JPH03240786A - Production of (1,2,4-triazol-1-yl)-substituted carbostyril derivative - Google Patents

Abstract

PURPOSE:To simply obtain the title high-purity compound without preparing substitution products at the 4-position as by-products by reacting a carbostyril derivative or salt thereof with 4-amino-1,2,4-triazole. CONSTITUTION:A compound shown by formula I (R<1> is H, lower alkyl or phenyl lower alkyl; R<2> is H, halogen, OH, etc.; Z is O, group shown by formula II, group shown by formula III, etc.; A is lower alkylene; X is halogen, lower alkylsulfonyloxy, etc.; carbon-carbon bond between the 3- and 4-positions of carbostyril skeleton is single or double bond) is reacted with preferably 1.5-5mols based on 1mol of the compound shown by formula I of 4-amino-1,2,4-triazole in a solvent such as methanol by adding an inorganic salt such as lithium bromide (preferably 0.5-3mols based 1mol of the compound shown by formula I) preferably at 50-150 deg.C for 1-20 hour to give the objective compound shown by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing (1,2,4-triazol-1yl)-substituted carbostyril derivatives.

Prior art and its problems General formula [wherein R1 represents a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group]. R2 represents a hydrogen atom, a halogen atom, a lower alkylsulfonyloxy group, a lower alkoxy group, or a hydroxyl group. Z represents an oxygen atom, a sulfur atom, a group -C 1 group -C- group -CH- (R3 is a hydrogen atom or 1 N-OH, OR3 is a lower alkyl group), or a group -NH-. A represents a lower alkylene group. X represents a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ] The (1.2.4-triazol-1yl)-substituted carbostyril derivative represented by these formulas is a useful compound having platelet adhesion inhibiting activity (see JP-A No. 64-6271).

According to the above publication, (1.2
．． 4-triazol-1-yl) substituted carbostyril derivatives have the general formula (
A) carbostyryl derivative represented by 1. 2.
It is produced by reacting with 4-triazole.

1 (A) 2 (1) + However, according to this method, the target general formula (
Along with the compound of formula (1), the compound represented by the general formula (B) is inevitably produced as a by-product. Therefore, in order to obtain the compound of the general formula (1) with high purity, purification by silica gel column chromatography, etc. is necessary. This requires a process that is complicated and takes a long time in mass production of the target product.
Furthermore, since a large amount of solvent is required, it has disadvantages such as high cost.

In recent years, Astleford (B, ^, ^5tleford
) have reported a method for synthesizing the compound of general formula (1) without producing the compound of general formula (B) as a by-product (J,
Org, Chem, , 54.731 (198
9)).

2 1 1 (B) That is, the present invention has a general formula. However, in this method, the nitrosation reaction and the nitrite oxidation reaction proceed as side reactions, so functional groups with high sensitivity to these reactions and electron density When using a compound having a high aromatic ring, the disadvantage is that the desired product can only be obtained in a low yield.

Means for Solving the Problems The object of the present invention is to provide a method for producing carbostyryl derivatives of general formula (1) which does not have the above-mentioned drawbacks.

R21 1 [wherein R1, R2Z, , A and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. X represents a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. ] or its salt di-4-amino-1,2,4-)lyazole is reacted to form (1.2゜4-triazol-1-yl) represented by the above general formula (1). The present invention relates to a method for producing a (1°2,4-triazol-1-yl)-substituted carbostyril derivative, which is characterized by obtaining a substituted carbostyryl derivative or a salt thereof.

In this specification, lower alkyl groups include methyl,
Ethyl, propyl, isopropyl, butyl, 1erl-
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as butyl, pentyl, and hexyl groups.

Examples of phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, L1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2- Examples include phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl-3-phenylpropyl group.

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

Examples of lower alkylsulfonyloxy groups include those having 1 to 6 carbon atoms, such as methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, butylsulfonyloxy, 'terj-butylsulfonyloxy, pentylsulfonyloxy, and hexylsulfonyloxy groups. Examples include straight chain or branched alkylsulfonyloxy groups.

Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1er! -butoxy, pentyloxy, hexyloxy, etc. having 1 or more carbon atoms
6, a straight chain or branched alkoxy group can be exemplified.

Examples of lower alkylene groups include carbon groups such as methylene, ethylene, trimethylene, 2-methyltrimethylene, 2゜2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, and hexamethylene groups. Examples include straight chain or branched alkylene groups having numbers 1 to 6.

Examples of the arylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,
Examples include -methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylphenylsulfonyloxy groups.

Examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy,
Examples include 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy groups.

According to the method of the invention, the reaction of the compound of general formula (2) with 4-amino-1,2,4-triazole is carried out in a suitable solvent. Examples of solvents include alcohols such as methanol, ethanol, isopropyl alcohol, and ferf-butanol, ketones such as acetone and methyl isobutyl ketone, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, dimethylformamide, formamide, Examples include aprotic polar solvents such as N-methylpyrrolidone, N,N'-dimethylimidazolidinone, dimethylsulfoxide, and hexamethylphosphoric triamide, and mixed solvents of these and water.

The ratio of the compound of general formula (2) and 4-amino-1,2,4-triazole is not particularly limited and can be appropriately selected from a wide range, but usually the latter is used in a ratio of 1 to 1 of the former. The amount is preferably about 10 to 10 times the molar amount, preferably about 1.5 to 5 times the molar amount.

In the above reaction system, bromides such as lithium bromide and potassium bromide, sodium iodide,
Inorganic salts such as iodides such as potassium iodide may be added.

The amount of such inorganic salt added is usually about 0.1 to 5 times the molar amount, preferably 0.5 to 3 times the amount of the compound of general formula (2).
It is preferable to use about twice the molar amount.

The reaction of the present invention is usually carried out at a temperature of around room temperature to about 200°C, preferably 50 to 150°C, and generally 1 to 2
Completed in about 0 hours.

In the present invention, when a low boiling point solvent is used as the solvent, a pressurized container may be used for the purpose of increasing the internal reaction temperature.

Effects of the Invention According to the method of the present invention, a compound substituted at the 1-position [compound of general formula (1)] can be selectively obtained without producing a compound substituted at the 4-position as a by-product, and complicated operations such as column chromatography purification are not necessary. The compound of general formula (1) can be produced in large quantities easily and with good productivity without the need for. In addition, in the reaction of the present invention, since the nitrosation reaction and nitrite oxidation reaction do not proceed as side reactions, compounds having functional groups that are sensitive to these reactions and aromatic rings with high electron density are used as raw material compounds. Even in this case, the target product can be obtained in high yield.

Example Examples are listed below.

Example 1 7-(3-chloro-1-propoxy)-2(LH)-
30 g of quinolinone was suspended in a mixed solvent of 30 xl of dimethylformamide and 9 xl of water, and 4-amino-1,2
, 52.6 g of 4-triazole (60% aqueous solution) and 22.6 g of sodium iodide were added, and the mixture was heated under reflux on an oil bath for 11 hours. After cooling the reaction solution, add sodium bisulfite 1.
3 g was added and extracted with methylene chloride. The organic layer was washed with water and dried over magnesium sulfate. After evaporating the solvent, the residue was dissolved in 5% aqueous hydrochloric acid solution (160 z/ml) and treated with activated carbon. After removing the activated carbon, the furnace solution was made alkaline using 25% sodium hydroxide, and then extracted with methylene chloride. After distilling off methylene chloride, the residue was dissolved in 1,2-dichloroethane, and the organic layer was washed with a 25% aqueous sodium hydroxide solution, then water, and dried over magnesium sulfate. After evaporating the solvent, the residue was recrystallized from a 25% aqueous ethanol solution to give 7-[3-(1,2,4-)riazol-1-yl)propoxy]-3,4-dihydrocarbostyryl 23
I got g.

Yield: 66% Colorless needle crystals, melting point 132-133.5°C Examples 2-2
1 Using appropriate starting materials, prepare the following 1st procedure in the same manner as in Example 1.
The compounds shown in the table were obtained.

(Hereafter Up) April 30, 1991

Claims (1)

[Claims] [1] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group. R^2 represents a hydrogen atom, a halogen atom, a lower alkylsulfonyloxy group, a lower alkoxy group, or a hydroxyl group. Z is oxygen atom, sulfur atom, group ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Groups ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^3 is a hydrogen atom or a lower alkyl group) or indicates a group -NH- . A represents a lower alkylene group. X represents a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ] 4-amino-1,2,4-triazole is reacted with the carbostyryl derivative or its salt represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1, R^2 , Z, A and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] (1,2,4-triazol-1-yl) represented by
1. A method for producing a (1,2,4-triazol-1-yl)-substituted carbostyryl derivative, which comprises obtaining a substituted carbostyril derivative or a salt thereof.