Synthetic method of β-ester group-γ-butyrolactam and γ-ester group-δ-valerolactam

Abstract

The invention belongs to the technical field of chemical engineering, and in particular relates to a method for synthesizing beta-ester group-gamma-butyrolactam and gamma-ester group-delta-valerolactam. The method comprises the following steps: by taking ZnEt2 as an alkylation reagent, performing selective alkylation on fumaric acid ester, itaconic acid ester and methylic glutarate at near room-temperature, and performing Mannich addition on imine, and performing a cyclization reaction. The method provided by the invention is common in reaction raw material and low in price, a transition metal catalyst is not needed, one-pot method synthesis is achieved in a same reaction container through serial reactions, separation process and product loss can be reduced, the method is simple and convenient to operate, efficient in process and mild in condition, and the reactions can be implemented at normal temperature or near room-temperature.

Description

technical field [0001] The invention belongs to the technical field of chemical industry, and specifically relates to a synthesis method of β-ester-γ-butyrolactam and γ-ester-δ-valerolactam. Background technique [0002] Cyclic lactams γ-butyrolactam and δ-valerolactam structures widely exist in various natural products and biopharmaceutical molecules [1] . Drugs such as piracetam, aniracetam, oxiracetam, and pyrithione, which are used to treat cerebral insufficiency and brain aging, all contain γ-butyrolactam structures. The γ-butyrolactam compound is also an important organic intermediate for the synthesis of drugs and bioactive molecules [2]-[4] . δ-valerolactam HDAC inhibitors have been found to have different degrees of anti-inflammatory and cytostatic activity, and these compounds have anti-inflammatory and anti-tumor activities by inhibiting cell growth and inducing cell differentiation [5] . β-carboxy-γ-butyrolactam and β-carboxy-δ-valerolactam are easily obtain...

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Problems solved by technology

Yoon et al. have reported that Rh catalyzes the intramolecular C-H bond activation reaction of diazo compounds to form γ-butyrolactam [7] , the reaction also requires the use of expensive Rh catalysts, and diazo compounds are dangerous

In 2007, Kim et al synthesized δ-valerolactam from phenyl chain primary amines through multi-step [8] , the synthetic δ-valerolactam HDAC inhibitors have been found to have different degrees of anti-inflammatory and cell growth inhibitory activities, but the reaction steps are more, and at the same time, there are limitations such as low yield

In 2007, William A et al obtained δ-valerolactam by Lindlar catalytic reduction and cyclization after the reaction of iodo eight-membered cyclic lactone and sodium azide [9] , the reaction steps are many, and sodium azide is dangerous, which is not conducive to large-scale application

Li Zhengning et al. used Cu compounds as catalysts to react α, β-unsaturated dicarboxylic acid esters with N-substituted imines and silanes to generate β-ester-γ-butyrolactam (Chinese patent application number 201410332597.X). Cyclic lactams can only introduce H atoms on the β-C of unsaturated diacid esters, but cannot introduce alkyl substituents, and the post-reaction treatment is more complicated

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