阅读说明：本技术 一种催化加氢合成1-氨基-4-甲基哌嗪的方法 (Method for synthesizing 1-amino-4-methylpiperazine by catalytic hydrogenation ) 是由 刘献刚 马梦林 程泓睿 黎鹏 王德祥 焦彦召 于 2020-05-11 设计创作，主要内容包括：本发明是一种催化加氢合成1-氨基-4-甲基哌嗪的方法,氧化铁和氧化亚铁负载的钯催化剂催化下1-甲基-4-亚硝基哌嗪在水和有机混合溶剂体系下氢化合成1-氨基-4-甲基哌嗪的绿色合成方法,1-甲基-4-亚硝基哌嗪加入顺磁性Pd/Fe<Sub>3</Sub>O<Sub>4</Sub>-FeO催化剂,在水、有机溶剂和催化剂三相体系下,一定的温度内进行加氢反应,最后通过减压蒸馏分离获得目标产物1-氨基-4-甲基哌嗪。本发明创新地使用了三相体系下催化氢化的方法制备1-氨基-4-甲基哌嗪,较传统的合成方法更为绿色环保,安全,节约成本。(The invention relates to a method for synthesizing 1-amino-4-methylpiperazine by catalytic hydrogenation, which is a green synthesis method for synthesizing 1-amino-4-methylpiperazine by hydrogenating 1-methyl-4-nitrosopiperazine under the catalysis of a palladium catalyst loaded by ferric oxide and ferrous oxide in a water and organic mixed solvent system, wherein paramagnetic Pd/Fe is added into 1-methyl-4-nitrosopiperazine 3 O 4 The FeO catalyst is subjected to hydrogenation reaction at a certain temperature in a three-phase system of water, an organic solvent and the catalyst, and finally the target product 1-amino-4-methylpiperazine is obtained by reduced pressure distillation and separation. The invention innovatively uses the catalytic hydrogenation method in a three-phase system to prepare the 1-amino-4-methylpiperazine, which is more environment-friendly, safer and more cost-saving than the traditional synthetic method.)

1. A catalytic hydrogenation method for synthesizing 1-amino-4-methylpiperazine adopts 1-methyl-4-nitrosopiperazine as a starting material and adopts paramagnetic Pd/Fe₃O₄-FeO is used as a catalyst, a liquid-liquid two-phase system of water-halogenated hydrocarbon is used as a solvent, and high-pressure hydrogenation reaction is carried out under a solid-liquid three-phase system formed by the solvent and the catalyst to prepare the 1-amino-4-methylpiperazineThe synthesis method comprises the following steps:

the halogenated hydrocarbon solution containing the starting material 1-methyl-4-nitrosopiperazine and a certain amount of Pd/Fe₃O₄Adding the FeO catalyst into a 1L high-pressure reaction kettle, adding a proper amount of water, and closing the high-pressure reaction kettle; stirring at room temperature for 30 minutes after nitrogen replacement, then replacing with hydrogen for 3 times, introducing hydrogen to initial pressure of 5.0Mpa, starting a stirrer, stirring at low speed, heating to 50 ℃, and reacting for 5 hours; the reaction mixture was transferred to a glass vial, a magnet was placed at the bottom of the vial, and Pd/Fe was paramagnetic₃O₄the-FeO catalyst is rapidly and completely precipitated to obtain a colorless and transparent solution at the upper layer, the supernatant liquid is poured out, and the paramagnetic Pd/Fe is recovered at the same time₃O₄-FeO catalyst; separating to obtain an organic layer and a water layer, recovering the halogenated hydrocarbon solvent from the organic layer under reduced pressure, distilling the water layer under heating (the temperature is controlled below 50 ℃) by a water pump under reduced pressure, distilling out the solvent water to obtain a crude product 1-amino-4-methylpiperazine, further distilling out the 1-amino-4-methylpiperazine product under the condition of high vacuum (the vacuum degree is 1mmHg) of an oil pump under the heating temperature controlled below 50 ℃, wherein the yield is 60-94%, and the purity of gas chromatography analysis is 95-99.9%; the aforementioned recovery of paramagnetic Pd/Fe₃O₄The FeO catalyst can be recycled after being treated.

2. The catalytic hydrogenation process for synthesizing 1-amino-4-methylpiperazine according to claim 1, wherein the starting material 1-methyl-4-nitrosopiperazine and paramagnetic Pd/Fe₃O₄The mass ratio of the FeO catalyst to the FeO catalyst is 100: 0.01-100: 20.

3. The catalytic hydrogenation process for synthesizing 1-amino-4-methylpiperazine according to claim 1, wherein the paramagnetic Pd/Fe₃O₄The metal Pd in the-FeO catalyst accounts for the whole paramagnetic Pd/Fe₃O₄The percentage of the-FeO catalyst is 1 to 30 percent.

4. The catalytic hydrogenation process for synthesizing 1-amino-4-methylpiperazine according to claim 1, wherein the paramagnetic Pd/Fe₃O₄In the catalyst of-FeOFe₃O₄The mass ratio of FeO to FeO is 20: 1-1: 30, and the optimal ratio is 10: 1-1: 5.

5. The method for synthesizing 1-amino-4-methylpiperazine by catalytic hydrogenation according to claim 1, wherein the halogenated hydrocarbon in the liquid-liquid two-phase system of water-halogenated hydrocarbon is one of halogenated alkane and halogenated aromatic hydrocarbon with density greater than that of water, such as dichloromethane, chloroform, chlorobenzene, 1, 2-dichloroethane, carbon tetrachloride and the like.

6. The catalytic hydrogenation process for synthesizing 1-amino-4-methylpiperazine according to claim 1, characterized in that paramagnetic Pd/Fe is used₃O₄The FeO catalyst can partially poison and deactivate the catalyst due to ferrous iron, so that the activity of the catalyst can be properly reduced, and the condition that the 1-methyl-4-nitrosopiperazine raw material is completely reduced by the high-activity catalyst such as Pd/C and the like to generate the byproduct N-1-methyl-piperazine is avoided.

7. The catalytic hydrogenation process for synthesizing 1-amino-4-methylpiperazine according to claim 1, characterized in that paramagnetic Pd/Fe is used₃O₄The catalyst can be quickly separated from a reaction system by strong magnet adsorption after the catalytic reaction is finished by using the FeO catalyst.

8. The method for synthesizing 1-amino-4-methylpiperazine by catalytic hydrogenation according to claim 1, characterized in that the raw material is 1-methyl-4-nitrosopiperazine, and the target product is 1-amino-4-methylpiperazine, and the structural formulas are respectively as follows:

9. the method for synthesizing 1-amino-4-methylpiperazine by catalytic hydrogenation according to claim 1, characterized in that paramagnetic Pd/Fe3O4-FeO catalyst is used to produce 1-amino-4-methylpiperazine with high selectivity under a three-phase system of water, organic solvent and catalyst, the product selectivity is high, no over-reduction byproduct N-1-methylpiperazine is produced, the target product yield is high, and the method is simpler and more efficient than the traditional method.

10. The method for synthesizing 1-amino-4-methylpiperazine by catalytic hydrogenation according to claim 1, characterized in that a water-organic two-phase solvent system is adopted for layered reaction under low-speed stirring, and raw materials are easily contacted with a catalyst in an organic solvent with high density to generate a target product in the reaction process; the target has good water solubility, and the generated target quickly enters a light solvent water layer to be separated from the contact with the catalyst, so that the generation of a byproduct N-1-methyl-piperazine by directly reducing the N-N bond of hydrazine in further cracking is avoided, and the target product is obtained with high selectivity.

Technical Field

The invention belongs to the field of a medical intermediate synthesis process, and particularly relates to a green synthesis method for preparing corresponding 1-amino-4-methylpiperazine by hydrogenating 1-methyl-4-nitrosopiperazine under the catalysis of a metal catalyst and under a three-phase system of water, an organic solvent and the catalyst.

Background

Rifampicin is a good anti-tuberculosis medicine, and some experts have very high evaluation on the anti-tuberculosis effect of the rifampicin, so that the current anti-tuberculosis treatment enters the rifampicin era, and the rifampicin can completely control the disease without an operation for treating tuberculosis needing an operation in the past. Rifampin has the following structural formula:

1-amino-4-methylpiperazine is an N-amino cyclic compound, an important intermediate for synthesizing rifampicin, and the structural formula is as follows:

zincate reduction is currently the most common synthetic method for preparing 1-amino-4-methylpiperazine from 1-methyl-4-nitrosopiperazine. Among the most used are the acetic acid and zinc systems, Auelbekov, s.a.; mirzaabductaev, A.B. et al, 1985, in Pharmaceutical Chemistry Journal, "Synthesis and antiviral activity of gossypol derivatives", reported the preparation of 1-amino-4-methylpiperazine by zinc reduction of 1-methyl-4-nitrosopiperazine under acetic acid conditions; 1-amino-4-methylpiperazine was synthesized by the zincate reduction method used in Wu, Yachuang and Zoho, Yan fang et al, published in European Journal of medicinal Chemistry, article "Synthesis and antibacterial activity evaluation of novel biochemical Synthesis a hydrophilic Synthesis of antibacterial agents", 2018; CN107721943 of oxazolidinone compound containing biaryl hydrazone structure and its preparation method, applied by Zhaoyanfang, Shenyang pharmaceutical university, also adopts zincic acid reduction method to prepare 1-amino-4-methylpiperazine. The process is mature, but generates a large amount of zinc oxide and zinc acetate waste residues, and is not environment-friendly.

We published in 2018 of Chemistry of Heterocyclic Compounds in the publication "Selective recovery of N-nitro aza-alcoholic cyclic Compounds to the same N-amino products using a zinc product in CO₂–H₂O medium "is also prepared by zincate reduction of 1-amino-4-methylpiperazine. The method is characterized in that carbonic acid is adopted to replace acetic acid, so that the method is relatively green, but a large amount of zinc carbonate and zinc oxide waste residues are also generated, and the method is also not friendly to the environment.

Lithium aluminum hydride reduction is also a common method for preparing 1-amino-4-methylpiperazine from 1-methyl-4-nitrosopiperazine. The "Synthesis of 4-methoxyphenoxyacetic acid and 3,4, 5-methoxyphenoxyacetic acid amides and hydrates as potential nitrogenous cyclic cardiopsis agents" published by Collection of Czechloroslovak chemical communications by Valenta, Vladimir and Hollebek, Jiri et al uses an ethereal solvent to reduce 1-methyl-4-nitrosopiperazine with lithium aluminum hydride to prepare 1-amino-4-methylpiperazine. The lithium aluminum hydride reduction also generates a large amount of aluminum-and lithium-containing waste residues, and simultaneously needs anhydrous operation, is very complicated and is not beneficial to industrial production.

In addition, a hydrazine hydrate cyclization method is adopted to prepare the 1-amino-4-methylpiperazine, and nitrogen mustard hydrochloride and hydrazine hydrate are cyclized to generate the target 1-amino-4-methylpiperazine. It uses highly toxic hydrazine hydrate as raw material, and its operation process is inflammable.

Catalytic hydrogenation is a green reduction method, but it is difficult to use it for the reduction of 1-methyl-4-nitrosopiperazine to prepare 1-amino-4-methylpiperazine because 1-methyl-4-nitrosopiperazine is more likely to further cleave the hydrazine N-N bond and be partially or fully directly reduced to N-1-methyl-piperazine without high selectivity to obtain the target 1-amino-4-methylpiperazine. Over 50% of 1-methyl-4-nitrosopiperazine is directly reduced to N-1-methyl-piperazine with conventional catalysts and catalytic conditions, so that hydrogenation is not currently suitable for this reaction.

Disclosure of Invention

The method for synthesizing the 1-amino-4-methylpiperazine by catalytic hydrogenation has the advantages of high yield of target products, simplicity, high efficiency and environmental friendliness compared with the traditional method.

A method for synthesizing 1-amino-4-methylpiperazine by catalytic hydrogenation is characterized in that 1-methyl-4-nitrosopiperazine is subjected to hydrogenation reaction at a certain temperature in a three-phase system of water, an organic solvent and a catalyst, and finally, the target product 1-amino-4-methylpiperazine is obtained by reduced pressure distillation and separation. The synthetic route is as follows:

the invention relates to a green synthesis method for preparing 1-amino-4-methylpiperazine by hydrogenating 1-methyl-4-nitrosopiperazine in a three-phase system under the catalysis of a metal supported catalyst, which comprises the following steps: dissolving 1-methyl-4-nitrosopiperazine in the mixture of water and halogenated alkane and aromatic hydrocarbon solvent with density greater than that of water, such as dichloromethane, chloroform, chlorobenzene, 1, 2-dichloroethane or carbon tetrachloride, and adding Pd/Fe₃O₄And (3) carrying out nitrogen replacement on the catalyst supported by FeO, stirring at room temperature for 30 minutes, introducing hydrogen to a certain pressure, reacting for about 2 hours, detecting by using GC, concentrating the reaction solution, recovering the solvent, and distilling under reduced pressure to obtain the target 1-amino-4-methylpiperazine.

Further elaboration is as follows:

by using 1-methyl4-nitrosopiperazine as initial material and paramagnetic Pd/Fe₃O₄The synthesis method for preparing the 1-amino-4-methylpiperazine by taking the FeO as the catalyst, taking a liquid-liquid two-phase system of water-halogenated hydrocarbon as a solvent and carrying out high-pressure hydrogenation reaction under a solid-liquid three-phase system formed by the solvent and the catalyst comprises the following synthesis steps: the halogenated hydrocarbon solution containing the starting material 1-methyl-4-nitrosopiperazine and a certain amount of Pd/Fe₃O₄Adding the FeO catalyst into a 1L high-pressure reaction kettle, adding a proper amount of water, and closing the high-pressure reaction kettle; stirring for 30 minutes at room temperature after nitrogen replacement, then replacing for 3 times by hydrogen, filling hydrogen to the initial pressure of 5.0Mpa, starting a stirrer to stir at low speed, heating to 50 ℃, and reacting for 5 hours. The reaction mixture was transferred to a glass vial, a magnet was placed at the bottom of the vial, and Pd/Fe was paramagnetic₃O₄the-FeO catalyst is rapidly and completely precipitated to obtain a colorless and transparent solution at the upper layer, the supernatant liquid is poured out, and the paramagnetic Pd/Fe is recovered at the same time₃O₄-FeO catalyst; separating to obtain an organic layer and a water layer, recovering the halogenated hydrocarbon solvent from the organic layer under reduced pressure, distilling the water layer under heating (the temperature is controlled below 50 ℃) by a water pump under reduced pressure, distilling out the solvent water to obtain a crude product 1-amino-4-methylpiperazine, further distilling out the 1-amino-4-methylpiperazine product under the condition of high vacuum (the vacuum degree is 1mmHg) of an oil pump under the heating temperature controlled below 50 ℃, wherein the yield is 60-86%, and the purity of gas chromatography analysis is 95-99.9%; the aforementioned recovery of paramagnetic Pd/Fe₃O₄The FeO catalyst can be recycled after being treated.

In the above synthesis method, the starting materials are 1-methyl-4-nitrosopiperazine and paramagnetic Pd/Fe₃O₄The mass ratio of the FeO catalyst is 100: 0.001-100: 50, and the optimal ratio is 100: 0.01-100: 20.

In the synthesis method, the paramagnetic Pd/Fe is characterized₃O₄The metal Pd in the-FeO catalyst accounts for the whole paramagnetic Pd/Fe₃O₄The percentage of the-FeO catalyst is 0.1-40%, and the optimal percentage is 1-30%.

In the synthesis method, the paramagnetic Pd/Fe is characterized₃O₄Fe in FeO catalyst₃O₄The mass ratio of FeO to FeO is 20: 1-1: 30, and the optimal ratio is 10: 1-1: 5.

The synthesis method is characterized in that the halogenated hydrocarbon in the liquid-liquid two-phase system of the water-halogenated hydrocarbon is one of halogenated alkane and halogenated aromatic hydrocarbon with density larger than that of water, such as dichloromethane, chloroform, chlorobenzene, 1, 2-dichloroethane, carbon tetrachloride and the like.

In the above synthesis method, paramagnetic Pd/Fe is used₃O₄The FeO catalyst can partially poison and deactivate the catalyst due to ferrous iron, so that the activity of the catalyst can be properly reduced, and the condition that the 1-methyl-4-nitrosopiperazine raw material is completely reduced by the high-activity catalyst such as Pd/C and the like to generate the byproduct N-1-methyl-piperazine is avoided.

In the above synthesis method, paramagnetic Pd/Fe is used₃O₄The catalyst can be quickly separated from a reaction system by strong magnet adsorption after the catalytic reaction is finished by using the FeO catalyst.

In the synthesis method, the raw material is 1-methyl-4-nitrosopiperazine, the target product is 1-amino-4-methylpiperazine, and the structural formula is respectively as follows:

in the synthesis method, the paramagnetic Pd/Fe3O4-FeO catalyst is used to generate the 1-amino-4-methylpiperazine in a three-phase system of water, organic solvent and catalyst with high selectivity, the product has high selectivity, no over-reduction byproduct N-1-methylpiperazine is generated, the target product yield is high, and the method is simpler and more efficient than the traditional method.

The synthesis method is characterized in that a water-organic two-phase solvent system is adopted for layered reaction under low-speed stirring, and raw materials are positioned in an organic solvent with high density in the reaction process and are easy to contact with a catalyst for hydrogenation to generate a target product; the target has good water solubility, and the generated target quickly enters a light solvent water layer to be separated from the contact with the catalyst, so that the phenomenon that the N-N bond of hydrazine is further cracked and is directly reduced to generate a byproduct 1-methyl-piperazine is avoided, and the target product is obtained at high selectivity.

Detailed Description

The following examples illustrate specific process steps of the present invention, but are not intended to limit the invention.