KR950008317B1 - The preparation process of benzoxazine derivatives - Google Patents

Abstract

This is new 9-halo-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de [1,4 benzoxazine-6- carboxylic acid and its parmaceutically acceptable salt of formula(I). This compd. is used as an antibacterial agent. In formula, X is halogen atom; R is H or C1-C6 alkyl; and A mono-, di- or the other hetero atom-containing cyclic substituted amino gp. These derivatives manufacturing method comprises; 1) reacting the compd. of formula(II) and compd. of (III) in polar solvent in the presence of acid acceptable compd.; 2) reducing the product; 3) cyclizing the reduced compd. in polar solvent in the presence of strong alkaline; 4) reacting the above product with diethylethoxymethylene malonate or dimethylmethoxymethylene malonate; 5) hydrolysing the product of (4); 6) and reacting with amine compd. of (IX). This compd has excellent antibacterial activity.

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] having the following general formula (I) to be used as an antibacterial agent. Benzoxazin-6-carboxylic acid derivatives and pharmaceutically acceptable salts thereof.

[Formula 1]

Wherein X represents a halogen atom, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A represents a cyclic substituted amino group containing a single substituted amino group or a substituted amino group or another heteroatom. As an example of a single substituted amino group, it includes a monomethyl amino group, a monoethyl amino group, and this substituted amino group includes a dimethyl amino group, a diethyl amino group. A cyclic substituted amino group refers to an amino group having a 4 to 7 membered ring, and examples thereof include azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl and homo piperazinyl, and more specifically 4-methyl-1- Piperazinyl, 1-piperazinyl, 1-phyllolidinyl, 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-piperidinyl, homo pipera Genyl, 1-pyrazolidyl, 2-methyl-1-pyrazolidyl and the like.

As a method for producing a compound of the present invention, the contents of the Republic of Korea Patent Publication (B1) Publication No. 84-2141 are represented by the reaction route as follows.

Scheme 1

This conventional reaction is subjected to a two-step cyclization reaction of a cyclization reaction through a hydrogenation reaction in which the reaction is performed under difficult conditions to form a benzoxazine ring structure, and a cyclization reaction forming a quinoline ring structure, Difficult separation process In contrast, the present invention provides a new production method that can avoid the same hydrogenation reaction but the same number of reaction processes.

The present invention relates to a method for preparing compound (I) with high purity under easy reaction conditions, which is characterized by having a completely different reaction route from the conventional method, and the following describes the reaction route of the present invention.

Scheme 2

Wherein X, R and A are as defined above.

The present invention will be described in detail as follows. The aromatic amine compound of formula (II) and the 2-halo ester compound of formula (III) are reacted in the presence of an acid acceptor to obtain a compound of formula (IV). At this time, an organic solvent having high polarity such as dimethyl sulfoxide, dimethylformamide, acetonitrile and the like is suitable.As the reaction condition, the acid acceptor may use 1.0-5.0 equivalents of sodium carbonate or potassium carbonate in molar ratio to the compound of formula (II). The reaction temperature is 90-150 ° C., the reaction time is 8-24 hours, and it is preferable to perform the reaction using crown ether as a solvent. After the reaction, extraction, drying, filtration, evaporation, and As a combined technique, a compound of general formula (IV) is obtained and the reducing agent such as lithium aluminum hydride (LiAlH ₄ ) or sodium borohydride (NaBH ₄ ) is added to the compound of general formula (IV) 1.0-1.5. Reduction using an equivalent yields the compound of formula (V) as extraction, drying, filtration, evaporation separation and combination techniques thereof. At this time, the reaction conditions are completed by using organic solvents such as methanol, ethanol and ether as a solvent and stirring at room temperature for 3-6 hours.

The obtained compound of formula (V) is selected from sodium hydride (NaH), potassium hydride (KH), potassium fluoride (KF), sodium alkoxide (RONa) and potassium alkoxide (ROK), wherein R is carbon number 1-3 To a compound of formula (VI) by reaction in the presence of a strong base such as dioxane, dimethylformamide, etc. as reaction conditions. The reaction temperature is 70-150 ° C. and the reaction time is 1-. 3 hours is preferred.

The compound of the general formula (VI) is reacted with diethylethoxymethylene malonate or dimethylmethoxymethylene malonate to obtain a compound of the general formula (VI). At this time, as the reaction conditions, the compound of general formula (VI) and diethylethoxymethylene malonate or dimethylmethoxymethylene malonate were reacted at a temperature of 100-200 ° C. for 2-6 hours in a solvent or without solvent. The ethanol generated during the reaction was distilled off under reduced pressure, and then cyclized at 150-250 ° C. for 2-4 hours using a solvent having a high boiling point such as diphenyl ether. To obtain the compound of formula (VII).

In addition, polyphosphoric acid or its ester may be used as a catalyst in a diphenyl ether solvent during the cyclization reaction, or the reaction may be carried out using polyphosphoric acid or its ester as a catalyst and solvent without a diphenyl ether solvent. .

The compound of formula (V) is hydrolyzed to obtain a compound of formula (V), which can be hydrolyzed under acidic or basic conditions, and sodium hydroxide in water, dioxane, methanol, ethanol and a mixed solvent thereof. After reacting with a base such as potassium hydroxide for about 1-4 hours at about 60-120 ° C, the reaction mixture is cooled and treated with acetic acid or hydrochloric acid to generate a solid, or in general form (HCl) in hydrochloric acid, acetic acid or a mixture thereof. After reacting the compound of about 1-4 hours at a temperature of 60-120 ℃ and cooling at room temperature, the solid produced by filtration, evaporation, recrystallization and a combination of these techniques to obtain a pure compound of general formula (Ⅷ) Get

The obtained compound of formula (VIII) is reacted with an amine compound of formula AH to obtain a compound of formula (I) as a target substance, wherein reaction conditions include an amine of formula AH corresponding to 1.2-5.0 equivalents in molar ratio. After reacting the compound of the formula (10) with a polar solvent such as dimethylformamide and dimethyl sulfoxide at a temperature of 100-150 ° C for 10-20 hours, cooling it to room temperature, it is filtered, extracted, evaporated, recrystallized and their The compound of general formula (I) can be obtained by the combined technique, and the obtained compound of general formula (I) is less toxic and has excellent antimicrobial activity against gram negative bacteria or gram positive bacteria.

The present invention is explained in detail by the following examples.

Example 1

1) Preparation of ethyl 2- (3,3,4-trifluorophenyl) aminopropanoic acid ester.

5.0 g of 2,3,4-trifluoroaniline, 4.7 g of potassium carbonate, 6.8 g of 2-bromopropanoic acid ethyl ester, and 0.5 g of 18-crown-6-ether were mixed with a dimethylformamide solvent to obtain 12 After heating for a while, the mixture was cooled and the reaction mixture was mixed with water and ethyl acetate. The organic layer was separated and dried to remove the solvent under reduced pressure. After removing the solvent, the resulting residue was purified by silica gel chromatography to obtain 5.0 g of ethyl 2- (2,3,4-trifluorophenyl) aminopropanoic acid ester.

2) Preparation of N- (1-hydroxypro-2-fil) -2,3,4-trifluoroaniline.

5.0 g of ethyl 2- (3,3,4-trifluorophenyl) aminopropanoic acid ester was dissolved in 100 ml of ether, 0.8 g of lithium aluminum hydride was added thereto, and reacted at room temperature for 1 hour, followed by reflux for 3 hours. After the reaction was neutralized with diluted hydrochloric acid, extracted with ethyl ether, dried and concentrated to obtain 3.3 g of N- (1-hydroxyprop-2- pil) -2,3,4-trifluoroaniline.

3) Preparation of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine.

3.0 g of N- (1-hydroxypro-2-fil) -2,3,4-trifluorobenzene and 0.9 g of potassium fluoride were mixed in 50 ml of dimethylformamide, refluxed for 3 hours, and cooled to room temperature. The solvent was removed under reduced pressure. The residue was mixed with chloroform and water, and then the organic layer was separated and dried to remove the solvent under reduced pressure, and the residue was purified by silica gel chromatography to obtain pure 7,8-difluoro-2,3-dihydro-3. 2.2 g of -methyl-4H-1,4-benzoxazine was obtained.

4) 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrid [1,2,3, -de] [1,4] benzoxazine-6- Preparation of Carboxylic Acids.

3.0 g of 7,8-difluoro-2,3-dihydro-3-methyl-4h-1,4-benzoxazine and 5.3 g of diethyl ethoxymethylene malonate were mixed without a solvent for 4 hours at 130 ° C. After heating for 2 hours, by-product ethanol was removed, and 20.0 g of polyphosphoric acid ethyl ester was added thereto, followed by heating for 4 hours. Cold water was added to the reaction vessel, and the mixture was extracted with chloroform. The chloroform layer was washed with an aqueous potassium carbonate solution, dried and concentrated under reduced pressure, and 50 ml of acetic acid-hydrochloric acid (2/1) was added to reflux for 4 hours. The reaction vessel was cooled to room temperature, and the resulting solid was filtered to give 9,10-7,8-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyride [1,2,3 -de] [1,4] benzoxazine-6-carboxylic acid 2.7 g was obtained.

5) 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido- [1,2,3-de] Preparation of [1,4] benzoxazine-6-carboxylic acid.

9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid 1.0 g, 0.5 g of N-methylpiperazine, 1.5 g of pyridine, and 5 ml of dimethyl sulfoxide were mixed and heated at a temperature of 120-140 ° C. for 12 hours, and then the solvent was removed under reduced pressure. Water was added to the reaction vessel, and the resulting solid was filtered and recrystallized with ethanol to obtain pure 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7- 0.84 g of oxo-7H-pyrido- [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid is obtained.

Melting Point: 250-257 ℃ (Decomposition)

Example 2

The reaction was carried out in the same manner as in Example 1, except that 5.0 g of 2,3,4-trichloroaniline was added instead of 2,3,4, -trifluoroaniline in the first step of Example 1. 9-chloro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido- [1,2,3-de] [1, 4] 0.82 g of benzoxazine-6-carboxylic acid was obtained.

Example 3

In the fifth step of Example 2, except that 0.45 g of piperazine was added instead of N-methylpiperazine, 9-fluoro-2,3-dihydro-3 was reacted in the same manner as in Example 1. 0.79 g of -methyl-10-piperazinyl-7-oxo-7H-pyrido- [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid was obtained.

Melting Point: 257-260 ℃ (Decomposition)

Claims (5)

The compound of formula (II) is reacted with a compound of formula (III) in a polar solvent in the presence of an acid acceptor compound to prepare a compound of formula (VI), and then reduced with a reducing agent to After the compound is prepared, it is cyclized in a polar solvent in the presence of a strong base to prepare a compound of formula (VI), and then the compound is reacted with diethylethoxymethylene malonate or dimethylmethoxymethylene malonate to give a general formula ( The compound of formula (I) characterized by reacting a compound of formula (VII) obtained by hydrolyzing this compound with an amine compound of formula (VII) in a polar solvent is prepared. Method for preparing halo-7-oxo-2,3--dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid derivative. Wherein X represents a halogen atom, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A represents a cyclic substituted amino group containing a single substituted amino group or a substituted amino group or another hetero atom. The 9-halo-7-oxo-2,3--dihydro-7H-pyrido of formula (I) according to claim 1, wherein the polar solvent is dimethylformamide or dimethyl sulfoxide. , 3-de] [1,4] benzoxazine-6-carboxylic acid derivative. The 9-halo-7-oxo-2,3--dihydro-7H-pyrido of formula (I) according to claim 1, wherein the acid acceptor compound is sodium carbonate or potassium carbonate. -de] [1,4] method of preparing benzoxazine-6-carboxylic acid derivative. The 9-halo-7-oxo-2,3--dihydro-7H-pyrido of formula (I) according to claim 1, wherein the reducing agent is lithium aluminum hydride or sodium borohydride. A process for preparing a 2,3-de] [1,4] benzoxazine-6-carboxylic acid derivative. The 9-halo-7-oxo-2,3--dihydro-7H-pyrido of formula (I) according to claim 1, wherein the strong base is sodium hydride, potassium hydride or potassium fluoride. Method for preparing 1,2,3-de] [1,4] benzoxazine-6-carboxylic acid derivative.