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Preparing method for tiagabine hydrochloride

A technology of tiagabine hydrochloride and tiagabine ethyl ester, which is applied in the field of preparation of tiagabine hydrochloride, can solve the problems of waste of materials, increase of production cost, low yield, etc., and achieve the effect of simple operation and increased yield

Active Publication Date: 2013-10-16
凯默斯医药科技上海有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The intermediate tiagabine ethyl ester is a viscous yellow oil, and the intermediate is solid after salt formation. Therefore, the operation of salt formation and crystallization can introduce better purification steps, such as WO2006013550A2. Salt improves the chemical purity and chiral purity of tiagabine finished products, but the patent application has a low yield of only about 70% in the operation of salt formation, crystallization and purification of intermediates, which causes waste of materials and increases cost of production

Method used

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  • Preparing method for tiagabine hydrochloride
  • Preparing method for tiagabine hydrochloride

Examples

Experimental program
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Embodiment 1

[0027] Take 570.00 g of tiagabine ethyl ester (detected by HPLC, the content is 70%) and dissolve it in 2300 mL of ethyl acetate, add 90.00 g of L-alanine, heat to dissolve at 75±5 °C and reflux, and continue to reflux for 30 min after complete dissolution. Stir and cool to room temperature, place at -25±5°C for cooling and crystallization for 5h to 6h, suction filtration to collect crystals; add 570 mL of ethyl acetate to the obtained crystals, heat to dissolve at 75±5°C and reflux, and reflux after complete dissolution 30min, stirred and cooled to room temperature, placed at -5±5°C for cooling and crystallization for 2h to 3h, suction filtered, and the crystals were collected; dried to obtain 456.10g of L-alanine salt of tiagabine ethyl ester (yield 93.64%) , chemical purity 99.97%, optical purity 99.93%). The obtained L-alanine salt of tiagabine ethyl ester was dissolved in 500 mL of ethanol, and an aqueous sodium hydroxide solution (400 mL, 11 M) was added dropwise, and th...

Embodiment 2

[0029] Dissolve 570.00 g of tiagabine ethyl ester (detected by HPLC, the content is 70%) in 800 mL of methanol, add 108.00 g of L-alanine, heat to dissolve at 75±5 °C and reflux, continue to reflux for 30 minutes after complete dissolution, and stir and cool To room temperature, place at -25±5℃ for cooling and crystallization for 5h~6h, suction filtration, and collect the crystals; add 500 mL of ethanol to the obtained crystals, heat and dissolve at 75±5℃, reflux for 30min after complete dissolution, and stir and cool to room temperature, cooled and crystallized at -5±5°C for 2h to 3h, suction filtered to collect crystals; dried to obtain 452.05g of L-alanine salt of tiagabine ethyl ester (yield 92.81%, chemical purity 99.99 %, optical purity 99.97%). The obtained L-alanine salt of tiagabine ethyl ester was dissolved in 500 mL of ethanol, and an aqueous sodium hydroxide solution (400 mL, 11 M) was added dropwise, and the reaction was carried out at room temperature for 8 h. Af...

Embodiment 3

[0031] Take 570.00 g of tiagabine ethyl ester (detected by HPLC, the content is 70%) and dissolve it in 1200 mL of ethyl acetate, add 135.00 g of L-alanine, heat to dissolve at 75±5 °C and reflux, and continue to reflux for 30 min after complete dissolution. Stir and cool to room temperature, place at -25±5°C for cooling and crystallization for 5h to 6h, suction filtration to collect crystals; add 570 mL of ethyl acetate to the obtained crystals, heat to dissolve at 75±5°C and reflux, and reflux after complete dissolution 30min, stirred and cooled to room temperature, placed at -5±5°C for cooling and crystallization for 2h to 3h, suction filtration to collect crystals; dry to obtain 450.64g of L-alanine salt of tiagabine ethyl ester (yield 92.52%). , chemical purity 99.95%, optical purity 99.93%). The obtained L-alanine salt of tiagabine ethyl ester was dissolved in 500 mL of ethanol, and an aqueous sodium hydroxide solution (400 mL, 11 M) was added dropwise, and the reaction ...

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Abstract

The invention provides a preparing method for tiagabine hydrochloride, which includes the following operating steps: firstly, taking tiagabine ethyl ester to be dissolved in solvent, adding L-configuration organic acid, performing heating reflux until the tiagabine ethyl ester is completely dissolved, then performing reflux for 30-60 min, cooling to the room temperature, cooling and crystallizing at the temperature of minus 30 -minus 20 DEG C, and collecting a solid matter A; secondly, adding solvent in the solid matter A, performing heating reflux until the tiagabine ethyl ester is completely dissolved, then performing reflux for 30-60 min, cooling to the room temperature, cooling and crystallizing at the temperature of minus 10-0 DEG C, and collecting a solid matter B; thirdly, dissolving the solid matter B, sequentially adding sodium hydroxide and hydrochloric acid to react, extracting and recrystallizing, so as to obtain the tiagabine hydrochloride. The preparing method provided by the invention not only remarkably improves the productivity by 90% above, but also guarantees the 99.9% of chemical and optical purity, is simple and convenient to operate, has no special requirement for equipment, and is more suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to a preparation method of tiagabine hydrochloride. Background technique [0002] Tiagabine (Formula 1) is a GABA reuptake inhibitor developed by Novo Nordisk in Denmark in 1997 and marketed in the United States and the United Kingdom in 1998. It can be used to treat partial seizures and grand mal seizures of epilepsy. As well as seizures that cannot be controlled by other antiepileptic drugs, it has the characteristics of good tolerance, small side effects and suitable for long-term use. In terms of mechanism of action, as a selective and reversible inhibitor of GABA reuptake in neurons and glial cells, tiagabine mainly inhibits mediator transmission in the central nervous system, increases the concentration of GABA in synapses, and reduces the sensitivity of neural excitation. , improve clinical. As a single optical isomer, the pharmacological activity of tiagabine in the R-configuration is much greater than that in th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14
Inventor 傅霖李文婕陈刚
Owner 凯默斯医药科技上海有限公司
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