KR970005310B1 - The process of preparing benzoxazine derivatives - Google Patents

Abstract

9-halo-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de [1,4 benzoxazine-6-carboxylic acid derivative and pharmaceutically acceptable salts thereof represented by the formula(I) is prepared by the following steps; a compound of formula(IV) is prepared by reacting a compound of formula(II) with a compound of formula(III), cyclizing the compound(IV) to prepare a compound of formula(V), and then reacting the compound(V) with diethylethoxymethylene malonate or dimethyl methoxymethylene malonate to prepare a compound of formula(VI) followed by reacting the compound(VII) obtained by hydrolysis of the compound(VI) with an amine compound of formula AH wherein, X is halogen, R is hydrogen or alkyl having 1-6 carbon atoms, A is single substituted amino, cyclized substituted amino having the substituted amino or different hetero atoms.

Description

Method for preparing benzoxazine derivatives

The present invention relates to 9-halo-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1.4] benzoxazine-6-carboxylic acid of the general formula (I) It relates to a derivative and a method for preparing a pharmaceutically acceptable salt thereof.

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. Examples of a single substituted amino group include a monomethyl amino group and a monoethyl amino group, and the substituted amino group includes a dimethyl amino group and a diethyl amino group. A cyclic substituted amino group refers to an amino group having a 4 to 7 membered ring, for example, azetidinyl, pyrrolidinyl, morpholinyl, pepperrazinyl and homopyrerazinyl, more specifically 4-methyl-1 Piperazinyl, 1-piperazinyl, 1-pinolidinyl, 3-hydroxy-4morpholinyl, 4- (2-hydroxyethyl) piperazinyl, 3,5-dimethyl-1-pipera Genyl, 4-dimethylamino-1-piperidinyl, homopiperazinyl, 1-pyrazolidyl, 2-methyl-1-pyrazolidyl and the like.

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

In the above formula, X, A, R are as defined above.

On the other hand, the present invention relates to a method for preparing compound (I) with a short reaction route and high purity, characterized in that it has a completely different reaction route from the conventional method as described above, and describes such a reaction route of the present invention. Is as follows.

In the above formulas, X, R and A are as defined above.

Hereinafter, the present invention will be described in detail.

The aromatic amine derivative of Formula (IV) is prepared by reacting the aromatic amine of Formula (II) with 2-ketoalcohol of Formula (III), followed by reduction with a reducing agent such as sodium borohydride.

Reaction of the 2-ketoalcohol of the general formula (III) with 1.0 to 2.0 equivalents of the aromatic amine of the general formula (II) is carried out in a polar organic solvent such as methanol or ethanol or directly without the reaction solvent. The reactor is refluxed for 3-6 hours using a reactor that can be completely sealed as a pressurized reactor and then cooled at room temperature.

0.5 to 1.0 equivalent of sodium borohydride was added to the reaction vessel with respect to the amine of formula (II) to react for 3-5 hours at room temperature, followed by extraction, drying, filtration, evaporation, and a combination thereof. The aromatic amine corresponding to formula (IV) is obtained.

The obtained compound of formula (IV) is reacted in the presence of strong bases such as sodium hydride (NaH), potassium hydride (KH), potassium fluoride (KF), sodium alkoxide (RONa) and potassium alkoxide (ROK) Obtaining the compound of Formula (V), At this time, dioxane, dimethylformamide, etc. are used as reaction conditions, The reaction temperature is 70-150 degreeC, The reaction time is 1-3 hours.

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

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

The compound of formula (VI) is hydrolyzed to obtain a compound of formula (V). The hydrolysis conditions are all possible 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 produce a solid, or a general formula (HCl) in After reacting the compound of VI) at a temperature of 60-120 ° C. for 1-4 hours and cooling to room temperature, the solid produced was filtered, evaporated, recrystallized, and a combination of these techniques to obtain a pure general formula. Obtain the compound.

The obtained compound of formula (VII) is reacted with an amine compound of formula AH to obtain a compound of formula (I) as a target product, wherein the reaction conditions are amines of general formula AH corresponding to 1.2-5.0 equivalents in molar ratio and general The compound of formula (VII) is reacted at a temperature of 100-150 ° C. for 10-20 hours using a polar solvent such as dimethylformamide and dimethyl sulfoxide, cooled to room temperature, filtered, extracted, evaporated, recrystallized and a combination thereof. By the method of the present technique, the pure compound of general formula (I) can be obtained, and the obtained compound of general formula (I) is less toxic and has excellent antimicrobial activity against gram negative bacteria and gram positive bacteria.

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

Example 1

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

5.0 g of 2,3,4-trifluoroaniline and 3.8 g of acetol are mixed in a methanol solvent and added to a reactor which can be sealed. The mixture is refluxed for 5 hours, cooled to room temperature, and 1.3 g of sodium borohydride is reacted. It was added to and stirred at room temperature for 4 hours. The reaction solution was neutralized with dilute hydrochloric acid, extracted with ether, dried and concentrated, and then the residue was purified by silica gel chromatography to give N- (1-hydroxypro-2-fil) -2,3,4-trifluoro. 5.5 g of aniline were obtained.

2). 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 then cooled to room temperature to obtain a solvent. Was removed under reduced pressure. After chloroform and water were added to the residue, 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-methyl. 2.2 g of -4H-1,4-benzoxazine was obtained.

3). 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzooxacin-6-carboxylic acid Manufacturing.

3.0 g of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine and 5.3 g of diethylethoxymethylene malonate were mixed without a solvent for 4 hours at 130 ° C. After heating for ethanol as a by-product 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, followed by extraction 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-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1 , 4] 2.7 g of benzoxacin-6-carboxylic acid was obtained.

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

9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzooxacin-6-carboxylic acid 1.0 g, N-methylpiperazine 0.5 g, pyridine 1.5 g, 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- Preparation of oxo-7H-pyrido [1,2,3-de] [1,4] benzooxacin-6-carboxylic acid. 0.84 g was obtained.

Melting Point: 250-257 ℃ (Decomposition)

Example 2

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 -Difluoro-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.

Melting Point: 275-276 ℃ (Decomposition)

Example 3

In Example 5, 9-halo-7-oxo-2,3-dihydro- was reacted in the same manner as in Example 1, except that 0.45 g was added instead of N-methylpiperazine. 0.79 g of 7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid was obtained.

Melting Point: 257-260 ℃ (Decomposition)

Claims (2)

After reacting a compound of formula (II) with a compound of formula (III) to prepare a compound of formula (IV), the compound is cyclized to prepare a compound of formula (V), and then this compound Was reacted with diethylethoxymethylene malonate or dimethylmethoxymethylene malonate to prepare a compound of formula (VI), and then a compound of formula (VII) obtained by hydrolysis of this compound with an amine of formula AH 9-halo-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine of general formula (I) characterized by reaction with a compound To prepare a -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, this substituted amino group or another hetero atom. The method according to claim 1, wherein the compound of formula (II) is reacted with a compound of formula (III) and reduced with sodium borohydride to obtain a compound of formula (IV).