Method for preparing phosphonyl methoxyl nucleotide analogue

A technology of phosphonomethoxy nucleotide and diethylphosphonomethoxy nucleotide is applied in the field of synthesizing phosphonomethoxy nucleotide analogs, and can solve the problems of high market price and high production cost of PMPA, To achieve the effect of easy control of process operation, low cost and safe reagents

Active Publication Date: 2009-09-16
江西迪赛诺制药有限公司
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  • Abstract
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Problems solved by technology

[0006] In the above-mentioned synthetic route, the deethylation reagent used in the above-mentioned method in the third step reaction is iodotrimethylsilane or bromotrimethylsilane, and the commercial prices of these two kinds of reagents are all relatively high, so the production cost of PMPA is relatively high at present. high

Method used

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  • Method for preparing phosphonyl methoxyl nucleotide analogue
  • Method for preparing phosphonyl methoxyl nucleotide analogue
  • Method for preparing phosphonyl methoxyl nucleotide analogue

Examples

Experimental program
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Effect test

Embodiment 1

[0020] (R)-9-[2-(phosphonomethoxy)propyl]-adenine (PMPA)

[0021] Dissolve 38.0g of PMPA diethyl ester in 38ml of acetonitrile, add 12.0g of sodium bromide, then control the system at 45°C, add 29.0g of trimethylchlorosilane dropwise, heat up to reflux after the addition, and reflux for 4 hours, TLC followed the reaction. The reaction was terminated after 3 hours, and evaporated to dryness under reduced pressure below 70°C. After cooling the residue to 20°C, 70ml of water was added to control the internal temperature not to exceed 50°C. Then cool to 20°C, add 60ml of dichloromethane and extract twice to remove less polar impurities. The separated aqueous layer was diluted with 50 ml of water and heated to 40°C. The pH meter measured about 1.1, and adjusted the pH value to 2.8 with 0.1N NaOH; then lowered the system temperature to 20°C, and solids began to precipitate after 0.5 hours. After a large amount of solids precipitated, adjust the pH value with 0.1N NaOH to 3.2, th...

Embodiment 2

[0024] (R)-9-[2-(phosphonomethoxy)propyl]-adenine (PMPA)

[0025] Dissolve 35.0g of PMPA diethyl ester in 38ml of acetonitrile, add 16.0g of sodium bromide, then control the system at 45°C, add 25.0g of trimethylchlorosilane dropwise, heat up to reflux after the addition, and reflux for 4 hours, TLC followed the reaction. Finish reaction after 4 hours, post-reaction treatment is basically the same as above, just add 0.2g PMPA obtained in Example 1 as seed crystal after adjusting the pH value to 2.8 with 0.1N NaOH, a large amount of solids are precipitated immediately after 5 minutes like this, other procedures are the same as above . 13.6g of the PMPA fine product obtained. It was analyzed by HPLC area normalization method, and the purity was 99.2%.

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Abstract

The invention provides a method for preparing phosphonyl methoxyl nucleotide analogue, including the following steps of: implementing reflux reaction of (R)-9-(2-(diethyl phosphonyl methoxyl) propyl)-adenine and trimethylchlorosilane in solvent in the presence of catalytic amount of catalyst, and then collecting the target product: (R)-9-(2-(diethyl phosphonyl methoxyl) propyl)-adenine from the reaction product, wherein the catalyst is sodium halide. In the method, the used agent is cheap, easily available, safe and low in cost; the process operation is easy to control and the purity of product can reach over 99 percent.

Description

technical field [0001] The present invention relates to methods for the synthesis of phosphonomethoxy nucleotide analogs. Background technique [0002] Tenofovir (PMPA for short, the same below) is the first nucleotide analogue approved by the US FDA for the treatment of HIV-1 infection, and the approved indications are combined with other antiretroviral drugs for the treatment of HIV — 1 Infection. Its chemical name is (R)-9-[2-(phosphonomethoxy)propyl]-adenine, and its structural formula is as follows: [0003] [0004] At present, the synthetic method of PMPA is mainly as EP206459, US5733788, the synthetic method of bibliographical reports such as US5935946, described method is raw material with adenine, generates (R)-hydroxypropyl adenine with (R)-propylene carbonate condensation, Then condense with diethyl p-toluenesulfonyloxymethyl phosphate under the catalysis of lithium hydride (sodium) or lithium tert-butoxide to generate (R)-9-[2-(diethylphosphonomethoxy) Pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61P31/18
Inventor 李金亮赵楠
Owner 江西迪赛诺制药有限公司
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