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WO2009093268A1 - Procédé d'élaboration de prulifloxacine hautement pure - Google Patents

Procédé d'élaboration de prulifloxacine hautement pure Download PDF

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Publication number
WO2009093268A1
WO2009093268A1 PCT/IN2009/000060 IN2009000060W WO2009093268A1 WO 2009093268 A1 WO2009093268 A1 WO 2009093268A1 IN 2009000060 W IN2009000060 W IN 2009000060W WO 2009093268 A1 WO2009093268 A1 WO 2009093268A1
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WO
WIPO (PCT)
Prior art keywords
acid
formula
solvent
prulifloxacin
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2009/000060
Other languages
English (en)
Inventor
Rahul Saxena
Naresh Kumar Verma
Kumar Jain Anshul
Venkateswaran Srinivasan Chidambaram
Lalit Wadhwa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IND-SWIFT LABORATORIES Ltd
Ind Swift Laboratories Ltd
Original Assignee
IND-SWIFT LABORATORIES Ltd
Ind Swift Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2009093268A1 publication Critical patent/WO2009093268A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention provides an improved process for the preparation of highly pure prulifloxacin of formula I, an oral fluoroquinolone antibacterial agent or pharmaceutically acceptable salt thereof.
  • the present invention provides a novel process for the purification of prulifloxacin acid addition salt.
  • the resulting product is then treated with ethyl malonate in the presence of potassium hydroxide in 1 ,4-dioxane, followed by treatment with methoxymethyl chloride to give diethyl l-(3,4-difluorophenylamino)-l-(methoxymethylthio)-methylenemalonate which is further purified with column chromatography and then cyclised to give ethyl 6,7- difluoro-4-hydroxy-2-methoxymethylthio- quinoline-3-carboxylate.
  • Another object of the present invention is to provide a process for the purification of the prulifloxacin acid addition salts.
  • Formula II (k) optionally purifying ulifloxacin of formula II;
  • the present invention provides a process for the preparation of prulifloxacin of formula I, which comprises the step of:
  • the process of the present invention is an improved and efficient process for the preparation of highly pure prulifloxacin of formula I.
  • prulifloxacin of formula I can be prepared starting from 3,4-difluoroaniline and reacting the same with carbon disulfide in the presence of a suitable base to obtain triethylammonium-(3,4-difluorophenyl)dithiocarbamate at a temperature of 0 to 30 0 C, preferably till the completion of the reaction.
  • Base employed in the reaction includes organic amines such as trialkylamine; or inorganic base such as alkali or alkaline metal hydroxides, carbonates, bicarbonates, hydrides or alkoxide thereof and the like.
  • the base used is selected from triethylamine, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.
  • Solvent includes aliphatic or aromatic hydrocarbon such as hexane, toluene, xylene; ethers such as isopropyl ether; halogenated solvents such as dichloromethane, chloroform; and the like or mixtures thereof. The reaction can also be performed in the absence of solvent.
  • suitable solvents includes halogenated solvents such as dichloromethane; aliphatic or aromatic hydrocarbon such as toluene, xylene; and the like or mixture thereof.
  • Suitable base are same as described above.
  • 3,4-difluoroaniline is treated with aqueous solution of inorganic base along with carbon disulfide at a temperature of 0-10 0 C.
  • the reaction mass is then stirred at a temperature of 35-55 0 C for 10-30 hours.
  • the reaction mixture is then cooled to a temperature of 20-35 0 C and filtered to remove salts.
  • Ethylchloroformate is added slowly to the filtrate at a temperature of 10- 20 0 C and stirred at 35-55°C for few hours and extracted with aliphatic or aromatic hydrocarbon such as hexane.
  • the organic layer is washed with water to isolate 3,4-difluorophenyl isothiocyanate.
  • the product is isolated by concentration under reduced pressure.
  • the resulting product i.e. 3,4-difluorophenyl isothiocyanate obtained by any methods can optionally be purified by the methods well known in the art like extraction with a solvent, recrystallization, distillation and the like or can be used as such for the next step.
  • 3,4- difluorophenyl isothiocyanate is purified by distillation under reduced pressure.
  • 3,4- Difluorophenyl isothiocyanate so obtained is having purity of more than 95% by HPLC.
  • Base can be organic or inorganic base.
  • Organic base includes trialkylamine.
  • Inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide and hydride thereof.
  • base used is potassium hydroxide.
  • present invention provides a process for the preparation of [[(3,4- difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester S-potassium salt of formula IV from 3,4-difluoroaniline by using same solvent for all the three steps.
  • Suitable solvents that can be used in first three steps includes aliphatic or aromatic hydrocarbon such as toluene, xylene; cyclohexane, hexane and the like or mixture thereof.
  • the solvent employed is toluene. It is advantageous to perform the reactions in the presence of a solvent which is same for the three steps of the reaction. Use of minimal number of solvents makes the process cost effective and commercially attractive.
  • the organic solvents includes aliphatic or aromatic hydrocarbon such as toluene, xylene, paraffin oil; esters such as ethyl acetate; ethers such as diphenyl ether and the like or mixture thereof.
  • Compound of formula V is insitu further cyclized to ethyl 4-hydroxy-6,7-difluoro-2- (ethylthio)quinoline-3-carboxylate of formula VI. It is optional to isolate the intermediate of formula V by the suitable techniques. Preferably the reaction is carried out in the ethylacetate or xylene.
  • the present invention provide a one pot process for the preparation of ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinoline-3-carboxylate of formula IX directly from 4-hydroxy compound of formula VI.
  • the reaction steps acetylation of 4-hydroxy compound followed by chlorination and then condensation with the piperazine moiety are carried out without isolation of the intermediates in same pot. This makes the process commercially attractive by reducing the time and requirement of workup of the intermediates for the isolation.
  • 4-Hydroxy compound of formula VI is acylated in the presence of a suitable reagent that includes acetyl halide, acetic anhydride and the like in the presence of a base in a solvent to obtain ethyl 4-acetoxy compound of formula VII.
  • Base can be organic or inorganic.
  • Organic base includes trialkylamine such as triethylamine and the like; inorganic base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide or hydrides thereof.
  • Solvent includes halogenated solvent such as dichloromethane, chloroform; aliphatic or aromatic hydrocarbon such as hexane and the like or mixture thereof.
  • the reaction is conducted at a temperature of about -5 to 10 °C and progress of the reaction is monitored by TLC. After the completion of the reaction, water and water immiscible solvents is added to the reaction mixture followed by distillation of the some part or whole of solvent.
  • the resulting residue can be used as such for the further reaction or product can be isolated using suitable techniques like isolation of the compound of formula VII by the addition of a suitable solvent which includes alcoholic solvent to the resulting residue.
  • the compound of formula VIII is further treated with an alkali metal acetate preferably sodium acetate in the presence of a solvent at a temperature of room temperature to reflux temperature of the solvent to form ethyl 6,7-difluoro-l-methyl-4-oxo-4H-(l,3)thiazeto(3,2-a)quinoline-3- carboxylate of formula IX.
  • the reaction takes about 1-10 hours for completion of reaction.
  • (l,3)Thiazeto compound of formula IX is then condensed with piperazine to obtain ulifloxacin ethyl ester of formula X.
  • the process involves the reaction of compound of formula IX with piperazine in a suitable solvent at ambient temperature to reflux temperature of the solvent.
  • suitable solvent includes amide solvents such as dimethylformamide, dimethylacetamide; nitrile solvent such as acetonitrile; ketone such as acetone; sulfoxide solvent such as dimethylsulfoxide; sulfolane; aprotic solvents and the like or mixture thereof. Reaction is conducted for a period of about 10-40 hours, preferably for 24 hours, more preferably till reaction completion.
  • the ulifloxacin ethyl ester is precipitated either by cooling of the reaction mixture or by addition of water; the precipitates are isolated by solvent removal using suitable techniques like filtration. Ulifloxacin ethyl ester of formula X is further hydrolysed to give ulifloxacin of formula II.
  • the hydrolysis of ester functionality present in the ulifloxacin ethyl ester of formula X can be performed with any method known in art for the hydrolysis of the ester. Specifically, the hydrolysis involves the treatment of ulifloxacin ethyl ester of formula X in the presence a suitable base or an acid in a suitable solvent.
  • Hydrolysis reaction is preferably conducted at a temperature of about ambient temperature to 100°C and it takes about 1-10 hours for complete hydrolysis.
  • Suitable base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate, alkoxide, hydride thereof.
  • Acid for the hydrolysis includes organic and inorganic acid selected from sulfuric acid, phosphoric acid or mixture thereof.
  • Solvent includes Ci -4 alcohols, water and mixture thereof, preferably selected from water, methanol, ethanol, propanol, butanol or mixture thereof. Ulifloxacin isolated from the reaction mixture can further optionally be purified by slurry wash with an organic solvent.
  • Solvent includes water, alcohols like methanol, ethanol, isopropanol; ketones such as acetone or mixtures thereof. The conversion of ulifloxacin to pure prulifloxacin represents the inventive part of the present invention.
  • ulifloxacin of formula II is condensed with 4-halomethyl-5-methyl-l,3-dioxolen-2- one of formula III, in the presence of a suitable base followed by treatment with a suitable acid to obtain prulifloxacin acid addition salt, which is then hydrolyzed in the presence of a base to yield pure prulifloxacin.
  • the process involves the condensation of ulifloxacin of formula II with 4- halomethyl-5-methyl-l,3-dioxolen-2-one of formula III in presence of a suitable base at a temperature of -1O 0 C to ambient temperature, preferably at a temperature of 0 to -5 0 C.
  • the reaction can be carried out in presence of absence of the solvent.
  • Polar aprotic solvent can be selected from amide solvents such as N,N-dimethylformamide, N- methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide, ethers such as diglyme, monoglyme, nitrile solvents such as acetonitrile and the like or mixture thereof.
  • the reaction time may vary depending upon the amount of starting material, type of solvent and base used and reaction temperature. After the completion of the reaction, water and water immiscible solvents are added to the reaction mixture followed by distillation of the some part or whole of solvent. Thereafter, a suitable acid is added to the resulting residue for the formation of acid addition salt of prulifloxacin.
  • Suitable acid addition salts which may be formed includes those formed with pharmaceutically acceptable organic or inorganic acids and are well known to those of skill in the art. Acids commonly employed to form such salts includes inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and the like; salts with organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, oxalic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, and the like.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and the like
  • salts with organic acids such as formic acid, acetic acid, tartaric acid
  • Preferred pharmaceutically acceptable acid addition salts includes those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as formic acid, fumaric acid, maleic acid, oxalic acid and succinic acid.
  • a particularly preferred acid addition salt is the hydrochloride.
  • Hydrochloric acid employed for the preparation of acid addition salts can be anhydrous, hydrochloric acid with suitable solvent that includes ethers, esters, amide solvents, alcohol, aliphatic or aromatic hydrocarbon or mixture thereof.
  • hydrochloric acid employed is selected from alcoholic hydrochloride such as methanolic hydrochloride; amide solvent with hydrogen chloride such as N, N- dimethylformamide hydrochloride; ethereal hydrochloride such as isopropylether hydrochloride; ester hydrochloride such as ethyl acetate hydrochloride; and the like, it is advantageous to carry out the generation of the prulifloxacin acid addition salt in anhydrous conditions.
  • alcoholic hydrochloride such as methanolic hydrochloride
  • amide solvent with hydrogen chloride such as N, N- dimethylformamide hydrochloride
  • ethereal hydrochloride such as isopropylether hydrochloride
  • ester hydrochloride such as ethyl acetate hydrochloride
  • other acid employed in the reaction can be used as such or with solvent as described above.
  • 4-halomethyl-5-methyl-l,3-dioxolen-2-one of formula III is reacted with ulifloxacin in the presence of a suitable base in a solvent at a temperature of about -10 to 10 0 C.
  • a suitable base in a solvent at a temperature of about -10 to 10 0 C.
  • the progress of reaction is monitored by TLC or HPLC.
  • the reaction mixture is diluted with halogenated solvent like dichloromethane and water.
  • the layers are separated and aqueous layer is extracted with dichloromethane. All organic layers are combined and dried over sodium sulfate.
  • the organic layer can be concentrated or the organic layer as such is treated with suitable acid to prepare corresponding acid addition salt.
  • prulifloxacin acid addition salt is prepared by using an alcoholic hydrochloride or amide solvents with hydrogen chloride. More preferably methanolic hydrochloride or N,N- dimethylformamide hydrochloride for the generation of prulifloxacin hydrochloride.
  • Suitable solvents includes amide solvents such as dimethylformamide, N-methylpyrrolidone; sulfoxide solvents such as dimethylsulfoxide, nitrile solvent such as acetonitrile; halogenated solvents such as chloroform; alcoholic solvents such as methanol, the like and/or mixtures thereof.
  • the reaction mass is preferably cooled to a temperature of about 10-35°C and maintained for about 10 minutes to about 24 hours to afford highly pure prulifloxacin acid addition salt having purity of more than 99.0% by high performance liquid chromatography (HPLC), preferably more than 99.3 % by HPLC.
  • HPLC high performance liquid chromatography
  • Prulifloxacin acid addition salt with or without purification is treated with a base in the presence of a suitable solvent to convert to highly pure prulifloxacin which is suitable for application in pharmaceutical compositions.
  • Base can be selected from, but not limited to organic and inorganic base such as triethylamine, ammonia, alkali or alkaline metal hydroxide, carbonates, bicarbonate, hydride or alkoxide thereof such as sodium bicarbonate, potassium bicarbonate and the like.
  • the prulifloxacin obtained by the process of the present invention is having purity greater than 99.0%, preferably greater than 99.3% by HPLC. If required, the product can further be purified using methods well known in the art like recrystallization from suitable solvent. Suitable solvents employed for the purification includes halogenated solvents such as chloroform; alcoholic solvents such as methanol; amide solvents such as methylformamide, dimethylformamide, dimethylacetamide; sulfoxide solvents such as dimethylsulfoxide; nitrile solvents such as acetonitrile; dimethylimidazolidinone and the like or mixtures thereof.
  • Compound of formula III can be procured from the commercial source or prepared by the methods known in prior art like US patent no. 3,020,290; 4,843,070 etc.
  • compound of formula III can be prepared by the halogenation of 4,5-dimethyl-[l,3]dioxol-2-one with a suitable halogenating agent.
  • the order and manner of combining the reactants at any stage of the process are not important and may be varied.
  • the reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order.
  • Method B To a solution of 3,4-difluoroaniline (25g, 0.19mol) and triethylamine (58.75g, 0.58mol) in toluene (75ml), carbondisulfide (58.7g, 0.77 mol) was added under ice cooling. The reaction mass was stirred at 25-30 0 C for 12 hours. The resulting precipitates were filtered, washed with toluene to give 56.8 g of triethylammonium(3,4-difluorophenyl)dithiocarbamate.
  • Example 2 Purification of 3,4-difluorophenyl isothiocyanate 3,4-Difluorophenyl isothiocyanate (571 g ) was distilled under reduced pressure of 5 mbar at 80 0 C to afford 296 g of pure title compound having purity 98.95 % by HPLC.
  • Example 3 Preparation of [[(3,4-Difluorophenyl)amino]-mercaptomethylene]-malonic acid diethyl ester S-potassium salt To a stirred suspension of potassium hydroxide (94.15 g) in toluene (2130 ml) was added slowly diethyl malonate (272.64 g).
  • Method B To a stirred solution of ethyl 4-hydroxy-6,7-difluoro-2-(ethylthio)quinoline-3- carboxylate (50 gm, 0.159mol), triethylamine (19.36g, 0.192mol) in dichloromethane (200 ml), was added acetyl chloride (15.0 g, 0.191 mol) at 0-5 0 C. After completion of reaction, water (75ml) was added followed by layer separation. The organic layer was washed with 5% solution of sodium bicarbonate and then with water. Organic layer was distilled off under reduced pressure.
  • Example 12 Preparation of prulifloxacin Method A: Dichloromethane (1.4It) was added to prulifloxacin hydrochloride (14Og) and the mixture was cooled to 0-5 0 C. Triethylamine (284g) was added to the reaction mixture at 0-5 0 C with slow stirring for 1.5 hours. The reaction mixture was filtered, washed with demineralized water and isopropyl alcohol, and then dried to obtain 99g of title compound having purity 99.35
  • Prulifloxacin (15g, 93.73% purity by HPLC) in dimethylformamide (13.5 ml) was heated to 110 to 115 0 C for 1 hour and cooled to 20- 25 0 C. The mixture was stirred for 2 hours, filtered and washed with dimethylformamide and isopropyl alcohol to give 12.27 g of the title compound having purity 98.46% by HPLC. Above compound was further purified in dimethylformamide

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé industriellement avantageux d'élaboration d'une prulifloxacine hautement pure représentée par la formule (I) et de ses sels pharmaceutiquement admis. L'invention concerne également un nouveau procédé de purification de sel d'addition acide de prulifloxacine.
PCT/IN2009/000060 2008-01-23 2009-01-22 Procédé d'élaboration de prulifloxacine hautement pure Ceased WO2009093268A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN193/DEL/2008 2008-01-23
IN193DE2008 2008-01-23
IN90/DEL/2009 2009-01-19
IN90DE2009 2009-01-19

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WO2009093268A1 true WO2009093268A1 (fr) 2009-07-30

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093393A (zh) * 2009-12-15 2011-06-15 南京长澳医药科技有限公司 一种制备普卢利沙星及其中间产物的方法
CN102198135A (zh) * 2010-03-22 2011-09-28 北京联木医药技术发展有限公司 一种新型稳定的普卢利沙星盐酸盐在制备抗感染药物中的应用
CN102198134A (zh) * 2010-03-22 2011-09-28 北京联木医药技术发展有限公司 一种新型稳定的尤利沙星盐酸盐在制备抗感染药物中的应用
CN102718781A (zh) * 2012-05-08 2012-10-10 四川科伦药物研究有限公司 一种普卢利沙星的制备方法
CN103113392A (zh) * 2013-02-20 2013-05-22 江苏济川制药有限公司 一种普卢利沙星的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5086049A (en) * 1987-11-07 1992-02-04 Nipponshinyaku Co., Ltd. 7[4-(5 methyl-2-oxo-1,3-dioxalen-4-yl)methyl 1-piperzinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids
WO2008111016A1 (fr) * 2007-03-14 2008-09-18 Ranbaxy Laboratories Limited Procédé de préparation de prulifloxacine pure

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5086049A (en) * 1987-11-07 1992-02-04 Nipponshinyaku Co., Ltd. 7[4-(5 methyl-2-oxo-1,3-dioxalen-4-yl)methyl 1-piperzinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids
WO2008111016A1 (fr) * 2007-03-14 2008-09-18 Ranbaxy Laboratories Limited Procédé de préparation de prulifloxacine pure

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANG WEI ET AL.: "Synthesis of the key intermediate of prulifloxacin.", CHINESE JOUNAL OF PHARMACEUTICALS, vol. 37, no. 5, 2006, pages 296 - 298 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093393A (zh) * 2009-12-15 2011-06-15 南京长澳医药科技有限公司 一种制备普卢利沙星及其中间产物的方法
CN102198135A (zh) * 2010-03-22 2011-09-28 北京联木医药技术发展有限公司 一种新型稳定的普卢利沙星盐酸盐在制备抗感染药物中的应用
CN102198134A (zh) * 2010-03-22 2011-09-28 北京联木医药技术发展有限公司 一种新型稳定的尤利沙星盐酸盐在制备抗感染药物中的应用
CN102198135B (zh) * 2010-03-22 2013-05-08 北京联木医药技术发展有限公司 一种新型稳定的普卢利沙星盐酸盐在制备抗感染药物中的应用
CN102198134B (zh) * 2010-03-22 2013-06-26 北京联木医药技术发展有限公司 一种新型稳定的尤利沙星盐酸盐在制备抗感染药物中的应用
CN102718781A (zh) * 2012-05-08 2012-10-10 四川科伦药物研究有限公司 一种普卢利沙星的制备方法
CN103113392A (zh) * 2013-02-20 2013-05-22 江苏济川制药有限公司 一种普卢利沙星的制备方法
CN103113392B (zh) * 2013-02-20 2016-01-20 济川药业集团有限公司 一种普卢利沙星的制备方法

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