阅读说明：本技术 一种合成对异丁氧基苄胺的方法 (Method for synthesizing p-isobutoxybenzylamine ) 是由 朱翼鸣 倪燕霞 于 2020-06-13 设计创作，主要内容包括：本发明提供了一种合成对异丁氧基苄胺的方法,采用对羟基苯甲醇为原料,该方法先将对羟基苯甲醇和卤代异丁烷反应得到对异丁氧基苯甲醇,然后经过氯代与氨解等一系列步骤得到对异丁氧基苄胺,避免使用相对苛刻具有一定危险性的还原条件,且产出的对异丁氧基苄胺纯度高,品质优良,是一条优异的具有工业化前景的路线。(The invention provides a method for synthesizing p-isobutoxybenzylamine, which adopts p-hydroxybenzyl alcohol as a raw material, the p-isobutoxybenzyl alcohol is obtained by the reaction of the p-hydroxybenzyl alcohol and halogenated isobutane, and then the p-isobutoxybenzylamine is obtained through a series of steps of chlorination, ammonolysis and the like, the use of relatively harsh reducing conditions with certain danger is avoided, and the produced p-isobutoxybenzylamine has high purity and excellent quality, and is an excellent route with industrial prospect.)

1. A synthetic method of p-isobutoxy benzylamine is characterized by comprising the following steps:

(1) synthesizing p-isobutoxy benzyl alcohol, namely performing substitution reaction on p-hydroxybenzyl alcohol and halogenated isobutane to obtain p-isobutoxy benzyl alcohol;

(2) synthesizing p-isobutoxy benzyl chloride, namely performing chlorination reaction on the p-isobutoxy benzyl alcohol obtained in the step (1) and a chlorination reagent to obtain p-isobutoxy benzyl chloride;

(3) and (3) synthesizing p-isobutoxy benzylamine, namely carrying out ammonolysis reaction on the p-isobutoxy benzyl chloride obtained in the step (2) and an ammonolysis reagent to obtain the p-isobutoxy benzylamine.

2. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (1), the substitution reaction of the p-hydroxybenzyl alcohol and the halogenated isobutane is carried out under the action of bases such as potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine and triethylamine, and potassium iodide, tetra-n-butylammonium bromide and the like can be added in the reaction process to promote the reaction.

3. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (1), the halogenated isobutane is one of chloroisobutane, bromoisobutane and iodoisobutane.

4. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (1), the molar ratio of the p-hydroxybenzyl alcohol to the halogenated isobutane to the alkali is 1:1-3:1-5, and the reaction temperature is 50-110 ℃.

5. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (1), the solvent is one of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like, and the weight ratio of the p-hydroxybenzyl alcohol to the solvent is 1: 2-6.

6. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (2), the chlorinated reagent is one of thionyl chloride, phosphorus oxychloride, phosphorus chloride and the like, N-dimethylformamide, pyridine and the like can be added in the reaction process to promote the reaction, the molar ratio of the p-isobutoxy benzyl alcohol to the chlorinated reagent is 1:2-10, and the reaction temperature is 30-80 ℃.

7. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (2), the solvent is one of no solvent or dichloromethane, dichloroethane, diethyl ether, dioxane and the like, and the weight ratio of the p-isobutoxy benzyl alcohol to the solvent is 1:2-5 in the presence of the solvent.

8. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (3), the catalyst for the ammonolysis reaction is one or a combination of more of copper oxide, cuprous chloride, copper chloride, cuprous iodide, urotropine and the like, and the weight ratio of the p-isobutoxy benzyl chloride to the ammonolysis catalyst is 1: 0.01-0.2.

9. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (3), the ammonolysis reagent is one of ammonia water, liquid ammonia, ammonium carbonate, ammonium acetate and the like, and the molar ratio of the p-isobutoxy benzyl chloride to the ammonolysis reagent is 1: 2-10.0.

10. The method for synthesizing p-isobutoxybenzylamine according to claim 1, comprising: in the step (3), the solvent is one of water, methanol, ethanol, isopropanol and ethyl acetate or is subjected to ammonolysis reaction in a solvent-free state, when the solvent is used, the weight ratio of the p-isobutoxy benzyl chloride to the solvent is 1:0.5-6.0, and the reaction temperature is as follows: 10 to 90 ℃.

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing p-isobutoxybenzylamine.

Background

Pimavanserin (Pimavanserin) is a new oral drug for treating Parkinson's disease, developed by acadia pharmaceutical company, usa, and has a trade name of Pimavanserin. P-isobutoxy benzylamine is a key intermediate for synthesizing pimavanserin (pimavanserin), and the structural formula is as follows:

。

the existing domestic and foreign patents and literature reports of p-isobutoxy benzylamine mainly focus on two starting materials, namely p-hydroxybenzaldehyde and p-hydroxybenzyl cyanide.

The p-hydroxybenzaldehyde is used as an initial raw material, after aldehyde group and ammonia or hydroxylamine are condensed into an intermediate, sodium borohydride reducing reagent is needed to be used or steps such as hydrogenation and the like are involved in the presence of catalysts such as palladium carbon, Raney nickel and the like to generate corresponding benzylamine, certain danger exists in industrial production, and the requirement on production equipment is high.

The method takes the p-hydroxyphenylacetonitrile as an initial raw material, and requires the use of lithium aluminum hydride in the nitrile group reduction process or the steps of hydrogenation and the like in the presence of a catalyst to generate corresponding benzylamine, so that certain dangers exist in the amplification process, and the method is not beneficial to industrial safety production.

In addition, in the domestic patent CN108250087A, p-hydroxyphenylacetic acid is used as a starting material, and p-isobutoxybenzylamine is synthesized through esterification, substitution, hydrolysis, chloro/ammonolysis, hofmann degradation, ester hydrolysis and the like in six steps, although the reaction conditions are mild, the reaction steps are relatively long, and reagents DBU, NBS and the like are used in the hofmann degradation step, which is not favorable for industrial production and cost reduction.

Disclosure of Invention

The invention provides a synthesis method of p-isobutoxy benzylamine, which has mild reaction conditions, does not involve the use of relatively dangerous reagents, has simple process post-treatment, higher yield and better product purity, and is a route with industrial prospect.

The specific scheme of the invention is that (1) p-hydroxybenzyl alcohol and halogenated isobutane generate substitution reaction to obtain p-isobutoxy benzyl alcohol, (2) p-isobutoxy benzyl alcohol reacts with a chlorination reagent to obtain p-isobutoxy benzyl chloride, and (3) p-isobutoxy benzyl chloride reacts with an ammonolysis reagent to obtain p-isobutoxy benzylamine.

The synthetic route of the p-isobutoxy benzylamine is as follows:

。

the specific synthesis process of the isobutoxy benzylamine is as follows.

In the step (1), the substitution reaction is carried out under the condition of a base, wherein the base is generally one of potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine and the like, and a certain amount of a catalyst such as potassium iodide, tetra-n-butylammonium bromide and the like can be added to promote the reaction, and preferably, the substitution reaction is carried out under the action of potassium carbonate.

In the step (1), the substitution reaction raw material is halogenated isobutane, the halogenated isobutane is generally one of chloroisobutane, bromoisobutane, iodoisobutane and the like, preferably, the substitution reaction raw material is bromoisobutane, and the reaction rate and the yield are relatively high.

In the step (1), the solvent is one of N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like, preferably, the N, N-dimethylformamide is used as the solvent in the substitution reaction, so that the raw materials and inorganic salts have good solubility, and the reaction rate is accelerated.

In the step (2), the chlorinating reagent is one of thionyl chloride, phosphorus oxychloride, phosphorus chloride and the like, and a certain amount of catalysts such as N, N-dimethylformamide, pyridine and the like can be added to promote the reaction.

In the step (2), the solvent is solvent-free or one of dichloromethane, dichloroethane, diethyl ether, dioxane and the like, preferably, the chlorination reaction is carried out in the dichloroethane solvent, and the recovery rate is high.

In the step (3), the catalyst for the ammonolysis reaction is one or a combination of more of cupric oxide, cuprous chloride, cupric chloride, cuprous iodide, urotropine and the like, and preferably, the ammonolysis reaction is carried out under the action of the catalyst cupric oxide, so that the yield is relatively high.

In the step (3), the ammonolysis reagent is one of ammonia water, liquid ammonia, ammonium carbonate, ammonium acetate and the like, preferably, the ammonolysis reaction is carried out in the ammonia water, so that the cost is relatively low, the industrial operation is simple and convenient, and the safety is high.

In the step (3), the solvent is one of water, methanol, ethanol, isopropanol and ethyl acetate or the ammonolysis reaction is carried out in a solvent-free state, and preferably, the ammonolysis reaction is carried out in solvent water.

Detailed Description

The present invention is further illustrated in detail below with reference to specific examples.