KR100320772B1 - Process for Preparation of (S)-Benzoxazine Derivatives and Process for Racemization of (R)-Benzoxazine Derivatives - Google Patents

Abstract

(RS) -3-alkyl-7,8-dihalogeno-2,3-dahydro-4H [1,4] benzoxazine racemic compound and (S) -2- (6-methoxynaphthyl- 2-yl) propionyl chloride is reacted by mixing in an organic solvent in a molar ratio of 1: 0.5 to 0.6; Aqueous acid solution containing N-[(2S) -2- (6-methoxynaphthyl-2-yl) propionyl]-(3S) -3- Separating the organic layer material containing alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine; The organic layer material was washed, dried, treated with activated carbon, filtered, and distilled under reduced pressure, followed by filtration by adding a nonpolar solvent under an ice container to obtain N-[(2S) -2- (6-methoxynaphthyl-2-yl]-( 3S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine I compound and compound II were separated; an acid was added to the benzoxazine I compound to hydrolyze it This gives (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative (S) -1 compound. An acid was added to the compound to hydrolyze it, and the above unreacted product containing a large amount of (R) -1 compound was added thereto, and 0.1 to 1 molar ratio of acid was added to the mixed solution, and 5 to 20 at a temperature of 100 to 150 ° C. A racemization reaction was performed for a time to prepare a (RS) -1 racemate compound.

Description

Process for Preparation of (S) -Benzoxazine Derivatives and Process for Racemization of (R) -Benzoxazine Derivatives}

Field of invention

The present invention relates to a method for preparing a (S) -benzoxazine derivative and a racemization method for a (R) -benzoxazine derivative. More specifically, the present invention provides a (S) -benzoxazine derivative, which is a useful intermediate for the preparation of levofloxacin and similar compounds having a strong antimicrobial activity, as a racemic benzoxazine (RS) -1 compound and a splitting agent (S). )-(6-methoxynaphthyl-2-yl) propionyl chloride, and reacted with the compound generated during the preparation of the (S) -benzoxazine derivative. A method of reacting a compound to racemate a (R) -benzoxazine compound.

Background of the Invention and Prior Art

Preparation of (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative (S) -1 compound, which is one of the (S) -benzoxazine derivatives Various methods are known for doing this. (S) -benzoxazine derivatives are useful intermediates for the preparation of levofloxacin and similar compounds having potent antibacterial action.

EP 206,283 describes a method for optically dividing racemate benzoxazine (RS) -1 compounds using P-toluenesulfonyl derivatives of L-proline. However, this method has a problem of using column chromatography to obtain a desired benzoxazine derivative (S) -1 compound with high optical purity. The patent also describes optical isomer separation using fat protein lipase but is not suitable for mass synthesis.

Japanese Patent Laid-Open No. 1-175,975 describes the optical cleavage of racemic benzoxazine (RS) -1 compounds using P-toluenesulfonyl derivatives of D-proline, but the D-proline used here is relatively expensive It is disadvantageous in terms of production cost because an excess of 1.2 moles or more per mole of racemic benzoxazine (RS) -1 compound must be used.

EP 304,684 discloses optical isomer separation using salt formation of (R)-(-)-camphor-10-sulfonic acid and racemic benzoxazine (RS) -1 compounds, but this method is known as high optical Purity (S) -1 compound could not be obtained.

In addition, European Patent Nos. 273,399 and 368,410 describe optical isomer synthesis methods, but complicated steps, low yields, and high optical purity (S) -1 compounds cannot be obtained.

In order to solve the above problems, the present inventors have high optical purity and inexpensively (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine It is early to develop a method for obtaining a derivative (S) -1 compound.

An object of the present invention is to obtain (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative (S) -1 compound having high optical purity It is intended to provide a way to do this.

Another object of the present invention is to provide a (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative (S) -1 compound at low cost. It is to provide a way.

Another object of the present invention arises during the preparation of (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative (S) -1 compound To provide a method of racemizing an unreacted (R) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative (R) -1 compound It is for.

The above and other objects of the present invention can be achieved by the present invention described below.

(S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivatives according to the invention [(S) -1], (R) -3- Alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivatives [(R) -1] and (RS) -3-alkyl-7,8-dihalogeno- The 2,3-dihydro-4H [1,4] benzoxazine derivative [(RS) -1] is represented by the formula:

Wherein X ₁ and X ₂ are the same or different halogen atoms from each other, preferably a fluorine atom, R is a lower alkyl group, preferably a methyl group.

The benzoxazine derivatives (S) -1 compounds are useful intermediates for the preparation of levofloxacin and similar compounds having strong antimicrobial activity.

The inventors have found that when the benzoxazine derivative (RS) -1 racemate compound is reacted with (S) -2- (6-methoxynaphthyl-2-yl) propionyl chloride, the (S) -1 compound is ( The reaction proceeds faster than the R) -1 compound, whereby N-[(2S) -2- (6-methoxynaphthyl-2-yl) propionyl]-(3S) -3-alkyl-dihalogeno- 2,3-Dihydro-4H [1,4] benzoxazine Derivative I Compound is N-[(2S) -2- (6-methoxynaphthyl-2-yl) propionyl]-(3S) -3- It was found to be produced faster than alkyl-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative II compounds and it was conceived that these compounds I and II could be partitioned according to the reaction rate.

Wherein X ₁ and X ₂ are the same or different halogen atoms from each other, preferably a fluorine atom, R is a lower alkyl group, preferably a methyl group.

In the present invention, by reacting (S) -2- (6-methoxynaphthyl-2-yl) propionyl chloride with (RS) -1 compound at 0.5 to 0.6 molar ratio, a large amount of compound I is produced compared to compound II. The desired compound I can be separated in the solid state and hydrolyzed with an acid to obtain the desired compound (S) -1. In the present invention, (S) -2- (6-methoxynaphthyl-2-yl) propionyl chloride is used as the dividing agent, and its amount used is almost half or less than the amount of the dividing agent used in the conventional method. Therefore, manufacturing cost can be reduced. For example, D-proline used as a dividing agent in Japanese Patent Laid-Open No. 1-175,975 is relatively expensive and an excess of 1.2 moles or more per mole of (RS) -1 compound should be used.

In the present invention, the compound (S) -1 having high optical purity can be obtained. The present invention has advantages in terms of yield and production cost by racemizing and reusing the previously discarded (R) -1 compound.

(S) -2- (6-methoxynaphthyl-2-yl) propionyl chloride is reacted when X1 and X2 are fluorine atoms and R is a methyl group in the (RS) -1 racemate compound. The reaction structure for obtaining the (S) -1 compound according to the invention and racemizing the unreacted (R) -1 compound is represented by the following formula:

(RS) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine racemic compound and (S) -2- (6-methoxynaphthyl- 2-yl) propionyl chloride is mixed and reacted in an organic solvent in a ratio of 1: 0.5 to 0.6 mol. Dichloromethane, 1,2-dichloroethane, or chloroform can be used as the organic solvent, and the reaction temperature is preferably in the range of -10 to 40 ° C. Trialkylamines or pyridine may be present in the organic solvent.

An acid solution was added to the reaction solution, and an unreacted substance containing a large amount of (R) -1 compound and N-[(2S) -2- (6-methoxynaphthyl-2-yl) propionyl]-(3S The organic layer material containing) -7,8-difluoro-2,3-dihydro-3-methyl-4H [1,4] benzoxazine is separated. The unreacted material containing the (R) -1 compound forms a water layer, which is recovered and reused in the racemization reaction.

The organic layer material was washed, dried, treated with activated carbon, filtered, and distilled under reduced pressure, and then filtered by adding a nonpolar solvent under an ice container to obtain N-[(2S) -2- (6-methoxynaphthyl-2-yl)-( 3S) -7,8-difluoro-2,3-dihydro-3-methyl-4H [1,4] benzoxazine I and II compounds are separated. The organic layer material is washed with water, dried with a desiccant, treated with activated charcoal and filtered, and the solvent is removed by distillation under reduced pressure. The solid produced by adding a non-polar solvent under an ice container is then filtered to separate the benzoxazine I compound. Compound II contained in the nonpolar solvent is recovered and reused in the racemization reaction. As the nonpolar solvent used here, hexane is preferable.

(S) -7,8-difluoro-2,3-dihydro-3-methyl-4H [1,4] benzoxazine derivative (S)-by hydrolysis by addition of an acid to the benzoxazine I compound obtained above 1 compound is obtained. Acids used herein are hydrochloric acid, sulfuric acid, acetic acid, or mixed acids thereof. An acid is added to the benzoxazine I compound and refluxed while heating. If acetic acid is used, distilled under reduced pressure to remove acetic acid and add water under an ice container. The resulting solid is filtered off and washed with water. The filtrate is adjusted to pH with aqueous sodium hydroxide solution. The solution is extracted with dichloromethane and washed with brine and the organic layer material is dried with a desiccant and filtered. The solvent is removed by distillation under reduced pressure to give a yellow oily (S) -1 compound.

An acid is added to the benzoxazine II compound separated in the above step to hydrolyze, and the unreacted substance containing a large amount of (R) -1 compound is added thereto. In this case too, hydrochloric acid, sulfuric acid, acetic acid or mixed acids thereof may be used. To the mixed solution was added 0.1-1 molar ratio of acid, followed by racemization at a temperature of 100-150 ° C. for 5-20 hours to prepare a (RS) -1 racemic compound. The acid used herein is methylsulfonic acid, sulfuric acid or a mixed acid thereof, preferably racemized for 8 to 14 hours at a temperature of 120 ± 10 ℃.

The invention will be further illustrated by the following examples, which are intended to illustrate the invention and are not intended to limit the protection scope of the invention.

Example

Example 1a: Preparation of (S) -2- (6-methoxynaphthyl-2-yl) propionyl chloride

19.0 g of (S) -2- (6-methoxynaphthyl-2-yl) propionic acid was dissolved in 250 ml of 1,2-dichloroethane and 0.1 ml of dimethylformamide and 7.8 ml of thionyl chloride were added. After stirring at 40 ° C. for 2.5 hours, the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain 20.5 g of the desired product as a solid.

1 H-NMR (CDCl 3) δ (ppm): 1.66 (3H, d), 3.71 (3H, s), 4.24 (1H, q), 7.12 to 7.76 (6H, m)

Example 1b N-[(2S) -2- (6-methoxynaphthyl-2-yl) propionyl]-(3S) -7,8-difluoro-2,3-dihydro-3- Preparation of Methyl-4H [1,4] benzoxazine

3.95 g of (RS) -7,8-difluoro-2,3-dihydro-3-methyl-4H [1,4] benzoxazine was dissolved in 30 ml of dichloromethane. To this was added 2.91 g of (S) -2- (6-methoxynaphthyl-2-yl) propionyl chloride dissolved in 30 ml of dichloromethane dropwise at room temperature. After stirring for 8 hours, 30 ml of 12% hydrochloric acid solution was added. The water layer is recovered and used for racemization. The organic layer was washed with water, dried over MgSO 4, and treated with activated carbon and filtered. The solvent was distilled off under reduced pressure, and 50 ml of hexane was added under an ice container, and the resulting solid was filtered to obtain 2.55 g of the desired product. The hexane filtrate is recovered and used for racemization.

m.p. 113 ~ 114 ℃

[α] D 20 +66.5 (c = 1.4, CHCl 3)

UV, λ (nm): 232

1 H-NMR (DMSO-d 6) δ (ppm): 0.49 (3H, d), 1.42 (3H, d), 3.83 (3H, s),

4.1 to 4.3 (2H, m), 4.54 (1H, q), 4.8 (1H, m),

6.80-7.81 (8H, m)

19F-NMR (DMSO-d6) δ (ppm, C6F6): 20.3 (1F), 1.57 (1F)

Elemental Analysis C23H21F2NO3

Found% C 69.70 H 5.33 N 3.53 F 9.54

Calculated% C 69.54 H 5.33 N 3.52 F 9.56

Example 1c: Preparation of (S) -7,8-difluoro-2,3-dihydro-3-methyl-4H [1,4] benzoxazine

In 20 ml of acetic acid, 20 ml of hydrochloric acid and 1.3 g of N-[(2S) -2- (6-methoxynaphthyl-2-yl) propionyl]-(3S) -7,8-difluoro-2, 3-dihydro-3-methyl-4H [1,4] benzoxazine was added and heated to reflux for 9 hours. Acetic acid was distilled off under reduced pressure and water was added under an ice container. The resulting solid was filtered off and washed with water. The filtrate was adjusted to pH 9 with 10N aqueous sodium hydroxide solution. Extracted with dichloromethane and washed with brine, the organic layer was dried over MgSO 4 and filtered. The solvent was distilled off under reduced pressure to yield 0.61 g of the desired product as a yellow oil.

[α] D 20 -8.9 (c = 3.5, CHCl 3)

UV, λ (nm): 244, 297

1 H-NMR (DMSO-d 6) δ (ppm): 1.09 (3H, d), 3.42 (1H, m), 3.67 (1H, dd),

4.24 (1H, dd), 5.9 (1H, s), 6.31 (1H, ddd),

6.66 (1 H, ddd)

19F-NMR (DMSO-d6) δ (ppm, C6F6): 9.36 (1F), 0.37 (1F)

Elemental Analysis C9H9F2NO

Found% C 58.45 H 4.78 N 7.72 F 20.30

Calculated% C 58.38 H 4.90 N 7.57 F 20.52

Example 2: Preparation of (RS) -7,8-difluoro-2,3-dihydro-3-methyl-4H [1,4] benzoxazine

The hexane filtrate recovered in Example 1b was concentrated, reacted in the same manner as in Example 1c, and the water layer obtained by filtration was mixed with the water layer recovered in Example 1b. The aqueous solution was adjusted to pH 9 with 10N aqueous sodium hydroxide solution. Extracted with dichloromethane and washed with brine, the organic layer was dried over MgSO 4 and filtered. The solvent was distilled off under reduced pressure to convert 2.37 g of (R) -7,8-difluoro-2,3-dihydro-3-methyl-4H [1,4] benzoxazine ((S) -naproxen) derivative. After (RS) -1 compound (HPLC analysis R: S = 86: 14) was recovered. 0.81 ml of methanesulfonic acid was added thereto and stirred at 110 ° C. for 13 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with an aqueous sodium bicarbonate solution and brine. The organic layer was dried over MgSO 4, filtered over silica gel, and the solvent was evaporated under reduced pressure to yield 2.13 g of the desired substance as a yellow oil.

[α] D 2 0 0 (c = 3.5, CHCl 3)

The present invention provides a low-cost (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative (S) -1 compound with high optical purity. And an unreacted (R) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzone that occurs during the preparation of the compound. Has the effect of providing a method of racemizing a photographic derivative (R) -1 compound

Simple modifications and variations of the present invention can be readily used by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (9)

Compound represented by the following structural formula (I): Wherein X ₁ and X ₂ are the same or different halogen atoms from each other, and R is a lower alkyl group. A compound according to claim 1, wherein X ₁ and X ₂ are fluorine atoms and R is a methyl group. (S)-to (RS) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine racemate compound represented by the following formula (RS) -1: 2- (6-methoxynaphthyl-2-yl) propionyl chloride is reacted in an organic solvent; N-[(2S) -2- (6-methoxynaphthyl-2-yl)-(3S) -3-alkyl-7,8-dihalogeno-2,3-dihydro represented by the following formula (I): -4H [1,4] benzoxazine compound is isolated; And Hydrolyzing the separated compound; Of (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative represented by the following formula (S) -1, comprising the steps Manufacturing Method: Wherein X ₁ and X ₂ are the same or different halogen atoms from each other, and R is a lower alkyl group. 4. (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1] according to claim 3, wherein X ₁ and X ₂ are fluorine atoms and R is a methyl group. , 4] method of preparing benzoxazine derivatives. 4. The (S) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine racemic compound according to claim 3, wherein the (S) -2- (S) -3-alkyl-7,8-dihalogeno-2,3- characterized by mixing (6-methoxynaphthyl-2-yl) propionyl chloride in a molar ratio of 1: 0.5 to 0.6. Method for preparing a dihydro-4H [1,4] benzoxazine derivative. 4. The compound according to claim 3, wherein the (RS) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine racemate compound is selected from the racemate compound and An acid was treated in a solution of (S) -2- (6-methoxynaphthyl-2-yl) propionyl chloride in an organic solvent and then an unreacted compound represented by the following formula (R) -1: R) -3-alkyl-7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivatives obtained by recovery and racemization (S) -3-alkyl Method for preparing a -7,8-dihalogeno-2,3-dihydro-4H [1,4] benzoxazine derivative. 7. The racemization method according to claim 6, wherein X ₁ and X ₂ are fluorine atoms, and R is a methyl group. 7. The racemization method according to claim 6, wherein the acid treatment is performed with methylsulfonic acid, sulfuric acid or a mixed acid thereof. The racemization method according to claim 6, wherein the acid treatment is performed for 5 to 20 hours in a temperature range of 100 to 150 캜.