KR940004811B1 - Process for preparing benzoxazine derivatives - Google Patents

Abstract

A method for preparing 9-halo-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de [1,4 benzoxazine-6-carboxylic acid derivs. of formula (I) comprises: (a) reacting a cpd. of formula (II) with dialkyl alkoxy methylene malonate of formula (III) to obtain a cpd. of formula (IV); (b) cyclizing (IV) in diphenylether solvent at 150-250 deg.C for 2-4 hrs.; (c) reacting the obtd. cpd. with a cpd. of formula (V); (d) hydrolyzing the obtd. cpd.; and (e) reacting the obtd. cpd. with AH. The catalyst of the cyclization reaction is pref. polyphosphoric acid or its acid ester. In the formulas, R = H or C1-6 alkyl; R1 = C1-2 alkyl; X = halogen; A = mono-, di- or ring-substd. amino gp. The cpds. (I) is useful as an antibacterial agent.

Description

Method for preparing benzoxazine derivatives

The present invention provides 9-halo-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzox of the following general formula used as an antimicrobial agent It relates to a photo-6-carboxylic acid derivative and a method for preparing a pharmaceutically acceptable salt thereof.

Wherein X represents a halogen atom, R represents a hydrogen atom or a lower alkyl group of 1 to 6 carbon atoms, and A represents a cyclic substituted amino group containing a single substituted amino group, a di (di) substituted amino group, or another hetero atom Indicates.

Examples of monosubstituted amino groups include monoethyl amino groups and monomethylamino groups, examples of di-substituted amino groups include dimethylamino groups and diethylamino groups, and cyclic substituted amino groups mean amino groups having 4-7 membered rings. Azetidinyl, pyrrolidinyl, morpholininyl, piperazinyl and homopiperazinyl, more specifically 4-methyl-1-piperazinyl, 1-piperazinyl, 1-pyrrolidinyl , 3-hydroxy-1-pyrrolidinyl, 1-piperidinyl, 4-hydroxy-1-piperidinyl, 3-hydroxy-1-piperidinyl, 4-morpholinyl, 4- (2 -Hydroxyethyl) piperazinyl, 3,5-dimethyl-1-piperazinyl, 4-dimethylamino-1-piperazinyl, homopiperazinyl, 1-pyrazolidyl, 2-methyl-1-pyra Zolidyl and the like.

The compounds of the present invention can produce acid addition salts with inorganic or organic acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, and the like, and can produce sodium, potassium, and the like carboxylic acid salts.

As a preparation method for the compound of the present invention, Korean Patent Publication No. 84-2141 discloses the preparation of the target compound by the following method.

This conventional manufacturing method is to perform a two-step cyclization reaction of the cyclization reaction to form a benzoxazine ring structure and the cyclization reaction through a hydrogenation reaction in which the reaction is carried out under difficult conditions to form a quinoline ring structure It is a method of producing a six-step manufacturing process from the starting material, such as a long reaction path is ineffective, and must undergo a hydrogenation reaction and a difficult separation process.

As a result of long research, the inventors of the present invention have developed a method for preparing a short route and a high purity compound (i), and the reaction route of the present invention is represented by the following reaction scheme.

In more detail, the compound of formula (I) is reacted with diethyl ethoxymethylenemalonate of formula (II) or dimethyl methoxymethylenemalonate to obtain a compound of formula (III).

In this case, the reaction conditions are obtained by reacting the compounds of the general formulas (I) and (II) for 2-4 hours at a temperature of 100 ° C. to 200 ° C., in the presence or absence of a solvent, and then cooling them to room temperature to obtain a solid. Using a solvent having a high boiling point such as phenyl ether, the reaction is cyclized at a temperature of 150 to 250 degrees for 2 to 4 hours, and then cooled to room temperature to obtain a compound of formula (IV).

In the cyclization reaction, polyphosphoric acid or its ester can be used as a catalyst or a solvent.

When the obtained compound of formula (IV) is reacted with a compound of formula (V), a compound of formula (IV) is obtained, wherein as the solvent, dimethylformamide having a high boiling point and a polar solvent is preferable, and the molar ratio is 5 After the reaction was carried out at about 90 to 150 degrees for 20 to 30 hours using an acid acceptor of 10 to 10 times, cooling to obtain a compound of the general formula (VI).

Herein, the compound of formula (V) may be used in a molar ratio of 1 to 5 times with respect to the compound of formula (IV). As the acid acceptor, carbonates, bicarbonates and the like of alkali metals such as potassium carbonate and sodium carbonate are preferable.

The compound of formula (VI) is hydrolyzed to obtain a compound of formula (VII). The hydrolysis conditions are all possible under acidic or basic conditions, and sodium hydroxide, potassium hydroxide, etc. in water, dioxane and mixed solvents thereof. After reacting with a base such as 60 to 120 degrees for about 1 to 3 hours, the mixture was cooled and treated with acetic acid or hydrochloric acid to obtain a compound obtained by the method of filtration, extraction, evaporation, recrystallization, and a combination thereof. Get)

The obtained compound of formula (VII) was reacted for 3-6 hours at 150-200 degrees using potassium fluoride corresponding to 3-6 times in molar ratio in polar solvent such as dimethylformamide and dimethyl sulfoxide. The compound of the general formula (VII) is obtained by reacting with an amine compound of the general formula (IV) corresponding to 1.5 to 5 times in molar ratio.

The reaction with the amine compound of the general formula is similarly preferably reacted for about 3-6 hours at a temperature of 150-200 degrees, and the resulting solids are filtered or extracted, evaporated, recrystallized, and mixed By the method of the technique, a pure compound of general formula can be obtained, and the obtained compound of general formula is less toxic and has excellent anti-silicone activity against gram negative bacteria and gram positive bacteria.

The present invention will now be described in detail by way of examples.

Example 1

10.0 g of 2,3,4-trifluoroaniline and 14.7 g of diethyl ethoxymethylenemalonate were mixed, heated at a temperature of 140-150 ° C. for 3 hours, and cooled to obtain a solid produced by filtration. After refluxing for about 1 hour in the presence of a phenyl ether solvent and cooling to room temperature, the resulting solid was filtered to obtain 8.7 g of 6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester.

5.0 g of 6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester, 12.8 g of 2-bromopropanol, and 6.4 g of potassium carbonate were mixed in 50 ml of dimethylformamide and mixed at 100 ° C for 24 hours. After cooling to reflux for a time, the solvent was removed and the resulting concentrate was extracted with chloroform and washed with water.

The chloroform portion was dried and then distilled under reduced pressure to remove the solvent, and 90.0 ml of 2N NaOH was added thereto, followed by reflux for 2 hours.

The reaction vessel was cooled to room temperature, acidified with acetic acid, filtered, and then recrystallized with dimethylformamide to obtain pure 6,7,8-trifluoro-1,4-dihydro-1- (1-hydroxypro- 3.0 g of 2-phil) -4-oxoquinoline-3-carboxylic acid were obtained.

2.0 g of 6,7,8-trifluoro-1,4-dihydro-1- (1-hydroxypro-2-fil) -4-oxoquinoline-3-carboxylic acid and 2.3 g of potassium fluoride After mixing in 10 ml of dimethylformamide and refluxing for about 1 hour, 1.3 g of N-methylpiperazine was added to the reaction vessel and refluxed for about 3 hours. The reaction vessel was cooled to room temperature, the solvent was removed under reduced pressure distillation, water was added, and the resulting solid was filtered and recrystallized with ethanol to give 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl 1.4 g of -1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid was obtained.

Melting Point: 250-257 degrees (decomposition)

Example 2

12.0 g of 2,3,4-tlychloroaniline and 14.9 g of diethyl ethoxymethylenemalonate were mixed, heated at a temperature of 155 ° C. for 3 hours, and cooled to obtain a solid produced by filtration. After refluxing for about 1 hour in the presence and cooling to room temperature, the resulting solid was filtered to obtain 8.5 g of 6,7,8-trichloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester.

5.0 g of this product, 12.8 g of 2-bromopropane and 6.4 g of potassium carbonate were mixed in 50 ml of dimethylformamide, refluxed at 100 ° C for 24 hours, cooled, and the solvent was extracted. The concentrated solution was extracted with fluoroform, and extracted with water. Wash. The chloroform part is dried and distilled under reduced pressure to remove the solvent, and 90.0 ml of 2N NaOH is added thereto, followed by reflux for 2 hours.

The reaction vessel was cooled to room temperature and acidified with acetic acid. The solid obtained was filtered and then recrystallized from dimethylformamide to obtain pure 6,7,8-trifluoro-1,4-dihydro-1- (1-hydroxypro- 3.1 g of 2-phil) -4-oxoquinoline-3-carboxylic acid were obtained.

2.0 g of this product and 2.3 g of potassium fluoride were mixed in 10 ml of dimethylformamide, refluxed for about 1 hour, and then reacted with 1.1 g of piperazine in the same manner as in Example 1 to react 9-fluoro-2,3-dihydro. -3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid 1.4 g was obtained.

Melting Point: 258-261 Degrees (Decomposition)

Example 3

The same procedure as in Example 1 except that 0.9 g of pyrrolidine was used instead of N-methylpiperazine, 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl- 1.3 g of 1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid was obtained.

Melting Point: 268-269 degrees (decomposition)

All temperatures used herein are in degrees Celsius.

Claims (2)

A compound of formula (I) is reacted with a dialkylalkoxymethylenemalonate of formula (II) to prepare a compound of formula (III), followed by a cyclization reaction to prepare a compound of formula (IV). The compound is reacted with a compound of formula (V) to prepare a compound of formula (VI), followed by hydrolysis to produce a compound of formula (VII), and then to react with the compound of formula (VII). 9-halo-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6 represented by the general formula A process for preparing a carboxylic acid derivative. The method of claim 1, wherein the cyclization is reacted in the presence of a catalyst selected from polyphosphoric acid and polyphosphoric acid esters. Wherein R is a hydrogen atom or a lower alkyl group having 1-6 carbon atoms, R ¹ is a lower alkyl group having 1-2 carbon atoms, X is a halogen atom, A is a monosubstituted amino group, a di (di) substituted amino group or It is a cyclic substituted amino group.