4-methoxy methyl acetoacetate preparation method

A technology of methyl methoxyacetoacetate and methyl acetate, which is applied in the field of preparation of methyl 4-methoxyacetoacetate, can solve problems such as unfavorable industrialized large-scale production, achieve safe use, reduce impurity content, reduce The effect of the introduction of impurities

Active Publication Date: 2015-04-01
ZHONGSHAN NIKEMEI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Therefore, there are certain defects in the synthetic route of methyl 4-methoxyacetoacetate disclosed in the above-mentioned patent documents, which is unfavorable for further industrialized large-scale production

Method used

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Experimental program
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Effect test

Embodiment 1

[0019] In a 2L reaction flask, add 250ml of solvent tetrahydrofuran (AR) in advance, and start stirring under the protection of argon. At this time, the temperature in the kettle is 25°C, and add 30g (0.75mol) of industrial sodium hydride (containing 40wt% mineral oil) in batches. And 53g (0.75mol) of potassium methylate, after the addition, continue to add 450ml of solvent tetrahydrofuran; slowly drop the mixed solution of 30g of methanol and 100g (0.68mol) of methyl 4-chloroacetoacetate at the temperature of 20°C in the kettle, and stir for 4h , raise the temperature in the kettle to 25°C and stir for 5 hours. TLC detects that the reaction is complete, and the system begins to cool down. The color of the solution is earthy yellow and a large amount of solids are suspended. to 0-5°C) until the pH of the system = 5; stand for stratification, after separation, the upper layer is concentrated and spin-dried to remove the solvent tetrahydrofuran, and the resulting residue is added...

Embodiment 2

[0021] In a 2L reaction flask, add 250ml of solvent tetrahydrofuran (AR) in advance, and start stirring under the protection of argon. At this time, the temperature in the kettle is 15°C, and add 30g (0.75mol) of industrial sodium hydride (containing 40wt% mineral oil) in batches. and 40.5g (0.75mol) sodium methoxide, after the addition, continue to add 450ml of solvent tetrahydrofuran; slowly add a mixed solution of 30g methanol and 100g (0.68mol) methyl 4-chloroacetoacetate dropwise at a temperature of 15°C in the kettle, and stir the reaction 6h, raise the temperature in the kettle to 20°C and stir for 15h, TLC detects that the reaction is complete, the system begins to cool down, the color of the solution is earthy yellow and a large amount of solids are suspended, when the temperature in the kettle drops to 10°C, slowly add 2M hydrochloric acid solution (pre- Cool to 0-5°C) until the pH of the system is 7; stand and separate the layers, concentrate the upper layer and spin...

Embodiment 3

[0023] In a 2L reaction flask, add 250ml of solvent tetrahydrofuran (AR) in advance, and start stirring under the protection of argon. At this time, the temperature in the kettle is 20°C, and add 30g (0.75mol) of industrial sodium hydride (containing 40wt% mineral oil) in batches. and 51g (0.75mol) sodium ethoxide, after the addition, continue to add 450ml of solvent tetrahydrofuran; slowly add dropwise a mixed solution of 30g methanol and 100g (0.68mol) methyl 4-chloroacetoacetate at a temperature of 5°C in the kettle, and stir for 5h , raise the temperature in the kettle to 25°C and stir for 4 hours. TLC detects that the reaction is complete, and the system begins to cool down. The color of the solution is earthy yellow and a large amount of solids are suspended. to 0-5°C) until the pH of the system = 6; stand for stratification, and after separation, the upper layer is concentrated and spin-dried to remove the solvent tetrahydrofuran, and the resulting residue is added with ...

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Abstract

The invention discloses a 4-methoxy methyl acetoacetate preparation method. The 4-methoxy methyl acetoacetate preparation method comprises the following steps of adding a solvent tetrahydrofuran into a reaction kettle and leading inert gas into the reaction kettle, setting the internal temperature of the reaction kettle to be 15 DEG C to 25 DEG C, adding industrial sodium hydride and a metal alkaline compound in a stirring state, then adding the solvent tetrahydrofuran, dropwise adding mixed liquid of methyl alcohol and methyl-4-chloroacetoacetate at the temperature of lower than 20 DEG C to perform reaction for 4-6 hours, rising the temperature to be 20 DEG C to 25 DEG C to continue to react for 4-15 hours, reducing the system temperature to be 6 DEG C to 10 DEG C after TLC detection reaction is completed, adding a hydrochloric acid solution with molar concentration of 2 mol / L to regulate the pH of a system to be 5 to 7, performing standing and laying, concentrating and spin-drying upper-layer liquid to remove the solvent tetrahydrofuran after liquid separation and then obtaining a colorless product 4-methoxy methyl acetoacetate through wiped-film molecular distillation. The 4-methoxy methyl acetoacetate can react at room temperature, a product can be produced at low temperature through distillation, and dangerousness in the production process and product impurity content can be directly and effectively reduced.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of methyl 4-methoxyacetoacetate. Background technique [0002] Methyl 4-methoxyacetoacetate is an important pharmaceutical intermediate. At present, this compound is mainly used in the synthesis of the new anti-AIDS drug Dolutegravir. Dolutegravir is an anti-AIDS integrase approved by the US FDA in 2013 by GSK Inhibitor, 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 has improved safety. 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 further synthesis of Dolutegravir. Therefore, the study on the synthesis of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/716C07C67/31
CPCC07C67/31C07C67/48C07C67/54C07C69/716
Inventor 毛龙飞李伟寇丽栋姜玉钦董文佩毛阿龙陈小华万众
Owner ZHONGSHAN NIKEMEI PHARMA
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