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A kind of method for synthesizing 4-fluorocyclohexanone

A technology of fluorocyclohexanone and cyclohexanedione monoethylene glycol ketal, which is applied in the field of synthesis of fluorine-containing compounds, can solve problems such as inability to meet the needs of industrial production, difficulty in large-scale industrial production, and cumbersome synthetic routes. Achieve the effects of saving production time and cost, simplifying the post-processing process, and reducing environmental pollution

Active Publication Date: 2021-03-16
SHANGHAI SINOFLUORO SCI
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  • Claims
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Problems solved by technology

[0003] 4-fluorocyclohexanone is a relatively important fluorine-containing compound, which is widely used in the synthesis of pharmaceutical intermediates and is an essential raw material for the preparation of fluorine-containing compounds. However, there are few literature reports on the direct synthesis of 4-fluorocyclohexanone Methods
[0008] This synthetic route is comparatively loaded down with trivial details, and total yield is only 5%, can't satisfy industrial production demand; The price of raw material is more expensive, and production cost is high, is also difficult to be applicable to large-scale industrial production; Waste liquid contains highly toxic chromium ion, and pollution is serious

Method used

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  • A kind of method for synthesizing 4-fluorocyclohexanone
  • A kind of method for synthesizing 4-fluorocyclohexanone
  • A kind of method for synthesizing 4-fluorocyclohexanone

Examples

Experimental program
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Effect test

Embodiment 1

[0045] (1) Synthesis of 8-fluoro-1,4-dioxaspiro[4.5]dec-7-ene:

[0046] Add 312g of dichloromethane, pyridine (237.3g, 3.0mol, 3.0eq), and 1,4-cyclohexanedione monoethylene glycol ketal (156.2g, 1.0mol, 1.0eq) into a 1000ml three-necked reaction flask in sequence .

[0047] Start the stirring, lower the temperature to 10±5°C, add DAST (193.4g, 1.2mol, 1.2eq) dropwise, control the internal temperature at 10±5°C, after the dropwise addition, raise the temperature by 5°C per hour to 25°C, and The reaction was carried out at 25°C for 12 hours. GC central control reaction process: GC central control monitors that the peak integral area of ​​raw materials on the GC spectrum / (integrated area of ​​raw material peak + product peak integral area) < 0.5%, that is, the GC central control monitors that the remaining amount of reaction raw materials < 0.5%, to end the reaction, the raw material here refers to 1,4-cyclohexanedione monoethylene glycol ketal, and the product here refers to...

Embodiment 2

[0058] (1) Synthesis of 8-fluoro-1,4-dioxaspiro[4.5]dec-7-ene

[0059] Add 312g of dichloromethane, triethylamine (303.6g, 3.0mol, 3.0eq), 1,4-cyclohexanedione monoethylene glycol ketal (156.2g, 1.0mol, 1.0eq) into 1000ml three-port reaction in sequence in the bottle.

[0060] Start the stirring, lower the temperature to 10±5°C, add DAST (193.4g, 1.2mol, 1.2eq) dropwise, control the internal temperature at 10±5°C, after the dropwise addition, raise the temperature by 5°C per hour to 25°C, and The reaction was carried out at 25°C for 12 hours. GC central control reaction process: GC central control monitors that the peak integral area of ​​raw materials on the GC spectrum / (integrated area of ​​raw material peak + product peak integral area) < 0.5%, that is, the GC central control monitors that the remaining amount of reaction raw materials < 0.5%, to end the reaction, the raw material here refers to 1,4-cyclohexanedione monoethylene glycol ketal, and the product here refers...

Embodiment 3

[0071] (一)8-氟-1,4-二氧杂螺[4.5]癸-7-烯的合成

[0072] 依次将312g二氯甲烷,DBU(456.6g,3.0mol,3.0eq),1,4-环己二酮单乙二 醇缩酮(156.2g,1.0mol,1.0eq)加入1000ml的三口反应瓶中。

[0073] 开启搅拌,降温至10±5℃,滴加DAST(193.4g,1.2mol,1.2eq),控制内温在 10±5℃,滴加完毕后,每小时升温5℃,升至25℃,并在25℃反应12小时。GC 中控反应进程。当GC中控监测到在GC谱图上原料出峰积分面积 / (原料出峰积分 面积+产物出峰积分面积)<0.5%时,即GC中控监测到反应原料剩余量<0.5%, 结束反应,这里的原料是指1,4-环己二酮单乙二醇缩酮,这里的产物是指8-氟-1,4- 二氧杂螺[4.5]癸-7-烯。

[0074] 反应结束后,将反应液缓慢加入750g冰水中,分出有机相,水相用312g二氯 甲烷萃取三次(二氯甲烷总用量为312g×3),合并全部有机相,用盐酸(750g, 1mol / L)洗涤数次,GC中控有机相无DBU残留,然后有机相用750g饱和碳酸氢 钠洗涤数次,直至pH值为7~8,再用无水硫酸钠干燥后过滤,将所得有机相滤液 减压浓缩得到粗品,粗品减压精馏,当温度升至80℃的时候开始接收馏分,得到 产品145g。

[0075] 对所得产品进行气相色谱(GC)和核磁共振氢谱(HNMR)检测,以确定其 结构式和纯度。由核磁共振氢谱谱图可以确定所得产品为8-氟-1,4-二氧杂螺[4.5] 癸-7-烯,GC测得纯度98.2%,计算收率为92%。

[0076] (二)8-氟-1,4-二氧杂螺[4.5]癸烷的合成

[0077] Same as Example 1.

[0078] (三)4-氟环己酮的合成

[0079] Same as Example 1.

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Abstract

The invention discloses a method for synthesizing 4-fluorocyclohexanone. The method comprises steps as follows: under the alkaline condition, 1,4-cyclohexanedione monoethylene ketal and a fluorinatingagent are subjected to highly selective reaction, and 8-fluoro-1,4-dioxaspiro[4.5]deca-7-ene is produced; 8-fluoro-1,4-dioxaspiro[4.5]decane is prepared from 8-fluoro-1,4-dioxaspiro[4.5]deca-7-ene and hydrogen under the action of a palladium-carbon catalyst; 8-fluoro-1,4-dioxaspiro[4.5]decane is subjected to deprotection with added acid, and 4-fluorocyclohexanone is obtained. According to the method, 1,4-cyclohexanedione monoethylene ketal which is widely sourced and low in cost is taken as a reaction raw material, a high-purity intermediate can be obtained maximumly in each reaction, so thatthe total yield of the whole reaction is high, purity of a final product is up to 98%, the economic benefit is quite remarkable, less environmental pollution is produced, and the method is particularly suitable for large-scale industrial application and popularization.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a synthesis method of fluorine-containing compounds. Background technique [0002] In recent years, with large-scale applications in chemical, pharmaceutical and agricultural industries, fluorine-containing compounds as organic intermediates are gradually showing great growth potential. In the pharmaceutical field, many pharmaceutical compounds need to use fluorine-containing compounds as organic intermediates in the synthesis process. Therefore, fluorine-containing compounds are becoming more and more important, and their research and development activities are also increasingly active. [0003] 4-fluorocyclohexanone is a relatively important fluorine-containing compound, which is widely used in the synthesis of pharmaceutical intermediates and is an essential raw material for the preparation of fluorine-containing compounds. However, there are few literatur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C45/59C07C49/463
CPCC07C45/59C07D317/72C07C49/463
Inventor 闾肖波陈靖
Owner SHANGHAI SINOFLUORO SCI
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