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Preparation method of 4-(1-hydroxy-1-methylethyl)-2-propylimidazolium iodide-5-carboxylate

A technology of propylimidazole and methyl ethyl, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of large environmental pollution, complicated process, and low yield, and achieve the effects of environmental friendliness, short process route, and high content

Active Publication Date: 2014-02-05
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the process of this method is complicated, there are many steps, and a large amount of organic solvents (such as ethyl acetate, ethanol) and corrosive inorganic acids (such as concentrated sulfuric acid) need to be used in the purification process, and there is also a problem of large environmental pollution. And the yield of this method is low (total yield is 69%)

Method used

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  • Preparation method of 4-(1-hydroxy-1-methylethyl)-2-propylimidazolium iodide-5-carboxylate
  • Preparation method of 4-(1-hydroxy-1-methylethyl)-2-propylimidazolium iodide-5-carboxylate
  • Preparation method of 4-(1-hydroxy-1-methylethyl)-2-propylimidazolium iodide-5-carboxylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Add 120mL (2mol / L, 0.24mol) of tetrahydrofuran solution of methylmagnesium bromide into a 250mL three-necked flask, preferably blown with nitrogen for protection, cool down to -10°C, and start adding 2-propylimidazole-4 dropwise, 10g (0.04mol) of ethyl 5-dicarboxylate in 30mL of dichloromethane solution, keep the temperature below 10°C during the dropwise addition, after the dropwise addition, control the temperature at 15°C to react for 1 hour, after the reaction , lower the temperature to 0°C, add 100mL ethyl acetate and 60mL saturated aqueous ammonium chloride solution, stir for 15 minutes, let stand, separate, and collect the organic phase; the water phase can be extracted twice with ethyl acetate, 30mL each time, combined and collected The organic phase was washed three times with saturated brine, 30 mL each time, and finally dried with anhydrous sodium sulfate, filtered, and the filtrate was collected, and then the solvent was removed by distillation under reduced ...

Embodiment 2

[0041] Adopt the method of Example 1 to obtain the oily substance, then add 100mL of dilute hydrochloric acid solution and 1g of activated carbon to the oily substance with a mass concentration of 10%, the addition of the activated carbon is 2-propylimidazole-4,5-dicarboxylate 10% of the mass of ethyl acetate, and then control the temperature at 50°C to conduct a salt-forming reaction for 30 minutes, filter while it is hot, wash the filter cake with cold water three times, 20ml each time, combine the filtrate, cool the filtrate to 0°C, and slowly add mass The concentration is 10% sodium hydroxide aqueous solution to adjust the pH to 7 to remove hydrochloric acid. After adjusting the pH value, stop stirring, and continue to cool the temperature of the reaction liquid (filtrate) to -5°C to make the filtrate completely condense into a solid, and then place it in Slowly melt the ice at room temperature, and a large amount of white solid precipitates out. Stir again for 5 minutes, f...

Embodiment 3

[0043] Add 120mL (2mol / L, 0.24mol) of tetrahydrofuran solution of methylmagnesium bromide into a 250mL three-necked flask, preferably blown with nitrogen for protection, cool down to -10°C, and start adding 2-propylimidazole-4 dropwise, 10g (0.04mol) of ethyl 5-dicarboxylate in 30mL of dichloromethane solution, keep the temperature at -10°C to 10°C during the dropwise addition, after the dropwise addition, control the temperature at 13°C for 1.5 hours , after the reaction, cool down to 0°C, add 100mL ethyl acetate and 60mL saturated aqueous ammonium chloride solution, stir for 15 minutes, let stand, separate, and collect the organic phase; the water phase can be extracted twice with ethyl acetate, each time 30 mL, combined the collected organic phases, washed three times with saturated brine, 30 mL each time, finally dried with anhydrous sodium sulfate, filtered, collected the filtrate, and then distilled under reduced pressure to remove the solvent to obtain 9.4 g of crude pro...

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Abstract

The invention relates to a preparation method of 4-(1-hydroxy-1-methylethyl)-2-propylimidazolium iodide-5-carboxylate, which belongs to the technical field of pharmaceutical intermediate synthesis. For solving the problems that the content of products is low, and a large amount of organic solvents are required to be adopted for recrystallization, a preparation method of 4-(1-hydroxy-1-methylethyl)-2-propylimidazolium iodide-5-carboxylate is provided. The method comprises the following steps: reacting 2-propylimidazolium iodide-4,5-dicarboxylate with methylmagnesium chloride so as to obtain an oily matter; adding an inorganic acid and activated carbon into the oily matter, and heating the obtained mixture so as to carry out a salt forming reaction, so that the obtained mixture is transferred into a corresponding acidic salt; filtering the acidic salt so as to obtain filter liquor of the corresponding acidic salt; and controlling the temperature of the filter liquor, adding an alkaline reagent into the filter liquor so as to adjust the pH value of the obtained mixture to 7, and then carrying out cooling crystallization on the obtained mixture so as to obtain 4-(1-hydroxy-1-methylethyl)-2-propylimidazolium iodide-5-carboxylate. The method disclosed by the invention is simple and short in process, an organic solvent is not required to be adopted for recrystallization, and the purity and yield of obtained products are high.

Description

technical field [0001] The invention relates to a preparation method of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate, which belongs to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Sartans have been widely used as angiotensin II receptor antagonists in the treatment of hypertension. Among them, olmesartan medoxomil has a great market prospect due to its good hypotensive effect and relatively small side effects. [0003] And ethyl 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylate is used as a key intermediate in the synthesis of olmesartan medoxomil, and the quality of its synthesis process directly affects the quality of olmesartan medoxomil. Product quality and cost of tannyl esters. The synthetic 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylate technique reported in most of the existing documents is all similar, all using 2-propylimidazole-4, It can be obtained by Grignard reac...

Claims

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Application Information

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IPC IPC(8): C07D233/90
CPCC07D233/90
Inventor 杨珍珍徐峰蒋军荣柯中炉陈红云姜建新
Owner ZHEJIANG LEPU PHARMA CO LTD
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