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Method for preparing tiagabine and precursor compound of tiagabine

A compound and product technology, applied in the field of drug preparation, can solve the problems of piperidine carboxylate waste, difficulty in large-scale production and low yield of N-alkylation, etc., to reduce production costs, easy product purification, simplify The effect of the purification process

Inactive Publication Date: 2012-12-19
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

[0055] Example 1: Preparation of compounds of formula III (R=C 2 H 5 )

[0056] Under the protection of N2, the compound of 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 toluene solution of the compound. The mixture was heated to reflux and stirred for 23h. The solution was spin-dried under reduced pressure to give a yellow oil. 1000 ml of n-hexane:acetone (9:1) was added to the oil, stirred, filtered, and the filtrate was concentrated to obtain 70.67 g of the compound of formula III with HPLC purity >80%. The obtained compound of formula III contains partially unremoved triphenylphosphine oxide, which is removed in the next step, and the sample for structure determination is purified by column chromatography (9:1 n-hexane...

Embodiment 2

[0057] Example 2: Preparation of compounds of formula IV

[0058] 12.0 mol / L NaOH (25 mL, 300 mmol) was added to the ethanol (300 mL) solution of the compound of chemical formula III (40.63 g, 151 mmol), stirred at room temperature for 4 h, after TLC monitoring was completed, the reaction was filtered, and the obtained solid was added to 200 ml of water, and the mixture was concentrated. The hydrochloric acid was acidified to pH 4, and a white solid was precipitated, which was stirred at room temperature for 2 h and filtered with suction. The filter cake was washed with water and dried in vacuo to obtain 30.78 g of the compound of formula IV with a yield of 90% and a HPLC purity of 96%. MS(ESI): 277.2; 1 H NMR (500MHz, Chloroform) δ: 2.17 (s, 6H), 3.49 (d, J=7.0 Hz, 2H), 6.53 (s, 1H), 7.19-7.03 (m, 2H), 7.64-7.49 (m , 2H).

Embodiment 3

[0059] Example 3: Preparation of compounds of formula V:

[0060] The compound of chemical formula IV (47.33 g, 170 mmol) was put into a reaction flask, 3000 ml of freshly distilled toluene was added, and the mixture was stirred to dissolve. After cooling in an ice bath, 20 ml of N,N-dimethylformamide was added dropwise. Keeping the temperature of the reaction system, 560 ml of thionyl chloride was slowly added dropwise at 20°C. After the dropwise addition was completed, the reaction was stirred at room temperature for 1 h, and then kept at 50°C for the reaction. The reaction progress was tracked by TLC (conditions: petroleum ether: ethyl acetate = 3:1), the reaction was complete after about 3h. Concentrate under reduced pressure to remove the solvent, add 500 ml of freshly distilled toluene and continue to concentrate until no solvent is concentrated, and the residue is dissolved in 500 ml of THF 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 drug preparation, in particular to a preparation method of an antiepileptic drug tiagabine and a precursor compound thereof. Background technique [0002] Tiagabine hydrochloride, chemical name (R)-(-)-N-[4,4-bis-(3-methyl-2-thienyl)3-butenyl]-3-piperidine Picolinate hydrochloride, originally developed by Novo Nordisk, Denmark. Tiagabine hydrochloride is the first marketed selective and reversible inhibitor of neuronal and glial gamma-aminobutyric acid (GABA) reuptake, inhibits mediator transmission in the central nervous system and increases GABA concentrations at synapses , reducing the sensitivity of nerve excitation, is a new mode of action of antiepileptic drugs. It is clinically used to treat partial seizures and grand mal seizures, or seizures that cannot be controlled by other antiepileptic drugs. Tiagabine hydrochloride has very low affinity for dopamine D1 or D2-receptors, β-receptors, and receptors su...

Claims

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Application Information

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Patent Type & Authority Applications(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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