Preparation method of 2-ethoxy-5-fluorouracil impurity

A technology of fluorouracil and ethoxy, applied in the field of drug synthesis, can solve the problems of no public data report, etc., and achieve the effects of short route, simple operation and high purity

Active Publication Date: 2020-12-04
JINGHUA PHARMA GRP NANTONG
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

There are few studies on 2-ethoxy-5-fluorouracil impurities in the Chinese Pharmacopoeia, and no public information has been r

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  • Preparation method of 2-ethoxy-5-fluorouracil impurity
  • Preparation method of 2-ethoxy-5-fluorouracil impurity
  • Preparation method of 2-ethoxy-5-fluorouracil impurity

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[0027] One aspect of the embodiments of the present invention provides a method for preparing 2-ethoxy-5-fluorouracil impurity, which comprises the following steps:

[0028] (1) Using methyl methoxyacetate or ethyl ethoxyacetate as raw material, sodium methoxide as alkali hydrogen extraction, and toluene as solvent, respectively drop raw material and ethyl formate in a uniform mixing system, and react to form 2 - Ethoxy-5-fluorouracil impurity intermediate;

[0029] (2) Add ethoxyisourea dropwise to the 2-ethoxy-5-fluorouracil impurity intermediate, adjust the pH to 9-10, then sequentially perform heating, vacuum distillation, adding water to dissolve, and purify to obtain 2 -Ethoxy-5-fluorouracil impurity crude product;

[0030] (3) Add water to dissolve the crude 2-ethoxy-5-fluorouracil impurity, and then sequentially cool and crystallize with ice water, suction filter, wash with water, and dry to obtain the 2-ethoxy-5-fluorouracil impurity.

[0031] In some preferred embo...

Embodiment 1

[0055] Synthesis of Impurity 1:

[0056] In a dry and clean 500mL three-necked flask, add 157g of methanol solution of sodium methoxide and stir, distill under reduced pressure to a fine powder, add 67g of solvent toluene, stir while adding, control the temperature at 10-15°C, add 56g of ethyl formate and 35g of methyl methoxyacetate, after the dropwise addition, it was naturally raised to room temperature, heated to 40°C, kept for 4-5h, and allowed to stand overnight after returning to room temperature.

[0057] Control the temperature of the reaction system at 10-15°C, add 95g of ethoxyisourea dropwise, adjust the pH to 9-10, heat to 40°C, and keep the reaction for 4-5h. The solvent was distilled off under reduced pressure, and the system was dark yellow viscous syrup. Add 100 g of water and stir to dissolve, add 30 ml of saturated saline to break the emulsion, extract with dichloromethane, collect the organic phase and concentrate to obtain 8.1 g of crude product. To the cr...

Embodiment 2

[0062] Synthesis of Impurity 1:

[0063] Add 157g of methanol solution of sodium methoxide into a dry and clean 500mL three-neck flask, stir, distill under reduced pressure to fine powder, add 67g of solvent toluene, stir while adding, control the temperature at 10-15°C, and add 56.2g of ethyl formate dropwise And 35.4g of methyl methoxyacetate, after the dropwise addition, it was naturally raised to room temperature, heated to 40°C, kept for 4-5h, and allowed to stand overnight after returning to room temperature.

[0064] Control the temperature of the reaction system at 10-15°C, add 99g of ethoxyisourea dropwise, adjust the pH to 9-10, heat to 40°C, and keep the reaction for 4-5h. The solvent was distilled off under reduced pressure, and the system was dark yellow viscous syrup. Add 100 g of water and stir to dissolve, add 30 ml of saturated saline to break the emulsion, extract with dichloromethane, collect and concentrate the organic phase to obtain 8.7 g of crude product...

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Abstract

The invention discloses a preparation method of a 2-ethoxy-5fluorouracil impurity. The preparation method of the 2-ethoxy-5-fluorouracil impurity comprises the following steps: (1) respectively dropwise adding a raw material and ethyl formate into a uniform mixing system which takes methyl methoxyacetate or ethyl ethoxyacetate as a raw material, sodium methoxide as alkali for hydrogen removal andtoluene as a solvent, and reacting to form a 2-ethoxy-5-fluorouracil impurity intermediate; (2) dropwise adding ethoxy isourea into the 2-ethoxy-5-fluorouracil impurity intermediate, adjusting the pHvalue to be 9-10, and then sequentially carrying out heating, reduced pressure distillation, water addition dissolution and purification treatment so as to obtain a 2-ethoxy-5-fluorouracil impurity crude product; and (3) adding water into the 2-ethoxy-5-fluorouracil impurity crude product for dissolving, and then sequentially carrying out ice water cooling crystallization, suction filtration, water washing and drying to obtain the 2-ethoxy-5-fluorouracil impurity. The preparation method disclosed by the invention is short in route and simple in post-treatment, and the prepared 2-ethoxy-5-fluorouracil impurity is relatively high in purity and can be applied to reference substance research.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to the preparation of a drug impurity, in particular to a method for preparing a 2-ethoxy-5-fluorouracil impurity. Background technique [0002] 2-Ethoxy-5-fluorouracil (CAS No.: 56177-80-1) is an odorless white crystalline powder with molecular formula C 6 h 7 FN 2 o 2 , molecular weight 158.13, insoluble in water, density 1.36g / cm 3 , melting point 180-184°C, flash point 116.9°C. 2-Ethoxy-5-fluorouracil is an important pharmaceutical intermediate. [0003] Drug impurities are closely related to the quality and safety of drugs. There are few studies on 2-ethoxy-5-fluorouracil impurities in the Chinese Pharmacopoeia, and no public information has been reported on impurities 1 (2-ethoxy-5-methoxy-4-(3H)-uracil) and Efficient synthesis of impurity 2 (2,5-diethoxy-4-(3H)-uracil). [0004] Contents of the invention [0005] The main purpose of the present invention is to provide ...

Claims

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Application Information

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IPC IPC(8): C07D239/60
CPCC07D239/60
Inventor 吴玉祥滕飞杨秋星
Owner JINGHUA PHARMA GRP NANTONG
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