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Synthesis method of tenofovir disoproxil fumarate intermediate impurity

A technology of tenofovir disoproxil fumarate and a synthetic method, which is applied in the field of drug synthesis, can solve the problems of unrelated literature and patent literature reports on impurity synthesis, separation and characterization, and achieve high product yield and simple steps Effect

Active Publication Date: 2016-04-20
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] At present, there is no relevant literature describing the structure, and there are no relevant literature and patent literature reports on the synthesis, separation and characterization of this impurity

Method used

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  • Synthesis method of tenofovir disoproxil fumarate intermediate impurity
  • Synthesis method of tenofovir disoproxil fumarate intermediate impurity
  • Synthesis method of tenofovir disoproxil fumarate intermediate impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add N,N-dimethylformamide (50ml), 1-aminoadenine-2-propanol (10.0g, 0.052mol) in the three-necked flask, R-propylene carbonate (6.94g, 0.068mol) and hydrogen Sodium oxide (3.12g, 0.078mol) was heated up to 130°C, kept for 8 hours, monitored by TLC analysis, cooled down after the reaction, added 30mL of water, extracted twice with 30mL of ethyl acetate, combined organic phase, concentrated to dry organic phase Then use dichloromethane and methanol mixed eluent (volume ratio dichloromethane:methanol=20:1~50:1) to get 1-[(9-((R)-2-hydroxypropyl)- 9H-Purin-6-yl)amino]-2-propanol (11.9 g, 91.5% yield, 98% purity).

Embodiment 2

[0037] Add N-methylpyrrolidone (50ml), 1-aminoadenine-2-propanol (10.0g, 0.052mol), R-propylene carbonate (6.94g, 0.068mol) and triethylamine (7.89 g, 0.078mol) to 130°C, keep the temperature for 8 hours, and monitor by thin-layer chromatography. After the reaction is completed, cool down, add 30 mL of water, and extract twice with 30 mL of ethyl acetate, combine the organic phases, concentrate and dry the organic phases, and then Use the mixed eluent of dichloromethane and methanol to pass through the column to obtain 1-[(9-((R)-2-hydroxypropyl)-9H-purin-6-yl)amino]-2-propanol (11.2g, Yield 86.2%, purity 98%).

Embodiment 3

[0039] Add N,N-dimethylformamide (50ml), 1-aminoadenine-2-propanol (10.0g, 0.052mol), R-propylene carbonate (8.17g, 0.080mol) and tris Ethylamine (9.54g, 0.094mol) was heated to 130°C, kept for 8 hours, and monitored by thin-layer chromatography. After the reaction was completed, 30ml of water was added after cooling down, and each 30ml of ethyl acetate was extracted twice. The organic phase was combined, and the organic phase was water Wash with 60ml, wash with 30ml of brine with a mass fraction of 10%, dry, and concentrate; the crude product is passed through a column with a mixed eluent of dichloromethane and methanol to obtain 1-[(9-((R)-2-hydroxypropyl)-9H-purine -6-yl)amino]-2-propanol (10.7 g, 82.3% yield, 99% purity).

[0040] Structure detection:

[0041] The HPLC figure of the 1-[(9-((R)-2-hydroxypropyl)-9H-purin-6-yl)amino]-2-propanol prepared in Example 1 is as follows image 3 shown. The HPLC chart of commercially available (R)-(+)-9-(2-hydroxypropyl)adenine is...

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Abstract

The invention discloses a synthesis method of a tenofovir disoproxil fumarate intermediate impurity. The method comprises steps as follows: 1-amino adenine-2-propanol and R-propylene carbonate react in the presence of an acid-binding agent, 1-[(9-((R)-2-hydroxypropyl)-9H-purine-6-yl)amino]-2-propanol system solution is obtained, and 1-[(9-((R)-2-hydroxypropyl)-9H-purine-6-yl)amino]-2-propanol is obtained through aftertreatment. The method for synthesizing 1-[(9-((R)-2-hydroxypropyl)-9H-purine-6-yl)amino]-2-propanol adopts simple steps, the product yield is high and is averagely higher than 80%, finally, the purity of a crude product is higher than 97% after column chromatography through silica gel, and a high-purity impurity reference substance is provided for the synthesis of (R)-(+)-9-(2-hydroxypropyl) adenine or tenofovir disoproxil fumarate, and besides, the tenofovir disoproxil fumarate intermediate impurity can be separately taken as an intermediate raw material for sale.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular to a tenofovir disoproxil fumarate intermediate impurity 1-[(9-((R)-2-hydroxypropyl)-9H-purin-6-yl ) The synthetic method of amino]-2-propanol. Background technique [0002] (R)-(+)-9-(2-hydroxypropyl)adenine is an intermediate in the synthesis of tenofovir disoproxil fumarate and is widely used in the production of antiviral drugs. [0003] (R)-(+)-9-(2-hydroxypropyl)adenine is generally obtained by the following synthetic method: [0004] [0005] At present, there are relevant literature reports that (R)-(+)-9-(2-hydroxypropyl)adenine synthesized by adenine and R-propylene carbonate under base-catalyzed conditions contains the isomer impurity 1-aminoadeno Purine-2-propanol (Process improvements for the manufacture of tenofovirdiso proxilfumarate at commercial scale, Organic process research & development, 2010, 14, 194-120), the reaction process is as follows: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34
CPCC07D473/34
Inventor 王冬冬郑裕义胡涛刘婕张桂菊
Owner JIANGXI FUSHINE PHARMA CO LTD