阅读说明：本技术 一种n-（3-氯-4-（2-吡啶甲氧基）苯基）-2氰基乙酰胺的合成方法 (Synthetic method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide ) 是由 张�杰 朱义胜 杨铎 吕红超 于 2019-12-13 设计创作，主要内容包括：本发明公开了一种N-(3-氯-4-(2-吡啶甲氧基)苯基)-2氰基乙酰胺的合成方法。该方法首先在碱性条件下,2-氯-4-溴苯酚与2-氯甲基吡啶盐酸盐反应生成化合物Ⅲ；在四氟硼酸亚硝催化下,化合物Ⅲ和丙二腈反应,生成N-(3-氯-4-(2-吡啶甲氧基)苯基)-2-氰基乙酰胺。该方法合成路线简单,反应条件温和,产品收率高,易于工业化生产。<Image he="344" wi="700" file="DDA0002316402230000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a synthetic method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide. The method comprises the steps of firstly, reacting 2-chloro-4-bromophenol with 2-chloromethylpyridine hydrochloride under an alkaline condition to generate a compound III; under the catalysis of nitroso tetrafluoroborate, the compound III reacts with malononitrile to generate N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide. The method has the advantages of simple synthetic route, mild reaction conditions, high product yield and easy industrial production.)

1. A synthetic method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide is characterized in that,

1) under the alkaline condition, 2-chloro-4-bromophenol reacts with 2-chloromethylpyridine hydrochloride to generate 3-chloro-4- (2-pyridylmethoxy) bromobenzene;

2) under the catalysis of nitroso tetrafluoroborate, 3-chloro-4- (2-pyridylmethoxy) bromobenzene reacts with malononitrile to generate N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide.

2. The method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to claim 1, wherein the alkali used in the alkaline condition in the step 1) is sodium hydroxide, potassium hydroxide or lithium hydroxide.

3. The method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to claim 1, wherein the reaction temperature in the step 1) is 20-80 ℃.

4. The method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to claim 1, wherein the reaction solvent in step 1) is acetonitrile, acetone, DMF, DMSO or dioxane.

5. The method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to claim 1, wherein the reaction temperature in step 2) is 0-80 ℃.

6. The method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to claim 1, wherein the reaction solvent in the step 2) is dichloromethane, chloroform or acetonitrile.

7. The process for the synthesis of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to any one of claims 1 to 6, comprising the steps of:

1) synthesis of 3-chloro-4- (2-pyridylmethoxy) bromobenzene

Adding 2-chloro-4-bromophenol, 2-chloromethylpyridine hydrochloride and alkali into a reaction solvent, heating to 40-55 ℃, carrying out heat preservation reaction, cooling to room temperature after the reaction is finished, adding water into the reaction solution, filtering, washing a filter cake, and drying to obtain 3-chloro-4- (2-pyridylmethoxy) bromobenzene;

2) synthesis of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide

Adding 3-chloro-4- (2-pyridinylmethoxy) bromobenzene and nitrosotetrafluoroborate into a reaction solvent, adding malononitrile under stirring, heating to 30-40 ℃, and carrying out heat preservation reaction; after the reaction is finished, adding methanol, evaporating the solvent to dryness, adding a mixed solution of ethanol and water, pulping, filtering and drying to obtain the N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide.

8. The method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to claim 7, wherein in the step 1), the molar ratio of 2-chloro-4-bromophenol: 2-chloromethylpyridine hydrochloride: the base is 1:1.0 to 1.2:2.0 to 2.4.

9. The method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide according to claim 7, wherein in the step 2), the molar ratio of 3-chloro-4- (2-pyridylmethoxy) bromobenzene: nitrosotetrafluoroborate salt: malononitrile is 1:1.0 to 1.1:1.0 to 1.2.

Technical Field

The invention relates to a synthesis method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide, belonging to the technical field of drug synthesis.

Background

N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide, of the formula shown below, is a starting material for the synthesis of 3-cyano-quinoline (see US20060270669, CN 101180269).

WO2006127205 introduces a synthetic method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide, and the synthetic route is shown as follows. The method uses palladium carbon hydrogenation reduction in synthesis, has certain potential safety hazard in actual production, is not suitable for safe production because the reaction in the last step is carried out at a high temperature of 160-180 ℃, has certain special requirements on equipment, and has the total yield of about 50% and lower yield in the three-step reaction.

Disclosure of Invention

Aiming at the problems, the invention provides a method for synthesizing N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide. The method comprises the steps of taking 2-chloro-4-bromophenol and 2-chloromethylpyridine hydrochloride as starting raw materials, firstly generating a compound III under an alkaline condition, and then reacting with malononitrile under the catalysis of nitroso tetrafluoroborate to obtain a compound N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide. The method has the advantages of simple synthetic route, mild reaction conditions, high product yield and easy industrial production.

The technical scheme of the invention is as follows: a synthetic method of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide is characterized in that,

1) under the alkaline condition, 2-chloro-4-bromophenol (compound I) reacts with 2-chloromethylpyridine hydrochloride (compound II) to generate 3-chloro-4- (2-pyridylmethoxy) bromobenzene (compound III);

2) under the catalysis of nitroso tetrafluoroborate (BF4NO), 3-chloro-4- (2-pyridinylmethoxy) bromobenzene reacts with malononitrile to generate N- (3-chloro-4- (2-pyridinylmethoxy) phenyl) -2-cyanoacetamide (compound V).

The synthetic route is as follows:

preferably, the alkali used in the alkaline condition of step 1) is sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide.

Preferably, the reaction temperature range of the step 1) is 20-80 ℃, and preferably 40-55 ℃.

Preferably, the reaction solvent of step 1) is acetonitrile, acetone, DMF, DMSO, dioxane, preferably acetonitrile.

Preferably, the reaction temperature range of the step 2) is 0-80 ℃, and preferably 30-40 ℃.

Preferably, the reaction solvent of step 2) is dichloromethane, chloroform, acetonitrile, preferably dichloromethane.

The synthesis method specifically comprises the following steps:

1) synthesis of 3-chloro-4- (2-pyridylmethoxy) bromobenzene

Adding 2-chloro-4-bromophenol, 2-chloromethylpyridine hydrochloride and alkali into a reaction solvent, heating to 40-55 ℃, carrying out heat preservation reaction, cooling to room temperature after the reaction is finished, adding water into the reaction solution, filtering, washing a filter cake, and drying to obtain 3-chloro-4- (2-pyridylmethoxy) bromobenzene;

2) synthesis of N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide

Adding 3-chloro-4- (2-pyridylmethoxy) bromobenzene and nitrosotetrafluoroborate (BF4NO) into a reaction solvent, adding malononitrile under stirring, heating to 30-40 ℃, and carrying out heat preservation reaction; after the reaction is finished, adding a small amount of methanol, evaporating the solvent to dryness, adding a mixed solution of ethanol and water, pulping, filtering and drying to obtain the N- (3-chloro-4- (2-pyridylmethoxy) phenyl) -2-cyanoacetamide.

In the step 1), the molar ratio of 2-chloro-4-bromophenol: 2-chloromethylpyridine hydrochloride: the base is 1:1.0 to 1.2:2.0 to 2.4. The volume ratio of the reaction solvent to water is 1: 1-5, and preferably 1: 3.

In the step 2), the molar ratio of 3-chloro-4- (2-pyridylmethoxy) bromobenzene: nitrosotetrafluoroborate (NOBF)₄): malononitrile is 1:1.0 to 1.1:1.0 to 1.2. The volume ratio of the ethanol to the water in the mixed solution of the ethanol and the water is 1:1. the volume ratio of the methanol to the reaction solvent is 1: 10-30, preferably 1: 20.

The invention has the beneficial effects that: the method has the advantages of simple synthetic route, mild reaction conditions (no low-temperature, high-temperature and high-pressure reaction), high product yield (the total yield is more than or equal to 90%), simple reaction steps and post-treatment, and easy industrial production.

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