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Method for synthesizing (R)-9-(2-phosphate methoxy propyl)adenine

A technology of methoxypropyl phosphate and a synthesis method, which is applied in the field of synthesis of -9-adenine, can solve the problems of low yield, high price and high cost of trimethylchlorosilane, and achieves no environmental pollution and low price. , the effect of high reaction yield

Inactive Publication Date: 2009-04-29
AURISCO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the above-mentioned method, the yield of using trimethylbromosilane and trimethylchlorosilane is low, and these two kinds of raw materials are expensive and make the cost on the high side, but use hydrobromic acid aqueous solution, then cause a large amount of waste water, a big environmental problem

Method used

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  • Method for synthesizing (R)-9-(2-phosphate methoxy propyl)adenine
  • Method for synthesizing (R)-9-(2-phosphate methoxy propyl)adenine
  • Method for synthesizing (R)-9-(2-phosphate methoxy propyl)adenine

Examples

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Embodiment 1

[0019] Synthesis of (R)-9-(2-hydroxypropyl)adenine (HPA)

[0020] Adenine (10.4g, 76.6mmol), sodium hydroxide (0.12g, 3mmol), (R)-1,2-propene carbonate (8.6g, 84.2mmol), DMF (72g) was heated to 132 to 138°C , keep the reaction until the cloudy liquid dissolves and then keep it warm for 1 hour. Cool to below 100°C, adjust PH≈7 with methanesulfonic acid. Cool to below 80°C, add 150ml of alcohol, stir and cool to below 10°C and keep warm for 3 hours, filter with suction, and dry to obtain 11g white powder with HPLC purity of 90-100% (yield is 74% in terms of adenine).

Embodiment 2

[0022] Synthesis of (R)-9-(2-(bisethylphosphono)methoxypropyl)adenine (PMPA diester) HPA (100 g, 0.518 mol) was dissolved in DMF (200 ml) at room temperature, Add magnesium tert-butoxide (71g, 0.415mol), heat to 60°C and keep it warm for 1 hour, raise the temperature to above 74°C, add diethyl-p-toluenesulfonate methylphosphonate (200g, 0.6216mol) dropwise in about 2 hours, Then keep it warm at 74-78°C for 5 hours. Cool to room temperature, add glacial acetic acid (60 g, 1.0 mol), stir for 15 minutes, and concentrate the solution under reduced pressure to obtain PMPA diester as a viscous liquid.

Embodiment 3

[0024] Synthesis of (R)-9-(2-(methoxypropyl phosphate)adenine (PMPA)

[0025] The viscous liquid obtained in Example 2 was added with 200ml DMF, cooled to below 0°C, and phosphorus tribromide (112g, 0.414mol) was added dropwise while keeping the temperature not exceeding 50°C, and the temperature was raised to 70°C for 5 hours after dropping. After the reaction is complete, cool to below 0°C, add 40 g of water dropwise, and then concentrate the reaction solution under reduced pressure. Add 300ml of water to the concentrated solution, wash twice with 150ml of dichloromethane, adjust the pH of the aqueous layer to ≈3 with 1N sodium hydroxide solution, cool to below 10°C, keep warm for 3 hours, and filter with suction. The obtained PMPA crude product is refined with water to obtain a finished product, and the HPLC purity is 98-100%. PMPA dry product 70g (yield is 47% based on HPA).

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Abstract

The invention discloses a method for synthesizing (R)-9-(2-phosphonomethoxypropyl) adenine. The method comprises the following steps: (R)-9-(2- hydroxypropyl) adenine and methyl phosphono diethyl p-toluenesulfonate are taken as raw materials to synthesize (R)-9-(2-( diethylphosphono) methoxypropyl) adenine and then diethyl is removed to give the (R)-9-(2-phosphonomethoxypropyl)adenine. The method has the advantages of readily available raw materials, low price, no pollution to environment, high yield of reactions, simple process and suitability for mass production.

Description

technical field [0001] The invention relates to drug synthesis, in particular to a synthesis method of (R)-9-(2-phosphomethoxypropyl)adenine. Background technique [0002] In recent years, due to the continuous spread of AIDS, it has become a worldwide epidemic. Tenofovir (tenofovir), chemical name: (R)-9-(2-phosphomethoxypropyl) adenine (PMPA) ), is the first FDA-approved nucleotide analog for the treatment of HIV-1 infection, its importance has been recognized by the World Health Organization, and is recommended as a first-line antiviral drug. At the same time, due to its outstanding effect in the field of antiviral therapy, it is also used for anti-hepatitis B virus therapy. [0003] The structural formula of (R)-9-(2-phosphomethoxypropyl) adenine is as follows: [0004] [0005] Regarding the synthetic method of Tenofovir, in the prior art, the technique of producing Tenofovir is to use (R)-9-(2-hydroxypropyl) adenine and diethyl p-toluenesulfonic acid methyl After...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61P31/18
Inventor 张毅褚定军
Owner AURISCO PHARMACEUTICAL CO LTD
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