Method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine

a technology of bromophenyl and pyrimidine, which is applied in the direction of physical/chemical process catalysts, metal/metal-oxide/metal-hydroxide catalysts, organic chemistry, etc., can solve the problems of increased production cost and waste of resources, and achieves easy separation, simple synthesis process and post-treatment steps.

Active Publication Date: 2020-02-13
ZHEJIANG XIANFENG TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0034]Compared with the prior art, the present invention has the following beneficial effects.
[0035]1. In the process of preparing Intermediate 1 in the present invention, a solid acid is used as a catalyst, which simplifies the synthesis process and the post-treatment steps, and the solid acid is easy to be separated, and recyclable, thereby saving resources and reducing the production cost.
[0036]2. In the present invention, a one-pot method is employed to prepare Intermediate 2 and Intermediate 3, and the solvent used in both steps of reactions is methanol, which saves the step of solvent change in the reaction system, makes the process simpler, and also improves the conversion rate.
[0037]3. In the process of preparing Intermediate 2 in the present invention, sodium methoxide is used as a base in place of sodium hydride or sodium amide used in the prior art, which improves the safety of the reaction and reduces the reaction cost.
[0038]4. The total conversion rate of the process route provided by the invention is high, and the obtained 5-(4-bromophenyl)-4,6-dichloropyrimidine has high purity and contains less impurities.

Problems solved by technology

However, use of concentrated sulfuric acid or thionyl chloride as a catalyst causes the disadvantages of complicated process and troublesome post-treatment, and the catalyst is difficult to recycle, leading to waste of resources and increase of production cost.

Method used

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  • Method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine
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  • Method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine

Examples

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example 1

[0045]In this embodiment, a method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine is provided, which comprises the following steps, specifically.

[0046]Step 1: To a 5.0 L reaction flask, 500 g of p-bromophenylacetic acid and 200 g of a solid acid catalyst were added. Then, 2.7 L of methanol was added, heated with stirring and reacted under reflux for 5 hours.

[0047]The solid acid catalyst may be a complex of iron oxide, zirconium oxide, titanium oxide, diatomaceous earth or silica gel with sulfate ions loaded thereon, and may be purchased from Qufu Shengquan Catalyst Application Technology Co., Ltd. The solid acid catalyst used in examples that follows was the same as that in this example, and thus will not be described there again. The reaction solution was cooled to 20° C. or below, the solid acid catalyst was recovered by filtering, and the resulting filtrate was distilled under reduced pressure to remove methanol. 2.0 L of toluene was added to dissolve the residue by stirr...

example 2

[0052]In this embodiment, a method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine is provided, which comprises the following steps, specifically.

[0053]Step 1: To a 5.0 L reaction flask, 500 g of p-bromophenylacetic acid and 300 g of a solid acid catalyst were added. Then, 2.7 L of methanol was added, heated with stirring and reacted under reflux for 6 hours. The reaction solution was cooled to 30° C., the solid acid catalyst was recovered by filtering, and the resulting filtrate was distilled under reduced pressure to remove methanol. 2.0 L of toluene was added to dissolve the residue by stirring, and the toluene was washed with water, and concentrated under reduced pressure, to obtain 499.6 g of Intermediate 1 (yield 93.8%).

[0054]Step 2: 250 g of Intermediate 1 obtained in Step 1 was added to a 5 L four-neck flask, then 250 g of sodium methoxide and 1000 g of methanol were added, and mechanically stirred. Then, 375 g of dimethyl carbonate was added, the air in the reactor w...

example 3

[0058]In this embodiment, a method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine is provided, which comprises the following steps, specifically.

[0059]Step 1: To a 5.0 L reaction flask, 500 g of p-bromophenylacetic acid and 250 g of a solid acid catalyst were added. Then, 2.7 L of methanol was added, heated with stirring and reacted under reflux for 5.5 hours. The reaction solution was cooled to 25° C., the solid acid catalyst was recovered by filtering, and the resulting filtrate was distilled under reduced pressure to remove methanol. 2.0 L of toluene was added to dissolve the residue by stirring, and the toluene was washed with water, and concentrated under reduced pressure, to obtain 505.4 g of Intermediate 1 (yield 94.9%).

[0060]Step 2: 250 g of Intermediate 1 obtained in Step 1 was added to a 5 L four-neck flask, then 200 g of sodium methoxide and 1000 g of methanol were added, and mechanically stirred. Then, 312.5 g of dimethyl carbonate was added, the air in the react...

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Abstract

A method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine is provided. The method comprises the steps of: preparing methyl p-bromophenylacetate (Intermediate I) by catalytic esterification of p-bromophenylacetic acid, and then reacting with dimethyl carbonate to synthesize 2-(4-bromophenyl)-malonic acid-1,3-dimethyl ester (Intermediate 2), cyclizing with formamidine hydrochloride to obtain 5-(4-bromophenyl)-4,6-dihydroxypyrimidine (Intermediate 3), and then chlorinating to give the product 5-(4-bromophenyl)-4,6-dichloropyrimidine. In the process of preparing Intermediate 1 in the present invention, a solid acid is used as a catalyst. Moreover, in the process of preparing Intermediate 2, sodium methoxide is used as a base in place of sodium hydride or sodium amide used in the prior art. Furthermore, Intermediate 3 is prepared by a one-pot process.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the priority benefit of China application serial no. 201810905221.1, filed on Aug. 9, 2018. The entirety of the above-mentioned patent application is hereby incorporated by reference herein and made a part of this specification.BACKGROUND1. Field of the Invention[0002]The present invention relates to the technical field of chemical synthesis of drugs, and to a method for preparing 5-(4-bromophenyl)-4,6-dichloropyrimidine.2. Description of Related Art[0003]Macitentan is a bi-directional endothelin receptor antagonist developed by Actelion Pharmaceuticals Inc. Macitentan was approved by the FDA on Oct. 18, 2013 under the trade name Opsumit for the treatment of pulmonary arterial hypertension (PAH) to delay the disease progression. Its chemical name is N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide.[0004]5-(4-bromophenyl)-4,6-dichloropyrimidine (CAS: 146533-41-7) is an i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D239/30B01J21/06B01J23/745B01J21/08B01J27/053
CPCB01J21/066C07D239/30B01J21/063B01J21/08B01J23/745B01J27/053
Inventor GAO, FEIFEIGAO, JUNLONGZHU, MINLIANGLU, WEILIU, YI
Owner ZHEJIANG XIANFENG TECH
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