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A kind of synthetic method of gliclazide intermediate amino nitrogen heterocycle hydrochloride

A synthesis method and nitrogen heterocycle technology are applied in the field of synthesis of gliclazide intermediate amino nitrogen heterocycle hydrochloride, which can solve the problems of low yield, large amount of solid waste and the like, achieve reduction of treatment waste residue and facilitate cleaning production effect

Active Publication Date: 2017-11-07
JIANGSU RUIKE MEDICAL SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are mainly disadvantages such as low yield and large amount of solid waste

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0019] The invention provides a method for synthesizing gliclazide intermediate aminoazaheterocycle hydrochloride, comprising the following steps:

[0020] (1) Add water to the reaction cylinder, Palladium / carbon, after replacing the air with nitrogen, slowly heat up to 55-60 °C, pass hydrogen to the reaction cylinder pressure of 1.5MP, at 55-60 °C, maintain the pressure at 1.0-1.5MP, when the pressure does not drop , the reaction ends;

[0021] (2) cooling the reaction steel bottle to below 15°C, and slowly removing the hydrogen in the bottle, replacing the hydrogen with nitrogen, then filtering to remove the palladium / carbon, and retaining the filtrate;

[0022] (3) add liquid caustic soda and toluene in the filtrate, then stir for 30 minutes, leave standstill for 30 minutes, divide the lower layer of water, and retain the upper layer of toluene;

[0023] (4) adding hydrochloric acid dropwise in the toluene layer to a pH of 2-3, stirring for 30 minutes, leaving standstill...

Embodiment 1

[0037] Add a certain amount of water to the reaction cylinder, as well as Amount of 4.5% palladium / carbon, after replacing the air with nitrogen for 3 times, slowly heat up to 55 ° C, pass hydrogen to the reaction cylinder pressure of 1.5MP, at this temperature, maintain the pressure at 1.0-1.5MP, when the pressure does not drop When the reaction was completed, the reaction flask was cooled to below 15°C, and the hydrogen in the flask was slowly removed, and replaced with nitrogen for 3 times. After completion, the palladium / carbon was removed by filtration, 30% liquid caustic soda was added to the filtrate, quantitative toluene was added, and the mixture was stirred for 30 minutes. Let stand for 30 minutes, remove the lower layer of water, add 30% hydrochloric acid dropwise to the toluene layer until the pH is 2-3, stir for 30 minutes, let stand for 30 minutes, after the water layer is distilled to dryness, add anhydrous ethanol, heat to dissolve , cooling and crystallizat...

Embodiment 2

[0039] Add a certain amount of water to the reaction cylinder, as well as Amount of 5% palladium / carbon, after replacing the air with nitrogen for 3 times, slowly heat up to 57 ° C, pass hydrogen to the reaction cylinder pressure of 1.5MP, at this temperature, maintain the pressure at 1.0-1.5MP, when the pressure does not drop When the reaction was completed, the reaction flask was cooled to below 15°C, and the hydrogen in the flask was slowly removed, and replaced with nitrogen for 3 times. After completion, the palladium / carbon was removed by filtration, 30% liquid caustic soda was added to the filtrate, quantitative toluene was added, and the mixture was stirred for 30 minutes. Let stand for 30 minutes, remove the lower layer of water, add 30% hydrochloric acid dropwise to the toluene layer until the pH is 2-3, stir for 30 minutes, let stand for 30 minutes, after the water layer is distilled to dryness, add anhydrous ethanol, heat to dissolve , cooling and crystallizatio...

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Abstract

The invention discloses a synthesis method of a gliclazide intermediate (amino azacyclo-hydrochloride). The method comprises the following steps: adding water, N-nitroso aza-cyclic compounds, and palladium / carbon into a reaction steel cylinder, introducing nitrogen gas into the steel cylinder to dispel the air, heating the steel cylinder to a temperature of 55 to 60 DEG C, introducing hydrogen gas into the reaction steel cylinder until the pressure reaches 1.5 MP, maintaining the pressure in a range of 1.0 to 1.5 MP, wherein when the pressure does not descend, the reactions are finished; cooling the reaction steel cylinder to a temperature lower than 15 DEG C, discharging hydrogen gas in the cylinder, replacing the hydrogen gas by nitrogen gas, filtering to remove palladium / carbon, saving the filtrate; adding liquid alkali and toluene into the filtrate, stirring, allowing the filtrate to stand still, removing the water in the lower layer, saving the upper toluene layer; adding hydrochloric acid into the toluene layer until the pH reaches 2-3, stirring, allowing the toluene layer stand still, removing the water layer, distilling the toluene layer until no water is left, adding anhydrous ethanol into the distillation residues, heating to dissolve the residues, cooling to dissolve out crystals, and filtering so as to obtain the gliclazide intermediate (amino azacyclo-hydrochloride). The provided method improves the yield and reduces the slag.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a method for synthesizing gliclazide intermediate aminoazaheterocycle hydrochloride. Background technique [0002] Gliclazide is a second-generation sulfonylurea hypoglycemic agent with a strong effect. Its mechanism is to selectively act on islet β cells and promote insulin secretion. Through the mechanism of insulin receptor action, it increases the activity of glycogen synthase in bones, promotes the utilization of glucose by muscles, and can reduce the aggregation and adhesion of platelets, which is helpful for the prevention and treatment of diabetic microangiopathy. Gliclazide intermediate amino nitrogen heterocyclic hydrochloride was previously synthesized by using toluene as reaction solvent, and using zinc powder to reverse the original, filtration, extraction, distillation, water crystallization, filtration and drying under anhydrous conditions. There are mainly dis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 赵小泉朱家伍
Owner JIANGSU RUIKE MEDICAL SCI & TECH CO LTD