JPH0227346B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to tetrazole derivatives, more specifically, compounds of the general formula [In the formula, R' is a lower alkyl group, a cycloalkyl group,
It represents a cycloalkyl lower alkyl group, a phenyl group, or a phenyl lower alkyl group, and the phenyl ring of the phenyl group and phenyl lower alkyl group may have a substituent. A is a lower alkylene group
represents a halogen atom] This invention relates to a novel method for producing a tetrazole derivative represented by:

The compound of general formula (1) obtained by the present invention is useful as an antithrombotic agent, a cerebral circulation improving agent, an anti-inflammatory agent, an anti-ulcer agent, an antihypertensive agent, an anti-asthmatic agent, and a phosphodiesterase inhibitor. It is useful as an intermediate for the synthesis of zolylalkoxycarbostyryl derivatives (see West German Publication P2934747-5).

The object of the present invention is to provide a novel and industrial method for producing the compound of general formula (1) with high purity, good yield, and from very inexpensive starting materials without requiring much labor or time. The objective is to provide an advantageous method.

That is, the present invention is based on the general formula A lactone derivative represented by the formula [wherein A is the same as above] is reacted with an amine represented by the general formula: R'NH ₂ (4) [wherein R' is the same as above] to form the general formula HO- A-CONHR' (2) [In the formula, R' and A are the same as above] A hydroxyamide derivative represented by the following is obtained, the hydroxyamide derivative is reacted with a halogenating agent, and then hydrazoic acid or its metal azide is reacted with a halogenating agent. The present invention provides a method for producing the tetrazole derivative of the above general formula (1), which is characterized by reacting the tetrazole derivative with the general formula (1).

In the present specification, the lower alkyl group includes a linear or branched alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. Examples of the phenyl lower alkyl group include:
Benzyl, α-phenethyl, β-phenethyl, 3
-phenylpropyl, 4-phenylbutyl, 1,
Examples include 1-dimethyl-2-phenylethyl and diphenylmethyl groups. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl,
Examples include cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Examples of cycloalkyl lower alkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclooctylmethyl, 2-cyclohexylethyl, 2-cyclooctylethyl, 1-methyl-2-cyclohexylethyl, 3 -cycloheptylpropyl, 4-cyclohexylbutyl, 1,1
-dimethyl-2-cyclohexylethyl, dicyclohexylmethyl group, and the like. Examples of the lower alkylene group include linear or branched alkylene groups, such as methylene, ethylene, trimethylene, propylene, tetramethylene, 2-ethylethylene, pentamethylene, hexamethylene, 2-methyltrimethylene, ,2-
Preferred examples include lower alkylene groups having 3 to 6 carbon atoms, such as dimethyltrimethylene and 1-methyltrimethylene groups.

The phenyl ring of the above phenyl lower alkyl group and phenyl group may have a suitable substituent, and examples of the substituent include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Lower alkoxy groups such as tert-butoxy, methyl, ethyl, propyl, isopropyl, butyl,
Lower alkyl groups such as isobutyl and tert-butyl, halogen atoms such as chlorine, fluorine and bromine, di-lower alkylamino groups such as dimethylamino, diethylamino, dipropylamino, dibutylamino and methylethylamino groups, nitro and lower alkylenedioxy groups such as lower alkylenedioxy groups such as methylenedioxy, ethylenedioxy, and trimethylenedioxy groups. Examples of those having the substituent include 4-chlorophenyl, 3,5-dichlorophenyl, 2-bromphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-nitrophenyl, 3,4,5-trimethoxy phenyl, 2-methylphenyl, 4-ethylphenyl,
Substituted phenyl groups such as 3,4-dimethylphenyl, 3,4-methylenedioxyphenyl, 2-chloro-4-nitrophenyl, 4-dimethylaminophenyl group, 4-chlorobenzyl, 3,5-diclobenzyl , β-2-bromphenethyl, 4-methoxybenzyl, β-3,4-dimethoxyphenethyl, 2-nitrobenzyl, β-3,4,5-trimethoxyphenethyl, 2-methylbenzyl, α-
4-ethylphenethyl, β-3,4-dimethylphenethyl, β-3,4-methylenedioxyphenethyl, 2-chloro-4-nitrobenzyl, β-4
Mention may be made of substituted phenyl lower alkyl groups such as the -dimethylaminophenethyl group. In addition, halogen atoms include iodine, bromine, chlorine,
Mention may be made of the fluorine atom.

In the present invention, first, an inexpensive lactone represented by the general formula (3) is reacted with an amino derivative represented by the general formula (4) to produce a hydroxyamide derivative represented by the general formula (2).

[In the formula, R' and A are the same as above] The reaction between the compound of general formula (3) and the compound of general formula (4) is carried out without a solvent or in a suitable solvent, such as methanol. , lower alcohols such as ethanol, hydrocarbons such as n-hexane and n-heptane, aromatic hydrocarbons such as benzene, toluene and xylene, and ethers such as tetrahydrofuran and dioxane. can be mentioned. The reaction is carried out without a catalyst or, if necessary, in the presence of a suitable alkali catalyst. Examples of the alkali catalyst include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; Examples include alcoholates such as alcoholate, sodium alcoholate, and potassium alcoholate, and organic bases such as trimethylamine, triethylamine, dimethylaniline, pyridine, and picoline. The amount of the compound of general formula (4) to be used is usually an excess amount,
Preferably, the amount is about equimolar to 10 times the molar amount. The reaction temperature can be varied over a wide range from room temperature to 300°C, preferably about 80 to 150°C, and the reaction time can be selected from a range of about 1 hour to about 2 days.

The method of the present invention can be easily carried out by reacting the compound of general formula (2) obtained as described above with a halogenating agent, and then reacting with hydrazoic acid or its metal azide, and achieves the objective. general formula to
Compound (1) can be obtained with high purity and good yield.

The reaction between the compound of general formula (2) of the present invention and the halogenating agent is carried out without a solvent or in a suitable solvent,
As the solvent, any inert solvent that does not adversely affect the reaction can be used, such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated aromatic hydrocarbons such as chlorobenzene and bromobenzene, and diethyl ether. , ethers such as tetrahydrofuran and dioxysan, and halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane. Examples of the halogenating agent include chlorinating agents such as phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, and thionyl chloride, phosphorus oxybromide, phosphorus tribromide,
A brominating agent such as thionyl bromide, preferably
Examples include phosphorus oxychloride, phosphorus pentachloride, and thionyl chloride. The amount of halogenating agent used is usually
The amount is about 1 to 50 times the amount of the compound of general formula (2), preferably about 1 to 2 times the amount of the compound of general formula (2). The reaction temperature is usually -20 to 100°C, preferably about 0 to 40°C, and the reaction time is about 30 minutes to 6 hours.

The above reaction solution is directly subjected to a reaction with hydrazidic acid or a metal azide. Hydroazidic acid or its metal azide may be used as it is, or as a solution in an inert solvent used in the reaction of the compound of general formula (2) with a halogenating agent. Examples of metal azides include group metal azides such as lithium azide, sodium azide, and potassium azide; group metal azides such as calcium azide, barium azide, and strontium azide; and aluminum azide. Examples include group metal azides. Preferred compounds are hydrazidic acid, sodium azide, and aluminum azide. The amount of hydrazidic acid or its metal azide to be used is usually about 1 to 5 times the mole, preferably about 1 to 3 times the mole of the compound of general formula (2) as the starting material. The reaction temperature is about 0 to 150°C, preferably about 0 to 100°C, and the reaction time is about 3 hours to 2 days.

The tetrazole derivative represented by the general formula (1) produced by the above method can be easily isolated from the reaction mixture by conventional isolation means such as filtration, recrystallization, column chromatography, preparative thin layer chromatography, distillation, etc. It is isolated and purified.

The method of the present invention will be explained in more detail with reference to Examples below.

Example 1 (1) 1 kg of δ-valerolactone and 1.05 kg of cyclohexylamine are mixed and heated at 110 to 120°C for 4 hours. The reaction solution was cooled to 30-40°C, ethyl acetate 4 was added thereto, cooled on ice, and the precipitated crystals were collected. The obtained crude crystals were recrystallized from ethyl acetate to obtain 1.63 kg of N-cyclohexyl-5-hydroxyvaleric acid amide in the form of colorless needles.

Melting point 76-78.5℃ (2) N-cyclohexyl in 500ml of chloroform
Dissolve 50 g of 5-hydroxyvaleramide, and add 100 g of phosphorus pentachloride in three portions. 1 under cooling
and then stirred at 30° C. for 3 hours. 40 g of sodium azide was added under ice cooling, and the mixture was stirred for 1 hour under cooling, at 20 to 30°C for 3 hours, and then heated under reflux for another 2 hours. Cool the reaction solution and pour into 700 ml of 2N aqueous sodium hydroxide solution with ice. Add 2N sodium hydroxide solution to the chloroform layer,
After washing with water, 2% hydrochloric acid, and then water, drying with magnesium sulfate. After concentration, add 500 ml of isopropyl ether and 2.5 g of activated carbon to the residue.
After heating under reflux for 2 hours, insoluble materials were removed. Concentrate the liquid, add n-hexane to the residue to crystallize it, and collect. After washing with n-hexane and drying,
Recrystallization from isopropanol-water gives 54 g of 1-cyclohexyl-5-(4-chlorobutyl)tetrazole in the form of colorless needles. Melting point 84.5~
86.5℃ Example 2 N-cyclohexyl-4 in 500ml of methylene chloride
- 50 g of hydroxybutyric acid amide is dissolved and 170 g of phosphorus oxychloride is added dropwise with cooling and stirring. After dripping,
Stir for 1 hour under cooling and 3 hours at 30°C. 500 ml of a 1N methylene chloride solution of hydroazidic acid was added dropwise under ice cooling, and the mixture was stirred for 1 hour under cooling and at 20 to 30°C for 3 hours, and then heated under reflux for an additional 4 hours. The reaction solution was treated in the same manner as in Example 1-(2) above, and isopropanol-
1-Cyclohexyl-5-(3-chloropropyl)terazol 55.6 recrystallized from water to give colorless needle-like crystals
get g.

Melting point: 82-85℃ Example 3 Dissolve 50g of N-benzyl-4-hydroxybutyric acid amide in 500ml of benzene, and dissolve 135g of thionyl chloride.
is added dropwise while stirring while cooling. 1 hour under cooling at 30℃
After stirring for 3 hours, 96 g of aluminum azide was added while cooling again. 3 at 30°C for 1 hour under cooling.
After stirring for an hour, the mixture is further heated under reflux for 3 hours. Cool the reaction solution and pour into 700 ml of 2N aqueous sodium hydroxide solution with ice. The benzene layer is washed with a 2N aqueous sodium hydroxide solution, water, 2% hydrochloric acid, and then water, and then dried over magnesium sulfate. After concentration, the residue is distilled under reduced pressure to obtain 54 g of 1-benzyl-5-(3-chloropropyl)tetrazole in the form of a pale yellow oil with a boiling point of 171-175°C (1.5 mmHg).

Example 4 In the same manner as in Example 1, the following compound is obtained.

1-Ethyl-5-(3-chloropropyl)tetrazole, colorless liquid, boiling point 160-163℃/20mmHg 1-phenyl-5-(3-chloropropyl)tetrazole, colorless liquid, boiling point 205-210℃/9.0mm
Hg 1-isopropyl-5-(3-chloropropyl)
Tetrazole, colorless liquid, NMRδ ^CDCl3 _ppn 1.55 (d,
6H), 2.30 (m, 2H), 2.95 (t, 2H), 3.65 (d,
2H), 4.7 (m, 1H) 1-cyclopentyl-5-(3-chloropropyl)tetrazole, colorless liquid, NMRδ ^CDCl3 _ppn 1.5~
2.7 (m, 10H), 3.1 (t, 2H), 3.7 (t, 2H), 4.6
~5.0 (m, 1H) 1-cyclohexylmethyl-5-(3-chloropropyl)tetrazole, colorless liquid, NMRδ ^CDCl3 _ppn
0.3-2.7 (m, 13H), 3.0 (t, 2H), 3.75 (t,
2H), 4.5(d, 2H) 1-cyclooctyl-5-(3-chloropropyl)tetrazole, colorless liquid, NMRδ ^CDCl3 _ppn 1.35~
2.65 (m, 16H), 3.0 (t, 2H), 3.67 (t, 2H),
4.2-4.7 (m, 1H) 1-benzyl-5-chloromethyltetrazole, colorless liquid, NMRδ ^CDCl3 _ppn 4.67 (s, 2H), 5.35
(s, 2H), 7.1-7.6 (m, 5H) 1-(2-chloro-4-nitrophenyl)-5-
Chloromethyltetrazole, yellow liquid,
NMRδ ^CDCl3 _ppn 4.8 (s, 2H), 7.76 (d, 1H), 8.25~
8.60 (m, 2H), 1-(4-ethylphenyl)-5-chloromethyltetrazole, colorless liquid, NMRδ ^CDCl3 _ppn 1.3 (t,
3H), 2.75 (q, 2H), 4.8 (s, 2H) 7.43 (s,
4H) 1-(β-3.4-dimethoxyphenethyl)-5-
(3-chloropropyl)tetrazole, yellow liquid,
NMRδ ^CDCl3 _ppn 1.80-2.25 (m, 2H), 2.45 (t, 2H)
,
3.70 (s, 3H), 3.75 (s, 3H), 4.40 (t, 2H),
6.30 (d, 1H), 6.45 (dd, 1H), 6.70 (d, 1H).

Claims (1)

[Claims] 1. General formula [Wherein, A represents a lower alkylene group] A lactone derivative represented by the general formula: R'NH ₂ [wherein, R' is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a phenyl group, or a phenyl lower alkyl group, the phenyl group and the phenyl ring of the phenyl lower alkyl group may have a substituent] to form the general formula HO-A-CONHR' [wherein, A general formula characterized by obtaining a hydroxyamide derivative represented by [R' and A are the same as above], reacting the hydroxyamide derivative with a halogenating agent, and then reacting with hydrazidic acid or a metal azide. [In the formula, R' and A are the same as above. A method for producing a tetrazole derivative represented by: X represents a halogen atom.