Synthesis and purification method of antiviral drug key intermediate

An antiviral drug and purification method technology, applied in the field of drug synthesis, can solve the problems of low total product yield, uncontrollable factors in the process, long reaction route, etc., to achieve controllable process, reduce reaction steps, and facilitate large-scale production Effect

Inactive Publication Date: 2020-04-17
SUZHOU ERYE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the long reaction route, and no intermediate (s)-N4-benzoyl-N 1 -[(2-phosphomethoxy-3-hydroxy)propyl]cytosine is purified, so the total yield of the product is low, and there are many uncontrollable factors in the process

Method used

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  • Synthesis and purification method of antiviral drug key intermediate
  • Synthesis and purification method of antiviral drug key intermediate
  • Synthesis and purification method of antiviral drug key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0022] (s)-N4-benzoyl-N 1 Synthesis of -[(2-diethylphosphomethoxy-3-trityloxy)propyl]cytosine

[0023] 50ml of anhydrous DMF and N4-benzamide cytosine (5.00g, 23.23mmol) were heated to 100°C, 60% NaH (0.23g, 5.81mmol) was added in one portion, and the slurry was stirred for 15min. Then S-trityloxymethyloxirane (8.82 g, 27.88 mmol) was added, and the temperature was raised to 110° C. for 3 h. Immediately after the reaction, NaH (1.86g, 46.46mmol) and diethyl p-toluenesulfonyloxymethylphosphate (11.23g, 34.85mmol) were added, and reacted overnight at 100°C. The reaction mixture was quenched with water, ethyl acetate was added to separate the organic phase, the organic phase was concentrated to dryness, and recrystallized with a mixed solvent of ethyl acetate and n-hexane to obtain about 10.8 g of off-white powdery solid (yield 68.2%).

Embodiment 2

[0025] The key intermediate of cidofovir (s)-N4-benzoyl-N 1 Synthesis of -[(2-phosphomethoxy-3-hydroxy)propyl]cytosine

[0026] (s)-N4-benzoyl-N that embodiment 1 obtains 1 -[(2-Diethylphosphomethoxy-3-tritylmethoxy)propyl]cytosine (4.00g, 5.87mmol) was dissolved in 40ml of dichloromethane, 16ml of 40% hydrobromic acid was added, at room temperature After reacting overnight, TLC monitored the disappearance of the raw material point, stopped the reaction, separated the liquid, adjusted the pH of the aqueous phase to neutral, and precipitated a white solid, which was filtered to obtain 1.88 g of the crude product of the target (yield 83.6%).

Embodiment 3

[0028] The key intermediate of cidofovir (s)-N4-benzoyl-N 1 Synthesis of -[(2-phosphomethoxy-3-hydroxy)propyl]cytosine

[0029] Dissolve 4.00g of CD-1 in 40ml of tetrahydrofuran, add 16ml of 40% hydrobromic acid, react at room temperature overnight, TLC monitors that the raw material point disappears, stop the reaction, evaporate the organic solvent under reduced pressure, and adjust the pH of the remaining water phase to neutral to precipitate a white solid , and filtered to obtain about 1.80 g of the target crude product (yield 87.1%).

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Abstract

The invention discloses a synthesis and purification method of a key intermediate (s)-N4-benzoyl-N<1>-[(2-phosphomethoxy-3-hydroxy)propyl]cytosine of an antiviral drug (s)-N<1>-[(2-phosphomethoxy-3-hydroxy)propyl]cytosine. The key intermediate is synthesized from (s)-N4-benzoyl-N<1>-[(2-diethylphosphate-3-triphenoxy)propyl]cytosine in one step under the catalysis of 40% HBr. After a reaction is finished, the pH value is adjusted to be 7, and filtering is carried out to obtain a crude product; and the crude product is recrystallized at 100 DEG C to obtain the refined product.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to the synthesis and purification method of (s)-N4-benzoyl-N1-[(2-phosphomethoxy-3-hydroxyl)propyl]cytosine. Key intermediate of viral drug cidofovir. Background technique [0002] Cidofovir (cidofovir, HPMPC) is a novel cytosine nucleoside phosphonomethyl ether derivative, a sterile hypertonic water-soluble injection for intravenous infusion developed by Gilead Corporation of the United States. It is supplied in clear glass vials, each containing 375 mg of anhydrous cidofovir in 5 mL of aqueous solution at a concentration of 75 mg / mL. The pH of the formulation was adjusted to 7.4 with sodium hydroxide and / or hydrochloric acid and contained no preservatives. The injection was launched in the United States in 1996 for the treatment of retinitis caused by CMV infection in AIDS patients. With the rising prevalence of HIV infection, the use of cidofovir in the prevention and treatment of ...

Claims

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Application Information

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IPC IPC(8): C07F9/6512
CPCC07F9/6512
Inventor 王蓓王晓东刘志孙迎基
Owner SUZHOU ERYE PHARMA
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