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Synthesis method of intermediate 1-methylindole-3-carboxylic acid of granisetron drug

A technology of methyl indole and granisetron, applied in the field of synthesis of granisetron drug intermediate 1-methyl indole-3-carboxylic acid, to reduce reaction temperature and reaction time, increase reaction yield, reduce The effect of the middle link

Inactive Publication Date: 2017-02-22
XIAMEN KAI ER LI INFORMATION TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no clear study on the pharmacological or pharmacokinetic interactions between this product and other drugs

Method used

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  • Synthesis method of intermediate 1-methylindole-3-carboxylic acid of granisetron drug

Examples

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Effect test

example 1

[0011] Add 130ml of propionitrile and 0.32mol of stannous chloride into the reaction vessel, control the stirring speed at 130rpm, add 0.053mol of 1H-indazole-3-carboxylic acid (2), raise the temperature of the solution to 50°C, reflux for 5h, and slowly add the amine Methane (3) 0.061mol, reflux for 8h, lower the solution temperature to 5°C, let stand for 30h, precipitate solid, filter, dissolve the solid in 150ml of 15% potassium bromide solution, filter and add 30% oxalic acid The pH of the solution was adjusted to 3, and the solid was precipitated, filtered with suction, washed with sodium sulfate solution, washed with nitromethane, dehydrated with anhydrous magnesium sulfate, and recrystallized in 90% ethyl acetate to obtain crystalline 1-methylindole -3-carboxylic acid 8.02g, yield 86%.

example 2

[0013] Add 130ml of propionitrile and 0.32mol of stannous chloride into the reaction vessel, control the stirring speed at 150rpm, add 0.053mol of 1H-indazole-3-carboxylic acid (2), raise the temperature of the solution to 53°C, reflux for 5h, and slowly add the amine Methane (3) 0.062mol, reflux for 8h, lower the solution temperature to 5°C, let it stand for 31h, precipitate solid, filter, dissolve the solid in 150ml of 17% potassium bromide solution with a mass fraction of 17%, add oxalic acid with a mass fraction of 32% after filtration The pH of the solution was adjusted to 3, and a solid was precipitated, filtered with suction, washed with potassium nitrate solution, washed with 82% nitromethane, dehydrated with phosphorus pentoxide, and recrystallized in 92% ethyl acetate to obtain crystal 1 -Methylindole-3-carboxylic acid 8.30g, yield 89%.

example 3

[0015] Add 130ml of propionitrile and 0.32mol of stannous chloride into the reaction vessel, control the stirring speed at 170rpm, add 0.053mol of 1H-indazole-3-carboxylic acid (2), raise the temperature of the solution to 55°C, reflux for 6h, and slowly add the amine Methane (3) 0.063mol, reflux for 9h, reduce the solution temperature to 9°C, let it stand for 32h, precipitate solid, filter, dissolve the solid in 150ml of 20% potassium bromide solution, filter and add 35% oxalic acid The pH of the solution was adjusted to 4, and a solid was precipitated, suction filtered, washed with sodium sulfate solution, washed with 85% nitromethane, dehydrated with anhydrous magnesium sulfate, and recrystallized in 95% ethyl acetate to obtain crystal 1 -Methylindole-3-carboxylic acid 8.68g, yield 93%.

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Abstract

A synthesis method of intermediate 1-methylindole-3-carboxylic acid of a granisetron drug comprises the steps as follows: adding 130 ml of acrylonitrile and 0.32 mol of stannous chloride to a reaction vessel, controlling the stirring speed at 130 to 170 rpm, adding 0.053 mol of 1H-indazole-3-formic acid, increasing the temperature of the solution to 50-55 DEG C, preforming reflux for 5-6 h, slowly adding 0.061-0.063 mol of amine methane, performing reflux for 8-9 h, reducing the temperature of the solution to 5-9 DEG C, leaving the solution to stand for 30-32 h, separating a solid out, performing filtration, dissolving the solid in 150 ml of a potassium bromide solution, performing filtration, adding an oxalic acid solution to adjust the pH of the solution to 3-4, separating a solid out, performing suction filtration, performing washing with a saline solution and washing with nitromethane, performing dehydration with a dehydrating agent, and performing recrystallization in ethyl acetate to obtain 1-methylindole-3-carboxylic acid crystals; the saline solution in the step is any one of sodium sulfate and potassium nitrate.

Description

technical field [0001] The invention relates to a method for synthesizing granisetron drug intermediate 1-methylindole-3-carboxylic acid. Background technique [0002] The drug granisetron is used for nausea and vomiting caused by radiation therapy and cytotoxic chemotherapy. This product will not affect or inhibit the cytochrome P-450 drug metabolizing enzyme system. At present, there is no clear study on the pharmacological or pharmacokinetic interactions between this product and other drugs. Because granisetron is metabolized by the cytochrome P-450 drug-metabolizing enzymes in the liver, any substance that affects or inhibits this enzyme will affect the metabolism and elimination half-life of granisetron. This product is a highly selective 5-HT3 receptor antagonist, which has good preventive and therapeutic effects on nausea and vomiting caused by radiotherapy, chemotherapy and surgery. Factors such as radiotherapy, chemotherapy, and surgery can cause enterochromaffin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42C07D231/56
CPCC07D209/42C07D231/56
Inventor 彭飞
Owner XIAMEN KAI ER LI INFORMATION TECH CO LTD
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