A rufinamide preparing method

A technology of rufinamide and reaction, which is applied in the field of preparation of rufinamide, can solve problems such as long production cycle, strong corrosion, and environmental pollution, and achieve the effects of shortened reaction time, shortened production cycle, and high safety

Inactive Publication Date: 2015-02-11
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The shortcoming of this synthesis method is that the toxicity of thionyl chloride reagent is big, c

Method used

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  • A rufinamide preparing method
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Preparation of 2,6-difluorobenzyl azide (III)

[0023] Add 2,6-difluorobenzyl alcohol (72.06g, content 98%, 0.50mol), diphenylphosphoryl azide (151.36g, 0.55mol) and toluene (600mL) into a 1L three-necked flask. Heated to reflux with stirring and reacted for 6 hours. Add 200 mL of purified water, and adjust the pH to 12 with sodium hydroxide while stirring. Liquid extraction was carried out, and the aqueous layer was extracted once with 100 mL of toluene. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate (100 g). After filtration, the filtrate was concentrated under reduced pressure, and toluene was recovered to obtain 77.81 g of oily liquid with a yield of 92.0%. ESI-MS(m / z): 170.1[M+H] + ; HPLC purity: 97.5%.

Embodiment 2

[0024] Example 2 Preparation of 2,6-difluorobenzyl azide (III)

[0025] Add 2,6-difluorobenzyl alcohol (72.06g, content 98%, 0.50mol), diphenylphosphoryl azide (275.2g, 1.0mol) and toluene (600mL) into a 1L three-necked flask. Heated to reflux with stirring and reacted for 6 hours. Add 200 mL of purified water, and adjust the pH to 12 with sodium hydroxide while stirring. Liquid extraction was carried out, and the aqueous layer was extracted once with 100 mL of toluene. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate (100 g). After filtration, the filtrate was concentrated under reduced pressure, and the toluene was recovered to obtain 78.35 g of oily liquid with a yield of 93.0%. ESI-MS(m / z): 170.1[M+H] + ; HPLC purity: 97.5%.

Embodiment 3

[0026] Example 3 Preparation of ethyl 1-(2,6-difluorophenyl)-1H-1,2,3-triazole-4-carboxylate

[0027] Add the product of Example 1 (76.11g, 0.45mol) into a 500mL three-neck flask, add 300mL of absolute ethanol, and dissolve completely under stirring. Ethyl propiolate (88.29 g, 0.90 mol) was added, and the mixture was heated under reflux for 4 hours. After cooling down to room temperature, a solid precipitated out. After filtering, the filter cake was washed with absolute ethanol to obtain 106.89 g of light yellow solid with a yield of 88.9%. ESI-MS(m / z): 268.0[M+H] + ; HPLC purity: 97.2%.

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Abstract

The invention belongs to the field of medicine synthesis and provides a rufinamide preparing method. 2,6-difluorobenzylalcohol is adopted as an initial raw material, and is reacted with an azidation agent diphenylphosphoryl azide to produce a critical intermediate 2,6-difluorobenzylazide, the 2,6-difluorobenzylazide is reacted with propargyl ester, and then the rufinamide is obtained by an ammonolysis reaction. The method has advantages of low toxicity, low pollution, high safety, short production period, simple and convenient operation, and the like, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of rufinamide. Background technique [0002] Rufinamide is a new generation of anti-epileptic drugs developed by Swiss Novartis pharmaceutical company. It was launched in the European Union in January 2007 under the product name Inovelon, and in the United States in November 2008 under the product name BANZEL. Rufinamide is used for adjuvant treatment of partial seizures and Lennox-Gastaut syndrome, suitable for children over 4 years old and adult patients. Clinical studies have shown that the adjuvant treatment of rufinamide is well tolerated by epilepsy patients, the number of seizures is reduced, and it still has an effect on patients with partial or generalized epilepsy who are resistant to treatment, and can be administered in combination or alone. Rufinamide has no effect on the pharmacokinetics of carbamazepine, phenytoin, and valp...

Claims

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Application Information

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IPC IPC(8): C07D249/04C07C247/10
CPCC07D249/04C07C247/10
Inventor 魏伟业王正泽王晓张敏杨之冬杨晓兵霍立茹李纬李战
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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