Method for synthesizing key intermediate for preparing camptothecine compounds

Abstract

The invention discloses a method for synthesizing key intermediate (S)-4-ethyl-4-hydroxyl-1,7-dihydro-tetrahydro-pyran[3,4-c]pyridine-3,8-one for preparing camptothecine compounds, which is characterized in that the intermediate is synthesized by using a nicotinic acid derivative as raw material and (2R)-1,2-O-isopropylidenedioxy-3-pentanone as a chiral inducing reagent and by the following steps: carrying out the nucleophilic reaction of an intermediate generated by the treating the nicotinic acid derivative with a lithium reagent and the chiral inducing reagent, and treating a resulting lactone compound with diluted hydrochloric acid; reducing the lactone into a glycol compound; protecting the glycol compound; removing N,N'-isopropylidene protecting groups; oxidizing an o-glycol compound into a formyl; oxidizing the formyl into an acid; removing an alcohol protecting group; hydrolyzing an ether to form a hydroxyl; and obtaining the target substance by tautomerism. The method has the advantages of high yield and high stereoselectivity.

Description

technical field [0001] The invention relates to a new synthesis method of camptothecin and a series of camptothecin derivatives, an intermediate in the synthesis process, and (S)-4-ethyl-4-hydroxyl-1,7-dihydro-4hydro - A new synthesis method of pyran[3,4-c]pyridin-3,8-one, which belongs to the technical field of organic synthesis. Background technique [0002] Camptothecin (CPT) is an alkaloid, which was isolated by American scientist Wall in 1966 from the unique Chinese plant camptothecin. Camptothecin has significant activity on rat leukemia L1210 system. Structurally, camptothecin is an alkaloid containing a pyridone structure. The specific structure is as follows, compound 1: [0003] [0004] This structure contains a five-ring structure, in which the E ring is a six-membered lactone ring, and the lactone ring contains an α-hydroxyl group whose absolute configuration is S. After the isolation of camptothecin, it has aroused great interest due to its good anti-leuke...

AI Technical Summary

Problems solved by technology

[0013] Although many important advances have been made in the total synthesis of camptothecin, it is regrettable that the research on the total synthesis of camptothecin has not yet achieved a substantial breakthrough.

The current total synthesis route generally has the following disadvantages: (1) the synthesis route is longer; (2) the total yield is low; (3) the production cost is higher, and many total synthesis methods are always applied to very expensive reagents, such as tert-butyl Lithium, such as expensive chiral inducing reagents to induce chiral (-)-8-phenylmenthol, (-)-trans-2-(2-isopropylphenyl)-cyclohexanol, etc.; (4) Reaction The operation is complicated and the multi-step reaction requires column chromatography to purify the product; (5) the ee value of the final product can only reach about 99%, and the clinical requirement is that its R configuration should not exceed 0.2%, that is, the ee value should be greater than 99.6%

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