KR20080021944A - The preparation method of optically active benzoxazine derivative - Google Patents

Abstract

A preparation method of optically active benzoxazine derivatives is provided to simplify the preparation procedures by eliminating the chromatography process, and improve optical purity by using (L)-alaninol as a natural amino acid, so that the method is useful for industrial production of the compounds. A preparation method of optically active benzoxazine derivatives represented by the formula(1) comprises the steps of: (a) adding trimethyl orthoformate into 2,3,4,5-tetrafluorobenzoylacetic acid ethyl represented by the formula(10) to prepare compounds represented by the formula(11); (b) substituting the compounds represented by the formula(11) by L-alaninol to prepare compounds represented by the formula(12); (c) cyclizing the compounds represented by the formula(12) in the presence of polar solvent and base to prepare intermediate compounds represented by the formula(13) and the formula(8); (d) reacting the intermediate compounds represented by the formula(13) and the formula(8) in the presence of polar solvent and base to prepare compounds represented by the formula(9); and (e) reacting the compounds represented by the formula(9) with C1-C6 4-alkyl-piperazine in the presence of polar solvent and base, wherein the polar solvent is methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide or dimethylsulfoxide; and the base of steps (c) and (d) is potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide or a mixture thereof, and the base of step (e) is pyridine, triethylamine or imidazol.

Description

The preparation method of optically active benzoxazine derivative

The present invention relates to a method for preparing an optically active benzoxazine derivative, and more particularly, to a new method for preparing an optically active benzoxazine derivative which can obtain a compound represented by the following Chemical Formula 1 useful as an antibiotic in high yield. .

Compound ((-)-9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido represented by Chemical Formula 1 [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid) is a conventional antimicrobial agent (±) -9-fluoro-2,3-dihydro-3 (S)- Methyl-10- (4-methylpiperazinyl) -7-oxo-7H-pyrido [1,2,3-de] -1-4-benzoxazine-6-carboxylic acid) It has weaker toxicity and acts as a powerful antibacterial activator (Japanese Patent Publication No. 7-47592)

The prior art for producing the optically active benzoxazine derivative of the formula (1), according to the following scheme 1 disclosed in Japanese Patent Application Laid-Open No. 7-47592. In Scheme 1, 3 (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H- [1,4] benzoxazine of Formula 5 and diethyl of Formula 6 Substituted benzoxazine derivatives of the following general formula (7) were produced from ethoxymethylenemalonate, and S (-)-pyridobenzoxazine derivatives of the following general formula (9) were generated from an acid catalyst using the compound of the general formula (7). (-)-9-halo-3 (S) -alkyl-10- (4-alkyl-1-piperazinyl) -7-oxo- 2 of formula (1) on basic conditions from 4-alkyl-piperazine ; 3 - Dihydro - 7H-pyrido [1,2,3 - dec] -1,4-benzoxazine-6-carboxylic acid was obtained.

However, the method has a low yield of 56% when synthesized from the compound of Formula 7 to the compound of Formula 9 by cyclization and hydrolysis. In addition, the compound of Chemical Formula 5 has a problem that it is difficult to apply industrially because the reaction route is very long and inefficient, such as to use an optical separation method, and to filter the first precipitation and then use column chromatography. In addition, in the process of synthesizing the compound of Formula 5, the optical purity of the compound of Formula 5 is no longer improved at 98%.

In order to solve the problems of the prior art as described above, an object of the present invention is to separate the filtrate through column chromatography after filtering the first precipitate by combining the (L) -proline derivative in the optical separation of the conventional benzoxazine derivatives In addition, it is to provide a method for producing a benzoxazine derivative in a high yield as an industrially useful method by improving the disadvantages such as going through several reaction steps and difficult to obtain more than 98% optical purity.

In order to achieve the above object, the present invention

a) preparing a compound of Formula 11 through addition reaction of trimethyl orthoformate using ethyl 2,3,4,5-tetrafluorobenzoyl acetate of Formula 10 as a starting material,

b) substituting the compound of Formula 11 and (L) -alaninol to prepare a compound of Formula 12,

c) preparing an intermediate compound of Chemical Formula 13 and Chemical Formula 8 by cyclization from the compound of Chemical Formula 12 under a polar solvent and basic conditions;

d) reacting an intermediate compound of Formula 13 with Formula 8 under polar solvent and basic conditions to prepare a compound of Formula 9, and

e) reacting the compound of formula 9 with 4-alkyl-piperazine of 1 to 6 carbon atoms under polar solvent and basic conditions

It provides a method for producing an optically active benzoxazine derivative represented by the following formula (1) comprising a.

[Formula 1]

[Formula 8] [Formula 9]

[Formula 10] [Formula 11]

[Formula 12] [Formula 13]

Hereinafter, the present invention will be described in more detail.

The present invention is (-)-9-fluoro-2,3-dihydro-3-methyl-10- (4-methylpiperazinyl) -7-oxo-7H- which is an optically active derivative represented by Chemical Formula 1 A method for producing pyrido [1,2,3-de] -1-4-benzoxazine-6-carboxylic acid.

The present inventors intend to prepare an optically active benzoxazine derivative in a simple reaction process and a high reaction yield, using trimethyl dimethylacetate (2,3,4,5-tetrafluorobenzoyl acetate) as a new starting material. The compound of formula 11 is synthesized through the addition reaction of orthoformate, and the compound of formula 12 is synthesized by substituting (L) -alaninol in an alcohol solvent, using a base catalyst in an organic solvent. Synthesis of the compound and confirmed that it can be synthesized from the benzoxazine derivative of the general formula (1) in high yield, to complete the present invention.

[Formula 1]

A preferred example of the method for producing the optically active benzoxazine of the present invention is shown in Scheme 2 below.

As in Scheme 2, the present invention is characterized by using ethyl 2,3,4,5-tetrafluorobenzoyl acetate of Formula 10 as a starting material, and reacted with trimethyl orthoformate in acetic anhydride solvent To prepare a compound of formula (11). At this time, the reaction conditions may be carried out for 2 to 10 hours, preferably 4 to 6 hours at a reaction temperature of 20 ~ 200 ℃, preferably 100 ~ 120 ℃. The trimethylorthoformate may be used in an amount of 1 to 4 equivalents based on the starting material.

Thereafter, the present invention is characterized in that the compound of Formula 11 is prepared by reacting the compound of Formula 11 with (L) -alaninol as a raw material of natural amino acid in the presence of a polar organic solvent. The reaction conditions may be carried out at a reaction temperature of -50 ~ 50 ℃, preferably 0 ~ 20 ℃, for 2 to 50 hours, preferably for 18 to 22 hours. The (L) -alanine may be used in an amount of 1 to 4 equivalents based on the compound of formula 11

As the polar organic solvent used in the reaction, it is preferable to use a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, and the like. Preferably ethanol is used.

Next, the present invention obtains the compound of formula 9 by reacting the compound of formula 12 with an alkali salt in a polar organic solvent and passing through the intermediate compounds of formula 13 and formula 8 through cyclization and hydrolysis with base. Can be. At this time, the reaction conditions are preferably carried out for 10 to 50 hours, preferably 20 to 35 hours at a reaction temperature of 10 ~ 100 ℃, preferably 40 ~ 60 ℃.

The polar organic solvent used in the reaction is preferably a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, more preferably acetonitrile Tetrahydrofuran is used after the use of reel.

The alkali salt in the reaction is preferably selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride and mixtures thereof, more preferably using potassium hydroxide after the initial use of potassium carbonate It is. The alkali salt may be used in an amount of 1 to 4 equivalents based on the compound of formula 12.

Finally, the present invention can be prepared in high yield by reacting the light-activated benzoxazine compound of the general formula (1) in a basic solvent from 4-alkyl-piperazine having 1 to 6 carbon atoms in a polar solvent.

The basic conditions are not particularly limited, but preferably, compounds such as pyridine, triethylamine, imidazole and the like may be used. The polar solvent used in the reaction may be a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like.

Hereinafter, preferred examples are provided to help understanding of the present invention, but the following examples are merely to illustrate the present invention, and the scope of the present invention is not limited to the following examples.

Example  1. Preparation of Compound of Formula 12

20.0 g of 2,3,4,5-tetrafluorobenzoyl acetate was dissolved in 45 mL of acetic anhydride and 16.0 g of trimethylorthoformate was added. Then, the mixture was stirred under reflux for 5 hours at 110-120 ° C., and the reaction mixture was concentrated under reduced pressure to prepare a compound of Formula 11. Thereafter, the obtained product was dissolved in 30 mL of ethanol, cooled to 0 ° C., and 6.4 g of L-alaninol ((S)-(+)-2-amino-1-propanol) was dissolved in 30 mL of ethanol. Added dropwise. The temperature was raised to room temperature, followed by stirring for 12 hours. The reaction mixture was concentrated under reduced pressure to give 26.2 g of a compound of formula 12 in oil form.

NMR (CDDl ₃ ) ppm: 1.0 (1H, t), 1.3 (3H, d), 1.89 (1H, d), 3.7 (3H, m), 4.1 (2H, q), 7.0 (1H, m), 8.2 (1H, m)

Example  2. Preparation of Compound of Formula 9

To 14.2 g of the obtained product in Example 1, 60 mL of acetonitrile was added and 6.92 g of potassium carbonate was added. Thereafter, the mixture was stirred at room temperature for 18 hours to pour the reaction mixture into 600 mL of water to precipitate an off-white powder of Formula 8 and Formula 13. 300 mL of tetrahydrofuran was added to the precipitate, and 240 mL of 10% potassium hydroxide was added thereto, followed by stirring at 70 ° C. for 3 hours. The reaction mixture is concentrated under reduced pressure to remove tetrahydrofuran, and the pH of the reaction mixture is adjusted to 4.0 with acetic acid to yield a pale yellow precipitate. The precipitate was filtered and dried to give 6.2 g of the compound represented by the formula (9) as a solid (3 (S) -9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H- Pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid) was obtained.

NMR (DMSO) ppm: 1.3 (3H, d), 4.5 (1H, dd), 4.7 (1H, dd), 5.0 (1H, m), 7.8 (1H, q), 9.0 (1H, s)

Example  3. Preparation of Compound of Formula 1

7.5 g of 1-methylpiperazine and 3.2 g of pyridine were added to 11 g of the compound of Formula 9 obtained in Example 2 and heated at 110-120 ° C. for 4 hours. The reaction mixture was distilled under reduced pressure and the solid obtained was suspended in 150 mL of 95% methanol, and 22 mL of triethylamine was added thereto. The mixture was heated to reflux for 25 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 150 mL of 10% hydrochloric acid and washed three times with chloroform. The washed solution was adjusted to pH 11 with 4N aqueous sodium hydroxide solution, and then adjusted to pH 7.3 using 1N hydrochloric acid. This solution was extracted three times with 500 mL of chloroform and the collected extracts were dried over sodium sulfate. Thereafter, chloroform was removed by distillation, and the resulting crystals were recrystallized in ethanol / diethyl ether to give the desired compound (3 (S) -9-fluoro-3-methyl-10- (4-methyl). -1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid) (Optical purity 99.8%) was obtained.

NMR (CDDl ₃ ) ppm: 1.6 (3H, d), 2.3 (4H, m), 2.5 (4H, m), 3.4 (3H, m), 4.3 (3H, m), 7.7 (1H, d), 8.6 (1H, s)

Comparative example

An acid chloride solution prepared from 61.9 g of (S) -Np-toluenesulfonylproline and thionylchloride in 350 mL of dried dichloromethane, 32.8 g in 300 mL of dried dichloromethane with stirring at room temperature It was slowly added dropwise to (±) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1,4] benzoxazine and 28 ml of pyridine solution. It was further stirred for 4 hours at room temperature. The reaction mixture was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and distilled to remove dichloromethane, and the oily residue was dissolved in 200 mL of ethyl acetate. 750 mL of n-hexane was slowly added dropwise to the solution with stirring to precipitate crystals of the 3R-methyl compound. Precipitated crystals were separated by filtration and the filtrate was concentrated to dryness under reduced pressure. The residue was subjected to column chromatography using 500 g of silica gel and eluted with benzene / ethyl acetate (50/1 to 25/1 volume ratio) to give an oily product.

The oily product is dissolved in 500 mL of ethanol, and the solution is left to stand for 1 day to allow room temperature to precipitate crystals. Distillation was carried out to remove ethanol, and diethyl ether and n-hexane were added to the thus recovered crystals and filtered. The solid was dried under reduced pressure to give 33.4 g of 3 (S) -7,8-difluoro-2,3-dihydro-3-methyl-4-[(S) -Np-toluenesulfonylprolyl] -4H-. [1,4] benzoxazine was obtained. 300 mL of 1N sodium hydroxide was added thereto, followed by refluxing for 3 hours. Ethanol was distilled off and the oily residue was extracted with benzene. The residue was purified by column chromatography using 200 g of silica gel and benzene as eluent to give 12.7 g of 3 (S) -7,8-difluoro-2,3-dihydro-3-methyl-4H- [1. , 4] benzoxazine was obtained. 24.0 g of diethyl ethoxymethylenemalonate was added thereto, and the mixture was stirred under reduced pressure at 130 to 140 ° C for 1 hour. After cooling, the reaction mixture was dissolved in 50 mL of acetic anhydride and slowly added dropwise with stirring 80 mL of a mixture of acetic anhydride and concentrated sulfuric acid (2: 1 volume ratio). After stirring for another hour at room temperature, the reaction mixture was stirred for 30 minutes in a hot vessel at 50-60 ° C. Ice water was added to the reaction mixture, which was neutralized by adding potassium carbonate powder. The mixture was extracted with chloroform and the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous sodium chloride solution and dried over sodium sulfate. Distillation removed the chloroform and diethyl ether was added to the residue to give crystals. The crystals thus formed were filtered to yield 20.0 g of the desired product. This crystal was dissolved in 150 mL of acetic acid, and 400 mL of concentrated hydrochloric acid was added thereto, followed by reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration and dried to give 16.2 g of 3 (S) -9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1, 2,3-dec] [1,4] benzoxazine-6-carboxylic acid was obtained.

The solid obtained was suspended in 600 mL of diethyl ether, and 70 mL of borontrifluoride diethyl etherate was added thereto, followed by stirring at room temperature for 5 hours. The supernatant was decanted off and diethyl ether was added to the residue followed by filtration. The product was dissolved in 100 ml dimethylsulfoxide and 14.2 mL of triethylamine and 7.3 mL of N-methylpiperazine were added to the solution. The mixture was stirred at rt for 18 h and distilled to remove solvent. Diethyl ether was added to the residue, followed by filtration. The collected yellow powder was suspended in 400 mL of 95% methanol, to which 25 mL of triethylamine was added. The mixture was heated to reflux for 25 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in 500 mL of 10% hydrochloric acid and washed three times with chloroform. The washed solution was adjusted to pH 11 with 4N aqueous sodium hydroxide solution, and then adjusted to pH 7.3 using 1N hydrochloric acid. This solution was extracted three times with 2 L of chloroform and the collected extracts were dried over sodium sulfate. Distillation removes chloroform, and the resulting crystals are recrystallized from ethanol / diethyl ether to give the desired product 3 (S) -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl)- 12.0 g of 7-oxo-2,3-dihydro-7H-pyrido [1,2,3-dec] [1,4] benzoxazine-6-carboxylic acid was obtained. (Optical purity 97.8%)

The preparation method of the optically active benzoxazine derivative of the present invention is a method of applying (L) -alaninol using ethyl 2,3,4,5-tetrafluorobenzoyl acetate as a starting material, and conventional optical separation It is industrially useful compared to the method using post-column chromatography, and since the natural amino acid uses the raw material (L) -alaninol, there is an advantage of obtaining an object having an optical purity of 99% or more.

Claims (5)

a) preparing a compound of Formula 11 through addition reaction of trimethyl orthoformate using ethyl 2,3,4,5-tetrafluorobenzoyl acetate of Formula 10 as a starting material, b) substituting the compound of Formula 11 with L-alaninol to prepare a compound of Formula 12, c) preparing an intermediate compound of Chemical Formula 13 and Chemical Formula 8 by cyclization from the compound of Chemical Formula 12 under a polar solvent and basic conditions; d) reacting an intermediate compound of Formula 13 with Formula 8 under polar solvent and basic conditions to prepare a compound of Formula 9, and e) reacting the compound of formula 9 with 4-alkyl-piperazine of 1 to 6 carbon atoms under polar solvent and basic conditions Method for producing an optically active benzoxazine derivative represented by the following formula (1) comprising a. [Formula 1]

[Formula 8] [Formula 9]

[Formula 10] [Formula 11]

[Formula 12] [Formula 13]

The method of claim 1, wherein the trimethyl orthoformate is used in an amount of 1 to 4 equivalents based on the starting material. The preparation of an optically active benzoxazine derivative according to claim 1, wherein the polar solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide and dimethyl sulfoxide. Way. The optically active benzoxazine according to claim 1, wherein the base in steps c) and d) is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride and mixtures thereof. Process for the preparation of derivatives. The method of claim 1, wherein the base in step e) is selected from the group consisting of pyridine, triethylamine and imidazole.