JPH0834775A - Production of tetrazol compound - Google Patents

Abstract

PURPOSE:To efficiently obtain the subject compound without using a highly dangerous azide compound as a reagent by reacting a nitrile with hydrogen sulfide and reacting the reaction product with hydrazine and a nitrous acid compound. CONSTITUTION:Anitrile of the formula R<1>CN (R<1> is 4-oxo-4H-benzopyranyl substitutable with hydroxy, a halogen, nitro, etc., or phenyl substitutable with X; X is phenyl, an alkyl, an alkoxy, a halogen, etc.) is reacted with hydrogen sulfide to give a thioamide of the formula R<1>C(=S). Then the compound is reacted with hydrazine to give an amidrazone of the formula R<1>C(=NH)NHNH2, which is reacted with a nitrous acid compound of the formula YONO (Y is H, a metal or a 1-20C alkyl) to give a tetrazole compound of the formula. The tetrazole compound is useful as an intermediate for medicines.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 2- (5-tetrazolyl) -4-oxo-without using an azide compound as a reagent.
The present invention relates to a method for industrially advantageously producing 4H-benzopyrans and 5-aryl-tetrazoles.

[0002]

2. Description of the Related Art 2- (5-Tetrazolyl) -4-oxo-4H-benzopyrans and 5-aryl-tetrazoles are useful as intermediates for medicines and the like. However, azide compounds are known to react with water or acid to generate toxic and explosive hydrogen azide, and to easily generate heavy metals and explosive salts. There is.

[0003]

As described above, the process using the azide compound has a problem in safety especially on an industrial scale.

[0004]

Means for Solving the Problems
As a result of intensive studies to solve the problems, nitrile compound
Via thioamide or amidrazone compound
Safe without using azide compounds as reagents
That the tetrazole compound can be produced efficiently
The present invention was found by further finding out various investigations. . You
That is, the present invention is represented by the general formula (1) R¹CN (1) (wherein R¹Is an optionally substituted 4-oxo-4
May be substituted with H-benzopyranyl group or X
Indicates a phenyl group. Where 4-oxo-4H-benzopy
The substituent of the ranyl group may be substituted with a phenyl group.
Alkoxy group, hydroxy group, halogen atom, nitro
Group or R²CONH, where R ²Is alkyl
Group, phenyl group, phenylalkyl group, alkylpheny
Group, alkoxyphenyl group, phenylalkylphenyl
Group or phenylalkoxyphenyl group,
And alkyl or alkoxy has 1 to 20 carbon atoms.
It X of the optionally substituted phenyl group is substituted with Y
Optionally substituted phenyl group, alkyl group, alkoxy
Group, halogen atom, phenylalkyl group or phenyl
Represents an alkoxy group, where alkyl or alkoxy
Shi has 1 to 20 carbon atoms. Optionally substituted
Y of the phenyl group is a hydroxyl group which may be protected by a protecting group.
An alkyl group having 1 to 20 carbon atoms substituted with, protected
Number of carbon atoms substituted with an amino group which may be protected by a group
Substituted with 1 to 20 alkyl groups or halogen atoms
An optionally substituted alkyl group having 1 to 20 carbon atoms, or
Substituted with a hydroxyl group which may be protected by a protecting group
Alkoxy group having 1 to 20 carbon atoms or halogen atom
An alkoxy having 1 to 20 carbon atoms which may be substituted with
Represents a group. ) Reacts nitriles with hydrogen sulfide
The general formula (2) R¹C (= S) NH₂ (2) (In the formula, R¹Has the same meaning as above. )
Thioamides were obtained, followed by hydrazine or its salts
By reacting the compound of the general formula (3) R¹C (= NH) NHNH₂ (3) (In the formula, R¹Has the same meaning as above. )
After obtaining an amidrazone or a salt thereof, a compound represented by the general formula (4) YONO (4) (Y is a hydrogen atom, a metal atom, or a C 1-20
Indicates an alkyl group. ) Reacted with nitrite compounds
General formula (5) characterized by(In the formula, R¹Has the same meaning as above. )
Method for producing tetrazole compound.

After reacting a thioamide represented by the general formula (2) with hydrazine or a salt thereof to obtain an amidrazone represented by the general formula (3) or a salt thereof, the amide is represented by the general formula (4). A method for producing a tetrazole compound represented by the general formula (5), which comprises reacting with a nitrous acid compound.

A tetrazole compound represented by the general formula (5), which comprises reacting an amidrazone represented by the general formula (3) or a salt thereof with a nitrite compound represented by the general formula (4). Manufacturing method.

R^{1 '}C (= S) NH₂ (2^') (Where R is^{1 '}Is an optionally substituted 4-oxo-4
May be substituted with H-benzopyranyl group or X
Indicates a phenyl group. Where 4-oxo-4H-benzopy
The substituent of the ranyl group may be substituted with a phenyl group.
Alkoxy group, hydroxy group, halogen atom, nitro
Group or R^{2 '}CONH, where R ^{2 '}Is alkyl
Group, phenyl group, phenylalkyl group, alkylpheny
Group, alkoxyphenyl group, phenylalkoxyphene
Represents a nyl group, where alkyl or alkoxy is charcoal.
The prime numbers are 1 to 5. Phenyl group which may be substituted
X of is a phenyl group which may be substituted with Y.
Y of the phenyl group which may be substituted is protected by a protecting group.
From 1 carbon atom which is substituted with an optional hydroxyl group
Substituted with 20 alkyl groups or halogen atoms
Optionally an alkyl group having 1 to 20 carbon atoms, or a protecting group
1 carbon atom substituted with an amino group which may be protected by
To 20 protected by an alkyl group or protecting group
Alkyl having 1 to 20 carbon atoms substituted with a hydroxyl group
It may be substituted with a coxy group or a halogen atom.
An alkoxy group having 1 to 20 carbon atoms is shown. )
Thioamides.

An amidrazone represented by the general formula (3 ′) R ^{1 ′} C (═NH) NHNH ₂ (3 ′) (wherein R ^{1 ′} has the same meaning as described above) or a salt thereof.

The present invention will be described in detail below. Examples of the protective group for the hydroxyl group in the definition of R ¹ in the general formula of the present invention include the followings. Aliphatic acyl groups such as acetyl, propionyl, pentylyl, halogen atoms such as chlorine atom, bromine atom, methyl, ethyl,
A benzyl group which may be substituted with an alkyl group such as propyl or butyl or an alkoxy group such as methoxy, ethoxy, propoxy or butoxy, a trimethylsilyl group, a triethylsilyl group, a dimethylphenylsilyl group, a dimethylbenzylsilyl group or methyldibenzylsilyl. Group, tribenzylsilyl group, dimethylbutylsilyl group, methyldiphenylsilyl group, triphenylsilyl group, trialkylsilyl group, dialkylphenylsilyl group, alkyldiphenylsilyl group, triphenylsilyl group, aralkyldialkylsilyl group, diaralkyl It is an alkylsilyl group or a triaralkylsilyl group, and such a phenyl group or aralkyl group may be substituted with a halogen atom, an alkyl group, an alkoxy group or the like. Furthermore, a tetrahydropyranyl group, a tetrahydrofuranyl group,
Ethers such as a 1- (alkoxy) ethyl group such as ethoxyethyl and propoxyethyl. As the amino-protecting group, those usually used as amino-protecting groups are used, and the following are exemplified. Methyl carbamate group, 2,2,2-trichloroethyl carbamate group, 1,1-dimethyl-2-chloroethyl carbamate group, cyclobutyl carbamate group, 1-adamantyl carbamate group, 8-quinolyl carbamate group, tershaributoxy carbamate group Groups such as carbamate groups, methoxymethyl groups such as alkoxymethyl groups, N-diphenylphosphinyl groups, N-dimethylthiophosphinyl groups such as phosphinyl groups, 2,4,6-trimethylbenzenesulfonyl groups, toluenesulfonyl groups And sulfonyl groups such as trifluoromethylsulfonyl group and methanesulfonyl group. Further, the amino group is an imidazolyl ring,
Examples thereof include those having a heterocyclic ring such as a benzimidazole ring, a purine ring, a pyrimidine ring and a triazole ring.

First, the step of reacting nitriles (1) with hydrogen sulfide to obtain thioamide (2) will be described.
Specific examples of the nitriles (1) used in this reaction include, for example, 5-hydroxy-2-cyano-4-oxo-4H-benzopyran and 6-chloro-2-cyano-4-.
Oxo-4H-benzopyran, 2-cyano-4-oxo-4H-benzopyran, 8- [4- (4-phenylbutoxy) benzoyl] amino-2-cyano-4-oxo-
4H-benzopyran, 8-nitro-2-cyano-4-oxo-4H-benzopyran, 5-methoxy-2-cyano-4-oxo-4H-benzopyran, 5-ethoxy-2
-Cyano-4-oxo-4H-benzopyran, 5-pentoxy-2-cyano-4-oxo-4H-benzopyran, 5-benzyloxy-2-cyano-4-oxo-4
H-benzopyran, 8-acetylamino-2-cyano-
4-oxo-4H-benzopyran, 8-propionylamino-2-cyano-4-oxo-4H-benzopyran,
8-nonanoylamino-2-cyano-4-oxo-4H
-Benzopyran, 8-benzoylamino-2-cyano-
4-oxo-4H-benzopyran, 8- (4-methoxybenzoyl) amino-2-cyano-4-oxo-4H-
Benzopyran, 8- (4-butoxybenzoyl) amino-2-cyano-4-oxo-4H-benzopyran, 6-
[4- (4-phenylbutoxy) benzoyl] amino-
2-cyano-4-oxo-4H-benzopyran, 6-nitro-2-cyano-4-oxo-4H-benzopyran,
8-Nitro-6-chloro-2-cyano-4-oxo-4
Nitriles having a 4-oxo-4H-benzopyranyl group such as H-benzopyran, 8-nitro-6-bromo-2-cyano-4-oxo-4H-benzopyran, 2-chlorobenzonitrile, 3-chlorobenzonitrile, 4-chlorobenzonitrile, 2-bromobenzonitrile, 3-
Bromobenzonitrile, 4-bromobenzonitrile, 2
-Fluorobenzonitrile, 3-fluorobenzonitrile, 4-fluorobenzonitrile, 2-methylbenzonitrile, 3-methylbenzonitrile, 4-methylbenzonitrile, 2-butylbenzonitrile, 3-butylbenzonitrile, 4-butyl Benzonitrile, 2-benzylbenzonitrile, 3-benzylbenzonitrile, 4-benzylbenzonitrile, 2-methoxybenzonitrile,
3-methoxybenzonitrile, 4-methoxybenzonitrile, 2-propoxybenzonitrile, 3-propoxybenzonitrile, 4-propoxybenzonitrile, 2-
Butoxybenzonitrile, 3-butoxybenzonitrile, 4-butoxybenzonitrile, 2-benzyloxybenzonitrile, 3-benzyloxybenzonitrile,
4-benzyloxybenzonitrile, 2-cyano-1,
1'-biphenyl, 2-cyano-4'-methyl-1,
1'-biphenyl, 2-cyano-4'-chloromethyl-
1,1'-biphenyl, 2-cyano-4'-methoxymethyl-1,1'-biphenyl, 2-cyano-4'-ethyl-1,1'-biphenyl, 2-cyano-4'-butyl-1 , 1'-biphenyl, 2-cyano-4'-octyl-1,1'-biphenyl, 2-cyano-4'-hydroxymethyl-1,1'-biphenyl, 2-cyano-4'-
(2-hydroxy) ethyl-1,1′-biphenyl, 2
-Cyano-4 '-(4-hydroxy) butyl-1,1'
-Biphenyl, 2-cyano-4 '-(8-hydroxy)
Octyl-1,1'-biphenyl, 2-cyano-4'-
Methoxymethyl-1,1'-biphenyl, 2-cyano-
4 '-(2-methoxy) ethyl-1,1'-biphenyl, 2-cyano-4'-(4-methoxy) butyl-1,
1'-biphenyl, 2-cyano-4 '-(8-methoxy) octyl-1,1'-biphenyl, 2-cyano-
4'-benzyloxymethyl-1,1'-biphenyl,
2-cyano-4'-aminomethyl-1,1'-biphenyl, 2-cyano-4 '-(2-amino) ethyl-1,
1'-biphenyl, 2-cyano-4 '-(4-amino)
Butyl-1,1'-biphenyl, 2-cyano-4'-
(8-Amino) octyl-1,1′-biphenyl, 2-
Cyano-4 '-(N-methylamino) methyl-1,1'
-Biphenyl, 2-cyano-4 '-(2-methylamino) ethyl-1,1'-biphenyl, 2-cyano-4'
-(Benzyloxycarbonylamino) methyl-1,
1'-biphenyl, 2-cyano-4 '-(2-benzyloxycarbonylamino) ethyl-1,1'-biphenyl, 2-cyano-4'-(tertiarybutoxycarbonylamino) methyl-1,1'- Biphenyl, 2-cyano-4 '-(2-tert-butoxycarbonylamino) ethyl-1,1'-biphenyl, 2-cyano-4'
-Bromomethyl-1,1'-biphenyl, 2-cyano-
4 '-(2-bromo) ethyl-1,1'-biphenyl,
2-cyano-4'-dichloromethyl-1,1'-biphenyl, 2-cyano-4'-trichloromethyl-1,1 '
-Biphenyl, 2-cyano-4'-dibromomethyl-
1,1'-biphenyl, 2-cyano-4'-tribromomethyl-1,1'-biphenyl, 2-cyano-4'-methoxy-1,1'-biphenyl, 2-cyano-4'-chloromethoxy -1,1'-biphenyl, 2-cyano-
Examples thereof include nitriles having an aryl group such as 4 '-(2-chloro) ethoxy-1,1'-biphenyl.

The hydrogen sulfide used in this reaction includes, for example, hydrogen sulfide gas and hydrogen sulfide water, and the amount thereof used is usually 1 to 50 mole times the nitriles (1). This reaction is usually carried out in the presence of a base, and examples of such a base include diethylamine, triethylamine, tributylamine, pyridine and 2-methyl-5.
-Organic amines such as ethylamine can be mentioned, and the amount thereof is usually 0.01 to 10 mol times with respect to the nitriles. A solvent is usually used in this reaction, and as the solvent, hydrocarbons such as benzene, toluene and hexane, halogenated hydrocarbons such as dichloromethane, dichloroethane and chlorobenzene, nitrated hydrocarbons such as nitrobenzene and nitromethane, Ethers such as diethyl ether and tetrahydrofuran, amides such as dimethylformamide, alcohols such as methanol and ethanol, and mixtures thereof are used, and the amount thereof is usually 1 to 200 times by weight that of nitriles.

The reaction temperature is usually -50 to 150 ° C, preferably -50 to 100 ° C, and the completion of the reaction can be easily confirmed by an analytical means such as liquid chromatography. The reaction can be terminated by the disappearance of). After completion of the reaction, the thioamides (2) can be isolated from the organic solvent, but can also be used in the next step without isolation.

Next, the step of reacting the thioamides (2) with hydrazine or a salt thereof to obtain an amidrazone (3) or a salt thereof will be described. Examples of the thioamides (2) used in this reaction include 5-hydroxy-2-thiocarbamoyl-4-oxo-4H-benzopyran, 6-chloro-2-thiocarbamoyl-4-oxo-4H-benzopyran, and 2 -Thiocarbamoyl-4-oxo-4H-benzopyran, 8- [4- (4-phenylbutoxy) benzoyl] amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-nitro-2-
Thiocarbamoyl-4-oxo-4H-benzopyran,
5-methoxy-2-thiocarbamoyl-4-oxo-4
H-benzopyran, 5-ethoxy-2-thiocarbamoyl-4-oxo-4H-benzopyran, 5-pentoxy-2-thiocarbamoyl-4-oxo-4H-benzopyran, 5-benzyloxy-2-thiocarbamoyl-4
-Oxo-4H-benzopyran, 8-acetylamino-
2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-propionylamino-2-thiocarbamoyl-
4-oxo-4H-benzopyran, 8-nonanoylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8-benzoylamino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8- (4- Methoxybenzoyl) amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 8- (4-butoxybenzoyl) amino-2-thiocarbamoyl-4-oxo-4
H-benzopyran, 8- [4- (4-phenylbutoxy) benzoyl] amino-2-thiocarbamoyl-4-
Oxo-4H-benzopyran, 6- [4- (4-phenylbutoxy) benzoyl] amino-2-thiocarbamoyl-4-oxo-4H-benzopyran, 6-nitro-2
-Thiocarbamoyl-4-oxo-4H-benzopyran, 8-nitro-6-chloro-2-thiocarbamoyl-
Thioamide having 4-oxo-4H-benzopyranyl group such as 4-oxo-4H-benzopyran, 8-nitro-6-bromo-2-thiocarbamoyl-4-oxo-4H-benzopyran, benzthioamide, 2-chlorobenz Thioamide, 3-chlorobenzthioamide, 4-chlorobenzthioamide, 2-bromobenzthioamide, 3
-Bromobenzthioamide, 4-bromobenzthioamide, 2-fluorobenzthioamide, 3-fluorobenzthioamide, 4-fluorobenzthioamide, 2-butylbenzthioamide, 3-butylbenzthioamide,
4-butylbenzthioamide, 2-benzylbenzthioamide, 3-benzylbenzthioamide, 4-benzylbenzthioamide, 2-methoxybenzthioamide, 3
-Methoxybenzthioamide, 4-methoxybenzthioamide, 2-propoxybenzthioamide, 3-propoxybenzthioamide, 4-propoxybenzthioamide, 2-butoxybenzthioamide, 3-butoxybenzthioamide, 4-butoxybenzthioamide, 2-benzyl Oxybenzthioamide, 3-benzyloxybenzthioamide, 4-benzyloxybenzthioamide, 2-thiocarbamoyl-1,1'-biphenyl, 2
-Thiocarbamoyl-4'-methyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-chloromethyl-
1,1'-biphenyl, 2-thiocarbamoyl-4'-
Methoxymethyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-ethyl-1,1'-biphenyl, 2-
Thiocarbamoyl-4'-butyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-octyl-1,1 '
-Biphenyl, 2-thiocarbamoyl-4'-hydroxymethyl-1,1'-biphenyl, 2-thiocarbamoyl-4 '-(2-hydroxy) ethyl-1,1'-biphenyl, 2-thiocarbamoyl-4' -(4-Hydroxy) butyl-1,1'-biphenyl, 2-thiocarbamoyl-4 '-(8-hydroxy) octyl-1,1'-
Biphenyl, 2-thiocarbamoyl-4'-methoxymethyl-1,1'-biphenyl, 2-thiocarbamoyl-
4 '-(2-methoxy) ethyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-(4-methoxy) butyl-1,1'-biphenyl, 2-thiocarbamoyl-
4 '-(8-methoxy) octyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-benzyloxymethyl-1,1'-biphenyl, 2-thiocarbamoyl-
4'-aminomethyl-1,1'-biphenyl, 2-thiocarbamoyl-4 '-(2-amino) ethyl-1,1'
-Biphenyl, 2-thiocarbamoyl-4 '-(4-amino) butyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-(8-amino) octyl-1,1'-biphenyl, 2-thio Carbamoyl-4 '-(N-methylamino) methyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-(2-methylamino) ethyl-1,
1'-biphenyl, 2-thiocarbamoyl-4 '-(benzyloxycarbonylamino) methyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-(2-benzyloxycarbonylamino) ethyl-1,1 ' -Biphenyl, 2-thiocarbamoyl-4 '-(tertiarybutoxycarbonylamino) methyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-(2-tertiarybutoxycarbonylamino) ethyl-1,1 ' -Biphenyl, 2-thiocarbamoyl-4'-bromomethyl-
1,1'-biphenyl, 2-thiocarbamoyl-4'-
(2-bromo) ethyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-dichloromethyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-trichloromethyl-1,1'-biphenyl, 2-thiocarbamoyl-
4'-dibromomethyl-1,1'-biphenyl, 2-thiocarbamoyl-4'-tribromomethyl-1,1'-
Biphenyl, 2-thiocarbamoyl-4'-methoxy-
1,1'-biphenyl, 2-thiocarbamoyl-4'-
Chloromethoxy-1,1'-biphenyl, 2-thiocarbamoyl-4 '-(2-chloro) ethoxy-1,1'-
Examples thereof include thioamide having an aryl group such as biphenyl.

The hydrazine used in this reaction is
Usually, anhydrous hydrazine, hydrazine aqueous solution, and the like,
The amount used is usually 1 to 20 mol times the thioamides (2). A solvent is usually used in this reaction, and examples of the solvent include hydrocarbons such as benzene, toluene and hexane, dichloromethane, dichloroethane,
Examples include halogenated hydrocarbons such as chlorobenzene, nitrated hydrocarbons such as nitrobenzene and nitromethane, ethers such as diethyl ether and tetrahydrofuran, amides such as dimethylformamide, alcohols such as methanol and ethanol, and mixtures thereof. The amount used is usually 3 to 200 times by weight that of the thioamides (2).

The reaction temperature is usually -50 to 150 ° C, preferably -50 to 100 ° C, and the completion of the reaction can be confirmed by liquid chromatography or the like. After confirming the completion of the reaction, the amidrazones (3) can be obtained from an organic solvent, but can also be used in the next step without isolation.

Next, the step of reacting an amidrazone (3) or a salt thereof with a nitrite compound (4) to obtain a tetrazole compound (5) will be described. Examples of the amidrazones used in this reaction include 2- (5-hydroxy-4-oxo-4H-benzopyranyl) -amidrazone, 2- (6-chloro-4-oxo-4H-benzopyranyl) -amidrazone, 2- (4-oxo-4H-benzopyranyl) -amidrazone, 2- [8- {4- (4
-Phenylbutoxy) benzoyl} amino-4-oxo-4H-benzopyranyl] -amidrazone, 2- (8-
Nitro-4-oxo-4H-benzopyranyl) -amidrazone, (5-methoxy-4-oxo-4H-benzopyran-2-yl) amidrazone, (5-ethoxy-4-
Oxo-4H-benzopyran-2-yl) amidrazone, (5-pentoxy-4-oxo-4H-benzopyran-2-yl) amidrazone, (5-benzyloxy-
4-oxo-4H-benzopyran-2-yl) amidrazone, (8-acetylamino-4-oxo-4H-benzopyran-2-yl) amidrazone, (8-propionylamino-4-oxo-4H-benzopyran-2- Yl) amidrazone, (8-nonanoylamino-4-oxo-4H-benzopyran-2-yl) amidrazone,
(8-benzoylamino-4-oxo-4H-benzopyran-2-yl) amidrazone, (8- (4-methoxybenzoyl) amino-4-oxo-4H-benzopyran-2-yl) amidrazone, (8- (4 -Butoxybenzoyl) amino-4-oxo-4H-benzopyran-2
-Yl) amidrazone, (6- [4- (4-phenylbutoxy) benzoyl] amino-4-oxo-4H-benzopyran-2-yl) amidrazone, (6-nitro-4
-Oxo-4H-benzopyran-2-yl) amidrazone, (8-nitro-6-chloro-4-oxo-4H-benzopyran-2-yl) amidrazone, (8-nitro-
6-bromo-4-oxo-4H-benzopyran-2-yl) amidrazone, etc., an amidrazone having a 4-oxo-4H-benzopyranyl group, 2-chlorobenzamidrazone, 3-chlorobenzamidrazone, 4-chlorobenzamide Razone, 2-bromobenzamido razone, 3
-Bromobenzamidrazone, 4-bromobenzamidrazone, 2-fluorobenzamidrazone, 3-fluorobenzamidrazone, 4-fluorobenzamidrazone, 2-methylbenzamidrazone, 3-methylbenzamidrazone, 4- Methylbenzamidrazone, 2-butylbenzamidrazone, 3-butylbenzamidrazone, 4-butylbenzamidrazone, 2-benzylbenzamidrazone, 3-benzylbenzamidrazone, 4
-Benzylbenzamidrazone, 2-methoxybenzamidrazone, 3-methoxybenzamidrazone, 4-methoxybenzamidrazone, 2-propoxybenzamidrazone, 3-propoxybenzamidrazone, 4-propoxybenzamidrazone, 2- Butoxybenzamidrazone, 3-butoxybenzamidrazone, 4-butoxybenzamidrazone, 2-benzyloxybenzamidrazone, 3-benzyloxybenzamidrazone,
4-benzyloxybenzamidrazone, (1,1'-
Biphenyl-2-yl) -amidrazone, (4'-methyl-1,1'-biphenyl-2-yl) -amidrazone, (4'-chloromethyl-1,1'-biphenyl-2
-Yl) -amidrazone (4'-methoxymethyl-1,
1'-biphenyl-2-yl) -amidrazone, (4 '
-Ethyl-1,1'-biphenyl-2-yl) -amidrazone, (4'-butyl-1,1'-biphenyl-2-
Yl) -amidrazone, (4'-octyl-1,1'-
Biphenyl-2-yl) -amidrazone, (4'-hydroxymethyl-1,1'-biphenyl-2-yl) -amidrazone, (4 '-(2-hydroxy) ethyl-1,
1'-biphenyl-2-yl) -amidrazone, (4 '
-(4-Hydroxy) butyl-1,1'-biphenyl-
2-yl) -amidrazone, (4 ′-(8-hydroxy) octyl-1,1′-biphenyl-2-yl) -amidrazone, (4′-methoxymethyl-1,1′-biphenyl-2-yl) -Amidrazone, (4 '-(2-methoxy) ethyl-1,1'-biphenyl-2-yl)-
Amidrazone, (4 '-(4-methoxy) butyl-1,
1'-biphenyl-2-yl) -amidrazone, (4 '
-(8-Methoxy) octyl-1,1'-biphenyl-
2-yl) -amidrazone-2-yl) -amidrazone, (4′-benzyloxymethyl-1,1′-biphenyl-2-yl) -amidrazone, (4′-aminomethyl-1,1′-biphenyl- 2-yl) -amidrazone, (4 ′-(2-amino) ethyl-1,1′-biphenyl-2-yl) -amidrazone, (4 ′-(4-amino) butyl-1,1′-biphenyl- 2-yl) -amidrazone, (4 '-(8-amino) octyl-1,1'
-Biphenyl-2-yl) -amidrazone, (4'-
(N-Methylamino) methyl-1,1′-biphenyl-
2-yl) -amidrazone, (4 ′-(2-methylamino) ethyl-1,1′-biphenyl-2-yl) -amidrazone, (4 ′-(benzyloxycarbonylamino) methyl-1,1′- Biphenyl-2-yl) -amidrazone, (4 ′-(2-benzyloxycarbonylamino) ethyl-1,1′-biphenyl-2-yl) -amidrazone, (4 ′-(tert-butoxycarbonylamino) methyl- 1,1'-biphenyl-2-yl)
-Amidrazone, (4 '-(2-tert-butoxycarbonylamino) ethyl-1,1'-biphenyl-2
-Yl) -amidrazone, (4'-bromomethyl-1,
1'-biphenyl-2-yl) -amidrazone, (4 '
-(2-Bromo) ethyl-1,1'-biphenyl-2-
Yl) -amidrazone, (4′-dichloromethyl-1,
1'-biphenyl-2-yl) -amidrazone, (4 '
-Trichloromethyl-1,1'-biphenyl-2-yl) -amidrazone, (4'-dibromomethyl-1,
1'-biphenyl-2-yl) -amidrazone, (4 '
-Tribromomethyl-1,1'-biphenyl-2-yl) -amidrazone, (4'-methoxy-1,1'-biphenyl-2-yl) -amidrazone, (4'-chloromethoxy-1,1 ') -Biphenyl-2-yl) -amidrazone, (4 '-(2-chloro) ethoxy-1,1'-
Examples thereof include amidrazone having an aryl group such as biphenyl-2-yl) -amidrazone.

Nitrite compound (4) used in this reaction
Are, for example, nitrite, or metal salts of nitrite such as sodium nitrite and potassium nitrite, or alkyl nitrite such as ethyl nitrite and isoamyl nitrite, and the amount thereof is relative to amidrazones (3). Usually, it is 1 to 50 mole times. In addition, nitrous acid or sodium nitrite,
When using a metal salt of nitrous acid such as potassium nitrite, an acid such as hydrochloric acid, acetic acid or methanesulfonic acid is usually used together.
A solvent is usually used in this reaction, and examples of the solvent include hydrocarbons such as benzene, toluene and hexane,
Halogenated hydrocarbons such as dichloromethane, dichloroethane and chlorobenzene, nitrated hydrocarbons such as nitrobenzene and nitromethane, ethers such as diethyl ether and tetrahydrofuran, amides such as dimethylformamide, alcohols such as methanol and ethanol,
Alternatively, organic acids such as acetic acid and butyric acid, and mixtures thereof can be mentioned. The amount used is usually 3 to 200 times by weight that of the amidrazones (3).

The reaction temperature is usually -50 to 150 ° C, preferably -50 to 50 ° C, and the completion of the reaction can be confirmed by liquid chromatography or the like. After completion of the reaction, the tetrazole compound (5) can be isolated from the organic solvent by a normal operation such as separation or filtration.
It may also be used in the next step without isolation.

[0019]

Thus, the tetrazole compound represented by the general formula (5) can be obtained, but according to the method of the present invention, a highly dangerous azide compound is not used as a reagent, and even under mild conditions. This is advantageous as an industrial production method of the tetrazole compound represented by the general formula (5) because the reaction can be proceeded efficiently.

[0020]

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

Example 1 2.0 g (4.56 mmol) of 8- [4- (4-phenylbutoxy) benzoyl] amino-2-cyano-4-oxo-4H-benzopyran was added to 52 g of toluene and 0.23 g of triethylamine. (2.2
(8 mmol) and suspended in a mixture of 15 g of methanol and 0.155 g of hydrogen sulfide gas (hydrogen sulfide: 4.7 mm
was blown at room temperature. After stirring for 3 hours at room temperature,
After confirming the completion of the reaction by liquid chromatography, the reaction mixture was concentrated to obtain the corresponding thioamide. Yield 2.15g Yield 99%, mp203-208 ° C

(Examples 2 to 11) As Example 1 except that the starting material 8- [4- (4-phenylbutoxy) benzoyl] amino-2-cyano-4-oxo-4H-benzopyran was replaced. The same reaction was performed to obtain the corresponding thioamide. The results are shown below.

(Example 2) Raw material: 2-cyano-4-oxo-4H-benzopyran Product: 2-thiocarbamoyl-4-oxo-4H-benzopyran Yield: 88%, mp225-231 ° C

(Example 3) Raw material: 5-hydroxy-2-cyano-4-oxo-4H
-Benzopyran Product: 5-hydroxy-2-thiocarbamoyl-4-
Oxo-4H-benzopyran Yield: 98%

(Example 4) Raw material: 6-chloro-2-cyano-4-oxo-4H-benzopyran Product: 6-chloro-2-thiocarbamoyl-4-oxo-4H-benzopyran Yield: 95% mp284 ~ 289 ℃

(Example 5) Raw material: 8-nitro-2-cyano-4-oxo-4H-benzopyran Product: 6-nitro-2-thiocarbamoyl-4-oxo-4H-benzopyran Yield: 97% mp223 ~ 228 ℃

(Example 6) Raw material: 3-bromobenzonitrile Product: 3-bromobenzthioamide Yield: 97%

(Example 7) Raw material: 2-cyano-1,1'-biphenyl Product: 2-thiocarbamoyl-1,1'-biphenyl Yield: 99%, m / z = 213

(Example 8) Raw material: 2-cyano-4'-methyl-1,1'-biphenyl Product: 2-thiocarbamoyl-4'-methyl-1,
1'-biphenyl yield: 97%, m / z = 227, mp111-115 ° C.

(Example 9) Raw material: 2-cyano-4'-chloromethyl-1,1'-biphenyl Product: 2-thiocarbamoyl-4'-chloromethyl-
1,1′-Biphenyl yield: 90%, m / z = 262

(Example 10) Raw material: 2-cyano-4'-methoxymethyl-1,1'-
Biphenyl Product: 2-thiocarbamoyl-4′-methoxymethyl-1,1-biphenyl Yield: 88%, m / z = 257

(Example 11) 8- [4- (4-phenylbutoxy) benzoyl] amino-2-thiocarbamoyl-
2.15 g of 4-oxo-4H-benzopyran (4.55
mmol) was suspended in a mixture of 50 g of toluene and 10 g of methanol, and 0.15 g of anhydrous hydrazine (4.5
6 mmol) was added at 0 ° C. After stirring at 0 to 5 ° C. for 8 hours, the reaction mixture was filtered [8- {4-
(4-Phenylbutoxy) benzoyl} amino-4-oxo-4H-benzopyran-2-yl] -amidrazone was obtained. Obtained amount 1.81 g, yield 85%, mp183-186
℃

(Examples 12 to 18) In Example 11, 8- [4- (4-phenylbutoxy) benzoyl] amino-2-thiocarbamoyl-4-oxo-4H-benzo-pyran is shown below. The reaction was performed in the same manner as in Example 11 except that the starting materials were used to obtain the corresponding amidrazone. The results are shown below. In addition, about Examples 16-19, reaction was performed at 50-60 degreeC, and the target compound was obtained by concentrating the reaction mixture after reaction. In addition, Example 1
For 8 and 19, anhydrous hydrazine was used in 3 molar equivalents to the thioamides.

(Example 12) Raw material: 2-thiocarbamoyl-4-oxo-4H-benzopyran Product: 2- (4-oxo-4H-benzopyran-2-
Yil) -amidrazone yield: 90%, m / z = 203

(Example 13) Raw material: 5-hydroxy-2-thiocarbamoyl-4-oxo-4H-benzopyran Product: 2- (5-hydroxy-4-oxo-4H-benzopyran-2-yl) -amidrazone Yield: 82%, m / z = 202

(Example 14) Raw material: 6-chloro-2-thiocarbamoyl-4-oxo-4H-benzopyran Product: 2- (6-chloro-4-oxo-4H-benzopyran-2-yl) -amidrazone Yield: 85%, m / z = 239

(Example 15) Raw material: 8-nitro-2-thiocarbamoyl-4-oxo-4H-benzopyran Product: 2- (8-nitro-4-oxo-4H-benzo-pyran-2-yl) -Amidrazone yield: 78%, m / z = 248

(Example 16) Raw material: 3-bromobenzthioamide Product: 3-bromobenzamidrazone Yield: 90%

(Example 17) Raw material: 2-thiocarbamoyl-1,1'-biphenyl Product: 1,1'-biphenyl-2-yl-amidrazone Yield: 85%, m / z = 211

(Example 18) Raw material: 2-thiocarbamoyl-4'-methyl-1,1 '
-Biphenyl product: (4'-methyl-1,1'-biphenyl-2-
Yil) -amidrazone yield: 82%, m / z = 225

(Example 19) 2.08 g of [8- [4- (4-phenylbutoxy) benzoyl] amino-4-oxo-4H-benzopyran-2-yl] -amidrazone
(4.11 mmol) was dissolved in 180 g of acetic acid,
60g water and 0.28g sodium nitrite (4.11mm
ol) was added and the mixture was stirred at 0 to 2 ° C. for 2 hours. After confirming the completion of the reaction, the reaction mixture is filtered to give 8- [4-
(4-Phenylbutoxy) benzoyl] amino-2-
(5-Tetrazolyl) -4-oxo-4H-benzo-pyran was obtained. Yield 1.97g, Yield 96%

(Examples 20 to 27) In Example 19
[8- [4- (4-phenylbutoxy) benzoyl] amino-4-oxo-4H-benzopyranyl] -amidrazone was reacted in the same manner as in Example 19 except that the raw materials shown below were used. A tetrazole compound was obtained. The results are shown below.

Example 20 Starting Material: 2- (4-oxo-4H-benzopyran-2-yl) -amidrazone Product: 2- (5-tetrazolyl) -4-oxo-4H
-Benzopyran yield: 99%

(Example 21) Starting material: 2- (5-hydroxy-4-oxo-4H-benzopyran-2-yl) -amidrazone Product: 5-hydroxy-2- (5-tetrazolyl)-
4-oxo-4H-benzopyran Yield: 95%

(Example 23) Raw material: 2- (6-chloro-4-oxo-4H-benzopyran-2-yl) -amidrazone Product: 6-chloro-2- (5-tetrazolyl) -4-
Oxo-4H-benzopyran Yield: 93%

(Example 23) Raw material: (8-nitro-4-oxo-4H-benzopyran-2-yl) -amidrazone Product: 8-nitro-2- (5-tetrazolyl) -4-
Oxo-4H-benzopyran Yield: 92%

(Example 24) Raw material: 3-bromobenzamidrazone Product: 5- (3-bromophenyl) -tetrazole Yield: 80%

(Example 25) Raw material: 1,1'-biphenyl-2-yl-amidrazone Product: 2- (5-tetrazolyl) -1,1'-biphenyl Yield: 81%

(Example 27) Raw material: (4'-methyl-1,1'-biphenyl-2-yl) -amidrazone Product: 2- (5-tetrazolyl) -4'-methyl-
1,1'-Biphenyl yield: 86%

(Example 28) The procedure is the same as in Example 19 except that isoamyl nitrite is used instead of water and sodium nitrite, and 60 g of water is added after the reaction is completed. A tetrazole compound was obtained. 1.9
2g yield 93%

(Example 29) 2.08 g of [8- [4- (4-phenylbutoxy) benzoyl] amino-4-oxo-4H-benzopyran-2-yl] -amidrazone
(4.11 mmol) was dissolved in a mixture of 30 g of DMF and hydrochloric acid (5 mol times), 60 g of water and 0.28 g (4.11 mmol) of sodium nitrite were added, and 0 to 2
The mixture was stirred at 0 ° C for 2 hours. After confirming the completion of the reaction, the reaction mixture was filtered to give 8- [4- (4-phenylbutoxy)
Benzoyl] amino-2- (5-tetrazolyl) -4-
Oxo-4H-benzo-pyran was obtained. Yield 97%

Example 30 2.08 g of [8- [4- (4-phenylbutoxy) benzoyl] amino-4-oxo-4H-benzopyran-2-yl] -amidrazone
(4.11 mmol) was dissolved in a mixture of 30 g of DMF and methanesulfonic acid (5 mol times), 60 g of water and 0.28 g (4.11 mmol) of sodium nitrite were added, and the mixture was stirred at 0 to 2 ° C for 2 hours. . After checking the completion of the reaction, the reaction mixture was filtered to give 8- [4- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-benzo-pyran.
95% yield

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 405/04 257

Claims (7)

[Claims] 1. General formula (1) R¹CN (1) (wherein R¹Is an optionally substituted 4-oxo-4
May be substituted with H-benzopyranyl group or X
Indicates a phenyl group. Where 4-oxo-4H-benzopy
The substituent of the ranyl group may be substituted with a phenyl group.
Alkoxy group, hydroxy group, halogen atom, nitro
Group or R²CONH, where R ²Is alkyl
Group, phenyl group, phenylalkyl group, alkylpheny
Group, alkoxyphenyl group, phenylalkylphenyl
Group or phenylalkoxyphenyl group,
And alkyl or alkoxy has 1 to 20 carbon atoms.
It X of the optionally substituted phenyl group is substituted with Y
Optionally substituted phenyl group, alkyl group, alkoxy
Group, halogen atom, phenylalkyl group or phenyl
Represents an alkoxy group, where alkyl or alkoxy
Shi has 1 to 20 carbon atoms. Optionally substituted
Y of the phenyl group is a hydroxyl group which may be protected by a protecting group.
An alkyl group having 1 to 20 carbon atoms substituted with, protected
Number of carbon atoms substituted with an amino group which may be protected by a group
Substituted with 1 to 20 alkyl groups or halogen atoms
An optionally substituted alkyl group having 1 to 20 carbon atoms, or
Substituted with a hydroxyl group which may be protected by a protecting group
Alkoxy group having 1 to 20 carbon atoms or halogen atom
An alkoxy having 1 to 20 carbon atoms which may be substituted with
Represents a group. ) Reacts nitriles with hydrogen sulfide
The general formula (2) R¹C (= S) NH₂ (2) (In the formula, R¹Has the same meaning as above. )
Thioamides were obtained, followed by hydrazine or its salts
By reacting the compound of the general formula (3) R¹C (= NH) NHNH₂ (3) (In the formula, R¹Has the same meaning as above. )
After obtaining an amidrazone or a salt thereof, a compound represented by the general formula (4) YONO (4) (Y is a hydrogen atom, a metal atom, or a C 1-20
Indicates an alkyl group. ) Reacted with nitrite compounds
General formula (5) characterized by(In the formula, R¹Has the same meaning as above. )
Method for producing tetrazole compound. 2. After reacting the thioamides represented by the general formula (2) with hydrazine or a salt thereof to obtain the amidrazones represented by the general formula (3) or a salt thereof, the compound represented by the general formula (4) is A method for producing a tetrazole compound represented by the general formula (5), which comprises reacting with a nitrite compound represented. 3. An amidrazone represented by the general formula (3) or a salt thereof is reacted with a nitrite compound represented by the general formula (4), which is represented by the general formula (5). Method for producing tetrazole compound. 4. R^{1 '}C (= S) NH₂ (2^') (Where R is^{1 '}Is an optionally substituted 4-oxo-4
May be substituted with H-benzopyranyl group or X
Indicates a phenyl group. Where 4-oxo-4H-benzopy
The substituent of the ranyl group may be substituted with a phenyl group.
Alkoxy group, hydroxy group, halogen atom, nitro
Group or R^{2 '}CONH, where R ^{2 '}Is alkyl
Group, phenyl group, phenylalkyl group, alkylpheny
Group, phenylalkylphenyl group, alkoxypheny
Group and phenylalkoxyphenyl group.
Rualkyl or alkoxy has 1 to 5 carbon atoms. Place
X of the optionally substituted phenyl group is substituted with Y
It is an optional phenyl group. Optionally substituted
Y of the phenyl group is a hydroxyl group which may be protected by a protecting group.
An alkyl group having 1 to 20 carbon atoms, which is substituted with
Is 1 to 2 carbon atoms which may be substituted with a halogen atom.
0 may be protected by an alkyl group or a protecting group.
An alkyl group having 1 to 20 carbon atoms substituted with an amino group,
Or substituted with a hydroxyl group which may be protected by a protecting group
Alkoxy group having 1 to 20 carbon atoms, or halogen
Alkenyl having 1 to 20 carbon atoms that may be substituted with
Indicates a koxy group. ) Thioamides represented by. 5. R^{1 '}C (= S) NH₂ (2^') (Where R is^{1 '}Is an optionally substituted 4-oxo-4
May be substituted with H-benzopyranyl group or X
Indicates a phenyl group. Where 4-oxo-4H-benzopy
The substituent of the ranyl group is a hydroxy group, a halogen atom, or a
Toro group or R ^{2 '}CONH, where R^{2 '}Is fe
Nyl group, alkoxyphenyl group or phenylalkoxy group
Represents a phenyl group, where alkyl or alkoxy
Shi has 1 to 5 carbon atoms. Fe that may be replaced
X of the nyl group is a phenyl group which may be substituted with Y '.
Is. Y'of the optionally substituted phenyl group is
Charcoal substituted with a hydroxyl group, which may be protected by a protective group
Place with an alkyl group having a prime number of 1 to 20 or a halogen atom.
An optionally substituted alkyl group having 1 to 20 carbon atoms,
A carbon substituted with an amino group which may be protected by a protecting group
The alkyl groups of the numbers 1 to 20 are shown. ) Represented by
Mids. 6. General formula (3 ′) R ^{1 ′} C (═NH) NHNH ₂ (3 ′) (In the formula, R ^{1 ′} is an optionally substituted 4-oxo-4.
H-benzopyranyl group or phenyl group which may be substituted with X is shown. Here, the substituent of the 4-oxo-4H-benzopyranyl group is an alkoxy group which may be substituted with phenyl, a hydroxy group, a halogen atom, a nitro group or R ^{2 ′} CONH, wherein R ^{2 ′} is an alkyl group, Phenyl group, phenylalkyl group, alkylphenyl group,
A phenylalkylphenyl group and a phenylalkoxyphenyl group are shown, wherein alkyl or alkoxy has 1 to 5 carbon atoms. X of the phenyl group which may be substituted is a phenyl group which may be substituted by Y.
Y of the phenyl group which may be substituted is an alkyl group having 1 to 20 carbon atoms which is substituted with a hydroxyl group which may be protected by a protecting group, or from 1 carbon atoms which may be substituted with a halogen atom. 20 carbon atoms substituted by an alkyl group or an amino group which may be protected by a protecting group
To an alkyl group having 1 to 20 or an alkoxy group having 1 to 20 carbon atoms which is substituted with a hydroxyl group which may be protected by a protecting group, or an alkoxy group having 1 to 20 carbon atoms which may be substituted with a halogen atom. Show. ) Amidrazones or salts thereof. 7. The general formula (3 ′) R^{1 '}C (= NH) NHNH₂ (3 ') (In the formula, R^{1 '}Is an optionally substituted 4-oxo-4
May be substituted with H-benzopyranyl group or X
Indicates a phenyl group. Where 4-oxo-4H-benzopy
The substituent of the ranyl group is a hydroxy group, a halogen atom, or a
Toro group or R ^{2 '}CONH, where R^{2 '}Is fe
Nyl group, alkoxyphenyl group or phenylalkoxy group
Represents a phenyl group, where alkyl or alkoxy
Shi has 1 to 5 carbon atoms. Fe that may be replaced
X of the nyl group is a phenyl group which may be substituted with Y '.
Is. Y'of the optionally substituted phenyl group is
Charcoal substituted with a hydroxyl group, which may be protected by a protective group
Place with an alkyl group having a prime number of 1 to 20 or a halogen atom.
An optionally substituted alkyl group having 1 to 20 carbon atoms, or
Or substituted with an amino group which may be protected by a protecting group.
And an alkyl group having 1 to 20 carbon atoms. )
Amidrazones or salts thereof.