Method for synthesizing five-membered carbocyclic nucleoside

Abstract

The invention relates to a method for synthesizing five-membered carbocyclic nucleoside, comprising the following steps of: 1) synthesizing a compound 26 in the reaction equation 1, and oxidizing the compound 26 into a dicarbonyl compound 34 by the use of a TEMPO-NaClO system; 2) carrying out selective protection on ketone carbonyl in the compound 34 to generate a compound 35; 3) reducing ketone carbonyl in the compound 35 into a compound 36 with a terminal containing a double bond; 4) performing an addition reaction between the compound 36 and hydrogen bromide by anti-Markovnikov's rule to obtain a bromide 37; and 5) carrying out lithium halogen exchange on the compound 37 to generate nucleophilic addition cyclization within the molecules so as to obtain a compound 38, namely five-membered ring carbasugars; and performing a routine reaction to obtain the five-membered carbocyclic nucleoside. By the adoption of the method provided by the invention, the yield of the five-membered ring carbasugars is greatly raised, and simultaneously usage frequency of extreme low temperature reaction is minimized. All the raw materials used are cheap and easily available.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method and application of a five-membered carbocyclic nucleoside. Background technique [0002] Nucleoside compounds play an important role in the research of antiviral drugs, and the structural modification of natural nucleosides is an important means to find new and more effective antiviral drugs. [0003] Nucleosides after structural modification should achieve the following goals: 1) can be used as substrates of certain kinases in cells, easily converted into triphosphate compounds, and can be coupled to nucleotides under the action of nucleoside polymerases In the sequence, the antiviral and antitumor effects of nucleosides can be fully exerted; 2) non-toxic or low-toxic; 3) have the ability to resist the action of certain enzymes (such as phosphorylase) in the body, so as to avoid the destruction of glycosidic bonds and failure . [0004] Carbocyclic nucleosides ...

AI Technical Summary

Problems solved by technology

[0021] For the synthetic method that Arita develops, existing problem is: 1) raw material is difficult to obtain; 2) the selective deesterification reaction of porcine liver lipase is difficult to control, selectivity is low; 3) ozonation reaction is difficult to control

[0022] For the method of synthesizing five-membered carbocyclic nucleosides using D-ribose as a raw material, there are problems: 1) In the reaction route, the oxidation method used in the step of oxidizing hydroxyl to carbonyl needs to be carried out at minus 70°C, which is relatively harsh; 2) ) The yield of the reaction of carbonyl with alkenyl Grignard reagent is very low, usually less than 10%; 3) The catalyst used in olefin metathesis reaction is extremely expensive

[0023] In summary, it is of great significance to develop a novel five-membered carbocyclic nucleoside synthetic method that can avoid the shortcomings of existing synthetic methods, such as difficult control of reaction conditions, harsh reaction conditions, and low yield.

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