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Preparation technique of fosphenytoin sodium

A technology for fosphenytoin sodium and preparation process, applied in the field of pharmaceutical synthesis, can solve the problems of difficult control of alkyl methanesulfonate, poor process controllability, heavy metal palladium residue, etc., and achieves shortened production cycle, high product purity, and related substance content. low effect

Active Publication Date: 2017-01-04
广安凯特制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Compared with the method of silver salt, this route reduces the use of heavy metal silver salt, but there are still problems such as heavy metal palladium residue, genotoxic impurity alkyl methanesulfonate that may be produced in the process, difficult to control, low yield, and poor process controllability.

Method used

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  • Preparation technique of fosphenytoin sodium
  • Preparation technique of fosphenytoin sodium

Examples

Experimental program
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Embodiment 1

[0050] (1) Add 10 g of phenytoin to 50 g of an aqueous solution of 37% by weight formaldehyde, react at 20-30°C for about 25 hours, filter, and dry the filter cake at 80-90°C under normal pressure until the water content is below 0.5%, to obtain 3-hydroxymethyl Base-phenytoin 10.2g, molar yield about 91%.

[0051] (2) Add 16g of 1,2,4-triazole into 130g of dichloromethane and stir, then add 29g of triethylamine, lower the temperature to 0-10°C, add 11g of phosphorus oxychloride dropwise, and keep the reaction for 1h after the dropwise addition, 10.0 g of 3-hydroxymethyl-phenytoin was added under temperature control at 0-10° C., and after the addition was completed, the reaction was kept for 1 h. Then add sodium bicarbonate 10g / water 100g solution under temperature control to adjust the pH value of the system to 7.5-8.0, stir the reaction for 1h, separate the liquid, take the water phase and add 100g ethanol to crystallize, then cool down to 0-10°C and keep stirring for 1h, fil...

Embodiment 2

[0054] (1) Add 10 g of phenytoin into a mixture of 50 g of 37% by weight formaldehyde solution and 10 g of ethanol, react at 20-30° C. for about 25 hours, filter, and dry the filter cake at 80-90° C. under normal pressure until the water content is below 0.5%. , to obtain 10.1 g of 3-hydroxymethyl-phenytoin with a molar yield of about 90.1%.

[0055] (2) Add 16g of 1,2,4-triazole into 130g of dichloromethane, add 29g of triethylamine to dissolve, lower to -5-5°C, add 11g of phosphorus oxychloride dropwise, and keep warm for 2h after the dropwise addition , add 10.0g of 3-hydroxymethyl-phenytoin at temperature control -5-10°C, keep warm for 1h, then add sodium carbonate 6g / water 100g solution at temperature control to adjust the pH value of the system to 7.5-8.0, stir for 1h, divide Add 100 g of acetone to the water phase to crystallize, cool to 0-10° C. and keep stirring for 1 h, and filter to obtain 13.4 g of fosphenytoin sodium crude product, with an HPLC purity of 99.15% an...

Embodiment 3

[0058] (1) Add 10 g of phenytoin into 50 g of an aqueous solution of 37% by weight formaldehyde, react at 28° C. for 28-30 h, filter, and dry the filter cake at 80-90° C. under normal pressure until the water content is below 0.5%, to obtain 3-hydroxymethyl- 10.2 g of phenytoin, the molar yield is about 91%.

[0059] (2) Add 16g of 1,2,4-triazole into 130g of dichloromethane, add 29g of triethylamine to dissolve, lower to 0-10°C, add 11g of phosphorus oxychloride dropwise, and keep warm for 1h after the dropwise addition, Add 10.0g of 3-hydroxymethyl-phenytoin under temperature control at 0-10°C, after the addition is complete, keep warm for 1 hour, then add 7g of sodium carbonate dissolved in 100g of water under temperature control to adjust the pH of the system to 8.0-9.0, and stir for 1 hour , liquid separation, adding 100 g of ethanol to the water phase for crystallization, cooling to 0-10 ° C and stirring for 1 h, filtering to obtain 13.4 g of fosphenytoin sodium crude pr...

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PUM

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Abstract

The invention discloses a preparation technique of fosphenytoin sodium. The technique comprises the following steps: carrying out hydroxymethylation on the initial raw material phenytoin to obtain 3-hydroxymethyl-phenytoin, reacting with phosphorus oxychloride and 1,2,4-triazole, and finally, salifying to obtain the fosphenytoin sodium. The technique has the advantages of simple operation steps, cheap and accessible raw materials, high yield, high product quality, low production cost, high safety, environment friendliness and the like, and is especially suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation process of fosphenytoin sodium. Background technique [0002] Fosphenytoin sodium is an anti-epileptic or arrhythmic drug developed by Lambert Company. It was launched in the United States in 1996 and in the United Kingdom and France in 1999. Its trade name is Cerebyx (the structural formula is shown below). Fosphenytoin is the phosphate prodrug of phenytoin sodium. Its water solubility is 4000 times that of phenytoin sodium. It is converted into phenytoin by phospholipase in the body. Therefore, fosphenytoin sodium for injection solves the problem that epileptic patients cannot take it orally when they have seizures. [0003] [0004] Han Ying, Huang Shuyun and others reported the preparation process of fosphenytoin sodium in the Journal of Tianjin University of Technology, Vol. 26, April 2010: Study on the synthesis process of fosphenytoin sodium, which ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6506
CPCC07F9/6506
Inventor 谭超周旭东张稳稳
Owner 广安凯特制药有限公司
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