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One-step synthesis method of 5-bromo-2-chloropyrimidine

A synthesis method and chloropyrimidine technology are applied in the field of one-step synthesis method of 5-bromo-2-chloropyrimidine, which can solve the problems of low utilization rate of raw materials, low efficiency, human body pollution and the like, and achieves simplified production process, improved production efficiency, The effect of improving economic efficiency

Pending Publication Date: 2022-06-07
杭州布朗生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to solve the existing 5-bromo-2-chloropyrimidine preparation system, the raw material utilization rate is low, and the efficiency is low, it is easy to cause relatively large pollution and there is significant harm to the human body, etc., the invention provides a 5- One-step Synthesis of Bromo-2-Chloropyrimidine

Method used

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  • One-step synthesis method of 5-bromo-2-chloropyrimidine
  • One-step synthesis method of 5-bromo-2-chloropyrimidine
  • One-step synthesis method of 5-bromo-2-chloropyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] A one-step synthesis method of 5-bromo-2-chloropyrimidine, the method is:

[0049] Take 112.1g (1mol) of 2-hydroxypyrimidine, mix 2-hydroxypyrimidine with 404.6g of hydrobromic acid with a concentration of 20wt%, the molar ratio of hydrogen bromide and 2-hydroxypyrimidine in the hydrobromic acid is 1:1, add 340 g of hydrogen peroxide with a concentration of 10wt%, the molar ratio of hydrogen peroxide and 2-hydroxypyrimidine in the hydrogen peroxide is 1:1; heated to 100°C in a reaction vessel for 8h insulation reaction to obtain 5-bromo-2-hydroxypyrimidine;

[0050] Add catalase in the proportion of 150IU / mL reaction solution, react for 30min, then cool down to ≤10℃, filter under reduced pressure to remove the filtrate, and blow dry at 75℃ for 5h;

[0051] Subsequently, 153.3g (1mol) of phosphorus oxychloride and 60.7g (0.6mol) of triethylamine were added to the reaction vessel, and the reaction vessel was heated to 120° C. for 8 hours, and the preparation of 5-bromo-2-...

Embodiment 2

[0057] A one-step synthesis method of 5-bromo-2-chloropyrimidine, the method is:

[0058] Take 112.1g (1mol) of 2-hydroxypyrimidine, mix 2-hydroxypyrimidine with 462.3g of hydrobromic acid with a concentration of 35wt%, the molar ratio of hydrogen bromide and 2-hydroxypyrimidine in the hydrobromic acid is 2:1, add 226.7g of hydrogen peroxide with a concentration of 30wt%, the molar ratio of hydrogen peroxide and 2-hydroxypyrimidine in the hydrogen peroxide is 2:1; heated to 40°C in a reaction vessel for 12 hours of insulation reaction to obtain 5-bromo-2-hydroxypyrimidine;

[0059] Catalase was added in the proportion of 150IU / mL reaction solution, reacted for 30min, cooled to ≤10℃, filtered under reduced pressure to remove the filtrate, and air-dried at 85℃ for 4h;

[0060] Subsequently, 191.7g (1.25mol) of phosphorus oxychloride and 65.8g (0.65mol) of triethylamine were added to the reaction vessel, and the reaction vessel was heated to 80°C for 6 hours, and the reaction was...

Embodiment 3

[0064] A one-step synthesis method of 5-bromo-2-chloropyrimidine, the method is:

[0065] Take 112.1g (1mol) of 2-hydroxypyrimidine, mix 2-hydroxypyrimidine with 485.5g of hydrobromic acid with a concentration of 50wt%, the molar ratio of hydrogen bromide and 2-hydroxypyrimidine in the hydrobromic acid is 3:1, add 340 g of hydrogen peroxide with a concentration of 50wt%, the molar ratio of hydrogen peroxide and 2-hydroxypyrimidine in the hydrogen peroxide is 5:1; heated to 30°C in a reaction vessel for 14 hours of insulation reaction to obtain 5-bromo-2-hydroxypyrimidine;

[0066] Add catalase in the proportion of 150IU / mL reaction solution, react for 30min and then cool down to ≤10℃, filter under reduced pressure to remove the filtrate, and blow dry at 70℃ for 6h;

[0067] Subsequently, 766.7g (5mol) of phosphorus oxychloride and 202.4g (2mol) of triethylamine were added to the reaction vessel, and the reaction vessel was heated to 50°C for 5h and the reaction was maintained ...

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Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a one-step synthesis method of 5-bromo-2-chloropyrimidine. The method comprises the following steps: by taking 2-hydroxypyrimidine and hydrobromic acid as raw materials, carrying out heating reaction by adopting hydrogen peroxide catalysis, then carrying out purification treatment to obtain an intermediate, by taking the intermediate and chloride as raw materials, carrying out heating reaction by adopting organic amine catalysis, and then carrying out purification to obtain 5-bromo-2-chloropyridine; the chloride is phosphorus oxychloride; the organic amine is triethylamine and / or diisopropylethylamine and / or N, N-dimethylaniline and / or N, N-dimethyl benzylamine. According to the invention, the production process of the 5-bromo-2-chloropyrimidine is greatly simplified, the synthetic route is optimized, the production efficiency is greatly improved, and the production efficiency in the actual industrial production process can be improved by more than 4 times; by optimizing and improving the synthetic route, the effective utilization rate of the bromine element can be increased by 100% or above compared with that of a traditional reaction system.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a one-step synthesis method of 5-bromo-2-chloropyrimidine. Background technique [0002] Macitentan is a small molecule drug developed by Actelion Pharmaceuticals Ltd. It is an ETAR antagonist and ETBR antagonist. At present, the highest research and development stage of the drug is approval and marketing for the treatment of pulmonary arterial hypertension and pulmonary hypertension. [0003] In the preparation of macitentan, 5-bromo-2-chloropyrimidine is an important intermediate. At present, 5-bromo-2-chloropyrimidine is achieved by glacial acetic acid / bromine system reaction to achieve bromine on 2-hydroxypyrimidine, but the utilization rate of bromine element in the actual industrial production of this reaction system is low, and because the bromine vapor has Strong irritant, corrosive and harmful, and glacial acetic acid itself has strong volatility, so in the traditional...

Claims

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Application Information

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IPC IPC(8): C07D239/30
CPCC07D239/30
Inventor 马肖克黄国祥徐华新
Owner 杭州布朗生物医药科技有限公司
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