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Preparation process of levofloxacin hemihydrate

A technology of levofloxacin and a preparation process, which is applied in the field of preparation of levofloxacin hemihydrate, can solve the problems of unfavorable quality and yield of finished levofloxacin hemihydrate, affecting the normal function of a wastewater treatment station, and high requirements for a vacuum equipment system, so as to maintain production order. , The effect of complete crystal form and short drying time

Active Publication Date: 2012-03-14
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Third, other patents related to the preparation of levofloxacin hemihydrate are classified according to their common characteristics: one is heavy odor, such as dimethyl sulfoxide (disproportionation reaction produces methyl sulfide, and then decomposes to produce malodorous methyl mercaptan), isopropyl Alcohol, acetonitrile and methyl ethyl ketone, etc.; second, high boiling point, such as dimethyl sulfoxide, dimethyl acetamide, etc., which consume a lot of energy during recovery, and have high requirements for vacuum equipment and systems; third, use dichloromethane and chloroform And dimethyl sulfoxide, etc., when discharged into wastewater, not only are microorganisms difficult to degrade, but also inhibit or even poison the growth of microorganisms, affecting the normal functions of wastewater treatment stations; the fourth is that the crystallization solvent is expensive such as tetrahydrofuran; the fifth is Use polarity too weak (such as chloroform, dichloromethane, 1,2-dichloroethane, n-hexane, cyclohexane, toluene, ethyl acetate and methyl acetate) and polarity too strong (such as dimethyl methylene sulfone and dimethylacetamide) organic solvent to crystallize and purify levofloxacin crude product, which is unfavorable for the improvement of levofloxacin hemihydrate finished product quality and yield

Method used

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  • Preparation process of levofloxacin hemihydrate
  • Preparation process of levofloxacin hemihydrate
  • Preparation process of levofloxacin hemihydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1 Ethylene glycol mono-tert-butyl ether: water (190: 20, w / w)

[0032] 25 grams of levofloxacin (0.0889 moles), 20 grams of N-methylpiperazine (0.1997 moles) were dropped into 250 milliliters of reaction flasks equipped with a reflux device, then 40 grams of dimethyl sulfoxide was added, at 110 ℃ heat preservation reaction for 7 hours. After the reaction is complete, recover the solvent under reduced pressure to dryness, add 150 ml of water to the residue in the bottle, stir at 80-85°C until the system is basically clear, add 0.5 g of activated carbon, keep warm for 0.5 hours to decolorize, filter, and add 250 ml of water to the filtrate Chloroform, stirring and extracting for 1 hour, adjusting the pH value of the water layer to 7.0-8.0 with liquid alkali, stirring and washing the extracted oil layer with 100 ml of water for 15 minutes, standing still for 1 hour, separating the organic layer of chloroform, heating and recovering to dryness, to obtain Crude l...

Embodiment 2

[0033] Embodiment 2 ethylene glycol monoethyl ether: water (110: 9, w / w)

[0034]25 grams of levofloxacin (0.0889 moles), 20 grams of N-methylpiperazine (0.1997 moles) were dropped into 250 milliliters of reaction flasks equipped with a reflux device, then 40 grams of dimethyl sulfoxide was added, at 110 ℃ heat preservation reaction for 7 hours. After the reaction is complete, recover the solvent under reduced pressure to dryness, add 150 ml of water to the residue in the bottle, stir at 80-85°C until the system is basically clear, add 0.5 g of activated carbon, keep warm for 0.5 hours to decolorize, filter, and add 250 ml of water to the filtrate Chloroform, stirring and extracting for 1 hour, adjusting the pH value of the water layer to 7.0-8.0 with liquid alkali, stirring and washing the extracted oil layer with 100 ml of water for 15 minutes, standing still for 1 hour, separating the organic layer of chloroform, heating and recovering to dryness, to obtain Crude levofloxa...

Embodiment 3

[0035] Example 3 Ethylene glycol tert-ethyl ether: ethylene glycol monoethyl ether: water (70:50:10, w / w / w)

[0036] 25 grams of levofloxacin (0.0889 moles), 20 grams of N-methylpiperazine (0.1997 moles) were dropped into 250 milliliters of reaction flasks equipped with a reflux device, then 40 grams of dimethyl sulfoxide was added, at 110 ℃ heat preservation reaction for 7 hours. After the reaction is complete, recover the solvent under reduced pressure to dryness, add 150 ml of water to the residue in the bottle, stir at 80-85°C until the system is basically clear, add 0.5 g of activated carbon, keep warm for 0.5 hours to decolorize, filter, and add 250 ml of water to the filtrate Chloroform, stirring and extracting for 1 hour, adjusting the pH value of the water layer to 7.0-8.0 with liquid alkali, stirring and washing the extracted oil layer with 100 ml of water for 15 minutes, standing still for 1 hour, separating the organic layer of chloroform, heating and recovering to...

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Abstract

The invention discloses a preparation process of levofloxacin hemihydrate. One existing method adopts organic solvents with low polarity or high polarity to crystallize and purify crude levofloxacin, which can not facilitate the improvement of the quality and yield of the finished levofloxacin hemihydrate. The invention adopts the following technical scheme that crude levofloxacin is generated through piperazine condensation reaction of levofloxacin carboxylic acid and N-methyl piperazine, and is characterized in that acicular levofloxacin hemihydrate is prepared through dissolving the crude levofloxacin in a mixed solvent formed by a single or composite ethylene glycol monoalkyl ether homologue HO-CH2CH2-OR and water, and then carrying out treatment. The solvent applied in the invention has proper polarity. Therefore, the yield of the prepared levofloxacin hemihydrate is equivalent to the yield of the ethanol process. Moreover, under the identical vacuum degree, the wet levofloxacin hemihydrate produced in the invention has the advantages of lower drying temperature and shorter drying period compared with the wet levofloxacin hemihydrate produced in the ethanol process.

Description

technical field [0001] The invention relates to a preparation process of levofloxacin hemihydrate. Background technique [0002] Levofloxacin (Levofloxacin) is a high-efficiency, broad-spectrum, low-toxic antibacterial fluoroquinolone drug developed by Japan's Daiichi Pharmaceutical Company. Its chemical name is (-)-(S)-9-fluoro-2,3-dihydro-3 -Methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3,-de]-[1,4]benzoxazine-6- Carboxylic acid (CAS Registry No. 100986-85-4). Levofloxacin includes anhydrous levofloxacin and levofloxacin hydrate, and anhydrous levofloxacin has polymorphism, and its crystal forms include type A, type B, type C, type F, type G and type H, while hydrate of levofloxacin includes levofloxacin hemihydrate and The crystal form of levofloxacin monohydrate belongs to the pseudopolymorphic form. The commonly used stable crystal form of levofloxacin is levofloxacin hemihydrate, and its appearance is light yellow needle-like crystalline powder, and its str...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/06
Inventor 张永塘钱沛良
Owner ZHEJIANG JINGXIN PHARMA
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