Synthetic method for flunarizine drug intermediate bis 4-fluorophenyl methyl alcohol

A technology of p-fluorophenyl and flucinnazine, which is applied in the field of synthesis of pharmaceutical intermediates and di-p-fluorophenylmethanol, a pharmaceutical intermediate of flucinnazine, can solve the problems of short reaction time and low yield, and achieve Yield improvement, the effect of yield improvement

Active Publication Date: 2016-08-17
北京远方通达医药技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Xiang Manwen (Xiang Manwen, Mo Fenzhu, Zhang Shichun, et al. Synthesis of flufenazine [J]. Journal of China Pharmaceutical University, 1984 (2).) with 4,4-difluorobenzophenone in hydrogen Synthesize di-p-fluorophenylcarbinol under the condition of adding zinc powder in sodium oxide ethanol solution. This synthetic method has simple reaction process and short reaction time, but the yield is not high. The laboratory verification yield is 60-65%. Therefore, It is necessary to propose a new synthetic method to improve the reaction yield

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  • Synthetic method for flunarizine drug intermediate bis 4-fluorophenyl methyl alcohol

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Embodiment 1

[0019] A kind of synthetic method of flufenazine medicine intermediate di-p-fluorophenylcarbinol, comprises the steps:

[0020] A. In a reaction vessel equipped with a reflux condenser, add 0.23mol of 4,4-difluorobenzophenone, 0.31mol of lithium isobutoxide with a mass fraction of 65%, 260ml of dimethylamine solution, and raise the temperature of the solution to 60 ℃, reflux reaction for 5h;

[0021] B. Preserve the temperature of the distillate at 45°C, distill under reduced pressure, distill off dimethylamine, add 300ml mass fraction of 35% ethyl acetate solution to the remaining solution, and separate out oil;

[0022] C. After pouring out the oil, add 350ml mass fraction of 60% cyclohexane solution, fully shake, precipitate solid, filter, recrystallize in 75% mass fraction of acetonitrile solution, and wash with mass fraction of 50% dichloromethane solution , the mass fraction is 25% triethylamine solution washing, and dehydrating with anhydrous magnesium sulfate dehydrat...

Embodiment 2

[0024] A kind of synthetic method of flufenazine medicine intermediate di-p-fluorophenylcarbinol, comprises the steps:

[0025] A. In a reaction vessel equipped with a reflux condenser, add 0.23mol of 4,4-difluorobenzophenone, 0.31mol of lithium isobutoxide, and 240ml of dimethylamine solution with a mass fraction of 62%, and raise the temperature of the solution to 58 ℃, reflux reaction for 4h;

[0026] B. Preserve the temperature of the distillate at 43° C., distill under reduced pressure, distill off dimethylamine, add 300 ml of 32% ethyl acetate solution to the remaining solution, and precipitate an oily substance;

[0027] C. After pouring out the oily matter, add 320ml mass fraction of 58% cyclohexane solution, shake fully, precipitate solid, filter, recrystallize in 72% acetonitrile solution, and wash with 43% dichloromethane solution , the mass fraction is 23% triethylamine solution washing, solid sodium hydroxide dehydrating agent dehydration, 42.50 g of colorless cr...

Embodiment 3

[0029] A kind of synthetic method of flufenazine medicine intermediate di-p-fluorophenylcarbinol, comprises the steps:

[0030] A, one in the reaction vessel that reflux condenser is installed, add 4,4-difluorobenzophenone 0.23mol, lithium isobutoxide 0.31mol, mass fraction is 60% dimethylamine solution 230ml, raise solution temperature To 55°C, reflux reaction for 3h;

[0031] B. Keep the temperature of the distillate at 40-45°C, distill under reduced pressure, distill off dimethylamine, add 300ml ethyl acetate solution to the remaining solution, and precipitate oily matter;

[0032] C. After pouring out the oily matter, add 300ml mass fraction of 55% cyclohexane solution, fully shake, precipitate solid, filter, recrystallize in 70% mass fraction of acetonitrile solution, and wash with mass fraction of 40% dichloromethane solution , with a mass fraction of 20% triethylamine solution, and dehydration with anhydrous magnesium sulfate dehydrating agent to obtain 44.05 g of colo...

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Abstract

The invention discloses a synthetic method for flunarizine drug intermediate bis 4-fluorophenyl methyl alcohol. The method comprises the steps that 4,4-difluorobenzophenone and isobutanol lithium are added into a dimethylamine solution, a backflow reaction is carried out on the warming condition, reduced pressure distillation is carried out to distill out dimethylamine, an ethyl acetate solution is added, grease is separated out, a cyclohexane solution is added after the grease is poured out, solid is separated out, filtration, recrystallization, washing and dehydration through a dehydrating agent are carried out, and clear crystal bis 4-fluorophenyl methyl alcohol is obtained. Compared with a synthetic method in the background technology, the reaction yield is greatly improved, and a new thought is provided through the novel synthetic method for further improving the yield.

Description

technical field [0001] The invention relates to a medicine intermediate, which belongs to the technical field of organic chemistry, in particular to a method for synthesizing di-p-fluorophenylcarbinol, a medicine intermediate of flufenazine. Background technique [0002] The drug flufenazine can inhibit vasoconstriction: it has a lasting inhibitory effect on the sustained vasoconstriction caused by vasoconstrictor substances, and the effect on the basilar artery and internal carotid artery is more obvious. When used for ischemic cerebrovascular disease, blood stealing phenomenon can be avoided. Protect brain tissue. When brain tissue ischemia and hypoxia can cause a large amount of calcium ions to flow into the cells and cause calcium overload, resulting in neuron damage. Flufenazine can pass through the blood-cerebrospinal fluid barrier, thereby reducing ischemic and hypoxic damage to brain cells. Protect vascular endothelial tissue: It can prevent hypoxic damage of endot...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07C29/143C07C29/78C07C29/80C07C29/86C07C33/46
CPCC07C29/143C07C29/78C07C29/80C07C29/86C07C33/46
Inventor关艮安
Owner北京远方通达医药技术有限公司