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Preparation method of tropisetron bisindole impurities

A technology of tropisetron and bisindole, which is applied in the field of drug synthesis to achieve the effects of mild reaction, good commercial value and high yield

Inactive Publication Date: 2018-06-12
SHANDONG QIDU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, there are no literature and patent reports on the preparation method of the tropisetron bisindole impurity. The preparation method has become a technical problem to be solved urgently

Method used

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  • Preparation method of tropisetron bisindole impurities

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Embodiment 1

[0023] 3-Indolecarboxylic acid (5.0g, 31mmol) was added to a 100mL reaction flask, 25mL of dichloromethane was added, and oxalyl chloride (5.3mL, 62mmol) was added to react at room temperature for 5h. TLC detected that the raw materials had been reacted (dichloromethane:methanol = 10:1). Post-treatment: filter, remove the filtrate, wash the filter cake twice with dichloromethane, and dry in vacuo to obtain 4.5 g of yellow solid powder with a yield of 81.2%.

Embodiment 2

[0025] 3-Indolecarboxylic acid (5.0 g, 31 mmol) was added to a 100 mL reaction flask, 25 mL of dichloromethane was added, and thionyl chloride (9.2 mL, 124 mmol) was added to react at room temperature for 4 h. It was detected by TLC that the reaction of the starting material had been completed (dichloromethane:methanol=10:1). Post-treatment: filter, remove the filtrate, wash the filter cake twice with dichloromethane, and dry in vacuo to obtain 4.3 g of yellow solid powder with a yield of 78.2%.

Embodiment 3

[0027] 3-Indolecarboxylic acid (5.0 g, 31 mmol) was added to a 100 mL reaction flask, 25 mL of ethyl acetate was added, and oxalyl chloride (15.9 mL, 186 mmol) was added to react at room temperature for 3 h. It was detected by TLC that the reaction of the starting material had been completed (dichloromethane:methanol=10:1). Post-treatment: Distill the solvent off under reduced pressure to obtain a viscous solid, add 10 mL of dichloromethane, beat for 1 hour, filter, remove the filtrate, wash the filter cake twice with dichloromethane, and dry in vacuo to obtain 3.9 g of yellow solid powder. The rate is 70.9%.

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of tropisetron bisindole impurities. The preparation method of the tropisetron bisindole impurities comprises the following steps: (1) dissolving 3-indolecarboxylic acid and an acylation reagent in a solvent and reacting, and carrying aftertreatment to obtain 3-indoloformyl chloride; and (2) dissolving tropisetron in tetrahydrofuran, cooling to the temperature of minus 15-20 DEG C, adding alkali, then dropwise adding a tetrahydrofuran solution of the 3-indoloformyl chloride, reacting for 2-10 hours at a room temperature after dropwise adding is finished, and carrying out aftertreatment to obtain tropisetron bisindole impurities. The preparation method is simple to operate, gentle in reaction, high in yield and high in purity of product, is suitable for mass spectrometry on crude drugs, and has quite high commercial value.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of tropisetron bisindole impurity. Background technique [0002] Tropisetron is a highly efficient and highly selective competitive antagonist of peripheral neurons and central nervous system 5-hydroxytryptamine 3 (5-HT3) receptors, which is used for the prevention and treatment of nausea and vomiting caused by cancer chemotherapy. Currently, the dosage forms listed in China include tablets, capsules and injections. The tropisetron raw material drug used to prepare tropisetron injection needs to meet the required purity, and the content of simple impurities must also meet the corresponding requirements. At present, the mainstream method for preparing tropisetron bulk drug is formed by condensation of indole-3-carboxylic acid and α-tropine alcohol. This process will generate bis-indole impurities, whose structure is shown in the attache...

Claims

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Application Information

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IPC IPC(8): C07D451/12
CPCC07D451/12
Inventor 孔令金张涛任继波杨学谦刘海萍李德凤黄翠萍王孟
Owner SHANDONG QIDU PHARMA
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