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A kind of preparation method of (r)-2-(2-phosphomethoxypropyl)-adenine

A technology of methoxypropyl phosphate and adenine, which is applied in the field of preparation of -2--adenine, and can solve the problems such as preparation method, purification method and identification method that are not mentioned.

Active Publication Date: 2021-03-09
北京鑫开元医药科技有限公司 +1
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  • Abstract
  • Description
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Problems solved by technology

[0004] However, there are few relevant literature reports on (R)-2-(2-phosphomethoxypropyl)-adenine, only in the article (Identification, synthesis and characterization of new impurities intenofovir, He Jun et al., Die Pharmazie, Volume 70, issue 5, 2015, p. 283-288) reported the substance, but did not mention its preparation method, purification method and identification method

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  • A kind of preparation method of (r)-2-(2-phosphomethoxypropyl)-adenine
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  • A kind of preparation method of (r)-2-(2-phosphomethoxypropyl)-adenine

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[0032] The embodiment of the present invention provides a preparation method of (R)-2-(2-phosphomethoxypropyl)-adenine, comprising:

[0033] Step S11, adding compound II, compound III and the first basic substance into the first reaction solvent, and reacting at the first temperature. After the reaction, adding ethanol to the system, separating the liquid and concentrating it to obtain a concentrated liquid; Add water and the first organic solvent to the concentrated solution, separate layers, dry the organic phase, and recrystallize to obtain intermediate IV, the compound II is adenine, the compound III is R-propylene carbonate, and the intermediate IV is (R)-(+)-2-(2-hydroxypropyl)adenine;

[0034] Step S12, adding the intermediate IV, the compound V having the structure of formula V and the catalyst into the second reaction solvent, and reacting at the second temperature. After the reaction, the temperature is lowered, the acid is adjusted to neutral pH, and ethyl acetate i...

Embodiment 1

[0053]

[0054] Step S1: Add 100.00g (0.74mol) of adenine, 90.6g (0.888mol) of R-propylene carbonate, 0.9g (0.022mol) of sodium hydroxide and 200mL of N-methylpyrrolidone into a 2L three-neck flask, and heat up to React at 125~135°C for 5 hours; after the reaction, cool the system to 80~90°C, add 1000mL of ethanol, stir slowly, cool down to room temperature, stir for 1 hour, and filter to obtain the filtrate; , to obtain a concentrated solution, add an appropriate amount of water to the concentrated solution, extract with dichloromethane to obtain an organic phase, dry the organic phase with anhydrous sodium sulfate, and finally concentrate under reduced pressure to obtain 14.5 g of a solid, add 70 mL of absolute ethanol, heat to reflux, dissolve cleared, cooled and crystallized to obtain 5.9 g of the target product (R)-(+)-2-(2-hydroxypropyl)adenine.

[0055] Step S2: Add 20.0 g (0.104 mol) of (R)-(+)-2-(2-hydroxypropyl) adenine obtained in the above step S1, magnesium ter...

Embodiment 2

[0066] Step S1: Add 100.00g (0.74mol) of adenine, 90.6g (0.888mol) of R-propylene carbonate, 0.9g (0.022mol) of sodium hydroxide and 200mL of N,N-dimethylformamide into a 2L three-neck flask , heated up to 125~135°C for reaction, and reacted for 5 hours; after the reaction, cooled the system to 80~90°C, added 1000mL of ethanol, stirred slowly, lowered to room temperature, stirred for 1 hour, and filtered to obtain the filtrate; the filtrate was concentrated to almost no liquid After dripping, a concentrated solution was obtained. Add an appropriate amount of water to the concentrated solution, extract with dichloromethane to obtain an organic phase, dry the organic phase with anhydrous sodium sulfate, and finally concentrate under reduced pressure to obtain 13.5 g of a solid, add 70 mL of absolute ethanol, and heat Reflux, dissolve, and crystallize by lowering the temperature to obtain 5.1 g of the target product (R)-(+)-2-(2-hydroxypropyl)adenine.

[0067]Step S2: Add 20.0 g ...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of (R)-2-(2-methoxypropyl phosphate)-adenine. The method comprises the following steps: adding a compound II, a compound III and a first alkaline substance into a first reaction solvent, reacting at a first temperature, and recrystallizing to obtain an intermediate IV; adding the intermediate IV, a compound V with a structure as shown in a formula V and a catalyst into a second reaction solvent, and reacting at a second temperature to obtain a solution of the second reaction solvent of the intermediate VI after the reaction is finished; and adding a compound VII with a structure shown in a formula VII into the solution of the second reaction solvent of the intermediate VI, and reacting at a third temperature to obtain the (R)-2-(2-methoxypropyl phosphate)-adenine after the reaction is finished. The synthesis of (R)-2-(2-methoxypropyl phosphate)-adenine is of great significance tothe effective control of the quality of tenofovir.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of (R)-2-(2-phosphomethoxypropyl)-adenine. Background technique [0002] Tenofovir is a new type of nucleotide reverse transcriptase inhibitor, which has been confirmed to have good antiviral activity against HIV virus and HBV virus. Currently, there are two prodrugs with tenofovir as the active ingredient in the market, namely tenofovir disoproxil and tenofovir alafenamide. These two kinds of prodrugs are respectively sold in various ready-made preparations in the market, and because of their good antiviral activity and safety, they have become important therapeutic drugs in the field of anti-AIDS and anti-hepatitis B. Since tenofovir disoproxil was launched in the United States in 2001, it has been approved for the treatment of AIDS and chronic hepatitis B in more than 100 countries around the world. Genvoya, which contains tenofovir alafena...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
CPCC07F9/65616
Inventor 孙学涛王永广于凯焦晓伟苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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