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Preparation method of methyl 4-methoxyacetoacetate

A technology of methyl methoxy acetoacetate and toluene, applied in the field of preparation of methyl 4-methoxy acetoacetate, can solve problems such as affecting product processing and purity, and achieves reduction in energy consumption, simplification of separation process, and reduction in usage amount of effect

Pending Publication Date: 2021-12-24
JIANGSU YUXIANG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the commonly used synthesis methods of methyl 4-methoxyacetoacetate mostly use methyl 4-chloroacetoacetate and methanol as raw materials, but different solvents, basic compounds and temperatures will affect the processing and purity of subsequent products

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 1) Add anhydrous toluene into the reactor, under a nitrogen atmosphere, control the temperature inside the reactor to 18-20°C, add industrial sodium hydride under stirring, rinse with anhydrous toluene at least 3 times, remove the rinsed toluene, Add new anhydrous toluene as solvent;

[0021] 2) Under nitrogen atmosphere, add methyl 4-chloroacetoacetate while stirring, control the temperature in the reactor to 10~15°C, add methanol solution of sodium methoxide dropwise, after the dropwise addition, stir, and control the temperature of the reactor. The temperature in the kettle is 20-25°C, and the reaction is carried out for 3-5 hours, and the reaction is detected by gas chromatography to obtain the sodium salt of methyl 4-methoxyacetoacetate;

[0022] The molar ratio of methyl 4-chloroacetoacetate, sodium hydride and sodium methoxide is 1:1:1.2.

[0023] In step 2), a methanol solution of sodium methoxide, wherein sodium methoxide accounts for 50 mol%.

[0024] 3) Con...

Embodiment 2

[0033] 1) Add anhydrous toluene into the reactor, under a nitrogen atmosphere, control the temperature inside the reactor to 18-20°C, add industrial sodium hydride under stirring, rinse with anhydrous toluene at least 3 times, remove the rinsed toluene, Add new anhydrous toluene as solvent;

[0034] 2) Under nitrogen atmosphere, add methyl 4-chloroacetoacetate while stirring, control the temperature in the reactor to 10~15°C, add methanol solution of sodium methoxide dropwise, after the dropwise addition, stir, and control the temperature of the reactor. The temperature in the kettle is 20-25°C, and the reaction is carried out for 3-5 hours, and the reaction is detected by gas chromatography to obtain the sodium salt of methyl 4-methoxyacetoacetate;

[0035] The molar ratio of methyl 4-chloroacetoacetate, sodium hydride and sodium methoxide is 1:1:1.2.

[0036] In step 2), a methanol solution of sodium methoxide, wherein sodium methoxide accounts for 52 mol%.

[0037] 3) Con...

Embodiment 3

[0046] 1) Add anhydrous toluene into the reactor, under a nitrogen atmosphere, control the temperature inside the reactor to 18-20°C, add industrial sodium hydride under stirring, rinse with anhydrous toluene at least 3 times, remove the rinsed toluene, Add new anhydrous toluene as solvent;

[0047]2) Under a nitrogen atmosphere, add methyl 4-chloroacetoacetate while stirring, control the temperature in the reactor to 10~15°C, add the methanol solution of sodium methoxide dropwise, after the dropwise addition, stir, and control the temperature of the reactor. The temperature in the kettle is 20-25°C, and the reaction is carried out for 3-5 hours, and the reaction is detected by gas chromatography to obtain the sodium salt of methyl 4-methoxyacetoacetate;

[0048] The molar ratio of methyl 4-chloroacetoacetate, sodium hydride and sodium methoxide is 1:1:1.2.

[0049] A methanol solution of sodium methoxide, wherein sodium methoxide accounts for 55 mol%.

[0050] 3) Control th...

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PUM

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Abstract

The invention discloses a preparation method of methyl 4-methoxyacetoacetate, the preparation method comprises the following steps: 1) rinsing industrial sodium hydride with anhydrous toluene in a nitrogen atmosphere; 2) adding methyl 4-chloroacetoacetate, dropwise adding a methanol solution of sodium methoxide at 10-15 DEG C, and stirring to react for 3-5 hours; and 3) adjusting pH with acid, standing for layering, carrying out reduced pressure distillation on a toluene layer, removing toluene, and carrying out reduced pressure distillation on a crude product to obtain a target product. The reaction can be carried out at room temperature, so that the energy consumption is reduced, and the side reaction is reduced; mineral oil in the industrial sodium hydride is completely removed through rinsing of methylbenzene, so that introduction of impurities is reduced, and the subsequent separation process is simplified; part of the sodium methoxide compound is directly added and is matched with newly generated sodium methoxide, so that the catalytic effect is ensured, the stable proceeding of the reaction is ensured, the generation of side reactions is further reduced, and the reaction yield is improved.

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 intermediate in the synthesis of the new anti-AIDS drug dolutegravir. Detegravir is the third HIV integrase inhibitor approved by the US Food and Drug Administration after raltegravir and elvitegravir. Compared with the existing raltegravir and eltgravir, the safety of the drug has been improved; at the same time, the drug does not need to be used in combination with drug accelerators, and has very strong drug resistance properties, according to analysts Detegevir is expected to become a blockbuster drug with annual sales of billions of dollars in the future. Therefore, methyl 4-methoxyacetoacetate is an important intermediate in the synthesis of detegevir, and it is of great significance to study a low-cost, high-quality synthet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/31C07C67/48C07C67/58C07C69/716
CPCC07C67/31C07C67/48C07C67/58C07C69/716
Inventor 程红伟程云涛陈中兵黄剑
Owner JIANGSU YUXIANG CHEM
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