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Preparation method for moxifloxacin and hydrochloride thereof

A technology of hydrochloride and boric acid, applied in the field of medicinal chemistry, can solve the problems such as the increase of impurities in the condensation reaction liquid, difficult drying, and chelation group shedding, so as to improve the yield and selectivity, ensure safety, and achieve zero discharge. Effect

Active Publication Date: 2013-04-03
ZHEJIANG NHU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The process for preparing moxifloxacin hydrochloride described above has the following defects: None of them mentioned the thermal effect in the preparation process of the chelating agent. In fact, there is a great thermal effect in the process of preparing the chelating agent, and its reaction initiation temperature is relatively high. There is a sudden rise in temperature in the one-pot method of feeding, which may cause the material to rush and explode. Potential safety hazard; In the process of chelate separation, ice water is used for crystallization to separate the chelate, resulting in a large amount of waste water and drying The water in the process chelate is difficult to dry completely, and some chelate will be hydrolyzed during the drying process, causing the chelating group to fall off, thus affecting the quality of the chelate, which is reflected in the decrease in the yield during the condensation reaction , the condensation reaction liquid impurities increase

Method used

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  • Preparation method for moxifloxacin and hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (a) Synthesis of borane chelates

[0034] Weigh 73.6g of acetic anhydride and add it to a 250ml four-neck flask, stir to raise the temperature to 90°C, add 13.6g of boric acid continuously, control the temperature of the reaction system at 90-95°C, keep the temperature at 90°C for 2 hours after the addition, cool down to 80°C, add 64.6 g mother nucleus (1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester) was stirred and heated to 105 °C, After 2 hours of reaction, the temperature was lowered to 60°C, and the reaction solution was slowly poured into 600ml of absolute ethanol, stirred to precipitate solids, filtered, and the filter cake was washed with 120ml of ice ethanol, dried and weighed: 80.7g, yield 95.5%.

[0035] (b) Synthesis of borane condensates

[0036] Add 80.7g of the chelate compound prepared in the previous step into a 500ml three-necked flask, then add 39.5g of potassium carbonate and 300ml of acetonitrile, stir...

Embodiment 2

[0042] (a) preparation of borane chelate

[0043] Weigh 73.6g of acetic anhydride and add it to a 250ml four-neck flask, stir to raise the temperature to 90°C, add 13.6g of boric acid in batches, control the temperature of the reaction system to stabilize at 90-100°C, keep the temperature at 90°C for 3 hours after the addition, and cool down after the reaction To 70°C, add 64.6g mother core, stir and raise the temperature to 105°C, react for 1.5h and cool down to 50°C, slowly pour the reaction solution into 600ml of isopropanol and vigorously stir to precipitate a solid, suction filter, filter cake with 120ml of ice isopropanol Alcohol washing, drying and weighing: 81.0g, yield 95.7%.

[0044] (b) Synthesis of borane condensates

[0045] Add 81.0g of the chelate compound prepared in the previous step into a 500ml three-necked flask, then add 52.8g of potassium carbonate and 300ml of acetonitrile, stir at 30°C, weigh 26.0g of the side chain, dilute with 50ml of acetonitrile an...

Embodiment 3

[0051] (a) Synthesis of borane chelates

[0052] Weigh 73.6g of acetic anhydride and add it to a 250ml four-neck flask, stir and heat up to 90°C, add 13.6g of boric acid in batches to ensure that the temperature is stable at 95-100°C, keep warm at 90°C for 2 hours after the addition, and cool down to 75°C after the reaction is complete. ℃, add 64.6g mother core and stir to raise the temperature to 110℃, react for 1h and cool down to 70℃, slowly pour the reaction solution into 600ml ethyl acetate and vigorously stir to precipitate solid, filter, wash the filter cake with 120ml glacial ethyl acetate, dry Dry weight: 80.0g. Yield 94.6%.

[0053] (b) Synthesis of borane condensates

[0054] Add 80.0g of the chelate compound prepared in the previous step into a 500ml three-necked flask, then add 78.3g of potassium carbonate and 300ml of acetonitrile, stir at 45°C, weigh 25.7g of the side chain and dilute it with 50ml of acetonitrile, and add it dropwise to the three-necked flask ...

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Abstract

The invention discloses a preparation method for moxifloxacin and hydrochloride thereof. A conventional process has the following defects that a one-pot material addition process has safety hidden troubles such as bumping materials and explosion which are caused by suddenly increased temperature, and a great amount of wastewater is produced because ice water is employed in a separation process of a borane chelate to perform crystallization process to separate the chelate. The method provided by the invention is characterized in that in a chelating reaction, solid boric acid is added in acetic anhydride in a continuous feeding manner to form a chelating agent through reaction, the chelating agent reacts with 1-cyclopropyl-6,7-difluoro-8-methoxyl-1,4-dihydro-4-oxo quinoline-3-ethyl carboxylate to prepare the borane chelate, and the borane chelate is purified through crystallization and separation by using an organic solvent. The preparation method is simple in process, mild in conditions and safe in the chelating reaction process and solves the problem of the great amount of the wastewater in a preparation process of the chelate. The method has high yield, good selectivity and high product purity and is suitable for industrialized production.

Description

[0001] technical field [0002] The invention relates to the field of medicinal chemistry, in particular to a safe, environmentally friendly and highly selective method for preparing moxifloxacin and its hydrochloride. Background technique [0003] [0004] Moxifloxacin hydrochloride: 1-cyclopropyl-6-fluoro-7-([S,S]-2,8-diazacyclo[4.3.0]-non-8-yl)-8-methoxy -4-Oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride is a broad-spectrum and 8-methoxyfluoroquinolone antibacterial drug with antibacterial activity. As an antibacterial drug for humans and animals, it can effectively treat infections caused by a variety of bacteria, showing good activity against Gram-positive bacteria and atypical pathogens (such as mycoplasma, chlamydia, legionella and anaerobic bacteria, etc.), It has better antibacterial activity than sparfloxacin and ciprofloxacin. The structural formula is as follows: [0005] EP0550903 discloses the use of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07D471/04
Inventor 彭俊华陈婷婷车来滨王晓军刘向成张建新
Owner ZHEJIANG NHU CO LTD
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