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Preparation and purifying method of tiagabine hydrochloride

A tiagabine hydrochloride and purification method technology, applied in the direction of organic chemistry, can solve the problems of laborious, time-consuming column chromatography operation, high cost, etc., and achieve the effect of lightening the color, reducing the cost and improving the purity

Active Publication Date: 2014-02-12
FUZHOU NEPTUNUS FUYAO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The column chromatography of the known process is time-consuming, labor-intensive, and expensive to operate in the scale-up production. It is necessary to get rid of the column chromatography and find a better purification method; in addition, it is necessary to develop a new method and use it directly R -Ethyl piperidine-3-carboxylate.L-tartrate

Method used

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  • Preparation and purifying method of tiagabine hydrochloride
  • Preparation and purifying method of tiagabine hydrochloride
  • Preparation and purifying method of tiagabine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: via 1,1-bis(3-methyl-2-thienyl)-4-bromo-1-butene (1) and R -Piperidine-3-ethyl carboxylate (5) to prepare tiagabine hydrochloride (control group for yield and purity)

[0032] R -Ethyl piperidine-3-carboxylate 20.4g (130mmol), anhydrous potassium carbonate 62.9g (456mmol), potassium iodide 1.08g, 1.1-bis(3-methyl-2-thienyl)-4-bromo-1- A mixture of 42.1 g (130 mmol) of butene and 600 ml of acetone was stirred electromagnetically for 72 hours at room temperature in the dark, filtered and washed, and the filtrate was concentrated to obtain an orange-red oil. The crude product was subjected to column chromatography [ f 45×300, silica gel 200-300 mesh, elution: petroleum ether→petroleum ether-acetone (20:1)] to obtain 39.7g of a light yellow oil in the distillate, with a yield of 76.0%.

[0033] The product of the previous step was dissolved in 200ml of 95% ethanol, 51ml of 4M LiOH solution was added, and stirred at room temperature for 3 hours. Under ic...

Embodiment 2

[0035] Embodiment 2: the yield verification of alkylation reaction——( R )-Piperidine-3-ethyl carboxylate. L-tartrate is directly charged, and the reaction of 1,1-bis(3-methyl-2-thienyl)-4-bromo-1-butene prepares tiagabine pure ethyl ester

[0036] ( R )-piperidine-3-carboxylic acid ethyl ester. L-tartrate 42.0g (137mmol), 1,1-bis(3-methyl-2-thienyl)-4-bromo-1-butene 44.7g (137mmol ), anhydrous K 2 CO 3 66.1 g (479 mmol), KI 1.16 g and acetone 630 ml, the reactant was protected from light, stirred at room temperature for 72 hours, filtered to remove inorganic salts, and the filtrate was rotary evaporated (bath temperature <50°C). The filter residue was washed three times with acetone, and the filtrate was rotary evaporated (bath temperature <50°C) to obtain a red oil, which was separated by column chromatography (silica gel, eluent: petroleum ether→petroleum ether-acetone) to obtain 43.7 g of a light yellow product, which was collected The rate is 77.5%.

[0037] ...

Embodiment 3

[0038] Embodiment 3: the yield verification of alkylation reaction——( R )-Piperidine-3-ethyl carboxylate. L-tartrate is fed directly and prepared by reaction with 1,1-bis(3-methyl-2-thienyl)-1-butene-4-methanesulfonate Pure Tiagabine Ethyl Ethyl

[0039] at room temperature R- Piperidine-3-carboxylic acid ethyl ester×L-tartrate 34.1g (111mmol), 1,1-bis(3-methyl-2-thienyl)-4-methanesulfonate-1-butene 40.1g ( 111mmol), anhydrous K 2 CO 3 A mixture of 53.6g (388mmol), KI 0.93g and acetone 550mL was stirred for 72 hours, filtered to remove inorganic salts, the filtrate was rotary evaporated, and the residue was purified by column chromatography (silica gel 300~400 mesh, petroleum ether:acetone=95:5) 33.7 g of yellow oil was obtained, with a yield of 75.5%, which was close to the reported yield of 74-77%.

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Abstract

The invention provides a preparation and purifying method of tiagabine hydrochloride. The method comprises the following steps: directly using R-piperidine-ethyl formateXL-tartrate(2), or R-piperidine-3-ethyl formate as raw material, reacting with alkylating agent 1,1-bi(3-methyl-2-thienyl)-4-X-1-butene(1, X is Cl, Br, I, O, Ts and OMs) in the presence of enough potassium carbonate, obtaining a crude product of tiagabine ethyl ester, directly performing alkali hydrolysis, performing the process of alkali solution in dichloromethane-water system and slat formation with hydrochloric acid on the tiagabine hydrochloride crude product for more than twice, removing various impurities in the tiagabine ethyl ester crude product to obtain pure tiagabine hydrochloride (4) with high purity. The process step is shortened, the column chromatography is abolished, the process program is simplified, the cost is greatly lowered, and the product with high purity is obtained.

Description

technical field [0001] The invention relates to a method for preparing and purifying antiepileptic drug tiagabine hydrochloride. Background technique [0002] ( R )-(-)-N-[4,4-bis(3-methyl-2-thienyl)-1-butyl-3-ene]piperidine-3-carboxylate hydrochloride, its common name is Tiagabine Hydrochloride. USP 5,010,090 (Andersen K. E. et al, J Med. Chem . 1993, 36 :1716-1725.) was the first to report the synthesis of tiagabine hydrochloride and its use as an inhibitor of GABA uptake proteins. It was first listed in Denmark and France by Novo Nordisk in 1996, and is now listed in many countries around the world. As a new antiepileptic drug with a new mode of action, this drug is an important breakthrough in the treatment of antiepileptic drugs. It has a significant effect on the approximately 30 percent of seizures that are refractory to existing medications. Compared with other antiepileptic drugs, its side effects are mild and there is no drug resistance, and clinical studie...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/14
CPCC07D409/14
Inventor 赵学清
Owner FUZHOU NEPTUNUS FUYAO PHARMA
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