1(2
,3,4-1 riaminophenyl)pentyl, 1-(2
,4-diaminophenyl)hexyl, 2nitrobenzyl, 1-(3-nitrophenyl)ethyl, 1-(4-nitrophenyl)propyl, 1-(2,4-dinitrophenyl)butyl, 1-(2,4 ,6-4linitrophenyl)pentyl,1-(210rho-4-nitrophenyl)
A halogen atom as a substituent on the phenyl ring, such as a (3-methyl-4-amino)benzyl group, or
Alkyl that may have 1 to 3 groups selected from the group consisting of 6 straight-chain or branched alkyl groups, nitro groups, amino groups, and straight-chain or branched alkoxy groups having 1 to 6 carbon atoms. Examples include phenylalkyl groups which are linear or branched alkyl groups having 1 to 6 carbon atoms.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.

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

Examples of lower alkanesulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, and
Examples include ert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy groups, etc., and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-methylphenylsulfonyloxy, −
Examples of the aralkylsulfonyloxy group include substituted or unsubstituted arylsulfonyloxy groups such as nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylphenylsulfonyloxy groups. Examples include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyl primary , 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy, and other substituted or unsubstituted aralkylsulfonyloxy groups.

General formula (2) used as a starting material in the present invention
The pyrazine derivative of is produced by the method shown below.

[Reaction formula-1] ORI ORI (5)
(2) [R1 and X in the formula
is the same as above. ] In the case of compound (2) in which X represents a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group, the compound (5) and the general formula % formula % (6) [wherein R2 is a lower alkanesulfonyl group, Indicates an arylsulfonyl group or an aralkylsulfonyl group. Xl represents a halogen atom. ] It is manufactured by reacting with the compound represented by.

The reaction between the compound of general formula (5) and the compound of general formula (6) is generally carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of inert solvents that can be used include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride, ethers such as tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether, acetic acid, and acetic acid. Ethyl, acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide,
Examples include hexamethylphosphoric acid triamide. Basic compounds include 3 carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium, and sodium amide. , metal alcoholades 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,O)undecene-7(
DBU), 1,4-diazabicyclo(2,2゜2)octane (DABCO), and other organic bases.As the usage ratio of the compound of general formula (5) and the compound of general formula (6), is not particularly limited and may be appropriately selected within a wide range, but it is preferable to use at least an equimolar amount of the latter to the former, preferably about equimolar - 1.5 times the molar amount of the latter.

The reaction is usually carried out at about -78 to 100°C, preferably about 30 to 70°C, and generally for 30 to 30 minutes.
The reaction completes in about an hour.

In addition, in the case of compound (2) in which X represents a halogen atom, tetra-n butylammonium iodide, tetra-n Reacting a tetraalkylammonium halide such as butylammonium bromide, an alkali metal halide such as sodium iodide, or a halogenating agent such as a phase transfer catalyst such as 18-crown-6 in an appropriate solvent. It can also be obtained by

As the solvent used here, any of the solvents used in the reaction between compound (5) and compound (6) can be used. The amount of the halogenating agent to be used is preferably at least equimolar, preferably equimolar to twice the molar amount of the starting material. The reaction is usually carried out at 0 to 100°C, preferably at 0
It is carried out at around 70° C. and is generally completed in about 10 minutes to 5 hours.

The pyrazine derivative of compound (5) as a starting material can be produced, for example, by the method shown below.

6 [Reaction formula (7) (8) (5) [In the formula, R1 and Xl are the same as above. R3 represents a lower alkenyl group, a tetrahydropyranyl group, or a lower alkoxy lower alkyl group. R4 represents a phenyl lower alkyl group which may have a group selected from the 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. M represents a hydrogen atom or an alkali metal salt such as sodium or potassium. ] Compound (8) in which R3 is a tetrahydropyranyl group,
It is produced by reacting compound (7) with dihydropyran in the presence of an acid in a suitable solvent. Examples of acids used include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid;
- Organic acids such as toluenesulfonic acid can be exemplified. Examples of the solvent used include ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, polar solvents such as acetonitrile, and mixed solvents thereof. The amount of dihydropyran used is compound (7)
The amount should be at least equimolar, preferably equimolar to 5 times the molar amount. The reaction is usually carried out at -30 to 150°C
, preferably proceeding suitably at 0 to 100°C, and generally at 0 to 100°C.
．． It will be completed in about 5 to 5 hours.

Compound (8), in which R3 is a lower alkenyl group or a lower alkoxy lower alkyl group, has the same general formula as compound (7) (% formula %) [wherein R5 represents a lower alkenyl group or a lower alkoxy lower alkyl group]. R2 represents a halogen atom. ] It is manufactured by reacting with the compound represented by.

The reaction between compound (7) and compound (11) is carried out in a suitable solvent in the presence of a basic compound.

9 Examples of the solvent used here include water, ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, and esters such as methyl acetate and ethyl acetate. Examples include ketones such as acetone and methyl ethyl ketone, polar solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphoric triamide, and mixed solvents thereof. Basic compounds used include, for example, inorganic bases such as silver oxide, potassium fluoride, and sodium hydride, triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, dimethylaminopyridine, N-methylmorpholine, 4- Methylaminopyridine, 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. Compound (11) is usually used in an amount of at least equimolar, preferably equimolar -1 to compound (7).
It is preferable to use 0 times the molar amount.

The reaction is usually carried out at 0 to 150°C, preferably room temperature to 100°C.
The reaction is generally completed in about 0.65 to 80 hours.

The reaction between compound (8) and compound (9) is generally carried out in a suitable inert solvent in the presence or absence of a basic compound.

As the basic compound and solvent used here, any of the basic compounds and solvents exemplified in the reaction of compound (5) and compound (6) in Reaction Formula-1 above can be used.

Further, as the solvent, R40H (R4 is the same as above) may be used.

The amount of compound (9) to be used is at least equimolar, preferably equimolar to 7 times the molar amount of compound (8). The reaction is usually carried out at a temperature of 0 to 1150°C, preferably around 0 to 100°C, and is generally completed in about 10 minutes to 10 hours.

In addition, in the reaction system of the reaction, ammonium salts such as tetra-n-butylammonium bromide, phenyltriethylammonium chloride, 18-crown-6, benzo-18-crown-6, dibenzo-18-crown-
Phase transfer catalysts such as crown ethers such as 6 and dicyclohexano 18-crown-6,12-crown-4,15-crown-5 may be added.

The reaction between compound (10) and compound (11) or compound (8) and compound (11) is the reaction between compound (8) and compound (9).
) is carried out under the same conditions as the reaction.

In the case of compound (12) in which R3 is a lower alkoxy lower alkyl group, the reaction that leads compound (12) to compound (5) is carried out using a mineral acid such as hydrobromic acid or hydrochloric acid or an organic acid such as p-1 luenesulfonic acid. In a mixture of acid and a solvent such as water, methanol, ethanol, or isopropyl alcohol, the temperature is usually 0 to 150°C, preferably room temperature to
Compound (5) is produced by treating compound (12) at 120°C or by hydrolyzing compound (12).

This hydrolysis is carried out in a suitable solvent in the presence of an acid. Examples of solvents include water, lower alcohols such as methanol, ethanol, and isopropyl alcohol, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, polar solvents such as acetonitrile, and mixtures thereof. Examples include solvents and the like. Examples of acids include hydrochloric acid, sulfuric acid,
Examples include mineral acids such as hydrobromic acid, Lewis acids such as boron trifluoride, aluminum chloride, and boron tribromide, iodides such as sodium iodide and potassium iodide, and mixtures of the above Lewis acids and iodides. I can do it. The reaction is usually 0 to 15
Proceeding suitably at 0°C, preferably room temperature to 100°C,
Generally, the process is completed in about 0.5 to 15 hours.

In the case of compound (12) in which R3 is a tetrahydropyranyl group or a lower alkenyl group, compound (5) can be obtained by hydrolyzing this.

Any conventional hydrolysis reaction conditions can be applied to this hydrolysis reaction, specifically, in the presence of mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, organic acids such as acetic acid, aromatic sulfonic acids, etc. The reaction is carried out in water, alcohols such as methanol, ethanol and isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and ethylene glycol dimethyl ether, solvents such as acetic acid, or a mixed solvent thereof. The reaction is usually carried out at 0 to 200°C.
, preferably at room temperature to around 150°C, and generally at 0.
．． It will be completed in about 5 to 15 hours.

3 [Reaction Formula (13) (14) [In the formula, R1 and X2 are the same as above. R6 is a lower alkyl group, a lower alkanoyl group, a succinimyl group, a lower alkoxycarbonyl group, a thiazolidinyl group that may have a thio group as a substituent, a methyleneiminium group or group -8R7 (R7 is pyridyl group, thiazolidinyl group, lower alkyl group, cycloalkyl group, phenyl group or phenyl lower alkyl group)
shows.

M' represents an alkali metal such as sodium or potassium.

] The reaction for leading compound (13) to compound (14) is carried out in a suitable solvent in the presence of an oxidizing agent.

Examples of the oxidizing agent used here include peracids such as performic acid, permaleic acid, peracetic acid, and pertrifluoroacetic acid. Examples of solvents used include water,
Examples include organic acids such as formic acid, acetic acid, and trifluoroacetic acid, halogenated hydrocarbons such as chloroform and dichloromethane, and mixed solvents thereof. The amount of oxidizing agent used is compound (1
It is preferable to use at least an equimolar amount, usually a large excess amount, based on 3). The reaction is usually carried out at 0 to 150°C, preferably at 0
The process is carried out at around 100°C and generally takes about 1 to 15 hours to complete.

The reaction between compound (14) and compound (15) is a reaction that leads compound (16) to compound (17), which is conducted under the same conditions as the reaction between compound (8) and compound (9) in Reaction Formula-2 above. is carried out under the same conditions as the hydrolysis reaction of compound (12) in which R3 in Reaction Formula-2 is a tetrahydropyranyl group or a lower alkenyl group. Furthermore, in addition to acids, the reaction may be carried out using basic compounds such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, and the like.

A reduction method using a hydrogenation reducing agent is preferably used for the reduction reaction of compounds (16) and (17).

Examples of the hydrogenation reducing agent used here include lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, diborane, lithium borohydride, calcium borohydride, etc., and the amount used is usually For compound (16) or (17),
The amount should be at least equimolar, preferably equimolar to 5 times the molar amount.

Examples of solvents used include water, lower alcohols such as methanol, ethanol, and isopropyl alcohol, ethers such as tetrahydrofuran, dioxane, diethyl ether, and diglyme, and halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride. , acetonitrile, dimethylformamide, or a mixed solvent thereof. The reaction is usually carried out at -60 to 70°C,
It is preferably carried out at -30 to 50°C for about 10 minutes to 2
Completed in about 0 hours. Note that when aluminum hydride or diborane is used as the reducing agent, an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc. is preferably used. When diisobutylaluminum hydride is used, aromatic hydrocarbons such as benzene, toluene, and xylene may be used in addition to the above-mentioned ether solvents.

The reaction between compound (18) and compound (19) is carried out under the same conditions as the reaction between compound (8) and compound (11) in Reaction Formula-2 above.

9 [Reaction formula-4] (18) (20) OR” 0 (5)
(21) [In the formula, R1, X2 and R6 are the same as above. ] compound (18) to compound (20
) is the reaction that leads to the compound (16
) is carried out under the same conditions as the reaction leading to compound (17).

The reduction reaction of compounds (18) and (20) is carried out under the same conditions as the reduction reaction of compound (16) and compound 0 (17) in Reaction Formula-3 above.

The reaction between compound (21) and compound (19) is carried out under the same conditions as the reaction between compound (18) and compound (one) in Reaction Formula-3 above.

Compound (7) used as a starting material is produced, for example, by the method shown below.

1 [Reaction formula-5] (26) (27) (28) (29) 9 XI OR+ (7) [In the formula, R1, XI and X2 are the same as above. R8 represents a hydroxyl group, a phenyl lower alkoxy group, a tetrahydropyranyloxy group, a tri-lower alkylsilyloxy group, or a lower alkoxy lower alkoxy group. ] The reaction that leads compound (22) to compound (23) is generally called the Strecker method, for example, in water, ethers such as diethyl ether, tetrahydrofuran, dioxane, aqueous ammonia, etc., or a mixed solvent thereof, It can be obtained by reacting with an ammonium halide salt such as ammonium chloride and a metal cyanide such as sodium cyanide or potassium cyanide. The amounts of ammonium halide salt 3 and metal cyanide to be used are preferably at least equimolar, preferably equimolar to twice the molar amount of the compound (22). The reaction is usually O~
It is carried out at 150°C, preferably around 0 to 100°C,
Generally, the process is completed in about 5 to 80 hours.

The reaction between compound (23) and compound (24) is carried out according to a conventional amide bond forming reaction. The amide bond formation reaction can be carried out by various known methods, such as (a) mixed acid anhydride method, for example, a method in which carboxylic acid (24) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with amine (23). (b) Active ester method, for example, carboxylic acid (24) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and the amine (23) is reacted with this. Method; (c) Carbodiimide method, that is, a method in which amine (23) is condensed with carboxylic acid (24) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Other methods, For example, carboxylic acid (24
) is converted into carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and this is reacted with amine (23).
) under high pressure and high temperature, carboxylic acid (24)
amine (2
3) can be carried out by a method of reacting, etc.

In addition, carboxylic acid (24) is activated with a phosphorus compound such as triphenylphosphine or diethyl chlorophosphate,
This can be reacted with the amine (23), or the carboxylic acid (24) may be converted into an N-carboxyamino acid anhydride with phosgene or chloroformic acid trichloromethyl ester, and then reacted with the amine (23).

In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is obtained by the usual Schotten-Baumann reaction, and by reacting it with the amine (23) without isolation, the general formula Compound (25) is produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine, trimethylamine, pyridine,
Dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo(4,3,
03 nonene-5 (DBN), 1°8-diazabicyclo(5,4,O) undecene-7 (DBU), 1.4-
Diazabicyclo(2,2゜2)octane (DABCO)
and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate.

The reaction is carried out at about -20 to 100°C, preferably from 0 to 550°C for about 5 minutes to 10 hours, preferably from 5 minutes to 2
It will be done in about an hour. The reaction between the obtained mixed acid anhydride and the amine (23) takes about 5 minutes to 10 hours, preferably about 5 minutes to 1 hour at about -20 to 150°C, preferably 10 to 50°C. It is done. The above mixed acid anhydride is generally a solvent commonly used in this type of mixed acid anhydride method, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. , diethyl ether, dioxane, diisopropyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polarity such as 1゜1.3.3-tetramethylurea, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. The reaction is carried out in or in the absence of a suitable solvent or mixed solvent such as a solvent. The alkylhalocarboxylic acids used in the production of the mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate,
Examples include ethyl bromoformate and isobutyl chloroformate. The alkylhalocarboxylic acid is usually used in an amount of at least equimolar to the amine (23), preferably about 1 to 1.5 times the molar amount. The amount of carboxylic acid (24) to be used is usually at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the amine (23).

The active ester method shown in (b) above, for example when using N-hydroxysuccinimide ester, can be carried out in the presence or absence of a basic compound in a suitable solvent that does not affect the reaction. It will be done. As the basic compound, any of the basic compounds used in the Schotten-Baumann reaction can be used. Examples of solvents include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, dioxane, tetrahydrofuran, and dimethoxyethane. Examples include esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, and mixed solvents thereof. The reaction is carried out at 0-150°C, preferably 10-100°C.
It will be completed in 5 to 30 hours. The ratio of amine (23) and N-hydroxysuccinimide ester used is usually at least equimolar, preferably equimolar to twice the molar amount of compound (24).

Further, a condensing agent such as dicyclohexylcarbodiimide or carbonylimidazole may be added to the reaction system of the reaction.

Alternatively, amine (23) and carboxylic acid (24) can be combined into triphenylphosphine, triphenylphosphine-2,2'
-dipyridyl sulfide, diethyl 9 chlorophosphate, diphenylphosphinyl chloride, phenyl N-phenylphosphoramide chloridate,
The compound (
25) can be obtained.

As the basic compound used here, a wide variety of known ones can be used, and for example, in addition to the basic compounds used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, etc. can be mentioned. In addition to the solvents used in the mixed acid anhydride method, examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, pyridine, acetone, acetonitrile, etc., or a mixed solvent of two or more of the above solvents. can be mentioned.

The reaction is usually carried out at about -20 to 150°C, preferably around 0 to 100°C, and generally takes 5 minutes to 30 minutes.
The reaction completes in about an hour. Condensing agent and carboxylic acid (
The amount of 24) to be used is preferably at least equimolar, preferably equimolar to twice the molar amount of amine (23).

The reaction of leading compound (25) to compound (26) is carried out in acetic acid, usually at room temperature to about 150°C, preferably at room temperature to about 100°C.
The process is usually completed in about 1 to 40 hours at about 0°C.

The reaction between compound (26) and compound (19) is carried out under the same conditions as the reaction between compound (8) and compound (11) in Reaction Formula-2 above.

The reaction for leading compound (27) to compound (28) can be carried out by reacting with a nitrite metal salt such as sodium nitrite or potassium nitrite in the presence of an acid in a solvent such as water to obtain a diazonium salt, or by reacting with a nitrite metal salt such as acetonitrile. 4] with lower alkyl nitride compounds such as t-butyl nitride and isoamyl nitride in a solvent.

This diazonium salt is then heated to about 150 to 200°C or a copper halide such as cupric chloride, cupric bromide, cuprous chloride, cuprous bromide, etc. Mixtures of copper halides such as chloride-controlled cupric chloride, cuprous bromide-hydrobromic acid, chloride-controlled hydrochloric acid, hydrobromic acid, caralum iodide, hydrochloric acid and other acids and copper powder. The reaction is carried out in the presence of a compound at room temperature to about 150° C. for about 10 minutes to about 5 hours. Examples of acids used here include hydrochloric acid, hydrobromic acid, sulfuric acid, tetrafluoroboric acid, and hexafluorophosphoric acid.

The amount of acid and metal nitrite to be used is usually about the same mole to about 5 times the mole of the compound (27), preferably about 3 times the mole, and about at least about the same mole of the latter.
Preferably, the amount is about equimolar to 3 times the molar amount.

The amount of the copper halide to be reacted with the diazonium salt is usually at least about 2 to 5 times the mole of the compound (27), preferably about 5 times the mole of the compound (27).

The reaction for converting compound (28) into compound (29) is carried out in the presence or absence of a basic compound, in an appropriate solvent, and in the presence of a catalyst. Examples of the basic compound used here include organic bases such as triethylamine, trimethylamine, diisopropylamine, ethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBNSDBU, and DASCO. Examples of the solvent used include water, alcohols such as ethanol, methanol, and isopropyl alcohol, and mixed solvents thereof.

The catalyst used is Wilkinson Complex 3. The amount of the catalyst used is usually 0.1 to 1 times the weight of compound (28).

The reaction is usually carried out at room temperature to 200°C, preferably at room temperature to 1.
The process is completed in about 1 to 5 hours at around 50°C.

The reaction of leading the compounds (two) to compound (7) is carried out under the same conditions as the hydrolysis reaction of compound (12) in which R3 in Reaction Formula-2 is a tetrahydropyranyl group or a lower alkenyl group.

4 [Reaction formula-6] (30) (7) [In the formula, R1, Re and XI are the same as above. ] Compound (13
) or (31) is carried out under the same conditions as the reduction reaction of compound (16) or (17) in Reaction Formula-3 above.

The reaction for leading compound (13) to compound (31) is 5.
) is carried out under similar conditions to the reaction leading to

The reaction of leading compound (30) to compound (7) is carried out under the same conditions as the reaction of leading compound (27) to compound (28) in Reaction Formula-5 above.

Compound (13) used as a starting material is produced, for example, by the following method.

[Reaction formula-7] (24) (33) (34) OR+ (13) 6 [In the formula, R8, R6, R2 and R1 are the same as above. ] The reaction between compound (24) and compound (32) is carried out under the same conditions as the reaction between compound (23) and compound (24) in Reaction Formula-5 above.

The reaction of leading compound (33) to compound (34) is carried out under the same conditions as the reaction of leading compound (25) to compound (26) in Reaction Formula-5 above.

The reaction between compound (34) and compound (19) is carried out under the same conditions as the reaction between compound (8) and compound (11) in Reaction Formula-2 above.

Compound (18) used as a starting material is produced, for example, by the method shown below.

7 [Reaction formula-8] (24) (36) (37) (38) (18) 8 [In the formula, R8 and R6 are the same as above. ] Compound (24)
The reaction between compound (35) and compound (35) is carried out under the same conditions as the reaction between compound (23) and compound (24) in Reaction Formula-5 above.

The reaction of leading compound (36) to compound (37) is carried out under the same conditions as the reaction of leading compound (16) to compound (17) in Reaction Formula-3 above.

For the reaction leading to compound (37) and compound (38), the same conditions as for the reaction between compound (23) and compound (24) in Reaction Formula-5 above can be adopted, and in particular triphenylphosphine-2,2'-dipyridyl disulfide A method using a phosphorus compound such as is preferred.

The methylation reaction of compound (38) is produced by reacting compound (38) with a methylating agent in a solvent in the presence or absence of a basic compound. Examples of the methylating agent include sulfonic acid esters such as dimethyl sulfate, fluorosulfonic acid methyl ester, methanesulfonic acid methyl ester, and trifluoromethane tetrasulfonic acid methyl ester;
Examples include methyl halides such as trimethyloxonium tetrafluoroborate, diazomethane, and methyl iodide. Examples of solvents include lower alcohols such as methanol, ethanol, and propatool, ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol monomethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, benzene, Aromatic hydrocarbons such as toluene and xylene, esters such as methyl acetate and ethyl acetate,
Examples include ketones such as acetone and methyl ethyl ketone, polar solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphate triamide, and mixed solvents thereof. The basic compounds used include, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and sodium hydride, and alkalis such as metallic sodium and metallic potassium. metals,
Alkali metal alcoholades such as sodium ethylate and sodium methylate, triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine,
Examples include organic bases such as diisopropylethylamine, 4-methylaminopyridine, DBN, DBU, and DABCO.

The amount of the methylating agent to be used may be at least equimolar, preferably equimolar to about 5 times the molar amount of compound (38). The reaction is usually carried out at -30 to 150°C, preferably around -20 to 100°C, and at a temperature of 0. 5-20
It took about an hour.

In the method of the present invention, first the compound obtained above (
Compound 1 Compound (4) is obtained by reacting 2) with an indole derivative and a salt thereof, preferably a salt thereof. Salts of indole derivatives include alkali metal salts such as lithium, sodium, and potassium;
g X 1 (X + is the same as above), 5nR93 (R
9 represents a lower alkyl group. ), Z n X' (X
' is the same as above. ) etc. can be exemplified.

Preferred salts include alkali metal salts such as lithium, sodium, and potassium, ZnX', and the like.

This reaction is usually carried out in a suitable solvent. The solvents used here include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and diethylene glycol dimethyl ether, and halogenated hydrocarbons such as chloroform, dichloromethane, and carbon tetrachloride. etc. can be mentioned.

The reaction is usually carried out at -30 to 150°C, preferably 0 to 10°C.
The process is completed in about 10 minutes to 50 hours at around 0°C. The amount of indole and its salt to be used is preferably at least equimolar, preferably equimolar to 5 times the molar amount of compound (2).

In the present invention, the compound (4) thus obtained is then reduced. This reduction reaction can be carried out, for example, by catalytic hydrogenation in a suitable solvent in the presence of a catalyst.

Examples of solvents used include water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether, ethyl acetate, Examples include esters such as methyl acetate, aprotic polar solvents such as dimethylformamide, and mixed solvents thereof. Examples of the catalysts used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. The amount of catalyst used is generally 0.02 to 0.02 to compound (4).
It is best to use 3 times the amount. The reaction temperature is usually around -20~100°C, preferably around 0~80°C, and the hydrogen pressure is usually around 1~10°C.
Atmospheric pressure is preferred, and the reaction generally takes about 0.5 to 20 hours. A basic compound such as sodium hydroxide may be added to the reduction reaction system.

The target compound obtained in each step in this way is
It can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

Effects of the Invention According to the method of the present invention, the target NF-1616-904 substance represented by formula (1) can be obtained with high purity and good yield through simple operations without using microorganisms.

Example 4 Reference examples and examples are listed below.

Reference Example 1 25-28% ammonia water 110-1 51 g of ammonium chloride and 38 g of sodium cyanide are added to 290-100 g of water. 56 g of α-allyloxyacetaldehyde was added dropwise to this solution over 2 hours at room temperature. After dripping, 3
React for the same time and temperature, and then add 150ml of diethyl ether.
Add Q and react for 3 days. After the reaction is completed, the aqueous layer is extracted with diethyl ether. After washing with saturated brine, drying with magnesium sulfate, and then distilling off the solvent, 52 g of 3
-Allyloxy-2-aminopropionitrile is obtained.

Brown oil NMR (CDCJh) δ; 1.81 (2H,br), 3.62 (2H,d, J=5Hz), 3.86 (I
H, br), Kei 4.08 (2H, dt, J=6Hz, IHz) 5.2
3 (IH, ddd, J=10Hz.

3Hz, IHz), 5.30 (IH, ddd, J=17Hz.

3Hz, IHz), 5.88 (IH, dat, J=17Hz.

10Hz, 6Hz) Reference example 2 3-allyloxy-2-aminopropionitrile 52g
1α-Hydroxyiminoisocaproic acid 40K and N-
34.9 g of hydroxysuccinimide and 75 g of dioxane
0-, further added 59.7 g of N,N'-dicyclohexylcarbodiimide, and reacted at room temperature for 16 hours.

After the reaction is completed, N,N'-dicyclohexylurea is eliminated and dioxane in the reactor solution is concentrated. 800 mQ of ethyl acetate is added to the resulting residue, washed with an aqueous sodium bicarbonate solution, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: 40 vOk% ethyl acetate/n-hexane) to obtain 67 g of 3-allyloxy-2-(α
-Hydroxyiminoisocaproylamino)propionitrile is obtained.

White crystal NMR (CDCJ23) δ; 0.91 (6H, d, J = 7Hz), 2.03 (I
H,5ept, J=7Hz), 2.52 (2H,d,
J=7Hz), 3.65 (LH, dd, J=10Hz
, 4Hz) 3.75 (2H, dd, J=10Hz, 4
Hz) 4.10 (2H, dt, J=6Hz, IHz)
, 5.08 (LH, dt, J=9Hz, 4Hz), 5
．． 25 (IH, ddd, J=10Hz, 3Hz, IH
z), 5.32 (IH, ddd, J=17Hz, 37 Hz, 1Hz), 5.88 (IH, dat, J=17Hz, 10Hz,
3Hz), 7, 36 (LH, b rd, J = 9Hz), 7.
87 (IH, brs) Reference Example 3 22 g of 3-allyloxy-2-(α-hydroxyiminoisocaproylamino)propionitrile was dissolved in 220 g of acetic acid.
- was added and reacted by heating at 85°C for 1 hour. After the reaction, acetic acid was distilled off under reduced pressure, and the resulting residue was purified by Florisil (6
0-100 mesh) (eluent; 30vo, Q% ethyl acetate-n-hexane-60% ethyl acetate-n-hexane). After washing with diethyl ether, recrystallization from benzene yielded 5 g of 3-allyloxymethyl-2-amino-6-isobutyl-4,5-dihydropyrazine-5.
-one 1-oxide is obtained.

mp149-151°C 8 Pale yellow platelet crystal Reference example 4 3-allyloxymethyl-2-amino-6-isobutyl-4,5-dihydropyrazin-3-one 1-oxide 2
．． 00 g and 570 μm of potassium carbonate were dissolved in 25 μm of dimethylformamide, 1.05 μm of benzyl bromide was further added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction is completed, 200% of ethyl acetate is added to the reaction solution and washed with water. The aqueous layer is extracted twice with ethyl acetate 5011Q, combined with the previous ethyl acetate layer, and washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (eluent: 40voj 2% ethyl acetate/n-hexane). Recrystallized from n-hexane to give 1.57 g of 3-allyloxymethyl-2
-Amino-5-benzyloxy-6-isobutylpyrazine 1-oxide is obtained.

White fine needle crystals mp56.3-57.2°C Reference example 5 3-allyloxymethyl-2-amino-5-benzyloxy-6-isobutylpyrazine 1-oxide 300■
352 mg of cupric chloride, 173 ml of cuprous chloride and 3 ml of acetonitrile were added to the mixture, and 350 μl of isoamyl nitrite was added dropwise at room temperature. After completion of the dropwise addition, stir at room temperature for 20 minutes. After the reaction is completed, the product is purified by silica gel column chromatography (eluent: 20vo, 9% ethyl acetate-n-hexane). It was further purified by silica gel thin layer chromatography (developing solution: 20vo, O% acetic acid ethyl acetate-hexane) to obtain 115μ of 3-allyloxymethyl-5-benzyloxy-2-chloro-6-isobutylpyrazine 1- Get oxide.

5 white needles mp 34-35°C Reference example 6 3-allyloxymethyl-5-benzyloxy 2-chloro-6-isobutylpyrazine 200μ of 1-oxide, 195μ of diisopropylethylamine, 1 Wilkinson catalyst vop% water-ethanol 4 (2) was added, and the mixture was heated and reacted at 85 to 90°C for 3 hours. After distilling off the catalyst, 260 mg of 3-
Obtained as a mixture of (1-propenyl)oxymethyl-5-benzyloxy-2-chloro-6-isobutylpyrazine 1-oxide cis/trans-ca.

Colorless oil O NMR (CDCJ) 3) δ; 0.93 (IH, d, J=6.8Hz), 1.
56 (3H, dd, J=6.8, 1.5Hz)
, 1.61 (3H, dcl, J=6.8. 1.5
Hz), 2.23 (IH, 5ept, J=7Hz),
2.85 (2H, d, J=7Hz), 4.9
2 (IH, s ix, J=6Hz), 4.48
(IH, qui, J=6Hz), 4, 18 (2H
,s) ,4.88 (2H,s) ,6, 31
(IH, dq, J=12Hz, 1.5Hz
), 6.08 (IH, dq, J=6Hz, 1.
5Hz), 7.4 (5H, m) Reference Example 7 3-(1-propenyl)o2oxy-5-benzyloxymethyl-2-chloro6-isobutylpyrazine 1-oxide mixture obtained in Reference Example 6 2601I1 g Add 5 drops of methanol and 5 drops of concentrated hydrochloric acid to 1.5 at room temperature.
Time reacts. After the reaction is complete, neutralize with sodium hydrogen carbonate and concentrate the solvent. The obtained residue was subjected to silica gel thin layer chromatography (developing solution; 30 v o j; j%
After purification with ethyl acetate-〇-hexane), recrystallization from diethyl ether-n-hexane yielded 151■ 3-hydroxymethyl-5-benzyloxy-2-chloro-6.
-isobutylpyrazine 1-oxide is obtained.

White plate-like crystals mp85.0-88.0°C Reference Example 8 α-hydroxyiminoisocaproic acid 19.5g and N
-To 16.2 g of hydroxysuccinimide was added 200- of dioxane, and to this was added 29.1 g of N,N'-dicyclohexylcarbodiimide and 50- of dioxane.
Drop the solution.

After dropping, stir at room temperature for 20 minutes. Furthermore, 22 g of ethyl α-amino-α-cyanoacetate and 1.64 g of 4-dimethylaminopyridine were added, and the mixture was heated and reacted at 50° C. for 14 hours. After N,N'-dicyclohexylurea is removed, dioxane as a p-liquid is distilled off. Add 500 d of ethyl acetate to the residue, add 150 d of water to 110% hydrochloric acid, and add 250 d of ethyl acetate.
-1 Wash with 150 g of water, 300 g of saturated sodium bicarbonate water, and 250 g of saturated brine, and dry with magnesium sulfate. The solvent was distilled off and 35 g of 2-cyano-2-
Ethyl (α-hydroxyiminoisocaproylamino)acetate is obtained.

Brown oil NMR (CDC, Q3) δ; 0.91 (6H, d, J = 7Hz), 1.36 (3
H, t, J=7Hz), 2.04 (IH, sep
t, J=7Hz), 0.5 2.53 (2H, d, J=7Hz), 4.36
(2H, q, J=7Hz), 5.51 (IH,
d, J=8Hz), 7.49 (IH,br
d.
Heat the reaction at 0°C for 1 hour.

After acetic acid is distilled off, toluene is added to the residue and distilled off, and this process is repeated several times. The residue was purified by silica gel column chromatography (eluent: 50voR% ethyl acetate-0-hexane) and recrystallized from ethanol to give 21.
3 g of 2-amino-3-ethoxycarbonyl-6-isobutyl-4,5-dihydropyrazin-5-one 1-oxide are obtained.

mp179-181°C 5 Yellow needle-like crystals Reference example 10 2-amino-3-ethoxycarbonyl-6-isobutyl-4,5-dihydropyrazin-5-one 1-oxide 1
．． 0Of, 1.18 g of potassium hydrogen carbonate (powder), 20-dimethylformamide and 932 μm of benzyl bromide were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into 50% of ethyl acetate and diluted with 30% of water.
Wash twice. The aqueous layer is extracted twice with ethyl acetate.

After washing twice with 30ml of water together with the ethyl acetate above,
Dry with magnesium sulfate. The solvent was distilled off, the resulting residue was recrystallized from ethanol, and 1.06 g of 2
-Amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylpyrazine 1-oxide is obtained.

Pale yellow fine needle crystals mpH 4.5-115.5°C 6 Reference Example 11 2-Amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylvirazine 1-oxide 670■
Add dichloromethane 14- to -35°C. A solution of 1 mol of diisobutylaluminum hydride in n-hexane was added dropwise over 5 minutes. After completion of the dropwise addition, reaction was carried out at -30°C for 40 minutes, water 1- was added, and the mixture was returned to room temperature.

Furthermore, 2% hydrochloric acid 30- was added, extracted with dichloromethane,
Dry with magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent;
After purification with 70vol 1% methanol-dichloromethane), recrystallization from benzene yielded 385μ of 2-amino-
5-benzyloxy-3-hydroxymethyl-6-isobutylvirazine 1-oxide is obtained.

mp129.0-131.3°C Pale yellow fine needle crystals Reference example 12 2-Amino-5-benzyloxy-3-hydroxymethyl-6-isobutylvirazine 1-oxide 2.17 g
, 2.89 g of cupric chloride, 1.42 g of cuprous chloride, and 22 g of acetonitrile are added, and the mixture is stirred at room temperature for 10 minutes. Furthermore, 2.88% of isoamyl nitrite is added at room temperature, and although the reaction is exothermic (40 to 45°C), the mixture is stirred for 30 minutes without cooling.

Add 60% of 2% hydrochloric acid and 50% of diethyl ether to the reaction mixture.
- and separate the liquids. The aqueous layer is extracted twice with 50% diethyl ether, combined with the diethyl ether layer, and dried over magnesium sulfate.

Silica gel column chromatography obtained by distilling off the solvent (eluent; 50vo, l; 1% ethyl acetate-n
-Hexane), recrystallized from diethyl ether-〇-hexane, and 1.73 g of 5-benzyloxy-
2-chloro-3-hydroxymethyl-6-isobutylvirazine 1-oxide 7 is obtained.

mp 85.0 to 88.0°C Pale yellow plate-like crystals Reference Example 13 5-benzyloxy-2-chloro-3-hydroxymethyl-6-isobutylvirazine 65μ of 1-oxide, 2-dichloromethane and 40μ of dihydrobilane To the mixture was added 4 parts of 1)-) luenesulfonic acid hydrate at room temperature, and the mixture was stirred at the same temperature for 1 hour. After washing the reaction mixture with saturated sodium hydrogen carbonate, the solvent was distilled off and the resulting residue was subjected to silica gel thin layer chromatography (developing solution: 2
Purified with 5voD% ethyl acetate-n-hexane),
78■ 3-benzyloxy-6-chloro-2-isobutyl-5-(2-tetrahydropyranyloxymethyl)
Pyrazine 1-oxide is obtained.

Colorless oil NMR (CDCJ23) δ; q8 0.93 (6H, d, J=7Hz), 1, 5-1
．． 9 (6H, m), 2.23 (1H, 5
ept, J = 7Hz), 2.85 (2H, d, J =
7Hz), 3.56 (IH, m), 3.94
(LH, m), 4.64 (LH, ABq, J=12
Hz), 4.83 (IH, ABq, J=12H2)
, 4.83 (IH, brt, J=3Hz), 5.4
2 (2H,s), 7.4 (5H,m) Reference Example 14 3-benzyloxy-6-chloro-2-ynbutyl-5
-(2-Tetrahydropyranyloxymethyl)pyrazine 1-oxide 170cm, tetrabutylammonium bromide 72cm, dimethylformamide 1. 5ntQ
, benzyl alcohol at 230 μC and 6% sodium hydride at 42.5 μC and stirred at room temperature for 40 minutes.

Diethyl ether was added to the reaction mixture, washed several times with water, and then dried over 0.0 magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel thin layer chromatography (developing solution;
Purified with 10vo, 0% ethyl acetate-benzene),
136 .mu. of 2,5-dibenzyloxy-6-isobutyl-3-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide are obtained.

Colorless oil NMR (CDCJ23) δ; 0.94 (6H, d, J=7Hz), 1, 45-1.
9 (6H, m), 2.28 (IH, sep t, J=7Hz), 2.
85 (2H, d, J-7Hz), 3.48 (LH,
m), 3.88 (IH, m), 4.43 (LH,
ABq, J=11Hz), 4.62 (IH, ABq,
J=11Hz), 4.72 (IH, brt, J=3H
z), 5.33 (2H, ABq, J=10Hz), 1 5.38 (2H, s), 7.3 to 7.5 (IOH, m) Reference example 15 Methanol 55μ2 160% sodium hydride 11■,
Tetrabutylammonium bromide 22μD, dimethylformamide 650μD and 3-benzyloxy-6-
A mixture of 65 μl of chloro-2-isobutyl-5-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide is stirred at room temperature for 1 hour. Diethyl ether is added to the reaction mixture, washed several times with water, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel thin layer chromatography (developing solution: 30VOW% ethyl acetate-n-hexane) to obtain 50μ of 3-benzyloxy-2-isobutyl-6-medoxy. 5-(
2-tetrahydropyranyloxymethyl)pyrazine 1
- Obtain oxide.

2 Colorless oil NMR (CDCj:I3) δ; 0.93 (6H, d, J=7Hz), 1, 5-1.
9 (6H, m), 2.22 (LH, 5ept, J=7Hz), 2.82
(2H, d, J=7Hz), 3, 55 (IH, m
), 3. 94 (IH, m), 4.05 (3H,
S), 4.53 (IH, ABq,, J=11Hz), 4.7
6 (LH, ABq, J=11Hz), 4.83 (L
H, brt, J=3Hz), 5.39 (2H,s)
, 7.4 (5H, m) Reference Example 16 3-benzyloxy-2-isobutyl-6-medoxy-5-(2-tetrahydropyranyloxymethyl)pyrazine 80 1-oxide, 1-methanol and 1-1 concentrated hydrochloric acid
The dropwise mixture is stirred at room temperature for 30 minutes. Diethyl ether was added to the reaction mixture, washed with saturated aqueous sodium bicarbonate solution, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel thin layer chromatography (developing solution: 50v
After purification with 2% ethyl acetate/n-hexane), recrystallization from diethyl ether-n-hexane yielded 63■ 3-benzyloxy-5-hydroxymethyl-2-isobutyl-6-medoxypyrazine 1- Get oxide.

White needle crystals mp68.0-69.2°C Reference Example 17 3-benzyloxy-5-hydroxymethyl-6-medoxy 2-isobutylpyrazine 1-oxide 210■
, dichloromethane 2- and triethylamine 184μρ
52μ of mesyl chloride was added to the mixture at 0°C,
Stir at the same temperature for 30 minutes. Diethyl ether is added to the reaction mixture, washed with water, and dried over magnesium sulfate. Solvent 4: The residue obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: 50VOJu 1% ethyl acetate/n-hexane) to obtain 260μ of 3-benzyloxy-2-isobutyl-6-medoxy. 5-Mesyloxymethylpyrazine 1-oxide is obtained.

Colorless oil NMR (CDCJ23) δ; 0.94 (6H, d, J-7Hz), 2.23 (I
H,5ept, J=7Hz), 2.84 (2H,d,
J=7Hz), 3.01 (3I(,,s), 4.0
9 (3H,s), 5.24 (2H,s), 5.3
8 (2H, s), 7.4 (5H, m) Reference Example 18 3-benzyloxy-2-isobutyl-6-medoxy 5-methyloxymethylpyrazine 1-oxide 140
(2) A mixture of 200 mg of benzene 7- and tetrabuty5 ammonium iodide was stirred at room temperature for 1.5 hours. After the reaction was completed, silica gel column chromatography (eluent; 30vo
J) % ethyl acetate-n-hexane) and recrystallized from diethyl ether-n-hexane to obtain 15 mg of 3-benzyloxy-5-iodomethyl-2-isobutyl-6-medoxyvirazine l-oxide.

mp78.3-79.5°C White needle crystals 1 reference example 2-amino-5-benzyloxy-3-ethoxycarbonyl-6-isobutylpyrazine 1-oxide 0.49
30% hydrogen peroxide in solution in 15 g of acetic acid 4. 5IL
Cl was added, and the mixture was heated and stirred at 90°C for 75 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing three times with saturated brine, sequentially with sodium thiosulfate aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine, dry over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: dichloromethane) to obtain 0.23 g of 3-benzyloxy-5-ethoxycarbonyl-2=isobutyl-6-nitropyrazine 1 - Obtain oxide.

Colorless oil NMR (CDCD3) δ: 0.94 (6H, d, J = 6.5Hz), 1.40
(3H, t, J=7Hz), 2.23-2.37 (I
H, m), 2.87 (2H, d, J=7Hz), 4.45 (2
H, q, J = 7 Hz), 5.54 (2 H, s), 7.32 to 7.52 (5 H, m) Reference Example 20 A 20 mQ solution of chloroform 7 containing 1.50 g of 70% hydrogen peroxide solution was cooled with water. Under stirring, maleic anhydride 1.50
After returning to room temperature, a chloroform solution 6 of 0.53 g of 2-amino-5-benzyloxy-3-ethoxycarbonyl 6-isobutylpyrazine 1-oxide was added, and the mixture was stirred at room temperature for 12 hours. After eliminating the precipitated crystals, the furnace solution is washed with a 5% aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution in this order. After drying over magnesium sulfate, the solvent was distilled off to obtain 0.59 g of 3-benzyloxy-5-ethoxycarbonyl-2-isobutyl-6-nitropyrazine 1-oxide.

Colorless oil NMR (13 to CDC) δ; 0.94 (6H, d, J=6.5Hz), 1.40
(3H, t, J=7Hz), 2, 23~2.37 (I
H, m), 2,87 (2H, d, J = 7Hz), 8 4.45 (2H, q, J = 7Hz), 5.5
4 (2H,s), 7, 32-7. 52 (5H, m) Reference Example 21 3-benzyloxy-5-ethoxycarbonyl-2-inbutyl-6-nitropyrazine 1-oxide 10.0
1.44 g of sodium methoxide is added to 200 g of anhydrous methanol solution, and the mixture is stirred at room temperature for 1.5 hours.

After making the mixture acidic by adding IN-hydrochloric acid 28- while cooling with water, the mixture was extracted with ethyl acetate, washed successively with saturated brine and saturated aqueous sodium bicarbonate solution, and dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (eluent: chloroform), and 5.
20 g of 3-benzyloxy-2isobutyl-6-medoxy-5-methoxycarbonylpyrazine 1-oxide are obtained.

Pale yellow oil 9 NMR (j3 to CDC) δ; 0, 94 (6H, d, J=6.5Hz)
, 2, 16-2.40 (IH, m), 2.85
(2H, d, J=7Hz) , 4.00 (
3H,s), 4. 10 (3H,s), 5.41
(2H,s), 7.30-7. 50 (5H, m) Reference Example 22 3-benzyloxy-2-isobutyl-6-medoxy 5-methoxycarbonylpyrazine 1-oxide 0.7
IN sodium hydroxide solution in 1 g of methanol 15-4
．． 1- was added, and the mixture was heated and stirred at room temperature for 14 hours. After diluting the reaction solution with water, it is extracted with dichloromethane. The aqueous layer was made acidic with 6.0% IN-hydrochloric acid under water cooling, and extracted with ethyl acetate. After washing twice with saturated brine, drying over magnesium sulfate, and distilling off the solvent under reduced pressure, 0.62 g of 6-benzyloxy-5-isobutyl-3-methoxy pyrazine-2-carboxylic acid 4-oxide was obtained.

NMR (CDCu3) δ; 0.97 (6H, d, J=6.5Hz), 2.18~
2.36 (IH, m), 2.88 (2H, d, J=7Hz), 4.14 (3
H,s), 4.71 (IH,s), 5.41 (2
H,s), 7, 28-7. 50 (5H, m) Reference Example 23 6-benzyloxy-5-isobutyl-3-methoxypyrazine-2-carboxylic acid 0.62 g of 4-oxide and 0.26 g of triethylamine in anhydrous tetrahydrofuran solution 10-0 with ethyl chlorocarbonate A solution of 18- in anhydrous tetrahydrofuran 2- is added dropwise at -15 to -10°C using a stirrer. After completion of the dropwise addition, the mixture was stirred at -10 to -5°C for 2 hours, and then a solution of 0.22 g of sodium borohydride in anhydrous dimethylformamide was added dropwise at -5°C, followed by stirring at room temperature for 113.5 hours. Excess sodium borohydride was decomposed by adding 7.0% of 1N hydrochloric acid under water cooling, extracted with ethyl acetate, washed three times with saturated brine, dried with magnesium sulfate, and then the solvent was distilled off under reduced pressure. , the obtained residual liquid was subjected to silica gel column chromatography (eluent; n-
Purify with hexane: ethyl acetate = 3: 1),
3-benzyloxy-5-hydroxymethyl-2-isobutyl 6-methoxypyrazine 1-oxide is obtained.

mp68. Cl-69, 2°C White needle-like crystals Reference example 24 3-benzyloxy-2-isobutyl-6-medoxy 5-methoxycarbonylpyrazine 1-oxide 12,
2.4 mg of lithium borohydride was added to 11 TIQ of anhydrous diethyl ether solution of 5.5 cm, and the mixture was stirred and refluxed for 6 hours under an argon atmosphere. Under water cooling, add 0.0% of 1N hydrochloric acid to the reaction mixture.
2- is added, further diluted with water, and extracted with ethyl acetate. After washing with saturated saline,
The residue obtained by drying magnesium sulfate and distilling off the solvent was purified by thin layer chromatography (developing solution: dichloromethane:methanol - 40:1) to obtain 3.5μ of 3-benzyloxy-5-hydroxymethyl. -6-Medoxy 2
-isobutylpyrazine 1-oxide is obtained.

mp68.0-69.2°C White needle crystals Reference example 25 Diethylaminomalonate hydrochloride 17. Water and 7.0 g of sodium hydrogen carbonate are added to a suspension of 5 g of dichloromethane and 7.0 g of sodium bicarbonate, and after 20 minutes, the dichloromethane layer is separated and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain diethylaminomalonate as a colorless oil. N,
15.7 g of N'-dicyclohexylcarbodiimide was added and stirred at room temperature for 16 hours. After filtration, ethyl acetate was added to the residue obtained by distilling off the filtrate, and 10% hydrochloric acid, water,
After washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution in that order, drying with magnesium sulfate, and distilling off the solvent, 29.
19 g of diethyl N-(2-hydroxyimino-4-methylpentanoyl)aminomalonate are obtained.

Colorless oil NMR (CDC, C!3) δ; 0.91 (6H, d, J=6.5Hz), 1.30
(6H, t, J=7°0Hz), 2.04 (IH, m
), 2.52 (IH, d, J=7.5Hz), 4.30
(4H, m), 5.21 (IH, d, J=7.0Hz), 7.76
(IH,brd,J=7.0Hz), 4 8.71 (IH,s) Reference Example 26 29.19g of diethyl N-(2-hydroxyimino-4methylpentanoyl)aminomalonate in 200% ethanol solution 2.8g of sodium hydroxide and 200g of water
After adding the solution and stirring at room temperature for 4 hours, the reaction solution was neutralized with 10% hydrochloric acid and concentrated. The residue was acidified with 10% hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, dried over magnesium sulfate, and the solvent was distilled off.
3. C) g N-(2-hydroxyimino-4-methylpentanoyl)aminomalonic acid monoethyl ester is obtained.

Pale yellow solid NMR (CDCJ23) δ; 0.91 (6H, d, J=6.5Hz), 1.32
(3H, d, I-7,0Hz), 2, 56 (LH,
m), 5 2.52 (2H, d, J=8.0Hz), 4.31
(2H, q, J=7.0Hz), 5.26
(LH, d, J-7, 5Hz), 7.85 (I
H,brd,J=7.5Hz) Reference Example 27 2. 15.2 g of 2'-dipyridyl disulfide is added, followed by 18.1 g of triphenylphosphine, and the mixture is stirred at room temperature for 1.5 hours.

After washing with a 2.5% aqueous potassium hydrogen sulfate solution and saturated brine, extraction with a saturated aqueous sodium hydrogen carbonate solution and washing with ethyl acetate. Acidify with concentrated hydrochloric acid, and remove the precipitated crystals.
．． 28 g of 5-ethoxycarbonyl-6-hydroxy-
2-Inbutylpyrazine 3-one 1-oxide is obtained.

Yellow solid 6mp 153-155°C Reference Example 28 5-Ethoxycarbonyl-6-hydroxy-2isobutylpyrazin-3-one A suspension of 5.45 g of 1-oxide in chloroform was heated to -15°C with a solution of diazomethane in diethyl ether. Slowly drip an equal amount. After 30 minutes, 0.5-acetic acid was added to the reaction solution, and after being left at room temperature for 30 minutes, the solvent was distilled off. 30 mQ chloroform was added to the resulting residue, dissolved under heat, and diisopropyl Ether 200- is gradually added to crystallize. Collect the precipitated product. Repeat this operation once and add 3.10g (7
) 5-ethoxycarbonyl-2-isobutyl-6-medoxyvirazin-3-one 1-oxide is obtained.

Pale yellow solid mp 153-155°C Reference example 29 7 5-ethoxycarbonyl-2-isobutyl-6methoxypyrazin-3-one 1-oxide 926, 0-chlorobenzyl chloride 0.66 and potassium carbonate 950
After stirring the dimethylformamide 20IILcl suspension of (2) at room temperature for 16 hours, the reaction solution was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. After distilling off the solvent, 1
．． 82 g of 3-(2-chlorobenzyloxy)-5-ethoxycarbonyl-2-isobutyl-6-methoxypyrazine 1-oxide are obtained.

Pale yellow oily NMR (CDCjlJ3) δ; 0.94 (6H, d, J = 6.5Hz), 1.45
(3H, t, J='7.0Hz), 2, 25 (IH,
m), 2.85 (2H, d, J=7.0Hz), 4.10
(3H, s), 4.45 (2H, q, J=7.0Hz), Q 5, 52 (2H, s), 7.26-7. 58 (4H, m) Reference Example 30 3-(2-chlorobenzyloxy)-5-ethoxycarbonyl-2-isobutyl-6-methoxypyrazine 1-
Add 2.0 ILQ of 1N sodium hydroxide to a 20-methanol solution of 1.82 g of oxide, stir at room temperature for 2 hours, dilute the reaction solution with ethyl acetate, extract with IN aqueous sodium hydroxide solution, and add concentrated hydrochloric acid. Make it acidic. After extraction with ethyl acetate and washing with saturated brine, drying with magnesium sulfate and distilling off the solvent, 1.09 g of 3-(2-chlorobenzyloxy)-5-carboxy-2-isobutyl-6-
Methoxypyrazine 1-oxide is obtained.

Pale yellow oily NMR (CDCJ23) δ; 0.95 (6H, d, J-6,5Hz), 2, 27
(LH, m), 9 2.89 (2H, d, J=7.0H2), 4.
14 (3H, s), 5.53 (2H, s),
7.30-7.53 (4H, m) Reference Example 31 3-(2-chlorobenzyloxy)-5-carboxy-
2-isobutyl-6-medoxypyrazine 1-oxide 1
．． 09 g, tetrahydrofuran 10-, triethylamine 0.42 uQ, ethyl chlorocarbonate 0.29-1, sodium borohydride 340 mg and dimethylformamide 6- to give 524 m
g of 3-(2-chlorobenzyloxy)-5-hydroxymethyl-2-isobutyl-6-medoxypyrazine 1-
Get oxide.

Colorless oil NMR (CDCj73) δ; 0.95 (6H, d, J = 6.5Hz), 2.24
(IH, m), 0 2.86 (2H, d, J = 7.0Hz), 3.0
7 (LH, t, J=5.5Hz), 4, 05
(3H, s), 4.69 (2H, d, J=5.5Hz), 7, 2
6-7. 32 (2H, m), 7.41-7.
50 (2H, m) Reference Example 32 3-(2-chlorobenzyloxy)-5-hydroxymethyl-2-isobutyl-6-methoxypyrazine 1-oxide 421■, dichloromethane 10d,) ethylamine 0.24mG and methyl chloride Using 0.106-
2-chlorobenzyloxy)-2-isobutyl-5-mesyloxymethyl-6-methoxypyrazine 1-oxide is obtained.

Colorless oil NMR (CDCJh) δ; 0.95 (6H, d, J = 6.5Hz), 2, 2
5 (IH, m), 2.85 (2H, d, J=7.0Hz), 3.0
6 (3H,s), 4.11 (3H,s), 5
．． 27 (2H,s), 5.48 (2H,s)
, 7, 26-7.33 (2H, m), 7.40-7
．． 51 (2H, m) Reference Example 33 3-(2-chlorobenzyloxy)-2-isobutyl-
5-Mesyloxymethyl-6-methoxypyrazine 1-
Using 520 μg of oxide, 10-benzene, tetrabutylammonium, and 630 mg of iodide, the same procedure as in Reference Example 18 was used to obtain 492 mg of 3-(2-chlorobenzyloxy)-5-iodomethyl-2-isobutyl-6. -Methoxypyrazine 1-oxide is obtained.

Pale yellow oily NMR (CDCu3) δ; 1 0.94 (6H, d, J=6.5Hz), 2.
23 (IH, m), 2.81 (2H, d, J=7.0Hz), 4.16
(3H, s), 4.45 (2H, s), 5.
47 (2H, s), 7, 25-7. 32 (2H, m), 7.3
8 to 7.54 (2H, m) Reference Example 34 5-Ethoxycarbonyl-2-isobutyl-6-medoxypyrazin-3-one A solution of 932 mg of 1-oxide in methanol (21) and IN sodium hydroxide aqueous solution (10) was added. After stirring at room temperature for 4 hours, the precipitated crystals were acidified with 10% hydrochloric acid, dissolved in chloroform-methanol, and the solvent was distilled off to give 830 μ of 5-carboxy-2.
-isobutyl-6-medoxypyrazin-3-one 1-
Get oxide.

White solid 3 NMR (CDCJh) δ; 0.98 (6H, d, J=6.5Hz),
2.28 (IH, m), 2.84 (2H, d, J=7.0Hz), 4
, 04 (3H, s) Reference Example 35 5-Carboxy-2-isobutyl-6-medoxyvirazin-3-one 1-15% in a solution of 730% of 1-oxide and 1.0% of triethylamine in 20% of tetrahydrofuran
0.70 ml of ethyl chlorocarbonate was added at °C, and after stirring at the same temperature for 2 hours, 330 cm of lithium borohydride was added, followed by stirring at room temperature for 18 hours. Add 10% hydrochloric acid 5- to the reaction solution, and dilute with ethyl acetate using a stirrer. After drying with magnesium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (eluent; 10VO
,G! % methanol-chloroform) to give 4
67 lbs of 2-isobutyl-45-hydroxymethyl-6-medoxypyrazin-3-one 1-oxide are obtained.

Pale yellow oil NMR (CDCJI;!3) δ; 0.95 (6H, d, J=6.5Hz), 2.22
(LH, m), 2.77 (2H, d, J=7.0Hz), 3.97
(3H,s), 4.70 (2H,s) Reference Example 36 2-isobutyl-5-hydroxymethyl-6methoxyvirazin-3-one 50.1mg of 1-oxide, 40μD of benzyl bromide and 61μD of potassium carbonate A suspension of tetrahydrofuran 20--hexamethylphosphoric acid triamide 8- is stirred for one day at room temperature. The reaction wave was diluted with ethyl acetate, washed with water, and dried with magnesium sulfate. The residue obtained by evaporating the solvent was purified by thin layer chromatography (developing solution: ethyl acetate: n-hexane = 2:1) and recrystallized from diethyl ether-n-hexane. 1 ■ 3-benzyloxy-5-hydroxymethyl-2-isobutyl-6-methoxypyrazine 1
- Obtain oxide.

White acicular mp68.0-69.2°C Example 1 3-benzyloxy-5-iodomethyl-2-isobutyl-6-methoxypyrazine 1-oxide10. Omg
and 300 μk of toluene to a mixture of 8.2 μl of indole
and 3.7 μm of 60% sodium hydride were added, and the mixture was stirred at room temperature for 14 hours. Diethyl ether was added to the reaction mixture, dried over magnesium sulfate, and then the solvent was distilled off. The obtained residue was purified by silica gel thin layer chromatography (developing solution: 50 voJ: i% ethyl acetate-n-hexane) and recrystallized from diethyl ether-〇-hexane to give 7.7μ of 3-benzyl Oxy-5-08(3-indolylmethyl)-2-isobutyl-6-methoxypyrazine 1-oxide is obtained.

mp139.6-141.9℃ White prismatic Example 2 3-benzyloxy-5-iodomethyl-2-isobutyl-6-methoxypyrazine To 13 mg of 1-oxide was added 400μ of toluene (and 14.2μ of indole,
12 mg of potassium t-butoxide are added at <0>C. Gradually raise the temperature and stir at room temperature for 3 hours. After treatment in the same manner as in Example 1, 8.5 mg of 3-benzyloxy-5-(
3-indolylmethyl)-2-isobutyl-6-methoxypyrazine 1-oxide is obtained.

mp139.6-141.9℃ White prismatic Example 3 Indole 117mg bis-[tri-n-7 butyltin(IV)] ((Bu3Sn)20) 320
(1) and toluene 2- were added, and the mixture was heated under reflux for 3 hours.

Water is removed using a Dean-Stark device. A 200 μm sample was taken from this reaction solution and 3-benzyloxy-5-
iodomethyl-2-isobutyl-6methoxypyrazine
In addition to an 800 μm toluene solution of 20 μm of 1-oxide,
The reaction is heated at 80 to 85°C for 14 hours. After treatment in the same manner as in Example 1, 14.5μ of 3-benzyloxy-5
-(3-indolylmethyl)-2-isobutyl-6-methoxypyrazine 1-oxide is obtained.

mp139.6-141.9°C White prismatic Example 4 Indole 117cm, tetrahydrofuran 1- and 1.
46 mole butyl lithium n-hexane solution 685 μB
and stirred at room temperature for 80 minutes.

Furthermore, 136 cm of zinc chloride was added and stirred at the same temperature for 1 hour. After distilling off the tetrahydrofuran, toluene 2- is added to the reaction solution, and 300 μm balls are taken from the reaction solution. 70 μg of 20 μm of 3-benzyloxy-5-iodomethyl-2-isobutyl-6-medoxypyrazine 1-oxide
Add to 0 μm toluene solution and stir at room temperature for 30 minutes.

Work-up was performed in the same manner as in Example 1 to obtain 17.7 μ of 3-benzyloxy-5-(3-indolylmethyl)-2-isobutyl-6-methoxypyrazine 1-oxide.

mp139.6-141.9°C White prismatic Example 5 3-benzyloxy-5-mesyloxymethyl-2-isobutyl-6-methoxypyrazine 1-oxide 8.8
300 mg of toluene to a mixture of 8.2 mg and indole
Add μD and 3.7 μ of 60% sodium hydride, and stir at room temperature for 16 hours.

Work-up was performed in the same manner as in Example 1 to obtain 5.8 μ of 3-benzyloxy-5-(3-indolylmethyl)-2-isobutyl-6-methoxypyrazine 1-oxide.

mp139.6-141.9°C White prismatic Example 6 3-benzyloxy-5-(3-indolylmethyl)-
2-isobutyl-6-medoxypyrazine 1-oxide 5
．． 0■, ethanol 500 μD and 10% Pb-C2
Add (2) and hydrogenate at room temperature for 30 minutes. After the reaction is complete, the catalyst is removed and the furnace liquid is concentrated. The obtained residue was subjected to silica gel thin layer chromatography (developing solution: 7voi1
% methanol-chloroform) and recrystallized from methanol-chloroform to obtain 3.9 mg of 5-(3-
Indolylmethyl)-2-isobutyl-6methoxypyrazin-3-one 1-oxide'j (substance NF-1616-904) is obtained.

mp 222-224°C Pale yellow prismatic example 170 μm of sodium hydride is added to a 20-kg solution of Findol in 498 μm of toluene and heated at 110° C. for 30 minutes. After cooling, 3-(2-chlorobenzyloxy)-2-isobutyl-5-iodomethyl-6-methoxypyrazine
Add a 10-toluene solution of 492 mg of 1-oxide,
Stir for 2 days at room temperature. After diluting with ethyl acetate, washing with water and drying with magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane = 1:5) to obtain 334.6 μm of 3-(2-chlorobenzyloxy)-
5-(3-indolylmethyl)-2-isobutyl-6-
Methoxypyrazine 1 oxide is obtained.

01 LJU Pale yellow oily NMR (CDC1) 3) δ; 0.92 (6H, d, J=6.5Hz), 2, 22
(LH, m), 2.80 (2H, d, J=7.0Hz), 4.18
(2H,s), 5.49 (2H,s), 7.07~
7.76 (8H, m), 7.78 (IH, d, J=8.0Hz), 8.19
(IH, brs) Example 8 3-(2-chlorobenzyloxy)-5-(3-indolylmethyl)-2-isobutyl-6-mexipyrazine 1-oxide 250°5■ ethanol 10- and I
10% Pb-C20 in a suspension of N sodium hydroxide 1-
mg was added, and hydrogenation was carried out at room temperature for 4 hours. The catalyst is thrown off the coast and the furnace liquid is distilled off. Recrystallization from methanol-dichloromethane yielded 128 μ of 5-(3-indolylmethyl)02 -2-isobutyl-6-nodoxypyrazin-3one 1
-oxide (NF-1616-904 substance) is obtained.

m　p　222～224°C pale yellow prismatic (that's all) 03 Procedural amendment (0 button) May 9, 1990 Display of incidents 1990 Patent Application No. 21936 name of invention Manufacturing method of NF-1616-904 substance person who makes corrections Relationship to the case Patent applicant Otsuka Pharmaceutical Co., Ltd.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a substituent on the phenyl ring selected from the group consisting of a halogen atom, a lower alkyl group, a nitro group, an amino group, and a lower alkoxy group. Indicates a phenyl lower alkyl group that may have a group. X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. ] General formula obtained by reacting a pyrazine derivative represented by the following with indole or its salt ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is the same as above. ] A method for producing the NF-1616-904 substance represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ characterized by reducing the indole derivative represented by.