CN108276296B

CN108276296B - Synthesis method of cyanide antidote

Info

Publication number: CN108276296B
Application number: CN201711326503.8A
Authority: CN
Inventors: 代恋; 孙芹
Original assignee: Weifang Runzhong Fine Chemical Co ltd
Current assignee: Weifang Runzhong Fine Chemical Co ltd
Priority date: 2017-12-13
Filing date: 2017-12-13
Publication date: 2020-09-11
Anticipated expiration: 2037-12-13
Also published as: CN108276296A

Abstract

The invention relates to a synthesis method of a cyanide antidote, which comprises the steps of adding a formaldehyde solution and p-nitroanisole into an ethanol solution, regulating the pH value to be 4 by hydrochloric acid, heating, slowly adding iron powder, and reacting after the addition is finished to obtain 4-dimethylaminobenzoic ether; adding 4-dimethylaminobenzene into toluene, adding aluminum trichloride, heating for refluxing, removing methyl, cooling, adding saturated sodium bicarbonate solution, filtering off solid while hot, separating liquid, washing toluene phase with water, evaporating toluene under reduced pressure after separating liquid, and heating to evaporate product. The product obtained by curing of the invention has the purity of more than 99 percent and the yield of more than 80 percent; the method has the advantages of cheap and easily-obtained raw materials, no dangerous operation, less produced wastewater, less environmental pollution and high overall yield, and is suitable for large-scale production.

Description

Synthesis method of cyanide antidote

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a cyanide antidote.

Background

4-Dimethylaminophenol is an aromatic compound containing phenol and amino groups, and has the chemical formula C₈H₁₁NO, 4-dimethylaminophenol is an antidote to cyanide poisoning by producing methemoglobin, but this is only applicable to acute poisoning conditions, after which sodium thiosulfate or cobalamin treatment is used, which in animal experiments has a role in intramuscular injection.

The prior art processes for producing 4-dimethylaminophenol have three types:

the method comprises the following steps: the synthetic route is as follows

The method has a large number of literature reports, the synthesis method is to add formaldehyde and sodium borohydride into an alcohol solvent, hydrogen is generated by using the sodium borohydride, the production is risky, and a large amount of intermediate 4-methylamino phenol is generated in the reaction and is not easy to remove.

The second method comprises the following steps: the synthetic route is as follows

The operation reported in the literature is mainly to add copper hydroxide as a catalyst into ethylene glycol, then add sodium hydroxide or potassium hydroxide as a strong base, heat and hydrolyze at 120 ℃, and then adjust alkali to obtain the product. The starting raw materials of the route are expensive, a large amount of salt and wastewater are generated in the production, and the large-scale production is not easy.

The third method comprises the following steps: the synthetic route is as follows:

the raw material 4-dimethylaminobenzene of the method is mainly prepared by the reaction of p-anisidine and dimethyl sulfate or methyl iodide under an alkaline condition, the reaction yield is low and is only about 50 percent, and the dimethyl sulfate and the methyl iodide have strong carcinogenic action and bring great risk to production; the second method is to use hydrobromic acid solution of acetic acid to reflux at 110 ℃ to obtain a product, and the reaction generates a large amount of waste acid water with certain environmental protection pressure.

Disclosure of Invention

In order to solve the technical problems, the invention provides a synthesis method of a cyanide antidote, and the product obtained by solidification has the purity of more than 99 percent and the yield of more than 80 percent; the method has the advantages of cheap and easily-obtained raw materials, no dangerous operation, less produced wastewater, less environmental pollution and high overall yield, and is suitable for large-scale production.

The invention is realized by the following technical scheme, and provides a synthesis method of a cyanide antidote, wherein the synthesis reaction formula is as follows:

adding a formaldehyde solution and p-nitroanisole into an ethanol solution, regulating the pH value to be 4 by hydrochloric acid, heating, slowly adding iron powder, and reacting to obtain 4-dimethylaminobenzoic ether;

and secondly, adding 4-dimethylaminobenzene into toluene, adding aluminum trichloride, heating and refluxing, removing methyl, cooling, adding a saturated sodium bicarbonate solution, filtering out solid while hot, separating liquid, washing a toluene phase with water, carrying out reduced pressure evaporation on toluene after liquid separation, and heating to evaporate a product.

Preferably, in the first step, the reaction temperature is 50 ℃ and the reaction time is 12 hours.

Preferably, in the first step, the product is purified after the reaction, and the purification steps are as follows: slowly adding a sodium carbonate solid into a reaction product, adjusting the pH value to be 10, filtering to remove iron powder, spin-drying an ethanol solution, adding ethyl acetate to dissolve, washing an ethyl acetate phase with saturated salt water, drying the ethyl acetate phase with anhydrous sodium sulfate after liquid separation, and spin-drying to obtain a yellow oily substance, namely 4-dimethylaminobenzoic ether.

Preferably, the temperature-raising reflux time in the second step is 6 hours.

Preferably, in the second step, after cooling to 80 ℃, a saturated sodium bicarbonate solution is added.

The invention has the beneficial effects that:

the product obtained by curing of the invention has the purity of more than 99 percent and the yield of more than 80 percent; the method has the advantages of cheap and easily-obtained raw materials, no dangerous operation, less produced wastewater, less environmental pollution and high overall yield, and is suitable for large-scale production.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.

FIG. 1 shows 4-dimethylaminophenol H¹An NMR spectrum;

FIG. 2 is a gas chromatogram of 4-dimethylaminophenol;

FIG. 3 shows 4-dimethylaminobenzoic ether H¹An NMR spectrum;

FIG. 4 is a gas chromatogram of 4-dimethylaminobenzoic acid ether.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The application of the principles of the present invention will be further described with reference to the accompanying drawings and specific embodiments. Example 1

Step one, adding 200ml of ethanol, 30.6g of p-nitroanisole and 60ml of 37% formaldehyde solution into a 500ml three-neck flask, then adding 5ml of concentrated hydrochloric acid, putting the mixture into an oil bath kettle, heating the mixture to 50 ℃ under stirring, slowly adding 33 g of iron powder, keeping the temperature after the addition, continuously stirring the mixture for 12 hours, slowly adding a sodium carbonate solid, adjusting the pH to 10, filtering the iron powder off, spin-drying the ethanol solution, adding 200ml of ethyl acetate to dissolve the ethyl acetate phase, washing the ethyl acetate phase with 100ml of saturated saline, drying the ethyl acetate phase with anhydrous sodium sulfate after liquid separation, and spin-drying the ethyl acetate phase to obtain 28.2 g of yellow oily matter with the purity of 98.8%;

and secondly, adding 28.2 g of oily matter, 200ml of toluene and 27 g of anhydrous aluminum trichloride into a 500ml three-neck bottle, heating up and refluxing for 6 hours in an oil bath pot, cooling to 80 ℃, slowly dropwise adding 100ml of saturated sodium bicarbonate solution to generate a solid, continuously stirring for 10 minutes, filtering out insoluble substances while hot, separating liquid while hot after filtering, adding 50 ml of water into toluene, heating to 80 ℃, stirring for 10 minutes, separating liquid, spin-drying the toluene phase, distilling under reduced pressure by using an oil pump, and curing to obtain 20.8 g of a product with the purity of 99.8% and the yield of 81%.

FIG. 1 shows 4-dimethylaminophenol H¹An NMR spectrum; FIG. 1 shows the hydrogen nuclear magnetic spectrum of the product, namely 4-dimethylamino phenol; FIG. 2 is a gas chromatogram of 4-dimethylaminophenol, FIG. 2 being used for analyzing the purity of the product; table 1 shows the percentage peak area data in the gas chromatogram of 4-dimethylaminophenol, and it can be seen from Table 2 and the figure that the purity of 4-dimethylaminophenol reaches 99.8%.

TABLE 1

FIG. 3 shows 4-dimethylaminobenzoic ether H¹An NMR spectrum; the hydrogen nuclear magnetic spectrum of the intermediate 4-dimethylaminobenzoic ether can be seen from the figure 1; FIG. 4 is a gas chromatogram of 4-dimethylaminobenzoic acid ether; table 2 shows the data of the percentage of peak area in the gas chromatogram of 4-dimethylaminobenzoic ether, and it can be seen from Table 2 and the figure that the purity of intermediate 4-dimethylaminobenzoic ether reaches 98.8%.

TABLE 2

Of course, the above description is not limited to the above examples, and the undescribed technical features of the present invention can be implemented by or using the prior art, and will not be described herein again; the above embodiments and drawings are only for illustrating the technical solutions of the present invention and not for limiting the present invention, and the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that changes, modifications, additions or substitutions within the spirit and scope of the present invention may be made by those skilled in the art without departing from the spirit of the present invention, and shall also fall within the scope of the claims of the present invention.

Claims

1. A method for synthesizing a cyanide antidote, which is characterized by comprising the following steps: the reaction formula of the synthesis is as follows:

2. The method of claim 1, wherein the cyanide antidote is selected from the group consisting of: in the first step, the reaction temperature was 50 ℃ and the reaction time was 12 hours.

3. The method of claim 1, wherein the cyanide antidote is selected from the group consisting of: in the first step, the product is purified after the reaction, and the purification steps are as follows: slowly adding a sodium carbonate solid into a reaction product, adjusting the pH value to be 10, filtering to remove iron powder, spin-drying an ethanol solution, adding ethyl acetate to dissolve, washing an ethyl acetate phase with saturated salt water, drying the ethyl acetate phase with anhydrous sodium sulfate after liquid separation, and spin-drying to obtain a yellow oily substance, namely 4-dimethylaminobenzoic ether.

4. The method of claim 1, wherein the cyanide antidote is selected from the group consisting of: in the second step, the temperature-raising reflux time was 6 hours.

5. The method of claim 1, wherein the cyanide antidote is selected from the group consisting of: in the second step, after cooling to 80 ℃, a saturated sodium bicarbonate solution is added.