Synthetic method of 2-chlorine-5-fluorine-6-ethylpyrimidin-2-amine

A technique for the synthesis of ethylpyrimidine and its synthesis method, which is applied in the synthesis of 2-chloro-5-fluoro-6-ethylpyrimidine and the synthesis of pyrimidine derivatives, and can solve the problems of long synthetic routes, environmental pollution, and low yields , to avoid pollution, improve safety and reduce costs

Inactive Publication Date: 2019-10-25
南京普锐达医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In order to solve the above problems, the present invention discloses a synthesis method of 2-chloro-5-fluoro-6-ethylpyrimidin...

Method used

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  • Synthetic method of 2-chlorine-5-fluorine-6-ethylpyrimidin-2-amine

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Embodiment 1

[0023] Synthesis of Compound A:

[0024] In a 3-liter three-necked flask, add 180 grams of sodium methoxide and 1500 milliliters of methanol, fully dissolve, cool down to room temperature, add 100 grams of urea, stir for half an hour, dropwise add 220 grams of ethyl 2-fluoropropionyl acetate, add After heating to reflux for 2 hours, the solvent was evaporated, dissolved in water, acidified with dilute hydrochloric acid, adjusted to pH 2.1, filtered and washed with water to obtain 150 g of Intermediate A, with a purity greater than 95% and a yield of 69.92%.

[0025] Synthesis of Compound B:

[0026] Suspend 150 grams of intermediate A in 700 grams of phosphorus oxychloride, add 200 grams of triethylamine dropwise at 39 ° C, stir at room temperature for half an hour, then heat up to 100 ° C for chlorination reaction for 2 hours, the mixture After cooling, it was concentrated under reduced pressure to remove excess phosphorus oxychloride, quenched by adding water, and then extr...

Embodiment 2

[0032] In a 3-liter three-necked flask, add 216 grams of sodium methoxide and 1800 milliliters of methanol, fully dissolve, cool down to room temperature, add 120 grams of urea, stir for half an hour, dropwise add 264 grams of ethyl 2-fluoropropionyl acetate, add After warming up to the reflux reaction for 2.5 hours, the solvent was evaporated, dissolved in water, acidified with dilute hydrochloric acid, adjusted to pH 2.3, filtered, washed with water to obtain 180 g of Intermediate A, the purity was greater than 95%, and the yield was 66.42%.

[0033] Synthesis of Compound B:

[0034] Suspend 180 grams of intermediate A in 1100 grams of phosphorus oxychloride, add 120 grams of diisopropylethylamine dropwise at 30 ° C, stir at room temperature for half an hour, and then heat up to 100 ° C for chlorination reaction 5 hours, the mixture was cooled, concentrated under reduced pressure to remove excess phosphorus oxychloride, quenched with water and then extracted with ethyl aceta...

Embodiment 3

[0038] In a 3-liter three-necked flask, add 270 grams of sodium methoxide and 2250 milliliters of methanol, fully dissolve, cool down to room temperature, add 150 grams of urea, stir for half an hour, dropwise add 330 grams of ethyl 2-fluoropropionyl acetate, add After warming up to reflux for 3 hours, the solvent was evaporated, dissolved in water, acidified with dilute hydrochloric acid, adjusted to pH 2.9, filtered, washed with water to obtain 232 g of Intermediate A, with a purity greater than 95% and a yield of 68.48%

[0039] Synthesis of Compound B:

[0040] Suspend 230 grams of intermediate A in 2050 grams of phosphorus oxychloride, add 250 grams of triisopropylamine dropwise at 35 ° C, stir at room temperature for half an hour, and then heat up to 100 ° C and carry out chlorination reaction for 4.5 hours, The mixture was cooled and concentrated under reduced pressure to remove excess phosphorus oxychloride, quenched by adding water, and then extracted with ethyl aceta...

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Abstract

The invention discloses a synthetic method of 2-chlorine-5-fluorine-6-ethylpyrimidin-2-amine. Step 1, sodium methoxide is dissolved in methyl alcohol, the temperature is lowered to the room temperature, carbamide is added, stirring is conducted after addition at the room temperature, 2-ethyl fluoropropioacetate is dropwise added, then the temperature is risen to reflux reaction for 2-3 hours, anda midbody A is obtained through purification; step 2, the midbody A, phosphorus oxychloride and organic alkali are mixed by weight ratio of 1 to 5-10 to 0.3-2, chlorination is conducted for 2-5 hoursat 25-100 DEG C, the mixture is cooled and subjected to vacuum concentration, extra phosphorus oxychloride is removed, after water is added for quenching, an organic solvent is used for extraction, drying and concentration are conducted, and then an intermediate product B is obtained; and step 3, ethyl alcohol, zinc powder and acetic acid are added in the intermediate product B, heating reflux reaction is conducted for 10-16 hours, the temperature is lowered, filtering is conducted, ethyl alcohol is removed by steaming, extraction is conducted through the organic solvent, a crude product is obtained through evaporation to dryness, and a pure product C is obtained through rectification under vacuum. According to the synthetic method of the 2-chlorine-5-fluorine-6-ethylpyrimidin-2-amine, theyield is increased, the reaction time is shortened, meanwhile the cost is lowered, and pollution on the environment is reduced.

Description

technical field [0001] The invention relates to a method for synthesizing pyrimidine derivatives, in particular to a method for synthesizing 2-chloro-5-fluoro-6-ethylpyrimidine, and belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Pyrimidine ring is one of the most common heterocycles in drugs and natural products. Pyrimidine heterocyclic compounds, as intermediates for the synthesis of such drugs, have important applications in the field of medicine, and are widely used in the research and development and clinical applications of anti-cancer drugs, anti-AIDS drugs, etc. Therefore, it is of great significance to develop and optimize the preparation process of such compounds. [0003] The main problems of the synthesis method of 2-chloro-5-fluoro-6-ethylpyrimidine in the prior art are: long synthesis route, low yield, high toxicity of raw materials and environmental pollution. SUMMARY OF THE INVENTION [0004] In order...

Claims

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Application Information

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IPC IPC(8): C07D239/30
CPCC07D239/30
Inventor 王小波
Owner 南京普锐达医药科技有限公司
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