Catalytic asymmetric synthesis method and application of chiral oxindole spiro analogue

Abstract

Five-membered and six-membered carbon ring chiral oxindole spiro skeletons widely exist in active natural products and drug molecules, and development of a high-efficiency synthesis method of the chiral spiro compounds and analogues thereof will promote development of new drugs. Indolone which is cheap and easy to obtain and an amphiphilic electroalkylating reagent are adopted as raw materials, novel and efficient [4 + 1] and [5 + 1] cyclization reactions are developed under the condition of asymmetric phase transfer catalysis, and therefore general synthesis of chiral oxoindole spiro rings containing five-membered and six-membered carbon rings can be rapidly constructed in one step, and the chiral oxoindole spiro rings containing five-membered and six-membered carbon rings can be obtained. And the one-step synthesis of the key chiral spiro intermediate of the medicine ubrogepant is realized. The method is mild in reaction condition and simple in process, the target compound can be obtained without water-free and oxygen-free operation, the requirement for production equipment is low, the substrate application range is wide, and the method has extremely high industrial application value.

Description

technical field [0001] The invention belongs to the field of organic synthesis methodology, and specifically prepares chiral five-membered and six-membered carbocyclic oxindole spiro compounds and analogues, and applies the new method to the synthesis of key intermediates of ubrogepant. Background technique [0002] The chiral oxindole spirocyclic skeleton with five-membered and six-membered carbon rings widely exists in active natural products and drug molecules, and has important drug development value. For example, the metabolite paraherquamide A isolated from Penicillium contains a five-membered carbocyclic oxindole spiro core skeleton, which exhibits good antiparasitic activity (Nat. Catal. 2020, 3, 497–506.); The clinical drug satavaptan, which is used to improve ascites in patients with cirrhosis, contains a six-membered carbocyclic oxindole spiro core skeleton (Nature Clinical Practice Gastroenterology & Hepatology 2008, 5, 534.). In particular, in 2019, the U.S. Fo...

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Problems solved by technology

[0018] (1) The structure of raw materials involved in the above reactions is complex, the synthesis route is long, and the preparation cost is high;

[0019] (2) The chiral ligands involved in the above reactions are difficult to prepare, which is not conducive to large-scale production;

[0020] (3) The above method is suitable for the synthesis of a single five-membered or six-membered chiral spiro compound, and cannot realize the unified and general synthesis of two types of important spiro ring structure compounds

[0021] (4) The synthetic route of the key chiral spiro ring intermediate of the drug ubrogepant is tedious, and the chiral intermediate is prepared by chiral resolution, the raw material utilization rate is extremely low, and the cost is high

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