Gliquidone preparation method

A technology for gliquinone and isoquinoline, applied in the field of drug synthesis, can solve the problems of high cost of raw materials, harsh reaction conditions, viscous waste water, etc., and achieve the effects of reducing production cost, easy operation and reaction, and easy recovery.

Inactive Publication Date: 2017-01-11
天津市亨必达化学合成物有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the existing method for synthesizing gliquidone has the following disadvantages: N, N-dimethylformamide, benzene, etc. are used as solvents, which are unfavorable for recovery and have high toxicity; sodium hydrogen, as an inflammable and explosive product, is easy to cause Fire, sodium hydroxide, and potassium hydroxide as alkalis tend to make the system viscous and produce a large amount of waste water; the reaction temperature is controlled at 0°C, and the reaction conditions are harsh; the reaction time is long, more than 24 hours, and the efficiency is low; It is good for recycling, and there is a safety hazard that is easy to catch fire

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: A kind of method for preparing gliquidone

[0033]

[0034] Isoquinoline (30 g, 74.6 mmol), solvent 2,5-dimethyltetrahydrofuran (300 mL) and anhydrous potassium carbonate (21 g, 151.9 mmol) were sequentially added into a 500 mL reaction flask. Turn on stirring and heating, keep warm at 40°C and stir for 30 minutes, then slowly add cyclohexyl isocyanate (11.2g, 89.5mmol), control the dropwise addition in about 30 minutes, raise the temperature after the dropwise addition, and heat to reflux at 90°C for reaction 4 Hour. The solvent 2,5-dimethyltetrahydrofuran was recovered under reduced pressure to obtain a white solid. Add 200 mL of water to the reaction bottle, slowly add hydrochloric acid dropwise to adjust the pH=3, cool down to 0-5°C and stir for 1 hour, and filter to obtain crude gliquidone with a yield of 98%.

[0035] Put the crude gliquidone obtained into a 5L three-necked bottle, add 3L methanol to the bottle, heat to 40°C, add ammonia / methano...

Embodiment 2

[0037] Embodiment 2: A kind of method for preparing gliquidone

[0038]

[0039] Isoquinoline (30 g, 74.6 mmol), solvent dichloromethane (150 mL) and sodium bicarbonate (15 g, 178.6 mmol) were sequentially added into a 500 mL reaction flask. Turn on stirring and heating, keep warm at 40°C and stir for 30 minutes, then slowly add cyclohexyl isocyanate (7.5g, 59.9mmol), control the dropwise addition to be completed in about 30 minutes, raise the temperature after the dropwise addition, and heat to reflux at 90°C for reaction 4 Hour. The solvent dichloromethane was recovered under reduced pressure to obtain a white solid. Add 200 mL of water to the reaction bottle, slowly add hydrochloric acid dropwise to adjust the pH=3, cool down to 0-5°C and stir for 1 hour, and filter to obtain crude gliquidone with a yield of 97.0%.

[0040] Put the crude gliquidone obtained into a 5L three-necked bottle, add 3L methanol to the bottle, heat to 40°C, add ammonia / methanol to the system, a...

Embodiment 3

[0041] Embodiment 3: A kind of method for preparing gliquidone

[0042]

[0043]Isoquinoline (30 g, 74.6 mmol), solvent pyridine (450 mL) and lithium hydroxide (15 g, 626.6 mmol) were sequentially added into a 500 mL reaction flask. Turn on stirring and heating, keep warm at 40°C and stir for 30 minutes, then slowly add cyclohexyl isocyanate (7.5g, 59.9mmol), control the dropwise addition to be completed in about 30 minutes, raise the temperature after the dropwise addition, and heat to reflux at 80°C for reaction 6 Hour. The solvent pyridine was recovered under reduced pressure to obtain a white solid. Add 200mL of water to the reaction flask, slowly add hydrochloric acid dropwise to adjust the pH=3, cool down to 0-5°C and stir for 1 hour, then filter to obtain the crude gliquidone with a yield of 97.1%.

[0044] Put the crude gliquidone obtained into a 5L three-necked bottle, add 3L methanol to the bottle, heat to 40°C, add ammonia / methanol to the system, adjust the pH ...

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Abstract

The invention discloses a gliquidone preparation method. According to the preparation method, isoquinoline and cyclohexyl isocyanate carry out condensation reactions in a solvent in the presence of an alkali to generate gliquidone. 2,5-dimethyl tetrahydrofuran is taken as the solvent, isoquinoline can be well dissolved in 2,5-dimethyl tetrahydrofuran, while gliquidone is difficult to dissolve in 2,5-dimethyl tetrahydrofuran; thus, only a little amount of water is needed in the post treatment, the generated wastewater is largely reduced; the used alkali is common inorganic alkalis such as anhydrous potassium carbonate, and the like, is nontoxic, and is easy to process. The boiling point of 2,5-dimethyl tetrahydrofuran is low, 2,5-dimethyl tetrahydrofuran is easy to recover, moreover, the system is not afraid of water, the solvent can be circularly used, the production cost is reduced, the refluxing temperature is adopted, the operation is easy, the reactions last for 6 hours, and the method is rapid and efficient.

Description

technical field [0001] The invention relates to a method for preparing gliquidone and belongs to the field of drug synthesis. Background technique [0002] Gliquidone is the second-generation oral sulfonylurea hypoglycemic drug, which is a highly active pro-islet β-cell agent. It binds to specific receptors on the islet β-cell membrane and can induce the production of an appropriate amount of insulin to reduce blood sugar concentration. The highest plasma concentration is reached after 2-2.5 hours of oral administration of this product, and it will be completely absorbed soon. The plasma half-life is 1.5 hours, and the metabolism is complete. Its metabolites have no hypoglycemic effect, and most of the metabolites are excreted through the biliary tract. [0003] In the prior art, for the synthesis of gliquidone, isoquinolines are used as raw materials, N, N-dimethylformamide, benzene, ethyl acetate are used as solvents, and sodium hydrogen, sodium hydroxide, and potassium h...

Claims

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Application Information

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IPC IPC(8): C07D217/24
CPCC07D217/24
Inventor 赵欣张智强王凯李连启任晓峰李果宋金津赵钊杨昕
Owner 天津市亨必达化学合成物有限公司
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