KR100355756B1 - Method for manufacturing a S-ofloxacin - Google Patents

Abstract

The present invention relates to a novel process for preparing S-Ofloxacin, wherein 2,3,4-trifluoroaniline is substituted with (S)-(-)-2-alkyl or allyl-substituted propionic acid ethyl ester or ( Reacting a S)-(-)-2-alkyl or allyl-substituted propionic acid group in the presence of a base to give a (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid compound A first step of manufacturing;

The (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid compound is reduced under a metal complex or an organic complex using a reducing agent without an acid catalyst or an acid catalyst (S)-(+) A second step of preparing -N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline;

(S)-(+)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline is directly condensed with diethyl ethoxy methylene malonate or (S)-(+ After protecting the alcohol group of) -N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline with various protecting groups, condensation with diethyl ethoxy methylene malonate and deprotection (S) -(-)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoro is subjected to a benzoxazine by cyclization of an anilino methylene malonate diethyl ester under a predetermined solvent and a base. After the preparation, an optically active 1,8-bridged-4-quinolone-3-carboxylate is prepared through a third step of cyclization with diphenyl ether, acetic anhydride and concentrated hydrochloric acid, ethyl polyphosphate, and the like. To provide a method for producing the desired (S) -Ofloxacin.

Description

Method for manufacturing a S-Ofloxacin {Method for manufacturing a S-ofloxacin}

The present invention relates to a method for producing S-Ofloxacin of Formula 1, and more particularly to a novel method for producing S-Ofloxacin as a quinolone antibacterial agent.

(I)

Wherein X is hydrogen, nitro, alkyl or halogen, Y is carboxyl, nitro, ester or acidamide, Z is oxygen or nitrogen and R _1, R _2, R _{3 and} R ₄ are each hydrogen or carbon 1-6 alkyl groups)

Compounds of the general formula (1) are disclosed in Japanese Patent Application Laid-Open No. 65-87577 (April 22, 1987), US Patent No. 4,382,893 (1983.5.10), European Patent Publication No. 0206283 (1986.6.20), and European Patent Publication No. 0368410 (1988.11.7), TL 37, No. 52, 9317-9320 (1996), J. Heterocycle.chem., 28. 329 (1991), US Pat. No. 5,664,056 (1995.6.7) and the like. This substance has strong antimicrobial activity against Gram-negative bacteria including Pseudomonas aeruginosa as well as Gram-positive bacteria, and is an excellent quinolone antibacterial agent having high blood concentration when administered orally or parenterally.

Japan's Daiichi Corporation developed off-roxacin and commercialized it as a racemate mixed with two stereoisomers, and then separated the 3-position methyl group of the pyrido benzoxazine nucleus into the (S) isomer. The development of levofloxacin resulted in a reduction in activity, good body dynamics and toxicity.

The techniques for separating the (R) and (S) stereoisomers of levofloxacin known to date can be summarized as follows.

First, racemic intermediate ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzo A technique obtained by separating the 3,5-dinitrobenzoyl ester intermediate of oxazine-6-carboxylate by high performance liquid chromatography and converting the resulting (S) isomer into levofloxacin is used. Hayakawa cs., Antimicrob.agents chemother, 29,163,1986).

Second, (S) obtained by separating racemic intermediate 3-acetoxymethyl-7,8-difluoro-3,4-dihydro-2H- [1,4] benzoxazine intermediate by an enzyme method. There is a technique obtained by converting isomers to levofloxacin (K. Sakano cs., Agric. Biol, chem. 51,1265, 1987).

Third, racemic intermediate 7,8-difluoro-3,4-dihydro-3-methyl-2H- [1,4] benzoxazine was replaced with NP-toluene sulfonyl- (L) -pyrrolidinylamide. A technique for preparing and separating the (R)-(+) and (S)-(-) isomers by crystallization and column chromatography to convert the required (S) into levofloxacin by a known method. (S. Atarasi cs., Chem. Pharm. Bull., 55, 1986,1987)

Fourth, 2,3,4-trifluoroaniline and hydroxyacetone are reacted under a hydrogen catalyst to produce racemic intermediate amino alcohol derivatives, which are subjected to crystallization by chiral column separation or racemic amino alcohol derivative salts with chiral acid. By separation or by the formation of diastereoisomeric amides of amino alcohol derivatives to obtain optically pure amino alcohol derivatives by hydrolysis, or to form racemic esters of amino alcohols, isolated using an enzyme such as lipoprotein lipase There is a technique of obtaining (S) isomer to produce (S) benzoxazine by cyclic reaction and converting to levofloxacin by a known method. (US Patent No. 5644056, 1995)

Fifth, the starting material 1- (2,3-difluoro-6-nitrophenoxy) -2-propanone was purified using Baker's Yeast (R)-(-)-1- (6- There is a technique for obtaining amino-2,3-difluorophenoxy) -2-propanone and separating the (S) isomer by intramolecular cyclic reaction in the presence of zinc chloride and converting it to levofloxacin by a known method. (TL 37, 52, 9317-9320, 1996)

Sixth, the starting material 1- (2,3-difluoro-6-nitrophenoxy) -2-propanol was converted to a cyclic imine-type compound, and then optically pure (S) -benzoxyl chloride was prepared using various chiral reduction reagents. There is a technique for making oxazine isomers and obtaining them by known methods. (J. Heterocyclic Chem., 28,320, 1991)

In addition, various methods are disclosed in DE-A-3639465, EP-A-0304684, EP-A-0273399, US Patent No. 4777253, and the like.

The conventional technical ideas discussed so far are to apply an active chiral compound in order to separate racemic mixtures, and then to separate them again, or to use expensive active chiral compounds. Due to the method used, the difficulty of using an expensive reducing agent was found to be the cause of the increase in the synthetic cost.

Representative of such conventional techniques, for example, there is a method as shown in the following scheme 1.

(Wherein X ₁ is hydrogen, nitro, alkyl group or halogen, X ₂ is halogen, alkyl group, alkylsulfonyl group or phenylsulfonyl group, X ₃ is halogen or nitro group, X ₄ is halogen, nitro group, alkoxy group, An alkyl mercapto or an alkylsulfonyl group, or an arylsulfonyl group, R ₁ and R ₂ are each hydrogen or a methyl group, R ₃ and R ₄ are each an alkyl or hydrogen atom having 1 to 3 carbon atoms, and the * symbol is R or S)

Represented by (I) in Scheme 1 represents S-Ofloxacin.

In the above scheme, the enamine (1) is reacted in anhydrous aprotic solvent in the presence of 1 equivalent of base to obtain 4-quinolone-3-carboxylic acid derivative (2), and the optically active 1,8-bridged-4-quinolone The cyclization reaction for obtaining -3-carboxylic acid ester (3) is carried out in the presence of 1 equivalent of base, and then the ester group is converted by a known method to condense with N-methylpiperazine to give the desired S-Ofloxacin (I ) Can be prepared.

At this time, S-ofloxacin (I) can also be manufactured by converting this compound into its salt as needed.

In Formula 2, R ₁ and R ₂ are each hydrogen or a methyl group, R ₃ and R ₄ are each an alkyl group having 1 to 3 carbon atoms or hydrogen, and the rest are the same as those of Scheme 1.

And the enol ether (4) is known or can be prepared by the following Scheme 3.

The method of hydrolyzing the ester to obtain the corresponding carboxylic acid in the last step can be carried out under known conventional acidic or basic conditions.

Therefore, the present inventors have conducted extensive and extensive research to develop a method for preparing an optically active (S) -ofloxacin compound in a simple and economical manner without going through the complicated process of the prior art, and thus, the novel and simple preparation Knowing how to complete the present invention.

It is an object of the present invention to provide a method for producing a novel S-Ofloxacin while being a simple and economical method.

S-Ofloxacin preparation method of the present invention for achieving the above object is as shown in Scheme 4.

(Where R is hydrogen or C1 to C3 lower alkyl or acetyl group, X is halogen atom, L is leaving group or protected oxy group)

2,3,4-trifluoroaniline to (S)-(-)-2-alkyl or allyl substituted propionic acid ethyl ester or (S)-(-)-2-alkyl or allyl substituted propionic acid A first step of reacting a group with a base in the presence of a (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid compound;

The (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid compound is reduced under a metal complex or an organic complex using a reducing agent without an acid catalyst or an acid catalyst (S)-(+) A second step of preparing -N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline;

(S)-(+)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline is directly condensed with diethyl ethoxy methylene malonate or (S)-(+ After protecting the alcohol group of) -N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline with various protecting groups, condensation with diethyl ethoxy methylene malonate and deprotection (S) -(-)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoro is subjected to a benzoxazine by cyclization of an anilino methylene malonate diethyl ester under a predetermined solvent and a base. After the preparation, an optically active 1,8-bridged-4-quinolone-3-carboxylate is prepared through a third step of cyclization with diphenyl ether, acetic anhydride and concentrated hydrochloric acid, ethyl polyphosphate, and the like. And it is characterized in that consisting of the step of preparing the desired (S)-Ofloxacin using N-methylpyreazine and quaternary ammonium salt and phosphonium salt and iodine complex.

Such a manufacturing method of S-Ofloxacin of the present invention has a simple and economical advantage compared to the prior art process.

Hereinafter, the configuration and operation of the present invention will be described in detail.

As described above, the present invention is a technique for producing S-Ofloxacin by a method different from the conventional method, that is, a novel method.

As a first step, 2,3,4-trifluoroaniline is converted to (S)-(-)-2-alkyl or allyl substituted propionic acid ethyl ester or (S)-(-)-2-alkyl or allyl Reaction of a substituted propionic acid group in the presence of a base to prepare a (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid compound, wherein the (S)-(-) Preferred compounds as -2-alkyl or allyl substituents are preferably selected from the group consisting of methanesulfonyloxy, 2-tetrahydropyranyloxy, 1-ethoxyethyl group, 1-benzyloxy, paratoluenesulfonyloxy group and the like. .

The reaction at this time is usually carried out at a temperature of -30 ° C to 100 ° C, and preferably at -30 ° C to room temperature.

The base may be inorganic salts such as potassium carbonate and potassium, sodium, and lithium hydroxy groups, and organic salts such as triethylamine, pyridine, and ethyldiisopropylamine may be used.

Thereafter, as a second step, the (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid or ester derivative is converted into an amino alcohol derivative by a reducing agent. This reduction reaction is a metal hydride complex such as lithium aluminum hydride, magnesium aluminum hydride, sodium borohydride, potassium borohydride or the like, or a borone complex compound such as borane dimethyl sulfide, borane pyridine, Borane tetrahydrofuran and the like. Moreover, it is preferable to use these metal complexes or a borane complex independently, or to use them together with Lewis acid, for example, aluminum chloride, iron chloride, etc.

The solvent used may be ether, dioxane, chloroform, methylene chloride, tetrahydrofuran, and the like. The reaction temperature is preferably from room temperature to reflux temperature.

Then as a third step, the (S)-(+)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline is condensed with diethyl ethoxy methylene malonate and given After cyclization reaction in a solvent and a base, it is cyclic with diphenyl ether, acetic anhydride and concentrated hydrochloric acid, ethyl polyphosphate and the like (-)-ethyl-9,10-difluoro-3-methyl-7-oxo- Prepare 2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylate.

The amino alcohol derivatives thus obtained are used with alkali metal compounds such as sodium, potassium, lithium or alkali metal alkoxides such as methoxides, ethoxides, thi- brooxides, or alkali metal hydrides such as sodium, potassium hydrides or alkalis. A cyclic reaction is carried out using a metal hydroxide or a carbonate such as sodium hydroxide, potassium carbonate, or a quaternary ammonium phosphonium salt.

At this time, suitable solvents include ethanol, butanol, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, 1-methyl-2-pyrrolidinone, hexamethyl phosphoric triamide and the like. The reaction temperature is preferably from room temperature to reflux temperature, preferably from room temperature to 110 ° C., and the reaction time is preferably from 1 hour to overnight, preferably 1 to 4 hours.

The (S)-(+)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline is also protected with an appropriate alcohol protecting group to condense with diethyl ethoxy methylene malonate. Deprotected and treated in the same manner as described above for (-)-ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3 -de] [1,4] -benzooxazine-6-carboxylate is prepared. The protecting group includes an acetyl group, a substituted methyl ether group, a substituted ethyl ether group, a substituted benzyl ether group, a silyl ether group, and the compound used for deprotection may be an acid or a basic substance.

Thus obtained (-)-ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzo Oxazine-6-carboxylate is hydrolyzed with the appropriate inorganic acid to give (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2 , 3-de] [1,4] benzoxazine-6-carboxylic acid is obtained.

Pure (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine- 1- 5 equivalents of 6-carboxylic acid, preferably 1-3 equivalents of N-methyl piperazine, a quaternary ammonium or phosphonium salt, and an iodine mixture are reacted in an appropriate solvent to give the desired (S) -Oflo A sax can be prepared.

In this case, the quaternary ammonium salt is tetramethylammonium bromide, tetramethylammonium hydroxide pentahydrate, benzyltrimethylammonium bromide, phenyltrimethylammonium chloride, and the fourth phosphonium salt is tetraphenylphosphonium bromide, tetraphenylphosphonium tetra Fluoroborate, benzyltriethylammonium hydroxide 40% methanol solution, tetra-ene-butylammonium bromide and the like are used in the amount of catalyst to 2 equivalents, preferably catalyst amount to 1 equivalent.

Suitable solvents include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, toluene and the like.

This gives pure (S) -Ofloxacin.

The invention is illustrated in more detail by the following examples, which, however, do not limit the scope of the invention in any way by these examples.

Example 1.Preparation of (S)-(-)-2-methanesulfonyl oxy propionic acid

8.3 ml (0.22 mol) of formic acid and 39.25 g (0.2 mol) of (S)-(-)-2-methanesulfonyl oxy propionic acid ethyl esters were added, and it heated at 60 degreeC and stirred for 4 hours. After the reaction was completed, excess formic acid and side reactions were removed by depressurization, and formic acid residue was removed several times with toluene to obtain 30 g (90%) of the title compound.

The following shows the properties of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.53 (d, 3H) 3.07 (s, 3H) 4.00 (q, 1H), 13.0 (s, 1H)

MS M / Z: 169 (M + H) ⁺

Example 2. Preparation of (S)-(-)-2- (2-tetrahydropyranyloxy) propionic acid

To 178 g (0.88 mol) of (S)-(-)-2- (2-tetrahydropyranyloxy) propionic acid ethyl ester, 2,000 ml of 0.8 N potassium hydroxide solution was added and reacted at 5 ° C for 4 hours.

The reaction solution was washed with 500 ml of ethyl acetate solution, the aqueous layer was acidified with 1N aqueous hydrochloric acid solution, and then extracted twice with 500 ml of ethyl acetate solution. The organic layer was dried and the solvent was distilled off under reduced pressure to obtain 138 g (90%) of the title compound.

The following shows the properties of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.30 (d, 3H) 1.4-1.9 (m, 6H) 3.50 (m, 2H) 3.88 (m, 1H) 4.0 (q, 1H)

MS M / Z: 175 (M + H) ⁺

Example 3. Preparation of (S)-(-)-2- (1-ethoxyethoxy) propionic acid

2,000 ml of 0.8 N potassium hydroxide solution was added to 167.6 g (0.881 mol) of (S)-(-)-2- (1-ethoxyethoxy) propionic acid ethyl ester, followed by stirring at 5 ° C. for 4 hours, followed by treatment as in Example 2. This gives 114.3 g (80%) of the title compound.

The following shows the properties of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.13 (tr, 3H) 1.21 (d, 3H) 1.30 (m, 6H) 4.00 (q, 1H)

MS M / Z: 163 (M + H) ⁺

Example 4. Preparation of (S)-(-)-2-benzyloxy propionic acid

184 g (0.882 mole) of (S)-(-)-2-benzyloxy propionic acid ethyl ester was added to 2,000 ml of 0.8 N potassium hydroxide solution, stirred overnight at room temperature, and treated in the same manner as in Example 2 to obtain 135 g (85%) of the title compound. Get)

The following shows the properties of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.40 (d, 3H) 4.0 (q, 1H) 4.10 (q, 2H) 7.10-7.32 (m, 5H)

MS M / Z: 181 (M + H) ⁺

Example 5. Preparation of (S)-(-)-2- (4-toluenesulfonyloxy) propionic acid

240 g (0.882 mole) of (S)-(-)-2- (4-toluenesulfonyloxy) propionic acid ethyl ester was added to 2,000 ml of 0.8 N potassium hydroxide solution, stirred at room temperature overnight, and then treated as in Example 2. 174.4 g (81%) of the title compound are obtained.

The following shows the properties of the title compound.

¹ H NMR (CDCl ₃ ): δ1.32 (d, 3H) 2.40 (s, 3H) 4.85 (q, 1H) 7.42 (d, 2H) 7.80 (d, 2H)

MS M / Z: 245 (M + H) ⁺

Example 6. Preparation of (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid

19.6 g (0.1 mol) of (S)-(-)-2-methanesulfonyloxy propionic acid ethyl ester was added to 200 ml of ethanol and 200 ml of dioxane, cooled to 0 ° C., 300 ml of 1N caustic soda solution was added, and the temperature was maintained at room temperature. And stirred for 3 hours. After the reaction is completed, the product is extracted with 500 ml of methylene chloride. The organic layer was washed with water, dried over magnesium sulfate, filtered, and 29.4 g (0.2 mol) of 2,3,4-trifluoroaniline was added to the solution, which was allowed to stand at room temperature overnight, refluxed for 6 hours, and then 50 ml of water was added for reaction. After completion, 50 ml of 1N potassium hydroxide solution is added and the product is extracted. The aqueous layer was washed three times with 50 ml of ethyl acetate solution, acidified with 1N aqueous hydrochloric acid solution, and extracted three times with 100 ml of ethyl acetate. The combined organic layers were washed with water, ammonium chloride and water in that order, dried over magnesium sulfate, filtered and dried under reduced pressure, and then crystallized with benzene-petroleum ether 1: 1 solution to obtain 17.67 g (80.6%) of the title compound.

The following shows the properties of the title compound.

[α] ²⁰ _D : -39.19 (C: 1.373, Chloroform)

¹ H NMR (CDCl ₃ ): δ 1.5 (d, 3H) 4.0 (q, 1H) 6.2 (m, 1H) 6.7 (m, 1H)

MS M / Z: 220 (M + H) ⁺

Example 7.

15.35 g (70%) of the Example 6 compound was obtained by using (S)-(-)-2- (2-tetrahydropyranyloxy) propionic acid in the same manner as in Example 6.

Example 8.

16.44 g (75%) of Example 6 compound is obtained by using (S)-(-)-2- (1-ethoxyethoxy) propionic acid in the same manner as in Example 6.

Example 9.

15.79 g (72%) of Example 6 compound was obtained using (S)-(-)-2-benzyloxy propionic acid in the same manner as in Example 6.

Example 10.

In the same manner as in Example 6, 15.35 g (70%) of the compound of Example 6 was obtained by using (S)-(-)-2- (4-toluenesulfonyloxy) propionic acid.

Example 11 Preparation of (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid

17.15 g (0.102 mol) of (S)-(-)-2-methanesulfonyl oxy propionic acid, 50 ml of benzene, 10.8 ml (0.102 mol) of 2,3,4-trifluoroaniline and 21 ml of triethylamine were added thereto at room temperature. After stirring overnight, 20 ml of water is added to terminate the reaction.

20 ml of 1N potassium hydroxide is added and extracted. The aqueous layer was washed with 10 ml of methylene chloride, acidified with 1N aqueous hydrochloric acid solution, and extracted with 100 ml of ethyl acetate. The organic layer was washed with water, dried, filtered and concentrated under reduced pressure and crystallized to obtain 17.1 g (78%) of the title compound.

Example 12.

In the same manner as in Example 11, using the Compound of Example 2 at a reaction temperature of 50-60 ° C. to obtain 16.7 g (76%) of Example 11 Compound.

Example 13.

In the same manner as in Example 11, 16.2 g (74%) of Example 11 compound was obtained by performing the compound of Example 3 at a reaction temperature of 40 to 50 ° C.

Example 14.

In the same manner as in Example 11, using the Example 4 compound at a reaction temperature of 60-70 ° C. to obtain 18 g (82%) of the Example 11 compound.

Example 15.

In the same manner as in Example 11, using the Example 5 compound at the reflux temperature to obtain 17.5 g (80%) of Example 11 compound.

Example 16 Preparation of (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid ethyl ester

Example 11 7 g (32 mmol) of the compound was dissolved in 50 ml of ethanol and cooled to 0 ° C. To this solution is added 4.2 ml of thionyl chloride slowly over 30 minutes and refluxed for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, 30 ml of water was added thereto, and the pH was adjusted to 10 with 1N sodium hydroxide solution. The aqueous layer is extracted with 100 ml of ethyl acetate and the organic layer is washed with water, dried, filtered and distilled under reduced pressure to obtain 6.3 g (79.7%) of crude product.

[α] ²⁰ _D : -31.16

Example 17. Preparation of (S)-(+)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline

Example 16 16 g (64.8 mmol) of the compound was dissolved in 200 ml of a mixed solvent of ethanol: water (7: 3), followed by slowly adding 8.63 g (0.228 mol) of sodium borohydride. After stirring at room temperature for 8 hours, 200 ml of hexane was added, the organic layer was washed with water, acidified with 1N aqueous hydrochloric acid solution, and then alkalined with 1N potassium hydroxide solution to separate the organic layer. The organic layer was washed with water, dried, filtered and distilled under reduced pressure to obtain 16 g (80%) of the title compound.

The following shows the properties of the title compound.

[α] ²⁰ _D : +10.34 (C: 16.67, Chloroform)

¹ H NMR (CDCl ₃ ): δ1.1 (d, 3H) 3.5 (m, 2H) 3.6 (m, 1H) 6.3 (m, 1H) 6.7 (m, 1H)

MS M / Z: 206 (M + H) ⁺

Example 18 Preparation of (S)-(+)-(N)-(3-hydroxy-2-propyl) -2,3,4-trifluoroaniline

59 ml of tetrahydrofuran is added to a three necked flask, cooled to 0 ° C., and 6.17 g of sodium borohydride are added. 22.67 g (0103 mol) of (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid was dissolved in 34 ml of tetrahydrofuran and slowly added dropwise through a separatory funnel. Next, the solution which mixed 43.8 ml of boron trifluoride ether in 46.4 ml of tetrahydrofuran solution was added dropwise over 2 hours, and it stirred at 0 degreeC for 1 hour, and then stirred at room temperature for 14 hours.

To the solution was added 93 ml of ether, stirred for 30 minutes, filtered, and washed with ether solution. To the filtrate is slowly added dropwise a solution of 46 ml of water and 46 ml of tetrahydrofuran. Then 12.4 g of caustic soda was added, heated to reflux for 2 hours. After cooling, the resultant was filtered and the tetrahydrofuran solvent was removed under reduced pressure. The residue was extracted twice with 210 ml of ethyl acetate. The organic layer was washed with 100 ml of water, 50 ml of ammonium chloride and 100 ml of water, dried over magnesium sulfate, filtered and dried under reduced pressure. Obtain 19.3 g (90%) of compound.

Example 19 Preparation of [(-)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoro aniline-4-yl] methylene malonate.

0.78 ml of diethyl ethoxymethylenemalonate (0.66 g (3.22 mmol) of (S)-(+)-(N)-(3-hydroxy-2-propyl) -2,3,4-trifluoroaniline 3.86 mmol) and heated at 130 ° C. to 140 ° C. for 2 hours. After cooling to 0 ° C., the residue was dissolved in 10 ml of ethyl acetate and 50 ml of hexane was added to form crystals. The resulting crystals were filtered and dried to obtain 1.09 g (90%) of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.10 (tr, 3H) 1.20 (tr, 3H), 1.60 (tr, 3H), 3.40 (tr, 2H) 3.60 (q, 2H) 4.10 (m, 2H), 4.50 (m, 1H), 6.9-7.0 (m, 1H), 7.05-7.10 (m, 1H) 7.70 (s, 1H)

MS M / Z: 376 (M + H) ⁺

Example 20 Diethyl [(S)-(-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzooxazin-4-yl] methylene malo Preparation of Nates.

(S)-(-)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoro aniline methylene malonate diethyl ester 0.34 g1 (0.91 mmol) in 1 mol of tetrabutyl It is added to 2.2 ml of ammonium fluoride THF solution and stirred under heating to reflux. After 4 hours, the mixture was cooled and extracted with 5 ml of n-hexane, and the extract was washed with saturated brine and water, dried and filtered to obtain 0.27 g (85%) of the target compound.

Example 21.Preparation of (+)-N- (3-acetoxy-2-propyl) -2,3,4-trifluoro aniline

15 g (73.08 mmol) of (+)-(N)-(3-hydroxy-2-propyl) -2,3,4-trifluoroaniline are dissolved in 150 ml of tetrahydrofuran, 7.6 ml of acetic anhydride and boron triflo 2.6 ml of lysaterate is added at room temperature and stirred overnight. After the reaction was completed, it was concentrated and washed three times with 30 ml of toluene under reduced pressure.

The residue is dissolved in 100 ml of chloroform and washed three times with 150 ml of water. Dry with forget-me-not, filter and concentrate to give 18.07 g (100%) of the title compound.

¹ H NMR (CDCl ₃ ): δ1.1 (d, 3H) 2.3 (s, 3H), 3.5 (m, 1H), 3.6 (m, 1H) 6.3 (m, 1H) 6.7 (m, 1H)

MS M / Z: 248 (M + H) ⁺

Example 22. Diethyl [(+)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoroanilin-4-yl] methylene malonate.

18 g (72.8 mM) of (+)-(N)-(3-hydroxy-2-propyl) -2,3,4-trifluoroaniline and 16.5 ml (82.3 mM) of diethyl ethoxy methylene malonate were mixed After heating and stirring for 9 hours at 155 ℃ to remove the ethanol produced under reduced pressure.

After the reaction was completed, the mixture was cooled and 330 ml of water was added to 650 ml of methanol and cooled to 0 ° C.

5.75 g of potassium carbonate is added to the mixed solution and stirred at room temperature for 30 minutes.

After completion of the reaction, the mixture was extracted with 200 ml of methylene chloride, washed once with 50 ml of 1N-HCl aqueous solution, washed with water and saturated brine, dried over forget-me-not, filtered, concentrated, and the residue was dissolved in 130 ml of ethyl acetate and dispersed in 600 ml of n-hexane. The crystals were filtered and dried to yield 23.2 g (85%) of the title compound.

Example 23. (-)-Ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4 ] Benzoxazine-6-carboxylate Preparation

1.14 g (3.21 mM) of diethyl [[(-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzooxazin-4-yl] malonate 5 g of ethyl polyphosphate was added and stirred at 140-145 ° C. for 1 hour and then cooled to 0 ° C. The reaction mixture is added to ice water and extracted three times with chloroform.

The organic layer was collected, washed with 5% sodium carbonate solution and water, dried over an organic layer with manganese, filtered and dried under reduced pressure, and the residue was crystallized with ether, filtered and washed to obtain 0.74 g (74.6%) of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.20 (tr, 3H) 1.45 (d, 3H), 4.38 (m, 4H), 4.90 (m, 1H)) 7.80 (d, 1H) 8.97 (s, 1H)

Example 24. (-)-(9,10) -Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4 ] Benzoxazine-6-carboxylic Acid

Example 23 4.5 g (14.5 mmol) of a compound are dissolved in 46 ml of acetic anhydride and stirred. 98 ml of concentrated hydrochloric acid is slowly added and heated to 130-140. After stirring for 2 hours, it is cooled to room temperature. The resulting solid was filtered and washed with 30 ml of water and 50 ml of ethanol to give 3.8 g (92.8%) of the title compound.

Example 25 S-Ofloxacin

Example 24 0.95 g of the compound, 5 ml of pyridine and 1.0 g of N-methylpiperazine were added and heated for 8 hours. After cooling the reaction mixture, excess pyridine is removed by reduced pressure, and 20 ml of water is added to crystallize. The resulting crystals were filtered, dried and recrystallized with ethanol and ether mixed solvent to obtain 1.0 g (82%) of the title compound.

Melting Point: 225-226 ℃

¹ H NMR (CDCl ₃ ): δ1.62 (d, 3H) 2.38 (s, 3H), 2.58 (br.s, 4H) 3.41 (m, 4H) 4.44 (ABq, 2H) 4.59 (m, 1H) 7.67 (d, 1 H) 8.65 (s, 1 H)

MS M / Z: 362 (M + H) ⁺

Example 26. S-Ofloxacin

Example 24 The compound 4.4g, pyridine 23ml, N-methylpyrrazine 6.3g, iodine 0.2g, benzyltrimethyl ammonium bromide was mixed and stirred under reflux at 110 ℃ for 7 hours.

The reaction mixture is cooled to room temperature and concentrated to remove pyridine. Water was added to the residue, the mixture was adjusted to pH 6 with 30% acetic acid while stirring, and the resulting crystals were filtered and dried.

The crude product is dissolved in 50% aqueous sodium hydroxide solution, the insolubles are removed and the filtrate is treated with activated carbon. The resulting crystals are filtered and dried by adjusting the mother liquor to pH 6 with acetic acid. Recrystallization from ethanol and ether mixed solvents gave 5.4 g (95%) of the title compound.

As described above, the present invention is directed to preparing (S)-(+)-N- (3-hydroxy-2-propyl) to prepare an optically active 1,8-bridged-4-quinolone-3-carboxylic acid derivative. ), 2,3,4-trifluoro aniline can be condensed directly with diethylethoxymethylenemalonate or protected with a suitable alcohol protecting group, followed by condensation to cyclize with an appropriate base and the desired condensing agent (S )-(-)-Ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzo Oxazine-6-carboxylate is prepared and the ester compound is hydrolyzed with the appropriate inorganic acid to give (S)-(-)-9,10-difluoro-3-methyl-7-oxo-2,3-di After obtaining hydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, the compound, N-methylpiperazine, quaternary ammonium salt and iodine are used. (By preparing S0-Ofloxacin, which is a simple process unlike the prior art The compound can be prepared, and as a result, the production cost of the target compound can be reduced.

Claims (9)

2,3,4-trifluoroaniline is reacted with (S)-(-)-2-alkyl or allyl substituted propionic acid groups in the presence of an organic salt to give (S)-(-)-2- (2, A first step of preparing a 3,4-trifluoroanilino) propionic acid compound; The (S)-(-)-2- (2,3,4-trifluoroanilino) propionic acid compound was reduced under a metal complex by using a reducing agent without an acid catalyst or an acid catalyst (S)-(+)-N- A second step of preparing (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline; (S)-(+)-N- (3-hydroxy-2-propyl) -2,3,4-trifluoroaniline is condensed directly with diethyl ethoxy methylene malonate and then cyclized with an appropriate base The reaction was carried out and cyclic with a predetermined solvent to give (S)-(-)-ethyl-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1 A third step of preparing 2,3-de] [1,4] benzoxazine-6-carboxylate; This ester compound was hydrolyzed with an appropriate inorganic acid to give (S)-(-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2, 3-de] [1,4] benzoxazine-6-carboxylic acid is obtained, and then (S) -Ofloxacin is prepared by using this compound, N-methylpyrazine, a quaternary ammonium salt and iodine. 4 step; S-Ofloxacin production method consisting of. The said (S)-(-)-2-alkyl or allyl substituent consists of methanesulfonyl group, 2-tetrahydropyranyl group, 1-ethoxyethyl group, benzyl group, paratoluenesulfonyl group, etc. Method for producing S-Ofloxacin, characterized in that selected from the group. The method of claim 1, wherein the organic salt of the first step is selected from the group consisting of triethylamine, pyridine, ethyldiisopropylamine, and the like. The method of claim 1, wherein the acid catalyst is a Lewis acid such as aluminum chloride, zinc chloride, boron trifluoride etherate, tin chloride, iron chloride, or the like. The method of claim 1, wherein the reducing agent is sodium borohydride. delete delete The quaternary ammonium salt of claim 1 or 5, wherein the quaternary ammonium salt is selected from the group consisting of tetramethyl ammonium bromide, tetra methyl ammonium hydroxide pentahydrate, benzyl trimethyl ammonium bromide, phenyltrimethyl ammonium chloride and the like. S-Ofloxacin production method. delete