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A kind of tenofovir disoproxil fumarate with large particle size and preparation method thereof

A technology of tenofovir disoproxil fumarate and disoproxil fumarate, which is applied in the field of large-particle tenofovir disoproxil fumarate and its preparation, can solve the problem of increased cost, long time consumption, and high product content Impurities and other problems can be reduced to achieve the effects of reducing production energy consumption, simple process operation, and controllable product quality

Active Publication Date: 2020-11-17
四川仁安药业有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The pore size of the filter medium is too small, which is not conducive to the rapid separation of solids and liquids, which will lead to more impurities in the product; and every time the centrifuge increases the centrifugal speed of a step, under the strong centrifugal force, there are huge requirements for equipment and technology. challenges, costs will increase substantially
Therefore, the filtration and washing of small particle size particles have high requirements on the centrifuge, and it takes a long time and consumes a lot, which will easily lead to an increase in the preparation cost, which is not conducive to the requirements of industrial production.

Method used

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  • A kind of tenofovir disoproxil fumarate with large particle size and preparation method thereof
  • A kind of tenofovir disoproxil fumarate with large particle size and preparation method thereof
  • A kind of tenofovir disoproxil fumarate with large particle size and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Under nitrogen protection, 30.0 kg of isopropanol was put into the reaction kettle, 5.0 kg of tenofovir disoproxil was added under stirring, and the temperature was raised to 55-65° C. to completely dissolve the solid to obtain a clear solution. Add 2.0kg of fumaric acid into the reaction kettle, stir until clarified, continue to stir for 1 hour; cool down to 37-40°C, add 3.0kg of acetone dropwise, stop stirring, and let stand for 60 minutes for crystallization. Stir and heat up to 50-53°C, continue stirring for 20 minutes; cool down to 38-42°C, stop stirring, and stand for crystallization for 60 minutes; stir and heat up to 50-53°C, continue stirring for 20 minutes; cool down to 38-42°C, Stop stirring, and let stand for crystallization for 60 minutes; cool the system to 30-34°C at a cooling rate of 1-2°C / min, stir and crystallize for 2 hours; continue to cool down to 5-10°C, stir and crystallize for 8 hours, centrifuge, The filter cake was rinsed with a small amount of...

Embodiment 2

[0052] Under the protection of nitrogen, 70.0 kg of isopropanol was put into the reaction kettle, 10.0 kg of tenofovir disoproxil was added under stirring, and the temperature was raised to 60-65° C. to completely dissolve the solid to obtain a clear solution. Add 4.0kg of fumaric acid into the reaction kettle, stir until clear, and continue stirring for 1 hour; cool down to 35-38°C, add 5kg of ethyl acetate dropwise, stop stirring, and stand for 60 minutes to crystallize. Stir and heat up to 52-55°C, continue stirring for 25 minutes; cool down to 35-38°C, stop stirring, and let stand for crystallization for 60 minutes; stir and heat up to 52-55°C, continue stirring for 25 minutes; cool down to 35-38°C, stop stirring, Stand still for crystallization for 60 minutes; cool the system to 25-30°C at a cooling rate of 1-2°C / min, stir and crystallize for 2 hours; continue to cool down to 5-10°C, stir and crystallize for 12 hours, centrifuge, filter cake with appropriate amount Wash w...

Embodiment 3

[0054] Under nitrogen protection, 12.0 kg of isopropanol was put into the reaction kettle, 2.0 kg of tenofovir disoproxil was added under stirring, and the temperature was raised to 55-60° C. to completely dissolve the solid to obtain a clear solution. Add 800.0 g of fumaric acid into the reaction kettle, stir until clear, and continue stirring for 1 hour; cool down to 35-40°C, add 1.2 kg of dichloromethane dropwise, stop stirring, and stand for crystallization for 1 hour. Stir and cool the system to 25-30°C at a cooling rate of 1-2°C, stir and crystallize for 1 hour; continue to cool down to -5-0°C, stir and crystallize for 10 hours, centrifuge, and rinse the filter cake with an appropriate amount of isopropanol. Tenofovir disoproxil fumarate was obtained. Particle size D90=119 microns, D50=10.2 microns, D10=2.14 microns; purity 99.51%.

[0055] current technology:

[0056] Under nitrogen protection, 12.0 kg of isopropanol was put into the reaction kettle, 2.0 kg of tenofov...

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Abstract

The invention belongs to the field of medicinal chemistry, and concretely relates to a preparation method for large-particle tenofovir disoproxil fumarate. The method comprises the following steps: (1) taking a mixed liquid of a tenofovir disoproxil fumarate and a good solvent, regulating the mixed liquid to a first temperature, then adding a poor solvent, and performing crystallization; (2) raising the temperature to a second temperature, then performing cooling to the first temperature, and performing crystallization; and operating the step zero time or more; (3) performing cooling to a third temperature, and performing crystallization; (4) performing cooling to a fourth temperature, and performing crystallization; and (5) separating solid and liquid to obtain the large-particle tenofovir disoproxil fumarate. The preparation method for the large-particle tenofovir disoproxil fumarate improves varieties and ratios of solvents adopted for product crystallization, thus process operation is simple, product quality is controllable, particle sizes of tenofovir disoproxil fumarate obtained by a conventional crystallization process are improved from 10-20 micrometers to 100-500 micrometers, production energy consumption is reduced, and product purity reaches 99.5% or more.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a large particle size tenofovir disoproxil fumarate and a preparation method thereof. Background technique [0002] Tenofovir Disoproxil Fumarate (Tenofovir Disoproxil Fumarate) is a new type of oral broad-spectrum antiviral drug developed by Gilead Sciences. The drug is a prodrug, an analog of adenosine monophosphate, with a non-cyclic nucleoside phosphodiester structure, which undergoes ester group hydrolysis and phosphorylation in vivo into tenofovir diphosphate. Nofovir diphosphate competes with the natural substrate deoxyadenosine 5'-triphosphate, inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase, and fuses with viral DNA, thereby terminating DNA chain extension. [0003] Tenofovir disoproxil fumarate is currently the first nucleotide analog approved by the FDA for the treatment of HIV-1 infection, and its importance has also b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561C07C51/43C07C57/15
CPCC07F9/65616
Inventor 崔阳文张平黄俊黄浩喜李英富苏忠海
Owner 四川仁安药业有限责任公司