HU200187B - Process for producing (1-substituted-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid-boric) anhydrides - Google Patents

Abstract

Dihydroquinoline cpds. of the formula (I) are new. R is cyclopropyl, -CH2CR5R6R7 or phenyl opt. mono- or di-substd. by halogen; R5, R6 and R7 are H or halogen; R1 and R2 are halogen, 2-6C aliphatic acyloxy opt. substd. by halogen, or 7-11C aromatic acyloxy; R3 is Cl or F; R4 is H or F. Pref. (I) are prepd. by reacting a cpd. of the formula (II) with HBF4, or BX3 or an ether complex of BX3 (X is F, Cl or Br) or a cpd. of the formula B(OCOR9)3 where R9 is 1-5C alkyl opt. halo substd. or 6-10C aryl. R8 is H or 1-4C alkyl. Reaction may be effected in water (for HBF4) or an organic solvent (for the other reagents).

Description

The present invention relates to novel (1-substituted 6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid boronic acid) anhydrides of the general formula (I).

Ethyl (1-fluorophenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate) is a 1-fluorophenyl-6-fluoro-1,4-dihydro Intermediate of -4-oxo-7- (4-methyl-1-piperazinyl) -3-quinolinecarboxylic acid (24th Intersci. Conf. Antimicrob. Agents. Chemother. 1984, Abst. 72-78). The latter compound can be prepared in two steps from ethyl (1-p-fluorophenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate). The 1β-fluorophenyl-o-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid obtained by ester hydrolysis is reacted with 1-methylpiperazine in the presence of a solvent at 100 ° C for 20 hours to give the for the desired 1? -fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) -3-quinolinecarboxylic acid (European Patent No. 131,839).

Compounds of formula (I) wherein R is halogen. C 2 -C 5 alkanoyloxy, R ² and R ² are the same or different, such as hydrogen or halogen such as fluorine, chlorine or bromine may be used ortho, meta or para), the lanolin derivative of formula (Π) (wherein R ³ is hydrogen or C 1 -C 4 alkyl and R ¹ , R ² are as defined above) and the formula (ΠΙ) fluoroboric acid, or a triacyl oxyborate derivative of formula (V) wherein R ⁴ is C 1-4 alkyl.

Using the novel compounds of formula (I) of the present invention, the 1-substituted-6-fluoro-1,4-dihydro-4-oxo-7- (optionally substituted piperazino) -3-quinolinecarboxylic acid derivatives can be prepared in a more advantageous manner than known in the art. live.

Fluoroboric acid (III) or compound (V) may be used in the reaction with 1-5 moles, preferably 1-5 moles, for the reaction with the compounds (Π). However, if desired, a different molar ratio may be selected.

The reaction may be carried out, if desired, in the presence of a solvent. Solvents include water, ketone, e.g. acetone, methyl ethyl ketone, hydrocarbons such as hexane, benzene, toluene, ethers such as diethyl ether, dioxane, tetrahydrofuran, organic acids, acetic acid, propionic acid, trifluoro acetic acid.

The reactions are carried out, if desired, at room temperature.

By increasing the reaction temperature, it is possible to use a shorter reaction time. Preferably, each reaction is conducted at room temperature to 150 ° C. The reaction temperature chosen will also depend on the particular solvent.

The resulting compounds of formula (I) are spontaneously released from the reaction mixture for brain cooling, such as removal by filtration.

Further details of the process are set forth in the Examples, without limiting the invention to the Examples.

Examples

Example 1 To a stirred solution of 50% aqueous hydrogen tetrafluoroborate (1 H) was added 3.64 g (0.01 m) of 1- (4-fluorophenyl) -6-fluoro-7-chloro-1. The ethyl 4-dihydro-4-oxoquinoline-3-carboxylic acid and the mixture are heated to 110 ° C and the resulting solution is stirred for 2 hours at 110 ° C, whereupon crystallization begins. The mixture was cooled and left on ice the next day. The resulting crystals of [1- (4-fluorophenyl) -6-fluoro-7-chloro-4-dihydro-4-oxoquinoline-3-carboxylate d ⁴ ] -difluoro-boron are suctioned off with 5 ml of water and wash with methanol. 3.66 g of white crystals are obtained, m.p. 324-326 ° C.

Elemental Analysis: Found C, 50.21; H, 1.92; N, 3.68 Found: C, 50.11; H, 1.84; N, 3.65.

Example 2

To a mixture of 0.93 g of boric acid and 15 mg of zinc chloride is added 459 g of acetic anhydride and the suspension is slowly heated with stirring. At 80 'C a clear solution is obtained. At 100 ° C, add dropwise to the solution

3.64 g (0.01 m) of ethyl 1- (4-fluorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 20 ml of 96% hot After stirring for 3 hours at 110 ° C, the mixture is cooled, 10 ml of water are added and the mixture is left standing on ice for the next day and the resulting [1- (4-fluorophenyl) -6-fluor-7-chloro-1] is added. Crystals of ³ -dihydro-4-dihydro-4-oxoquinoline-3-carboxylate borane diacetate are suctioned off, washed with 5 ml of water and 5 ml of ethanol. 454 g of white crystals are obtained, which decomposes at 248-250 ° C.

Found: C, 52.01; H, 2.91; N, 3.07. Found: C, 52.01; H, 2.91; N, 3.02.

Example 3

To a mixture of 0.93 g of boric acid and 15 mg of zinc chloride is added 55 g of 97% propionic anhydride and the suspension is slowly heated with stirring. At 90 'C, a clear solution is obtained. Add to the solution

1- (4-Fluoro-phenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (3.64 g, 0.01 m), stirred for 1/2 hour After stirring at 110 ° C, cool and add 6 ml of water. Leave to stand overnight on ice. The next day, the resulting [1- (4-fluorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4 Crystals of 3-oxo-choline-3-carboxylate ³ , ³ -j-dipropionate-boron are suctioned off, washed with 5 ml of water and 5 ml of ethanol. 4.72 g of crystalline material are obtained, which decomposes at 278-280 ° C.

Elemental analysis: Calculated for C22H17NO7BF2Cl: C, 53.75; ½, 3.49; N, 2.85. Found: C, 53.71; ½ 359; N, 2.79.

Example 4 3.82 g of 1- (2-difluorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxo are added with stirring to a 50% aqueous solution of hydrogen tetrafluoroborate (III). quinoline-3-carboxylic acid ethyl ester was added and the mixture was stirred for 2 hours at 110 ° C while crystallization began. The reaction mixture was cooled and kept in the refrigerator for 1-2 hours. The crystals are filtered off, washed with a little water and methanol and dried.

-2HU 200,187 Β give 3.86 g of [l- (2,4-difluorophenyl) -6-fluoro-7-klór1.4- dihydro-4-oxoquinoline-3-kartx) xylan H ³ Q ^4] - difluoroboron is obtained. 300 ° C.

Found: C, 47.77; H, 1.43; N, 3.56. Found: C, 47.77; H, 13 L; N, 3.49.

Example 5

383 g of 1- (2,4-difluorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester and 93 g of 10-boronic acid are suspended in 60 ml of 96% acetic acid. , and the suspension is slowly heated to 110 ° C. After stirring for 15 minutes, a slow dropwise addition of acetic anhydride (45.8 g, 283 mL) is started. The reaction mixture is initially a clear solution, and after 3 to 4 minutes crystallization begins. After stirring for 2 hours, the suspension is cooled, the precipitated crystals are filtered off, washed several times with methanol and dried. Thus 46.9 g of [l- (2,4-f «IIL) -6-fluoro-7-chloro-l, 4-dihydro-4-oxoquinoline-3-carboxylate ^3-yl ^ j-boron diacetate yielding a compound. Melting point 300 'C.

Found: C, 49.97; H, 2.44; N, 2.99 Found: C, 49.88; H, 231; N, 2.91.

Example 6

383 g of 1- (2,4-difluorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester and 93 g of boric acid in 60 ml of 96% acetic acid and suspend slowly at 110 ° C. After stirring for 15 minutes 30 g of the propionic anhydride (54 g) is slowly added dropwise. After 3-4 minutes, the reaction mixture initially begins to precipitate.

After stirring for 2 hours, the suspension is cooled, the precipitated crystals are filtered off, washed several times with water once with methanol, and dried.

Thus, 48.1 g of [1- (2,4-dichlorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate- ³ , 3'-dipropionate boron are obtained. compound was obtained. Melting point 300 'C.

Found: C, 51.94; H, 334; N, 2.69 Found: C, 51.85; H, 3.16; N, 2.76.

Example 7 3.98 g of 1- (4-fluoro-3-chlorophenyl) -6-fluoro-7-chloro-1,4 is added to 50 ml of a 50% aqueous solution of hydrogen tetrafluoroborate (III). Ethyl dihydro-4-oxoquinoline-3-carboxylic acid is added and the mixture is stirred for 2 hours at 110 ° C, whereupon crystallization begins. The reaction mixture was cooled and kept in a 50 refrigerator for 1-2 hours. The crystals were filtered off, washed with a little water and methanol and dried.

332 g of [1- (4-fluoro-3-chlorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained. Melting point 300 'C. 55

Found: C, 45.88; H, 1.43; N, 336. Found: C, 45.87; H, 1.45; N, 3.35.

Example 8 60

39.8 g of 1- (4-fluoro-3-chlorophenyl) -fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester and 93 g of boric acid in 60 ml of 96% slurry in acetic acid and slowly warm to 110 ° C. After stirring for 15 minutes, a slow dropwise addition of acetic anhydride (45.8 g, 283 mL) was started. The reaction mixture initially began to crystallize after 3-4 minutes. After stirring for two years, the suspension is cooled, the precipitated crystals are filtered off, washed several times with water, once with methanol and dried. 47.9 g of [1- (4-fluoro-3-chlorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-quinoxyl] -r, N-diacetate-boron are obtained. Melting point 300 'C.

Found: C, 50.35; H, 3.04; N, 2.80. Found: C, 50.35; H, 3.06; N, 2.66.

EXAMPLE 10 4.15 g of 1- (3,4-dichlorophenyl) 6-fluoro-7-chloro-1,4-dihydro-4 were added to a 50% aqueous solution of hydrogen tetrafluoroborate (in) with stirring. Oxoquinoline-3-carboxylic acid ethyl ester was added and the mixture was stirred for 2 hours at 110 ° C while crystallization began. The reaction mixture was cooled, washed with a little water and methanol, and dried.

There is thus obtained 432 g of [1- (3,4-dichlorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxo-choline-3-carboxylate (N, N-difluoro-boron).

Found: C, 4437; H, 133; N, 3.16. Found: C, 4437; H, 139; N, 332.

Example 11

413 g of 1- (3,4-dichlorophenyl) -6-fluoro-7-chloro-1,4-dibydro-4-oxoquinoline-3-carboxylic acid ethyl ester and 93 g of boric acid are suspended in 60 ml of 96% acetic acid. and slowly slurry to 110 ° C. After stirring for 15 minutes, a slow dropwise addition of acetic anhydride (453 g, 283 mL) was started. After 3 to 4 minutes, the reaction mixture initially began to crystallize. After stirring for two hours, the suspension is cooled, the precipitated crystals are filtered off, washed several times with water, once with methanol and dried. 48.1 g of [1- (3,4-dichlorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate] N-diacetate-boron are obtained. Melting point: 300 'C.

Found: C, 46.57; H, 2.44; N, 2.69. Found: C, 46.57; H, 235; N, 2.72.

Example 12

41.5 g of 1- (3,4-dichloro-phenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester and 93 g of boric acid in 60 ml of 96%. slurry in acetic acid and slowly warm to 110 ° C. After stirring for 15 minutes, a slow dropwise addition of propionic anhydride (54.0 g) was started. The reaction mixture initially began to form a clear solution, after 3-4 minutes crystallization began. After stirring for 2 hours, the suspension is cooled, the precipitated crystals are filtered off, washed several times with water, once with methanol and dried.

49.9 g of [1- (3,4-dichlorophenyl) -6-flucyl] -7-chloro-1,4-dihydro-4-oxochiroline-3-carboxylate, indipropionate boron are obtained. . Mp: 300 'C.

Found: C, 48.58; H, 234; N, 2.65. Found: C, 48.58; H, 2.97; N, 2.58.

Claims (3)

PATENT CLAIMS -3HU 200187 Β cananyloxy group, R ¹ and R ² are identical or different A process for the preparation of a compound of the formula I in the formula R is halogen, C 2 -C 5 al, such as hydrogen or halogen, such as fluorine, chlorine or bromine. A compound of formula (Π) - wherein R ³ is hydrogen or C 1 -C 4 alkyl- and R ^1, R ² are as defined above- (a) for the preparation of compounds of formula (I) wherein R is halogen with hydrogen fluoride (bor), or b) reacting a boron derivative of formula V wherein R ⁴ is C 1-4 alkyl to form a compound of formula I wherein R is C 2 -C 5 alkanoyloxy. Process (a) according to claim 1, characterized in that the compound of formula (II) - wherein R ¹ , R ² and R ³ are as defined in claim 1 - and the reaction of the compound of formula (HI) is carried out in an aqueous medium. Process b) according to claim 1, characterized in that the compound of formula (H) - wherein R ¹ , R ² and R ³ have the meaning given in claim 1 - with the compound of formula V - wherein R ⁴ is as defined in claim 1 in the presence of a solvent.