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Tiagabine ethyl ester hydrochloride and preparation method thereof

A technology of tiagabine ethyl ester and hydrochloride, which is applied in the field of tiagabine ethyl ester hydrochloride and its preparation, can solve the problems of difficult separation and purification, and achieve the effect of easy control of impurity content and high purity

Active Publication Date: 2014-02-05
凯默斯医药科技上海有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The inventors have found through research that there will be a main impurity in the finished product of tiagabine hydrochloride prepared by the above process, whose properties are similar to those of tiagabine hydrochloride, and it is difficult to separate and purify

Method used

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  • Tiagabine ethyl ester hydrochloride and preparation method thereof
  • Tiagabine ethyl ester hydrochloride and preparation method thereof
  • Tiagabine ethyl ester hydrochloride and preparation method thereof

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Embodiment 1

[0031] The preparation method of embodiment 1 tiagabine ethyl ester hydrochloride

[0032] Dissolve 10g of tiagabine hydrochloride finished product in 50mL of ethanol, add 6mL of concentrated hydrochloric acid dropwise, heat the reaction at 50°C, and monitor the end point of the reaction by HPLC (high performance liquid chromatography). After the reaction was completed, the reaction system was cooled to room temperature, concentrated to dryness under reduced pressure, then dissolved in 100 mL of water, adjusted to the aqueous solution with hydrochloric acid and maintained at an acidic environment with pH<7, then extracted with ethyl acetate, and collected the organic layer, concentrated to dryness to obtain 8.2 g of crude product.

[0033] The crude product was purified by silica gel column (eluent: dichloromethane / methanol = 15:1), traced by TLC, collected product points, and concentrated to dryness to obtain an oily substance. Add 10 mL of acetone and 50 mL of diethyl ether...

Embodiment 2

[0039] The preparation method of embodiment 2 tiagabine ethyl ester hydrochloride

[0040] Dissolve 10g of tiagabine hydrochloride finished product in 50mL of ethanol, add 6mL of concentrated hydrochloric acid dropwise, heat the reaction at 70°C, and monitor the end point of the reaction by HPLC (high performance liquid chromatography). After the reaction was completed, the reaction system was cooled to room temperature, concentrated to dryness under reduced pressure, then dissolved in 100 mL of water, adjusted to the aqueous solution with hydrochloric acid and maintained at an acidic environment with pH<7, then extracted with ethyl acetate, and collected the organic layer, concentrated to dryness to obtain 8.3 g of crude product.

[0041] The crude product was purified by silica gel column (eluent: dichloromethane / methanol = 15:1), traced by TLC, collected product points, and concentrated to dryness to obtain an oily substance. Add 30 mL of ethanol to the obtained oil, heat ...

Embodiment 3

[0042] The preparation method of embodiment 3 tiagabine ethyl ester hydrochloride

[0043] Dissolve 10g of tiagabine hydrochloride finished product in 100mL of ethanol, add 15mL of concentrated hydrochloric acid dropwise, heat the reaction at 70°C, and monitor the end point of the reaction by HPLC (high performance liquid chromatography). After the reaction was completed, the reaction system was cooled to room temperature, concentrated to dryness under reduced pressure, then dissolved in 100 mL of water, adjusted to the aqueous solution with hydrochloric acid and maintained at an acidic environment with pH<7, then extracted with ethyl acetate, and collected the organic layer, washed with 30 mL of saturated NaCl×3, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 8.3 g of crude product.

[0044] The crude product was purified by a silica gel column (eluent: dichloromethane / methanol = 10:1), traced by thin layer, collected product points, and ...

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Abstract

The invention provides a tiagabine ethyl ester hydrochloride as shown in a formula 3. The invention also provides a preparation method of the compound as shown in the formula 3. The tiagabine ethyl ester hydrochloride provided by the invention can be used as an impurity reference substance for tiagabine hydrochloride, and more convenient for control over the impurity content in the product production process and the finished product quality detection process. According to the preparation method provided by the invention, the tiagabine ethyl ester hydrochloride having the purity of more than 99.9% is finally prepared from specific reaction raw materials in combination with a corresponding refining process, and the product can be directly used as the reference substance to control the content of related substances of tiagabine hydrochloride.

Description

technical field [0001] The invention relates to tiagabine ethyl ester hydrochloride and a preparation method thereof. Background technique [0002] Tiagabine hydrochloride (Tiagabine hydrochloride, 1) is the first marketed neuron and glial γ-aminobutyric acid (GABA) reuptake selective and reversible inhibitor, which can inhibit mediator transmission in the central nervous system, It increases the concentration of GABA in the synapse and reduces the sensitivity of nerve excitation. It is an antiepileptic drug with a very clear mechanism of action. The chemical name of tiagabine hydrochloride is (R)-(-)-N-[4,4-bis-(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid Hydrochloride, the structural formula is as follows: [0003] [0004] The synthetic route of the now reported tiagabine hydrochloride mainly takes 2-bromo-3-methylthiophene as starting material, synthesizes N-alkylating reagent by different methods, and then reacts with chiral ethyl piperidinecarboxyla...

Claims

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Application Information

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IPC IPC(8): C07D409/14
CPCC07D409/14
Inventor 傅霖宿磊陈刚
Owner 凯默斯医药科技上海有限公司
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