KR100589429B1 - Process for preparation of quinolone derivatives substituted by aminopyridyl moieties at n-1 site - Google Patents

Abstract

The present invention relates to a method for preparing a quinolone derivative substituted with an aminopyridyl group at the N-1 position, wherein the ethoxyethylene produced by the reaction of a 3-oxo-propionic acid ethyl ester derivative and triethylorthoformate according to the present invention 3,5-difluoro-6-amino at the N-1 position of the formula (1) comprising the step of introducing 2-amino-3,5,6-trifluoropyridine to the derivative followed by cyclization and introducing an amino group In the method for preparing a pyridyl-substituted quinolone derivative, CCR can be produced in a high yield with a 3,5-difluoro-6-aminopyridyl group-substituted quinolone derivative at the N-1 position through an easy process for industrial application. (cellular chemokine receptor) 5 It can be useful for the production of anti-infective agents as well as the preparation of a modulator (modulator).

Wherein R ¹ is hydrogen, amino or methyl; R ² is fluorine, chlorine, methylamino, 2-hydroxyethylamino, N-methyl-N- (2-hydroxyethyl) amino, 2-methoxyethyl amino or (pyrrolidin-3-yl) amino ; W is CH, N, CF, CCl, CBr, COCH ₃ or CCH ₃ .

Description

PROCESS FOR PREPARATION OF QUINOLONE DERIVATIVES SUBSTITUTED BY AMINOPYRIDYL MOIETIES AT N-1 SITE}

The present invention is to prepare a quinolone derivative substituted with an aminopyridyl group at the N-1 position useful for the production of CCR (modulators) and anti-infective agents as a major intermediate of the bioactive substance It is about a method.

Quinolone-based antimicrobial derivatives having an aminopyridyl group substituted at the N-1 position have been developed as a major intermediate of physiologically active substances exhibiting excellent antimicrobial activity and good body dynamics. As a technique for preparing a quinolone antibacterial derivative having an aminopyridyl group substituted at a representative N-1 position, a process as shown in Scheme 1 is disclosed in Korean Patent Publication No. 2000-53224 (priority claim JP 1997-178462, JP 1996-317693). Is disclosed.

Wherein X is chlorine or fluorine; R ¹ is hydrogen, amino or methyl; R ² is fluorine, chlorine, methylamino, 2-hydroxyethylamino, N-methyl-N- (2-hydroxyethyl) amino, 2-methoxyethylamino or (pyrrolidin-3-yl) amino; And W is CH, N, CF, CCl, CBr, COCH ₃ or CCH ₃ .

However, this synthesis method is a 2,6-diamino-3,5-difluoropyridine (M. Ma et al. , J. Chem. Soc. Perkin Transaction I , 817-821, 1980), and because of the poor solubility of intermediates introduced with 2,6-diamino-3,5-difluoropyridine, quinolone-based antimicrobial derivatives substituted with aminopyridyl groups at the N-1 position are inefficient. There is a problem to be manufactured.

It is an object of the present invention to provide a method for preparing a quinolone derivative in which an aminopyridyl group is substituted at the N-1 position by an easy process for industrial application.

According to the above object, in the present invention

1) reacting the 3-oxo-propionic acid ethyl ester derivative of Formula 2 with triethylorthoformate;

2) reacting the ethoxyethylene derivative of Formula 3 produced in Step 1 with 2-amino-3,5,6-trifluoropyridine;

3) acid hydrolysis of the pyridylenamin derivative of Formula 4 produced in step 2 in the presence of an organic solvent and a base, followed by cyclization; And

4) a quinolone derivative having a 3,5,6-trifluoropyridyl group substituted in the N-1 position of the formula (5) generated in step 3, comprising the step of introducing an amino group by treatment with ammonia water, Provided is a method for producing a quinolone derivative having a 3,5-difluoro-6-aminopyridyl group substituted at the N-1 position.

<Formula 1>

Wherein X is chlorine or fluorine; R ¹ is hydrogen, amino or methyl; R ² is fluorine, chlorine, methylamino, 2-hydroxyethylamino, N-methyl-N- (2-hydroxyethyl) amino, 2-methoxyethylamino or (pyrrolidin-3-yl) amino ; And W is CH, N, CF, CCl, CBr, COCH ₃ or CCH ₃ .

Hereinafter, the present invention will be described in detail.

In the present invention, in reacting an ethoxyethylene derivative with an aminopyridyl derivative, 2-amino-3,5,6-trifluoropyridine is used instead of 2,6-diamino-3,5-difluoropyridine. It is characterized by introducing an amino group after using.

The preparation method of the present invention can be represented by the following scheme 2.

Wherein X, R ¹ , R ² and W are the same as described above.

Specifically, step 1 of the present invention is triethyl to 3-oxo-propionic acid ethyl ester derivative (Compound 2) according to a conventional method for preparing an ethoxyethylene derivative (Compound 3) (Korean Patent Publication No. 2000-53224). React with orthoformate.

In step 2 of the present invention, the ethoxyethylene derivative (compound 3) produced in step 1 is substituted with 2-amino-3,5, instead of 2,6-diamino-3,5-difluoropyridine, which has been used in conventional methods. React with 6-trifluoropyridine. In this case, 2-amino-3,5,6-trifluoropyridine may be commercially available from commercially available materials, and preferably 2,3,5,6-tetrafluoropyridine, for example, as shown in Scheme 3 below. The hydrazino group may be introduced into and then used under mild reaction conditions for reducing with hydrogen.

2-amino-3,5,6-trifluoropyridine can be used in the range of 1 to 4 equivalents, preferably 1.2 to 2 equivalents based on compound 3. Further, in step 2, lower alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol and t-butanol may be used as the solvent, and the solvent may be 3 to 15 weight based on compound 3. Pear, preferably in the range of 2 to 7 weight times. The reaction of step 2 may be carried out at 10 to 100 ° C., preferably at 20 to 40 ° C. for 2 to 10 hours, preferably 2 to 8 hours.

Usable bases of step 3 include potassium carbonate, sodium carbonate, potassium fluoride, sodium fluoride, sodium hydride and the like, and can be used in the range of 1 to 10 equivalents, preferably 2 to 8 equivalents based on compound 4. The amount of the organic solvent of step 4 may be used in the range of 10 to 30 times by weight, preferably 12 to 20 times by weight, based on compound 4. The quinolone derivative ester in which the 3,5,6-trifluoropyridyl group is substituted at the N-1 position thus obtained by cyclization is acid hydrolyzed in the same lower alcohol solvent as in step 2, wherein hydrochloric acid is preferable as the acid used. The amount of the acid and the lower alcohol is independently 10 to 30 times by weight, preferably 15 to 20 times by weight, based on the quinolone derivative ester having 3,5,6-trifluoropyridyl group substituted at the N-1 position. Can be used. In addition, the acid hydrolysis reaction of step 3 may be carried out at 50 to 120 ℃.

The alcohol solvent of step 4 is also the same as the lower alcohol solvent usable in step 2, and may be used in the range of 20 to 40 weight times, preferably 20 to 30 weight times based on compound 5. In addition, in step 4, ammonia water is preferably used diluted to 28%, it can be used in the range of 3 to 20 equivalents, preferably 5 to 12 equivalents based on compound 6. The reaction of step 4 may be carried out for 10 to 30 hours, preferably 10 to 20 hours at 0 to 40 ℃, preferably 15 to 30 ℃.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example 1: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7-chloro-4-oxo-1,4-dihydro [1,8] -naphthyridine Preparation of 3-carboxylic acid

<Step 1> Preparation of 3- (2,6-dichloro-5-fluoropyridine-3-carbonyl) -3-ethoxyacrylic acid ethyl ester

30 g of 3- (2,6-dichloro-5-fluoropyridin-3-yl) -3-oxo-propionic acid ethyl ester (LG Chem) was dissolved in 30 ml of acetic anhydride, and 26.7 ml of triethylorthoformate was added thereto. The mixture was heated to reflux for 2 hours, filtered off under reduced pressure to give 32.6 g of the title compound.

1 H-NMR (200 MHz, CDCl 3): δ 1.12 (3H, t, J = 7.1 Hz), 1.48 (3H, t, J = 7.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.40 (2H, q, J = 7.1 Hz), 7.54 (1H, d, J = 7.1 Hz), 7.87 (1H, s)

<Step 2> Preparation of 3- (2,6-dichloro-5-fluoropyridine-3-carbonyl) -3- (3,5,6-trifluoropyridin-2-ylamino) acrylic acid ethyl ester

20 ml of ethanol was added to 8.04 g of 3- (2,6-dichloro-5-fluoropyridine-3-carbonyl) -3-ethoxyacrylic acid ethyl ester obtained in step 1, followed by cooling to 10 ° C. or lower, and then To a solution of 3.54 g of 3-amino-3,5,6-trifluoropyridine in 20 ml of ethanol was slowly added. It was stirred at room temperature for 2 hours, filtered, washed with 10 ml of ethanol and dried to give 9.44 g of the title compound.

1 H-NMR (300 MHz, CDCl 3): δ 0.97 & 1.18 (3H, t, J = 7.5), 4.10-4.21 (2H, m), 7.42-7.62 (2H, m), 8.02 & 8.06 (1H, d, J = 12 Hz), 11.55 & 12.70 (1H, d, J = 12 Hz)

<Step 3> 1- (3,5,6-Trifluoropyridin-2-yl) -6-fluoro-7-chloro-4-oxo-1,4-dihydro- [1,8] -naphthyridine- Preparation of 3-carboxylic acid ethyl ester

9.4 g of 3- (2,6-dichloro-5-fluoropyridine-3-carbonyl) -3- (3,5,6-trifluoropyridin-2-ylamino) acrylic acid ethyl ester obtained in step 2 was added. After dissolving in 50 ml of dimethylformamide, 2.08 mg of potassium carbonate was added and reacted at 70-75 ° C. for 1 hour. The reaction mixture was dispersed in 100 mL of distilled water and the resulting solid was filtered and washed with 50 mL of distilled water and 20 mL of ethanol and dried to obtain 7.1 g of the target compound.

1 H-NMR (300 MHz, CDCl 3): δ 1.41 (3H, t, J = 7.2 Hz), 4.42 (2H, q, J = 7.2 Hz), 7.75 (1H, q, J = 7.2 Hz), 8.47 (1H, d, J = 7.2 Hz), 8.67 (1H, s)

<Step 4> 1- (3,5,6-Trifluoropyridin-2-yl) -6-fluoro-7-chloro-4-oxo-1,4-dihydro [1,8] -naphthyridine-3 Preparation of Carboxylic Acids

1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7-chloro-4-oxo-1,4-dihydro- [1,8] -naphthyridine obtained in step 3 above 6.9 g of 3-carboxylic acid ethyl ester was suspended in 20 ml of isopropanol, and 38 ml of 6 N HCl was added thereto, followed by stirring for 3 hours at reflux. When the reaction was completed, it was cooled and the solid was filtered, washed with distilled water and acetone and dried to obtain 6.38 g of the target compound.

1 H-NMR (300 MHz, DMSO-d 6): δ 8.73-8.82 (2H, m), 9.16 (1H, s), 13.64 (1H, brs)

Step 5 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6,7-difluoro-4-oxo-1,4-dihydro [1,8] -naphthyridine- Preparation of 3-carboxylic Acid

1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7-chloro-4-oxo-1,4-dihydro- [1,8] -naphthyridine obtained in step 4 above 3 g of -3-carboxylic acid was added dropwise with 80 ml of isopropanol and 40 ml of methylene chloride, and 60 ml of an aqueous 28% ammonia solution was added thereto, followed by stirring at 30 ° C for 15 hours. The reaction mixture was cooled to room temperature and the filtrate was filtered and evaporated under reduced pressure, and the obtained residue was separated by tube chromatography (eluent: methylene chloride: methanol = 20: 1) to obtain 2.25 g of a white solid title compound.

1 H-NMR (300 MHz, DMSO-d 6): δ 8.71-8.74 (1 H, m), 9.16 (1 H, s), 13.64 (1 H, brs)

Example 2: of 1- (3,5, -difluoro-6-aminopyridin-2-yl) -6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Produce

<Step 1> Preparation of 2,4,5-trifluorobenzoyl chloride

50 g of 2,4,5-trifluorobenzoic acid (Fluorochem) was dissolved in 350 ml of dried methylene chloride, and then 26.9 ml of purified thionyl chloride and 0.5 ml of dimethylformamide were added thereto, followed by reaction at 70 to 80 ° C for 10 hours. I was. After completion of the reaction, the solvent and excess thionyl chloride were removed under reduced pressure, and the residue was distilled under reduced pressure to give 48.97 ml of a colorless title compound.

Boiling point (20 mmHg); 65 ~ 70 ℃

<Step 2> Preparation of 2- (2,4,5-trifluorobenzoyl) malonic acid diethyl ester

14.9 g of magnesium pieces were suspended in 44 ml of anhydrous ethanol, and 4 ml of carbon tetrachloride was added thereto, followed by stirring for 10 minutes at 45 ° C. A mixture of 92.7 ml of diethyl malonate, 60 ml of anhydrous ethanol, and 330 ml of toluene was added dropwise at a temperature of 50 to 60 ° C, stirred for 1 hour at the same temperature, and then cooled to -10 ° C. A solution of 108.5 g of 2,4,5-trifluorobenzoyl chloride produced in step 1, diluted in 60 ml of anhydrous toluene was added dropwise to the reaction mixture, and stirred for 1 hour at 0 to 5 ° C., which was left at room temperature overnight. It was. An aqueous layer of 12.67 ml of concentrated sulfuric acid was added to 300 ml of ice water, and the organic layer was separated. The aqueous layer was extracted twice with 200 ml of toluene, and the remaining organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the remaining syrup-like material was dried in a high vacuum at 50 ° C. to obtain 288 g of the title compound. This compound was used as it was for the next reaction without purification.

<Step 3> Preparation of 3-oxo-3- (2,4,5-trifluorophenyl) propionic acid ethyl ester

51.3 g of 2- (2,4,5-trifluorobenzoyl) malonic acid diethyl ester obtained in step 2 was added to 150 ml of water, and then 0.6 g of a catalytic amount of toluenesulfonic acid was added thereto, followed by reflux with vigorous stirring for 6 hours. The reaction solution was cooled to room temperature, extracted with 100 ml of methylene chloride, the aqueous layer was extracted two more times with the same solvent, and the remaining organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, an oily compound was obtained, which was distilled under reduced pressure to obtain 174.6 g of the title compound as a white crystalline phase.

Boiling point (0.05 mmHg): 85 to 90 ° C, Melting point: 50 ° C

Step 4 Preparation of 3-ethoxy-2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester

24.6 g of 3-oxo-3- (2,4,5-trifluorophenyl) propionic acid ethyl ester obtained in step 3, 30.4 ml of triethylorthoformate and 34.5 ml of acetic anhydride were mixed and heated at 150 ° C. for 12 hours. And stirred. After distilling the reaction mixture at 150 ° C. until the distillation product disappeared, the temperature was lowered to 120 ° C. and the solvent was distilled off under reduced pressure to obtain 29.0 g of the title compound. It was used as it was for the next reaction without purification.

Step 5 Preparation of 2- (2,4,5-trifluorobenzoyl) -3- (3,5,6-trifluoropyridin-2-yl) aminoacrylic acid ethyl ester

To 7.65 g of 3-ethoxy-2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester produced in step 4, 20 ml of ethanol was added and cooled to 10 ° C or lower, and 2-amino-3,5 A solution of 3.75 g of, 6-trifluoropyridine in 20 ml of ethanol was slowly added. It was stirred at room temperature for 2 hours and then filtered, washed with 10 ml of ethanol and dried to give 9.04 g of the title compound.

1 H-NMR (300 MHz, CDCl 3): δ 1.20 (3H, t, J = 7.5 Hz), 4.19 (2H, q, J = 7.5 Hz), 6.87-6.95 (1H, m), 7.31-7.39 (1H, m ), 7.54 (1H, q, J = 7.5 Hz), 8.94 (1H, d, J = 12 Hz), 12.43 (1H, d, J = 12 Hz)

Step 6 Preparation of 1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester

9.04 g of 2- (2,4,5-trifluorobenzoyl) -3- (3,5,6-trifluoropyridin-2-yl) aminoacrylic acid ethyl ester obtained in step 5 was dissolved in 120 ml of DMF at room temperature. Then, 1.69 g of sodium fluoride was added thereto, and the mixture was heated and stirred at 130 ° C. for 10 hours. After cooling to room temperature, 200 ml of water was added thereto, and the resulting precipitate was filtered and separated by tube chromatography (eluent: ethyl acetate: hexane = 1: 2) to obtain 7.4 g of the title compound as a white solid.

1 H-NMR (300 MHz, CDCl 3): δ 1.40 (3H, t, J = 7.2 Hz), 4.40 (2H, q, J = 7.2 Hz), 6.77-6.83 (1H, m), 7.84 (1H, q, J = 7.2 Hz), 8.31 (1H, dd, J1 = 8.6 Hz, J2 = 10.1 Hz), 8.46 (1H, d, J = 0.3 Hz)

<Step 7> of 1- (3,5-difluoro-6-hydrazinopyridin-2-yl) -6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Produce

1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester obtained in step 6 above 5.4 The suspension was suspended in 30 ml of isopropanol, and 30 ml of 6N HCl was added thereto, followed by stirring for 3 hours at reflux. The reaction mixture was cooled and the resulting solid was filtered, which was washed with distilled water and acetone and dried to obtain 3.4 g of the title compound.

1 H-NMR (300 MHz, DMSO-d6): δ 7.85 (1H, dd, J1 = 6.6 Hz, J2 = 11.7 Hz), 8.33 (1H, dd, J1 = 8.7 Hz, J2 = 10.2 Hz), 8.83 (1H, dd, J1 = 8.4 Hz, J2 = 16.2 Hz), 9.17 (1H, s), 14.13 (1H, brs)

Step 8 Preparation of 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

1- (3,5-Difluoro-6-hydrazinopyridin-2-yl) -6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid obtained in step 7 above 2.0 g was added to a mixed solution of 80 ml of isopropanol and 40 ml of methylene chloride, and then 60 ml of an aqueous 28% ammonia solution was added dropwise with stirring, followed by stirring at 30 ° C. for 20 hours. The reaction mixture was cooled to room temperature, and the filtrate was filtered and evaporated under reduced pressure. The residue was separated by tube chromatography (eluent: methylene chloride: methanol = 20: 1) to obtain 0.78 g of a white solid title compound.

1 H-NMR (300 MHz, DMSO-d6): δ 6.78 (2H, s), 7.55 (1H, m), 8.02 (1H, m), 8.18 (1H, m), 8.64 (1H, s)

Example 3: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- Preparation of Carboxylic Acids

1- (3,5-difluoropyridin-6-amino-2-yl in the same manner as in Example 2, using 103 g of 2,4,5-trifluoro-3-methoxybenzoic acid (Fluorochem) as a starting material 38.6 g of 6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

1 H-NMR (300 MHz, CDCl 3): δ 4.00 (3H, s), 6.73 (2H, s), 7.91 (1H, m), 8.18 (1H, m), 8.62 (1H, s)

Example 4: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7-methylamino-8-chloro-4-oxo-1,4-dihydroquinoline-3 Preparation of Carboxylic Acids

<Step 1> 1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Manufacture

1- (3,5,6-trifluoropyridine-2 according to the method of steps 1 to 7 of Example 2 using 35.0 g of 2,4,5-trifluoro-3-chlorobenzoic acid (Fluorochem) as starting material 27.7 g of -yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

1 H-NMR (300 MHz, CDCl 3): δ 3.65 (3H, s), 7.78 (1H, d), 8.12 (1H, s), 8.18 (1H, m), 8.54 (1H, s), 8.70

<Step 2> 1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7-methylamino-8-chloro-4-oxo-1,4-dihydroquinoline-3-car Preparation of Acids

1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxyl produced in step 1 3.90 g of acid was added to 50 ml of isopropanol, and 20 ml of 40% aqueous methylamine solution was added dropwise while stirring, followed by stirring at 30 DEG C for 20 hours. The reaction mixture was cooled to room temperature, and the filtrate was filtered and evaporated under reduced pressure. The residue was separated by tube chromatography (eluent: methylene chloride: methanol = 20: 1) to obtain 3.78 g of a white solid target compound.

1 H-NMR (300 MHz, DMSO-d6): δ 3.09 (3H, dd, J = 5 Hz, J = 8 Hz), 6.28 (1H, m), 6.72 (2H, brs), 7.90 (1H, t, J = 10 Hz ), 8.47 (1 H, s)

Step 3 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7-methylamino-8-chloro-4-oxo-1,4-dihydroquinoline-3 Preparation of Carboxylic Acids

1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7-methylamino-8-chloro-4-oxo-1,4-dihydroquinoline-3- obtained in step 2 above 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7-methylamino- according to the method of step 8 of Example 2 using 2.02 g of carboxylic acid as starting material 1.62 g of 8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared.

 1 H-NMR (300 MHz, DMSO-d6): δ 3.09 (3H, dd, J = 5 Hz, J = 8 Hz), 6.28 (1H, m), 6.72 (2H, brs), 7.55 (1H, brs), 8.10 ( 1H, m), 8.63 (1H, s)

Example 5: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -5-amino-6,8-difluoro-7-methylamino-4-oxo-1,4-dihydro Preparation of Quinoline-3-carboxylic Acid

84 g of 2,3,4,5-tetrafluoro-6-aminobenzoic acid (chemical lead) was used as a starting material, and 1- (3,5-difluoro-6-aminopyridine-2- 64.3 g of 1) -5-amino-6,8-difluoro-7-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

1 H-NMR (300 MHz, DMSO-d6): δ 3.09 (3H, dd, J = 5 Hz, J = 8 Hz), 6.26 (1H, m), 6.72 (2H, brs), 7.57 (1H, brs), 7.90 ( 1H, m), 8.47 (1H, s)

Example 6: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -5-methyl-6-fluoro-7-methylamino-8-bromo-4-oxo-1,4- Preparation of Dihydroquinoline-3-carboxylic Acid

1- (3,5-difluoro-6-aminopyridine in the same manner as in Example 4 using 38.6 g of 2,4,5-trifluoro-3-bromo-6-methylbenzoic acid (chemical lead) as a starting material 18.28 g of 2-yl) -5-methyl-6-fluoro-7-methylamino-8-bromo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

1 H-NMR (300 MHz, DMSO-d6): δ 2.02 (3H, s), 3.09 (3H, dd, J = 5 Hz, J = 8 Hz), 6.28 (1H, m), 6.72 (2H, brs), 7.55 ( 1H, brs), 8.48 (1H, s)

Example 7: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- {N-methyl-N- (2-hydroxyethyl)} amino-8-chloro Preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

<Step 1> 1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Manufacture

1- (3,5,6-trifluoropyridine) according to the method given in steps 1 to 7 of Example 2 using 42.0 g of 2,4,5-trifluoro-3-chlorobenzoic acid (Fluorochem) as starting material 31.3 g of 2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

1 H-NMR (300 MHz, CDCl 3): δ 3.65 (3H, s), 7.78 (1H, d), 8.12 (1H, s), 8.18 (1H, m), 8.54 (1H, s), 8.70

<Step 2> 1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- {N-methyl-N- (2-hydroxyethyl)} amino-8-chloro-4 Preparation of -oxo-1,4-dihydroquinoline-3-carboxylic acid

1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline-3-car generated in step 1 above 3.90 g of acid was dissolved in 50 ml of isopropanol, and 2.1 g of N-methyl-N- (2-hydroxyethyl) amine was added thereto with stirring, followed by stirring at 30 ° C for 20 hours. The reaction mixture was cooled to room temperature and the filtrate was filtered and evaporated under reduced pressure, and the residue was separated by tube chromatography (eluent: methylene chloride: methanol = 20: 1) to obtain 3.91 g of a white solid of the title compound.

1 H-NMR (300 MHz, DMSO-d6): δ 2.09 (3H, s), 3.57 (2H, m), 3.82 (2H, m), 5.30 (1H, brs), 7.64 (1H, brs), 8.14 (1H , m), 8.63 (1H, s)

<Step 3> 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- {N-methyl-N- (2-hydroxyethyl)} amino-8-chloro Preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid

1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- {N-methyl-N- (2-hydroxyethyl)} amino-8-chloro produced in step 2 above 1- (3,5-Difluoro-6-aminopyridine in the same manner as in Step 8 of Example 2, using 3.10 g of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as starting material -2-yl) -6-fluoro-7- {N-methyl-N- (2-hydroxyethyl)} amino-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 2.42 g were prepared.

1 H-NMR (300 MHz, DMSO-d6): δ 2.09 (3H, s), 3.57 (2H, m), 3.82 (2H, m), 5.30 (1H, brs), 6.78 (2H, s), 7.55 (1H , brs), 8.14 (1H, m), 8.63 (1H, s)

Example 8: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- (2-methoxyethyl) amino-8-chloro-4-oxo-1,4 Preparation of -dihydroquinoline-3-carboxylic acid

<Step 1> 1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- (2-methoxyethyl) amino-8-chloro-4-oxo-1,4-di Preparation of Hydroquinoline-3-carboxylic Acid

1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline produced in step 1 of Example 7 above 2.67 g of -3-carboxylic acid was added to 50 ml of isopropanol, and 2.1 g of 2-methoxyethylamine was added thereto under stirring, followed by stirring at 30 DEG C for 20 hours. The reaction mixture was cooled to room temperature, and the filtrate was filtered and evaporated under reduced pressure, and the residue was separated by tube chromatography (eluent: methylene chloride: methanol = 20: 1) to give 2.21 g of the title compound as a white solid.

1 H-NMR (300 MHz, DMSO-d6): δ 2.64 (2H, m), 3.41 (2H, s), 3.54 (3H, m), 4.86 (1H, m), 7.75 (1H, m), 7.94 (1H , m), 8.8.52 (1 H, s)

<Step 2> 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- (2-methoxyethyl) amino-8-chloro-4-oxo-1,4 Preparation of -dihydroquinoline-3-carboxylic acid

1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- (2-methoxyethyl) amino-8-chloro-4-oxo-1,4 produced in step 1 above 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6- in the same manner as in step 8 of Example 2, at 50 ° C using 3.10 g of -dihydroquinoline-3-carboxylic acid 2.42 g of fluor-7- (2-methoxyethyl) amino-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

1 H-NMR (300 MHz, DMSO-d6): δ 2.64 (2H, m), 3.41 (2H, s), 3.54 (3H, s), 4.86 (1H, m), 6.72 (2H, m), 7.62 (1H) , m), 7.94 (1H, m), 8.8.52 (1H, s)

Example 9: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- (2-hydroxyethyl) amino-8-chloro-4-oxo-1,4 Preparation of -dihydroquinoline-3-carboxylic acid

<Step 1> 1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- (2-hydroxyethyl) amino-8-chloro-4-oxo-1,4-di Preparation of Hydroquinoline-3-carboxylic Acid

1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline produced in step 1 of Example 7 above 1.39 g of -3-carboxylic acid was dissolved in 30 ml of isopropanol, and 1.4 g of 2-hydroxyethylamine was added thereto under stirring, followed by stirring at 30 ° C for 20 hours. The reaction mixture was cooled to room temperature and the filtrate was filtered and evaporated under reduced pressure, and the residue was separated by tube chromatography (eluent: methylene chloride: methanol = 20: 1) to obtain 1.41 g of a white solid title compound.

1 H-NMR (300 MHz, DMSO-d6): δ 3.09 (3H, dd, J = 5 Hz, J = 8 Hz), 6.28 (1H, m), 6.72 (2H, brs), 7.90 (1H, t, J = 10 Hz ), 8.47 (1 H, s)

<Step 2> 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- (2-hydroxyethyl) amino-8-chloro-4-oxo-1,4 Preparation of -dihydroquinoline-3-carboxylic acid

1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- (2-hydroxyethyl) amino-8-chloro-4-oxo-1,4- obtained in step 1 above. 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6- according to the method given in step 8 of Example 2 using 2.15 g of dihydroquinoline-3-carboxylic acid as starting material 1.78 g of fluor-7- (2-hydroxyethyl) amino-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

1 H-NMR (300 MHz, DMSO-d6): δ 2.64 (2H, m), 3.41 (2H, m), 4.86 (1H, brs), 5.44 (2H, brs), 7.90 (1H, m), 7.94 (1H) , brs), 8.49 (1H, m)

Example 10 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- (pyrrolidin-3-yl) amino-8-chloro-4-oxo-1 Preparation of 4,4-dihydroquinoline-3-carboxylic acid

Step 1 1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- (pyrrolidin-3-yl) amino-8-chloro-4-oxo-1,4 Preparation of -dihydroquinoline-3-carboxylic acid

1- (3,5,6-trifluoropyridin-2-yl) -6,7-difluoro-8-chloro-4-oxo-1,4-dihydroquinoline produced in step 1 of Example 7 above 2.80 g of -3-carboxylic acid was dissolved in 30 ml of isopropanol, and then 2.10 g of 3-aminopyrrolidine was added thereto with stirring, followed by stirring at 30 ° C. for 20 hours. The reaction mixture was cooled to room temperature, the filtrate was filtered and evaporated under reduced pressure, and the residue was separated by tube chromatography (eluent: methylene chloride: methanol = 20: 1) to give 2.74 g of a white solid of the title compound.

1 H-NMR (300 MHz, DMSO-d6): δ 3.09 (3H, dd, J = 5 Hz, J = 8 Hz), 6.28 (1H, m), 6.72 (2H, brs), 7.90 (1H, t, J = 10 Hz ), 8.47 (1 H, s)

<Step 2> 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6-fluoro-7- (pyrrolidin-3-yl) amino-8-chloro-4-oxo-1 Preparation of 4,4-dihydroquinoline-3-carboxylic acid

1- (3,5,6-trifluoropyridin-2-yl) -6-fluoro-7- (pyrrolidin-3-yl) amino-8-chloro-4-oxo-1 obtained in step 1, 1- (3,5-Difluoro-6-aminopyridin-2-yl)-according to the method given in step 8 of Example 2 using 2.65 g of 4-dihydroquinoline-3-carboxylic acid as starting material 2.31 g of 6-fluoro-7- (pyrrolidin-3-yl) amino-8-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid were prepared.

 1 H-NMR (300 MHz, DMSO-d6): δ 1.75 (2 H, m), 2.07 (1 H, m), 2.85-3.07 (4 H, brs), 4.43 (1 H, m), 5.92 (1 H, m), 6.77 (2H, brs), 7.96 (1H, brs), 7.99 (1H, m), 8.69 (1H, s)

Example 11: 1- (3,5-Difluoro-6-aminopyridin-2-yl) -6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-car Preparation of Acids

(3,5-Difluoropyridin-6-amino-2-yl) -6 according to the method of Example 2 using 25.9 g of 2,4,5-trifluoro-3-methylbenzoic acid (Fluorochem) as starting material 7.92 g of, 7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared.

1 H-NMR (300 MHz, DMSO-d6): δ 2.09 (3H, s), 6.28 (1H, m), 6.72 (2H, brs), 7.90 (1H, t, J = 10 Hz), 8.47 (1H, s)

As described above, in the preparation method according to the present invention, after reacting 2-amino-3,5,6-trifluoropyridine instead of 2,6-diamino-3,5-difluoropyridine, which has been conventionally used, By introducing an additional amino group, a quinolone derivative having a 3,5-difluoro-6-aminopyridyl group substituted at the N-1 position can be prepared in high yield, and thus a cellular chemokine receptor (CCR) is a major intermediate of a bioactive substance. It can be useful for the preparation of receptor) 5 modulators as well as for the preparation of anti-infective agents.

Claims (1)

1) reacting the 3-oxo-propionic acid ethyl ester derivative of Formula 2 with triethylorthoformate; 2) reacting the ethoxyethylene derivative of Formula 3 produced in Step 1 with 2-amino-3,5,6-trifluoropyridine; 3) acid hydrolysis of the pyridylenamin derivative of Formula 4 produced in step 2 in the presence of an organic solvent and a base, followed by cyclization; And 4) a quinolone derivative having a 3,5,6-trifluoropyridyl group substituted in the N-1 position of the formula (5) generated in step 3, comprising the step of introducing an amino group by treatment with ammonia water, Method for preparing a quinolone derivative having 1, 3,5-difluoro-6-aminopyridyl group substituted at the N-1 position: <Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

<Formula 5>

Wherein X is chlorine or fluorine; R ¹ is hydrogen, amino or methyl; R ² is fluorine, chlorine, methylamino, 2-hydroxyethylamino, N-methyl-N- (2-hydroxyethyl) amino, 2-methoxyethylamino or (pyrrolidin-3-yl) amino ; W is CH, N, CF, CCl, CBr, COCH ₃ or CCH ₃ .