JPS5919095B2 - Quinoline derivatives and their production method - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel quinoline derivatives.

The compound of the present invention has the general formula (wherein X represents a halogen atom).

Moreover, R_1, R_2 and R_3 represent a hydrogen atom or a lower alkoxy group. However, when R_1 and R_3 are lower alkoxy groups, R_2 is a hydrogen atom, R_ and R_3
When is a hydrogen atom, R_2 is a lower alkoxy group, and when R_1 and R_2 are hydrogen atoms, R_3 is a lower alkoxy group). The compound itself has antibacterial activity and is useful as an antibacterial agent, and is also useful as an intermediate for pharmaceutical synthesis. R_ in general formula [I]
The lower alkoxy group represented by 1-R_3 can include straight chain or branched alkoxy groups having 1 to 4 carbon atoms, specifically methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Examples include groups.

Examples of the halogen atom represented by X include chlorine atom, bromine atom, and iodine atom. Representative compounds of the present invention are listed below. O2.4-dichlororu5
-Propoxyquinoline ○ 2,4-dichloro-6-methoxyquinoline.

2,4-dichloro-8-methoxyquinoline The compound of the present invention can be synthesized by various methods, but one preferred example is from a benzene derivative represented by the known general formula [] as shown in the following reaction scheme-1. can be manufactured.

Reaction Scheme-1 That is, a compound of the known general formula [] is subjected to a ring-closing reaction in the presence of a known condensing agent to obtain the compound of the general formula [1].
-1] is produced, and a compound represented by the general formula [1-1] is produced.
] A compound represented by the general formula [-2] is produced by hydrolyzing the compound.

The compound represented by the general formula [-3] is produced by subjecting a compound of the known general formula [] to a ring-closing reaction in the presence of a known condensing agent. The compound of general formula [1-1] can also be produced by halogenating the compound of general formula [1-3]. The compound of general formula [1-1] is prepared by adding phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, etc. to the compound of general formula [] without a solvent or in a common inert solvent. The condensing agent such as a halogen compound is usually 30 to 15
It is produced by reacting at 0°C, preferably 50 to 100°C, for about 1 to 24 hours. Examples of such inert solvents include halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane, ethers such as ether and dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. can. The ratio of the compound of general formula [] and the condensing agent to be used is not particularly limited and can be selected appropriately from a wide range, but usually the latter is used in a molar range of 2 to 20 times, preferably 7 to 12 times the former. Good. The hydrolysis reaction of the compound of general formula [1-1] can be carried out using commonly used hydrolysis catalysts, such as hydrohalic acids such as hydrochloric acid and hydrobromic acid, inorganic acids such as sulfuric acid and phosphoric acid, potassium hydroxide, water, etc. Usually in the presence of an alkali metal hydroxide such as sodium oxide, an inorganic alkali compound such as sodium carbonate, hydrium carbonate, sodium bicarbonate, etc.
Heating to 150℃, preferably 70 to 100℃ for 3 to 2
It is enough to react for about 4 hours. The compound of general formula [1-2] can also be produced by treating the compound of general formula [1-1] with an alkali metal alkoxide and then hydrolyzing the same.

The reaction between the compound of general formula [1-1] and an alkali metal alkoxide can be carried out using a conventional inert solvent, such as lower alcohols such as methanol, ethanol, butanol, and tert-butanol, ethers such as ether, dioxane, benzene, and toluene. , aromatic hydrocarbons such as xylene, dimethyl sulfoxide, dimethyl formamide, etc., usually within the range of room temperature to the boiling point of the solvent, preferably 60 to 8
It may be carried out at 0°C for about 5 minutes to 10 hours. A wide variety of known alkali metal alkoxides can be used, and specific examples include sodium methoxide, potassium ethoxide, potassium butoxide, and sodium Te.
Examples include rt-butoxide and potassium tert-butoxide. Of these, sodium tert-butoxide and potassium tert-butoxide are most preferred. The ratio of the compound of general formula [11] and the alkali metal alkoxide is not particularly limited and is appropriately selected within a wide range, but the latter is usually equal to 2 times the amount of the former, preferably equal to 1 times the amount of the latter. It is preferable to use .5 times the molar amount. The compound of general formula [1-3] is produced by ring-closing the compound of general formula [] using a condensing agent without a solvent or in a common inert solvent.

Examples of condensing agents used in this case include Lewis acids such as phosphorus pentoxide, hydrogen fluoride, sulfuric acid, polyphosphoric acid, aluminum chloride, and zinc chloride, and examples of inert solvents include chloroform, dichloromethane, 1,2- Examples include halogenated hydrocarbons such as dichloroethane, ethers such as ether and dioxane, and aromatic hydrocarbons such as nitrobenzene and chlorobenzene. Polyphosphoric acid is most preferred as the condensing agent. The ratio of the compound of the general formula [] and the condensing agent to be used is not particularly limited and may be appropriately selected from a wide range, but the latter is usually used in an equimolar to 10 times molar amount, preferably 3 to 6 times the molar amount of the former. It is better to do so. In particular, when polyphosphoric acid is used, it is usually used in an equivalent amount to 10 times the amount (by weight), preferably 3 to 5 times the amount (by weight) of the compound of the general formula [] in the absence of a solvent. This ring-closing reaction is usually carried out at 50-250°C.
The reaction is preferably carried out at a temperature of 70 to 200°C, and the reaction time is usually about 20 minutes to 6 hours. General formula [1-1]
The compound can also be produced by halogenating the compound of general formula [1-3] in the presence of a halogenating agent without a solvent or in a conventional inert solvent.

As the halogenating agent used in such a reaction, a wide variety of known agents can be used, such as phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, thionyl chloride, etc. can. The ratio of the compound of general formula [1-3] and the halogenating agent is not particularly limited and is appropriately selected from a wide range, but when the reaction is carried out in a solvent, the latter is usually 2 to 10% of the former. It is preferable to use twice the mole, preferably 3 to 6 times the mole, and when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former. Examples of inert solvents used in this reaction include halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane, ethers such as ether and dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. can be mentioned. This halogenation reaction is usually carried out at room temperature to 100°C, preferably at 30 to 8°C.
The reaction is preferably carried out at 0°C, and the reaction time is usually about 1 to 12 hours. The compound of the present invention thus produced can be easily isolated and purified by conventionally known methods such as filtering, extraction, recrystallization, etc.

The compound of the present invention thus obtained, for example, a 5,8-dialkoxy-4-halogenocarbostyryl derivative, is a 5,8-dihydroxy intermediate for the synthesis of β-Protka as shown in the following reaction scheme-2. -3,4-dihydrocarbostyryl.

Reaction Scheme-2 (In the above formula, R represents a lower alkyl group, and X is the same as above) Conventionally, as a method for producing 5,8-dihydroxy-3,4-dihydrocarbostyryl, Japanese Patent Publication No. 46-38
No. 788, JP-A-51-6971, JP-A-51-69
No. 72, JP-A-51-6973 and JP-A-51-69
The only known method is a combination of the methods described in No. 74 as shown in Reaction Scheme-3 below.

Reaction Scheme-3 However, in the above conventional method, the starting materials are expensive, the reaction is complicated, and the overall yield is extremely low at 8 to 12%, making it extremely difficult to commercialize.

In contrast, the compound of the general formula [], which is the raw material for the production of the present invention, is a compound that can be easily obtained from the benzene derivative of the general formula [], which is inexpensive and easily available, as shown in the reaction scheme [] below. (In the above formula, R1 is the same as above) Using the compound of general formula [] as a starting material, passing through the compound of general formula [] and the compound of the present invention, 5,8-dihydroxy-3,4
-The method for obtaining dihydrocarbostyril has an overall yield of 32
%, the yield is much higher than that of the conventional method, the starting materials are also much cheaper, and the production cost is 1/20 of the conventional method, making it an extremely preferable production method.

To remove the hydroxyl group at position 4 of the compound of general formula [1-3] of the present invention, a usual reaction for removing a phenolic hydroxyl group can be applied, but for example, the compound of general formula [1-3] may be directly reduced or converts the 4-position hydroxyl group to a group R3O- (R3 is an alkylsulfonyl group, an arylsulfonyl group, or [][, }), which is a group for eliminating a normal phenolic hydroxyl group, and then reduces this. Even if it gets twisted, it can be removed.

Examples and reference examples are listed below in order to further clarify the present invention.

Example 1 268f of N-carboxyacetyl-2,5-dimethoxyaniline was added to 3l2OOml of POCl and refluxed for 2 hours.

After collecting POCl3, add ice water 10. Open slowly to e. Collect the precipitated crystals, wash with water, and dry to obtain 2,4-dichloro-5,8-
Dimethoxyquinoline 2537 is obtained. Melting point 121-12
This was recrystallized at 6°C from 2200 ml of methanol. Yellow needle crystals, melting point 129-130°C Example 2 4-Hydroxy-5,8-dimethoxycarbostyryl 2
．． 57 was added to 325 ml of POCl and refluxed for 3 hours, then concentrated under reduced pressure. Water was added to the resulting residue to collect precipitated crystals, which were recrystallized from methanol to give 2.4 yellow needle-shaped crystals.
-Dichloro-5,8-dimethoxyquinoline 2,17 is obtained.

Melting point: 129-130°C Reference example 1 2,4-dichloro-5,8-dimethoxyquinoline 57,
5 ml of concentrated sulfuric acid and 500 ml of 50% ethanol aqueous solution are refluxed for 9 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure and dried, and then 500ml of water was added.
Add a lot of precipitated crystals, and dry. This was recrystallized from a 90% aqueous methanol solution to form yellow amorphous crystals of 4-chloro-
2.37 of 5,8-dimethoxycarbostyryl are obtained. Melting point: 208-209°C Reference example 2 2,4-dichloro-5,8-dimethoxyquinoline 26y
was dissolved in 400 ml of tert-butanol, 1.5 equivalents of potassium tert-butoxide were added, and the mixture was refluxed for 3 hours under a nitrogen atmosphere.

After the reaction is complete, add about 200ml of tert-butanol under reduced pressure.
After distilling off, it was poured into 1,000 ml of water, and then 100 ml of concentrated hydrochloric acid was added to bring the pH to about 1, and then the pH was heated to 1 at 70°C.
Heat for an hour. After cooling, collect the precipitated crystals, wash with water, and dry for 90 minutes.
% methanol aqueous solution to obtain 4-chloro-5,8-dimethoxycarbostyryl as yellow amorphous crystals. Yield 22.57, melting point 208-209℃Example 34-hydroxy-8-methoxycarbostyryl 1.57 was PO
After adding to 20 ml of Cl and refluxing for 3 hours, it was concentrated under reduced pressure. Water was added to the obtained residue to collect a lot of precipitated crystals, and recrystallized from methanol to give pale yellow needle-like crystals of 2,4-dichloro-8. -Methoxyquinoline is obtained.

Yield: 1.37, melting point: 144°C Reference Example 3 Add 200% of 2,4-dichloro-8-methoxyquinoline to 37% of concentrated sulfuric acid, 10ml of water and 10ml of ethanol,
After refluxing for 5 hours, the mixture was concentrated under reduced pressure, water was added to the resulting residue, the precipitated crystals were collected, and recrystallized from benzene to obtain colorless needle-like crystals of 4-chloro-8methoxycarbostyryl.

Yield 180, melting point 186-187°C Example 4 N-carboxyacetyl-2-methoxyaniline 2.5
y was added to 3 liters of POCl (2 ml) and refluxed for 2 hours.

After removing POCl3 under reduced pressure, the mixture was poured into 100 ml of ice water to collect the precipitated crystals, and recrystallized from methanol to obtain 2,4-dichloro-8-methoxyquinoline in the form of pale yellow needles. Yield 1.8y, melting point 144°C Example 5N-carboxyacetyl-4-methoxyaniline 137 was POC
1360ml and refluxed for 2 hours.

After concentrating POCl3 under reduced pressure, it was gradually poured into ice water 11. Collect the precipitated crystals, wash with water, and dry. The obtained crude crystals are recrystallized from methanol to obtain colorless needle-like crystals of 2,4-dichloro-6-methoxyquinoline. Yield 127, melting point 175-176°C Reference example 4 4-chloro-5,8-dimethoxycarbostyryl 157
60% methanol 500ml or ethanol 300ml
1 and then add 1.5y of reduction catalyst and an equivalent amount of N
Add aOH aqueous solution, H2lOk9/Cd, 50-60
Stir at ℃ for 2 hours.

The catalyst was removed and dried to obtain 5,8-dimethoxy-3,4 dihydrocarbostyryl. Yield 11.5y, Yield 88
45%, melting point 98-99°C Reference Example 5 5,8-dimethoxy-3,4-dihydrocarbostyryl 57 was added to 50ml of 47% HBr and refluxed for 2 hours.

After cooling, the precipitated crystals were poured into a 100 ml pot of water. Once melted, it precipitates again. Sawatori, washing with water, drying 5.
8-dihydroxy-3,4-dihydrocarbostyryl is obtained. Yield 3.57, yield 81.4%, melting point 223-2
The results of measuring the antibacterial properties of the compounds of the present invention at temperatures below 24.5°C are shown. The chemical was applied to French bean leaves with a brush, and after air-drying, a fungal disc of French bean Sclerotinia fungi was placed on the leaves and kept in a greenhouse at 22°C for 3 days to investigate the onset of disease.

In addition, treatment area or non-treatment area (3 each) determined according to the following criteria.
The average disease index of each ward (5 leaves per ward) was taken as the respective disease severity. The control value was calculated according to the following formula.

The results are shown below. The evaluation of the control value in the table shows the following.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, When it is a lower alkoxy group, R_2 is a hydrogen atom, R_1 and R_3
is a hydrogen atom, R_2 represents a lower alkoxy group, and when R_1 and R_2 are hydrogen atoms, R_3 represents a lower alkoxy group).