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Preparation method of ciprofloxacin key intermediate

A technology for ciprofloxacin and intermediates, which is applied in the field of preparation of key intermediates of ciprofloxacin, can solve the problems of high cost, environmental protection pressure, high toxicity, low price, etc., and achieves avoiding three waste treatment costs and low production costs. , the effect of reducing the three wastes

Active Publication Date: 2022-03-01
SHANDONG GUOBANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the dimethyl sulfate used in the reaction process is a toxic control product, which is highly toxic and harmful, while N,N-dimethylformamide has a strong smell during use, and the price is relatively high. Faced with greater costs and environmental protection pressure

Method used

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  • Preparation method of ciprofloxacin key intermediate
  • Preparation method of ciprofloxacin key intermediate
  • Preparation method of ciprofloxacin key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] (1) Carbonylation reaction: Take a 250ml autoclave, add 20g of methyl 2,4-dichloro-5-fluorobenzoylacetate, 4.16g of solid sodium methoxide (2,4-dichloro-5-fluorobenzoyl 1.02 equivalents of methyl acetoacetate), 100 g of cyclohexane (the amount of solvent used is 5 times that of methyl 2,4-dichloro-5-fluorobenzoylacetate), and the kettle was closed. Use nitrogen 0.5MPa to replace the air in the kettle three times, use carbon monoxide to replace the nitrogen in the kettle three times, and fill the carbon monoxide pressure to 3.0MPa, raise the temperature in the water bath to the temperature in the kettle to 50°C, always pay attention to the pressure in the kettle and keep the pressure at 3.0MPa for 3 hours. . After the reaction was completed, cool to room temperature to carefully discharge carbon monoxide, cool to 10°C, filter with suction, rinse with 20g of methanol, and dry at 40°C to obtain 23.01g of (1Z)-3-(2,4-dichloro-5-fluorophenyl )-2-(methoxycarbonyl)-3-oxoprop-...

Embodiment 2

[0026] (1) Carbonylation reaction: take a 250ml autoclave, add 20g of methyl 2,4-dichloro-5-fluorobenzoylacetate, 4.24g of sodium methoxide solid (2,4-dichloro-5-fluorobenzoyl 1.04 equivalents of methyl acetoacetate), 100 g of cyclohexane (the amount of solvent used is 5 times that of methyl 2,4-dichloro-5-fluorobenzoylacetate), and the kettle was closed. Use nitrogen 0.5MPa to replace the air in the kettle three times, use carbon monoxide to replace the nitrogen in the kettle three times, and fill the carbon monoxide pressure to 3.0MPa, raise the temperature in the water bath to the temperature in the kettle to 50°C, always pay attention to the pressure in the kettle and keep the pressure at 3.0MPa for 3 hours. . After the reaction was completed, cool to room temperature to carefully discharge carbon monoxide, cool to 10°C, filter with suction, rinse with 20g of methanol, and dry at 40°C to obtain 23.09g of (1Z)-3-(2,4-dichloro-5-fluorophenyl )-2-(methoxycarbonyl)-3-oxoprop-...

Embodiment 3

[0030] (1) Carbonylation reaction: Take a 250ml autoclave, add 20g of methyl 2,4-dichloro-5-fluorobenzoylacetate, 4.16g of solid sodium methoxide (2,4-dichloro-5-fluorobenzoyl 1.02 equivalents of methyl acetoacetate), 100 g of cyclohexane (the amount of solvent used is 5 times that of methyl 2,4-dichloro-5-fluorobenzoylacetate), and the kettle was closed. Use nitrogen 0.5MPa to replace the air in the kettle three times, use carbon monoxide to replace the nitrogen in the kettle three times, and fill the carbon monoxide pressure to 3.0MPa, raise the temperature in the water bath to the temperature in the kettle to 25°C, always pay attention to the pressure in the kettle and keep the pressure at 3.0MPa for the reaction 3h. After the reaction was completed, cool to room temperature to carefully discharge carbon monoxide, cool to 10°C, filter with suction, rinse with 20g of methanol, and dry at 40°C to obtain 20.37g of (1Z)-3-(2,4-dichloro-5-fluorophenyl )-2-(methoxycarbonyl)-3-ox...

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Abstract

The invention provides a preparation method of a key intermediate of ciprofloxacin, and solves the technical problems that the existing preparation method is unreasonable, expensive in raw material price, high in toxicity, complex to operate, high in cost, low in yield and unsuitable for industrial production. The preparation method comprises the following steps: carrying out a carbonylation reaction to generate (1Z)-3-(2, 4-dichloro-5-fluorophenyl)-2-(methoxycarbonyl)-3-oxopropyl-1-ene-1-sodium alkoxide, and carrying out an ammonification reaction on the (1Z)-3-(2, 4-dichloro-5-fluorophenyl)-2-(methoxycarbonyl)-3-oxopropyl-1-ene-1-sodium alkoxide and cyclopropylamine hydrochloride to generate 3-(cyclopropylamino)-2-(2, 4-dichloro-5-fluorobenzoyl) propyl-2-olefine acid methyl ester. The method can be widely applied to the technical field of organic synthesis.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and more specifically relates to a preparation method of a key intermediate of ciprofloxacin. Background technique [0002] Patent CN104292159 A "A Preparation Method for Norfloxacin, Ciprofloxacin and Enrofloxacin" uses 2,4-5-fluorochlorobenzoyl chloride to combine with n,n-dimethyl After the reaction of amino acrylate, it is prepared by amine exchange with cyclopropylamine in an organic solvent. The reaction steps are simple, but the cost of raw materials is high, the reaction conditions are long, and the amount of organic solvent is large, and the use of various inorganic bases for catalysis leads to high difficulty in post-treatment, and high pressure on equipment and waste treatment. [0003] (Cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)prop-2-enoic acid methyl ester is a key intermediate for the synthesis of ciprofloxacin. At present, the industrial production at home and a...

Claims

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Application Information

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IPC IPC(8): C07C227/08C07C229/34C07C67/36C07C69/738
CPCC07C227/08C07C67/36C07C2601/02C07C69/738C07C229/34
Inventor 刘聪邱正洲赵建伟周洪亮陈飞
Owner SHANDONG GUOBANG PHARMA
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