阅读说明：本技术 一种催化剂、其制备方法和应用 (Catalyst, preparation method and application thereof ) 是由 俞磊 陈颖 于士龙 张明 张亚鹏 于 2021-08-23 设计创作，主要内容包括：本发明公开了一种催化剂、其制备方法和应用。该制备方法包括如下步骤：在盐酸溶液中添加取代苯胺、2-甲氧基吡咯、一水合醋酸铜以及过氧化氢溶液,混合均匀后静置,然后过滤即得所述催化剂。本发明以廉价的取代苯胺以及一水合醋酸铜为原料,用2-甲氧基吡咯做引发剂,在酸性环境中用过氧化氢氧化聚合制备铜催化剂,该催化剂可催化氯代烃参与嘧啶-2-胺及其衍生物的偶联反应,效果显著,具有很好的工业应用价值。(The invention discloses a catalyst, a preparation method and application thereof. The preparation method comprises the following steps: adding substituted aniline, 2-methoxy pyrrole, copper acetate monohydrate and hydrogen peroxide solution into hydrochloric acid solution, mixing uniformly, standing, and filtering to obtain the catalyst. The invention takes cheap substituted aniline and copper acetate monohydrate as raw materials, takes 2-methoxy pyrrole as an initiator, and prepares the copper catalyst by hydrogen peroxide oxidative polymerization in an acid environment, and the catalyst can catalyze chlorohydrocarbon to participate in the coupling reaction of pyrimidine-2-amine and derivatives thereof, has obvious effect and has good industrial application value.)

1. A preparation method of a catalyst is characterized by comprising the following steps: adding substituted aniline, 2-methoxy pyrrole, copper acetate monohydrate and hydrogen peroxide solution into hydrochloric acid solution, mixing uniformly, standing, and filtering to obtain the catalyst.

2. The method for preparing a catalyst according to claim 1, wherein the amount of substituted aniline used is 5.0 to 5.5g, the amount of 2-methoxypyrrole used is 0.2 to 0.4g, the amount of copper acetate monohydrate used is 22.0 to 23.0mg, and the amount of hydrogen peroxide solution used is 1mL, per 0.1mol of hydrogen chloride in the mixed solution.

3. The method for preparing a catalyst according to claim 1, wherein the amount of substituted aniline used is 5.1 to 5.4g, the amount of 2-methoxypyrrole used is 0.2 to 0.4g, the amount of copper acetate monohydrate used is 22.2 to 22.8mg, and the amount of hydrogen peroxide solution used is 1mL, per 0.1mol of hydrogen chloride in the mixed solution.

4. The method of preparing a catalyst according to claim 1, wherein the mixed solution contains 5.2g of substituted aniline, 0.3g of 2-methoxypyrrole, 22.6mg of copper acetate monohydrate, and 1mL of hydrogen peroxide per 0.1mol of hydrogen chloride.

5. The method for preparing a catalyst according to any one of claims 1 to 4, wherein the substituted aniline is one or more of para-fluoroaniline, para-methylaniline, para-methoxyaniline, para-phenylenediamine, 2-methoxy-para-phenylenediamine, 2-ethoxy-para-phenylenediamine, 2-isopropoxy-para-phenylenediamine, and 2-fluoroaniline.

6. The method for producing a catalyst according to any one of claims 1 to 4, wherein the hydrogen peroxide solution has a mass concentration of 30%.

7. The method for preparing a catalyst according to any one of claims 1 to 4, wherein the components are uniformly mixed and then left to stand at 0 to 50 ℃ for 24 hours or more.

8. The method for preparing a catalyst according to claim 7, wherein the standing temperature is 25 ℃.

9. A catalyst, characterized by being produced by the production method according to any one of claims 1 to 8.

10. Use of a catalyst according to claim 9 in the synthesis of a medicament.

Technical Field

The invention relates to a catalyst, in particular to a catalyst for drug synthesis, a preparation method and application thereof.

Background

Pyrimidine-2-amine and derivatives thereof are common structures in many antineoplastic drugs, and the coupling reaction thereof can be used for drug synthesis, such as the synthesis of imatinib base. The reaction can realize the introduction of a pyrimidine-2-amine structure, can be applied to the modification of pyrimidine-2-amine, and provides a powerful tool for the synthesis of medicaments.

Halogenated hydrocarbon is a common reaction raw material, coupling of brominated hydrocarbon and iodohydrocarbon is reported at present, most of the used catalysts are catalysts made of expensive metals, and the problems of large amount of ligands, unrecoverable catalyst, low catalyst conversion number and the like are needed.

As one of the halogenated hydrocarbons, chlorinated hydrocarbons are inexpensive compared to brominated hydrocarbons and iodocarbons, but in practical applications, chlorinated hydrocarbons are difficult to react because of the high carbon-chlorine bond energy. In addition, if the reaction substrates are subjected to reasons of large steric hindrance, low activity and the like, the related chlorinated hydrocarbon can not participate in the coupling reaction basically when the heterogeneous catalyst with large steric hindrance is used for catalysis.

Based on cost considerations, it is necessary to develop a catalyst capable of catalyzing the participation of chlorinated hydrocarbons in coupling.

Disclosure of Invention

The invention provides a catalyst, a preparation method and application thereof, aiming at solving the problem that chlorinated hydrocarbon is difficult to participate in the coupling reaction of pyrimidine-2-amine and derivatives thereof in the synthesis of imatinib base catalyzed by a heterogeneous catalyst at present.

In order to achieve the above object, an aspect of the present invention provides a method for preparing a catalyst, the method comprising the steps of: adding substituted aniline, 2-methoxy pyrrole, copper acetate monohydrate and hydrogen peroxide solution into hydrochloric acid solution, mixing uniformly, standing, and filtering to obtain the catalyst.

It is known that in aniline polymerization reactions, electron-rich aniline substrates polymerize easily, while electron-poor aniline substrates polymerize poorly (Synlett, 2019,30, 1703-1707). The 2-methoxy pyrrole is taken as an electron-rich substance and can firstly react to generate a reactive intermediate, thereby inducing a reaction chain of electron-deficient aniline polymerization. In addition, the 2-methoxy pyrrole is also beneficial to improving the activity of the catalyst for preparing aniline. Compared with the common electron-rich aniline initiator, the use amount of the 2-methoxy pyrrole used as the initiator can be obviously reduced, so that the activity of the prepared catalyst cannot be damaged due to too high electron-rich components of the system.

Specifically, the mixed solution contains 5.0-5.5 g of substituted aniline, 0.2-0.4 g of 2-methoxypyrrole, 22.0-23.0 mg of copper acetate monohydrate, and 1mL of hydrogen peroxide solution per 0.1mol of hydrogen chloride.

The proportion can fully load the copper catalyst, avoid catalyst agglomeration, control the polymerization speed of the polyaniline catalyst, ensure the prepared catalyst to have the highest activity and greatly improve the yield of the coupling reaction of the pyrimidine-2-amine and the derivative thereof.

Preferably, the mixed solution contains 5.1-5.4 g of substituted aniline, 0.2-0.4 g of 2-methoxypyrrole, 22.2-22.8 mg of copper acetate monohydrate, and 1mL of hydrogen peroxide solution per 0.1mol of hydrogen chloride.

More preferably, the mixed solution contains 5.2g of substituted aniline, 0.3g of 2-methoxypyrrole, 22.6mg of copper acetate monohydrate, and 1mL of hydrogen peroxide per 0.1mol of hydrogen chloride.

Preferably, the substituted aniline is one or more of para-fluoroaniline, para-methylaniline, para-methoxyaniline, para-phenylenediamine, 2-methoxy para-phenylenediamine, 2-ethoxy para-phenylenediamine, 2-isopropoxy para-phenylenediamine and 2-fluoroaniline.

The activity of the prepared polyaniline catalyst can be adjusted by changing the substituent on the aniline monomer.

Among them, para-fluoroaniline is preferred, and the catalyst prepared by using the raw material has the highest activity, so that the yield of the coupling reaction of the pyrimidine-2-amine and the derivative thereof can be greatly improved.

Preferably, the hydrogen peroxide solution has a mass concentration of 30%.

Specifically, the components are uniformly mixed and then are kept stand for more than 24 hours at the temperature of 0-50 ℃.

Preferably, the resting temperature is 25 ℃.

The raw materials can be fully polymerized at the temperature, and the copper catalyst can be well adsorbed.

The second aspect of the present invention provides a catalyst obtained by the above-mentioned production method.

In a third aspect, the invention provides a use of the above catalyst in drug synthesis.

For example, the method can be used for synthesizing imatinib base, and the reaction process is as follows:

through the technical scheme, the invention has the following beneficial effects:

1. the invention discloses a copper catalyst prepared by taking cheap substituted aniline and copper acetate monohydrate as raw materials, taking 2-methoxy pyrrole as an initiator and oxidizing and polymerizing by using hydrogen peroxide in an acidic environment, wherein the catalyst can catalyze chlorohydrocarbon to participate in the coupling reaction of pyrimidine-2-amine and derivatives thereof, has obvious effect and has good industrial application value.

2. The invention has simple catalyst preparation process and obviously improved yield.

Detailed Description

The following examples are provided to explain the present invention in detail. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.

Example 1

5.2g of para-fluoroaniline, 0.3g of 2-methoxypyrrole, 22.6mg of copper acetate monohydrate, 100mL of 1mol/L hydrochloric acid and 1mL of 30 wt% hydrogen peroxide solution are mixed, the mixture is kept stand at 25 ℃ for 24 hours, and black precipitate obtained after filtration is the catalyst.

20mg of catalyst is weighed and added into 2mL of 1, 4-dioxane solution containing 1.5mmol of compound 1(CAS registry number: 66521-66-2) in the reaction formula (1), 1mmol of compound 2(CAS registry number: 1300740-74-2) in the reaction formula (1) and 2mmol of potassium tert-butoxide, and the mixture is heated and stirred for 24 hours at 110 ℃ under the protection of nitrogen to obtain compound 3, namely imatinib base, in the reaction formula (1), wherein the yield can reach 92%. The copper content of the catalyst was very low, only 0.71% by mass, by ICP analysis, thus giving the catalyst a higher conversion number (TON value).

Example 2

The properties of the materials synthesized using the different substituted anilines were examined under otherwise the same conditions as in example 1, and the results are shown in Table 1.

TABLE 1 Properties of materials synthesized from different substituted anilines

As can be seen from Table 1, in the case of preparing the catalyst without substituted aniline, the catalyst has no catalytic effect on the reaction of the pyrimidine-2-amine derivative and the chlorinated hydrocarbon, and in the case of preparing the catalyst with substituted aniline, the activity of the prepared catalyst is very high, the substituted aniline used is preferably para-fluoroaniline, the catalyst synthesized by using the para-fluoroaniline as the raw material has the best catalytic effect, and when the substituted aniline is used as the coupling reaction, the coupling reaction yield is the highest and reaches 92%.

Example 3

The effect of the ratio of the substituted aniline to hydrogen peroxide was examined under otherwise the same conditions as in example 1, and the results are shown in Table 2.

Table 2 examination of the effectiveness of the ratio of the different substituted anilines to the hydrogen peroxide

As can be seen from the results in Table 2, the catalysts prepared by using the above proportions of substituted aniline and hydrogen peroxide have high activity, and the coupling reaction yield reaches 78% at the lowest when the catalysts are used for catalyzing coupling reaction, wherein the preferred proportion is 5.2g/mL, and the coupling reaction yield can reach 92% when the catalysts prepared by using the proportions are used for catalyzing coupling reaction.

Example 4

The other conditions were the same as in example 1, with varying amounts of 2-methoxypyrrole: 0.2g of 2-methoxy pyrrole is used for synthesizing the catalyst and is applied to the coupling reaction, and the yield of imatinib alkali is 75 percent; 0.4g of 2-methoxy pyrrole is used for synthesizing the catalyst and is applied to the coupling reaction, and the yield of imatinib alkali is 68 percent; without the use of 2-methoxypyrrole, the resulting polyaniline material was catalytically inactive in the coupling reaction for the synthesis of imatinib base described in example 1.

Example 5

The effect of different ratios of hydrated copper acetate to hydrogen peroxide was examined as in example 1 under the other conditions, and the results are shown in Table 3.

TABLE 3 examination of the effectiveness of the ratio of different copper acetate monohydrate to hydrogen peroxide

As is clear from the results in Table 3, the ratio of copper acetate monohydrate to hydrogen peroxide is preferably 22.0 to 23.0mg/mL, and the yield of imatinib base in the catalyst prepared by the ratio is 80% or more, more preferably 22.6 mg/mL.

Example 6

The properties of the materials prepared under the different standing temperatures were examined under the same conditions as in example 1, and the results are shown in Table 4.

TABLE 4 examination of the effects of different resting temperatures

From the results in Table 4, it is understood that the catalyst prepared at a standing temperature of 25 ℃ is the most effective.

The preferred embodiments of the present invention have been described in detail with reference to the examples, but the present invention is not limited to the details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.

It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.