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

Abstract

The invention discloses a preparation method of (R)-9-[2-(phosphoryl phenol methoxyl)propyl]adenine. The preparation method comprises the following steps: adding (R)-9-[2-(phosphoryl methoxy) propyl] adenine represented by the formula (I) into a solvent, controlling the temperature at -10 to 115 DEG C, adding triphenyl phosphite, starting to stir, controlling the temperature at -10 to 115 DEG C, carrying out a reaction, post-treating the reaction liquid obtained after completion of the reaction, and thus obtaining (R)-9-[2-(phosphoryl phenol methoxy)propyl]adenine represented by the formula (II). The preparation method is simple to operate, high in product yield, low in production cost, and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of (R)-9-[2-(phosphorylphenoxymethoxy)propyl]adenine (CAS Registry Number: 379270-35-6). Background technique [0002] Due to the poor stability of BIS (POC) prodrugs in the presence of liver and plasma lipases, and two molecules of formaldehyde that are harmful to the body are produced during the metabolic process; It is hydrolyzed under the action and has good stability in plasma. However, due to the high stability of bisphosphamide prodrugs, the antiviral activity of this type of prodrugs is reduced. Gilead Sciences combines the characteristics of these two chemical structure modifications, An esterified amidated PMPA prodrug (TAF) was synthesized. [0003] Gilead Sciences Corporation used different amino acid esters and phenyl groups as masking groups to synthesize a series of aminophosphonate derivatives of PMPA---tenofovir amidated prodrugs, and carried out their in vitro biological activities. eval...

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Problems solved by technology

[0014] 1. Use acetonitrile as the reaction solvent, which is expensive and not the best solvent for industrial production;

[0015] 2. Using triethylamine and DMAP as alkali, together with acetonitrile as the reaction solvent, is not easy to recover in industrial scale-up, and the recovery is not a single solvent, which is inconvenient for purification and separation;

[0016] 3. The reaction time exceeds 48 hours, the time is too long, and the energy consumption is too large during industrial scale-up, so it is not suitable for industrial production;

[0017] 4. The end point of the reaction needs to be monitored by nuclear magnetic phosphorus spectroscopy, which is too expensive;

[0018] 5. The post-processing method is too complicated, not only to adjust the acid-base, but also to extract and separate the liquid, which is troublesome to deal with

[0023] 1. Using DCC as a condensation agent will produce a large amount of DCU and a large amount of waste residue;

[0024] 2. Using N-methylpyrrolidone (NMP) as a solvent has a too high boiling point and is not easy to recycle, which objectively increases the cost of the reaction;

[0025] 3. Reaction at 100°C for 22 hours consumes too much energy and is not suitable for industrial production;

[0026] 4. Sodium hydroxide and hydrochloric acid are used for acid-base adjustment in the post-treatment process, resulting in a large amount of salt. Since the product and raw materials are water-soluble, the salt produced by acid-base adjustment will be mixed with the product, which is difficult to remove

[0033] 3. Triphenoxy silicon needs to be synthesized by itself, and there is an extra step in the control point;

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