Preparation method of (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine

A technology of phosphonomethoxy and diethylphosphonomethoxy, which is applied in the field of preparation of AIDS antiviral drugs, can solve the problems of complicated process and difficulty in industrialization, and achieve improved product yield, easy industrial chemical industry, and raw materials Easy to get effect

Active Publication Date: 2016-06-08
扬州三友合成化工有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] 2. Protect the amino group of (R)-hydroxypropyl adenine first, and then react with diethyl p-toluenesulfonyloxymethylphosp

Method used

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  • Preparation method of (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine
  • Preparation method of (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine
  • Preparation method of (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine

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Embodiment Construction

[0036] 1. Preparation of (R)-9-[2-(diethylphosphonomethoxy)propyl]-adenine (referred to as PMPA diethyl ester):

[0037] In the drying system, add 10g (R)-hydroxypropyl adenine, 47g DMF (N,N-dimethylformamide), 6.2g magnesium tert-butoxide into the four-necked flask, and raise the temperature to 70±5°C under stirring After keeping the temperature for 1h, add 21g of diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) dropwise, then keep the temperature for 4h, and take samples under the control of HPLC. When HPA2 O (p-toluenesulfonic acid monohydrate) and 18.5g DMF mixed solution, after the dropwise addition, the temperature was raised to 80°C, DMF was evaporated under reduced pressure, 350g ethyl acetate was added, filtered while hot, the filtrate was distilled, and ethyl acetate was evaporated Esters to obtain PMPA diethyl ester.

[0038] 2. Preparation of (R)-9-[2-(phosphonomethoxy)propyl]-adenine (PMPA for short):

[0039] Add the PMPA diethyl ester obtained in the previ...

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Abstract

The invention discloses a preparation method of (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine, and relates to a preparation method of an antiviral drug for an acquired immune deficiency syndrome. The method comprises the steps that when (R)-9-[2-(diethyl phosphoryl methoxyl)propyl]-adenine is prepared, (R)-hydroxypropyl adenine and diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) are subjected to a condensation reaction under the action of magnesium tert-butoxide to generate the (R)-9-[2-(diethyl phosphoryl methoxyl)propyl]-adenine; PMPA diethyl ester is subjected to deethylation through trimethylbromosilane by taking water as solvent to obtain the (R)-9-[2-(phosphoryl methoxyl)propyl]-adenine (PMPA). According to the technology, the product yield is increased, the technology is cleaner, the production cost is lowered, the product yield is increased, the raw materials are easy to obtain, and industrialization is easy to achieve.

Description

technical field [0001] The invention relates to a preparation method of AIDS antiviral drugs, in particular to the technical field of production of drug intermediates. Background technique [0002] (R)-9-[2-(phosphonomethoxy)propyl]-adenine is an HIV antiretroviral drug (tenofovir) and the better HIV antiretroviral drug Tylenol fumarate The key intermediate of Fuvir dipivoxil. Due to the good anti-AIDS activity of tenofovir, especially tenofovir disoproxil fumarate, it is widely used clinically. Tenofovir, as the first nucleotide analogue approved by the FDA for the treatment of HIV-1 infection, has also 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. At the same time, because...

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 李辉宁
Owner 扬州三友合成化工有限公司
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