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Method for preparing tenofovir disoproxil fumarate

A technology of tenofovir fumarate and disoproxil, applied in the field of medicine, can solve the problem of reducing the total yield of tenofovir fumarate, poor reaction effect of 2-propanediol and affecting product yield. problems such as yield and purity, to achieve the effects of high yield, less side reactions, and improved yield and purity

Inactive Publication Date: 2015-05-13
SHANDONG NEWTIME PHARMA
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Problems solved by technology

[0003] In the Chinese patent CN101279987A, a tenofovir production process is disclosed. The obtained (R)-9-(2-hydroxypropyl) adenine has inhomogeneous mixing of materials in the reaction system, resulting in the raw material (R)-1 , the 2-propanediol reaction effect is relatively poor, which affects the yield and purity of the product. In the synthesis of (R)-9-(2-hydroxypropyl) adenine, after the reaction is complete, directly add a solvent to carry out crystallization, resulting in the failure of this step low yield
[0004] In the Chinese patent CN101574356A, a tenofovir medicinal salt and its preparation are disclosed, which discloses the route of synthesizing tenofovir disoproxil fumarate with (R)-ethyl lactate as the starting material , the synthesis reaction conditions of this route are relatively mild, but this route uses the process of protection and deprotection, increases the steps of the synthetic route, and reduces the total yield of the final tenofovir disoproxil fumarate

Method used

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  • Method for preparing tenofovir disoproxil fumarate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] (1) Preparation of (R)-4-methyl-1,3-dioxolane-2-one

[0039]Add 33.0g (R)-1,2-propanediol, 0.8g sodium hydroxide, 51.3g diethyl carbonate, and 10ml absolute ethanol into a 500ml three-necked flask, stir, heat up to 95°C for reaction, and detect the reaction by thin-layer chromatography Whether it is complete (the developer is ethyl acetate (V / ml):petroleum ether (V / ml)=3:2; iodine fumigation for color development), after the reaction is complete, heat up to 120°C and continue to evaporate the solvent under reduced pressure to obtain 40.6 g of (R)-4-methyl-1,3-dioxolane-2-one as pale yellow oil, with a purity of 98.0% and a molar yield of 91.6%.

[0040] 1 HNMR (500MHz, CDCl 3 ): δ4.87-4.86(m, 1H), 4.58-4.55(m, J=8.5Hz, 1H), 4.05-4.02(m, J=8.5Hz, 1H), 1.50-1.49(d, J=6.5 Hz, 3H).

Embodiment 2

[0042] (2) Synthesis of (R)-9-(2-hydroxypropyl)adenine

[0043] Add 575ml of N,N-dimethylformamide, 49.5g (R)-4-methyl-1,3-dioxolan-2-one, 45.0g adenine and 0.85g hydrogen to a 2000ml three-necked flask Potassium oxide, stirred, heated to 145°C, kept warm for 22 hours, detected by thin-layer chromatography (developing solvent is dichloromethane (V / ml):methanol (V / ml)=9:1), after confirming that the reaction is complete, Lower the temperature to 90°C and begin to distill off 4 / 5 of the reaction solvent under reduced pressure. After the evaporation is complete, add 672ml of isopropanol, heat up to 80°C and stir to dissolve, then cool down to 0°C and stir for crystallization for 1 hour, then filter and dry the filter cake in vacuum After 8 hours, 57.7 g of white solid was obtained, namely (R)-9-(2-hydroxypropyl)adenine, the molar yield was 85.5%, and the HPLC purity was 98.3%.

[0044] 1 H NMR (500MHz, CDCl 3 ): δ4.87-4.86(m, 1H), 4.58-4.55(m, J=8.5Hz, 1H), 4.05-4.02(m, J=8.5H...

Embodiment 3

[0046] (2) Synthesis of (R)-9-(2-hydroxypropyl)adenine

[0047] Add 575ml of 1 N,N-dimethylformamide, 31.5g (R)-4-methyl-1,3-dioxolan-2-one, 45.0g adenine and 0.85g Potassium hydroxide, stirred, heated to 135°C, kept warm for 22 hours, detected by thin layer chromatography (developing solvent is dichloromethane (V / ml):methanol (V / ml)=9:1), after confirming that the reaction is complete , the temperature was lowered to 80°C, and 4 / 5 of the reaction solvent was evaporated under reduced pressure. After the evaporation was completed, 672ml of isopropanol was added, heated to 70°C and stirred to dissolve, then cooled to 5°C, stirred and crystallized for 1 hour, and suction filtered. The cake was vacuum-dried to obtain 57.7 g of white solid, namely (R)-9-(2-hydroxypropyl)adenine, with a molar yield of 84.7% and an HPLC purity of 97.9%.

[0048] 1 H NMR (500MHz, CDCl 3 ): δ4.87-4.86(m, 1H), 4.58-4.55(m, J=8.5Hz, 1H), 4.05-4.02(m, J=8.5Hz, 1H), 1.50-1.49(d, J=6.5 Hz, 3H).

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Abstract

The invention relates to a method for preparing high-purity tenofovir disoproxil fumarate. The method comprises the following steps: preparing (R)-4-methyl-1,3-dioxolan-2-one, synthesizing (R)-9-(2-hydroxypropyl)adenine, synthesizing a tenofovir hydrate, refining by virtue of dehydrating and synthesizing tenofovir disoproxil fumarate. The corresponding product is refined and the target product is detected by dehydrating through tenofovir and using alkali-soluble acid-analysis manners, the reaction, separation and purification processes in the subsequent steps are facilitated and the purity and yield of the product are increased. The technical scheme disclosed by the invention has the advantages of simple operation, relatively inexpensive selected reagents, small side effects, high yield and less three wastes produced in the reaction and the environmental protection is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for synthesizing tenofovir disoproxil fumarate, a medical raw material used in the field of AIDS and hepatitis B treatment. Background technique: [0002] Tenofovir disoproxil fumarate is a new type of oral broad-spectrum antiviral drug, an acyclic cluster nucleoside reverse transcriptase inhibitor, and a nucleotide reverse transcriptase developed by Gilead Sciences in the United States. Inhibitors (nucleotide reverse transcriptase inhibitors, NtRTIs), chemical name 5-(((1R)-2(6-amino-9H-purin-9-yl)-1-methylethoxy)methyl)-2 , 4,6,8-tetraoxo-5-phosphazelaic acid diisopropyl-5-oxide fumarate, common name tenofovir disoproxil fumarate, developed by Gilead Sciences of the United States, trade name Viread, rich Tenofovir disoproxil maleate is currently the first nucleotide analog approved by the FDA for the treatment of HIV-1 infection. It has good tolerance, low drug resista...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 张贵民尹少宏陈波
Owner SHANDONG NEWTIME PHARMA
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