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Synthetic method of 4-methoxyethyl acetoacetate

A technology of ethyl methoxyacetoacetate and ethyl chloroacetoacetate, which is applied in the field of synthesis of ethyl 4-methoxyacetoacetate, can solve the problems of unaffordable and expensive molecular distillation equipment, and achieve simple and effective removal The effect of removing

Inactive Publication Date: 2016-04-13
ANHUI TWISUN HI TECH PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method can effectively reduce the amount of sodium hydride used, reduce the interference of mineral oil, and avoid the occurrence of ester hydrolysis by-products, but the molecular distillation equipment is relatively expensive, and generally small businesses cannot afford it

Method used

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  • Synthetic method of 4-methoxyethyl acetoacetate
  • Synthetic method of 4-methoxyethyl acetoacetate
  • Synthetic method of 4-methoxyethyl acetoacetate

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Add 250mL tetrahydrofuran to the 2L reaction bottle in advance, and start stirring under the protection of argon. At this time, the internal temperature is 25°C, and 55g (1.35mol) sodium hydride (containing 40% mineral After the addition, continue to add 450 mL of tetrahydrofuran; slowly add a mixed solution of 30 g of methanol and 100 g (0.61 mol) of ethyl 4-chloroacetoacetate dropwise at an internal temperature of 20 ° C, and adjust the stirring speed at about 310 rpm , the addition was completed in about 4 hours; the internal temperature rose to 20-25°C and stirred for 5 hours, and the reaction was detected by TLC; the system began to cool down, and it could be seen that the color of the solution was light yellow and a large amount of solids were suspended. , when the internal temperature drops to -5°C, slowly add 100mL of hydrochloric acid solution with a molar concentration of 2mol / L, keep the internal temperature below -2°C, and finish adding in about 20 minutes. A...

Embodiment 2

[0025] Add 250mL tetrahydrofuran to the 2L reaction bottle in advance, and start stirring under the protection of argon. At this time, the internal temperature is 25°C, and 55g (1.35mol) sodium hydride (containing 40% mineral After the addition, continue to add 450 mL of tetrahydrofuran; slowly add a mixed solution of 30 g of methanol and 100 g (0.61 mol) of ethyl 4-chloroacetoacetate dropwise at an internal temperature of 20 ° C, and adjust the stirring speed at about 310 rpm , the addition was completed in about 4 hours; the internal temperature rose to 20-25°C and stirred for 5 hours, and the reaction was detected by TLC; the system began to cool down, and it could be seen that the color of the solution was light yellow and a large amount of solids were suspended. , when the internal temperature drops to -5°C, slowly add 100mL of hydrochloric acid solution with a molar concentration of 2mol / L, keep the internal temperature below -2°C, and finish adding in about 20 minutes. A...

Embodiment 3

[0027]Add 250mL tetrahydrofuran to the 2L reaction bottle in advance, and start stirring under the protection of argon. At this time, the internal temperature is 25°C, and 55g (1.35mol) sodium hydride (containing 40% mineral After the addition, continue to add 450 mL of tetrahydrofuran; slowly add a mixed solution of 30 g of methanol and 100 g (0.61 mol) of ethyl 4-chloroacetoacetate dropwise at an internal temperature of 20 ° C, and adjust the stirring speed at about 310 rpm , the addition was completed in about 4 hours; the internal temperature rose to 20-25°C and stirred for 5 hours, and the reaction was detected by TLC; the system began to cool down, and it could be seen that the color of the solution was light yellow and a large amount of solids were suspended. , when the internal temperature drops to -7°C, slowly add 100mL of hydrochloric acid solution with a molar concentration of 2mol / L, keep the internal temperature below 0°C, and finish adding in about 20 minutes. At ...

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Abstract

The invention discloses a synthetic method of 4-methoxyethyl acetoacetate. The method concretely comprises the following steps: 1, adding tetrahydrofuran to a reaction kettle, introducing an inert gas, setting the internal temperature to be 15-25DEG C, adding sodium hydride, controlling the system temperature to be 20DEG C, adding a methanol and 4-chloroethyl acetoacetate mixed liquor in a dropwise manner, reacting for 4-6h, heating the obtained system to 20-25DEG C, continuously reacting for 3-5h, and carrying out TLC detection until the reaction is finished; 2, cooling the above reaction system to -7-0DEG C, adding a hydrochloric acid solution to adjust the pH value of the reaction system to 11-13, and carrying out pumping filtration on the above obtained reaction solution to obtain a white solid; and 3, adding the obtained white solid to ethyl acetate, adding the hydrochloric acid solution in a dropwise manner at 0DEG C to gradually dissolve the solid and adjust the pH value of the reaction system to 2-4, carrying out pumping filtration on the obtained reaction solution, separating out an organic layer from the obtained filtrate, decolorizing the organic phase through a decolorizing agent, and steaming out the above solvent to obtain pure 4-methoxyethyl acetoacetate. The method has the advantages of implementation of the reaction at room temperature, obtaining of the above product after steaming at a low temperature, direct and effective reduction of the danger in the production process, and reduction of the content of impurities in the product.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing ethyl 4-methoxyacetoacetate. Background technique [0002] Ethyl 4-methoxyacetoacetate is a colorless transparent liquid with an aromatic smell and is an important pharmaceutical intermediate compound. At present, this type of compound is mainly used in the synthesis of the new anti-AIDS drug dulutevir, which is GlaxoSmithKline's anti-AIDS integrase inhibitor approved by the US FDA in 2013, the trade name is Tivicay. As an FDA priority review drug, dulutevir is the fourth new drug launched by GSK in 2013, and its sales in 2020 are expected to reach 1.62 billion US dollars. Compared with the existing HIV integrase inhibitors raltegravir and evitagravir, the safety of the drug is improved. Ethyl 4-methoxy acetoacetate is used as the starting material for the synthesis of dolutevir, and its quality and price have a great influence on the further...

Claims

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Application Information

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IPC IPC(8): C07C69/716C07C67/31C07C67/30
CPCC07C67/30C07C67/31C07C67/48C07C69/716
Inventor 李伟穆开蕊索华俊毛龙飞徐桂清郭晶晶陈长坡
Owner ANHUI TWISUN HI TECH PHARM CO LTD
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