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Chiral carbazole-4-ketone derivative, preparation method thereof and R(-)ondansetron prepared by the compound

A technology of ondansetron and derivatives, applied in the field of preparation of chiral drugs, which can solve the problems of increased energy consumption and emissions

Inactive Publication Date: 2012-09-05
HINYE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, racemic ondansetron is used to prepare R(-) ondansetron through resolution. Compared with the present invention, the preparation of equivalent R(-) ondansetron needs to consume more than 2 times 2-methylimidazole, but also need to use larger capacity production equipment, energy consumption and emissions will increase

Method used

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  • Chiral carbazole-4-ketone derivative, preparation method thereof and R(-)ondansetron prepared by the compound
  • Chiral carbazole-4-ketone derivative, preparation method thereof and R(-)ondansetron prepared by the compound
  • Chiral carbazole-4-ketone derivative, preparation method thereof and R(-)ondansetron prepared by the compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Preparation of R(-)9-methyl-3-(morpholinyl-N)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one

[0020] Step 1: Take (±) 60.0g of 9-methyl-3-(morpholinyl-N)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one and put it in a 1000ml three-necked bottle Add 600ml of acetone and 30.0g of L(+)-tartaric acid, heat to reflux to dissolve, react under stirring for 1 hour, cool to 0°C, stir for 2 hours, white crystals precipitate, filter, take the filter cake and dry it in vacuum at 50°C , to get L(+)-tartrate of R(-)9-methyl-3-(morpholinyl-N)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 27.0g (yield: 60.0%, the purity determined by chiral HPLC is 98.4%);

[0021] Step 2: Take the L ( +)-Tartrate 20.0g was dissolved in 200ml of water, added 10% NaOH solution, adjusted to pH 7, white crystals were precipitated, filtered, and the filter cake was vacuum-dried at 50°C to obtain R(-)9-methyl-3-(morphine Linyl-N)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one 12.6 g (yield 94.4%, purity determined by c...

Embodiment 2

[0024] Preparation of R(-)9-methyl-3-(dimethylamino)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one

[0025] Step 1: Take (±) 62.0g of 9-methyl-3-(dimethylamino)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one and put it in a 1000ml three-necked bottle , add 500ml of acetone and 36.0g of L(+)-tartaric acid, heat to reflux to dissolve, react under stirring for 1 hour, cool to 0°C, stir for 2 hours, white crystals precipitate, filter, take the filter cake and dry it in vacuum at 50°C, Obtain 28.6 g of L(+)-tartrate of R(-)9-methyl-3-(dimethylamino)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one (Yield: 58.3%, the purity determined by chiral HPLC is 98.4%);

[0026] Step 2: Take the L of R(-)9-9-methyl-3-(dimethylamino)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one obtained in the previous step (+)-Tartrate 20.0g was dissolved in 200ml water, added 10% NaOH solution, adjusted to pH 7, white crystals were precipitated, filtered, and the filter cake was vacuum-dried at 50°C to obtain R(-)9-methy...

Embodiment 3

[0028] Preparation of R(-)ondansetron

[0029] In a 1000ml three-necked flask, add 60.0g of R(-)9-methyl-3-(morpholinyl-N)methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 300ml of n-butanol, adjust the pH to 6 with 2mol / l hydrochloric acid, then add 50.0g of 2-methylimidazole, heat, stir and react at 120°C for 12 hours, cool to below 10°C, precipitate crystals, filter, take the solid, and use Recrystallized from methanol and dried under vacuum at 50°C to obtain 49.8 g of R(-)ondansetron (84.9% yield, 99.6% purity as determined by chiral HPLC).

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Abstract

The invention relates a chiral carbazole-4-ketone derivative, a preparation method thereof and R(-)ondansetron prepared by the compound. In clinic, R(-)ondansetron is used to prevent and cure the emesis and gastrointestinal syndrome caused in the radiotherapy and chemotherapy of tumor, the dosage of R(-)ondansetron is only half dosage of ondansetron, and Q-T wave spacing can not be prolonged so that the use is safer.

Description

field of invention [0001] The present invention relates to the preparation of chiral drugs by utilizing chiral sources. technical background [0002] Ondansetron is currently the most commonly used 5-HT in clinical 3 Receptor antagonist, used for the treatment and prevention of vomiting and gastrointestinal syndrome caused by tumor radiotherapy and chemotherapy. The study found that ondansetron is a mixture of 50% R(-) ondansetron and 50% S(+) ondansetron, in which S(+) ondansetron not only cannot play the role of 5- HT 3 The pharmacological effect of receptor antagonism can also cause the prolongation of the Q-T wave gap, which has certain cardiotoxicity, especially when it is used in combination with other drugs that can cause Q-T wave gap prolongation, the possibility of safety events increases. These studies 在美国专利US5629333A、US5712302A、US2002051815A1、US2004058973A1中公开,在Bodhankar SL,Maurya OP.Effectof racemate ondansetron and its isomers on QTc interval in rats.Pharmacol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/88C07D403/06
Inventor 王衡新
Owner HINYE PHARM CO LTD