Method for synthesizing (R)-9-(2-hydroxy propyl) adenine

A technology of hydroxypropyl and adenine, which is applied in the field of medicinal chemistry, can solve the problems of affecting the yield, increasing the difficulty of industrial operation, and restricting the development of drugs, so as to achieve the effects of reducing production costs, increasing product yield, and increasing selectivity

Active Publication Date: 2013-11-27
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the presence of the C-6 amino group, the by-product (R)-6-(2-hydroxypropyl) adenine is produced while generating (R)-9-(2-hydroxypropyl) adenine, The yield of this step reaction has been seriously affected, and the separation of the by-product and the target product is difficult, resulting in an increase in the difficulty of industrial operation, affecting the overall yield of tenofovir disoproxil products, and restricting the development of this class of drugs

Method used

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  • Method for synthesizing (R)-9-(2-hydroxy propyl) adenine
  • Method for synthesizing (R)-9-(2-hydroxy propyl) adenine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] In a 250mL three-neck flask, add adenine (13.5g, 0.10mol), then add 40mL N,N-dimethylformamide, add pyridine (9.5g, 0.12mol) and 4-dimethylaminopyridine (1.2g, 0.01mol), stirring and lowering the temperature to 5°C, adding acetic anhydride (11.2g, 0.11mol) dropwise, raising the temperature to 85°C and stirring for 6 hours. Cool down to room temperature, adjust the pH to 10 with sodium carbonate, then add propylene carbonate (12.2 g, 0.12 mol), raise the temperature to 130°C and stir for reaction for 4 hours. Cool down to 70°C, add 80 mL of toluene dropwise with stirring, then slowly lower to room temperature with stirring, keep stirring for 2 hours, filter with suction, wash with 10 mL of toluene, and dry to obtain (R)-6-acetyl-9-(2- Hydroxypropyl) adenine 22.0g, yield 93.8%, high performance liquid chromatography (HPLC) purity 98.6%.

[0025] In a 100mL three-necked flask, (R)-6-acetyl-9-(2-hydroxypropyl)adenine (23.5g, 0.10mol) was added to 60mL of 10% sodium hydroxi...

Embodiment 2

[0027] In a 250mL three-neck flask, add adenine (13.5g, 0.10mol), then add 30mL N,N-dimethylformamide, 10mL N-methylpyrrolidone, add triethylamine (12.1g, 0.12mol) and 4 -Dimethylaminopyridine (1.2g, 0.01mol), cooled down to 0°C with stirring, added dropwise acetic anhydride (11.2g, 0.11mol), heated to 80-85°C and stirred for 6 hours after dropping. Cool down to room temperature, adjust the pH to 10 with sodium carbonate, then add propylene carbonate (12.2 g, 0.12 mol), raise the temperature to 135°C and stir for 3 hours. Cool down to 75°C, add 80mL of toluene dropwise under heat preservation and stirring, then slowly lower to room temperature under stirring, stir for 2 hours, filter with suction, wash with 10mL of toluene, and dry to obtain (R)-6-acetyl-9-(2- Hydroxypropyl) adenine 22.0g, yield 93.8%, HPLC purity 98.9%.

[0028] In a 100mL three-neck flask, add (R)-6-acetyl-9-(2-hydroxypropyl)adenine (23.5g, 0.10mol), add 60mL of 10% sodium hydroxide aqueous solution, and he...

Embodiment 3

[0030] In a 250mL three-neck flask, add adenine (13.5g, 0.10mol), then add 20mL N,N-dimethylformamide, 20mL N-methylpyrrolidone, add triethylamine (12.1g, 0.12mol) and 4 -Dimethylaminopyridine (1.2g, 0.01mol), cooled down to 0°C with stirring, added dropwise acetic anhydride (12.2g, 0.12mol), heated to 80-85°C and stirred for 6 hours after dropping. Cool down to room temperature, adjust the pH to 9 with sodium carbonate, then add propylene carbonate (12.2 g, 0.12 mol), raise the temperature to 130°C and stir for reaction for 4 hours. Cool down to 80°C, add 80mL of toluene dropwise under heat preservation and stirring, then slowly lower to room temperature under stirring, stir for 2 hours, filter with suction, wash with 10mL of toluene, and dry to obtain (R)-6-acetyl-9-(2- Hydroxypropyl) adenine 21.2g, yield 90.3%, HPLC purity 98.2%.

[0031] In a 100mL three-neck flask, add (R)-6-acetyl-9-(2-hydroxypropyl)adenine (23.5g, 0.10mol), add 60mL of 10% sodium hydroxide aqueous solu...

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Abstract

The invention discloses a method for synthesizing (R)-9-(2-hydroxy propyl) adenine. The method sequentially comprises the following steps: (1) primary amino acetylation: dissolving adenine in an organic solvent, adding alkali and a catalyst, stirring, and dripping acetic anhydride at 0-10 DEG C; holding at 80-85 DEG C, stirring and reacting for 6-10 h to obtain reaction liquid; (2) N-hydroxy propylation: regulating the pH of the reaction liquid to 9-10, adding propylene carbonate, stirring and reacting at 120-140 DEG C, cooling to 70-80 DEG C, adding toluene, stirring for 2-3 h, and separating and drying to obtain a solid product; (3) deacetylation reaction: adding the solid product into a sodium hydroxide aqueous solution, stirring to react at 90-95 DEG C for 2-4 h, cooling to the room temperature, neutralizing the pH to 6-8 through concentrated hydrochloric acid, separating and drying to obtain the product. The method provided by the invention is used for greatly increasing the reaction selectivity, avoiding the generation of byproduct (R)-6-(2-hydroxy propyl) adenine, increasing the yield of the (R)-9-(2-hydroxy propyl) adenine by more than 90% and greatly lowering the production cost of tenofovir disoproxil fumarate.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a method for synthesizing a tenofovir disoproxil intermediate, in particular to a method for synthesizing (R)-9-(2-hydroxypropyl)adenine. Background technique [0002] In recent years, AIDS has spread continuously, and there is a trend of worldwide epidemic. Tenofovir disoproxil (tenofovir), chemical name: (R)-9-(2-phosphomethoxypropyl) adenine bis(isopropyl) Oxycarbonyloxymethyl) ester is the first nucleoside analog approved by the FDA for the treatment of HIV infection. Its importance has been recognized by the World Health Organization and recommended as a first-line antiviral drug. The market demand is increasing bigger. (R)-9-(2-hydroxypropyl)adenine is the key intermediate for the production of tenofovir disoproxil, and the production of tenofovir disoproxil is generally based on (R)-9-(2-hydroxypropyl)adenine Synthesize (R)-9-(2-(diethylphosphoryl) methoxypropyl) adenine ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34
Inventor 李家全李佳陈环宇王卫蔡会敏胡瑞华孙智源朱冲
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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