GB2291421A - A process for preparing a quinoline carboxylic acid - Google Patents

Abstract

A process for preparing danofloxacin by reacting the corresponding 7-fluoro-quinolinecarboxylic acid or an alkyl ester or salt thereof with 2-methyl-2,5-diazabicyclo[2.2.1]heptane or its dihydrobromide in water in the presence of substantially stoichiometric amounts of potassium or sodium hydroxide.

Description

A PROCESS FOR PREPARING A QUINOLINE CARBOXYLIC ACID Background of the Invention This invention relates to a process for preparing 1 -cyclopropyl-6-fluoro-l ,4- dihydro-7-(2-methyl-2,5-diazabicyclo[2.2 ]hept-2-y1)4-oxo-3-quinolinecarboxylic acid, also known as danofloxacin, an animal health antibacterial agent.

U.S. Patent No. 4,861,779 discloses that compounds such as danofloxacin may be prepared by reacting a compound of the formula

wherein Hal is halogen such as fluoro, chloro or bromo, A may be carbon, Y may be cyclopropyl, and R1 may be hydrogen or alkyl, with a compound of the formula R2H such as 2-methyl-2,5-diazabicyclo-[2.2.1]heptane. The '779 patent discloses that the reaction may be performed with a solvent, including water, which is non-reactive under the reaction conditions, and is preferably carried out in the presence of an acid acceptor such as an inorganic or organic base, e.g. an alkali metal or alkaline earth metal carbonate or bicarbonate or a tertiary amine.

U.S. Patent No.4,571,396 discloses a coupling reaction similar to that disclosed in the '779 patent. Convenient solvents are non-reactive solvents including water.

This invention provides a novel process for preparing and isolating danofloxacin in greater yields and higher purity than known methods.

Summarv of the Invention This invention relates to a process for preparing danofloxacin by reacting 1 cyclopropyl-6 ,7-ditluoro-1 ,4-dihydrn4-oxo-3quinolinecarboxylic acid (hereafter the difluoroquinolinecarboxylic acid starting material) or its C1 -C4 alkyl ester or its alkali metal salt with 2-methyl-2,5-diazabicyclo[2.2.1]heptane (hereafter the diamine) or 2methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide in water in the presence of substantially stoichiometric amounts of potassium hydroxide or sodium hydroxide.

Preferably, aqueous alkali metal bicarbonate such as sodium bicarbonate is added after the reaction is substantially terminated.

Detailed DescriPtion of the Invention The process of the invention is effected in water in the presence of substantially stoichiometric quantities of potassium or sodium hydroxide resulting in higher yields and cleaner reaction products than obtained by prior art methods using organic solvents such as pyridine, and organic bases. The use of water is economically and environmentally advantageous since the handling of noxious organic solvents such as pyridine is avoided and the disposal of organic solvents is eliminated. The amount of water used is about 2 to 15 volumes based on the volume of the difluoroquinolinecarboxylic acid starting material. The reaction temperature ranges from about 80 to about 1700C and the reaction time from about 2 to about 24 hours.

The substantially stoichiometric amounts of sodium hydroxide or potassium hydroxide may be defined in the following equations: [Substantially stoichiometric amounts of sodium hydroxide or potassium hydroxide]= [the amount of sodium hydroxide or potassium hydroxide in milliequivalents] = [0.8 to 1.2]x[the amount of titratable acids in milliequivalents]; and [the amount of titratable acids in milliequivalents] = [the amount of the difluoroquinolinecarboxylic acid starting material in mmole] + [the amount of the diamine monohydrobromide in mmole] + 2x [the amount of the diamine dihydrobromide in mmole].

In addition, substantially one equivalent of sodium hydroxide or potassium hydroxide is required to saponify the ester of the difluoroquinolinecarboxylic acid, if used as the starting material.

Less than stoichiometric amounts of alkali metal hydroxides result in lower reaction rates and yields due to lower conversion whereas more than stoichiometric amounts of alkali metal hydroxides result in formation of byproducts from competitive side reactions.

The difluoroquinolinecarboxylic acid starting material is substantially or totally insoluble in water. The formation of its alkali metal salt faciiitates dissolution. 2-Methyl 2,5-diazabicyclo[2.2.1]heptane is soluble in water as its free base or dihydrobromide salt. After determination that substantially all of the difluoroquinolinecarboxylic acid, ester or salt starting material is consumed, the reaction slurry is cooled and 2 to 15 volumes of aqueous sodium bicarbonate solution, based on the volume of the reaction mixture, is added. The concentration of the aqueous sodium bicarbonate solution ranges from about 3% by weight to saturation.The addition of the aqueous sodium bicarbonate solution to the crude aqueous reaction mixture leads to a rapid and substantially quantitative precipitation of danofloxacin zwitterion under basic conditions at a pH of about 9.5 to about 10.5. The precipitation and isolation of danofloxacin under basic conditions improve product quality since residual reactants and reaction byproducts are soluble under alkaline conditions. After filtration, the crude danofloxacin is conveniently reslurried in water to remove residual salts such as alkali metal fluoride.

The present process may be conducted at elevated temperatures of about 120 to 1300C and elevated pressures of about 20 to 30 p.s.i. to increase the reaction rate and so increase the productivity of the process.

Danofloxacin is an antibacterial agent which may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, it can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the forms of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, it is advantageously contained in an animal feed or drinking water in a concentration of 5-5000 ppm, preferable 25-500 ppm. It can be injected parenterally, for example, intramuscularly, intravenously or subcutaneously.

For parenteral administration, it is best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to make the solution isotonic. In the case of animals, compounds can be administered intramuscularly or subcutaneously at dosage levels of about 0.1-50 mg/kg/day, advantageously 0.2-10 mg/kg/day given in a single daily does or up to 3 divided doses.

Danofloxacin can be administered to humans for the treatment of bacterial diseases by either the oral or parenteral routes, and may be administered orally at dosage levels of about 0.1-500 mg/kg/day, advantageously 0.5-50 mg/kg/day given in a single dose or up to 3 divided doses. For intramuscular or intravenous administration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day. While intramuscularly administration may be a single dose or up to 3 divided doses, intravenous administration can include a continuous drip. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen.

The following Examples illustrate the invention.

EXAMPLE 1 To a 125 ml, 3-neck round bottom flash equipped with a mechanical stirrer, thermometer, and reflux condenser topped with a nitrogen inlet was charged 5.30 grams (0.020 moles) of 1 -cyclopropyl-6,7-difluoro-1 ,4-dihydro-4-oxo-3quinolinecarboxylic acid, 6.57 grams (0.024 moles) of (1 S)-2-methyl-2,5-diazabicyclo [2.2.1] heptane dihydrobromide, and 40 ml of distilled water. The slurry was stirred for 10 minutes under nitrogen and then 4.38 grams (0.068 moles) of 87% active potassium hydroxide was added. The slurry was heated to reflux (1 03 0 C) and maintained at reflux for 24 hours under nitrogen. A high performance liquid chromatography (hplc) assay showed that nearly all the difluoroquinolinecarboxylic acid was consumed.The thin reaction slurry was cooled to 40 - 500C and then 22.4 ml of a 7% by weight aqueous sodium bicarbonate solution was added. The resulting slurry was cooled to 20250C and granulated for 1 hour. The slurry was further cooled to 5 - 1000 and then granulated for 2 hours. The off-white product was filtered and the cake was washed with 5 ml of deionized water. The wet cake was reslurried in 45 ml of cold (5 - 1000) deionized water for one hour, filtered, and then dried in vacuo at 450C for 8 hours. The zwitterionic product (6.50 grams) was isolated in 91% overall yield and the product possessed a 98.5% purity by hplc.

EXAMPLE 2 Ethyl 1 -cyclopropyl-6,7-difluoro-1 ,4-dihydro4-oxo-3-quinolinecarboxylate (75.0 grams; 0.256 moles), distilled water (43.3 mls), 2-propanol (150 mls), and 1 N KOH (256.6 ml) were combined in a one-liter, 4-neck round bottom flask which was equipped with a thermometer, reflux condenser, and a nitrogen inlet. The mixture was heated at 53-550C for 5.5 hours and then cooled to room temperature for a reaction completion assay. Thin-layer chromatography (methylene chloride/methanol 8.2) showed that the ethyl quinolinecarboxylate was completely saponified.The mixture was reheated to reflux and 174 ml of distillate was removed overhead while the pot temperature rose from 800C to 980 C. The solution was cooled to 700C and then 70.1 grams (0.256 moles) of (1 S)-2-methyl-2,5-diazabicyclo[2.2.1] heptane dihydrobromide and 32.9 gram (0.510 moles) of 87% KOH in 150 ml distilled water were added. The mixture was reheated to reflux (101 0C) and held at reflux for 41.5 hours. High pressure liquid chromatography showed that the coupling reaction was complete. The mixture was cooled to 600C and 340 ml of a saturated sodium bicarbonate was added. The slurry was cooled to 0-50C and then granulated for 2 hours. The off-white product was filtered and the wet cake washed with water (2 X 100 ml). The wet cake was resuspended in 1.05 liters of deionized water at 0 - 50C and stirred for 2 hours. The filtration and aqueous wash sequence was repeated. The product was dried in vacuo at 500C with an air bleed. (1 S)-1-Cyclopropyl-6-fluoro-1 ,4-dihydro-7-(5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl)4-oxo-3-quinolinecarboxylic acid (81.8 grams; 98.9% pure) was obtained in 89.5% overall yield. The bicarbonate-precipitated product contained no residual starting materials nor the possible reaction byproduct, 1 -cyclopropyl-6- fluoro-7-hydroxy-1 ,4-dihydrn4-oxo-3-quinolinecarboxylate. In addition, the reaction mother liquors contained only 1.2% residual danofloxacin.

Claims (5)

1. A process for preparing a compound of the formula

which comprises reacting the difluoroquinolinecarboxylic acid compound of the formula

wherein R is hydrogen, C1-C4 alkyl or alkali metal, with (1 S)-2-methyl-2,5 diazabicyclo[2.2.1] heptane or (1 S)-2-methyl-2,5-diazabicyclo[2.2. 1 ]heptane dihydrobromide in the presence of substantially stoichiometric amounts of potassium hydroxide or sodium hydroxide in water.

2. A process according to claim 1 wherein an aqueous alkali metal bicarbonate solution is added after said reaction is terminated.

3. A process according to claim 1 or 2 wherein 2 to 15 volumes of water are present based on the volume of said difluoroquinolinecarboxylic acid compound.

4. A process according to claims 1, 2 or 3 wherein 2 to 15 volumes of an aqueous sodium bicarbonate solution is added after said reaction is terminated.

5. A process according to claim 4 wherein the concentration of said aqueous sodium bicarbonate solution ranges from about 3% by weight to saturation.