Tenofovir preparation method

Abstract

The invention discloses a tenofovir preparation method. The method comprises reactions with equations shown in the specification; and in the equations, A is a C1-C4 alkylcarbonyl group or an aryl-substituted C1-C4 alkylcarbonyl group, B is H, a C1-C4 alkylcarbonyl group or an aryl-substituted C1-C4 alkylcarbonyl group, R is a C1-C3 alkyl group or a phenyl group, R' is H, a C1-C3 alkyl group or a phenyl group, a reaction a is characterized in that a compound of formula III reacts with (R)-propylene carbonate and dialkyl (tosyloxy)methylphosphonate to generate an intermediate II, and a reaction b is characterized in that the intermediate II is hydrolyzed under the action of an inorganic acid to remove a protection group in order to obtain tenofovir. The method can realize synthesis of highly pure tenofovir in low cost and high yield by using cheap and easily available raw materials through simple operation under mild reaction conditions, has the advantages of energy saving and environmental protection, is suitable for large scale production, and has significant values for realizing the industrial production of tenofovir.

Description

technical field [0001] The invention relates to a method for preparing tenofovir, which belongs to the technical field of medicinal chemistry. Background technique [0002] Tenofovir, as the first nucleotide analogue approved by the FDA for the treatment of HIV-1 infection, has been recognized by the World Health Organization and recommended as a first-line antiviral drug. Due to the important impact of the drug, India accepted the request of Cipla, an Indian generic drug manufacturer, in September 2009 to refuse patent protection for Tenofovir to ensure that the drug can be more easily accepted by low-income countries. Its chemical structural formula is as follows: [0003] [0004] At the same time, because tenofovir also has outstanding effects in the field of antiviral treatment, in addition to its application in anti-AIDS treatment, it also shows a good therapeutic effect in anti-hepatitis B virus. [0005] In the journal literature published in 2010: Organic Proce...

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Problems solved by technology

[0008] 1. In the reaction of generating intermediate 2, when the magnesium salt mixture is converted to tenofovir, the magnesium salt mixture must be separated from the system after forced analysis with ethyl acetate, because the magnesium salt mixture is easy to absorb moisture and Adsorption products require high operational requirements and are very cumbersome in actual processing;

[0009] 2. Since intermediate 2 needs to dissociate two ethyl groups, harsh dissociation conditions must be used;

[0010] 3. In terms of cost, due to the use of a large excess of trimethylsilane and sodium bromide, there are serious defects in both production cost and environmental protection

[0016] Although the method simplifies the process operation, reduces the cost, and is beneficial to industrialized production, the method is the same as the preparation process of tenofovir in the prior art: adenine is the starting material, and adenine and R - Propylene carbonate reaction will produce a 7-substituted by-product: (R)-7-(2-hydroxypropyl) adenine, generally this by-product is above 7%; and regardless of changing the catalyst, solvent or temperature There is no way to reduce the content of the by-product, and this isomer will also participate in the follow-up reaction, thereby causing the difficulty of follow-up treatment and the increase of cost, so that it still cannot ideally meet the needs of industrialized preparation of high-purity tenofovir

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