NO178574B - New 5-fluoronicotinic acid derivatives - Google Patents

Abstract

5-Fluoronicotinic acid derivative of the formula. wherein a hydrogen atom or a C-Calkyl group ;. R 2 represents a halogen atom, a hydroxyl group, an azido group ,. enj-Calkoks, Cx-Calkylthio-, phenylthio-, -. alkanesulfinyl-, benzenesulfinyl-, C 1 -C 4 alkanesulfonyl- ,. benzenesulfonyl-, C-calkanesulfonyloxy,. trifluoromethylsulfonyloxy, benzenesulfonyloxy (where the benzene ring may be substituted with C 1 -C 4 alkyl or halogen or with a nitro group), naphthalenesulfonyloxy, di-C 1 -C 8-alkoxyphosphineyloxy or diphenyloxyphosphineyloxy. group, a. , 3-amino-1-pyrrolidinyl group wherein the amino group may be protected with C 1 -C 4 alkanoyl or N, N-dimethylaminomethylene, or a 1-piperazinyl group where the imino group may be protected with C 1 -C 4 alkanoyl; and X represents a hydrogen or fluorine atom, or a salt of the derivative or a reactive derivative of the carboxyl group. The new derivatives are suitable as intermediates in the preparation of oxonaphthyridine derivatives described in patent 163,227.

Description

This invention relates to new starting materials for the production of 1-substituted-aryl-1,4-dihydro-4-oxonaphthyridine derivatives of the general formula (I-1) or a salt thereof:

where R<1> means a hydrogen atom or a C 1 -C 4 alkyl group;

R<2> means a halogen atom, a hydroxyl group, an azido group,

a C 1 -C 6 alkoxy-, C 1 -C 2 alkylthio-, phenylthio-, C 2 -C 3 alkane-

sulfinyl-, benzenesulfinyl-, C^-C^ alkanesulfonyl-, benzenesulfonyl-,

cl_c4 alkanesulfonyloxy-, benzenesulfonyloxy- (where the benzene ring may be substituted with 1-3 C1-C4 alkyl or halogen or with a nitro group), naphthalenesulfonyloxy-, di-C1-C4-alkyloxy-

phosphinyloxy or diphenyloxy-phosphinyloxy group, a 3-amino-1-pyrrolidinyl group where the amino group may be protected with 0^-04 alkanoyl or N,N-dimethylaminomethylene, or a 1-piperazinyl-

group where the imino group may be protected with C 1 -C 4 alkanoyl;

and X means a hydrogen or fluorine atom, or a salt thereof.

From Program and Abstracts of the 24th I.C.A.A.C., pages 102-104

and published Japanese patent application Kokai no. 228,479/85, it appears that 1-substituted-aryl-1,4-dihydro-4-oxonaphthyridine derivatives of formula (I-1) and salts thereof have strong anti-bacterial effects against Gram-positive and Gram-negative bacteria, that by oral or parenteral administration they lead to high blood levels and that they have excellent properties such as a high degree of safety and the like.

The invention relates to compounds with the formula (V)

where R<1>, R<2> and X are as indicated above.

The compounds of formula (V) can be converted into compounds of formula (II):

where R1<a> is C, -C4 alkyl, and R2 and X are as above.

Preparation of the compounds of formula (I) is the subject of patent 163,227 and is illustrated in the process (1) below.

The starting material with formula (II) used there is the subject of patent 174,888, and can be produced from a compound (V) according to the present invention, as illustrated in the process (2) below (where V-1 is V with R<1> = H).

Preparation of the compounds of formula (V) is illustrated in process (3) (where V-a is V with R<2> = OH).

A compound of formula (V) where R<2> is OH, can be converted into a compound where R<2> has another of the meanings stated above. Likewise, other conversions can be made not only with R<2>, but also with R<1> and X.

In the following examples means:

Example 1

(1) In 300 ml of ethyl acetate, 50 g of ethyl 3-imino-3-phenoxypropionate hydrochloride and 27.8 g of 2,4-difluoroaniline were suspended, after which the resulting suspension was allowed to react under reflux conditions for 2 hours. The deposited crystals were filtered off and washed with two 200 ml portions of ethyl acetate to obtain 47 g (yield 82.2%) of ethyl N-(2,4-difluorophenyl)amidino-acetate hydrochloride with a melting point of 196-197°C .

IR (KBr) cm"<1>: vc=0 1730

NMR (DMSO-d6) 6 values: 1.26 (3H, t, J=7Hz), 4.07 (2H, s),

4.19 (2H, q, J=7Hz), 7.02-7.78 (3H, m), 9.11 (1H, bs), 10.26 (1H, bs), 12.28 (1H, bs).

In the same way as above, the following compounds were obtained: Methyl N-(2,4-difluorophenyl)amidinoacetate hydrochloride Melting point: 19 2-193°C

IR (KBr) cm"<1>: vc=Q 1735

NMR (DMSO-d6): 6 values: 3.74 (3H, s), 4.09 (2H, s),

6.91-7.73 (3H, m), 9.15 (1H, bs), 10.31 (1H, bs), 12.29 (1H, bs).

Methyl N-(4-fluorophenyl)amidinoacetate hydrochloride Melting point: 134-135°C

IR (KBr) cm"<1>: vc=Q 1730

NMR (DMSO-d6) 6 values: 3.74 (3H, s), 4.05 (2H, s), 7.01-7.59 (4H, m), 8.96 (1H, bs), 10.06 (1H, bs) , 12.26 (1H, bs) .

(2) In a mixture of 9 2 ml of water and 92 ml of methylene chloride was

23.0 g of methyl N-(2,4-difluorophenyl)amidinoacetate hydrochloride were dissolved, after which the pH of the solution was adjusted to 13 with 2N sodium hydroxide solution. The organic layer was then separated, washed successively with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. To the solution was then added 27.1 g of the sodium salt of ethyl-α-formyl-α-fluoroacetate at room temperature and the resulting mixture reacted under reflux for 4 hours, after which the solvent was removed by distillation under reduced pressure. The residue obtained was added to 9 2 ml of water and 46 ml of ethyl acetate and the precipitated crystals from filtr ert. The crystals were suspended in 184 ml of water which was adjusted to pH 1.0 with 6N hydrochloric acid, whereupon the crystalline material obtained was added to 46 ml of water and 46 ml of isopropanol. The crystals were then filtered off, whereby 15.0 g (yield 57.9%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate with a melting point of 222-223°C were obtained.

Melting point: 222-223°C (recrystallized from ethyl acetate)

IR (KBr) cm"<1>: \) Q=Q 1700

NMR (TFA-d-j) 6 values: 4.06 (3H, s) , 6.71-7.65 (3H, m) ,

8.12 (1H, d, J=11Hz).

In the same manner as above, the following compounds were obtained: Ethyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate. Melting point: 177-178°C (recrystallized from ethyl acetate)

IR (KBr) cm"<1> vc=0 1700

NMR (TFA-d^) 6 values: 1.52 (3H, t, J=7Hz), 4.50 (2H, q,

J=7Hz), 6.80-7.65 (3H, m), 8.15

(1H, d, J=1lHz).

Methyl 5-fluoro-2-(4-fluorophenylamino)-6-hydroxynicotinate. Melting point: 227-228°C (recrystallized from ethyl acetate)

IR (KBr) cm"<1>: vc=Q 1690

NMR (TFA-d 2 ) 6 values: 4.05 (3H, s), 6.89-7.53 (4H, m).

8.11 (1H, d, J=11Hz). (3) In a mixture of 5 ml of water and 5 ml of methylene chloride, 500 mg of methyl N-(2,4-difluorophenyl)amidinoacetate hydrochloride was dissolved and the pH of the resulting solution was adjusted to 13.0 with 2N sodium hydroxide solution. The organic layer was separated and washed successively with 3 ml of water and 3 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. To the solution was added 820 mg of ethyl 3-(4-methylbenzenesulfonyloxy)-2-fluoroacrylate and then 120 mg of sodium methoxide (purity: 9 2.3%) and 5 ml of methanol at room temperature, after which the resulting mixture was reacted at the same temperature for 24 hours. The solvent was then removed by distillation under reduced pressure and the residue obtained added to 10 ml of water and 2 ml of ethyl acetate. The pH of the resulting solution was adjusted to 1.0 with 6N hydrochloric acid and the precipitated crystals were filtered off and washed successively with 2 ml of water and 2 ml of isopropanol to obtain 370 mg (yield 65.7%) of methyl-2-(2,4 -^it Luorphenylamino)-5-fluoro-6-hydroxynicotinate.

The physical properties of this compound were identical to those of the compound (2) obtained above.

(4) The procedure under (3) was repeated, except that one of the 3-substituted-2-fluoroacrylates shown in Table 2 was used instead of ethyl 3-(4-methylbenzenesulfonyloxy)-2-fluoroacrylate to obtain the results shown in Table 2.

The physical properties of the respective compounds were identical to the properties of the compounds obtained under (2).

Example 2

200 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate was dissolved in 6 ml of tetrahydrofuran, to which was added a solution of approx. 40 mg of diazomethane in diethyl ether under ice-cooling, after which the resulting mixture was allowed to react at room temperature for 30 minutes. Acetic acid was then added until foaming in the reaction mixture ceased, after which the solvent was removed by distillation under reduced pressure. The crystals thus obtained were washed with 6 ml of isopropanol to give 150 mg (yield 71.6%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate with a melting point of 160-161°C .

Melting point: 160.5-161.5°C (recrystallized from ethyl acetate).

IR (KBr) cm"<1>: vc=Q 1690

NMR (CDCl 3 ) 6 values: 3.89 (3H, s), 3.98 (3H, s) , 6.57-7.08 (2H m), 7.81 (1H, d, J=11Hz) , 8.10-8.97 (1H, m) , 10.24 (1H, bs) .

Example 3

In 5 ml of N,N-dimethylformamide, 200 mg of methyl-2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate was dissolved, to which were added 110 mg of potassium carbonate and 93 mg of dimethyl sulfate at room temperature, whereupon the resulting mixture was allowed to react at the same temperature for 2 hours. Then 20 ml of water and 20 ml of ethyl acetate were added, after which the organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the obtained crystalline material added to 5 ml of isopropanol, whereupon the crystals were filtered off to give 180 mg (yield 86.0%) of methyl-2-(2,4-difluorophenyl-amino) 5-f luor-6-methoxynicotinate. The compound had the same physical properties as the compound obtained in Example 2.

Example 4

200 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate was dissolved in 5 ml of N,N-dimethylformamide, to which 110 mg of potassium carbonate and 0.11 g of methyl iodide were added at room temperature, after which the the resulting mixture was allowed to react at the same temperature for 1 hour. To the reaction mixture was then added 20 ml of water and 20 ml of ethyl acetate, whereupon the organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate" The solvent was removed by distillation under reduced pressure, whereupon it was obtained 5 ml of isopropanol was added to the crystalline material. The crystals were then filtered off to give 190 mg (yield 90.7%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxy-nicotinate. The compound had the same physical properties as the compound obtained in Example 2 .

Example 5

A mixture of 9.5 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, 26.5 g of phosphorus pentachloride and 46.9 g of phosphorus oxychloride was reacted at 70-80°C for 4 hours. The reaction mixture was then gradually added to 285 ml of water and the crystals thus deposited were filtered off and washed with 57 ml of water. The crystals were purified by column chromatography [Wako Silikagel C-200, eluent: toluene] to give 3.5 g (yield 34.7%) of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinate with a melting point of 137-139°C.

Pour point: 1 39.5-140.5°C (recrystallized from diisopropyl ether)

IR (KBr) cm"<1>: vc=Q 1695

NMR (CDCl 3 ) 6 values: 3.93 (3H, s), 6.61-7.06 (2H, m),

7.94 (1H, d, J=9Hz), 8.15-8.57

(1H, m), 10.13 (1H, bs).

Example 6

In 10 ml of methylene chloride, 500 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate was suspended, to which were added 440 mg of 2,4,6-trimethylbenzenesulfonyl chloride and 220 mg of triethylamine, whereupon the resulting mixture was react at room temperature for 3 hours. The solution was added to 15 ml of water and the organic layer separated, washed with 15 ml of water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting crystalline material added to 15 ml of diethyl ether, whereupon the crystals were filtered off to give 660 mg (yield 81.9%) of methyl-2-(2,4-difluorophenylamino)-5- fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinate with a melting point of 153-155°C.

Melting point: 155-156°C (recrystallized from ethyl acetate)

IR (KBr) cm"<1>: vc=Q 1700

NMR (CDCl 3 ) 6 values: 2.33 (3H, s), 2.59 (6H, s), 3.92

(3H, s), 6.32-6.84 (2H, m), 6.92 (2H, s), 7.35-7.94 (1H, m), 8.05 (1H, d, J =9Hz), 10.17 (1H, bs).

In the same manner as above, the following compounds were obtained: Methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methanesulfonyl-oxynicotinate.

Melting point: 120-121°C (recrystallized from ethyl acetate)

IR (KBr) cm"<1>: vc=Q 1690

NMR (CDCl 3 ) 6 values: 3.30 (3H, s), 3.94 (3H, s), 6.60-7.15 (2H, m),

7.73-8.33 (m) _ 10'00 (1H bs) 8.07 (d, J=9Hz)>

Ethyl 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-triisopropylbenzenesulfonyloxy)nicotinate.

Melting point: 147-148°C (recrystallized from ethyl acetate)

IR (KBr) cm"<1>: vc=Q 1700

NMR (CDCl 3 ) 6 values: 1.21 (12H, d, J=7Hz), 1.28 (6H, d,

J=7Hz), 1.40 (3H, t, J=7Hz), 2.55-3.30 (1H, m),

3.70-4.60 (m) \(4H)^

4.73 (q, J=7Hz)J

6.20-7.30 (m) ) (4R)^

7.20 (s)

7.50-8.30. (m) (2H) ^ 10^3 (1H bs) 8.10 (d, J=9Hz)/

Example 7

In 7 ml of N,N-dimethylformamide, 700 mg of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinate was suspended, to which were added 340 mg of triethylamine and 210 mg of ethanethiol at room temperature, after which the resulting mixture was allowed to react for 4 hours at 50°C" 40 ml of ethyl acetate and 30 ml of water were then added to the reaction mixture and the pH of the mixture was adjusted to 2 with 2N hydrochloric acid. The organic layer was separated, washed successively with 20 ml of water and 20 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the crystalline material obtained added to 10 ml of hexane, whereupon the crystals were filtered off to give 620 mg (yield 81.9%) of methyl-6-ethylthio-2-(2,4-difluorophenylamino) )-5-fluoronicotinate with a melting point of 113-114°C.

Melting point: 113.5-114°c (recrystallized from diisopropyl ether).

IR (KBr) cm<-1>: vc=Q 1680

NMR (CDCl 3 ) 6 values: 1.29 (3H, t, J=7Hz), 3.07 (2H, q,

J=7Hz), 3.90 (3H, s), 6.50-7.20

(2H, m), 7.66 (1H, d, J=10Hz), 7.80-8 .50 (1H, m), 10.00 (1H, bs) .

In the same manner as above, methyl 2-(2,4-difluorophenyl-amino)-5-fluoro-6-phenylthionicotinate was obtained.

Melting point: 128-128.5°C (recrystallized from diisopropyl ether).

IR (KBr) cm"<1>: vc=Q 1685

NMR (CDCl 3 ) 6 values: 3.90 (3H, s), 6.0-8.0 (m) (9R)

7.77 (d, J=10Hz)' 10.25 (1H, bs).

Example 8

In 10 ml of N,N-dimethylformamide, 1.00 g of methyl-6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinate was suspended, to which were added 750 mg of 3-aminopyrrolidine dihydrochloride and 1.44 g of triethylamine , whereupon the resulting mixture was allowed to react for 30 minutes at 70°C.

To the reaction mixture was then added 50 ml of chloroform

and 50 ml of water and the organic layer separated, washed successively with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the crystalline material obtained added to 5 ml of diethyl ether, whereupon the crystals were filtered off to give 1.10 g (yield 95.1%) of methyl-6-(3-amino-1-pyrrolidinyl) )-2-(2,4-difluorophenyl-amino)-5-fluoronicotinate with a melting point of 139-140°C.

IR (KBr) cm~<1>: vc=Q 1670

NMR (CDCl 3 ) 6 values: 1.58-2.27 (2H, m) , 3.17-4.10 (mn (8H)

3.84 (s) 6.57-7.12 (2H, m), 7.58 (1H, d, J=14Hz), 8.10-8.62 (1H, m), 10.32

(1H, bs).

In the same manner as above, methyl 6-(4-acetyl-1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate was obtained.

Melting point: 172-173°C (recrystallized from ethyl acetate) IR (KBr) cm"<1>: vc=0 1680, 1650

NMR (CDCl 3 ) 6 values: 2.13 (3H, s), 3.32-4.12 (m) \ (11R)

3.85 (s) 6.57-7.07 (2H, m), 7.68 (1H, d, J=13Hz), 7.77-8.18 (1H, m), 10.05

(1H, bs) .

Example 9

In 6.5 ml of chloroform, 650 mg of methyl 6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate were dissolved, to which was added 190 mg of acetic anhydride, after which the resulting mixture was react for 10 minutes at room temperature. The solvent was then removed by distillation under reduced pressure. The obtained crystalline material was added to 2 ml of diethyl ether, after which the crystals were filtered off to give 720 mg (yield 99.4%) of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)- 5-fluoronicotinate with a melting point of 199-200°C.

Melting point: 202-203°C (recrystallized from ethyl acetate) IR (KBr) cm"<1>: vc=Q 1675

NMR (CDCl3-DMSO-dg) 6 values: 1.63-2.27 (m) \ ^5Hj 1.91 (s)

3.38-4.62 (mn (8H) ,

3.82 (s)

6.63-7.17 (2H, m), 7.62 (1H, d, J=14Hz), 7.83-8.60 (2H, m), 10.30 (1H, bs).

Example 10

In 3 ml of N,N-dimethylformamide, 120 mg of 3-aminopyrrolidine dihydrochloride was suspended, to which was added 250 mg of triethylamine, whereupon the resulting mixture was allowed to react for 5 minutes at room temperature. To the reaction mixture was then added 300 mg of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinate, after which the resulting mixture was allowed to react for 1.5 hours at room temperature. To the reaction mixture was then added 10 ml of chloroform and 10 ml of water, after which the organic layer was separated, washed successively with 10 ml of water and 10 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was then added with 100 mg of acetic anhydride, whereupon the resulting mixture was allowed to react at room temperature for 10 minutes, before the solvent was removed by distillation under reduced pressure. The obtained crystalline material was added to 5 ml of diethyl ether and the crystals were filtered off to give 210 mg (yield 82.4%) of methyl-6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenyl-amino)- 5-fluoronicotinate. The compound had the same physical properties as the compound obtained in Example 9.

In the same manner as above, methyl 6-(4-acetyl-1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate was obtained.

This compound had the same physical properties

as the compound obtained in Example 8.

Example 11

In 39 mg of N,N-dimethylformamide, 3.89 g of methyl-2-(2,4-difluorophenylamino)-5-fluoro-e-tmesitylene-sulfonyloxy)nicotinate were dissolved, to which was added 1.34 g of thiophenol and

1.23 g of triethylamine, whereupon the resulting mixture was allowed to react at room temperature for 5 hours. 120 ml of ethyl acetate and 120 ml of water were then added to the reaction mixture and the pH of the mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was separated, washed successively with 80 ml of water and 80 ml of saturated aqueous sodium chloride solution and then dried

over anhydrous magnesium sulfate. The solvent was removed

by distillation under reduced pressure and the obtained crystalline material added to 20 ml of n-hexane, whereupon the precipitated crystals were filtered off to give 2.85 g (yield 90.2%) of methyl-2-(2,4-difluorophenylamino)- 5-fluoro-6-phenylthionicotinate with a melting point of 126-128°C.

This compound had the same physical properties as the compound obtained in Example 7.

In the same manner as above, methyl 2-(2,4-difluorophenyl-amino)-6-ethylthio-5-fluoronicotinate was obtained. This compound had the same physical properties as the compound obtained in Example 7.

Example 12

In 30 ml of methanol, 3.00 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate were suspended, to which 16.1 ml of 2N sodium hydroxide solution was added at room temperature, after which the resulting mixture was reacted under - running cooling for 4 hours. The reaction mixture was then added to

added to a mixture of 60 ml of ethyl acetate and 60 ml of water, after which the aqueous layer was separated. The aqueous layer was adjusted to pH 1.0 with 6N hydrochloric acid and the precipitated crystals filtered off, washed successively with 15 ml of water and 15 ml of isopropanol to obtain 2.68 g (yield 93.7%) of 2-(2.4 -difluorophenylamino)-5-fluoro-6-hydroxynicotinic acid with a melting point of 213-216°C.

Melting point: 215-216°C (recrystallized from acetone-

ethanol (1:1 parts by volume))

IR (KBr) cm"<1>: vc=Q 1700

NMR (DMSO-d6) 6 values: 6.65-7.58 (2H, m), 7.86 (1H, d,

J=11Hz), 8.12-8.68 (TH, m),

10.49 (1H, bs).

In the same manner as above, 5-fluoro-2-(4-fluorophenyl-amino)-6-hydroxynicotinic acid was obtained.

Melting point: 216-217°C (recrystallized from acetone-

methanol (1:1 parts by volume))

IR (KBr) cm~<1>: vc=Q 1685 (sh)

NMR (DMSO-dg) 6 values: 6.84-7.94 (5H, m), 10.33 (1H, bs).

Example 1 3

2.00 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate were dissolved in 60 ml of tetrahydrofuran, to which was added 25.5 ml of 1N aqueous sodium hydroxide solution at room temperature, after which the resulting mixture was reacted under reflux cooling for 7 hours. The solvent was then removed by distillation under reduced pressure and the resulting residue added with 100 ml of ethyl acetate and 100 ml of water, whereupon the resulting mixture was adjusted to pH 2.0 with 2N hydrochloric acid. The organic layer was washed successively with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the obtained crystalline material added to 10 ml of diethyl ether, whereupon the crystals were filtered off to give 1.40 g (yield 73.3%) of 2-(2,4-difluorophenylamino)-5-fluoro- 6-Methoxynicotinic acid with a melting point of 237-240°C.

Melting point: 239-240°C (recrystallized from acetone)

IR (KBr) cm"<1>: vc=0 1665

NMR (DMSO-dg) 6 values: 3.98 (3H, s), 6.76-7.48 (2H, m), 7.86 (1H, d, J = 11Hz), 8.10-8.60

(1H, m) , 10.51 (1H, bs) .

In the same manner as above, the following compounds were obtained: 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid. Melting point: 226-228°C (recrystallized from benzene).

IR (KBr) cm"1: vc=Q 1680

NMR (acetone-dg) 6 values: 6.60-7.41 (2H, m),

7.90-8.50 (m) | {2H)^ 8.10 (d, J=9Hz)'

10.30 (1H, bs), 10.64 (1H, bs)

2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinic acid.

Melting point: 179-180°C (recrystallized from benzene).

IR (KBr) cm"<1>: vc=Q 1665

NMR (acetone-dg) 6 values: 2.32 (3H, s), 2.55 (6H, s),

6.37-8.52 (m)

7.05 (s) ) (7H)

8.24 (d, J=9Hz) )

10.37 (1H bs)

2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-triisopropyl-benzenesulfonyloxy)nicotinic acid.

Melting point: 163.5-164.5°C (recrystallized from benzene) IR (KBr) cm"<1>: vc_0 1675

NMR (CDCl3-DMSO-dg) 6 values: 1.22 (12H, d, J=7Hz),

1.30 (6H, d, J=7Hz), 2.55-3.30 (1H, m), 3.70-4.40 (2H, m), 6.20-8.30 (m)

7.22 (s) (6H) , 8.18 (d, J=9Hz)

9.66 (1H, bs), 10.57 (1H, bs)

6-Ethylthio-2-(.2,4-difluorophenylamino)-5-fluoronicotinic acid. Melting point: 209-210°C (recrystallized from benzene).

IR (KBr) cm"<1>: vc=01665

NMR (acetone-dg) 5 values: 1.30 (3H, t, J=7Hz), 3.14 (2H,

q, J=7Hz), 6.70-7.50 (2H, m), 7.60-8.50 (a) j {2H)^

7.80 (d, J=9Hz) [

9.70 (1H, bs), 10.27 (1H, bs)

2-(2,4-difluorophenylamino)-5-fluoro-6-phenylthionicotinic acid. Melting point: 264-265°C (recrystallized from ethyl acetate-ethanol (1:1) parts by volume))

IR (KBr) cm~<1>: vc=0 1660

NMR (DMSO-dg) 6 values: 6.00-7.73 (8H, m), 7.85 (1H, d,

J=10Hz), 10.58 (1H, bs)

Example 14

In a mixture of 30 ml of tetrahydrofuran, 10 ml of methanol and

980 mg of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate were suspended in 4 ml of water, to which was added 5.3 ml of 1N aqueous sodium hydroxide solution, after which the resulting mixture was allowed to react at 65°C for 3 hours. The reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of water and the aqueous layer was separated, after which the pH of the layer was adjusted to 2.0 with 1N hydrochloric acid. The crystals thus deposited were filtered off and successively washed with 2 ml of water and 2 ml of ethanol to obtain 880 mg (yield 93.0%) of 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid with a melting point of 232-234°C.

Melting point: 233.5-236°C (recrystallized from acetone-methanol (1:1 parts by volume) )

IR (KBr) cm"<1>: vc=Q 1645

NMR (TFA-d.1 ,) 6 values: 2.00-2.68 (m) > )(5H)

2.28 (s) \ 3.62-5.03 (5H,m)

6.82- 7.80 (3H, m), 8.27 (1H, d, J=13Hz).

In the same manner as above, 6-(4-acetyl-1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid was obtained.

Melting point: 24 3-244°C (recrystallized from ethyl acetate-ethanol (1:1 parts by volume))

IR (KBr) cm"<1> vc=0 1670, 1635 (sh)

NMR (TFA-d^) 6 values: 2.48 (3H, s) , 3.47-4.40 (8H,m),

6.83- 7.82 (3H, m), 8.47 (1H d, J=13Hz).

Example T5

130 mg of methyl 6-(4-acetyl-1-piperazinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate were suspended in 3.9 ml of methanol, to which was added 3.33 ml of 2N aqueous sodium hydroxide solution , whereupon the resulting mixture was reacted under reflux for 2 hours. The reaction mixture was added with 2 ml of water and the pH of the mixture was adjusted to 8.5 with 1N hydrochloric acid, after which the crystals thus deposited were filtered off and washed with 2 ml of water to obtain 110 mg (yield 98.2%) of 2-(2,4- difluorophenylamino)-5-fluoro-6-(1-piperazinyl)nicotinic acid with a melting point of 279-281°C.

IR (KBr) cm"<1>: vc=Q 1625 (sh)

NMR (TFA-d^) δ values: 3.53-4.33 (8H, m), 6.87-7.77 (3H, m)

8.53 (1H, d, J=13Hz)

In the same manner as above, 6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid was obtained.

Melting point: 249-250°C

IR (KBr) cm"<1> vc=Q 1630 (sh)

NMR (TFA-d^) 5 values: 2.47-2.92 (2H, m) , 3.72-4.23

(2H, m), 4.23-4.73 (3H, m), 6.95-7.77 (3H, m), 8.36 (1H, d, J=13Hz)

Claims (3)

1. 5-fluoronicotinic acid derivative, characterized by the formula, where R<1> means a hydrogen atom or a C-1-C4 alkyl group; R<2> means a halogen atom, a hydroxyl group, an azido group, a C1-C4 alkoxy-, C1-C4 alkylthio-, phenylthio-, C1-C4 alkanesulfinyl-, benzenesulfinyl-, C1-C4 alkanesulfonyl-, benzenesulfonyl -, C^-C^-alkanesulfonyloxy-, benzenesulfonyloxy- (where the benzene ring may be substituted with 1-3 C^-C^ alkyl or halogen or with a nitro group), naphthalenesulfonyloxy-, di-C1-C4-alkoxyphosphinyloxy- or diphenyloxyphosphinyloxy group , a 3-amino-1-pyrrolidinyl group where the amino group may be protected with C 1 -C 4 alkanoyl or N,N-dimethylaminomethylene, or a 1-piperazinyl group where the imino group may be protected with C 1 -C 4 alkanoyl; and X means a hydrogen or fluorine atom, or a salt thereof. 2. 5-fluoronicotinic acid derivative or a salt thereof according to claim 1, characterized in that R<2> means a halogen atom, a hydroxyl group, a 3-amino-1-pyrrolidinyl group where the amino group can be protected with C-1-C4 alkanoyl or N,N- dimethylaminomethylene, a 1-piperazinyl group where the imino group may be protected with C1-C4 alkanoyl or a C1-C4 alkoxy, C1-C4 alkylthio, phenylthio, C1-C4 alkanesulfonyloxy or benzenesulfonyl group and X is a fluorine atom. 3. 5-fluoronicotinic acid derivative or a salt thereof according to claim 2, characterized in that R<2> means a halogen atom, a hydroxyl group, a 3-amino-1-pyrrolidinyl group where the amino group can be protected with C1-C4 alkanoyl or N,N- dimethylaminomethylene C1-C4 alkoxy or benzenesulfonyl group.