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Synthetic method of methyl 4-methoxyacetoacetate

A technology of methyl methoxy acetoacetate and a synthesis method, applied in the field of synthesis of methyl 4-methoxy acetoacetate, can solve problems such as expensive and unaffordable molecular distillation equipment, achieve safe use and reduce usage , saving and using simple effects

Inactive Publication Date: 2016-03-23
HENAN NORMAL UNIV
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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 methyl 4-methoxyacetoacetate
  • Synthetic method of methyl 4-methoxyacetoacetate
  • Synthetic method of methyl 4-methoxyacetoacetate

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 30g (0.74mol) sodium hydride (containing 40wt% Mineral oil) and 50g (0.74mol) of potassium methylate, after the addition, continue to add 450mL of tetrahydrofuran; slowly drop a mixed solution of 30g of methanol and 100g (0.67mol) of methyl 4-chloroacetoacetate at an internal temperature of 20°C, Adjust the stirring rate at about 310 rpm, and finish adding in about 4 hours; the internal temperature rises to 20-25°C and stirs for 5 hours, TLC detects that the raw materials have reacted completely, and the system begins to cool down. It can be seen that the color of the solution is light yellow and a large amount of solids are suspended. Add 200mL of tetrahydrofuran at 11°C, and when the internal temperature drops to -2°C, slowly add 100mL of hydrochloric acid solution with a molar concentration of 2mol / L (pre...

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 30g (0.74mol) sodium hydride (containing 40wt% mineral Oil) and 50g (0.74mol) of potassium methylate, after the addition, continue to add 450mL of tetrahydrofuran; slowly add a mixed solution of 30g of methanol and 100g (0.67mol) of methyl 4-chloroacetoacetate dropwise at an internal temperature of 20°C to adjust The stirring rate is around 310 rpm, and the addition is completed in about 4 hours; the internal temperature rises to 20-25°C and stirs for 5 hours, and TLC detects that the raw materials have completely reacted; Add 200mL of tetrahydrofuran at 11°C, and when the internal temperature drops to -2°C, slowly add 100mL of hydrochloric acid solution with a molar concentration of 2mol / L (pre-cooled to 0-5°C), and keep the internal temperature below 0°C. After adding in about 20 minutes, the pH of the re...

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 30g (0.74mol) sodium hydride (containing 40wt% mineral oil) and 50g (0.74mol) of potassium methylate, after the addition, continue to add 450mL of tetrahydrofuran, and slowly add a mixed solution of 30g of methanol and 100g (0.67mol) of methyl 4-chloroacetoacetate dropwise at an internal temperature of 20°C to adjust The stirring rate is around 310 rpm, and the addition is completed in about 4 hours; the internal temperature rises to 20-25°C and stirs for 5 hours, and TLC detects that the raw materials have completely reacted; Add 200mL of tetrahydrofuran at 11°C, and when the internal temperature drops to -2°C, slowly add 100mL of hydrochloric acid solution with a molar concentration of 2mol / L (pre-cooled to 0-5°C), and keep the internal temperature below 0°C. After adding in about 20 minutes, the pH of the...

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Abstract

The invention discloses a synthetic method of methyl 4-methoxyacetoacetate. The synthetic method comprises the following specific steps: (1) adding tetrahydrofuran into a reaction kettle, introducing an inert gas, controlling the internal temperature of the reaction kettle to be 15-25 DEG C, adding sodium hydride and potassium methoxide, adding tetrahydrofuran again, controlling the temperature of the system to be 20 DEG C, dropwise adding a mixed solution of methanol and methyl4-chloroacetoacetate for reaction for 4-6 hours, and heating up to 20-25 DEG C for continuous reaction for 3-5 hours; (2) cooling down to -5-0 DEG C, adding hydrochloric acid solution to adjust the pH value of the reaction system to be 10-12, and performing suction filtration on reaction liquid to obtain a white solid; and (3) adding the white solid into ethyl acetate, dropwise adding hydrochloric acid solution at 0 DEG C to adjust the pH of the reaction system to be 3-5, then performing suction filtration on the reaction liquid to separate out an organic layer from the filtrate, decolorizing an organic phase by using a decolorant, and then performing evaporation to remove the solvent, thereby obtaining a pure product namely methyl 4-methoxyacetoacetate. According to the synthetic method disclosed by the invention, reaction can be carried out at room temperature, and a product can be evaporated out at a relatively low temperature, so that the risk of the production process is directly and effectively reduced, and the impurity content of the product is reduced.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing methyl 4-methoxyacetoacetate. Background technique [0002] Methyl 4-methoxyacetoacetate is a colorless and transparent liquid with an aromatic odor. It is an important pharmaceutical intermediate compound. At present, this type of compound is mainly used in the synthesis of the new anti-AIDS drug Dolutegravir. Dolutegravir was approved by GSK in 2013. The anti-AIDS integrase inhibitor approved by the U.S. FDA, the trade name is Tivicay. Dolutegravir, as an FDA priority review drug, is the fourth new drug launched by GSK in 2013, and its sales in 2020 are expected to reach US$1.62 billion. Compared with the existing HIV integrase inhibitors raltegravir and slvitegravir, the drug is safer. Methyl 4-methoxyacetoacetate is used as the starting material for the synthesis of Dolutegravir, and its quality and price have a great influence on the fur...

Claims

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Application Information

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IPC IPC(8): C07C67/31C07C67/30C07C69/716
CPCC07C67/31C07C67/30C07C69/716
Inventor 李伟索华俊穆开蕊毛龙飞姜玉钦郭晶晶陈长坡
Owner HENAN NORMAL UNIV
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