Simple and convenient synthesis method of N9-alkylate nucleoside analogs on purine framework

Abstract

The invention discloses a simple and convenient synthesis method of N9-alkylate nucleoside analogs on a purine framework. The method comprises the following steps that 2,6-site substituted purine derivatives and excessive alkyl ether are added into a reactor; next, non-metallic catalysts and oxidizing agents are added; oxidization coupling reaction is performed under the heating and stirring conditions; thin layer chromatography is used for tracking the reaction; after the reaction is completed, the materials are cooled to the room temperature; vacuum concentration is performed to remove solvents; column chromatography purification is performed; the N9-alkylate nucleoside analogs on the purine framework are obtained. The synthesis method provided by the invention has the advantages that the raw materials are cheap and can be easily obtained; the reaction conditions are mild; the reaction steps are few; the operation is simple; the problems of easy poisoning by metal catalysts, compatibility difficulty of active groups and many reaction sites in the purine derivatization reaction in the prior art are solved; the N9-alkylate nucleoside analogs on the purine framework can be efficiently synthesized.

Description

Technical field [0001] The invention relates to the technical field of nucleoside analog synthesis, in particular to an N9-alkylated nucleoside analog on a purine skeleton and a simple synthesis method thereof. Background technique [0002] Nucleoside drugs play a very important role in clinical antiviral therapy. The modified or modified nucleoside analogues have a certain similarity to natural nucleosides, and their targets are the reverse transcriptase of RNA virus and the polymerase of DNA virus, and they are inserted into the viral DNA chain in competition with nucleotides. , Inhibit or terminate the extension and synthesis of the viral DNA chain, thereby inhibiting the replication of viral DNA. The modified and modified nucleoside analogues have unique biological activities. So far, the antiviral nucleoside drugs that have been used in clinical treatment are: Acyclovir (ACV), which can interfere with viral DNA polymerase and inhibit viral Replication; Ganciclovir (Gancicl...

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Problems solved by technology

[0003] At present, the main methods for the synthesis of traditional nucleoside analogs are: 1. Use a halogenated alkyl compound to undergo a nucleophilic substitution reaction with a purine. This method requires pretreatment of the alkylating agent, and usually requires the addition of a strong base to promote the reaction, and The formation of by-products at other reaction sites of purines cannot be avoided, resulting in difficulties in subsequent separations (Kotek, V.; Chudíkova′, N.; Tobrman, T.; Dvoròa′k, D.; Selective Synthesis of 7-Substituted Purines via 7, 8-Dihydropurines. Org. Lett., 2010, 12, 5724)

2. Traditional transition metal-catalyzed cross-coupling reactions. This method requires transition metals as catalysts, and transition metals are generally expensive and easily chelated or coordinated with purines, resulting in catalyst poisoning (Kim, D.; Jun, H.; Lee, H.; Hong, S-S.; Hong, S., Development of New Fluorescent Xanthines as Kinase Inhibitors. Org. Lett., 2010, 12, 1212)

4. In 2013, Liu jinhua's research group published a CuCl 2 As a catalyst, TBHP is an oxidizing agent. Under the regulation of ligands, a series of purine N9 derivatives were synthesized through the coupling reaction of purine and ether compounds. However, this reaction requires ligand regulation, which increases the complexity of the reaction process and affects Its industrial application (Huang, R.; Xie, C.; Huang, L.; Liu, J., Copper-catalyzed N-alkoxyalkylation of nucleobases involving direct functionalization of sp3 C–H bonds adjacent to oxygen atoms. Tetrahedron 2013,69,577 -582.)

Therefore, seeking a kind of cheap and easy-to-obtain raw materials, mild reaction conditions, few reaction steps, simple operation, and efficient synthesis of N9-alkylated nucleoside analogues on the purine skeleton is based on solving the problem of metal catalysts in the purine derivatization reaction. Poisoning, incompatibility of active groups, many reaction sites, etc., and the synthesis of nucleoside drugs with potential pharmacological activity is imminent and urgent

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