Refining method for improving quality of imipenem key intermediate

Abstract

The invention discloses a refining method for improving the quality of an imipenem key intermediate. The method comprises the following steps of adding raw materials N-(4-methoxyphenyl)-4-acetyl-3-[1-(tert-butyl dimethyl-siloxy) ethyl] azetidinone and sodium acetate into a reaction bottle, and controlling the temperature to be within 0-10 DEG C, dropwise adding an oxidant for 3 hours; then, conducting a reaction for 16 hours at 20-25 DEG C, and controlling the reaction endpoint by high-performance liquid chromatography; and dropwise adding the sodium sulfite to neutralize excessive oxidant until the color of starch potassium iodide does not change after the reaction is finished, adding hexane to conduct extraction for 5 times, drying the mixed hexane with anhydrous sodium sulfate, reclaiming the hexane at a reduced pressure until the residue is dry, adding absolute methanol to conduct heating and dissolving, adding activated carbon, coudcting refluxing and insulating for 30 minutes, conducting filtering when the mixture is hot, cooling the filtrate to 5 DEG C below zero, filtering the filtrate, and baking the filter cake at 40 DEG C at a reduced pressure until the filter cake is dry so as to obtain a dried product. The method can be used for remarkably improving the product quality and has a remarkable economic benefit.

Description

technical field

[0001] The invention belongs to the field of basic chemical industry, and in particular relates to a method for improving imipenem key intermediate N-(4-methoxyphenyl)-4-acetoxy-3-{1-(tert-butyldimethylsilyl) Oxygen) ethyl} azetidinone quality refining method. Background technique

[0002] N-(4-methoxyphenyl)-4-acetoxy-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone, the key intermediate of imipenem Using hexane as the reaction extraction solvent, the extract was concentrated under reduced pressure to obtain N-(4-methoxyphenyl)-4-acetoxy-3-{1-(tert-butyldimethylsilyloxy)ethyl Base} azetidinone. The method mainly has problems such as low purity, many by-products, and poor quality, and these factors of poor quality will directly affect the quality of the final product imipenem. Contents of the invention

[0003] The technical problem to be solved by the present invention is to provide a refining method for improving the quality of the key intermediate o...

Examples

Embodiment 1

[0030] Add N-(4-methoxyphenyl)-4-acetyl-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone and sodium acetate into the reaction flask, 50% hydrogen peroxide is added dropwise under control at 0-10°C for about 3 hours, reacted at 20-25°C for 16 hours, and the end point of the reaction is controlled by high-performance liquid chromatography. After the reaction is over, add 10% sodium sulfite dropwise to neutralize the excess oxidant until the starch potassium iodide does not change color, add hexane to extract 5 times, combine the hexane layer and dry it with anhydrous sodium sulfate, recover the hexane under reduced pressure to dryness, add 6 Heat and dissolve twice the amount of anhydrous methanol, then add 2% of the theoretical amount of activated carbon, reflux for 30 minutes, filter while it is hot, cool the filtrate to -5°C, filter, dry the filter cake under reduced pressure at 40°C until dry, and batch the filtrate Applied mechanically, the dry product has a purity of 98....

Embodiment 2

[0032] Add N-(4-methoxyphenyl)-4-acetyl-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone and sodium acetate into the reaction flask, 50% hydrogen peroxide is added dropwise under control at 0-10°C for about 3 hours, reacted at 20-25°C for 16 hours, and the end point of the reaction is controlled by high-performance liquid chromatography. After the reaction is over, add 10% sodium sulfite dropwise to neutralize the excess oxidant until the starch potassium iodide does not change color, add hexane to extract 5 times, combine the hexane layer and dry it with anhydrous sodium sulfate, recover the hexane under reduced pressure to dryness, add 7 Heat and dissolve twice the amount of anhydrous methanol, then add 2% of the theoretical amount of activated carbon, reflux for 30 minutes, filter while it is hot, cool the filtrate to -5°C, filter, dry the filter cake under reduced pressure at 40°C until dry, and batch the filtrate Applied mechanically, the purity of the dry product is 99...

Embodiment 3

[0034] Add N-(4-methoxyphenyl)-4-acetyl-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone and sodium acetate into the reaction flask, 50% hydrogen peroxide is added dropwise under control at 0-10°C for about 3 hours, reacted at 20-25°C for 16 hours, and the end point of the reaction is controlled by high-performance liquid chromatography. After the reaction is over, add 10% sodium sulfite dropwise to neutralize the excess oxidant until the starch potassium iodide does not change color, add hexane to extract 5 times, combine the hexane layer and dry it with anhydrous sodium sulfate, recover the hexane under reduced pressure to dryness, add 8 Heat and dissolve twice the amount of anhydrous methanol, then add 2% of the theoretical amount of activated carbon, reflux for 30 minutes, filter while it is hot, cool the filtrate to -5°C, filter, dry the filter cake under reduced pressure at 40°C until dry, and batch the filtrate Applied mechanically, the dry product has a purity of 99....

technical field

[0001] The invention belongs to the field of basic chemical industry, and in particular relates to a method for improving imipenem key intermediate N-(4-methoxyphenyl)-4-acetoxy-3-{1-(tert-butyldimethylsilyl) Oxygen) ethyl} azetidinone quality refining method. Background technique

[0002] N-(4-methoxyphenyl)-4-acetoxy-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone, the key intermediate of imipenem Using hexane as the reaction extraction solvent, the extract was concentrated under reduced pressure to obtain N-(4-methoxyphenyl)-4-acetoxy-3-{1-(tert-butyldimethylsilyloxy)ethyl Base} azetidinone. The method mainly has problems such as low purity, many by-products, and poor quality, and these factors of poor quality will directly affect the quality of the final product imipenem. Contents of the invention

[0003] The technical problem to be solved by the present invention is to provide a refining method for improving the quality of the key intermediate o...

Examples

Embodiment 1

[0030] Add N-(4-methoxyphenyl)-4-acetyl-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone and sodium acetate into the reaction flask, 50% hydrogen peroxide is added dropwise under control at 0-10°C for about 3 hours, reacted at 20-25°C for 16 hours, and the end point of the reaction is controlled by high-performance liquid chromatography. After the reaction is over, add 10% sodium sulfite dropwise to neutralize the excess oxidant until the starch potassium iodide does not change color, add hexane to extract 5 times, combine the hexane layer and dry it with anhydrous sodium sulfate, recover the hexane under reduced pressure to dryness, add 6 Heat and dissolve twice the amount of anhydrous methanol, then add 2% of the theoretical amount of activated carbon, reflux for 30 minutes, filter while it is hot, cool the filtrate to -5°C, filter, dry the filter cake under reduced pressure at 40°C until dry, and batch the filtrate Applied mechanically, the dry product has a purity of 98....

Embodiment 2

[0032] Add N-(4-methoxyphenyl)-4-acetyl-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone and sodium acetate into the reaction flask, 50% hydrogen peroxide is added dropwise under control at 0-10°C for about 3 hours, reacted at 20-25°C for 16 hours, and the end point of the reaction is controlled by high-performance liquid chromatography. After the reaction is over, add 10% sodium sulfite dropwise to neutralize the excess oxidant until the starch potassium iodide does not change color, add hexane to extract 5 times, combine the hexane layer and dry it with anhydrous sodium sulfate, recover the hexane under reduced pressure to dryness, add 7 Heat and dissolve twice the amount of anhydrous methanol, then add 2% of the theoretical amount of activated carbon, reflux for 30 minutes, filter while it is hot, cool the filtrate to -5°C, filter, dry the filter cake under reduced pressure at 40°C until dry, and batch the filtrate Applied mechanically, the purity of the dry product is 99...

Embodiment 3

[0034] Add N-(4-methoxyphenyl)-4-acetyl-3-{1-(tert-butyldimethylsilyloxy)ethyl}azetidinone and sodium acetate into the reaction flask, 50% hydrogen peroxide is added dropwise under control at 0-10°C for about 3 hours, reacted at 20-25°C for 16 hours, and the end point of the reaction is controlled by high-performance liquid chromatography. After the reaction is over, add 10% sodium sulfite dropwise to neutralize the excess oxidant until the starch potassium iodide does not change color, add hexane to extract 5 times, combine the hexane layer and dry it with anhydrous sodium sulfate, recover the hexane under reduced pressure to dryness, add 8 Heat and dissolve twice the amount of anhydrous methanol, then add 2% of the theoretical amount of activated carbon, reflux for 30 minutes, filter while it is hot, cool the filtrate to -5°C, filter, dry the filter cake under reduced pressure at 40°C until dry, and batch the filtrate Applied mechanically, the dry product has a purity of 99....