HU198728B - Process for producing quinolinecarboxylic acid derivatives - Google Patents

Abstract

The present invention relates to a general process I for the preparation of compounds of the formula EMI2.1 wherein: R and R1 is the same halogen or 2-5 a C 1-4 alkanoyloxy group. a compound of formula II wherein R 1 is a halogen or C 1-4 alkyl, hydrogen fluoroborate, or with a boron tn halide - or an ether complex thereof with a boron derivative of formula B (OCOR4) 3 Wherein R4 is 1-4 C 1 -C 4 alkyl -. with. The compounds of formula I are as intermediates piperazine derivatives having anlibacterial activity may be used the preparation.

Description

FIELD OF THE INVENTION The present invention relates to the preparation of novel 1-cyclopropyl-6-methyl-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid boronic acid anhydrides.

Ethyl (1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate) is an antibacterial agent for 1-cyclopropyl-6-fluoro-1,4-dihydro-4. ino-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (Eur. J. Clin. Microbiol. 1983, 2, 111). The latter compound can be prepared in two steps, from ethyl (1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate). The 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid obtained by ester hydrolysis is reacted with piperazine in the presence of a solvent at 135-140 ° C for 2 hours to give the to the desired 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (German Publication Nos. 3.033.157 and 3.142.854) . According to other literature, the reaction yield is 79% and the reaction time is 9.5 hours. The disadvantage of this process is that the reaction is not regioselective, and the reaction of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with piperazine gives 13% of the undesired by-product ( the 6-position fluorine atom reacts with the piperazine).

Compounds of formula I (wherein R and R are each independently halogen or C2 -C5 alkanoyloxy) are prepared by reacting a compound of formula II wherein R is hydrogen or C1-C4 alkyl. with hydrogen tetrofluoroborate of formula IV or a boron trihalide of formula IV wherein X is a fluorine, chlorine or bromine atom or a complex thereof with an ether or a boron base of formula V wherein R ⁴ is alkyl having 1 to ⁴ carbon atoms. group - react.

Using the novel compounds of formula I of the present invention, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (optionally substituted piperazino) -3-quinolinecarboxylic acid derivatives are obtained in higher yields than known in the art. 88%), regioselectively (1-2% by-product).

The compound of formula IV may be boron trifluoride, boron tribromide, boron trichloride, or an ether complex or an aqueous side thereof. The complex of boron trifluoride with tetrahydrofuran, diethyl ether, methanol or propanol is preferably used. If desired, the boron trihalide may be used with aliphatic hydrocarbons such as hexane, halogenated hydrocarbons such as dichloromethane or carboxylic acids such as acetic acid. trifluoroacetic acid or propionic acid.

The hydrogen tetrafluoroborate of formula III, the boron trihalide of formula IV or the compound of formula V may be used in the reaction of 1 to 50 mol, preferably 1 to 5 mol, with the compounds of formula II. 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, trifluoroacetic acid.

If desired, the reaction is carried out at room temperature.

By increasing the reaction temperature, a shorter reaction time is possible. 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 precipitated from the reaction mixture either spontaneously or for cooling, for example, by filtration.

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

Example 1

To a mixture of 0.93 g of boric acid and 1.5 mg of zinc chloride is added 4.6 g of acetic anhydride and the suspension is slowly heated while stirring. At 80 ° C, a clear solution is obtained. At 100 ° C, 3.1 g of ethyl (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-oxoquinoline-J-carboxylate) (3.1 g) in hot 96% of a solution of acetic acid. The reaction mixture was stirred for 2 hours at 110 ° C, then cooled to 10 ° C and water (10 ml) was added. The resulting suspension is stirred for 2 hours at 10 ° C. The resulting butter crystals were filtered off, washed with a little water and then with ethanol and dried. In this way, 4.02 g of (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate-O, O) -diacetate boron are obtained, m.p. C decomposes.

Elemental Analysis for C p H 1 O 3 NBClF;

Calculated: C, 49.86; H, 3.45; N, 3.42. Found: C, 50.03; H, 3.41; N, 3.50.

Example 2

To a mixture of 0.93 g of boric acid and 1.5 mg of zinc chloride is added 5.36 g of 97% propionic anhydride and the suspension is slowly heated with stirring. A solution is obtained at 90 ° C. Ethyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (3.1 g) was added to the reaction mixture. After a few minutes the crystalline precipitate begins to form from the crude solution. The mixture was cooled and water (6 mL) was added with stirring. The thus prepared yl-Cyclopropyl-6-fluoro-7-chloro-1,4 - _{aíhidro-4-oxo-quinoline-3-carboxylate-1} 0i = 0) ~ dipronionát boron compound is filtered off, 5 ^- washed ml methanol . 4.18 g of product are obtained, m.p. 181-182 ° C.

Elemental analysis according to the formula C ^ HHigNOjBClF:

H, 4.15; N, 3.20. Found: C, 52.23; H, 4.11; N, 3.31.

Example 3 To a stirred 50% aqueous solution of hydrogen tetrafluoroborate in stirring was added 3.1 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. ethyl ester was added and the mixture heated at 80-90 ° C for 2 hours. The resulting solution was cooled to room temperature. The precipitated crystal is filtered off, washed with 3 ml of methanol and dried.

3.22 g of (1-Cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O) -) difluoro-boron are obtained, m.p. 283-285. ° C.

Elemental analysis based on the formula CjjH ^ OjNBFjCl:

Found: C, 47.39; H, 2.45; N, 4.25. Found: C, 47.54; H, 2.40; N, 4.34.

Example 4

3.1 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxodynoline-3-carboxylic acid ethyl ester are heated in 15 ml of 43% aqueous boron trifluoride solution at 80-100 ° C for 3 hours. over. The solution is cooled, the precipitated crystals are filtered off, washed with water and dried. There are thus obtained 3.25 g of (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate-1-yl) difluoroZ-boron, m.p. 284-285. V

Elemental analysis for C ^ HHgC ^ · NBFjCl:

H, 2.45; N, 4.25. Found: C, 47.48; H, 2.39; N, 4.09.

Claims (4)

PATENT CLAIMS A process for the preparation of a compound of formula I in the formula R and R are the same as halogen or C 2 -C 5 alkanoyloxy, characterized in that a compound of formula II wherein R 1 is hydrogen or C 1 -C 4 alkyl is substituted with hydrogen ^t or a boron trihalide of formula IV, wherein X is fluorine, chlorine or bromine, or an ether complex thereof, or a boron derivative of formula V, wherein R ⁴ is C 1 -C 4 alkyl. Process according to claim 1, characterized in that the reaction of the compound of formula III, wherein R ² is as defined in claim 1, with the compound of formula 111, is carried out in an aqueous medium. The process of claim 1, wherein the compound of formula II, wherein R ² is as defined in claim 1, and the compound of formula IV, wherein X is as defined in claim 1, are reacted in the presence of a solvent. The process of claim 1, wherein the compound of formula III wherein R ² is as defined in claim 1 is a compound of formula V wherein R ⁴ is as defined in claim 1 in the presence of a solvent.