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Preparation method of high-purity topiramate

A topiramate and high-purity technology is applied in the field of preparation of high-purity topiramate, can solve problems such as unfavorable industrial production, reactor blockage, inconvenient operation, etc., and achieves the effects of less by-products, mild reaction, and easy operation.

Active Publication Date: 2018-11-09
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method disclosed in WO2004 / 89965A2 requires the use of azide, which may explode during post-processing, posing a certain safety hazard
The synthesis methods published in patents EP0533483 and US5387700 use ammonia gas as the ammonia source. This method is simple and convenient, but because the reaction raw materials are easily hydrolyzed and become by-products in the reaction, the solvent needs to be specially anhydrous treated, and the operation is extremely inconvenient. convenient
"Chinese Journal of Pharmaceutical Technology" 2011, 42 (9), pages 645-646 reported that ammonium carbonate was used as ammonia source to synthesize topiramate, but ammonium carbonate was decomposed by heat, but ammonia gas and acid were cooled and recombined at the reactor bottle mouth Ammonium salts will cause blockage of the reactor, which is very dangerous and not conducive to industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] At room temperature, 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate (15 g, 0.042 mmol) was dissolved in tetrahydrofuran ( 130 mL) and acetonitrile (13 mL), then added ammonium acetate (8.1 g, 0.105 mmol), heated to 60° C., and stirred for 3 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product as a pale yellow solid. The crude product of topiramate was recrystallized from n-hexane (45mL)-absolute ethanol (15mL), filtered with suction, and dried to obtain 9.66g of topiramate with an HPLC purity greater than 99%. The product recrystallized for the first time was recrystallized and refined again with n-hexane: anhydrous ethanol mixed solvent with a volume ratio of 3: 1 to obtain 8.67 g of topiramate with an HPLC purity greater than 99.5%.

[0023] 1 H NMR (400MHz, CDCl 3 )δ5.10 (s, 2H), 4.62 (dd, J = 7.9, 2.6Hz, 1H), 4.37-4.28 (m, 2H), 4.28-4.18 (m, 2H), 3.9...

Embodiment 2

[0025] At room temperature, 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate (60 g, 0.167 mol) was dissolved in tetrahydrofuran ( 550 mL) and acetonitrile (50 mL), ammonium acetate (36.0 g, 0.468 mol) was added, heated to 60° C., and stirred for 3 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product as a pale yellow solid. The crude product of topiramate was recrystallized from n-hexane (180 mL)-absolute ethanol (60 mL), filtered with suction, and dried to obtain 40.34 g of topiramate with an HPLC purity greater than 99%. The product recrystallized for the first time was recrystallized and refined again with a mixed solvent of n-hexane: absolute ethanol with a volume ratio of 3:1 to obtain 35.79 g of topiramate, with an HPLC purity greater than 99.5%.

[0026] 1 H NMR (400MHz, CDCl 3 )δ5.10 (s, 2H), 4.62 (dd, J = 7.9, 2.6Hz, 1H), 4.37-4.28 (m, 2H), 4.28-4.18 (m, ...

Embodiment 3

[0028] At room temperature, 2,3:4,5-bis-O-(1-methylethylene)-β-D-fructopyranose chlorosulfonate (350 g, 0.978 mol) was dissolved in tetrahydrofuran ( 3000 mL) and acetonitrile (300 mL), then added ammonium acetate (226 g, 2.934 mol), heated to 60° C., and stirred for 4 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product as a pale yellow solid. The crude product of topiramate was recrystallized from n-hexane (1200mL)-absolute ethanol (400mL), filtered by suction and dried to obtain 225.37g of topiramate with an HPLC purity greater than 99%. The product recrystallized for the first time was recrystallized and refined again with n-hexane: anhydrous ethanol mixed solvent with a volume ratio of 3:1 to obtain 202.17 g of topiramate with an HPLC purity greater than 99.5%.

[0029] 1 H NMR (400MHz, CDCl 3 )δ5.10 (s, 2H), 4.62 (dd, J = 7.9, 2.6Hz, 1H), 4.37-4.28 (m, 2H), 4.28-4.18 (m, 2H), 3...

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Abstract

The invention discloses a preparation method of high-purity topiramate. The topiramate is obtained by using 2,3,4,5-bis-O-(1-methylethylene)-beta-D-pyran fructose chlorosulfonate as a raw material and tetrahydrofuran and acetonitrile as solvents, adding ammonia-source ammonium acetate and performing amination under a heating condition, wherein the purity of the topiramate is not lower than 99.5%. The preparation method is low in cost, easy and convenient to operate, safe and efficient, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis technology, and in particular relates to a preparation method of high-purity topiramate. Background technique [0002] Topiramate is the general name of 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate, which is a listed antiepileptic drug. It was developed by Johnson & Johnson Pharmaceuticals of the United States and launched in the UK in 1995. It was approved by the FDA in 1996 for the treatment of primary partial epilepsy in adults and in 2000 for the treatment of children with epilepsy. In 2004, the FDA approved the drug for the prevention of migraine in adults. In July 2012, the FDA approved the launch of Qsymia, a compound weight-loss drug containing topiramate and phentermine from Vivus Pharmaceuticals of the United States. It is the second new weight-loss drug approved by the United States in 13 years. [0003] The listing of topiramate has been generally ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H9/04C07H1/00
Inventor 胡文浩王信彭丹丹
Owner EAST CHINA NORMAL UNIV
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