Novel method for preparing hydroxypyrimidine by continuously oxidizing dihydropyrimidinone

A technology for oxidizing dihydropyrimidinone and hydroxypyrimidine, which is applied in chemical instruments and methods, organic chemistry, chemical/physical processes, etc., can solve the problems of being unfriendly and not substantially improving the environment of excessive nitric acid, so as to reduce safety risks, The effect of reducing EHS safety risks and improving efficiency

Active Publication Date: 2021-01-05
ZHEJIANG HONGYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Still adopted in these technical schemes a large excess of nitric acid (9 ~ 14 molar equivalents), did not substantially improve the environmentally unfriendly impact of excessive nitric acid

Method used

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  • Novel method for preparing hydroxypyrimidine by continuously oxidizing dihydropyrimidinone
  • Novel method for preparing hydroxypyrimidine by continuously oxidizing dihydropyrimidinone
  • Novel method for preparing hydroxypyrimidine by continuously oxidizing dihydropyrimidinone

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1: technical scheme described in the present invention

[0056]

[0057] The microchannel reactor was cleaned with drinking water, and the temperature of the temperature control device of the reactor was set to 30°C, and the oxygen cylinder was connected to the inlet C of the microchannel reactor through a stainless steel pipeline for standby. Weigh 10g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-dihydropyrimidin-2(1H)-one dihydrochloride (27.4mmol) into 100mL beaker A, then add 50mL drinking water to beaker A, stir to dissolve, set aside. Weigh 0.9g of 68% concentrated nitric acid (9.6mmol, 0.35eq) into a 10mL graduated test tube B, add water to dilute to 10mL, and set aside. Prepare 30mL of 10% sodium hydroxide solution, pour it into beaker D, put a magnetic stirrer in beaker D and place it on the magnetic stirrer, connect the pipe at outlet D to the top of beaker D, and set aside.

[0058] Turn on feeding pump A, set the flow rate of feedi...

Embodiment 2

[0060] Embodiment 2: implement the technical scheme of the present invention in the traditional tank reactor

[0061] Add 10g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-dihydropyrimidin-2(1H)-one dihydrochloride successively to a 250mL three-necked flask (27.4mmol), 50mL of drinking water, stirring to dissolve. Under the condition of reaction temperature of 20-30°C, 0.9g of 68% concentrated nitric acid (9.6mmol, 0.35eq) was added. At the same time, oxygen was constantly fed into the reaction solution. After the reaction was stirred at 20-30° C. for 5 hours, 30 mL of 10% sodium hydroxide solution was added dropwise to the reaction solution. The obtained suspension was stirred for 20-30 minutes, filtered, and the filter cake was washed with 10 mL×2 drinking water. The wet cake was dried under reduced pressure at 50-60°C for 6 hours to obtain 8.33 g of white solid. The HPLC purity is 15.3%, and the main raw material remains 81.8%. A large amount of main raw mate...

Embodiment 3

[0062] Embodiment 3: the technical scheme disclosed in the patent CN200510106423.2 (HNO 3 :3.0eq)

[0063]

[0064]Add 10g (27.4mmol) 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-dihydropyrimidine-2( 1H)-Kone dihydrochloride and 5ml acetic acid. 7.6 g (82.2 mmol, 3.0 eq) of 68% nitric acid were slowly added to the mixture. A violent exotherm was observed during the dropwise addition. After the dropwise addition, 0.07 g (1 mmol) of sodium nitrite was added to the mixture, and the mixture was reacted at room temperature for 1 hour. After the reaction, gradually add 30% sodium hydroxide solution to the reaction solution to adjust the pH to 7-8, and stir the resulting suspension for 20-30 minutes. Filter and wash the filter cake with 10mL×2 drinking water. The wet cake was dried under reduced pressure at 50-60°C for 6 hours to obtain 6.88 g of white solid. The HPLC purity is 58.2%, and the main raw material remains 39.9%. A large amount of main raw materials have...

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Abstract

The invention provides a novel method for preparing a hydroxyl pyrimidine compound by continuously oxidizing a dihydropyrimidinone compound, and particularly relates to a novel method for preparing the 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonyl pyrimidine in a micro-channel continuous flow reactor by taking oxygen as a main oxidant, concentrated nitric acid as an auxiliary oxidantand 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3, 4-dihydropyrimidin-2(1H)-ketone dihydrochloride as a main raw material. The new method provided by the invention is extremely low in EHS risk, simple and convenient to operate, environment-friendly, green and environment-protecting, high in production efficiency and high in yield, and is a green process suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry and medicinal chemistry, and relates to a new method for continuously oxidizing dihydropyrimidinone compounds to prepare hydroxypyrimidine compounds. More specifically, the present invention relates to a method for preparing hydroxypyrimidine compounds by continuously oxidizing dihydropyrimidinone compounds with oxygen as the main oxidant and concentrated nitric acid as the auxiliary oxidant in a continuous flow reactor. Background technique [0002] Cardiovascular disease is currently the world's number one health killer. According to the relevant report of the World Health Organization (WHO), 1 out of every 3 deaths is caused by cardiovascular disease. Therefore, the development of therapeutic drugs for cardiovascular diseases still has a very important position in the field of health and hygiene. Rosuvastatin calcium, chemical name: bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[(N-met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/36B01J19/00
CPCB01J19/0093B01J2219/00894C07D239/36
Inventor 方真荣汪海波梅光耀张春娥林京都张伟王飞刘学晟况洪福徐陈力
Owner ZHEJIANG HONGYUAN PHARMA
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