Preparation method of chiral bicyclic gamma-butyrolactone compound

Abstract

The invention discloses a preparation method of a chiral bicyclic gamma-butyrolactone compound, the chiral bicyclic gamma-butyrolactone compound is a main skeleton of many compounds and drug molecules and is an important active intermediate, for example, a natural product podophyllotoxin and a derivative thereof are widely applied to clinical treatment as an antitumor drug; wherein the vorapaxar sulfate serving as a marketed drug is also used as an initiative oral PAR-1 inhibitor. According to the present invention, through the double Michael addition reaction of gamma-dimethyl furanone and alpha,beta-unsaturated ketone catalyzed by (1S,2S)-1, 2-diphenylethylenediamine, so that the functional chiral bicyclic gamma-butyrolactone compound with the yield of 80%, the stereoselectivity of more than 20:1 and the higher value can be rapidly obtained through the one-step reaction. The method and the thought are provided for the synthesis of the drug active intermediate, so that synthesis difficulty of the compound in the current medicine research and development field is solved.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical compounds, in particular to a preparation method of chiral bicyclic γ-butyrolactone compounds. Background technique [0002] Chiral bicyclic γ-butyrolactone compounds are the main skeleton of many terpenoids and drug molecules, such as itoposide and teniposide, which are already on the market, as topoisomerase II inhibitors, have antitumor Pharmacological effects; Vorapaxar sulfate is a first-in-class protein kinase receptor 1 antagonist, which is an antithrombotic drug for antiplatelet agents; there are other natural products such as podophyllotoxin and its analogs and heliolide compounds with various biological activities. Therefore, bicyclic γ-butyrolactone compounds with multiple chiral centers widely exist in various terpenoids and drug molecules with biological activity. It has been reported in the literature that α,β-unsaturated ketones react with nitroalkenes, α,β-unsaturated k...

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Problems solved by technology

For example, the Chinese invention patent CN111138443A "A Preparation Method for Total Synthesis of 4'-Demethyl Epipodophyllotoxin" discloses a process method of an antineoplastic drug wooden box, which relates to a preparation method of epipodophyllotoxin: using Syringaldehyde is used as an initial material to react with 4-vinyl dihydrofuran-2-one to obtain an intermediate, and the synthesis method is complicated

[0005] In the oral report "Reactions Based on Furanones: Chiral Diprimary Amines Catalyzed Asymmetric D-A Reaction of Furanones with α, β-Unsaturated Ketones" previously reported by the inventors, it was proposed that furanones and α, β-unsaturated Saturated ketones undergo asymmetric reactions, but there are no absolute configurations and specific examples of previously reported products in the prior art

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