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Method for preparing tiagabine and precursor compound of tiagabine

The technology of a compound and tiagabine, which is applied in the field of pharmaceutical preparation, can solve the problems of low N-alkylation yield, difficulty in large-scale production and application, waste of piperidine formate, etc., and achieves simplified purification process and easy product purification. , the effect of reducing production costs

Inactive Publication Date: 2014-11-05
YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The N-alkylation yield in the existing route is low, the waste of expensive chiral reagent piperidine carboxylate is still not well resolved, and the purification steps in the whole process use chromatographic columns, which is difficult for industrialized large-scale production and application

Method used

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  • Method for preparing tiagabine and precursor compound of tiagabine
  • Method for preparing tiagabine and precursor compound of tiagabine
  • Method for preparing tiagabine and precursor compound of tiagabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of the compound of chemical formula III (R=C 2 h 5 )

[0047] Under N2 protection, the compound of chemical formula I (wherein R=C 2 h 5 ) (100.86g, 245mmol) was dissolved in 500ml of dry toluene, the compound of chemical formula II (50.0g, 223mmol) was suspended in 1500ml of dry toluene, and the toluene suspension of the compound of chemical formula II was dropped into chemical formula I under stirring solution of the compound in toluene. Heated to reflux and stirred for 23h. The solution was spin-dried under reduced pressure to obtain a yellow oil. Add 1000ml of n-hexane: acetone (9:1) to the oil, stir, filter, and concentrate the filtrate to obtain 70.67g of compound of chemical formula III, HPLC purity>80%. The obtained compound of chemical formula III contains part of unremoved triphenylphosphine oxide, which will be removed in the next step, and the sample used for structure determination is purified by column chromatography (9:...

Embodiment 2

[0048] Embodiment 2: Preparation of the compound of chemical formula IV

[0049] Add 12.0mol / L NaOH (25mL, 300mmol) to the ethanol (300mL) solution of the compound of chemical formula III (40.63g, 151mmol), stir at room temperature for 4h, after TLC monitors that the reaction is complete, filter, the resulting solid is added to 200ml of water, and dilute with concentrated Acidify with hydrochloric acid to pH 4, a white solid precipitates out, stir at room temperature for 2 hours, and then filter with suction. The filter cake was washed with water and dried in vacuum to obtain 30.78 g of the compound of chemical formula IV, with a yield of 90% and a purity of 96% by HPLC. MS(ESI-):277.2; 1 H NMR (500MHz, Chloroform) δ: 2.17(s, 6H), 3.49(d, J=7.0Hz, 2H), 6.53(s, 1H), 7.19–7.03(m, 2H), 7.64–7.49(m ,2H).

Embodiment 3

[0050] Embodiment 3: Preparation of the compound of chemical formula V:

[0051] Put the compound of chemical formula IV (47.33g, 170mmol) into the reaction flask, add 3000ml freshly distilled toluene, stir to dissolve. After cooling in an ice bath, 20ml of N,N-dimethylformamide was added dropwise. Keeping the temperature of the reaction system, 560ml of thionyl chloride was slowly added dropwise at 20°C. After the dropwise addition was completed, the reaction was stirred at room temperature for 1h, and then the reaction was incubated and stirred at 50°C. TLC followed the reaction process (condition: petroleum ether: ethyl acetate = 3:1), the reaction was complete after about 3 hours. Concentrate under reduced pressure to remove the solvent, add 500ml of freshly distilled toluene and continue to concentrate until no solvent is concentrated, and add 500ml of THF to dissolve the residue for later use.

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Abstract

The invention relates to a method for preparing tiagabine and a precursor compound of the tiagabine, and in particular discloses a method for preparing the tiagabine and raceme and S-configuration products of the tiagabine. The method is characterized by comprising the step that a compound with a chemical formula V and a compound with a chemical formula VI are reacted with each other to prepare a compound with a chemical formula VII, wherein X is selected from a group which consists of chlorine, bromine and iodine; and R1 is selected from groups in a group which consists of free hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted aryl, is preferably hydrogen, C1-C4 alkyl or benzyl, and is more preferably hydrogen, methyl, ethyl or benzyl. The method uses an alkylation method to change the chiral piperidinecarboxylicacid ester, and utilizes acylation transformation to complete alkylation, thus, the utilization ratio of chiral piperidinecarboxylicacid ester is greatly increased, and the total yield of the whole N-alkylation is kept above 80%.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of an antiepileptic drug tiagabine and a precursor compound thereof. Background technique [0002] Tiagabine hydrochloride (tiagabine hydrochloride), the chemical name is (R)-(-)-N-[4,4-di-(3-methyl-2-thienyl)-3-butenyl]-3- Piperidine carboxylate hydrochloride was originally developed by the Danish company Novo Nordisk. Tiagabine hydrochloride is the first marketed selective and reversible inhibitor of γ-aminobutyric acid (GABA) reuptake in neurons and glial cells, which can inhibit the transmission of mediators in the central nervous system and increase the concentration of GABA in synapses , reduce nerve excitation sensitivity, is a new mode of action of antiepileptic drugs. It is clinically used to treat partial seizures, generalized grand mal seizures, or seizures that cannot be controlled by other antiepileptic drugs. Tiagabine hydrochloride has ex...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/14C07D333/24
Inventor 谢义鹏孟娜娜曹康平彭熙林周维兰李元波蓝海
Owner YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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