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Preparation process of methyl 4-methoxyacetoacetate

A technology for the preparation of methyl methoxyacetoacetate, which is applied in the field of medicinal chemistry, can solve the problems of high risk and high cost, and achieve the effects of safe and reliable production, low cost and high yield

Inactive Publication Date: 2019-03-12
南京莱克施德药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses sodium hydride, industrial production is very dangerous, and the cost of this route is relatively high

Method used

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  • Preparation process of methyl 4-methoxyacetoacetate
  • Preparation process of methyl 4-methoxyacetoacetate
  • Preparation process of methyl 4-methoxyacetoacetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Under nitrogen protection, in a 5L four-necked flask, add 1500ml of anhydrous toluene, 400g (2.2mol) of 30% sodium methoxide in methanol, and dropwise add 150.6g (1.0 mol) of 4-chloroacetoacetate methyl ester at 20-25°C mol), after the dropwise addition, continue to stir at room temperature for 2 hours; heat to 65-70°C, keep warm for 3h, cool to room temperature, and produce a large amount of white solid. Adjust the pH to 5-6 with 2N hydrochloric acid, and continue stirring for 30 minutes. Adjust the pH to 3-4 with 2N hydrochloric acid, separate the toluene layer; extract the water layer once with 500ml of toluene. The toluene layers were combined and washed with saturated sodium chloride solution until neutral. Distill under reduced pressure to remove toluene to obtain crude product. The crude product was distilled under reduced pressure (90-100°C / 10mmHg) to obtain 108 g of a colorless transparent liquid with a GC purity of 99% and a yield of 74%.

[0025] Product H...

Embodiment 2

[0028] Under nitrogen protection, in a 5L four-necked flask, add 1500ml of anhydrous toluene, 185g (1.0mol) of 30% sodium methoxide in methanol, and dropwise add 150.6g (1.0mol) of 4-chloroacetoacetate methyl ester at 20-25°C. mol), after the dropwise addition, continue to stir at room temperature for 2 hours; heat to 65-70°C, keep warm for 3h, cool to room temperature, and produce a large amount of white solid. Adjust the pH to 6 with acetic acid, and continue stirring for 30 minutes. Adjust the pH to 3-4 with 2N hydrochloric acid, separate the toluene layer; extract the water layer once with 500ml of toluene. The toluene layers were combined and washed with saturated sodium chloride solution until neutral. Distill under reduced pressure to remove toluene to obtain crude product. The crude product was distilled under reduced pressure (90-100°C / 10mmHg) to obtain 58 g of a colorless transparent liquid with a GC purity of 99% and a yield of 40%.

[0029] Product H Spectrum: ...

Embodiment 3

[0032] Under nitrogen protection, in a 5L four-necked flask, add 1500ml of anhydrous toluene, 400g (2.2mol) of 30% sodium methoxide in methanol, and dropwise add 150.6g (1.0 mol) of 4-chloroacetoacetate methyl ester at 20-25°C mol), after the dropwise addition, continue to stir at room temperature for 2 hours; heat to 65-70°C, keep warm for 3h, cool to room temperature, and produce a large amount of white solid. Adjust the pH to 6 with acetic acid, and continue stirring for 30 minutes. Adjust the pH to 3-4 with 2N hydrochloric acid, separate the toluene layer; extract the water layer once with 500ml of toluene. The toluene layers were combined and washed with saturated sodium chloride solution until neutral. Distill under reduced pressure to remove toluene to obtain crude product. The crude product was distilled under reduced pressure (90-100°C / 10mmHg) to obtain 110 g of a colorless transparent liquid with a GC purity of 99% and a yield of 75%.

[0033] Product H Spectrum: ...

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Abstract

The invention discloses a preparation process of methyl 4-methoxyacetoacetate, comprising the following process steps: step 1, taking anhydrous toluene as a solvent, adding a methanol solution of sodium methoxide in the solvent as a base, at room temperature, dropwise adding methyl 4-chloroacetoacetate in the solvent, after dropwise adding, stirring, heating to 65-70 DEG C during stirring, and reacting for 3 to 5 hours to obtain a sodium salt of methyl 4-methoxyacetoacetate; step 2, acidifying the sodium salt, adjusting with acid to achieve the pH of 5-6, stirring for 30 min, and adjusting thepH to 3-4 to obtain a toluene layer and an aqueous layer, washing the toluene layer to neutral with a saturated sodium chloride solution, performing reduced pressure distillation to remove toluene and obtain a crude product of methyl 4-methoxyacetoacetate, and performing reduced pressure distillation on the crude product to obtain a target product with the purity of 99 percent. The invention discloses the preparation process of methyl 4-methoxyacetoacetate to realize effective, high-quality and low-cost synthesis.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing organic compounds, specifically a method for preparing methyl 4-methoxyacetoacetate. Background technique [0002] Methyl 4-methoxyacetoacetate is an important intermediate in the synthesis of the new anti-HIV / AIDS drug dulutevir. Dolutegravir (Dologevir, Dolutegravir, Tivicay) is a new anti-HIV drug owned by the British pharmaceutical giant GlaxoSmithKline (GSK). On August 12, 2013, the US Food and Drug Administration (FDA) approved the use of Treatment-experienced or newly-treated HIV-1 adults and children aged 12 and over weighing at least 40 kg. Dolutegravir is a once-daily drug, which has achieved comparable efficacy to Merck's HIV / AIDS drug Raltegravir (Isentress) in phase III clinical trials. Raltegravir is taken twice a day, both of which are inhibitors of HIV integrase. FDA officials said that HIV-infected people need targeted treatm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/31C07C67/317C07C67/54C07C69/716
CPCC07C67/31C07C67/317C07C67/54C07C69/716
Inventor 黄尔青孙亚杰
Owner 南京莱克施德药业有限公司
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