FI89710C - FOER FARING FOER FRAMSTAELLNING AV KINOLINKARBOXYLSYROR - Google Patents

Description

P C; 7 1 r; / I o

This invention relates to a novel process for the preparation of 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-5-quinoline-3-carboxylic acid derivatives and their pharmaceutically acceptable salts.

It is known that 1-cyclopropyl-7-substituted

6-Fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives of general formula I

C 0 ° H

RXv

15 A

wherein R represents a piperazinyl, 4-methylpiperazinyl or 4-ethylpiperazinyl group, has a strong antibacterial effect (Eur. J. Clin. Microbiol.

1983, 2, page 111; J. Clin. Pharmacol. 1985, 25, page 82; 20 Drugs Exptl. Clin. Res. 1985, 5, page 317).

The quinolinecarboxylic acids of general formula I can be prepared by reacting 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and a cyclic amine in the presence of a solvent at a temperature of 135 to 140 ° C 2 hours (German applications 3 033 157 and 3 142 854).

It is also known to prepare these compounds by reacting the corresponding 6-fluoro-7-chloro-quinolinecarboxylic acid or its ester with piperazine or N-methylpiperazine [see EP 0047005 and US 4,146,719 (ofloxacin); US 4,472,579 and DE 2,840,910 (norfloxacin); DE 28 43 66 (perfloxacin); EP 004935 (cyprofloxacin); EP 090424 (amifloxacin)].

The disadvantage of said known methods is that with piperazine or N-methylpiperazine, 2-· · ~ \ ry s, -¾

'· V / | «J

the amination to be performed does not occur selectively at the 7-position, but the nucleophilic substitution reaction takes place at both the 6-position and the 7-position. In the manufacture of cyprofloxacin, the amount of by - product has been found to increase to 5 16% by weight in experiments performed by the applicant. By-product formation in the preparation of norfloxacin is described in J. Med. Chem. 23, 1358 (1980).

To improve selectivity, two solutions have been proposed: the use of 10 (1) a more active F substituent instead of chlorine at the 7-position and, in the case of ofloxacin, at the 10-position and / or (2) the activation of said positions.

BF2 chelate starting materials (JP 59-122470, JP 58-29789 and FI patent 76,345) were first used to activate station 7 and station 10, respectively. However, the preparation of BF2 chelate requires temperatures above 200 ° C as well as special chemical reagents and equipment. In addition, the process generates a large amount of fluorinated, acidic waste 20, making the method unsuitable for large-scale production. To avoid this drawback, boric anhydride (JP 58-188138 and JP 60-75489) has been used in the preparation of ofloxacin. According to the publications, the symbols Xx and X2 at positions 9 and 10 independently of one another denote halogen, but in all examples 9,10-difluoro starting materials have been used.

It has now been found that using the tricyclic starting material described in JP 58-1881138 having a fluorine substituent at the 9-position (corresponding to the 6-position of the starting material of the present application) and a chlorine substituent at the 10-position (corresponding to the starting position of the starting material of the present application) position), nucleophilic replacement of the chlorine substituent by piperazine or N-alkylpiperazine does not occur under the reaction conditions described in JP or in the present application. Thus, at the temperature of 3 β 9 710, no reaction takes place. At 80 ° C and 110 ° C, instead of the desired product, only the by-product, 10-chloro-2,3-dihydro-3-methyl-9- (1-piperazinyl) -7-oxo-7H-pyrido [1,2,3 -5 de] [1,4] -benzoxazine-6-carboxylic acid. From Comparative Examples 1 to 3 below, it is therefore surprising that the use of the 6-fluoro-7-chloro starting material according to the present application gives the desired final product in high yield and in high purity.

10 The method applied for cannot therefore be deduced from the prior art.

With regard to JP 59-122470, it should be noted that the BF2 group activates the 7- and 10-positions much more strongly than the boronic anhydride group. This is shown by m.m. the fact that using (9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] - [1,4] benzoxate -siini-6-carboxylate 06.07) -difluoriboorivhdistettä.

(9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-view-do [1,2,3-de] [1,4] benzoxazine-6-carboxylate O6; 07) instead of -20 bis (aceto-O) -boron, the desired product is obtained (Comparative Example 4).

The present invention therefore relates to a new process for the preparation of 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives of the general formula I. For the preparation of derivatives (in which R has the same meaning as mentioned above), which process is characterized in that R1 R2 ·· of the compound of general formula II; 30 oV0 FXXV1 "

• S35 A

Γ; <a '* /! L-4 wherein R1 and R2 are the same or different and represent an aliphatic acyloxy group having 2 to 6 carbon atoms, optionally substituted with halogen, or an aromatic acyloxy group having 7 to 11 carbon atoms, is reacted with a cyclic amine having the general formula RJN NH 11111 wherein R3 represents hydrogen, methyl or ethyl, or a salt thereof, and the compound of general formula IV thus obtained r 'r!

15 Y

"k wherein R, R1 and R2 are the same as mentioned above, are hydrolyzed.

. ·. The process according to the invention thus has the advantage that it makes it possible to obtain the desired compound of the general formula I in a simple manner in the highest yields and short reaction times, and preferably without isolating the borate derivative of the formula IV.

The borate derivative of the general formula IV is a novel compound.

The borate derivative of general formula II and the cyclic amine of general formula III can be reacted in the presence of an optionally inert organic solvent and an acid scavenger.

* 3 7 I 1 '5

As inert organic solvents, acid amides (e.g. dimethylformamide, dimethylacetamide), ketones (e.g. acetone, methyl ethyl ketone), ethers (e.g. dioxane, tetrahydro-furan, diethyl ether), esters (e.g. ethyl acetate, ethyl), methyl acetate, methyl acetate can be used. , sulfoxides (e.g. methyl sulfoxide), alcohols (e.g. methanol, ethanol, 1-decanol, butanol).

An organic or inorganic base can be used as the acid scavenger. Among the group of organic bases, mention may be made of trialkylamines (e.g. triethylamine, tributylamine), cyclic amines (e.g. pyridine, 1,5-diazabicyclo [5.4.0] undec-5-ene, 1,5-diazabicyclo [4.3] .0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane), while alkali or alkaline earth metal hydroxides or carbonates can be used as the inorganic base. Thus, as the acid-binding agent, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc., or an excess of the amine of the general formula III can be used primarily.

The boron derivative of the general formula II and the cyclic amine of the general formula lii can be reacted at a temperature in the range of 0 to 200 ° C, depending on the solvent used. The reaction time may vary depending side. Between 25 hours and 10 hours depending on the reaction temperature. If the reaction is carried out at an elevated temperature, the reaction time can be shortened. The above reaction conditions are only preferred values and other conditions may be used as well.

The borate derivative of general formula IV can be hydrolyzed to the desired quinoline-3-carboxylic acids of general formula I, with or without isolation, under acidic or basic conditions. The compound of general formula IV can be precipitated from the reaction mixture, e.g. by cooling, and can be isolated by 6 r · η A «

•. III

· '* W' eg by filtration or centrifugation if desired.

The basic hydrolysis can be carried out primarily by heating an aqueous solution of alkali metal hydroxides or carbonates or alkaline earth metal hydroxides. Preferably, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide or potassium bicarbonate can be used.

Organic amines (eg triethylamine) can also be used in the hydrolysis step.

Acid hydrolysis can be performed primarily using an aqueous mineral acid solution. The hydrolysis of the borate of the general formula IV can be carried out primarily by heating it with an aqueous solution of hydrochloric acid, hydrobromic acid, hydrochloric acid or phosphoric acid. Hydrolysis can also be performed using organic acids (e.g., acetic acid, propionic acid, etc.).

The hydrolysis of the compounds of general formula IV can also be carried out in an aqueous medium in the presence of a water-miscible organic acid. For this purpose, for example, alcohols (e.g. methanol, ethanol), ketones (e.g. acetone), ethers (e.g. dioxane), acid amides (e.g. formamide, dimethylformamide), sulfoxides (e.g. dimethylsulfoxide) can be used. dia), or pyridine.

The quinoline-3-carboxylic acid of the general formula I thus obtained can be isolated, e.g., by adjusting the pH of the aqueous solution to a suitable value, and by isolating the precipitated crystals, e.g., by filtration or centrifugation or lyophilization of the aqueous reaction mixture.

The compounds of general formula I can be converted into their pharmaceutically acceptable salts by methods known per se. Thus, primarily oxygen is formed. 35 addition salts of hydrogen halides, sulphonic acids, sulfur 7 / ·, · +

- / I, I '/! U

with acid and organic acids. Chlorides, bromides, 4-methylphenyl sulfonates, methanesulfonates, maleates, fumarates and benzoates can be formed primarily. The compounds of the general formula I form salts with alkali or alkaline earth metal ions or also with other metal ions. Accordingly, e.g. sodium, potassium, magnesium, silver or copper salts can be prepared.

The compounds of general formula I and their pharmaceutically acceptable salts can be converted into hydrates (e.g. hemihydrates, trihydrates, etc.) by methods known per se.

The starting materials of the general formula II can be prepared, for example, by reacting 1-cyclopropyl-6-fluoro-7-chloro-15-oxo-1,4-dihydroquinoline-3-carboxylic acid (DE-A-3 141 854) with a boron derivative such as a compound , of the general formula V is R1 ', where R1, R2 and R5 represent an aliphatic acyloxy group having 2 to 6 carbon atoms, optionally substituted with halogen, or aromatic acyloxy group having 7 to 11 carbon atoms) or with fluoroborate in an aqueous or organic medium.

8 "--- 710

VgEtailMgfimeriyjL

Comparative Example 1 N, N-desmethylfloxacin To the starting material, 2.07 g (5 mmol) (9 fluoro-10-chloro-r-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-karboksyklaatto 06.07 ) -bis (acetate-O) -boron compound (prepared from ethyl 9-fluoro-10-chloro-2R-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3 -de] [1,4] -benzoxazine-6-carboxylate, acetic anhydride and boric acid), dimethyl sulfoxide (10 mL), piperazine (1.29 g, 15 mmol) and triethylamine (0.5 g) were added and the mixture was heated to 110 ° C for 2 hours. Mixture 30 was allowed to refrigerate overnight. No precipitate formed. The triethylamine was then removed under reduced pressure, and acetone (15 ml) was added. The pH was adjusted to 1 with concentrated hydrochloric acid, and the mixture was stirred for 30 minutes, after which the pH was adjusted to 3 with concentrated ammonium hydroxide solution, and the mixture was placed in a refrigerator at 9 ° π * * X 'ι / ». 1 '' i '* w overnight. The precipitate was collected and recrystallized from methanol. 0.49 g of crystalline product was obtained, m.p. > 270 ° C.

The product obtained showed a decrease in melting point as a mixture of 2,3-dihydro-9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [ 1,4] benzoxazine-6-carboxylic acid (N-desmethylofloxacin). N-des-methylofloxacin has a melting point of 258-260 ° C (dec.)

The NMR spectrum also showed that the product was not N-des-10-methylofloxacin.

Elemental analysis of the product (calculated for C17H18C1N30A) was as follows:

Calculated Found C 56.12% 56.02% 15 H 4.98% 5.08% N 11.55% 11.64%

Cl 9.74% 9.23%, i.e. the product was apparently 10-chloro-2,3-dihydro-3-methyl-9- (piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] [ 1,4] benz-20 oxazine-6-carboxylic acid.

Comparative Example 2 To the starting material, 2.07 g (5 mmol) of (9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] [ 1,4] -Benzoxazine-6-carboxylate-05.07) -bis (acetate-O) -25 boron compound (prepared from ethyl 9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo -7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate, acetic anhydride and boric acid), dimethyl sulfoxide (10 mL), piperazine (1.29 g, 15 mmol) were added. ) and triethylamine (0.5 g) and the mixture was heated at 80 ° C for 1 hour. The triethylamine was then removed in vacuo and acetone (25 mL) was added. The pH was adjusted to 1 with concentrated hydrochloric acid and the mixture was stirred for 30 minutes. The resulting precipitate was collected, 40 ml of ethanol and 5 ml of conc. 35 ammonium hydroxide solution and refluxed for 10 '. The ethanol was distilled off in vacuo and the remaining mixture was kept in the refrigerator overnight.

The precipitate was collected, washed with water, dried and recrystallized from methanol to give 0.49 g of crystalline product, m.p. 270 ° C. The product showed a decrease in melting point as a mixture with N-desmethylofloxacin. The NMR spectrum also showed that the product was not N-desmethylofloxacin.

Elemental analysis of the product (calculated for C17H18ClN3O4) 10 was as follows:

Calculated Found C 56.12% 56.02% H 4.98% 5.08% N 11.55% 11.64% 15 Cl 9.74% 9.23% i.e. the product was apparently 10-chloro-2.3 -dihydro-3-methyl-9- (1-piperidinyl) -7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid.

Comparative Example 3 Example 1 was repeated except that the reaction was performed at room temperature (22 ° C). No reaction occurred.

Comparative Example 4: - 25 frylX0 "O11

· DM50 HO ° C

- 3o 2 · Hydrolysyl-1AhA 5 N-desmethylfloxacin To the starting material, 1.73 g (5 mmol) of (9-fluoro-10-chloro-3H-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de] (1,4] - Γ "r-7 / * .-»

m ·, /: I

11 · »X yj Benzoxazine-6-carboxylate-O6.07) -difluoro-boron compound (prepared from ethyl 9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H pyrido] [1,2,3-de] [1,4] benzoxazine-6-carboxylate and boron trifluoride), dimethyl sulfoxide (8 mL), piperazine (1.29 g, 15 mmol) and triethylamine ( 0.5 g) and the mixture was heated at 110 ° C for 2 hours. The reaction mixture was then cooled, the precipitate was filtered off, washed with methanol (5 ml) and recrystallized from a mixture of chloroform, methanol and water. 0.64 g (58%) of crystalline product were obtained, m.p. > 256-260 ° C (dec.)

The melting point of the product did not decrease when N-desmethylofloxacin was mixed with it (m.p. 258-260 ° C).

The NMR spectrum showed characteristic signals at δ 8.64 ppm (1H, singlet) or C (5) H, and 7.76 ppm (1H, doublet) or C (8) H.

Tablet C (8) for H indicates the presence of a fluorine group at the 9-position.

Elemental analysis of the product (calculated for C17H18FN3O4 * 3/2 for 20 HzO) was as follows:

Calculated Found C 54.69% 54.72% V H 5.40% 5.48% N 11.25% 11.14% '25 This also indicates that N-desmethylofloxacin was involved.

The following examples illustrate the invention.

Example 1 4.1 g of [1-cyclopropyl-6-fluoro-7-chloro-1,4-di-30-hydro-4-oxoquinoline-3-carboxylate-030A] -bis- [acetate-OJ-boron compound and 2.8 g of N-methylpiperazine in 16 ml of dimethyl sulfoxide were heated with stirring at 110 ° C. To the brownish red solution was added 40 ml of a 3% (w / v) aqueous solution of sodium hydroxide and the reaction mixture was refluxed.

12: v 1 'U

for less than 1 hour. The hot pale yellow solution was filtered and the pH was adjusted to 7 by the addition of 1.8 mL of 96% acetic acid. The reaction mixture was cooled to room temperature, the precipitated white crystals were filtered off, washed with water and methanol and dried. The crude product was purified by extraction with 10 ml of boiling water. There was thus obtained 2.9 g of 1-cyclopropyl-6-fluoro-7- [4-methyl-piperazino] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, which decomposed at 248-250 ° C.

Example 2 4.1 g of [1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate-03.04] -bis- [acetate-O] boron compound and 3.7 g of N-ethylpiperazine were heated in 16 ml of dimethyl sulfoxide with stirring at 90 ° C. After 10 minutes, 40 ml of 3% by weight aqueous sodium hydroxide solution was added and the reaction mixture was refluxed for 1 hour. The hot solution was filtered off and washed with water. There were thus obtained 3.3 g of 1-cyclopropyl-7- [4-ethylpiperazinyl] -6-fluoro-20H-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 183-185 ° C.

Analysis for C19H22FN3O3:

Calculated C 63.35% H 6.17% N 11.69%

Found C 63.31% H 6.21% N 11.70%

Claims (7)

1. Process for Preparation of Compounds of the General Formation of Axooh raXX Wherein R represents a piperazinyl, 4-methylpiperazinyl or 4-ethylpiperazinyl group, and of their pharmaceutically acceptable salts, characterized in that a compound of the general formula II is 2 x 2 ° F wherein RTC and R₂ are an aliphatic acyloxy group having 2-6 carbon atoms and optionally substituted with a halogen, or an aromatic acyloxy group having 7-11 carbon atoms, reacted with a piperazine derivative of the general formula m 30, (III) R3N NH4f wherein R3 represents hydrogen, methyl or ethyl, or with a site thereof, and the compound of formula IV C'fert A, thus obtained; Wherein R, R 1 and R a site thereof, or the acid is released from its site. A process according to claim 1, characterized in that a compound of the general formula II is reacted with a piperazine derivative of the general formula III in the presence of an organic solvent, preferably an acid amide, a sulfoxide, a ketone, an alcohol, an ether or an ester. The process according to claim 2, wherein it comprises the use of dimethyl sulfoxide as an organic solvent. 4. A process according to claim 1, characterized in that the reaction of the compounds of general formulas II and III takes place in the presence of an acid-binding agent. 5. A process according to claim 4, characterized in that as an acid binding agent an amine is used or an excess of the compound of the general formula III. 6. A process according to claim 1, characterized in that the hydrolysis is carried out in a basic medium. 7. A process according to claim 6, wherein an alkali metal hydroxide, an alkaline earth metal hydroxide or an organic base, preferably an aqueous triethylamine solution, is used.