KR880001634B1 - Method for preparing benzo heterocyclic compound - Google Patents

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Description

Method for preparing benzo heterocyclic compound

The present invention relates to a process for the preparation of a novel benzoheterocyclic compound of general formula (I) useful as an antibacterial agent.

Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or a hydroxy group, or a lower alkanoyl group which may be substituted with a halogen atom, X is A hydrogen atom or a halogen atom, n is an integer of 1 or 2, provided that when n is 1, R ² cannot be a lower alkyl group substituted with a halogen atom.

It is an object of the present invention to provide a novel process for the preparation of benzo-heterocyclic compounds of formula (I) which allows to obtain the desired compounds in high purity and in good yield.

Accordingly, the present invention provides a process for the preparation of a compound of formula (I), characterized in that the benzoheterocyclic association of formula (II) is closed.

Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or a hydroxy group, or a lower alkanoyl group which may be substituted with a halogen atom, X is A hydrogen atom or a halogen atom, n is an integer of 1 or 2, provided that when n is 1, R ² cannot be a lower alkyl group substituted with a halogen atom, and R ³ and R ⁴ are the same or different; Lower alkyl group.

In another aspect, the present invention is characterized in that the quinoline compound of formula (III) is closed to form a benzoheterocyclic compound of formula (IV), and then hydrolyzed it. Provided is a method for preparing a benzoheterocyclic compound.

In the above formula,

R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or a hydroxy group, or a lower alkanoyl group which may be substituted with a halogen atom,

X is a hydrogen atom or a halogen atom,

n is an integer of 1 or 2,

Provided that when n is 1, R ² cannot be a lower alkyl group substituted with a halogen atom, and R ³ and R ⁴ are the same or different and are each lower alkyl group.

In another aspect, the present invention is characterized in that the quinoline compound of general formula (III) is closed to form a benzoheterocyclic compound of general formula (IV), and then hydrolyzed it. Provided is a method for preparing a benzoheterocyclic compound.

Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or a hydroxy group, or a lower alkanoyl group which may be substituted with a halogen atom, X is A hydrogen atom or a halogen atom, n is an integer of 1 or 2, provided that when n is 1, R ² cannot be a lower alkyl group substituted with a halogen atom, and R ⁵ is a lower alkyl group.

The attachment position of the substituent X in the general formulas (II) and (III) is preferably the 5-position (when n is 1) and the 6-position (when n is 2) of the benzoheterocyclic ring. Preferably X is chlorine or fluorine.

The term "lower alkyl group" as used herein refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl, hexyl and the like.

The term "lower alkyl group which may be substituted with halogen atom or hydroxy group" refers to methyl, ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, trichloromethyl, dichloromethyl, tribro Methyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-chloroethyl, 1,2-dichloroethyl, 3,3,3-trichloropropyl, 3-fluoropropyl 1, such as 4-chlorobutyl, 3-chlorobutyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 2-hydroxypropyl, etc. It refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms which may be substituted with from 3 halogen atoms or hydroxy groups.

The term "lower alkanoyl group which may be substituted with a halogen atom" refers to formyl, acetyl, propionyl, butyryl, isobutyryl, valteryl, isovaleryl, hexanoyl, trifluoroacetyl, trichloroacetyl, tetra Straight chains having 1 to 6 carbon atoms which may be substituted with from to halogen atoms such as libromoacetyl, 2,2-dichloropropionyl, monochloroacetyl, 2-chlorobutyryl, pentafluoropropionyl, heptafluorobutyryl, etc. Refers to a branched alkanoyl group.

The term "halogen" refers to iodine, chlorine, bromine, fluorine and the like.

Some of the compounds of formulas (II) and (III) are novel and can be prepared by the methods shown in Schemes -1 and -2 below.

Reaction equation-1

In the general formula, R ⁶ and R ⁷ are the same or different, each is a lower alkyl group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X are as defined above.

The nitration reaction of the general formula (V) compound can be carried out using a nitration material under the conditions normally used to nitrate the nitro group of an aromatic compound, for example in the absence of a solvent or in the presence of an inert solvent. Examples of inert solvents include acetic acid, acetic anhydride, concentrated sulfuric acid, and the like. Examples of suitable nitrofires include fuming nitric acid, concentrated nitric acid, mixed acids (mixtures of nitric acid with sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), mixtures of alkali metal nitrates (e.g. potassium nitrate, sodium nitrate, etc.) and sulfuric acid. to be. The amount of nitrating agent used is at least 1 mole per mole of starting material. Usually, a large amount of nitrating agent is used. The reaction can be advantageously carried out at 0 to 15 ° C. for 1 to 4 hours.

The reduction reaction of the nitro group in the compound of general formula (VI) obtained by the above process is, for example, a mixture of iron, zinc, tin or tin chloride with an acid (eg hydrochloric acid, sulfuric acid, etc.) or iron, sulfuric acid. Reducing agents such as mixtures of ferrous iron, zinc or tin and alkali metal hydroxides, sulfates, sulfites and the like may be carried out in a suitable inert solvent. Alternatively, the reaction may be carried out using a catalyst for catalytic reduction such as palladium-carbon or the like. Can be carried out catalytically. Examples of the inert solvent include water, acetic acid, methanol, ethanol, dioxane and the like. The reaction conditions may be appropriately selected depending on the type of reducing agent used. For example, the reaction can be advantageously carried out at 70-100 ° C. for about 0.5-1 hour when using a mixture of stannous chloride and hydrochloric acid as the reducing agent. The reducing agent may be used in an amount of 1 mole, preferably 1 to 2 moles per mole of starting material.

The reaction of the compound of formula (VII) with the compound of formula (X) can be carried out in the absence of solvent or in the presence of a dehydrogen condensing agent in a suitable solvent. Examples of dehydrogen condensing agents that can be used include condensed phosphoric acid such as polyphosphoric acid: phosphoric acid such as orthophosphoric acid, pyrophosphoric acid, metaphosphoric acid, and phosphorous acid such as orthophosphoric acid; Phosphoric anhydrides such as phosphorus pentoxide; Acids such as hydrochloric acid, sulfur phase, boric acid and the like; Metal phosphates such as sodium phosphate, boron phosphate, ferric phosphate, aluminum phosphate and the like; Activated alumina; Sodium bicarbonate; Raney nickel etc. Among these, polyphosphoric acid, phosphoric acid, and phosphorus pentoxide are preferable.

The amount of dehydrogen condensing agent used is not particularly limited and may vary widely. Usually, a dehydrogen condensation agent is used in the storage amount with respect to the compound of general formula (VII). It is preferably used in an amount of about 0.5 to 1.5 moles per mole of the formula compound.

Solvents include high boiling point solvents such as dimethylformamide, tetralin and the like.

At least about 1 mole, preferably 1 to 2 moles of the compound of the general formula and the compound of the general formula is used.

The reaction can be carried out in an atmosphere of inert gas in order to prevent oxidation reactions which act against the reaction. The reaction can be carried out at atmospheric pressure or under pressure. The reaction is preferably carried out at atmospheric pressure in terms of the efficiency of the operation.

The reaction can proceed at about 100 to 350 ° C., preferably 125 to 300 ° C., and can generally complete the reaction within about 3 to 10 hours.

The reduction reaction of the pyridine ring in the compound of formula (VII) obtained above can be carried out by catalytically reducing the compound of formula (IV) under acidic conditions in a suitable inert solvent. Any acid capable of forming a salt with quinoline can be used for the reduction reaction. For example, acetic acid, hydrochloric acid, conversion, and the like can be used. Dioxane, tetrahydrofuran, acetic acid, water, etc. can be mentioned as an inert solvent. Examples of catalysts that can be used in the catalytic reduction reaction are platinum-carbon, palladium-carbon, radium-carbon, ruthenium-carbon and the like. The reduction reaction can advantageously proceed for about 1 to 10 hours at room temperature to 50 ℃.

The reaction of the compound of formula (VII) with the compound of formula (VII) can be carried out in the absence of solvent or in the presence of a suitable solvent. Examples of the solvent are alcohols such as methanol, ethanol, isopropanol and the like, aromatic hydrocarbons such as benzene, toluene and the like, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethyl phosphate triamide and the like. The reaction is preferably carried out in the absence of solvent. The ratio of the general compound and the general compound is usually at least 1 mole, preferably 1 to 1.5 moles of the general formula (XI) compound per mole of the general compound. The reaction is usually carried out at about room temperature to 150 ° C., preferably 60 to 120 ° C., and can generally complete the reaction within about 0.5 to 6 hours, easily obtaining the compound of formula (IIa).

The reaction between the compound of formula (VII) and the compound of formula (XII) may be carried out under reaction conditions similar to those used for the reaction of the compound of formula (X) with the compound of formula (XI). , The compound of the general formula (IIIa) is easily obtained.

In addition, in Scheme-1, a compound in which R ² represents a hydrogen atom in the general formula (IX) compound may be substituted with a halogen atom or a hydroxy group for the compound of formula (IX) in which R ² represents a hydrogen atom. By reacting with a lower alkyl halide which may be substituted, or with a lower alkanoyl halide which may be substituted with a halogen atom or a hydroxy group, R ² may be substituted with a lower alkyl group that may be substituted with a halogen atom or a hydroxy group, or with a halogen atom Lower alkanoyl groups, which can be converted into compounds of formula (IX).

Reaction equation -2

의 그룹을 형성하며, R¹⁰은 저급알킬 그룹이고, R¹,R²,R³,R⁴,R⁶,R⁷및 X는 상기 정의한 바와 같다.Wherein X ¹ , X ² and X ³ are the same or different and each is a halogen atom, R ⁸ is a hydrogen atom, R ⁹ is a lower alkanoyl group and R ⁸ and R ⁹ together with the nitrogen atom to which they are attached constitutional formula

Wherein R ¹⁰ is a lower alkyl group and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and X are as defined above.

In Scheme-2, aniline compounds of formula (XIII) can be converted to aniline compounds of formula (II) by reacting compounds of formula (XIII) with acid anhydrides or acid halides in a suitable solvent. Examples of solvents that can be used are lower alcohols such as methanol, ethanol, isopropanol and the like, ethers such as dioxane and tetrahydrofuran, acetic acid, pyridine, dimethylformamide, dimeltyl sulfoxide and the like. Acid anhydrides include acetic anhydride and phthalic anhydride. Acid halides include acetyl chloride, propionyl chloride, butyryl bromide and the like. The amount of acid anhydride or acid halide used is usually at least about 1 mole, preferably 1 to 3 moles per mole of aniline compound of general formula (XIII). The reaction is usually carried out at about room temperature to 200 ° C., preferably at room temperature to 160 ° C., and can generally complete the reaction within about 0.5 to 5 hours.

The nitration reaction of the general formula (XIV) compounds is conventional, such as fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, fuming sulfuric acid, phosphoric or acetic anhydride and nitric acid), alkali metal nitrates such as potassium nitrate, sodium nitrate, and a mixture of sulfuric acid. It can be carried out using nitrohases. The amount of the nitrating agent used is at least about 1 mole, preferably 1 to 1.5 moles per mole of the general formula (XIV) compound. The reaction is carried out at about −20 to 50 ° C., preferably at −10 ° C. to room temperature, and can generally complete the reaction in about 1 to 7 hours.

The reaction between the compound of formula (XV) and the piperazine compound of formula (XVI) can be carried out in the presence of a solvent. Examples of solvents that can be used include aromatic hydrocarbons such as benzene, toluene, xylene and the like, lower alcohols such as methanol, ethanol and isopropanol, ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and diethyl ether, and N-methylpi Polar solvents such as rolidone, thymethylformamide, dimethylsulfoxide, hexamethyl phosphate triamide and the like.

The reaction is advantageously carried out in the presence of a basic compound as an acid acceptor. Examples of basic compounds are carbocarbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, tertiary amines (eg triethylamine, tripropylamine, etc.), pyridine, quinoline and the like. The amount of piperazine compound of general formula (XVI) is usually about 1 to 10 moles, preferably 3 to 7 moles per mole of general formula (XV) compound. The reaction is usually carried out at about 50 to 150 to 100 ° C. and can generally be completed in about 1.5 to 10 hours.

In the reduction of the general formula (X ') compound, a conventional reduction reaction with respect to the nitro group is used. For example, firstly, in a solvent such as water, methanol, ethanol, isopropanol, tetrahydrofuran, diethyl ether, etc., using a reduction catalyst such as platinum oxide, palladium black, palladium-carbon, etc., usually 1 to 10 atm, preferably Preferably a catalytic reduction under a hydrogen gas pressure of 1 to 3 atm, usually at -30 ° C. to a boiling point of the solvent, preferably at 0 ° C. room temperature. Second, anhydrous solvents such as diethyl ether, tetrahydrofuran and the like. Among them, a method of performing reduction using lithium aluminum hydride as a reducing agent, and third, metal compounds such as iron, zinc, tin, stannous chloride, and the like, in a solvent such as water, ethanol, methanol, acetic acid and the like, such as hydrochloric acid, acetic acid, and the like The method of performing reduction using a mixture with an acid, etc. can be used. The third of these methods is preferred.

The reaction is usually carried out at about 0 to 100 ° C., preferably at 10 to 50 ° C., and the reaction can be completed in about 10 minutes to 3 hours. The amount of the metal compound to be used is at least about 1 mole, preferably 2 to 5 moles per mole of the general formula (X ') compound.

Halogenation of the compound of formula (XVIII) is carried out by converting the compound of formula (XVIII) to the corresponding diazonium salt using an acid such as sulfuric acid, hydrochloric acid, bromic acid, boric acid and the like and sodium nitrite in a solvent such as water. Thereafter, the obtained diazonium salt is reacted with copper powder or halogenated copper (eg cuprous bromide, cuprous chloride, etc.) in the presence of halogenated hydrochloric acid (eg bromic acid, hydrochloric acid, etc.), or the diazonium salt is copper It can be carried out by reacting with potassium iodide in the presence or absence of a powder. The reaction is preferably carried out by reacting a compound of the general formula (XVIII) with a copper powder in the presence of hydrogen halide acid.

The amount of sodium nitrite used is usually 1 to 2 moles, preferably 1 to 1.5 moles per mole of the general formula (XVIII) compound. On the other hand, the amount of copper powder used is usually 1 to 3 moles, preferably 1 to 2 moles per mole of the general formula (XVIII) compound. The reaction is usually carried out at a temperature of about −20 ° C. to room temperature, preferably −5 to 5 ° C., and may generally complete the reaction within about 10 minutes to 5 hours.

The deamination reaction of the general formula (XVIII) compound is carried out by the reaction of the compound of the general formula (XVIII) with a corresponding diazonium salt using an acid such as sulfuric acid, hydrochloric acid, bromic acid, boric acid, and sodium nitrite in a solvent such as water. After conversion, the obtained diazonium salt can be carried out by reacting with an alcohol such as ethanol, an aldehyde such as alkaline formaldehyde, a metal such as zinc or copper, or a hydrogenation reagent such as hypophosphoric acid. The amount of sodium nitrite used is usually 1 to 2 moles, preferably 1.5 moles per mole of the general formula (XVIII) compound. On the other hand, the amount of hydrogenation reagent used is usually excessive, preferably 5 to 1.5 moles per mole of the general formula (XVIII) compound. The reaction is usually carried out at a temperature of about -20 ° C to room temperature, preferably -5 to 5 ° C, and can generally be completed within about 5 to 24 hours.

In addition, the compound of formula (XX) may be prepared by reacting a compound of formula (XX) with a halide such as chloride, bromide or the like. The reaction is carried out in Lewis solvents such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, and concentrated sulfuric acid in solvents such as halogenated hydrocarbons such as dichloromethane, chloroloam, carbon tetrachloride, acetic acid and concentrated sulfuric acid. The acid or sulfuric acid can be carried out in the presence of a catalyst such as iodine or the like, usually at a temperature from room temperature to 100 ° C. and generally completes the reaction within about 0.5 to 5 hours. The amount of halide used is usually at least about 1 mole, preferably 1 to 3 moles per mole of the general formula (XIX) compound.

The hydrolysis reaction of the compound of general formula (XX) can be carried out in the presence of a basic compound in a suitable solvent. Examples of suitable solvents that can be used are water, methanol, ethanol, isopropanol and the like. Examples of suitable basic compounds include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate and the like. The amount of the basic compound used is usually excessive, preferably 4 to 8 moles per mole of the general formula (XX) compound. The reaction is usually carried out at a temperature of about room temperature to 150 ° C., preferably 50 to 100 ° C., and can generally be completed in about 10 minutes to 5 hours.

The reaction of the aniline derivative of formula (XXI) with the halogenating agent can be carried out in a suitable solvent. Any conventional solvent may be used that does not adversely affect the reaction. Examples of suitable solvents include halogenated hydrocarbons such as chloroform, methylene chloride, ethers such as dioxane, diethyl ether, tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, xylene, lower alcohols such as methanol, ethanol, isopropanol, dimethyl sulfoxide Polar solvents such as sides, hexamethyl phosphate triamide, acetonitrile and the like. As the halogenating agent, various compounds that can be used in a conventional halogenation reaction can be used. Representative examples thereof include N-bromo succinimide, N-chloro succinimide, sodium hypobromite, sodium hypochlorite, bleach powder, thionyl chloride, tert-butyl hypochloride, and the like. The amount of hydrogenation reagent used is usually at least 1 mole, preferably 1 to 1.5 moles per mole of starting material. The reaction is generally carried out at about −78 to 0 ° C., preferably at −60 to −10 ° C., and can usually complete the reaction in minutes.

Thus, an intermediate compound of formula (XXII) is obtained. Compounds of formula (XXII) can be separated from the reaction system and introduced into subsequent reaction steps. Alternatively, the compound can be introduced in a subsequent reaction with the thio compound of formula (XXII) without separating from the reaction system.

The reaction of the intermediate compound of formula (XXII) with the thio compound of formula (XXIII) can usually be carried out under the temperature conditions as mentioned above in the solvent as mentioned above in the presence of a basic compound. Examples of suitable basic compounds that can be used include inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride and the like, tertiary amines such as triethylamine, tripropylamine, pyridine, Organic basic compounds such as quinoline. The ratio of the general formula (XXII) compound and the general formula (XXII) compound is usually at least 1 mole, preferably 1 to 1.5 moles, of the former compound per mole of the latter compound. The reaction can usually be completed in about 1 to 5 hours. Thus, indole derivatives of the general formula (XXIV) according to the present name can be obtained.

The desulfurization reaction of the general formula (XXIV) compound can be carried out in a solvent in the presence of a suitable catalyst. Examples of suitable catalysts include aluminum amalgam, lithium lower alkyl amines, rannickel, ranicobalt, triethylphosphite, triphenylphosphine and the like, alcohols such as ethanol, isopropanol, dioxane, tetrahydrofuran, diethyl ether and the like. Same ether. The reaction can be carried out at a temperature of about 0 to 200 ° C., preferably about room temperature, and complete the reaction in about 1 to 5 hours. The amount of the catalyst used is about 1 to 10 parts by weight per weight part of the indole derivative of the general formula (XXIV).

The dehalogenation reaction of the obtained general formula (XXV) compound can be carried out by a method similar to conventional dehalogenation. For example, a method in which zinc powder is used in acetic acid or a catalytic reduction method may be used. The former method can usually be carried out at a temperature of about 50 to 150 ° C. for about 2 to 5 hours. The amount of zinc powder used is usually about 2 to 5 moles per mole of the general formula (XXV) compound. The catalytic reduction method is advantageously carried out using a catalyst such as palladium-carbon, palladium black, etc. in a suitable solvent such as alcohol such as methanol, ethanol, isopropanol, ether such as diethyl ether, dioxane, tetrahydrofuran and acetic acid. can do. The reaction can be carried out at a temperature of about 0 ° C. to room temperature under a pressure of about 1 to 3 atm for about 0.5 to 3 hours. The amount of the catalyst used is conventionally used, for example, from about 1/10 to about 1/20 parts by weight per weight part of the general formula (XXV) compound. It is also possible to add sodium acetylate or the like during the catalytic reduction reaction.

Compounds of formula (XXVI) may also be prepared directly from indole derivatives of formula (XXIV). Any solvent exemplified in the desulfurization reaction may be used. As the catalyst, triethyl phosphite, triphenylphosphine, ranickel and the like can be used, and of these, ly nickel is preferable. Reaction temperature is 0-220 degreeC normally, Preferably it is 50-100 degreeC. Other conditions are the same as in the desulfurization reaction.

Reduction of the general formula (XXVI) compound obtained above can be carried out using a catalyst in a suitable inert solvent.

Examples of suitable inert solvents are alcohols such as methanol, ethanol, isopropanol and the like, ethers such as dioxane, tetrahydrofuran, diethyl ether, acetic acid, water and the like. Examples of reducing catalysts include platinum, lannickel, palladium black, copper chromate, platinum-carbon, palladium-carbon, lithium-carbon, and uterium-carbon. The reduction reaction may advantageously be carried out at 0 to 200 ° C. for about 0.5 to 10 hours under an input of 1 to 250 atm. The amount of the catalyst is usually about 1/10 to 1/20 parts by weight per weight part of the general formula (XXVI) compound.

Alternatively, the reduction reaction of the general formula (XXVI) compound obtained for the process is, for example, a mixture of iron, zinc, tin or tin tin with an acid (eg hydrochloric acid, sulfur phase, etc.) or iron in a suitable solvent. And reducing agents, such as mixtures of ferrous sulfate, zinc or tin with alkali metal hydroxides, sulfates, sulfites. As an inert solvent, water, acetic acid, methanol, ethanol, dioxane, etc. can be mentioned, for example. The reaction conditions may be appropriately selected depending on the type of reducing agent used. For example, the reaction can be advantageously carried out at 0 to 50 ° C. for about 0.5 to 1 hour when using a mixture of stannous chloride and hydrochloric acid as the reducing agent. The reducing agent may be used at least 1 mole, preferably 1 to 2 moles per mole of starting material.

Reaction of the general formula (XXVII) compound with the general formula (XI) compound and the reaction of the general formula (XXVII) compound with the general formula (XII) compound are the general formula (X) compound and the general formula (XI) or (XII) It can be carried out under conditions similar to those used for the reaction of the compounds.

In addition, in the above Scheme-2, a compound in which R ² represents a hydrogen atom in the compound of formula (XXVI) may be substituted with a hydroxy group for the compound of formula (XXVI) in which R ² represents a hydrogen atom. Reacted with a lower alkyl halide or a lower alkanoyl halide which may be substituted with a halogen atom, where R ² represents a lower alkyl group which may be substituted with a hydroxy group or a lower alkanoyl group that may substitute a halogen atom (XXVI) Can be converted into a compound.

The ring closure reaction of the general formula (II) or (III) compounds can be carried out in various conventional ring closure reactions, such as ring closure using acidic substances such as ring closure, phosphorus oxychloride, phosphorus pentachloride, phosphorus acid chloride, thionyl chloride, dark yellow phase, polyphosphoric acid, etc. on heating. This can be done using When closed by heating, the reaction is usually from 100 to 250 ° C., preferably 150, in solvents such as hydrocarbons and ethers having high boiling points (eg, tetralin, diphenyl ether, diethylene glycol diethyl ether, etc.). To 200 ° C. In the case of ring closure using an acidic substance, the reaction may be carried out for about 0.5 to 6 hours at a temperature of 1 mol to large excess, preferably 10 to 150 캜, per mole of the compound of formula (II) or (III). .

When the compound of formula (II) is used as a starting material, the target compound of formula (I) can be obtained according to the ring closure reaction.

In addition, in the case of using the compound of formula (III) as starting material, the compound of formula (IV) can be obtained according to the ring closure reaction, and the compound of formula (IV) Can be introduced into the subsequent hydrolysis reaction.

Hydrolysis reaction of the general formula (IV) compound is a conventional method. For example, it may be carried out in the presence of a conventional catalyst which is a basic compound such as sodium hydroxide, potassium hydroxide, barium hydroxide, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, or an organic acid such as acetic acid, aromatic sulfonic acid and the like.

The reaction can generally be carried out in conventional solvents such as water, methanol, ethanol, isopropanol, dioxane, ethylene glycol, acetone, methyl ethylkerone, acetic acid. The reaction temperature is usually room temperature to 200 ° C, preferably 50 to 150 ° C. From this, the compound of general formula (I) can be manufactured.

The obtained benzoheterocyclic compound of formula (I) may be separated from the reaction mixture upon completion of the reaction, and may be prepared by conventional methods, for example, filtration, solvent extraction, dilution, precipitation, recrystallization, column chromatography, and preliminary thin layer. It can be refine | purified by chromatography.

According to the method of the present invention, the compound of the general formula (I) can be obtained in high purity and excellent yield by a very simple operation.

Also in the process of the invention, the compounds of formula (II) or (III) can be provided directly to the next step without separation, from which the compounds of formula (I) are obtained in much increased yield. can do.

The invention is described in more detail by the following reference examples and examples, which are not intended to limit the invention.

Reference Example 1

6-Chloroquinaldine (11 g) is dissolved in concentrated sulfuric acid (15 ml) and the solution is ice cooled. To this was added dropwise a solution of potassium nitrate (7.1 g) in concentrated sulfuric acid (20 ml) at a temperature not exceeding 10 ° C. After completion of the dropwise addition, the mixture is stirred at the above-mentioned temperature for 1 hour and the reaction mixture is poured onto 200 g of ice. The reaction mixture is then made alkaline by the addition of 10% aqueous sodium hydroxide solution, taking care not to exceed an internal temperature of 20 ° C. As a result, a pale yellow precipitate is formed. The precipitates are collected by filtration, washed with water and recrystallized with ethanol to give 12.3 g of 5-nitro-6-chloroquinaldine. Light yellow rhombus crystal, melting point 123-124 캜.

Reference Example 2

Tintin chloride (25 g) is dissolved in concentrated hydrochloric acid (50 ml), and 5-nitro-6-chloroquinaldine (6.7 g) is added to this solution. The mixture is kept at 80 to 90 ° C. and then reacted for 30 minutes in a water bath. The reaction mixture is annealed and made alkaline (pH 10) with 30% aqueous sodium hydroxide solution, then filtered and extracted using chloroform (50 ml) and celite. The chloroform layer is dried over anhydrous sodium sulfate, concentrated and recrystallized with benzene-hexane to afford 4.5 g of 5-amino-6-chloroquinaldine. Colorless plate, melting | fusing point 196-197 degreeC.

Reference Example 3

The mixture of 5-amino-6-fluoroquinaldine (22 g) and polyphosphoric acid (100 g) is heated to 150 ° C. with stirring. N-methyldiethanolamine (100 g) is added dropwise to the mixture for 30 minutes and the mixture is maintained at an internal temperature of 180 ° C. The water formed from the reaction system is removed while the reaction is continued at this temperature for 8 hours. The disappearance of the spots corresponding to the chul compound is confirmed by thin layer chromatography, then the reaction mixture is slowly cooled. After the internal temperature was lowered to 80 ° C., water (100 ml) was added to the reaction mixture to form a homogeneous solution, which was then neutralized with an aqueous sodium hydride solution and extracted three times with hexane (200 ml). The hexane layers are all washed with water (250 ml), dehydrated with anhydrous magnesium sulfate and filtered. The treated hexane layer is then concentrated until its total amount is reduced to 100 ml. Activated charcoal (2 g) is added and the concentrate is refluxed for 30 minutes. Filter the activated carbon while hot. After cooling, the precipitated crystals are collected by filtration to give 23 g of 5- (4-methyl-1-piperazinyl) -6-fluoroquinaldine. Light yellow crystal, melting point 87-89.5 占 폚.

Reference Example 4

5- (4-methyl-1-piperazinyl) -6-fluoroquinaldine (3.7 g) is dissolved in a mixed solvent consisting of acetic acid (100 ml) and ethyl acedate (10 ml). After addition of 5% platinum-carbon (1 g), the solution is left in a glass autograve and stirred for 3 hours at room temperature under hydrogen gas pressure of 5 kg / cm 2. After removing the hydrogen gas, the contents are taken to remove the catalyst and the contents are dried and concentrated. Chloroform (100 ml) is then added to the residue. After dissolving, the solution is neutralized with 5% aqueous sodium hydroxide solution (50 ml). After separation, the chloroform layer is washed twice with water (100 ml). After drying, the chloroform layer is dried and concentrated and hexane (20 ml) and activated carbon (0.5 g) are added dropwise to the residue to heat the mixture to dissolve the residue. After removing the activated carbon by filtration, the hexane layer was cooled and the formed crystals were collected by filtration to obtain 3.5 g of 5- (4-methyl-1-piperazinyl) -6-fluoro-1,2,3,4-tetrahydroqui Obtain naldine. Light yellow crystal, melting point 64.5-65.5 占 폚.

Reference Example 5

3-chloro-4-fluoroaniline (50 g) is dissolved in 150 ml of acetic acid and acetic anhydride (70.2 g) is added dropwise. After stirring for 30 minutes at room temperature, the reaction mixture is placed in water and the precipitated solid is collected by filtration. After washing with water, the solid is dissolved in ethyl acetate. The ethyl acetate layer is washed with a dilute aqueous solution of potassium carbonate, dried over magnesium sulfate and the solvent is evaporated. This gives 62 g of 3-chloro-4-fluoroacetanilide. Melting point 116 to 117 ° C.

Reference Example 6

3-chloro-4-fluorouroaniline (10 g) and phthalic anhydride (10.2 g) are dissolved in dimethylformamide (30 ml) and the solution is refluxed for 2 hours. Water is added to the reaction mixture and the formed crystals are collected by filtration. The crystals are dissolved in ethyl acetate. After washing with aqueous sodium hydrogen carbonate solution, the solution is dried over magnesium sulfate to yield 14.4 g of N- (3-chloro-4-fluoro-1-phenyl) phthalimide. Melting point 192-193 ° C.

Reference Example 7

3-chloro-4-fluoroacetanilide (10 g) is dissolved in concentrated sulfuric acid (35 ml) and a solution of potassium nitrate (6.5 g) in concentrated sulfuric acid (25 ml) is added dropwise at 0 ° C for 30 minutes. After the addition, the mixture is stirred at 0 ° C. for 1 hour 30 minutes. The reaction mixture is poured into ice water (400 ° C.) and the crystals formed are collected by filtration, washed with water and dried to afford 12.3 g of 2-nitro-4-fluoro-5-chloroacetanilide. Melting point 111-112 ° C.

Reference Example 8

While maintaining at a temperature of 15-20 ° C., N- (3-chloro-4-fluoro-1-phenyl) phthalimide (14 g) was dissolved in concentrated sulfuric acid (75 ml) and potassium nitrate in concentrated sulfuric acid (20 ml) ( 5.6 g) of the solution is added dropwise at -5 ° C for 30 minutes. After stirring at −5 to 0 ° C. for 1 hour, the reaction mixture is poured into ice water (1.5 g) and the crystals formed are collected by filtration. After washing with water, the crystals are dissolved in dichloromethane and the solution is dried over magnesium sulfate. Evaporate the solvent to afford 15.4 g of N- (2-nitro-4-fluoro-5-chloro-1-phenyl) phthalimide. Melting point 222-224 캜.

Reference Example 9

2-nitro-4-fluoro-5-chloroacetanilide (12 g) and methyl piperazine (25.8 g) are dissolved in 120 ml of dimethylformamide and the solution is stirred at 70 ° C. for 23 hours. Excess methylpiperazine and dimethylformamide are evaporated under reduced pressure. Water (25 ml) is added to the residue and the formed crystals are collected by filtration. After washing with water, the crystals are recrystallized with methanol-water and then recrystallized with isopropanol to give 14.3 g of 2-nitro-4-fluoro-5- (4-methyl-1-piperazinyl) acetanilide. Melting point 133-135 캜.

Reference Example 10

A solution of 2-nitro-4-fluoro-5- (4-methyl-1-piperazinyl) acetanilide (10 g) and potassium hydroxide (9.5 g) in water (8 ml) is dissolved in methanol (100 ml), The solution is refluxed for 30 minutes. After cooling, water (50 ml) is added to the reaction mixture. The precipitated solid is collected by filtration, washed with water and recrystallized with isopropanol to yield 8.0 g of 2-nitro-4-fluoro-5- (4-methyl-1-pyrerazinyl) aniline. Melting point 151 to 153 ° C.

Reference Example 11

2-nitro-4-fluoro-5- (4-methyl-1-piperazinyl) acetanilide (25 g) is dissolved in hydrochloric acid (250 ml) and tin tin dihydrate (57.2 g) in concentrated hydrochloric acid (250 ml) The solution of is added at once. The temperature of the reaction mixture in the reaction is raised to 40 ° C. After cooling for 1 hour with stirring, the precipitated solid is collected by filtration and dissolved in a small amount of water. The aqueous solution is made alkaline with aqueous sodium hydroxide solution under ice cooling and extracted with dichloromethane. After drying with potassium carbonate the solvent is evaporated. N-hexane was added to the residue and the formed crystals were collected by filtration and dried to give 15.7 g of 2-amino-4-fluoro-5- (4-methyl-1-piperazinyl) acet anilide. Melting point 168-169 degreeC.

Reference Example 12

2-amino-4-fluoro-5- (4-methyl-1-piperazinyl) acetanilide (3.0 g) is dissolved in a mixture of water (10 ml) and concentrated hydrochloric acid (30 ml) and nitrous acid is added to the resulting solution. An aqueous sodium solution (0.77 g of sodium nitrite solution in 5 ml of water) is added dropwise, followed by stirring for 2 minutes.

After 2 drops of n-octanol, copper powder (0.96 g) is added at once. After stirring for 30 minutes, the reaction mixture is poured into water, made alkaline with aqueous sodium hydroxide solution and extracted with dichloromethane. After drying over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol = 4: 1) to 0.90 g of 3- (4-methyl-1-piperazinyl) -4 -Fluoro-acetanilide is obtained. Melting point 175 to 176 ° C.

Reference Example 13

Silver sulfuric acid (0.60 g) was dissolved in concentrated hydrochloric acid (10 ml) and 3- (4-methyl-1-piperazinyl) -4-fluoroacet-anilide (0.80 g) was added with stirring. After adding bromine (0.61 g), the solution is stirred at an internal temperature of 30 to 40 ° C. for one hour. The reaction mixture is poured into water and the insoluble matter is filtered off. The filtrate is made alkaline by addition of aqueous sodium hydroxide solution and extracted with dichloromethane. After concentration, the extract was purified by silica gel column chromatography (eluent: chloroform-methanol = 8: 1) to 0.21 g of 2-bromo-4-fluoro-5- (4-methyl-1-piperazinyl Acetanilide is obtained. Melting point 126-127 ° C.

Reference Example 14

2-Bromo-4-fluoro-5- (4-methyl-1-piperazinyl) acetanilide (0.10 g) is added to 47% bromic acid (5 ml) and the mixture is refluxed for one hour. After evaporation of 47% bromic acid, the residue is made alkaline by addition of aqueous sodium hydroxide solution. The precipitated insolubles are collected by filtration and dried to yield 0.08 g of 2-bromo-4-fluoro-5- (4-methyl-1-piperazinyl) aniline. Melting point 122-124 ° C.

Reference Example 15

2-bromo-4-fluoro-5- (4-methyl-1-piperazinyl) -aniline (145 g) is dissolved in methylene chloride (1ι) and the solution is below -50 ° C on a dry ice-acetone bath. Cool to a temperature of. Tert-butyl hypochlorite (60 g) is added dropwise to the solution at the temperature as described above, wherein the reaction mixture turns from a heterogeneous mixture to a homogeneous solution. Methylthio-2-propanone (67 g) is then added dropwise in this solution and the mixture is allowed to react for 2 hours at the temperature as described above. Triethylamine (80 ml) is then added dropwise to the reaction mixture. After the addition is complete, the temperature of the mixture is slowly raised to room temperature. After reaching room temperature, water (1ι) is added to the reaction mixture to separate the methylene chloride layer. After condensation on sodium sulfate, the methylene chloride layer is concentrated under reduced pressure and recrystallized from ethanol-water to give 150 g of 2-methyl-3-methylio-5-fluoro-4- (4-methyl-1-piperazinyl) -7-Bromo-Indole is obtained.

Elemental Analysis Value: C ₁₅ H ₁₉ N ₃ SBr F

C H N

Calculated Value (%): 48.39, 5.14, 11.29

Found (%): 48.25, 5.03, 11.38

Reference Example 16

2-bromo-4-fluoro-5- (4-methyl-1-piperazinyl) aniline (800 g) is dissolved in anhydrous methylene chloride (4ι) and the solution is cooled to -60 ° C. A solution of tert-butyl hypochlorite (350 g) in methylene chloride (500 ml) is then added dropwise to the solution at the temperature as described above. Then a solution of ethylthio-2-propanone (680 g) in dichloromethane (ι) is added dropwise to the mixture. After the addition, the resulting mixture is allowed to react for 2 hours at the temperature as described above and a solution of triethylamine (325 g) in methylene chloride (1ι) is added dropwise to the reaction mixture. After the end of the addition, the temperature of the mixture is slowly raised to new temperature. After adding water (5ι) and stirring, the methylene chloride layer was separated, dried over magnesium sulfate and concentrated under reduced pressure, 0.95 kg of 2-methyl-3-ethylthio-4- (4-methyl-1-pipera Genyl) -5-fluoro-7-bromoindole is obtained.

Reference Example 17

Dissolve in 2-methyl-5-fluoro-4- (4-methyl-1-piperazinyl) indole acetic acid (1.5ι) and add tin metal (200 g) to this solution to reflux the mixture. Concentrated hydrochloric acid (1.5ι) is added dropwise under reflux for one hour. After the addition, the mixture is allowed to react for 2 hours at the temperature as described above. After the reaction is complete, the solvent is evaporated under reduced pressure. Water (1ι) is added to the residue and the pH of the solution is adjusted to 13 using 20% aqueous sodium hydroxide solution. After diethyl ether (1ι) is added and stirred, the insoluble matter is removed by filtration. The diethyl ether layer is separated from the filtrate and dried over anhydrous potassium carbonate. Diethyl ether was evaporated to afford 75 g of 2-methyl-4- (4-methyl-1-piperazinyl) -5-fluoroindolin.

Reference Example 18

2-methyl-3-methyldio-4- (4-methyl-1-piperazinyl) -5-fluoro-7-bromoindole (214 g) is dissolved in ethanol (3ι). Ranickel (1.5 kg) is added to the solution and the mixture is allowed to react for 3 hours. After cooling, the nickel is removed by filtration and the filtrate is concentrated to give 101 g of 2-methyl-4- (4-methyl-1-piperazinyl) -5-fluoroindole.

Reference Example 19

2-Methyl-3-methylthio-4- (4-methyl-1-piperazinyl) -5-fluoro-7-bromoindole (58 g) is dissolved in dioxane (1ι). Ranickel (400 g) is added to the solution and the mixture is allowed to react at room temperature for 4 hours. After the reaction was finished, the Ranickel was removed by filtration and the filtrate was concentrated under reduced pressure. The residue is recrystallized from ethanol-water to give 33 g of 2-methyl-4-methyl-1-piperazinyl) -5-fluoro-7-bromoindole.

Elemental Analysis Value: C ₁₄ H ₁₇ N ₃ F Br

C H N

Calculated Value (%): 51.55, 5.25, 12.88

Found (%): 51.42, 5.37, 12.74

Reference Example 20

2-methyl-4- (4-methyl-1-piperazinyl) -5-fluoro-7-bromoindole (24 g) is dissolved in ethanol (200 ml). 5% palladium-carbon (1 g) and 20% aqueous sodium hydroxide solution (15 ml) are added to the solution in order. The mixture is introduced to a catalytic reduction reaction at room temperature under atmospheric pressure. The reaction is continued until the theoretical amount of hydrogen gas (about 1.7?) Is absorbed, and then the catalyst is removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (Wako gel C-200; eluent: chloroform: n-hexane = 5: 1) to give 11.8 g of 2-methyl-4- (4- Methyl-1-piperazinyl) -5-fluoroindole is obtained.

Elemental Analysis Value: C ₁₄ H ₁₈ N ₃ F

C H N

Calculated Value (%): 67.99, 67.34, 16.99

Found (%): 67.84, 7.20, 17.13

Reference Example 21

2-Amino-4-fluoro-5- (4-methyl-1-piperazinyl) -acetanilide (1.94 g) is dissolved in a mixture of water (7 ml) and bromic acid (20 ml). To the obtained solution was added dropwise a solution of sodium nitrite (0.53 g) in water (3 ml) at 0 ° C. After 5 minutes, one drop of n-octanol (antifoaming agent) is added, followed by addition of copper powder (0.46 g) at once. Bubbles immediately occur. After bubbling is completed, the mixture is stirred for an additional 3 minutes at 0-5 ° C. Half dilute the mixture with water to make it alkaline. The precipitated solids are collected by filtration and dissolved in a mixed solvent of methanol-chloroform to remove insoluble matters. After concentration, the residue is purified by column chromatography to shrink 1.6 g of 2-bromo-4-fluoro-5- (4-methyl-1-piperazinyl) acetanilide. Melting point 126-127 ° C.

Example 1

(a) 5- (4-methyl-1-piperazinyl) -6-fluoro-1,2,3,4-tetrahydroquinaldine (10 g) and isopropylidedenyl-methoxymethylenemaloate (8 g ) Is mixed at room temperature and heated for 30 minutes with stirring at 100 ° C. to form a solid. The solid was recrystallized from chloroform-n-hexane to give 14.6 g (92%) of cyclic isopropylidedenyl [5- (4-methyl-1-piperazinyl) -6-fluoro-1,2,3, 4-tetrahydro-1-quinaldiyl] methylenemalonate is obtained.

White crystals.

Elemental Analysis Value: C ₂₂ H ₂₈ O ₄ N ₃ F

C H N

Calculated Value (%): 63.29, 6.79, 10.07

Found (%): 63.42, 6.59, 10.05

(b) polyphosphoric acid (50 g) prepared from phosphorus pentoxide (25 g) and phosphoric acid (25 g) and the cyclic isopropylidedenyl [5- (4-methyl-1-piperazinyl) obtained in step (a). -6-fluoro-1,2,3,4-tetrahydro-1-quinaldinyl] methylenemalonate (14.0 g) is heated for 1 hour with stirring at 100 ° C. After cooling to 80 ° C., water (60 ml) is added to the mixture to form a solution, which is then neutralized with 20% aqueous sodium hydroxide solution and extracted twice with chloroform (200 ml). After dehydration and drying over anhydrous magnesium sulfate, the chloroform layer is dried and concentrated. Methanol (40 ml) and activated carbon (0.5 g) are added to the obtained crystals to heat the mixture. After removing activated carbon from the resulting solution and cooling, the formed crystals were collected by filtration to give 10.2 g (86.6%) of 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl-6, Obtain 7-dihydro-1-oxo-1H, 5N-benzo [ij] quinolizine-2-carboxylic acid. White rhombic grain, melting point 262-263 degreeC.

Example 2

In a similar manner to Example 1, the compounds shown in Table 1 are prepared from suitable starting materials.

In the following Table 1, each compound is represented by a combination of R ¹ , R ² and X in formula (Ia), and the melting point and yield of the compound in step (b) are also indicated.

TABLE 1

Example 3

(a) Diethyl ethoxymethylenemalonate (9 g) was added to 5-4 (4-pryl-1-piperazinyl) -6-chloro-1,2,3,4-tetrahydroquinaldine (8.5 g). In addition, the mixture is heated at 160 ° C. for 30 minutes to form a solid. This solid was then recrystallized from chloroform-n-hexane to give 12.7 g (92%) of diethyl [5- (4-formyl-1-piperazinyl) -6-chloro-1,2,3,4-tetra Hydro-1-quinaldinyl] methylenemaronate.

Elemental Analysis Value: C ₂₃ H ₂₀ O ₅ N ₃ Cl

C H N

Calculated Value (%): 59.34, 6.52, 9.06

Found (%): 59.49,6.53, 9.07

(b) polyphosphoric acid (70 g) prepared from phosphorus pentoxide (35 g) and phosphoric acid (35 g) and diethyl [5- (4-formyl-1-piperanyl) -6- obtained in step (a). Chloro-1,2,3,4-tetrahydro-1-quinaldinyl] -methylenemalonate (12.5 g) is heated at 140-150 ° C. for 1 hour. After the reaction is rounded, the reaction mixture is poured into ice water (200 g) and the pH of the mixture is adjusted to 6-7 using 10N aqueous sodium hydroxide solution. The precipitate formed is collected by filtration and added to concentrated hydrochloric acid (60 ml). After the mixture was refluxed for 1 hour, water (100 ml) was added to the reaction mixture and the formed crystals were collected by filtration, washed with water and dried. Recrystallized from methanol, 8.9 g (82.5%) of 8- (4-formyl-1-piperazinyl) -9-chloro-5-methyl-6,7-dihydro-1oxo-1H, 5H-benzo [ jj] quinolizine-2-carboxylic acid is obtained. White rhombus crystal, melting point 262-265 캜.

Example 4

In a similar manner to Example 3, the compounds of Table 2 are prepared from suitable starting materials. In Table 2, each compound is represented by a combination of R ¹ , R ² and X in general formula (Ia), and is represented by the melting point and yield of the compound in step (b).

TABLE 2

Example 5

Diethyl ethoxymethylenemalonate (6.0 g) was added to 5- (4-methyl-1-piperazinyl) -6-fluoro-1,2,3,4-tetrahydroquinaldine (6.6 g) and the mixture Heated at 160 ° C. for 30 min. To this was added polyphosphoric acid (48 g) prepared from phosphorus pentoxide (24 g) and phosphoric acid (24 g) and the resulting mixture was heated at 150 to 160 ° C for 1 hour. After completion of the reaction, the reaction mixture is poured into ice water (150 g) and the precipitate formed is collected by filtration, washed with water and dried. 10% aqueous sodium hydroxide solution (70 ml) is added to the obtained crystals, and the mixture is reacted at 100 to 110 ° C for 1 hour. After cooling, the reaction mixture is acidified with concentrated hydrochloric acid to form crystals. The crystals were collected by filtration, washed with water and recrystallized with methanol to give 7.6 g (84%) of 8- (4-methyl-1-piperazinyl) -9-fluoro-5-methyl-6, 7dihydro-1 Oxo-1H, 5H-benzo [jj] quinolizine-2-carboxylic acid is obtained. White rhombus crystal, melting point 262-263 캜.

Example 6

(a) 4- (4-methyl-1-piperazinyl) -5-fluoro-2-methylindolin (9.6 g) and isopropylidedenyl methoxymethylene malonate (8 g) were mixed at room temperature and the mixture was The mixture was heated at 100 DEG C for 30 minutes while stirring to form a solid, and then recrystallized from chloroform-n-hexane to give 14.0 g of cyclic isopropylidedenyl [4- (4-methyl-1-piperazinyl) -5- Fluoro-2-methyl-1-indolinyl] methylenemalonate.

Elemental Analysis Value: C ₂₁ H ₂₆ N ₃ O ₄ F

C H N

Calculated Value (%): 59.18, 6.33, 9.99

Found (%): 59.31,6.16, 9.88

(b) polyphosphoric acid (50 g) prepared from phosphorus pentoxide (25 g) and phosphoric acid (25 g) and the cyclic isopropylidedenyl [4- (4-methyl-1-piperazinyl) obtained in step (a). -5-fluoro-2-methyl-1-indolinyl] -methylenemalonate (13.5 g) is heated at 100 ° C. for 1 hour with stirring. After cooling to 80 ° C., water (60 ml) is added to the mixture and the resulting solution is neutralized with 20% sodium hydroxide demand and extracted twice with chloroform (200 ml). The chloroform layer is dehydrated, dried over anhydrous magnesium sulfate and concentrated to dryness. Methanol (40 ml) and activated carbon (0.5 g) are added to the obtained crystals and the mixture is heated to form a solution. After activated charcoal was removed by filtration and cooled, the formed crystals were collected and 9.8 g of 9- (4-methyl-1-piperazinyl) -8-fluoro-2-methyl-1.2-dihydro-6-oxo-pi Roll gives [3,2,1-jj] quinoline-5-carboxylic acid. White rhombus crystal, melting point 242-244 degreeC.

Example 7

In a similar manner to Example 6, the compounds of Table 3 are prepared from suitable starting materials.

In Table 3, each compound is represented by a combination of R ¹ , R ² and X in formula (Ib), and is represented by the melting point and yield of the compound in step (b).

TABLE 3

Example 8

(a) Dimethyl ethoxymetallenmalonate (9 g) was added to 4- (1-peperazinyl) -5-chloro-2-methylindolin (6.8 g), and the mixture was heated at 160 DEG C for 30 minutes to obtain a solid. After formation, recrystallization with chloroform-n-hexane afforded 10.2 g (92%) of diethyl [4 (1-piperazinyl) -5chloro-2-methylindolin] methylenemalonate.

Elemental Analysis Value: C ₂₁ H ₂₆ N ₃ O ₄ Cl

C H N

Calculated Value (%): 60.22, 6.12, 10.14

Found (%): 60.07, 6.24, 10.01

(b) polyphosphoric acid (65 g) prepared from phosphorus pentoxide (32.5 g) and phosphoric acid (32.5 g) and diethyl [4- (1-piperazinyl) -5-chloro- obtained in step (a). 2-methyl-indolinyl] methylenemalonate (100 g) is heated at 140-150 ° C. for 1 hour. After completion of the reaction, the reaction mixture is poured into ice water (200 g) and the pH of the mixture is adjusted to 6-7 with 10N aqueous sodium hydroxide solution. The precipitate formed is collected by filtration and added to concentrated hydrochloric acid (60 ml). After the mixture was refluxed for 1 hour, water (100 ml) was added to the reaction mixture, the formed crystals were collected by filtration, washed with water and dried. Recrystallize from methanol to give 7.1 g (82.5%) of 9- (1-piperazininyl) -8-chloro-2-methyl-1,2-dihydro-6-oxo-pyrrolo [3,2,1-jj Obtain quinoline-5-carboxylic acid. Light yellow tetragonal crystal, melting point 258-260 degreeC.

Example 9

In a similar manner to Example 8, the compounds of Table 4 are prepared from suitable starting materials. In Table 4, each compound is represented by a combination of R ¹ , R ² and X in formula (Ib) and the melting point and yield of the compound in step (b).

TABLE 4

Example 10

Diethyl ethoxymethylenemalonate (6.0 g) was added to 4- (4-methyl-1-piperazinyl) -5-fluoro-2-methylindolin (6.2 g) and the mixture was heated at 160 ° C. for 30 minutes. Let's do it. Then polyphosphoric acid (48 g) prepared from phosphorus pentoxide (24 g) and (24 g) is added and the resulting mixture is heated at 150 to 160 ° C for 1 hour. After completion of the reaction, the reaction mixture is poured into ice water (150 g) and the precipitate formed is collected by filtration, washed with water and dried. 10% aqueous sodium hydroxide solution (70 ml) is added to the obtained crystals, and the mixture is reacted at 100 to 110 ° C for 1 hour. After cooling, the reaction mixture is acidified with concentrated hydrochloric acid to form crystals. Collected by crystal heat filtration, washed with water and recrystallized with methanol, and 7.1 g (84%) of 9- (4-methyl-1-piperazinyl) -8-fluoro-2-methyl-1,2-dihydro- 6-oxo-pyrrolo gives [3,2,1-ij] quinoline-5-carboxylic acid. White rhombus crystal, melting point 242-244 degreeC.

Although the present invention has been described in detail with particular embodiments thereof, it will be apparent to those skilled in the art that various modifications may be made without departing from the spirit and scope of the invention.

Claims (21)

A method for producing a benzoheterocyclic compound of formula (I), characterized by ring closure of the benzoheterocyclic compound of formula (II).

Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or a hydroxy group, or a lower alkanoyl group which may be substituted with a halogen atom, X is A hydrogen atom or a halogen atom, n is an integer of 1 or 2, provided that when n is 1, R ² cannot be a lower alkyl group substituted with a halogen atom, R ³ and R ⁴ are the same or different, and Lower alkyl group. The process according to claim 1, wherein the ring closure reaction is carried out by heating the compound of general formula (II) to a temperature of about 100 to 250 캜 in a solvent. The process of claim 2 wherein the reaction is carried out at 150 to 200 ° C. The process according to claim 2 or 3, wherein the solvent is a high boiling hydrocarbon or a high boiling ether. The method according to claim 4, wherein the solvent is tetralin, diphenyl ether or diethylene glycol dimethyl ether. The method of claim 1, wherein the ring closure reaction is carried out at about 100 to 150 ° C. for about 0.5 to 6 hours using at least 1 mole to a large excess of acid per mole of the compound of formula II. 7. The process according to claim 6, wherein the amount of acidic substance is 10 to 20 moles per mole of the compound of formula II. 8. Process according to claim 6 or 7, wherein the acidic material is phosphorus oxychloride, phosphorus pentachloride, phosphorus acid chloride, thionyl chloride, concentrated sulfuric acid or polyphosphoric acid. Forming a benzoheterocyclic compound of formula (IV) by ring-closing the quinoline compound of formula (III), and then hydrolyzing it, to prepare a benzoheterocyclic compound of formula (I) Way.

In the above formula R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom, a lower alkyl group which may be substituted with a halogen atom or a hydroxy group, or a lower alkanoyl group which may be substituted with a halogen atom, X is a hydrogen atom or A halogen atom, n is an integer of 1 or 2, provided that when n is 1, R ² cannot be a lower alkyl group substituted with a halogen atom, and R ⁵ is a lower alkyl group. 10. The process of claim 9, wherein the ring closure reaction is carried out by heating the compound of formula III in a solvent to a temperature of about 100 to 250 < 0 > C. The method of claim 10, wherein the reaction is carried out at 150 to 200 ° C. 12. The process of claim 10 or 11 wherein the solvent is a high boiling hydrocarbon or a high boiling ether. 13. The process of claim 12 wherein the solvent is tetralin, diphenyl ether or diethylene glycol dimethyl ether. 10. The process of claim 9, wherein the ring closure reaction is carried out at about 100 to 150 [deg.] C. for about 0.5 to 6 hours using at least 1 mole to a large excess of acid per mole of the compound of formula III. The method according to claim 14, wherein the amount of the acid used is 10 to 20 moles per mole of the general formula (III) compound. The process according to claim 14 or 15, wherein the acidic material is phosphorus oxychloride, phosphorus trichloride, thionyl chloride, concentrated sulfuric acid or polyphosphoric acid. The process of claim 9 wherein the hydrolysis is carried out at room temperature to 200 ° C. in the presence of a catalyst. 18. The process of claim 17, wherein the hydrolysis is carried out at 50 to 150 ° C. 19. The method of claim 18, wherein the hydrolysis is carried out in a solvent. The method of claim 17, wherein the catalyst is a basic compound. 18. The process of claim 17, wherein the catalyst is an inorganic acid or an organic acid.