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Method for preparing (R)-9-(2-phosphorylmethoxypropyl)adenyl-di(isopropoxycarbonylmethyl)ester

A technology of chloromethyl isopropyl carbonate and tenofovir dipivoxil, which is applied in the field of synthesis of 9-adenine diester, can solve the problems of incomplete condensation reaction and lower reaction conversion rate, and achieve easy source High yield, low cost and high yield

Active Publication Date: 2012-05-16
YANCHENG DESANO PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] We also found in the experiment that the presence of PMPA moisture also caused the condensation reaction to be incomplete, reducing the reaction conversion rate

Method used

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  • Method for preparing (R)-9-(2-phosphorylmethoxypropyl)adenyl-di(isopropoxycarbonylmethyl)ester
  • Method for preparing (R)-9-(2-phosphorylmethoxypropyl)adenyl-di(isopropoxycarbonylmethyl)ester
  • Method for preparing (R)-9-(2-phosphorylmethoxypropyl)adenyl-di(isopropoxycarbonylmethyl)ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Under argon protection, 50.0 g of PMPA (6.8% moisture content) was added to 150 ml of acetonitrile, stirred at room temperature for 5 minutes, 60 ml of triethylamine was added, and most of the solids were dissolved. The temperature was raised to 50°C and stirring was continued for 30 minutes. Then the temperature was raised to 75°C, and the solvent was distilled off under reduced pressure, and the measured moisture content of the residue was 0.8%. Cool down to 50°C, add 200 ml of N-methylpyrrolidone, 38 ml of triethylamine, and 55.0 g of tetrabutylammonium bromide to the residue, and stir for 30 minutes. Add 100ml of chloromethyl isopropyl carbonate dropwise within 30 minutes, and keep warm for 4 hours after dropping. After the reaction was completed, it was cooled to below 20°C with an ice bath, and the reaction mixture was added dropwise to 1500 ml of brine at 0°C. Stir until solidified, stir for another 5 hours, and filter. The filter cake was dissolved with 600ml...

Embodiment 2

[0036] Under argon protection, 10.0 g of PMPA (6.8% moisture content) was added to 20 ml of acetonitrile, stirred at room temperature for 5 minutes, 12 ml of triethylamine was added, and most of the solids were dissolved. The temperature was raised to 60°C and stirring was continued for 30 minutes. Then the temperature was raised to 75°C, and the solvent was distilled off under reduced pressure, and the measured moisture content of the residue was 1.6%. Cool down to 60°C, add 40ml of N-methylpyrrolidone and 7.6ml of triethylamine to the residue, and stir for 30 minutes. Add 20ml of chloromethyl isopropyl carbonate dropwise within 30 minutes, and keep it warm for 4 hours after dropping. After the reaction was completed, it was cooled to below 20°C with an ice bath, and the reaction mixture was added dropwise to 300 ml of brine at 0°C. Stir until solidified, stir for another 5 hours, and filter. The filter cake was dissolved with 150 ml of isopropyl acetate and washed with wa...

Embodiment 3

[0038] Under argon protection, 10.0 g of PMPA was added to 80 ml of acetonitrile, stirred at room temperature for 5 minutes, 12 ml of triethylamine was added, and most of the solids were dissolved. The temperature was raised to 50°C and stirring was continued for 30 minutes. Then the temperature was raised to 75° C., the solvent was evaporated under reduced pressure, and the measured moisture content of the residue was 0.5%. Cool down to 60°C, add 40ml of N-methylpyrrolidone and 12ml of triethylamine to the residue, and stir for 30 minutes. Add 20ml of chloromethyl isopropyl carbonate dropwise within 30 minutes, and keep it warm for 4 hours after dropping. After the reaction was completed, it was cooled to below 20°C with an ice bath, and the reaction mixture was added dropwise to 300 ml of brine at 0°C. Stir until solidified, stir for another 5 hours, and filter. The filter cake was dissolved with 150 ml of isopropyl acetate and washed with water. It was dried over anhydr...

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Abstract

The invention discloses a novel synthesis method of (R)-9-(2-phosphorylmethoxypropyl)adenyl-di(isopropoxycarbonylmethyl)ester, which comprises the following steps; after tenofovir used as a raw material and triethylamine are salified in acetonitrile, evaporating to remove acetonitrile, remaining triethylamine and water in the tenofovir triethylamine salt, and carrying out condensation reaction with chloromethylisopropyl carbonate to obtain the (R)-9-(2-phosphorylmethoxypropyl)adenyl-di(isopropoxycarbonylmethyl)ester. The method disclosed by the invention has the advantages of cheap and accessible raw material, easily controlled technological operation, high yield and low cost, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a synthesis method for synthesizing (R)-9-(2-phosphonomethoxypropyl) adenine bis(isopropoxycarbonyloxymethyl) ester. Background technique [0002] The chemical name of tenofovir dipivoxil is (R)-9-(2-phosphonomethoxypropyl) adenine bis(isopropoxycarbonyloxymethyl) ester, and its structural formula is as follows: [0003] [0004] Tenofovir dipivoxil is a prodrug of tenofovir (PMPA for short, the same below), has good anti-HIV activity, and its effect on HIV resistant to other drugs has been verified. In addition, existing research results have shown that its anti-HBV activity is also quite good. [0005] The synthetic route of tenofovir dipivoxil is mainly the following route reported in US5935946 at present: [0006] [0007] Reaction formula (1) [0008] The above report uses adenine as a raw material, condenses with (R)-propylene carbonate to generate (R)-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 李金亮赵楠
Owner YANCHENG DESANO PHARMA CO LTD
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