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A kind of preparation method of 2-ethoxy-5-fluorouracil impurity

A technology of fluorouracil and ethoxy, which is applied in the field of drug synthesis, can solve the problems of no public information reports, etc., and achieve the effect of short route and simple post-processing

Active Publication Date: 2022-07-01
JINGHUA PHARMA GRP NANTONG
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  • Abstract
  • Description
  • Claims
  • Application Information

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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 reported on impurities 1 (2-ethoxy-5-methoxy-4-(3H)-uracil) and Efficient Synthesis of Impurity 2 (2,5-diethoxy-4-(3H)-uracil)

Method used

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  • A kind of preparation method of 2-ethoxy-5-fluorouracil impurity
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  • A kind of preparation method of 2-ethoxy-5-fluorouracil impurity

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[0027] One aspect of the embodiment of the present invention provides a kind of preparation method of 2-ethoxy-5-fluorouracil impurity, it comprises the steps:

[0028] (1) take methyl methoxyacetate or ethyl ethoxyacetate as raw material, sodium methoxide is used as alkali extraction hydrogen, and toluene is used as the uniform mixing system of solvent to drip raw material and ethyl formate respectively, and react to form 2 -Ethoxy-5-fluorouracil impurity intermediate;

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

[0030] (3) adding water to the 2-ethoxy-5-fluorouracil impurity crude product to dissolve, and then successively cooling and crystallizing with ice water, suction filtration, washing with water, and drying to obtain 2-ethoxy-5-fluorouracil impurity....

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, and control the temperature to 10-15°C, add 56g of ethyl formate and 56g of ethyl formate dropwise respectively. 35 g of methyl methoxyacetate was naturally raised to room temperature after the dropwise addition, heated to 40° C., incubated for 4-5 hours, returned to room temperature and left to stand overnight.

[0057] The temperature of the reaction system was controlled to 10-15°C, 95 g of ethoxyisourea was added dropwise, the pH was adjusted to 9-10, the temperature was heated to 40°C, and the reaction was maintained for 4-5h. The solvent was distilled off under reduced pressure, and the system was in the form of a dark yellow viscous sugar syrup. Add 100 g of water and stir to dissolve, add 30 ml of saturated brine to break the demul...

Embodiment 2

[0062] Synthesis of Impurity 1:

[0063] 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 to 10-15℃, and add 56.2g of ethyl formate dropwise. and 35.4 g of methyl methoxyacetate. After the dropwise addition, the mixture was naturally raised to room temperature, heated to 40° C., incubated for 4-5 hours, returned to room temperature, and left to stand overnight.

[0064] The temperature of the reaction system was controlled to 10-15°C, 99 g of ethoxyisourea was added dropwise, the pH was adjusted to 9-10, the temperature was heated to 40°C, and the reaction was maintained for 4-5h. The solvent was distilled off under reduced pressure, and the system was in the form of a dark yellow viscous sugar syrup. Add 100 g of water and stir to dissolve, add 30 ml of saturated brine to break the demulsification, extr...

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Abstract

The invention discloses a preparation method of 2-ethoxy-5-fluorouracil impurity. The preparation method of the 2-ethoxy-5-fluorouracil impurity comprises: (1) uniform mixing using methyl methoxyacetate or ethyl ethoxyacetate as raw material, sodium methoxide as alkali extraction hydrogen, and toluene as solvent The raw material and ethyl formate are respectively added dropwise in the system and reacted to form a 2-ethoxy-5-fluorouracil impurity intermediate; (2) ethoxylate is added dropwise to the 2-ethoxy-5-fluorouracil impurity intermediate base isourea, adjust pH=9-10, then carry out heating, underpressure distillation, water-dissolving, purification treatment successively to obtain 2-ethoxy-5-fluorouracil impurity crude product; (3) to 2-ethoxy- The 5-fluorouracil impurity crude product is dissolved in water, and then ice-water cooling and crystallization, suction filtration, washing and drying are performed successively to obtain the 2-ethoxy-5-fluorouracil impurity. The preparation method of the invention has short route, simple post-treatment, and the prepared 2-ethoxy-5-fluorouracil has high impurity purity, which can be applied to the research of reference substances.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis and relates to the preparation of a pharmaceutical impurity, in particular to a preparation method of 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 ℃, flash point 116.9 ℃. 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 impurity in the Chinese Pharmacopoeia, and so far there is no published data reporting the impurity 1(2-ethoxy-5-methoxy-4-(3H)-uracil) and Efficient synthesis of impurity 2 (2,5-diethoxy-4-(3H)-uracil). [0004] SUMMARY OF THE INVENTION [0005] The main purpose of the present inve...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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