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Synthesizing method of ofloxacin and levofloxacin

A technology of levofloxacin and levofloxacin carboxylic acid, which is applied in the chemical field, can solve the problems of many impurities in related substances, unfriendly production environment, and poor reaction selectivity, and achieve the effects of good product quality, improved product appearance, and mild reaction conditions

Inactive Publication Date: 2018-11-27
HUAXIASHENGSHENG PHARMA BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of this process uses DMF, DMSO, or N-methylpiperazine as a solvent for high-temperature reaction, which generates more impurities in related substances, especially poor reaction selectivity, which easily leads to the substitution of 9-position fluorine atoms to generate 9-position N-methyl The impurity substituted by piperazine is particularly difficult to remove; the high temperature reaction also causes poor appearance of the product (requires multiple times of activated carbon decolorization); in addition, the reaction uses a large amount of triethylamine or pyridine, which is not friendly to the production environment and is harmful to the human body

Method used

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  • Synthesizing method of ofloxacin and levofloxacin
  • Synthesizing method of ofloxacin and levofloxacin
  • Synthesizing method of ofloxacin and levofloxacin

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Embodiment 1

[0021] The preparation of embodiment 1 intermediate 1A

[0022] Throw 4.8g (77.6mmol) of boric acid and 33g (324mmol) of acetic anhydride into a 250ml flask, under nitrogen protection, stir and react at 75°C for 45min; raise the temperature of the system to 115°C and continue the reaction for 1h;

[0023] After the reaction of the above-mentioned borate ester system was completed, the temperature was lowered to 70°C, and 18g (64mmol) ofloxacin carboxylic acid was thrown into the flask; the temperature was raised to 90°C, and the reaction was carried out for 3h; the reaction was monitored by TLC (the developing agent was DCM: MeOH=20 :1). After the reaction, the system was poured into 200ml of 40% methanol-water mixed solvent (10°C), crystallized and stirred for 0.5h. Suction filtration, the filter cake was rinsed with 40ml of methanol. After drying to constant weight, 21 g of intermediate 1A was obtained with a yield of 80%.

Embodiment 2

[0024] The preparation of embodiment 2 intermediate 1A

[0025] Throw 4.8g (77.6mmol) of boric acid and 60g (461.5mmol) of propionic anhydride into a 250ml flask, under the protection of nitrogen, stir and react at 85°C for 30min; raise the temperature of the system to 115°C and continue the reaction for 2h;

[0026] After the reaction of the above-mentioned borate ester system was completed, the temperature was lowered to 80°C, and 16g (51.8mmol) ofloxacin ethyl carboxylate was thrown into the flask; the temperature was raised to reflux at 105°C, and the reaction was carried out for 1.5h; the reaction was monitored by TLC (developing agent was DCM : MeOH=20:1). After the reaction, pour the system into 200ml (0-10°C) 50% ethanol water, crystallize and stir for 0.5h. Suction filtration, the filter cake was rinsed with 40ml ethanol. After drying to constant weight, 20 g of intermediate 1A was obtained with a yield of 88%.

Embodiment 3

[0027] The preparation of embodiment 3 intermediate 1

[0028] Throw 4.8g (77.6mmol) of boric acid and 122.6g (776mmol) of butyric anhydride into a 250ml flask, under the protection of nitrogen, stir and react at 90°C for 1h; raise the temperature of the system to 120°C and continue the reaction for 2h;

[0029] After the reaction of the above-mentioned borate ester system was completed, the temperature was lowered to 75°C, and 13g (44mmol) of levofloxacin carboxylate methyl ester was thrown into the flask; the temperature was raised to 115°C, and the reaction was carried out for 2 hours; the reaction was monitored by TLC (the developing agent was DCM:MeOH=20:1 ). After the reaction, pour the system into 200ml (0-10°C) 30% benzyl alcohol water, crystallize and stir for 0.5h. Suction filtration, the filter cake was rinsed with 40ml ethanol. After drying to constant weight, 20 g of intermediate 1 was obtained, and the yield was 100%.

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Abstract

The invention relates to a novel method for preparing ofloxacin and levofloxacin. The method includes: using ofloxacin carboxylic acid (ester) or levofloxacin carboxylic acid (ester) as the raw material, allowing the ofloxacin carboxylic acid (ester) or levofloxacin carboxylic acid (ester) to have reaction with borate to generate intermediate 1A or intermediate 1, allowing the intermediate 1A or intermediate 1 to have reaction with N- methyl piperazine to generated intermediate 2A or intermediate 2, hydrolyzing the intermediate 2A or intermediate 2 under an acid condition to obtain levofloxacin / ofloxacin salt, and freeing and extracting the levofloxacin / ofloxacin salt under a corresponding alkaline condition to obtain levofloxacin / ofloxacin or hydrate thereof. The method has the advantagesthat the initial materials and reagents used by the method are easy to obtain, the method is simple to operate, mild in reaction conditions, high in yield, low in cost and suitable for industrial production, and the purity of the levofloxacin / ofloxacin or hydrate thereof prepared by the method reaches up to 99.9%.

Description

technical field [0001] The invention belongs to the field of chemistry, in particular to a method for synthesizing levofloxacin and ofloxacin. Background technique [0002] Levofloxacin and ofloxacin are quinolone drugs, with high efficiency, low toxicity and broad-spectrum antibacterial properties, they have achieved great success in clinical anti-infection treatment. Their structural formulas are as follows: [0003] [0004] Currently, there are three methods for the synthesis of levofloxacin reported in the literature: (1) enzymatic resolution (K, Sakano, Agina Biol. Chem. : 1987, 51, 1265) and high-pressure liquid phase resolution (EP206283); Tetrafluorobenzoic acid was used as the starting material to prepare levofloxacin (US4777253); (3) Trifluoronitrobenzene was used as raw material to prepare levofloxacin (EP36841 and EP273399). At present, method 2 is mostly used in industrial synthesis methods, and there are many domestic patent reports, such as CN200410155139...

Claims

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Application Information

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IPC IPC(8): C07D498/06
CPCC07D498/06
Inventor 吕新安张同波周受辛
Owner HUAXIASHENGSHENG PHARMA BEIJING CO LTD
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