WO2005123746A1 - Techniques de préparation de levofloxacine et d'ofloxacine - Google Patents

Techniques de préparation de levofloxacine et d'ofloxacine Download PDF

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Publication number
WO2005123746A1
WO2005123746A1 PCT/CN2004/000954 CN2004000954W WO2005123746A1 WO 2005123746 A1 WO2005123746 A1 WO 2005123746A1 CN 2004000954 W CN2004000954 W CN 2004000954W WO 2005123746 A1 WO2005123746 A1 WO 2005123746A1
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WO
WIPO (PCT)
Prior art keywords
reaction
added
ofloxacin
levofloxacin
solvent
Prior art date
Application number
PCT/CN2004/000954
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English (en)
Chinese (zh)
Inventor
Weidong Ye
Weidong Zhang
Zhuhong Yang
Original Assignee
Zhe Jiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory
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
Application filed by Zhe Jiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory filed Critical Zhe Jiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory
Publication of WO2005123746A1 publication Critical patent/WO2005123746A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Definitions

  • the invention belongs to the field of chemistry, and specifically relates to a method for preparing levofloxacin and ofloxacin.
  • Resolution method including high-pressure liquid phase resolution EP206283 (1986) and enzyme resolution (K, Sakano, Agina Biol. Chem .: 1987, 51, 1265) This method is not suitable for industrial production;
  • Levofloxacin UP4777253 (1988) was prepared from tetrafluorobenzoic acid in 7 steps.
  • the synthetic route in this paragraph has the following disadvantages: 1) Due to the different solvents in each step of the reaction (N, N-dimethylformamide or dimethylsulfoxide and water are generally used), the same reaction cannot be performed Continuous operation in the reactor requires four-step operation, large solid transfer volume, dust, and difficult to ensure a satisfactory recovery and application rate of the solvent; 2) In order to meet the two loops at the same time, the reaction is not easy to carry out, making the The temperature is 120 ⁇ 150 ° C and the time is 4 ⁇ 5hr.
  • the reaction time at high temperature is long and side reactions are easy to occur. Product quality and appearance will be affected; 3) A large amount of glacial acetic acid is required, the production cost is large, the hydrolysis reaction time is 5 to 6 hours, the dissolution is difficult, the hydrolysis is not easy to complete, the separation after the reaction is difficult, and the impact on the environment is large.
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the prior art mentioned above, provide a process route for quickly synthesizing levofloxacin and ofloxacin from the compound (V), shorten the reaction time, and simplify the process.
  • the preparation method of levofloxacin is a synthesis method using tetrafluorobenzoic acid as a raw material, which is characterized in that: a) a solvent is added to the crude compound (V), and L is added dropwise by freezing; -Aminopropanol, then incubate until the conversion is complete, add a base, and react at 50-9CTC. After the reaction is complete, add N-methylpiperazine to the mother liquor, stir the reaction at 55 ⁇ 95 ° C for 1-3 hours and reduce the pressure. N-methylpiperazine was recovered, and the reaction temperature was raised to 120-130 ° C, and the temperature was maintained for 0.1 to 1.0 hours. The reaction was ended.
  • the preparation method of ofloxacin is a synthesis method using tetrafluorobenzoic acid as a raw material, which is characterized in that: a) a solvent is added to the crude compound (V), DL-aminopropanol is added dropwise by freezing, and then the temperature is maintained until the conversion is complete Then, add a base and react at 50-90 ° F. After the reaction is completed, add N-methylpiperazine to the mother liquor, stir the reaction at 70-80 ° C for 1-3 hours, and then recover the N-methylpiperazine under reduced pressure. Reaction temperature The temperature was raised to 120_130 ° C, and the temperature was maintained for 0.1 to 1.1 hours. The reaction was terminated.
  • a first ring is firstly placed at a low temperature (60 to 70 ° C), then a methylpiperazinyl group is added, then a second ring is placed at a high temperature (120-13CTC), and finally hydrolyzed.
  • the above-mentioned stepwise ring formation method (which is totally different from the prior art synchronous ring formation method) is adopted, that is, two rings are formed at two different temperatures, the present invention makes the reaction time in the high temperature stage short (0. 1-1 0 hours), most of the reaction time is in the low temperature stage of 60 ⁇ 80 ° C, and the product quality and appearance have been significantly improved.
  • the three reaction processes can be completed in one step in the same reactor, so the compound (V)
  • the preparation of the final product is actually a two-step reaction, which shortens the reaction time.
  • the solvent can be recovered and applied centrally, which reduces the production cost.
  • the hydrolysis is in a fully dissolved state Completed, easier to hydrolyze completely, greatly shortening the reaction time.
  • the solvent is isoamyl alcohol, xylene, dioxane, N, N-dimethylformamide (DMF) or dimethyl sulfoxide ( DMS0), different solvents have an effect on the yield of the reaction.
  • the base in step a is potassium carbonate, sodium bicarbonate, triethylamine or pyridine.
  • the present invention provides a method for preparing levofloxacin and ofloxacin, which has the following beneficial effects: 1) By controlling the reaction temperature, the first ring is added first, then the methylpiperazinyl group is added, and then The second ring is finally hydrolyzed, and the reaction is easy to perform, which shortens the high temperature time and the entire reaction time; 2) The same solvent is used in the reaction process, and the compound (V) can be prepared in the same reactor as the compound (IX) or (X) The inner step is completed, the operation is convenient, the reaction steps are shortened, and the process is simplified; 3) it is convenient to perform centralized recovery of the solvent and apply it, and it has a good recovery and application rate, which reduces the production cost; 4) water The solution is fast and complete; 5) Due to the short high temperature time, the product quality and appearance have been significantly improved.
  • levofloxacin (I) In a 500ml three-necked flask, 50.5g of the compound (IX) obtained in step a, 150ml of water, and 50ml of concentrated hydrochloric acid were sequentially put in and stirred under reflux for half an hour, and the solid was completely dissolved. The reaction is over. After the solution was slightly cold, 150 ml of water and 30. OgNaOH lye were added to adjust the pH to 7.0, and then extracted with 50 ml / times x 5 times of chloroform, and the concentrated chloroform layers were combined to obtain 38.5 g of levofloxacin, Yield: 94.2%.
  • Example 2 3% ⁇ The difference from Example 1 is that using isoamyl alcohol as a solvent, the base added is sodium bicarbonate, the yield obtained in step a is 45.7%, and the yield obtained in step b is 92.3%.
  • Example 3 The difference from Example 3 is that xylene was used as the solvent, the base added was pyridine, the yield obtained in step a was 23.7%, and the yield obtained in step b was 94.6%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne des techniques de préparation d'agents anti-infectieux, de levofloxacine et d'ofloxacine. Ces techniques utilisent des acides tétrafluorobenzoïques et une matière brute, et se caractérisent en ce qu'un solvant est ajouté à l'éthyl-2 -(2,3,4,5­tétrafluoro-benzoyl)-3-(1-hydroxyméthylethamino)acrylate brut et le L­-aminopropanol ou DL-aminopropanol de congélation est ajouté goutte à goutte, puis on maintient la température des réactifs de façon à obtenir une réaction complète. À la solution résultante une base est ajoutée et le mélange de réaction réagit à une température comprise entre 50 et 90 degrés Celsius pendant qu'on mélange ces composés, après la fin de la cyclisation. On ajoute N-méthylpiperazine dans la solution mère et on laisse réagir pendant une à trois heures à une température comprise entre 55 et 95 °C, puis on retrouve N-méthylpiperazine à une pression réduite. Puis le mélange résultant est chauffé à une température comprise entre 120 et 130°C et maintenu à cette température pendant 0,1 à une heure. Après suspension de la réaction, la solution de réaction est versée dans l'eau, mélangée, refroidie et filtrée. À ce filtrat sont ajoutés de l'eau et de l'acide et le mélange de réaction est mélangé à la température de reflux jusqu'à ce que l'hydrolyse soit terminée. Ensuite, la solution est réglée à un pH de 7,0 avec une solution basique et extraite avec un réactif d'extraction, puis on concentre la couche extraite de façon à obtenir le produit objectif. Ces techniques raccourcissent le processus de réaction, raccourcissent la procédure et facilitent le recueil et la récupération de solvant et le recyclage.
PCT/CN2004/000954 2004-06-22 2004-08-16 Techniques de préparation de levofloxacine et d'ofloxacine WO2005123746A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410155139.X 2004-06-22
CNB200410155139XA CN100412075C (zh) 2004-06-22 2004-06-22 左旋氧氟沙星和氧氟沙星的制备方法

Publications (1)

Publication Number Publication Date
WO2005123746A1 true WO2005123746A1 (fr) 2005-12-29

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Application Number Title Priority Date Filing Date
PCT/CN2004/000954 WO2005123746A1 (fr) 2004-06-22 2004-08-16 Techniques de préparation de levofloxacine et d'ofloxacine

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CN (1) CN100412075C (fr)
WO (1) WO2005123746A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101514208B (zh) * 2008-10-17 2011-03-16 浙江京新药业股份有限公司 氧氟沙星的绿色合成工艺
CN114507242A (zh) * 2022-01-26 2022-05-17 上虞京新药业有限公司 高光学纯度左氧氟沙星的制备方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101648960B (zh) * 2009-09-04 2011-08-10 诚达药业股份有限公司 氧氟沙星的制备方法
CN103113388B (zh) * 2013-02-01 2016-02-10 浙江国邦药业有限公司 一种左氧氟沙星的制备方法
CN105198904B (zh) * 2014-06-25 2017-08-15 上虞京新药业有限公司 左氧氟沙星及氧氟沙星的制备方法
CN107677735A (zh) * 2016-08-02 2018-02-09 上海朴颐化学科技有限公司 一种(s)‑2‑氨基丙醇的hplc分析方法
CN112552261A (zh) * 2019-09-26 2021-03-26 宜昌东阳光长江药业股份有限公司 左氧氟沙星及其中间体的制备方法

Citations (4)

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Publication number Priority date Publication date Assignee Title
JPS62215591A (ja) * 1986-03-14 1987-09-22 Dainippon Pharmaceut Co Ltd ピリドベンズオキサジン誘導体の製造法およびその中間体
US4777253A (en) * 1986-04-25 1988-10-11 Abbott Laboratories Process for preparation of racemate and optically active ofloxacin and related derivatives
US5639886A (en) * 1993-12-10 1997-06-17 Bayer Aktiengesellschaft One-pot process for the preparation of 3-quinolonecarboxylic acid derivatives
JP2001031654A (ja) * 1999-07-22 2001-02-06 Fuji Yakuhin:Kk 新規なキノリンカルボン酸誘導体及びその製法と使用方法

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JPS5746986A (en) * 1980-09-02 1982-03-17 Dai Ichi Seiyaku Co Ltd Pyrido(1,2,3-de)(1,4)benzoxazine derivative
IL161164A0 (en) * 2001-10-03 2004-08-31 Teva Pharma Preparation of levofloxacin and forms thereof

Patent Citations (4)

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JPS62215591A (ja) * 1986-03-14 1987-09-22 Dainippon Pharmaceut Co Ltd ピリドベンズオキサジン誘導体の製造法およびその中間体
US4777253A (en) * 1986-04-25 1988-10-11 Abbott Laboratories Process for preparation of racemate and optically active ofloxacin and related derivatives
US5639886A (en) * 1993-12-10 1997-06-17 Bayer Aktiengesellschaft One-pot process for the preparation of 3-quinolonecarboxylic acid derivatives
JP2001031654A (ja) * 1999-07-22 2001-02-06 Fuji Yakuhin:Kk 新規なキノリンカルボン酸誘導体及びその製法と使用方法

Non-Patent Citations (5)

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Title
QI J. ET AL: "SYNTHESIS OF OFLOXACIN AND ITS OPTICAL ISOMERS", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 29, no. 6, 1998, pages 243 - 245 *
YANG Y. ET AL: "A NEW PRACTICAL ROUTE TO STEREOSPECIFIC SYNTHESIS OF (S)-(-)-OFLOXACIN", ACTA PHARMACEUTICAL SINICA, vol. 33, no. 11, 1998, pages 828 - 831 *
YANG Y. ET AL: "STUDIES ON SYNTHESIS ANTIBACTERIAL AND ANTITUMOR ACTIVITY OF (S)-(-)-OFLOXACIN ANALOGUES", ACTA PHARMACEUTICA SINICA, vol. 34, no. 2, 1999, pages 119 - 124 *
YANG Y. ET AL: "SYNTHESIS AND STRUCTURE ACTIVITIES RELATIONSHIP OF LEVOFLOXACIN ANALOGUES", ACTA PHARMACEUTICA SINICA, vol. 34, no. 2, 1999, pages 197 - 202 *
YANG Y.-S. ET AL: "A practical stereoselective synthesis of (S)-(-)-ofloxacin", CHINESE JOURNAL OF CHEMISTRY, vol. 17, no. 5, 1999, pages 539 - 544 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101514208B (zh) * 2008-10-17 2011-03-16 浙江京新药业股份有限公司 氧氟沙星的绿色合成工艺
CN114507242A (zh) * 2022-01-26 2022-05-17 上虞京新药业有限公司 高光学纯度左氧氟沙星的制备方法

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CN1594320A (zh) 2005-03-16
CN100412075C (zh) 2008-08-20

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