4-methoxy ethyl acetoacetate and synthetic method thereof

Abstract

The invention discloses 4-methoxy ethyl acetoacetate and a synthetic method thereof. The synthetic method comprises the following specific steps: (1) adding tetrahydrofuran in a reaction kettle, introducing inert gas, setting the internal temperature to be 15-25 DEG C, adding sodium hydride, controlling the system temperature to be 20 DEG C, dropwise adding mixed liquid of methanol and 4-chloroacetoacetate to react for 4-6 hours, raising the temperature to 20-25 DEG C to continuously react for 3-5 hours and completing TLC detection reaction; (2) reducing the temperature of a reaction system to 7 DEG C below zero to 0 DEG C, adding a hydrochloric acid solution, regulating the pH of the reaction system to be equal to 11-13 and performing suction filtration on reaction liquid to obtain a white solid; (3) adding the obtained white solid into ethyl acetate, dropwise adding a hydrochloric acid solution at a temperature of 0 DEG C, gradually dissolving the solid, regulating the pH of the reaction system to be equal to 2-4, performing suction filtration on reaction liquid, separating an organic layer from a filtrate, de-coloring an organic phase through a de-coloring agent and steaming a solvent to obtain a pure product, namely the 4-methoxy ethyl acetoacetate. The 4-methoxy ethyl acetoacetate and the synthetic method thereof disclosed by the invention have the benefits that the reaction can be performed at a room temperature, and the product can be steamed at a lower temperature, so that the risk in the production process is directly and effectively reduced, and the product impurity content is reduced.

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...

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