Tenofovir disoproxil salt preparation method

A technology of tenofovir disoproxil and tenofovir, which is applied in the field of preparation of tenofovir disoproxil salt, can solve the problems that the content of a single impurity in the final product exceeds the standard, can only reach 36.5%, and the product cost is high. Improve market competitiveness, reduce residence time, improve the effect of purity and yield

Inactive Publication Date: 2014-11-05
NINGBO MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The Chinese invention patent application with publication number CN101870713A "A Industrialized Production Process for Tenofovir Disoproxil" (Application No.: 201010185710.8) also discloses a method. First recrystallize and purify in ethyl acetate, and then form a salt in isopropanol, that is, this method has increased a post-treatment step compared with the existing production process, although the increase of this step can improve the purity of the product, but Inevitably, the setting reduction of this step reduces the yield of the product to a great extent, and the yield of the product can only reach 36.5%, and there is no market competitive advantage
[0006] In

Method used

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  • Tenofovir disoproxil salt preparation method

Examples

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Effect test

Embodiment 1

[0029] (1) Control the temperature at 25°C to 35°C, N 2 Under protection, add 1000mL of N-methylpyrrolidone and 950g of chloromethyl isopropyl carbonate to a 5L four-neck flask successively, then slowly add 700mL of triethylamine dropwise, then add 40g of tetraethylammonium bromide, and heat up to 40°C ~45°C, add 400g of tenofovir or tenofovir monohydrate, continue to heat up to 50°C and react for 3h;

[0030] After the reaction is completed, cool down to 25°C to 30°C, filter the reactant with suction, rinse the filter cake with 4000mL of ethyl acetate, transfer the filtrate to a 20L four-necked flask, add 4800mL of tap water to the four-necked flask, The temperature was controlled at 25°C to 30°C, stirred for 5 minutes, and allowed to stand for 10 minutes to separate layers, the upper layer was ethyl acetate layer A1, and the lower layer was water layer B1;

[0031] The water layer B1 was extracted four times with ethyl acetate, using 1000 mL of ethyl acetate each time, stir...

Embodiment 2

[0040] (1) Control the temperature at 25°C to 35°C, N 2 Under protection, 1000mL of N,N-dimethylformamide and 950g of chloromethyl isopropyl carbonate were successively added into a 5L four-necked flask, then 700mL of triethylamine was slowly added dropwise, and then 38g of sodium lauryl sulfate was added. Raise the temperature to 40°C-45°C, add 400g of tenofovir or tenofovir monohydrate, and continue the reaction at 40°C-45°C for 5 hours;

[0041] After the reaction is completed, lower the temperature to 25°C to 30°C, filter the reactant with suction, rinse the filter cake with 3000mL isopropyl acetate, transfer the filtrate to a 20L four-necked flask, and add 4500mL of tap water to the four-necked flask , the temperature is controlled at 25°C to 30°C, stirred for 5 minutes, and allowed to stand for 10 minutes to separate layers, the upper layer is the isopropyl acetate layer A1, and the lower layer is the water layer B1;

[0042] Extract the water layer B1 with isopropyl ac...

Embodiment 3

[0051] (1) Control the temperature at 25°C to 35°C, N 2 Under protection, add 1000mL of dimethyl sulfoxide and 950g of chloromethyl isopropyl carbonate in sequence to a 5L four-neck flask, then slowly add 700mL of triethylamine dropwise, then add 40g of tetrabutylammonium bromide, and heat up to 40°C ~45°C, add 400g of tenofovir or tenofovir monohydrate, continue to heat up to 60°C, and then keep warm at this temperature for 2h;

[0052] After the reaction is completed, lower the temperature to 25°C to 30°C, filter the reactant with suction, rinse the filter cake with 4500mL of 1,2-chloroethane, transfer the filtrate to a 20L four-necked flask, and add 5000mL of tap water, the temperature is controlled at 25°C to 30°C, stirred for 5 minutes, and allowed to stand for 10 minutes to separate layers, the upper layer is 1,2-chloroethane layer A1, and the lower layer is water layer B1;

[0053] The aqueous layer B1 was extracted four times with 1,2-chloroethane, using 1200 mL of 1,...

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Abstract

The invention relates to a tenofovir disoproxil salt preparation method; first tenofovir or tenofovir monohydrate is used as a starting material for condensation reaction with chloromethyl isopropyl carbonate in a strong polar organic solvent in the presence of a phase transfer catalyst to prepare tenofovir disoproxil, then the tenofovir disoproxil is salified with succinic acid and fumaric acid to prepare a tenofovir disoproxil salt; in the stage of esterification reaction for removing the organic solvent, a thin film evaporator is used for distillation for removing rapidly the solvent at low temperature, the material flows through the evaporator in a very short time about 10 seconds, the problems of reactant decomposition caused by too high distillation temperature and long heating time in the prior art can be avoided, and the product purity and yield are greatly improved. The final finished product HPLC (high performance liquid chromatography) is more than or equal to 99.85%, the single impurity content is less than 0.1%, and the yield is 62%-67%.

Description

technical field [0001] The invention relates to a preparation method of tenofovir disoproxil salt. Background technique [0002] Tenofovir disoproxil is a nucleotide antiviral drug developed by Gilead in the United States. It was approved by the FDA in 2001 for the treatment of human immunodeficiency virus infection. Due to its definite therapeutic effect, good applicability and appropriate dosage, tenofovir disoproxil has become the first-line HIV drug recommended by multiple treatment guidelines. , is the first-line AIDS antiretroviral drug recommended by the World Health Organization WHO AIDS treatment guidelines, and is listed as a national free second-line AIDS antiretroviral treatment in China. [0003] There are many research reports on the synthesis process of tenofovir disoproxil or its salts. The Chinese invention patent application "New Synthesis Process of Tenofovir Disoproxil" (application number: 201310281153.3) with the publication number CN103304601A disclos...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 林祖峰杜亚军姚成志
Owner NINGBO MENOVO PHARMA
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