WO2006004561A1 - Procede de preparation de gatifloxacine et de regeneration de produits de degradation - Google Patents

Procede de preparation de gatifloxacine et de regeneration de produits de degradation Download PDF

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Publication number
WO2006004561A1
WO2006004561A1 PCT/SI2005/000017 SI2005000017W WO2006004561A1 WO 2006004561 A1 WO2006004561 A1 WO 2006004561A1 SI 2005000017 W SI2005000017 W SI 2005000017W WO 2006004561 A1 WO2006004561 A1 WO 2006004561A1
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WO
WIPO (PCT)
Prior art keywords
cyclopropyl
gatifloxacin
oxo
dihydro
carboxylic acid
Prior art date
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PCT/SI2005/000017
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English (en)
Inventor
Milos Ruzic
Milenka Relic
Zdenka Tomsic
Mirjana Mirtek
Original Assignee
Krka, Tovarna Zdravil, D.D., Novo Mesto
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Application filed by Krka, Tovarna Zdravil, D.D., Novo Mesto filed Critical Krka, Tovarna Zdravil, D.D., Novo Mesto
Publication of WO2006004561A1 publication Critical patent/WO2006004561A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the invention relates to the field of organic synthesis, namely to the field of synthesis of active pharmaceutical substances.
  • Gatifloxacin is the generic name for the sesquihydrate of the active substance ( ⁇ )-l- cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl- 1 -piperazinyl)-4-oxo- 1 ,4- dihydroquinoline-3-carboxylic acid, which, due to its extremely high activity, is used as an antibiotic for treating infections with Gram-positive and Gram-negative bacteria and, besides, is also used against anaerobic bacteria and Mycoplasmi, which otherwise show a lesser susceptibility to conventional quinolone carboxylic acids. It was discovered independently by the companies Kyorin and Sankyo/Ube, with Kyorin having the earlier priority. It is usually administered once a day, orally or intravenously, and the usual daily dose is 400 mg. The active ingredient is present in medicinal forms as a racemate with the isomers having practically the same bioavailability and activity.
  • the synthesis disclosed in claim 3 is a nucleophilic substitution of fluorine in 7- position in the compound l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo- 3-quinoline carboxylic acid by 2-methylpiperazine.
  • the purification of the compound as disclosed in this patent is carried out by column chromatography, which is not economical on an industrial scale and is difficult to carry out, the yields are relatively low and this additionally contributes to the synthesis process not being economical.
  • EP 0 805 156 a process for the preparation of gatifloxacin sesquihydrate is claimed.
  • the process is carried out in such a way that ( ⁇ )-l-cyclopropyl-6-fluoro-l,4- dihydro-7-(3-methyl-l-piperazinyl)-8-methoxy-4-oxo-3-quinoline carboxylic acid is suspended in water at a neutral pH, heated to 80-90 0 C and hot filtered.
  • the present invention solves the problem of chemical yields and of the presence of impurities in gatifloxacin synthesis and includes the HPLC analysis method for monitoring the rate of conversion of the starting compound l-cyclopropyl-6,7- difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid to gatifloxacin.
  • the following scheme shows an improved synthesis process, which includes a process of regeneration of the side product l-cyclopropyl- ⁇ jT-difluoro-l ⁇ -dihydro- ⁇ -hydroxy- 4-oxo-3-quinoline carboxylic acid.
  • the process according to the invention is based on the fact that precipitation should take place at an appropriate pH value of the solution at a determined temperature.
  • both at the same and at changed pH values of the solution besides the main product there are also precipitated side products such as l-cyclopropyl-6,7- difluoro-l,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid, ( ⁇ )-l- cyclopropyl-6-fluoro-l,4-dihydro-8-hydroxy-7-(3-methyl-l-piperazinyl)-4-oxo-3- quinoline carboxylic acid, ( ⁇ )-l-cyclopropyl-6-fluoro-l,4-dihydro-7-(3,5-dimethyl-l- piperazinyl)-8-methoxy-4-oxo-3-quinoline carboxylic acid, ( ⁇ )-l-cyclopropyl-6- fluoro-l,4-dihydro-8-
  • the problem of preparing gatifloxacin may be surprisingly improved by the principle of numerical determination of critical parameters and by including regeneration into the process of the preparation of gatifloxacin.
  • the critical parameters it has been surprisingly found that, due to the property of a markedly slow precipitation of the crude product from the reaction solution having a pH value of 9.5-11, preferably between 10.1 and 10.7, at a temperature of from 20°C to 35 0 C, it is very suitable that this precipitation takes place for more than 5 hours and preferably for 24 hours. In this way a maximum yield of the synthesis with a suitable quality of the product is achieved.
  • the product so prepared is also essentially better filterable and products of a high purity grade are isolated in a high yield.
  • the present invention relates to an improved process for the preparation of gatifloxacin sesquihydrate, characterized in that in the isolation step to a suspension or a solution of gatifoxacin in DMSO or in a mixture of DMSO and water an aqueous hydrochloric acid solution is added so that, under stirring, the pH value is maintained in the range of 9.5-11, preferably between 10.1 and 10.7, and in the temperature range between 20 0 C and 35°C, preferably between 20 0 C and 30 0 C, and the product is filtered after a prolonged precipitation time of more than 5 hours, preferably 24 hours.
  • an essential part of the invention is also the regeneration of degradation products, especially of l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-hydroxy-4-oxo-3- quinoline carboxylic acid, which is formed in large quantities, and the use of CaCl 2 , KCl, CaSO 4 or Na 2 SO 4 , preferably CaCl 2 , for improving f ⁇ lterability. It has also been found that the addition of some other salts does not improve f ⁇ lterability (e.g. MgSO 4 , K 2 CO 3 ).
  • the suitably pure l-cyclopropyl- ⁇ J-difluoro-l ⁇ -dihydro- ⁇ -hydroxy- ⁇ oxo-S- quinoline carboxylic acid so prepared is methylated to l-cyclopropyl-6,7-difluoro-l,4- dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid or its methyl ester.
  • the latter is hydrolyzed to l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid in an aqueous alkali metal carbonate solution, preferably potassium carbonate solution.
  • an aqueous alkali metal carbonate solution preferably potassium carbonate solution.
  • the process for the preparation of gatifloxacin from DMSO or a mixture of DMSO and water is characterized in that it includes the regeneration of the side product 1 - cyclopropyl-6,7-difluoro-l,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid in such a way that to the filtrate a suitable salt (preferably CaCl 2 , optionally KCl, CaSO 4 , Na 2 SO 4 ) is added and with this salt the filterability is surprisingly improved, the pH value is adjusted in the range between 3 and 4 and the precipitated degradation product is filtered and then regenerated with a suitable methylating agent to 1- cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid or 1- cyclopropyl-6,7-difluoro- 1 ,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid
  • methylating agents dimethyl sulfate, methyl halides, e.g. methyl iodide, methyl bromide, or some other methylating agent well-known to someone skilled in the art may be used.
  • dimethyl sulfate is used.
  • the methylation level may be adjusted in such a way that either l-cyclopropyl-6,7-difluoro-l,4- dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid methyl ester or 1-cyclopropyl- 6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid is isolated.
  • the process for the preparation of gatifloxacin is further characterized in that 1- cyclopropyl-6,7-difluoro-l ,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid methyl ester prepared by regeneration is hydrolyzed to l-cyclopropyl-6,7-difluoro- l,4-dihydro-4-oxo-3-quinoline carboxylic acid and the latter is in the next step reacted with 2-methylpiperazine. If the regeneration was carried out to obtain 1-cyclopropyl- 6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid, the step of the hydrolysis of the ester is not necessary.
  • the process for the preparation of gatifloxacin is characterized in that the process of purification of ( ⁇ )- 1 -cyclopropyl- ⁇ -fluoro- 1 ,4-dihydro-7-(3 -methyl- 1 -piperazinyl)-8- methoxy-4-oxo-3-quinoline carboxylic acid is carried out by recrystallization in a MeOH/water mixture in a volume ratio from 8:2 to 9.5:0.5, preferably 9: 1.
  • Gatifloxacin sesquihydrate may be prepared according to EP 0 805 156 in an aqueous solution at 85°C.
  • the present process for the preparation of gatifloxacin is characterized by a product containing together less than 0.5% of impurities and not more than 0.2% of any single impurity.
  • the content of impurities of gatifloxacin sesquihydrate so prepared is less than 0.3% and no single impurity is present in a concentration of more than 0.1%.
  • One of the preferred features of the present invention is also the HPLC analysis method, which allows monitoring the conversion of the starting compound 1- cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid to gatifloxacin.
  • the area percent method the starting compound l-cyclopropyl-6,7- difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and the impurity 1 -cyclopropyl- ⁇ -difluoro- 1 ,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid are determined. They are detected at from 220 to 254 nm since at 292 nm there is a too weak response and at lower concentrations they cannot be seen.
  • the advantage of this HPLC method over the HPCL method disclosed in WO 2004/069825 Al to TEVA Pharmaceutical Industries Ltd. resides in UV detection.
  • the starting compound l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3- quinoline carboxylic acid and the impurity l-cyclopropyl-6,7-difluoro-l,4-dihydro-8- hydroxy-4-oxo-3-quinoline carboxylic acid are detected at from 220 to 254 nm. In TEVA's case the detection is at 285 nm where the starting compound as well as the impurity exhibit a minimum absorption and therefore they cannot be correctly evaluated.
  • the present invention is illustrated by the following Examples.
  • Example 1 Synthesis of crude gatifloxacin base (( ⁇ )-l-cyclopropyl-6-fluoro-l,4- dihydro-7-(3-methyl- 1 -piperazinyl)-8-methoxy-4-oxo-3-quinoline carboxylic acid)
  • the reaction mixture was cooled to 25°C in 45 minutes (40-50 minutes).
  • the pH of the suspension was measured and adjusted to the pH value of 10.2 with a 15% HCl solution (27.5 mL of 15% HCl) and the suspension was stirred for 24 hours.
  • the pH of the suspension was periodically checked and adjusted to the desired value of 10.2 if necessary.
  • When adjusting the pH vapours were formed, which were sucked off by underpressure and led through a trap with a solution of calcium hydroxide, which irreversibly bound fluoride ions.
  • the product was then filtered over a filter MN 640 (black ribbon) and washed with methanol (165 mL). The product was thoroughly sucked off and the humidity was determined.
  • Estimated yield of the dry gatifloxacin base 52.0-54.7%.
  • the filtration lasted 3 minutes (2-5 minutes) and the washing and sucking-off lasted 90 minutes (60-120 minutes).
  • Example 2 First recrystallization of crude gatifloxacin base (( ⁇ )-l-cyclopropyl-6- fluoro- 1 ,4-dihydro-7-(3-methyl- 1 -piperazinyl)-8-methoxy-4-oxo-3-quinoline carboxylic acid)
  • Example 3 Second recrystallization of crude gatifloxacin base (( ⁇ )-l-cyclopropyl- ⁇ - fluoro- 1 ,4-dihydro-7-(3-methyl- 1 -piperazinyl)-8-methoxy-4-oxo-3-quinoline carboxylic acid)
  • the filtration was carried out as quickly as possible, the solution was returned to the reactor and again quickly heated to 71 0 C. The obtained solution was then cooled to 5 0 C in 120 minutes and stirred at this temperature for 30 minutes. It was filtered over a filter MN 640 (black ribbon) and washed with a methanol/water mixture (125 mL; 100:25, v/v). The product was thoroughly sucked off and the humidity was determined. The estimated overall yield of dry gatifloxacin base after the second recrystallization was 38.2-44.8%.
  • the filtration lasted 6 minutes (2-12 minutes) and the washing and sucking-off lasted 55 minutes (40-70 minutes).
  • Humid twice recrystallyzed gatifloxacin base was put into a reactor with a working volume of 1000 mL and demineralized water (710 mL) was added. It was stirred for 10 minutes to obtain a homogenous suspension, which was then heated in 75 minutes to 85°C. It was stirred for 30 minutes at 85°C and then cooled in 110 minutes to 25 0 C. It was stirred for 15 minutes at 25°C, the stirring intensity was enhanced just before filtering, it was filtered over a filter MN 640 (black ribbon) and washed with demineralized water (71 mL). The filtration lasted 4 minutes (2-6 minutes) and the washing and sucking-off lasted 90 minutes (20-150 minutes). The product was thoroughly sucked off and dried in an air drier at 40-50 0 C for 60-120 minutes. The yield of the complete synthesis with regard to the weight of appropriately dried gatifloxacin sesquihydrate was 37.0-42.0%.
  • a volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl 2 (approximately 33 g) was added. The mixture was cooled under stirring to 0-5 0 C (-5°C-25°C) in 30 minutes. The pH was adjusted to the value of 4 with a 15% HCl aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5 0 C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1- cyclopropyl-6,7-difluoro- 1 ,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90% was isolated.
  • Example 6 Process monitoring in gatifloxacin synthesis
  • the analysis took place on chromatographic column Inertsil ODS3, 3 ⁇ m, 150 mm x 4.0 mm I.D., at the column temperature of 4O 0 C, by gradient elution.
  • the flow was approximately 1.2 mL/min. UV detection was used, the detection wavelengths were from 220 to 254 nm and 292 nm.
  • the injection volume was 20 ⁇ L.

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  • Chemical & Material Sciences (AREA)
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Abstract

La présente invention concerne un procédé de synthèse amélioré comprenant un procédé de régénération d'un produit secondaire de gatifloxacine ainsi qu'une méthode d'analyse pour le contrôle du procédé lors de la synthèse de gatifloxacine (Formule I).
PCT/SI2005/000017 2004-06-30 2005-06-30 Procede de preparation de gatifloxacine et de regeneration de produits de degradation WO2006004561A1 (fr)

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Application Number Priority Date Filing Date Title
SIP-200400195 2004-06-30
SI200400195A SI21799A (sl) 2004-06-30 2004-06-30 Postopek za pripravo gatifloksacina in regeneracija razpadnih produktov

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102757419A (zh) * 2012-08-08 2012-10-31 四川百利药业有限责任公司 一种加替沙星的纯化方法
CN110903045A (zh) * 2019-12-09 2020-03-24 汪文杰 一种工业废渣仿天然石膏及其制备方法和应用
CN110988167A (zh) * 2019-12-06 2020-04-10 珠海润都制药股份有限公司 一种加替环合酯中基因毒杂质的检测方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230295A2 (fr) * 1986-01-21 1987-07-29 Kyorin Pharmaceutical Co., Ltd. Acide 8-alkoxyquinoléine et ses sels avec une toxicité sélective excellente et un procédé pour leur préparation
EP0241206A2 (fr) * 1986-03-31 1987-10-14 Sankyo Company Limited Dérivés d'acide quinoléine-3-carboxylique, leur préparation et utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0230295A2 (fr) * 1986-01-21 1987-07-29 Kyorin Pharmaceutical Co., Ltd. Acide 8-alkoxyquinoléine et ses sels avec une toxicité sélective excellente et un procédé pour leur préparation
EP0241206A2 (fr) * 1986-03-31 1987-10-14 Sankyo Company Limited Dérivés d'acide quinoléine-3-carboxylique, leur préparation et utilisation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102757419A (zh) * 2012-08-08 2012-10-31 四川百利药业有限责任公司 一种加替沙星的纯化方法
CN110988167A (zh) * 2019-12-06 2020-04-10 珠海润都制药股份有限公司 一种加替环合酯中基因毒杂质的检测方法
CN110903045A (zh) * 2019-12-09 2020-03-24 汪文杰 一种工业废渣仿天然石膏及其制备方法和应用
CN110903045B (zh) * 2019-12-09 2021-10-19 汪文杰 一种工业废渣仿天然石膏及其制备方法和应用

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