WO2003010144A2 - A process for synthesis of fluoroquinolonic derivatives - Google Patents
A process for synthesis of fluoroquinolonic derivatives Download PDFInfo
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- WO2003010144A2 WO2003010144A2 PCT/YU2002/000014 YU0200014W WO03010144A2 WO 2003010144 A2 WO2003010144 A2 WO 2003010144A2 YU 0200014 W YU0200014 W YU 0200014W WO 03010144 A2 WO03010144 A2 WO 03010144A2
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- 0 C*C(C(c1c2)=O)=CN(C3CC3)c1cc(NCCNN)c2F Chemical compound C*C(C(c1c2)=O)=CN(C3CC3)c1cc(NCCNN)c2F 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Definitions
- the suggested invention is related to the area of organic chemical technology, specificly to the process for obtainig of antibiotics belonging to the group of fluoroquinolonic derivatives, with general formula I and salts and hydrates thereof,
- R and R2 denote a hydrogen atom, or an alkyl group with C ⁇ - C4, and R ⁇ denotes an alkyl group with C ⁇ - C4 or an cycloalkyl group (eg. cyclopropyl group).
- ciprofloxacin (l-cyclopropyl-6- fluoro- 1 ,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid) of formula II
- ciprofloxacin hydrochloride monohydrate (1 -cyclopropyl-6-fluoro-l ,4-dihydro-4- oxo-7 -piper azino-quinol ⁇ ne-3-carboxylic acid hydrochloride monohydrate
- norfloxacin (l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7- piperaz ⁇ no-quinol ⁇ ne-3-carboxylic acid) of formula IV.
- the suggested original invention solves the problem of obtaining of pure product, introducing the purification phase, which enables obtaining of entire palette of pharmaceutically acceptable salts with pharmacological purity.
- This technical problem is solved by precipitation of the product with an inorganic acid (e.g. concentrated hydrochloric acid), as well as with an organic acid (e.g. acetic acid) and use of active charcoal, which enables higher yield and avoids energy loss with distillation during subsequent purification.
- the problem of stability of the product is also solved within one working phase, without previous drying, preventing degradation of the product and unwanted secondary reactions, and the secondary products are removed from the reaction mixture. Background of the invention
- ciprofloxacin of formula II is obtained in reaction between piperazine and 7-chloro- l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid, in the presence of dimethylsulphoxide, at rised temperature, and the product is isolated from the reaction mixture by distillation under extremely low vacuum, while the residue is rinsed in water and ethanol and dried, and obtained product is, in the next phase, converted, using 10% HCl, into ciprofloxacin hydrochloride.
- ciprofloxacin hydrate with 2,5 mol of hydration water is obtained by decomposition of previously synthetized and dried compound l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-l-piperazino-quinoline-3- carboxylate ethylate using concentrated hydrochloric acid and appropriate isolation from the corresponding solvent.
- ciprofloxacin hydrochloride monohydrate of formula III is obtained by decomposition of previously synthetuzed and dried p-toluol sulphonyl compound of ciprofloxacin into ciprofloxacin hydrate with 2,5 mol of hydration water, and formed dried ciprofloxacin hydrate with 2,5 mol of hydration water is in the next phase suspended in the mixture of solvents, through which the gas hydrogen chloride at suitable flow rate, until wanted concentration in the solution is achieved, and formed product ciprofloxacin hydrochloride monohydrate is isolated from the mixture of solvents.
- Disadvantages of the described patent are use of gaseous hydrogen chloride, which increases the risk and requires special equipment for performing of the synthesis.
- the stated invention avoids the disadvantages of the known processes, primarily given in Eastern-Gemany patent DE 202, 560, European patent EP 2, 078, 362, Israeli patent IL 66243/3, as well as in Spanish patents ES 2, 006, 098 and ES 2, 006, 099.
- degradation of the product which is heath, moisture, light and air oxygen sensitive, occures, and all the secondary products from the synthesis phase, still remains in reaction mixture, and unwanted reactions with the product are also possible, so, what is obtained, is not the pure product for pharmaceutical use, and the additional purification is required.
- the suggested original invention solves the problem of obtaining of pure product, by introducing of purification phase, which enables obtaining of entire pallete of pharmaceutically acceptable salts, with pharmacological purity, by precipitation with an inorganic acid (e.g. concentrated hydrochloric acid) as well as with an organic acid (e.g. acetic acid) and using active charcoal.
- an inorganic acid e.g. concentrated hydrochloric acid
- an organic acid e.g. acetic acid
- active charcoal active charcoal
- the suggested invention shows simplified reaction procedure of piperazine or piperzin derivatives, of general formula V:
- reaction is carried out in an inert solvent of pharmacopoeic purity - p.a. quality, belonging to the group of organic solvents such as alcohols, ethers, as well as acetonitrile, benzene, dimethylsulphoxide, pyridine, dimethylformamide, at atmospheric pressure and at temperature of reaction mixture in range between 20 and 200° C.
- an inorganic acid e.g. hydrochloric acid
- organic acid e.g. acetic acid
- R and R2 denote hydrogen atom, or alkyl group with C ⁇ - C4, and R ⁇ denotes alkyl or cycloalkyl group (e.g. cyclopropyl group).
- Fluoroquinolonic compounds of general formula I have acid- and base-centers, which, according to the suggested invention enables purification using acids and bases.
- the product is isolated in the range of pH between 4 and 8, and is further purified suspending of the precipitate into 5 to 15 time greater quantity of water in regard to the starting volume of solvent used in the phase of synthesis.
- Precipitate of the compound of general formula I is purified from the secondary products by addition of active charcoal, converting with suitable inorganic acid such as hydrochloric and sulphuric or organic acid (such as acetic, lactic, tartaric, maleic, citric) with stirring and cooling and isolating in the forms of salts chlorides, sulphates, lactates, acetates, tartarates, maleates. Then, by alkalization, with alkaline aqueos solution such as ammonium hydroxide, sodium carbonate, sodium hydroxide or potassium hydroxide, with stirring and cooling, the compound of general formula I is obtained.
- suitable inorganic acid such as hydrochloric and sulphuric or organic acid (such as acetic, lactic, tartaric, maleic, citric)
- suitable inorganic acid such as hydrochloric and sulphuric or organic acid (such as acetic, lactic, tartaric, maleic, citric)
- suitable inorganic acid such as
- Obtained product is further hydrochlorated by instillation of hydrochloric acid aqueous solution.
- the reaction mixture is heated at 40-80°C, afterwards, it is effluxed into an organic solvent belonging to the group of alcohols such as methanol, absolute ethanol, isopropanol.Cooltd mixture is filtrated, and the precipitate is rinsed with mentioned solvent.
- the product is dried using vacuum, which gives the compound of general formula I in the form of pharmaceutically acceptable salt (chloride, sulphate, lactate, citrate, acetate, tartarate, maleate) and/or hydrate of pharmacological purity.
- antibiotics belonging to the group of fluoroquinolonic derivatives have: ciprofloxacin (l-cyclopropyl-6fluoro-l, 4-dihydro-4-oxo- 7 -piperazino-quinoline-3- carboxylic acid) of formula II,
- norfloxacin l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-piperazino-quinoline- 3-carboxylic acid
- processed compounds can be used in pharmaceutical form of tablets, pills, dragees, capsules, ampullas or suppositories, with usual pharmaceutical additives, for obtaining of pharmaceutical preparations for use as antibiotics in human and veterinary medicine, and as a food additive.
- Crude precipitate is suspended in water and dissolved, by addition of 2mol/dm ⁇ of hydrochloric acid.
- the solution is, after addition of active charcoal, heated with stirring at 50°C and filtered.
- 2mol/dm3 of sodium hydroxide is added.
- Formed suspension is filtered, and the precipitate is rinsed with distilled water.
- 49,46gr of ciprofloxacin hydrochloride monohydrate (l-cyclopropyl-6-fluoro-l ,4- dihydro-4-oxo- 7-piperazino-quinoline-3-carboxylic acid hydrochloride monohydrate) of formula III is obtained, in the form of white crystals, melting point 308-310°C with decomposition (73% yield).
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Abstract
A simple and for use convenient procedure for obtaining of antibiotics from the group of fluoroquinolonic derivatives, of general formula (I), is developed where R and R2 denote hydrogen atom, or alkyl group with C1-C4, and R1 denotes alkyl group with C1-C4 or cycloakyl group (such as cyclopropyl group, for example), and/or salts and hydrates thereof, by reaction of piperazin or piperazin derivatives with the compound of general formula VI in an inert solvent of pharmacopoeic purity, at risen temperature. The lower reaction temperature, work at atmospheric pressure, technical simplicity of the procedure of purification by conversion and isolation in the form of pharmaceutically acceptable salts, yield increase, reducing prices on the procedure for industrial use, as well as pharmacopoeic purity of the product, enabled their use as the antibiotics in human and veterinary medicine.
Description
A PROCESS FOR SYNTHESIS OF FLUOROQUINOLONIC DERIVATIVES
The field of technique
The suggested invention is related to the area of organic chemical technology, specificly to the process for obtainig of antibiotics belonging to the group of fluoroquinolonic derivatives, with general formula I and salts and hydrates thereof,
(I) wherein R and R2 denote a hydrogen atom, or an alkyl group with C\ - C4, and R\ denotes an alkyl group with C\ - C4 or an cycloalkyl group (eg. cyclopropyl group). Of special interest, concerning clinical practice are: ciprofloxacin (l-cyclopropyl-6- fluoro- 1 ,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid) of formula II, ciprofloxacin hydrochloride monohydrate (1 -cyclopropyl-6-fluoro-l ,4-dihydro-4- oxo-7 -piper azino-quinolιne-3-carboxylic acid hydrochloride monohydrate) of formula III, as well as norfloxacin (l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7- piperazιno-quinolιne-3-carboxylic acid) of formula IV.
(II) (III) (IV)
These compounds are used in therapy as antibiotics, in human and veterinary medicine. According to the International Classification of patents the invention belongs to the class C 07 D 215/02, 215/04, 215/18, 215/56, C 07 D 241/04, C 07 D 295/04, C 07 D 401/04, 401/10.
Technical problem
There was a need to come to the technically more convenient and economic process for obtaining of antibiotics belonging to the group of fluoroquinolonic derivatives. Contemporary pharmaceutical technology sets the more strict demands for increasingly higher purity of the products, in comparison with already existing patents from the eighties, which had lower criteria. The existing patents do not have the product purification phase after evaporation of solvent, and for that reason, the pure product for pharmaceutical use is not obtained, and an additional purification is required. During purification by distillation, degradation of the product occur, for the reason it is heath, moisture, light and oxygen sensitive, and all the secondary products from the phase of synthesis, still stay in the reaction mixture, and side effects of the product are possible.
The suggested original invention solves the problem of obtaining of pure product, introducing the purification phase, which enables obtaining of entire palette of pharmaceutically acceptable salts with pharmacological purity. This technical problem is solved by precipitation of the product with an inorganic acid (e.g. concentrated hydrochloric acid), as well as with an organic acid (e.g. acetic acid) and use of active charcoal, which enables higher yield and avoids energy loss with distillation during subsequent purification. The problem of stability of the product is also solved within one working phase, without previous drying, preventing degradation of the product and unwanted secondary reactions, and the secondary products are removed from the reaction mixture.
Background of the invention
In professional and patent literature, there are number of ways for obtaining of antibiotics belonging to the group of fluoroquinolonic derivatives of general formula I.
It is known from before that the compounds of l-ethyl-6-fluoro-4-oxo— piperazino-quinoline-3-carboxylic acid (Eur. J. Med. Chem., 12,541-547, 1977), as well as of l-ethyl-6-fluor-4-oxo—piperazino-quinoline-3-carboxylic acid (J. Med. Chem., 23,1358,1980) possess antibiotic properties.
According to the process described in Eastern-Germany patent DE 202, 560, European patent EP 2, 078, 362, as well as in Israeli patent and IL 66243, ciprofloxacin of formula II is obtained in reaction between piperazine and 7-chloro- l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid, in the presence of dimethylsulphoxide, at rised temperature, and the product is isolated from the reaction mixture by distillation under extremely low vacuum, while the residue is rinsed in water and ethanol and dried, and obtained product is, in the next phase, converted, using 10% HCl, into ciprofloxacin hydrochloride. A deficit of the processes in the mentioned patents was the way of isolation, ie. purification of ciprofloxacin from the reaction mixture, which contributes to the obtaining of the product in lower yield and purity, as well as to the rising of production costs. The product obtained in such way, is not pure enough for pharmaceutical use, so, instead of vacuum distillation, the phase of additional purification is introduced.
Obtaining of ciprofloxacin hydrochloride monohydrate of formula III, is described in Spanish patents ES 2, 006, 098 and ES 2, 006, 099.
According to the process described in Spanish patent ES 2, 006, 098 ciprofloxacin hydrochloride monohydrate of formula III, is obtained when previously synthetized and dried ciprofloxacin hydrate with 2,5 mol of hydration water, is in the next phase suspended and isolated from isopropanol and isobutanol. Here mentioned ciprofloxacin hydrate with 2,5 mol of hydration water is obtained
by decomposition of previously synthetized and dried compound l-cyclopropyl-6- fluoro-l,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-l-piperazino-quinoline-3- carboxylate ethylate using concentrated hydrochloric acid and appropriate isolation from the corresponding solvent.
According to the process described in Spanish patent ES 2, 006, 099 ciprofloxacin hydrochloride monohydrate of formula III, is obtained by decomposition of previously synthetuzed and dried p-toluol sulphonyl compound of ciprofloxacin into ciprofloxacin hydrate with 2,5 mol of hydration water, and formed dried ciprofloxacin hydrate with 2,5 mol of hydration water is in the next phase suspended in the mixture of solvents, through which the gas hydrogen chloride at suitable flow rate, until wanted concentration in the solution is achieved, and formed product ciprofloxacin hydrochloride monohydrate is isolated from the mixture of solvents. Disadvantages of the described patent are use of gaseous hydrogen chloride, which increases the risk and requires special equipment for performing of the synthesis.
Description of technical problem solution with examples
The stated invention avoids the disadvantages of the known processes, primarily given in Eastern-Gemany patent DE 202, 560, European patent EP 2, 078, 362, Israeli patent IL 66243/3, as well as in Spanish patents ES 2, 006, 098 and ES 2, 006, 099. In the quoted patents, during purification, degradation of the product, which is heath, moisture, light and air oxygen sensitive, occures, and all the secondary products from the synthesis phase, still remains in reaction mixture, and unwanted reactions with the product are also possible, so, what is obtained, is not the pure product for pharmaceutical use, and the additional purification is required.
The suggested original invention solves the problem of obtaining of pure product, by introducing of purification phase, which enables obtaining of entire pallete of pharmaceutically acceptable salts, with pharmacological purity, by precipitation with an inorganic acid (e.g. concentrated hydrochloric acid) as well as with an organic acid (e.g. acetic acid) and using active charcoal. Higher yield is achieved, and higher stability of the product, earring out the proces within one work phase, without previous drying, which avoids energy loss that occures with distillation, prevents degradation and unwanted secondary reactions, and possibly formed secondary products are removed from the reaction mixture.
The suggested invention shows simplified reaction procedure of piperazine or piperzin derivatives, of general formula V:
R-N N— H
(V) wherein R denotes hydrogen atom, or alkyl group with Ci - C4, with a compound of general formula VI:
(VI) wherein Rj denotes α/£y/ group with C\ - C4 or cycloalkyl group (e.g. cyclopropyl group), and R2 denotes hydrogen atom, or α ^ group with Cj - C4. The reaction is carried out in an inert solvent of pharmacopoeic purity - p.a. quality, belonging to the group of organic solvents such as alcohols, ethers, as well as acetonitrile, benzene, dimethylsulphoxide, pyridine, dimethylformamide, at atmospheric pressure and at temperature of reaction mixture in range between 20 and 200° C. To a cooled reaction mixture at temperature of 20 to 70°C, with stirring and cooling, a quantity of an inorganic acid (e.g. hydrochloric acid), or organic acid (e.g. acetic acid), 3 to
5 times greater than starting number of mols of the compound of general formula
VI, is added, obtainig fluoroquinolonic derivatives of general formula I
Obtained product is further hydrochlorated by instillation of hydrochloric acid aqueous solution. The reaction mixture is heated at 40-80°C, afterwards, it is effluxed into an organic solvent belonging to the group of alcohols such as methanol, absolute ethanol, isopropanol.Cooltd mixture is filtrated, and the precipitate is rinsed with mentioned solvent. The product is dried using vacuum, which gives the compound of general formula I in the form of pharmaceutically acceptable salt (chloride, sulphate, lactate, citrate, acetate, tartarate, maleate) and/or hydrate of pharmacological purity.
Special interest in clinical practice in human and veterinary medicine, as antibiotics belonging to the group of fluoroquinolonic derivatives have: ciprofloxacin (l-cyclopropyl-6fluoro-l, 4-dihydro-4-oxo- 7 -piperazino-quinoline-3- carboxylic acid) of formula II,
(II) ciprofloxacin hydrochloride monohydrate (l-cyclopropyl-6-fluoro-l,4-dihydro-4- oxo-7 -piper azino-quinoline-3-carboxylic acid hydrochloride monohydrate) of formula III,
(IV) or the pharmaceutically acceptable salts thereof (chlorides, sulphates, lactates, cutrates, acetates, tartarates, maleates) and/or pharmacologically pure hydrates thereof.
In such way processed compounds can be used in pharmaceutical form of tablets, pills, dragees, capsules, ampullas or suppositories, with usual pharmaceutical additives, for obtaining of pharmaceutical preparations for use as antibiotics in human and veterinary medicine, and as a food additive.
The procedure is in more details described in the following examples, but should not be considered as restrictive.
EXAMPLE 1: Synthesis of ciprofloxacin hydrochloride monohydrate (1- cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo- 7-piperazino-quinoline-3-carboxylic acid hydrochloride monohydrate) of formula III
Mixture of 49,25gr of 7-chloro-l -cyclopropyl-6-fluoro-l ,4-dihydro-4-oxo- quinoline-3-carboxylic acid, 72,25gr of piper azine and 250cm3 of dimethylsulphoxide is heated for 1,5 to 2 hours at temperature of 140°C. To the cooled reaction mixture at temperature of 70°C, 985cm^ of distilled water is added. With stirring and cooling, to the reacting mixture 62,5cm3 of concentrated hydrochloric acid is instillated. Formed suspension is filtered, and the precipitate is rinsed with distilled water. Crude precipitate is suspended in water and dissolved, by addition of 2mol/dm^ of hydrochloric acid. The solution is, after addition of active charcoal, heated with stirring at 50°C and filtered. To the filtrate, with
stirring and cooling, 2mol/dm3 of sodium hydroxide is added. Formed suspension is filtered, and the precipitate is rinsed with distilled water.
Crude precipitate is, with stirring suspended in water and 60 cm^ of 2mol/dm3 hydrochloric acid is instillated. The reaction mixture is heated for 30 minutes at 75-80°C, and afterwards, it is effluxed into 1750cm3 of absolute ethanol. The mixture cooled to 0-5°C is filtered, and the precipitate is rinsed three times with 30cm3 of absolute ethanol each time. The product is dried in vacuum drier at 80°C. 49,46gr of ciprofloxacin hydrochloride monohydrate (l-cyclopropyl-6-fluoro-l ,4- dihydro-4-oxo- 7-piperazino-quinoline-3-carboxylic acid hydrochloride monohydrate) of formula III is obtained, in the form of white crystals, melting point 308-310°C with decomposition (73% yield).
EXAMPLE 2: Synthesis of ciprofloxacin (l-cyclopropyl-6-fluoro-l,4-dihydro-4- oxo- 7-piperazino-quinoline-3-carboxylic acid)
Mixture of 49,25 gr of 7 -chloro-l-cyclopropyl-6-fluoro-l ,4-dϊhydro-4-oxo- quinoline-3-carboxylic acid, 72,25 gr of piperazin and 400 cir of pyridine is heated for 1,5 to 2 hours at 110°C. Into cooled reaction mixture 985 cm- of distilled water is added. With stirring and cooling, 62,5 cm of concentrated hydrochloric acid is instillated into the reaction mixture. The formed suspension is filtered, and the precipitate is rinsed with distilled water. Crude precipitate is suspended in water and disolved by addition of 2 mol/dm^ sodium hydroxide.Tht solution is, after addition of active charcoal, heated to 50°C and filtered. Into filtrate, with stirring and cooling, 2 mol/dm^ of hydrochloric acid is added. The formed suspension is filtered, and the precipitate is rinsed with distilled water, and then, three times with 30 cm^ of absolute ethanol each time. The product is dried in vacuum drier at 100°C. 50gr of ciprofloxacin (l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- piperazino-quinoline-3-carboxylic acid) is obtained, in the form of white crystals, melting point 255-257°C (86% yield). Obtained product can be further hydrochlorated in the way, already described in example 1.
EXAMPLE 3: Synthesis of norfloxacin (l-ethyl-6-fluoro-l ,4-dϊhydro-4-oxo-7 - piper azino-quinoline- -carboxylic acid)
The synthesis is carried out analogously to the procedure explained in example 2, with the difference that instead of the compound 7-chloro-l- cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid, compound 7- chloro-l-ethyl-6-fluoro-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid is used, when norfloxacin (l-ethyl-6-fluoro-l, 4-dihydro-4-oxo- 7 -piper azino-quinoline-3 - carboxylic acid) is obtained in the yield of 68% in the form of crystals with melting point 220-22 IOC.
Claims
1. The procedure for obtaining of antibiotics, fluoroquinolonic derivatives, of general formula I
(I) wherein R and R2 denote hydrogen atom, or alkyl group with C\ - C4, and R\ denotes alkyl or cycloalkyl group, such as cyclopropyl group, by reaction of piperazin, or piperazin derivatives, of general formula V:
R-N — H
(V) wherein R denotes hydrogen atom, or alkyl group with C \ - C4, with compound of general formula VI:
(VI) wherein Rj denotes alkyl or cycloalkyl group, such as cyclopropyl group, and R2 denotes hydrogen atom, or alkyl group with C\ - C4, in an inert solvent, of pharmacopoeic purity - p.a. quality, belonging to the group of organic solvents such as alcohols, ethers, as well as acetonitrile, benzene, dimethylsulphoxide, pyridine, dimethylformamide, at atmospheric pressure and temperature of the reaction mixture in range between 20 and 200°C, denoted by the fact, that into the cooled reaction mixture, at temperature of 20 to 70°C, with stirring and cooling, 3 to 5 times greater quantity of an inorganic acid, such as hydrochloric acid, or an organic acid, such as acetic acid, is added, in relation to the starting number of mols of the compound of general formula VI, while, with stirring and cooling fluoroquinolonic derivative of general formula I is precipitated, and the precipitate is suspended in 5 to 15 times greater quantity of water, in relation to the volume of used solvent from the phase of synthesis and with active charcoal, is further purified from the secondary products by conversion, using inorganic acids such as: hydrochloric, sulphuric or organic acids, such as: acetic, lactic, tartar ic, maleic, citric, with stirring and cooling and by isolation in the forms of salts chlorides, sulphates, lactates, citrates, acetates, tartarates, maleates, and afterwards, using alkalization with alkali aqueaus solution such as ammonium hydroxide, sodium hydroxide, potassium hydroxide or sodium carbonate and with the corresponding acid, purified fluoroquinolonic derivative of general formula I is obtained, and it is further hydrochlorated by instillation of hydrochloric acid aqueous solution at temperature between 40 and 80°C and effluxated into an organic solvent such as methanol, absolute ethanol, isopropanol, which gave the compound of general formula I in the form of the pharmaceutically acceptable salt and/or hydrate of pharmacological purity.
2. A procedure, according to the patent claim 1, denoted by the fact, that the precipitate is isolated in pH range between 4 and 8.
3. Antibiotic, ciprofloxacin (l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- piperazino-quinoline-3-carboxylic acid) obtained according to the procedure according to the patent claims 1 and 2.
4. Antibiotic ciprofloxacin hydrochloride monohydrate (1 -cyclopropyl-6-fluoro- 1, 4-dihydro-4-oxo- 7-piperazino-quinoline-3-carboxylic acid hydrochloride monohydrate) obtained according to the procedure according to the patent claims 1 and 2.
5. Antibiotic norfloxacin (l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7 '-piper -azino- quinoline-3 -carboxylic acid) obtained according to the procedure according to the patent claims 1 and 2.
6. Pharmaceutical preparation for use in human and veterinary medicine, as an antibiotic in the form of tablets, pills, dragees, capsules, ampullas or suppositories, and as food additives, denoted by the fact, that it contains the compound obtained according to the patent claims 1 to 5, with usual pharmaceutical additives.
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| YUP-534/01 | 2001-07-25 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321121C (en) * | 2005-04-21 | 2007-06-13 | 浙江医药股份有限公司新昌制药厂 | Preparation and post-treatment method of levofloxacin |
| FR2916446A1 (en) * | 2007-05-24 | 2008-11-28 | Biocodex Sa | NOVEL PROCESS FOR SYNTHESIZING FLUOROQUINOLONES |
| CN104447537A (en) * | 2014-11-17 | 2015-03-25 | 河南大学 | 3,3'-methylene-bisfluoroquinolone derivative containing ethylquinoline rings as well as preparation method and application thereof |
| CN113788828A (en) * | 2021-10-26 | 2021-12-14 | 黄河水利职业技术学院 | Isolophylline analogues, preparation method and application from norfloxacin to isolemenine analogues |
| CN119264048A (en) * | 2024-09-30 | 2025-01-07 | 中南大学 | A crystal form X norfloxacin and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2006098A6 (en) * | 1988-03-03 | 1989-04-01 | Investchemi S A | Ciprofloxacine hydrochloride mono:hydrate prepn. |
| ES2006099A6 (en) * | 1988-03-03 | 1989-04-01 | Investchemi S A | Ciprofloxacine hydrochloride mono:hydrate prepn. |
| ES2010135A6 (en) * | 1989-02-10 | 1989-10-16 | Union Quimico Farma | Norfloxacin bactericide prepn. |
| ES2012307A6 (en) * | 1989-05-05 | 1990-03-01 | Union Quimico Farma | Improvements in the object of Patent 8801824 for procedure for obtaining ciprofloxacin |
| DE19930557B4 (en) * | 1999-07-02 | 2005-12-08 | Bayer Healthcare Ag | Process for the preparation of hydrates of ciprofloxacin and of ciprofloxacin anhydrate containing pharmaceutical compositions |
-
2002
- 2002-07-24 WO PCT/YU2002/000014 patent/WO2003010144A2/en not_active Ceased
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321121C (en) * | 2005-04-21 | 2007-06-13 | 浙江医药股份有限公司新昌制药厂 | Preparation and post-treatment method of levofloxacin |
| FR2916446A1 (en) * | 2007-05-24 | 2008-11-28 | Biocodex Sa | NOVEL PROCESS FOR SYNTHESIZING FLUOROQUINOLONES |
| JP2009001560A (en) * | 2007-05-24 | 2009-01-08 | Biocodex | Novel synthesis of fluoroquinolones |
| EP2138490A1 (en) * | 2007-05-24 | 2009-12-30 | Biocodex | New method for synthesis of fluoroquinolones |
| US8093381B2 (en) | 2007-05-24 | 2012-01-10 | Biocodex | Method of synthesis of fluoroquinolones |
| CN104447537A (en) * | 2014-11-17 | 2015-03-25 | 河南大学 | 3,3'-methylene-bisfluoroquinolone derivative containing ethylquinoline rings as well as preparation method and application thereof |
| CN113788828A (en) * | 2021-10-26 | 2021-12-14 | 黄河水利职业技术学院 | Isolophylline analogues, preparation method and application from norfloxacin to isolemenine analogues |
| CN113788828B (en) * | 2021-10-26 | 2023-06-30 | 黄河水利职业技术学院 | Preparation method and application of isofraxine analogue from norfloxacin to isofraxine analogue |
| CN119264048A (en) * | 2024-09-30 | 2025-01-07 | 中南大学 | A crystal form X norfloxacin and preparation method thereof |
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| WO2003010144A3 (en) | 2003-10-16 |
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