Preparation method of ethyl (2,3,4,5-tetrafluorobenzoyl) acetate

Abstract

The invention relates to a preparation method of ethyl (2,3,4,5-tetrafluorobenzoyl) acetate, comprising the following process steps of: 1: reacting diethyl malonate as a raw material and absolute ethyl alcohol as a solution with potassium hydroxide to prepare potassium ethyl malonate; 2: reacting 2,3,4,5-tetrafluorobenzoyl chloride with the potassium ethyl malonate in a solvent under the condition of the coexistence of magnesium chloride and organic base; and 3: hydrolyzing a reaction product, purifying and crystallizing. According to the preparation method disclosed by the invention, the raw material used for an original synthesizing process is mainly changed so that reaction can be fast carried out at normal temperature, and therefore, energy sources are saved, the defects of the original synthesizing process on the restriction of the moisture of a reaction environment are overcome and then reaction is not influenced by the environment; in addition, according to the ethyl (2,3,4,5-tetrafluorobenzoyl) acetate prepared by the invention, technical indexes can be achieved as follows: appearance is white powder, purity is higher than 98.5 percent, and yield is 78-95 percent.

Description

technical field

[0001] The invention relates to the technical field of organic chemistry, in particular to a preparation method of ethyl 2,3,4,5-tetrafluorobenzoyl acetate, a pharmaceutical intermediate. Background technique

[0002] 2,3,4,5-Tetrafluorobenzoyl ethyl acetate is an important intermediate in the synthesis of levofloxacin, a third-generation quinolone broad-spectrum antibacterial drug. Levofloxacin is a broad-spectrum quinolone antibacterial drug, which has the advantages of broad anti-drug spectrum and low toxicity. It is widely used clinically in the treatment of respiratory tract infection, urinary tract infection, ophthalmic infection and intestinal infection.

[0003] The synthetic method of traditional 2,3,4,5-tetrafluorobenzoic acid ethyl acetate is as follows: the first step reacts in ethanol with diethyl malonate and magnesium powder earlier, generates the intermediate product of similar Grignard reagent, Release the by-product hydrogen simultaneousl...

Examples

Embodiment 1

[0019] 1. In a 500mL round-bottomed flask equipped with a thermometer, mechanical stirring, and a reflux condenser, add 125mL of absolute ethanol and 35 (0.22mol) g of monoethyl malonate, stir and dissolve at room temperature, and weigh 12.3g in a beaker (0.22mol) Potassium Hydroxide, dissolved in 125mL absolute ethanol to make a solution. Keep the temperature in the bottle at 20-25°C, start to drop the ethanol solution of potassium hydroxide, control the temperature in the bottle at 20-25°C, add dropwise for about 1 hour, then stir and react at this temperature for 12 hours, the reaction system Heat up to about 80°C to dissolve, stir and reflux for 1 hour, cool down to below -5°C, a flaky solid precipitates in the bottle, wash with a small amount of ether after suction filtration, and dry to obtain 29.5g of white flaky potassium monoethyl malonate (theoretical yield 95%), the next reaction can be carried out directly without purification.

[0020] 2. In a 500mL four-neck ro...

Embodiment 2

[0022] 1, the preparation of monoethyl malonate potassium is with example 1.

[0023] 2. In a 500mL four-neck round bottom flask, add 23.8g (0.14mol) monoethyl malonate potassium salt, 190.4g dichloromethane, stir and mix, cool the solution to 0°C, and add 35.4g triethylamine (0.35mol), 6g (0.168mol) of anhydrous magnesium chloride, and then 21.2g (0.1mol) of 2,3,4,5-tetrafluorobenzoyl chloride was added dropwise, and the addition was completed in about half an hour. The temperature was raised to 25°C, and the reaction was stirred for 10 hours. After the reaction of the raw materials was detected by TLC, the organic phase was separated, washed twice with 50 mL of 13% hydrochloric acid, and washed twice with 50 mL of water. Dry the organic phase with anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, add 20g of petroleum ether to dissolve, then cool down to 0°C to precipitate a white flaky solid, and filter it to obtain the product 2,3,4,5-tetrafluoroben...

example 3

[0025] 1, the preparation of monoethyl malonate potassium is with example 1.

[0026] 2. In a 500mL four-neck round bottom flask, add 23.8g (0.14mol) monoethyl malonate potassium salt, 142.8 g dichloromethane, stir and mix, cool the solution to 0°C, and add 35.4g triethylamine (0.35mol), 6g (0.168mol) of anhydrous magnesium chloride, and then 21.2g (0.1mol) of 2,3,4,5-tetrafluorobenzoyl chloride was added dropwise, and the addition was completed in about half an hour. Raise the temperature to 20°C, stir and react for 15 hours. After the reaction of the raw materials was detected by TLC, the organic phase was separated and washed twice with 50 mL of 13% hydrochloric acid each time, and then washed twice with 50 mL of water. Dry the organic phase with anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, add 20g of petroleum ether to dissolve, then cool down to 0°C to precipitate a white flaky solid, and filter it to obtain the product 2,3,4,5-tetrafluoroben...

technical field

[0001] The invention relates to the technical field of organic chemistry, in particular to a preparation method of ethyl 2,3,4,5-tetrafluorobenzoyl acetate, a pharmaceutical intermediate. Background technique

[0002] 2,3,4,5-Tetrafluorobenzoyl ethyl acetate is an important intermediate in the synthesis of levofloxacin, a third-generation quinolone broad-spectrum antibacterial drug. Levofloxacin is a broad-spectrum quinolone antibacterial drug, which has the advantages of broad anti-drug spectrum and low toxicity. It is widely used clinically in the treatment of respiratory tract infection, urinary tract infection, ophthalmic infection and intestinal infection.

[0003] The synthetic method of traditional 2,3,4,5-tetrafluorobenzoic acid ethyl acetate is as follows: the first step reacts in ethanol with diethyl malonate and magnesium powder earlier, generates the intermediate product of similar Grignard reagent, Release the by-product hydrogen simultaneousl...

Examples

Embodiment 1

[0019] 1. In a 500mL round-bottomed flask equipped with a thermometer, mechanical stirring, and a reflux condenser, add 125mL of absolute ethanol and 35 (0.22mol) g of monoethyl malonate, stir and dissolve at room temperature, and weigh 12.3g in a beaker (0.22mol) Potassium Hydroxide, dissolved in 125mL absolute ethanol to make a solution. Keep the temperature in the bottle at 20-25°C, start to drop the ethanol solution of potassium hydroxide, control the temperature in the bottle at 20-25°C, add dropwise for about 1 hour, then stir and react at this temperature for 12 hours, the reaction system Heat up to about 80°C to dissolve, stir and reflux for 1 hour, cool down to below -5°C, a flaky solid precipitates in the bottle, wash with a small amount of ether after suction filtration, and dry to obtain 29.5g of white flaky potassium monoethyl malonate (theoretical yield 95%), the next reaction can be carried out directly without purification.

[0020] 2. In a 500mL four-neck ro...

Embodiment 2

[0022] 1, the preparation of monoethyl malonate potassium is with example 1.

[0023] 2. In a 500mL four-neck round bottom flask, add 23.8g (0.14mol) monoethyl malonate potassium salt, 190.4g dichloromethane, stir and mix, cool the solution to 0°C, and add 35.4g triethylamine (0.35mol), 6g (0.168mol) of anhydrous magnesium chloride, and then 21.2g (0.1mol) of 2,3,4,5-tetrafluorobenzoyl chloride was added dropwise, and the addition was completed in about half an hour. The temperature was raised to 25°C, and the reaction was stirred for 10 hours. After the reaction of the raw materials was detected by TLC, the organic phase was separated, washed twice with 50 mL of 13% hydrochloric acid, and washed twice with 50 mL of water. Dry the organic phase with anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, add 20g of petroleum ether to dissolve, then cool down to 0°C to precipitate a white flaky solid, and filter it to obtain the product 2,3,4,5-tetrafluoroben...

example 3

[0025] 1, the preparation of monoethyl malonate potassium is with example 1.

[0026] 2. In a 500mL four-neck round bottom flask, add 23.8g (0.14mol) monoethyl malonate potassium salt, 142.8 g dichloromethane, stir and mix, cool the solution to 0°C, and add 35.4g triethylamine (0.35mol), 6g (0.168mol) of anhydrous magnesium chloride, and then 21.2g (0.1mol) of 2,3,4,5-tetrafluorobenzoyl chloride was added dropwise, and the addition was completed in about half an hour. Raise the temperature to 20°C, stir and react for 15 hours. After the reaction of the raw materials was detected by TLC, the organic phase was separated and washed twice with 50 mL of 13% hydrochloric acid each time, and then washed twice with 50 mL of water. Dry the organic phase with anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, add 20g of petroleum ether to dissolve, then cool down to 0°C to precipitate a white flaky solid, and filter it to obtain the product 2,3,4,5-tetrafluoroben...

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