HU200464B - Process for producing dihydroquinolinecarboxylic acid derivatives - 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 (6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid boronic acid) anhydrides of the formula I and to their preparation.

The 1-position is provided as 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (English 2,087,440, Belgian 887,574, European 106,689 and 15,049). German Patent No. 3,433,924; Japanese Patent No. 60,006,684; Japanese Patent No. 61,085,381; Portuguese Patent No. 80,187; Portuguese Patent No. 80,187)

7-substituted-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (J. Med. Chem. 1986, (29), 445, Drugs Fut. 1984 (9), 246). 23rd Intersci., Conf. Antimicrob. Agents Chemother. 1983, Abstr. 658, 7th Int. Symp. Fut Trends Chemother. 1986, 80).

Using the novel compounds of formula (I) according to the invention, ethyl 6,8-difluoro-1,4-dihydro-4-oxo-7-substituted-quinoline-3-carboxylic acid is used as starting material. derivatives (Belgian, 887 574,

British Patent Nos. 057,444; Australian Patent Nos. 537,813; 106,689;) may be prepared in a more advantageous manner. No. 887,574. The yield is increased compared to the process of the Belgian patent, the reaction time is reduced.

Compounds of formula I (wherein R is halogen, C 2 -C 5 alkanoyloxy, R ¹ , R ² and R ³ are the same or different, such as hydrogen or halogen), the quinol of formula IT in (R ⁴ is hydrogen or C 1 -C 4 alkyl, R ¹ , R ² and R ³ are as defined above) and the fluoroboric acid of formula (III) or the trihalogen borate of formula (IV) X is fluorine, chlorine or bromine) or is prepared by reacting a triacyl oxyborate derivative of formula (V) wherein R ⁵ is C 1 -C 4 alkyl.

Boron trifluoride, boron tribromide, boron trichloride, or complexes thereof, or aqueous solutions thereof may be used. Preferred are complexes with ethers and alcohols such as boron trifluoride with tetrahydrofuran, diethyl ether, methanol, propanol. If desired, solutions of the skin trihalide in aliphatic hydrocarbons such as hexane, halogenated hydrocarbons such as dichloromethane or carboxylic acids such as acetic acid, trifluoroacetic acid, propionic acid can be used.

The fluoroboric acid of formula (ΠΙ), the boron trihalide of formula (IV) or the compound of formula (V) may be used in the reaction with the compounds of formula (H) in an amount of 1 to 50 mol, preferably 1 to 5 mol. However, if desired, we may choose a different molar ratio,

The reactions may be carried out, if desired, in the presence of a solvent. Solvents include water, ketone such as acetone, methyl ethyl ketone, hydrocarbons such as hexane, benzene, toluene, ethers such as diethyl ether, dioxane, tetrahydrofuran, organic acids, acetic acid, propionic acid, trifluoroacetic 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 of the re2 operations is carried out at room temperature to 150 ° C. The reaction temperature chosen will also depend on the particular solvent.

The resulting compounds of formula I are precipitated from the reaction mixture either spontaneously or by cooling, for example, they can be removed by filtration.

Compounds of formula (Π) are known in the literature or may be prepared in an analogous manner from commercially available intermediates.

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

EXAMPLES

Example 1

3.0 g of ethyl (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate) in 15 ml of a 50% aqueous solution of hydrogen fluoroboric acid for 2.5 hours for 80-90 hours. 'C'. After half an hour, crystalline precipitation begins from the crude solution. At the end of the reaction time, a thick slurry was obtained. The reaction mixture was cooled to room temperature and allowed to stand in the refrigerator overnight. The precipitated crystals are filtered off, washed with water and a little methanol. After drying, 3.1 g of [(1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-5-carboxylato-OLO] -difluoro-boron) are obtained. C decomposes.

H, 2.21; N, 4.40. Found: C, 45.26; H, 2.18; N, 4.32 Found: C, 45.18; %.

Example 2

A mixture of 0.93 g of boric acid and 6.9 g of propionic anhydride was stirred at 95-100 ° C for 30 minutes. Ethyl (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate) (3.0 g) was dissolved in 12 ml of propionic acid warm and added to the above solution without interrupting the heating of the reaction mixture. The resulting red solution was stirred at 110 ° C for 5 hours. The reaction mixture was cooled to room temperature and water (150 ml) was added. The precipitated crystals are filtered off, washed with water and a little methanol. After plowing 4.1 g of [(l-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylato-O ^3, ORI) dipropionate borohydride] superadditive immunosuppressive obtained which decomposes at 195196C.

H, 4.01; N, 3.29. Found: C, 50.72; H, 4.11; N, 3.31 Found: C, 50.72; H, 4.01; %.

Example 3

To a mixture of 1.85 g of boric acid and 20 mg of zinc chloride is added 10 ml of acetic anhydride and the suspension, in which dissolution begins immediately, is stirred. The temperature of the reaction mixture rises to 80 ° C and then begins to decrease. After stirring for another hour at 110 ° C, 6.0 g of ethyl (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate) are added. of a warm solution of 96 ml of 96% acetic acid was added dropwise. After stirring for 2 hours at 110 ° C, the reaction mixture is cooled to room temperature and 150 ml of water are added and the resulting suspension is stirred for 3 hours under cooling. The precipitated crystals are filtered off with suction, washed with water and a little methanol. After drying, 7.7 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-ch

GB 200,464 Β quinoline-3-carboxylato-O ³ <7 *) - boron diacetate dry and weighed obtained, decomposing at 211 ° C.

Analysis calculated for C16 H13 BF3 NO7: C, 48.15; H, 3.28; N, 3.52. Found: C, 48.12; H, 3.28; N, 3.54. %.

Example 4

3.17 g Ethyl [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate] in 15 ml 50% w / v stirred in an aqueous solution of hydrogen fluoroboric acid for 2 hours at 80-90 ° C. After half an hour, crystalline precipitation begins from the crude solution and a thick slurry is obtained after the reaction time. The crystal was filtered off and washed with water, methanol. After drying

3.27 g (97%) of [l- (2-fluoroethyl) -6,7,8-trifluoro-l, 4-dihydro-4-oxoquinoline-3-kartx) xiláto-0 ^{3 4} 0 ] -difluoro-boron, m.p.> 280 ° C.

H, 1.79; N, 4.16. Found: C, 42.52; H, 82%; N, 4.25. %.

Example 5

To a mixture of 9.2 g of boric acid and 0.1 g of zinc chloride is added 50 ml of acetic anhydride and the suspension is stirred. During dissolution, the temperature rises to 78 ° C and then begins to decrease. After stirring for another half hour at 110 ° C, 31.7 g of ethyl [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline Carboxylate] in 100 ml of 96% acetic acid was added dropwise and the reaction mixture was stirred at 110 ° C for an additional 1.5 hours. After cooling, 600 ml of water was added. The crystal was filtered off, washed with water, methanol. After drying, 40.7 g (97.6%) of [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-5-carboxylate-10-O There is thus obtained a N, N-diacetato-boron compound having a melting point of 259-260 ° C.

H, 2.90; N, 3.36. Found: C, 46.12; H, 2.82; N, 3.25. Found: C, 46.12; H, 2.90; .

Example 6

A mixture of 9.3 g of boric acid and 69 g of propionic anhydride was stirred at 95-100 ° C for 30 minutes. Ethyl [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate] (31.7 g) was dissolved in propionic acid (120 ml) and the while the heating of the reaction mixture was continued. The red solution is further

Stir at 110 ° C for 2.5 hours. It is then cooled and 1.5 l of water are added. The precipitated crystal was filtered off and washed with water, methanol. After drying, 43.1 g (96.8%) of [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-1-carboxylate] -? dipropionato boron is obtained. Decomposition point 221-222 'C.

H, 3.62; N, 3.14. Found: C, 48.62; H, 3.62; N, 3.25 Found: C, 48.57; H, 3.62; %.

Example 7

To a mixture of 9.2 g of boric acid and 0.1 g of zinc chloride is added 50 ml of acetic anhydride and the suspension is stirred. During dissolution, the temperature rises to 78 ° C and then begins to decrease. After stirring for another half hour at 110 ° C, 35.3 g of ethyl [1- (2,2,2-trifluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo A warm solution of 3-quinolinecarboxylate] in 96 ml of 96% acetic acid was added dropwise and the reaction mixture was stirred at 110 ° C for an additional 1.5 hours. After cooling, 600 ml of water was added. The crystal was filtered off, washed with water, methanol. After drying, 43.4 g (95.0%) of [1- (2,2,2-trifluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate-0 ^{3, 4} Ö] diacetate boron compound. 243-244 ° C.

H, 2.22; N, 3.09. Found: C, 42.33; H, 2.12; N, 3.05. %.

Claims (4)

PATENT CLAIMS A process for the preparation of compounds of formula (I) - in the formula R is halogen or C 2 -C 5 alkanoyloxy and R ¹ , R ² and R ³ are the same or different, such as hydrogen or halogen, characterized in that a compound of formula (Π) - wherein R ⁴ is hydrogen or (C 1 -C 4) alkyl, and R ¹ , R ² and R ³ are as defined in the foregoing, hydrogen fluoroborate of formula (ΠΓ) or a boron trihalide of formula (IV) wherein X is fluorine, chlorine or bromine or with complexes with ethers, or (V) bórszármazékkal formula wherein R ⁵ represents a C 1-4 alkyl group - is reacted. A process according to claim 1 wherein the compound of formula (Π) - wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and reacting the compound of formula (ΙΠ) in an aqueous medium. The process of claim 1 wherein the compound of formula (Π) wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and the compound of formula (IV) wherein X is as defined in claim 1 reacting in the presence of a solvent. A process according to claim 1 wherein the compound of formula II wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and the compound of formula V - wherein R ⁵ is as defined in claim 1; reacting in the presence of a solvent.