Tenofovir preparation method suitable for industrialized production

Abstract

The invention provides a tenofovir preparation method suitable for industrialized production. According to the method, tenofovir is obtained through catalyzing and hydrolyzing a raw material intermediate (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine via trimethylbromosilane, wherein the raw material intermediate (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine is obtained through the following steps: firstly, obtaining (R)-9-(2-hydroxypropyl)adenine via the ring-opening condensation of adenine and (R)-epoxypropane under an alkaline condition; secondly, catalyzing the (R)-9-(2-hydroxypropyl)adenine through lithium t-butoxide; thirdly, conducting etherification on the catalyzed (R)-9-(2-hydroxypropyl)adenine and p-benzenesulfonyloxymethyl phosphoric acid diethylester, so as to obtain the (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine. The method is characterized in that purified water of appropriate proportion is added in a mixed product obtained through catalyzing and hydrolyzing the (R)-9-[2-(diethylphosphonomethoxy)propyl] adenine via trimethylbromosilane; the tenofovir is obtained through spontaneous crystallization at an appropriate temperature and cooling rate, as well as at an appropriate stirring speed. According to the invention, the obtained tenofovir product has the characteristics of high yield, strong indissolubility in operation under room temperature, simplicity in filtration and collection due to large particles, short production time, low energy consumption, and the like.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to an antiviral drug 9-[(R)-2-[[bis[(isopropoxyacyloxy)methoxy]phosphono]methoxy]propyl ] Synthesis of adenine fumarate intermediate. Background technique [0002] Tenofovir disoproxil fumarate, [Chinese alias] (R)-9-(2-phosphomethoxypropyl) adenine bis(isopropoxycarbonyloxymethyl) ester fumarate, [chemical name 】(R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate, It is a nucleotide reverse transcriptase inhibitor and a prodrug of tenofovir (PMPA), which is mainly used clinically to treat human immunodeficiency virus (HIV) infection. The structural formula is as follows: [0003] [0004] Chinese patent CN1244200 has reported a kind of synthetic technique of tenofovir disoproxil fumarate: (S)-glycidol is reduced to (R)-1,2-propanediol by catalytic hydrogenation, then reacts with diethyl carbonate to obtain ...

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Problems solved by technology

[0006] The (R)-9-[2-(diethylphosphonomethoxy) propyl group] adenine hydrolysis step in the above-mentioned technical route mainly has the following problems in the actual production process: Precipitation is purified to obtain the method for tenofovir, the amount of added water is too little (only 3 times), this makes the reaction solution extremely viscous, which hinders the crystallization of tenofovir, and the crystals of tenofovir obtained are too fine and less in amount, which makes it very difficult to filter and requires strict filtering equipment; moreover, the operating temperature Slightly higher (≥5°C), the phenomenon that the precipitate will be redissolved in the reaction mixture solution will seriously affect the yield of the industrialized large-scale production process. At the same time, the filtration process requires low temperature operation, which virtually increases the process cost; The process is to adjust the pH to about 0.9-1.3 at 35-50°C while maintaining the temperature at about 45°C, add PMPA seeds to the mixture, and then adjust the pH to about 2.6-3.0 while maintaining the temperature at about 35-50 ℃, under slow to moderate stirring without splashing the contents, take about 3-20 hours to cool the solution to about 35 ℃ and the product begins to precipitate

In actual production and application, it is found that the above method takes too long at the heating temperature and is unnecessary. It is often impossible to cause crystallization when the seed crystal is put in at 45°C, and the tenofovir product is also often lowered to 35°C after cooling down. Failure to precipitate normally, poor reproducibility in production

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