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New method for preparing tenofovir disoproxil fumarate

A technology of tenofovir disoproxil fumarate and tenofovir, which is applied in the field of organic compound synthesis, can solve the problems of increased difficulty in diesterization, difficult processing, and increased environmental protection pressure, and achieves a small burden on the treatment of three wastes and a low reaction rate The overall yield is high and the effect of reducing the pressure of environmental protection

Inactive Publication Date: 2016-04-13
SUZHOU HOMESUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The existing production technology of tenofovir disoproxil fumarate is to synthesize tenofovir disoproxil after esterification reaction from tenofovir monohydrate or anhydrate as starting material and chloromethyl isopropyl carbonate, and then Salify with fumaric acid to get tenofovir disoproxil fumarate, but the reaction conversion rate is low in the existing synthetic technology, the main reason is that tenofovir is first monoesterified during esterification, and then continues to react Diesterification, but after monoesterification, due to the increase in steric hindrance, the reaction activity decreases, and the difficulty of diesterification increases, resulting in the presence of monoester in the reaction and affecting the reaction yield.
And because there are a large number of single-substituted products, post-reaction treatment is also more difficult, and product quality is more difficult to guarantee
Although the positive progress of the reaction is promoted by increasing the amount of raw materials, this will greatly increase the production cost, and when the raw materials increase to a certain amount, the forward reaction will reach an equilibrium, and the conversion will not continue
In addition, the esterification reaction in the existing synthesis technology uses a solvent with a high boiling point, and tenofovir disoproxil is unstable at high temperature and cannot be directly recovered, so a large amount of ice water is generally used for salting out or a large amount of Washing with water causes a large amount of solvent to enter the sewage treatment system, which not only increases the pressure on environmental protection, but also causes the product cost to be too high because the solvent cannot be recycled

Method used

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  • New method for preparing tenofovir disoproxil fumarate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Such as figure 1 As shown, the synthesis process of tenofovir disoproxil fumarate is a total of 2-step reactions, and tenofovir disoproxil fumarate is obtained as a starting material through esterification and salt formation.

[0028] 1. Esterification:

[0029] Add 400ml of acetonitrile, 50ml of dimethylacetamide and 40g of tenofovir monohydrate into a 1000ml reaction bottle, start stirring, control the temperature at 20°C, add 91g of potassium carbonate dropwise, and continue to dropwise add 100g of chloromethyl carbonate Isopropyl ester, after dripping, raise the temperature of the reaction system to 50°C and keep it warm for 8 hours to detect that the monoester in the reaction is less than 10%. Concentrate the reaction solution under reduced pressure below 40°C until no liquid flows out, and add 500ml Ethyl acetate, 200ml of 6% sodium bicarbonate solution, layered extraction after stirring, the organic phase continued to be washed twice with 200ml of purified water...

Embodiment 2

[0033] Such as figure 1 As shown, the synthesis process of tenofovir disoproxil fumarate is a total of 2-step reactions, and tenofovir disoproxil fumarate is obtained as a starting material through esterification and salt formation.

[0034] 1. Esterification:

[0035] Add 900ml of acetonitrile, 100ml of dimethylacetamide and 100g of tenofovir anhydrate into a 2000ml reaction bottle, start stirring, control the temperature at 25°C, add 230g of potassium carbonate dropwise, and continue to dropwise add 250g of chloromethyl carbonate Isopropyl ester, after dripping, raise the temperature of the reaction system to 60°C and keep it warm for 10 hours. It is detected that the monoester in the reaction is less than 10%. Concentrate the reaction solution under reduced pressure below 40°C until no liquid flows out, and add 500ml Ethyl acetate, 400ml of 6% sodium bicarbonate solution, stirred and extracted by layers, the organic phase was washed three times with 400ml of purified water...

Embodiment 3

[0039] Such as figure 1 As shown, the synthesis process of tenofovir disoproxil fumarate is a total of 2-step reactions, and tenofovir disoproxil fumarate is obtained as a starting material through esterification and salt formation.

[0040] 1. Esterification:

[0041]Add 400ml of acetonitrile, 40ml of dimethylacetamide and 40g of tenofovir monohydrate into a 1000ml reaction bottle, start stirring, control the temperature at 22°C, add 91g of potassium carbonate dropwise, and continue to dropwise add 100g of chloromethyl carbonate Isopropyl ester, after dripping, raise the temperature of the reaction system to 55°C and keep it warm for 9 hours. It is detected that the monoester in the reaction is less than 10%. Concentrate the reaction solution under reduced pressure below 40°C until no liquid flows out, and add 500ml Ethyl acetate, 250ml of 6% sodium bicarbonate solution, layered extraction after stirring, the organic phase continued to be washed twice with 200ml of purified ...

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Abstract

The invention provides a new method for preparing tenofovir disoproxil fumarate. Reaction conditions are mild, production cost is low, product yield is high, quality is good, and industrial production can be conveniently realized.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a new method for preparing tenofovir disoproxil fumarate. Background technique [0002] Tenofovir disoproxil fumarate is a novel nucleotide reverse transcriptase inhibitor. Inhibits reverse transcriptase in a similar manner to nucleoside reverse transcriptase inhibitors, thereby possessing potential anti-HIV-1 activity. Tenofovir bisphosphate, the active ingredient of tenofovir, can inhibit viral polymerase by directly competitively binding to natural deoxyribose substrates, and terminate the chain by inserting into DNA. Tenofovir is almost not absorbed through the gastrointestinal tract, so it is esterified and salt-formed to become tenofovir disoproxil fumarate. Tenofovir disoproxil is water-soluble and can be rapidly absorbed and degraded into the active substance tenofovir, which is then converted into the active metabolite tenofovir bisphosph...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 樊超
Owner SUZHOU HOMESUN PHARMA