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Preparation method of tenofovir disoproxil fumarate

A technology of tenofovir disoproxil fumarate and disoproxil fumarate, which is applied in the field of synthesis of tenofovir disoproxil fumarate, can solve the problem of high organic residues, achieve less side reaction products, overcome organic residues and Excessive side reactants and the effect of removing organic residues

Active Publication Date: 2015-03-25
山东世博金都药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The technical problem to be solved in the present invention is: to overcome the deficiencies of the prior art, to provide a preparation method of tenofovir disoproxil fumarate, which overcomes the organic residues and by-products in the process of step three refining and recrystallization The problem of too high, the total yield can reach more than 40%, and the content of tenofovir disoproxil fumarate in the final product is high, the recrystallization process is easy to operate, low in cost, and has no toxic and harmful side reactions and products

Method used

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  • Preparation method of tenofovir disoproxil fumarate
  • Preparation method of tenofovir disoproxil fumarate
  • Preparation method of tenofovir disoproxil fumarate

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Embodiment 1

[0033] Embodiments 1 to 3 are specific embodiments of the present invention, wherein embodiment 1 is the best embodiment.

[0034] Example 1

[0035] The preparation method of this embodiment includes the following steps: preparing tenofovir disoproxil, preparing crude tenofovir disoproxil fumarate, and refining tenofovir disoproxil fumarate;

[0036]First, the specific operation of the step of preparing tenofovir disoproxil is:

[0037] 1) Add 49.25kg of N-methylpyrrolidone into the reaction kettle, then add 12kg of tenofovir into the reaction kettle and stir well, then add 17.2kg of triethylamine and 12kg of tetrabutylammonium bromide When the reaction kettle is heated to 46°C under the conditions, add 30.3kg of chloromethyl isopropyl carbonate dropwise, control the reaction temperature not to exceed 55°C, and continue to stir and react for 4 hours, then lower the temperature until the liquid in the reaction kettle is cooled to 40°C 50 kg of cyclohexane was added twice f...

Embodiment 2

[0049] The preparation method of this embodiment includes the following steps: preparing tenofovir disoproxil, preparing crude tenofovir disoproxil fumarate, and refining tenofovir disoproxil fumarate;

[0050] First, the specific operation of the step of preparing tenofovir disoproxil is:

[0051] 1) Add 49.25kg of N-methylpyrrolidone into the reaction kettle, then add 12kg of tenofovir into the reaction kettle and stir well, then add 17.2kg of triethylamine and 12kg of tetrabutylammonium bromide When the reaction kettle is heated to 46°C under the conditions, add 30.3kg of chloromethyl isopropyl carbonate dropwise, control the reaction temperature not to exceed 55°C, and continue to stir and react for 4 hours, then lower the temperature until the liquid in the reaction kettle is cooled to 40°C 50 kg of cyclohexane was added twice for washing, stirred for 30 minutes, allowed to stand for 15 minutes to separate layers, and the cyclohexane phase was discarded, and the liquid af...

Embodiment 3

[0063] 1) Add 49.25kg of N-methylpyrrolidone into the reaction kettle, then add 12kg of tenofovir into the reaction kettle and stir well, then add 17.2kg of triethylamine and 12kg of tetrabutylammonium bromide When the reaction kettle is heated to 46°C under the conditions, add 30.3kg of chloromethyl isopropyl carbonate dropwise, control the reaction temperature not to exceed 55°C, and continue to stir and react for 4 hours, then lower the temperature until the liquid in the reaction kettle is cooled to 40°C 50 kg of cyclohexane was added twice for washing, stirred for 30 minutes, allowed to stand for 15 minutes to separate layers, and the cyclohexane phase was discarded, and the liquid after washing was retained;

[0064] 2) Add 50 kg of water and 110 kg of ethyl acetate to the washed liquid for extraction, separate layers, and keep the ethyl acetate phase. Wash the aqueous phase twice with 55kg ethyl acetate twice, and combine the ethyl acetate phases;

[0065] 3) Wash the...

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Abstract

The invention discloses a preparation method of tenofovir disoproxil fumarate, belonging to the technical field of synthesis of tenofovir disoproxil fumarate. The preparation method comprises the following steps: preparing tenofovir disoproxil, preparing a tenofovir disoproxil fumarate crude product and refining the tenofovir disoproxil fumarate, wherein in the step of refining the tenofovir disoproxil fumarate, by virtue of a 65% ethanol solution which is used as a tenofovir disoproxil fumarate recrystallizing solvent, the tenofovir disoproxil fumarate is kept in an environment at 5-10 DEG C for 3-6h until the tenofovir disoproxil fumarate is naturally separated out and crystallized. The preparation method disclosed by the invention can be used for solving the problems of high contents of organic residue and side reactant in the process of preparing the tenofovir disoproxil fumarate, and the total yield can reach more than 40%; in addition, the tenofovir disoproxil fumarate occupies a high content in a final product, and the preparation method is simple and convenient to operate in the recrystallizing process, low in cost, and free from toxic and harmful side reactions or products.

Description

Technical field [0001] A preparation method for a pomochexolinoolvyryl aromis is the field of pomolic acid norofovir two pyrarododidae synthesis technology. Background technique [0002] Famolic acid is norofovir diezolin, with a molecular weight of 635.51.Molecular C 19 H 30 N 5 O 10 P · C 4 H 4 O 4 EssenceThere is one hand center in the abalinolic acid pyorvir (pyrarodigolita molecules, which is R-to reflect the body.Fogaolic acid telofovir two pyrarododolita structure: [0003] [0004] First of all, the existing technologies have a low income after synthesis after synthesis, and the synthesis method is more complicated.Secondly, the existing synthetic method is more organic residue in the pomocoliolic norofovir two pyrarododolite.The income rate is low, and the cost of refined methods is high, which is prone to produce the product of side reaction. Invention content [0005] The technical problem to be solved by the present invention is to overcome the lack of existing tec...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07C57/15C07C51/41
Inventor 闫敬武邸春盛王迪杰张大权杜成德
Owner 山东世博金都药业有限公司
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