Preparation method of tenofovir disoproxil fumarate impurities

A technology of tenofovir disoproxil fumarate and tenofovir, applied in the field of preparation of tenofovir disoproxil fumarate impurities

Inactive Publication Date: 2015-02-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are very few reports on the synthesis of tenofovir disoproxil fumarate impurities at home and abroad, especially for the tenofovir disoproxil methoxycarbonyloxymethyl ester impurity (VI) and tenofovir disopr

Method used

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

Examples

Experimental program
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Effect test

Embodiment 1

[0045] The preparation of embodiment 1 (R)-9-(2-phosphomethoxypropyl) adenine isopropoxycarbonyloxymethyl ester isopropyl ester (IV)

[0046] Put 3.7g of (R)-9-(2-methoxypropyl phosphate) adenine diisopropyl in a 100mL three-neck flask, add 40mL of water and 0.4g of sodium hydroxide at room temperature, and stir at room temperature for 8h. After the reaction was complete, it was concentrated, and the concentrate was separated by column chromatography to obtain 2.7 g of a white solid, with a yield of 82.8%.

[0047] Put 2.7g of the white solid obtained above into a 100mL three-necked flask, add 6.2g of chloromethyl isopropyl carbonate, 4.1g of triethylamine, 60mL of DMF at room temperature, heat and stir at 60°C for 8h, cool to room temperature, and add 30mL of acetic acid Ethyl ester was stirred for 30 min, separated, and the organic phase was washed with water and saturated NaCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, and the concentrate was separa...

Embodiment 2

[0051] The preparation of embodiment 2 (R)-9-(2-phosphomethoxypropyl) adenine isopropoxycarbonyloxymethyl ester methoxycarbonyloxymethyl ester (VI)

[0052] Place 4g of (R)-9-(2-methoxypropyl phosphate) adenine mono(isopropoxycarbonyloxymethyl) ester in a 100mL three-neck flask, add 3.7g of methyl chloromethyl carbonate at room temperature , 3g triethylamine, 60mL DMF, heated and stirred at 60°C for 8h, cooled to room temperature, added 30mL ethyl acetate, stirred for 30min, separated, the organic phase was washed with water and saturated NaCl aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated The product was separated by column chromatography to obtain 1.7 g of light yellow oil. Yield 34.8%.

[0053] Its structural identification data are as follows:

[0054] 1 H-NMR (400Mz, DMSO-d 6 )δ: 1.05 (d, J=6.4Hz, 3H, CH 3 ), 1.24(m, 6H, 2×CH 3 ), 3.77 (s, 3H, OCH 3 ), 3.93~4.03 (m, 3H, CHO, CH 2 P), 4.23 ~ 4.28 (m, 2H, CH 2 N), 4.78~4.85(m, 1...

Embodiment 3

[0056] The preparation of embodiment 3 (R)-9-(2-phosphomethoxypropyl) adenine isopropoxycarbonyloxymethyl ester n-propoxycarbonyloxymethyl ester (VII)

[0057] Place 4g of (R)-9-(2-methoxypropyl phosphate) adenine mono(isopropoxycarbonyloxymethyl)ester in a 100mL three-necked flask, add 4.6g of n-propyl chloromethyl carbonate at room temperature Esters, 3g triethylamine, 60mL DMF, heated and stirred at 60°C for 8h, cooled to room temperature, added 30mL ethyl acetate, stirred for 30min, separated, the organic phase was washed with water and saturated NaCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, The concentrate was separated by column chromatography to obtain 1.9 g of light yellow oil. Yield 36.5%.

[0058] Its structural identification data are as follows:

[0059] 1 H-NMR (400Mz, DMSO-d 6 )δ: 0.87 (m, 3H, CH 3 ), 1.02~1.06 (d, J=6.4Hz, 3H, CH 3 ), 1.22~1.24(m, 6H, 2×CH 3 ), 1.56~1.65 (m, 2H, CH 2 ), 3.91~3.99 (m, 3H, CHO, CH 2 P), 4.00 ~ 4...

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Abstract

The invention relates to a novel synthesis method of three impurities of tenofovir disoproxil fumarate, and the method has an important significance for synthesizing high-quality tenofovir disoproxil fumarate. The invention mainly aims at researching the synthesis of a tenofovir disoproxil fumarate isopropyl ester impurity (R)-9-(2-phosphonomethoxy propyl) adenyl isopropyl oxycarbonyl methoxy isopropyl ester (IV), a tenofovir disoproxil fumarate methoxycarbonyl methoxy ester impurity (R)-9-(2-phosphonomethoxy propyl) adenyl isopropyl oxycarbonyl methoxy ester methoxycarbonyl methoxy ester (VI) and a tenofovir disoproxil fumarate n-propyl oxycarbonyl methoxy ester impurity (R)-9-(2-phosphonomethoxy propyl) adenyl isopropy oxycarbonyl methoxy ester n-propyl oxycarbonyl methoxy ester (VII). The synthetic routes of the three impurities of tenofovir disoproxil fumarate are as shown in the specification.

Description

technical field [0001] The invention relates to a preparation method of tenofovir disoproxil fumarate impurity. Background technique [0002] Tenofovir disoproxil fumarate (tenofovir disoproxil fumarate), chemical name (R)-9-(2-phosphomethoxypropyl) adenine bis(isopropoxycarbonyloxymethyl) ester fumarate , is a novel nucleotide reverse transcriptase inhibitor. The compound was developed by Gilead Sciences of the United States and was launched in the United States in 2001 for the treatment of HIV infection in adults. In 2008, it was approved by the FDA for the treatment of chronic HBV infection in adults. This product is rapidly transformed into tenofovir after oral administration, and is phosphorylated into tenofovir diphosphate under the action of cellular kinases, which inhibits viral polymerase and inserts into the virus by competitively combining with natural deoxyribose substrates NDA causes DNA chain elongation and termination, thereby inhibiting HIV and HBV activity...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 陈国华林庆志郑赫宏
Owner CHINA PHARM UNIV
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