A kind of tenofovir preparation method suitable for industrialized production

A technology of tenofovir and its products, which is applied in the field of drug synthesis, can solve the problems affecting the yield of industrialized large-scale production process, demanding filtering equipment, and hindering the crystallization of tenofovir, so as to achieve convenient industrial production, easy operation and reproducibility good sex effect

A technology of tenofovir and its products, which is applied in the field of drug synthesis, can solve the problems affecting the yield of industrialized large-scale production process, demanding filtering equipment, and hindering the crystallization of tenofovir, so as to achieve convenient industrial production, easy operation and reproducibility good sex effect

CN104098605BActive Publication Date: 2015-09-30FUJIAN COSUNTER PHARMA CO LTD
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  • A kind of tenofovir preparation method suitable for industrialized production
  • A kind of tenofovir preparation method suitable for industrialized production
  • A kind of tenofovir preparation method suitable for industrialized production

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Experimental program
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preparation example Construction

[0033] Preparation of tenofovir

[0034] Reaction formula:

[0035]

Embodiment 1

[0037] Feed 20kg of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine and 160L of acetonitrile. Dissolve at 60°C, add 60kg of trimethylbromosilane dropwise, and react under reflux at 80°C. After the reaction was completed, it was filtered, and the filtrate was concentrated. After the concentration is completed, add 160L of water (the amount of water added: (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine=8:1), let the layers stand, and collect the lower liquid . Add 50% sodium hydroxide to adjust the pH value to ≈3.0, use gradient cooling, first cool down to 20°C for crystallization for 4 hours, then cool down to 10°C for 4 hours, then cool down to 0°C for 8 hours, and stir slowly during the process (stirring speed 100r / min, stirring for 5 minutes every hour). The product was suction filtered, dried, and weighed to obtain tenofovir 10.50kg.

Embodiment 2

[0039] Feed 20kg of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine and 160L of acetonitrile. Dissolve at 60°C, add 60.00kg of bromotrimethylsilane dropwise, and react under reflux at 80°C. After the reaction was completed, it was filtered, and the filtrate was concentrated. After the concentration is completed, add 120L of water (the amount of water added: (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine=6:1), let the layers stand, and collect the lower liquid . Add 50% sodium hydroxide to adjust the pH value to ≈2.5, use gradient cooling, first cool down to 20°C for crystallization for 4 hours, then cool down to 10°C for 8 hours, then cool down to 0°C for 12 hours, and stir slowly during the process (stirring speed 200r / min, stirring for 5 minutes every hour). Suction filtration, dry, weigh, obtain tenofovir 9.73kg.

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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 ...

Claims

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Application Information

Patent Timeline
30 Sep 2015
Publication
CN104098605B
IPC
C07F9/6561
Inventors
林桂坤; 吴文强