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Method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine

A technology of bromoethyl and synthetic methods, which is applied in the field of chemical drug synthesis, can solve problems such as high requirements for reaction equipment control and container pressure, large irritating odor at the production site, and high price of 5-fluorouracil. The effect of low requirements, elimination of potential safety hazards, and cheap raw materials

Active Publication Date: 2014-07-02
JUHUA GROUP TECH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantage is that the raw material 5-fluorouracil is expensive, and the oxidation reaction is not easy to handle, which increases the production cost and is not conducive to industrial production
[0006] The method disclosed in Chinese Patent Publication No. CN102060784A also uses ethyl fluoroacetate and propionyl chloride as raw materials to first synthesize ethyl α-fluoropropionyl acetate. The disadvantage is that the post-processing of this method is troublesome and relatively expensive
The disadvantage is that ammonia gas is introduced in this method, the production site has a strong irritating smell, there are potential safety hazards, and the reaction yield is low, the requirements for reaction equipment control and container pressure are high, and the investment in equipment is large.

Method used

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  • Method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine
  • Method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Step (1): Synthesis of ethyl 2-fluoropropionoacetate

[0035] In a 500mL three-necked flask, add 300mL THF, 30.8g sodium ethoxide, and 1.6g triethylamine, cool down to below 10°C, slowly add 31.8g ethyl 2-fluoroacetate, 55.2g propionyl chloride dropwise. Under reaction 16h. After the reaction was completed, THF was recovered by distillation under reduced pressure, and then 30 mL of water was added, extracted with 30 mL of ethyl acetate to obtain an organic phase, which was dried with anhydrous magnesium sulfate, and then rectified to obtain the product ethyl 2-fluoropropionoacetate 45.9 g, colorless liquid, yield 85%, gas chromatography purity 90%.

[0036] Step (2): Synthesis of 6-ethyl-5-fluoro-4-hydroxypyrimidine

[0037] In a 500mL three-necked flask, add 200mL of methanol, slowly add 27.5g of sodium methoxide, cool down to 10°C, add dropwise 45.9g of ethyl 2-fluoropropionoacetate prepared by the method in the above step (1), and add acetic acid in one go Formami...

Embodiment 2

[0043] Step (1): Synthesis of ethyl 2-fluoropropionoacetate

[0044] In a 500mL three-necked flask, add 300mL of methyl tert-butyl ether, 30.4g of sodium ethoxide, and 2.2g of triethylamine, cool down to below 10°C, slowly add 31.6g of ethyl 2-fluoroacetate, 54.9g of propionyl chloride dropwise, After that, react at 20°C for 14h. After the reaction was completed, methyl tert-butyl ether was recovered by distillation under reduced pressure, and then 30 mL of water was added, extracted with 30 mL of ethyl acetate to obtain an organic phase, which was dried with anhydrous magnesium sulfate, and then rectified to obtain the product 2-fluoropropane Ethyl acetoacetate 42.8g, colorless liquid, yield 78%, gas chromatography purity 88%.

[0045] Step (2): Synthesis of 6-ethyl-5-fluoro-4-hydroxypyrimidine

[0046] In a 500mL three-neck flask, add 200mL of ethanol, slowly add 25.1g of sodium methoxide, cool down to 10°C, add dropwise 42.8g of ethyl 2-fluoropropionoacetate prepared by t...

Embodiment 3

[0052] Step (1): Synthesis of ethyl 2-fluoropropionoacetate

[0053] In a 500mL three-necked flask, add 300mL of isopropyl ether, 17.8g of sodium hydride, and 2.8g of triethylamine, lower the temperature to below 10°C, slowly add 31.3g of ethyl 2-fluoroacetate, and 54.3g of propionyl chloride dropwise. React at 25°C for 12h. After the reaction, distill under reduced pressure to recover isopropyl ether, then add 30 mL of water, extract with 30 mL of ethyl acetate to obtain an organic phase, dry the organic phase with anhydrous magnesium sulfate, and then rectify to obtain the product ethyl 2-fluoropropionoacetate Ester 40.8g, colorless liquid, yield 77%, gas chromatography purity 89%.

[0054] Step (2): Synthesis of 6-ethyl-5-fluoro-4-hydroxypyrimidine

[0055] In a 500mL three-neck flask, add 200mL of ethanol, slowly add 30.5g of sodium ethoxide, cool down to 10°C, dropwise add 40.8g of ethyl 2-fluoropropionoacetate prepared by the method of the above step (1), and add Form...

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Abstract

The invention discloses a method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine. The synthesis method comprises the steps of reacting 2-fluoro-ethyl acetate which is inexpensive and readily available and is used as an initial material with propionyl chloride under basic conditions in a solvent to synthesize an intermediate product 2-fluoro propionyl ethyl acetate; then carrying out cyclization on 2-fluoro propionyl ethyl acetate and formamidine acetate as well as a base in a solvent to obtain a cyclized product; then chlorinating the cyclized product with a chlorinating reagent; and finally adding a brominating reagent and brominating the chlorinated product in the presence of an initiator to obtain 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine. The synthesis method disclosed by the invention has the advantages of simple process, available raw materials, high yield, safety and environmental protection, and is convenient to industrialize.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, more specifically, to a method for synthesizing voriconazole intermediate 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine. Background technique [0002] Voriconazole is a fluconazole derivative and a new broad-spectrum triazole antifungal drug, which inhibits the biosynthesis of ergosterol by inhibiting the demethylation of 14α-sterol mediated by cytochrome P450 in fungi. The drug was developed by Pfizer of the United States and first launched in the United States in 2002. Clinically, it is mainly used for the treatment of acute or chronic deep fungal infections, such as the treatment of systemic deep fungal infections caused by Aspergillus, Cryptococcus and Candida. Voriconazole can be used in the treatment of humans and animals, it can effectively treat infections caused by a variety of bacteria, and can also be used for preservation of materials. 4-(1-Bromoethyl)-5-fluoro-6-chloropyrimidi...

Claims

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Application Information

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IPC IPC(8): C07D239/30
CPCC07D239/30
Inventor 杨建荣葛承胜李建
Owner JUHUA GROUP TECH CENT
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