阅读说明：本技术 一种以间苯三酚为平台分子合成甲氧胺的方法 (Method for synthesizing methoxyamine by using phloroglucinol as platform molecule ) 是由 薛李冰 刘长宝 王春艳 赵立成 王国慧 纪红岩 于 2021-07-06 设计创作，主要内容包括：本发明提供了一种以间苯三酚为平台分子合成甲氧胺的方法,包括以下步骤：A)将间苯三酚与羟胺水溶液混合进行肟化反应,得到环己间三肟；B)将环己间三肟在碱性条件下与甲基化试剂进行甲基化反应,得到环己间三甲氧肟；C)将所述步骤B)中的反应液pH调节至4～5,加热水解,得到甲氧胺。本发明以间苯三酚为平台分子,通过肟化、甲基化和水解三步反应得到甲氧胺。本发明中的方法既回避了亚硝酸钠磺化法生成大量废盐的弊端,又克服了乙酸乙酯为平台分子时,平台分子不能直接套用的缺点,达到了减少了固体废物的生成并提高原料利用率的效果。实验结果表明,以环己间三肟计,甲氧胺收率为85.3％。(The invention provides a method for synthesizing methoxyamine by using phloroglucinol as a platform molecule, which comprises the following steps: A) mixing phloroglucinol and hydroxylamine aqueous solution for oximation reaction to obtain cyclohexyl-m-trioxime; B) performing methylation reaction on the cyclohexyl-m-trioxime and a methylating agent under an alkaline condition to obtain cyclohexyl-m-trimethoxy oxime; C) adjusting the pH value of the reaction liquid in the step B) to 4-5, and heating for hydrolysis to obtain methoxyamine. The invention takes phloroglucinol as a platform molecule and obtains the methoxyamine through three steps of reactions of oximation, methylation and hydrolysis. The method of the invention not only avoids the defect that a sodium nitrite sulfonation method generates a large amount of waste salt, but also overcomes the defect that the platform molecule can not be directly used when ethyl acetate is used as the platform molecule, thereby achieving the effects of reducing the generation of solid waste and improving the utilization rate of raw materials. The experimental result shows that the yield of the methoxyamine is 85.3 percent based on the cyclohexane-oxime.)

1. A method for synthesizing methoxyamine by using phloroglucinol as a platform molecule comprises the following steps:

A) mixing phloroglucinol and hydroxylamine aqueous solution for oximation reaction to obtain cyclohexyl-m-trioxime;

B) performing methylation reaction on the cyclohexyl-m-trioxime and a methylating agent under an alkaline condition to obtain cyclohexyl-m-trimethoxy oxime;

C) adjusting the pH value of the reaction liquid in the step B) to 4-5, and heating for hydrolysis to obtain methoxyamine.

2. The method according to claim 1, wherein the reaction solution obtained in step A) is subjected to solid-liquid separation, the solid phase is cyclohexane-oxime, and the liquid phase is directly used in the next oximation reaction.

3. The method of claim 1, wherein the methylating agent is dimethyl sulfate or methyl halide;

the molar ratio of the methylating agent to the cyclohexane-oxime is (0.3-0.35): 0.1.

4. The method according to claim 1, wherein the alkaline condition in step B) is pH 9-10.

5. The method according to claim 1, wherein the temperature of the methylation reaction is 0-10 ℃, and the time of the methylation reaction is 3-4 hours.

6. The method as claimed in claim 1, wherein the temperature of hydrolysis in the step C) is 80-90 ℃; the hydrolysis time is 0.5-2 hours.

7. The method as claimed in claim 1, wherein methoxyamine and phloroglucinol in the hydrolysate obtained in the step C) are separated, and the obtained phloroglucinol is returned to the step A) to participate in oximation reaction.

8. The process of claim 7, wherein the methoxyamine and phloroglucinol in the hydrolysate are separated by distillation.

9. The process according to claim 8, characterized in that the residual solution from which methoxyamine is separated by distillation is subjected to a concentrated desalting to obtain phloroglucinol which is returned to step A) for the oximation reaction.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing methoxyamine by taking phloroglucinol as a platform molecule.

Background

The methoxyamine is an important pharmaceutical and chemical intermediate, and can react with a carbonyl compound to generate methoxyoxime. The water solution or hydrochloride thereof is a key raw material for synthesizing the beta-lactam antibiotic cefuroxime and the bactericide of the phenoxy bacteria ester.

At present, the synthesis method has two major types, namely, sodium bisulfite, sulfur dioxide, sodium nitrite and dimethyl sulfate are taken as main raw materials and are subjected to main reactions such as sulfonation, methylation and hydrolysis, for example, the method disclosed in british patent GB930389A (1959) can be called sodium nitrite sulfonation, and the reaction formula is as follows.

Na₂S₂O₅+H₂O→2NaHSO₃

SO₂+H₂O→H₂SO₃

The sodium nitrite sulfonation process is also a route adopted by domestic manufacturers. It can be calculated that the production of one ton of pure methoxyamine theoretically produces about ten tons of waste salt, and the main component of the waste salt is sodium sulfate. The yield of the mainstream manufacturer in China is 60%, and the waste salt yield is about 17 tons of waste salt/ton of methoxyamine, which does not include unconverted raw materials, so that the environmental protection pressure is huge.

The other is a compound which is used as a platform and is reacted with hydroxylamine, then the methylation of hydroxyl is carried out, and finally the hydrolysis is carried out to obtain methoxyamine, and the typical method is a synthetic route which takes ethyl acetate and hydroxylamine as raw materials, and is shown in Chinese patent CN101357895B (2012) and Japanese patent JP09012524A (1997), which can be called a platform molecular method, and the reaction formula is as follows.

The platform molecular method is characterized in that hydroxylamine and a methylating agent are used as raw materials, hydroximes and methoxy oximes are sequentially assembled on one platform molecule, and then the methoxy oximes are obtained by hydrolysis.

However, in the synthesis route using ethyl acetate as a platform molecule, after the methoxyamine is obtained by hydrolysis, another hydrolysate is acetic acid instead of ethyl acetate, i.e. the platform molecule cannot be directly used, which is not beneficial to reducing the production cost.

Disclosure of Invention

The invention aims to provide a method for synthesizing methoxyamine by using phloroglucinol as a platform molecule, which not only avoids the defect that a large amount of waste salt is generated by a sodium nitrite sulfonation method, but also overcomes the defect that the platform molecule cannot be directly used when ethyl acetate is used as the platform molecule, reduces the generation of solid waste and improves the utilization rate of raw materials.

The invention provides a method for synthesizing methoxyamine by using phloroglucinol as a platform molecule, which comprises the following steps:

A) mixing phloroglucinol and hydroxylamine aqueous solution for oximation reaction to obtain cyclohexyl-m-trioxime;

B) performing methylation reaction on the cyclohexyl-m-trioxime and a methylating agent under an alkaline condition to obtain cyclohexyl-m-trimethoxy oxime;

C) adjusting the pH value of the reaction liquid in the step B) to 4-5, and heating for hydrolysis to obtain methoxyamine.

Preferably, the reaction solution obtained in the step A) is subjected to solid-liquid separation, the solid phase is cyclohexane-oxime, and the liquid phase is directly used in the next batch of oximation reaction.

Preferably, the methylating agent is dimethyl sulfate or methyl halide;

the molar ratio of the methylating agent to the cyclohexane-oxime is (0.3-0.35): 0.1.

Preferably, the alkaline condition in the step B) is pH 9-10.

Preferably, the temperature of the methylation reaction is 0-10 ℃, and the time of the methylation reaction is 3-4 hours.

Preferably, the hydrolysis temperature in the step C) is 80-90 ℃; the hydrolysis time is 0.5-2 hours.

Preferably, the methoxyamine and the phloroglucinol in the hydrolysate obtained in the step C) are separated, and the obtained phloroglucinol returns to the step A) to participate in the oximation reaction.

Preferably, the methoxyamine and phloroglucinol in the hydrolysate are separated by distillation.

Preferably, the residual solution from which the methoxyamine is separated by distillation is concentrated for desalting to obtain phloroglucinol which is returned to step A) to participate in the oximation reaction.

The invention provides a method for synthesizing methoxyamine by using phloroglucinol as a platform molecule, which comprises the following steps: A) mixing phloroglucinol and hydroxylamine aqueous solution for oximation reaction to obtain cyclohexyl-m-trioxime; B) performing methylation reaction on the cyclohexane-oxime and a methylation reagent under an alkaline condition to obtain the cyclohexane-oxime; C) adjusting the pH value of the reaction liquid in the step B) to 4-5, and heating for hydrolysis to obtain methoxyamine. The invention takes phloroglucinol as a platform molecule and obtains the methoxyamine through three steps of reactions of oximation, methylation and hydrolysis. The method of the invention not only avoids the defect that a sodium nitrite sulfonation method generates a large amount of waste salt, but also overcomes the defect that the platform molecule can not be directly used when ethyl acetate is used as the platform molecule, thereby achieving the effects of reducing the generation of solid wastes and improving the utilization rate of raw materials. The experimental result shows that the yield of the methoxyamine is 85.3 percent based on the cyclohexane-oxime.

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 embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is a process flow diagram of the synthesis of methoxyamine in example 1 of the present invention.

Detailed Description

The invention provides a method for synthesizing methoxyamine by using phloroglucinol as a platform molecule, which comprises the following steps:

A) mixing phloroglucinol and hydroxylamine aqueous solution for oximation reaction to obtain cyclohexyl-m-trioxime;

B) performing methylation reaction on the cyclohexyl-m-trioxime and a methylating agent under an alkaline condition to obtain cyclohexyl-m-trimethoxy oxime;

C) adjusting the pH value of the reaction liquid in the step B) to 4-5, and heating for hydrolysis to obtain methoxyamine.

The process of the present invention involves the following chemical reactions:

the invention firstly prepares the cyclohexane-oxime through phloroglucinol, carries out oximation reaction on the phloroglucinol and hydroxylamine aqueous solution, the cyclohexane-oxime obtained by the reaction is insoluble, and the cyclohexane-oxime and a liquid phase product are obtained through solid-liquid separation.

The liquid phase product contains unreacted phloroglucinol, hydroxylamine, monoxime, dioxime and other intermediates, and can be directly applied to the next batch of oximation reaction, wherein the monoxime and dioxime intermediates can continuously participate in the oximation reaction to produce the cyclohexane-oxime.

In the present invention, the molar ratio of the phloroglucinol to hydroxylamine is preferably 0.1: (0.3 to 0.35); the mass concentration of the hydroxylamine aqueous solution is preferably 30 to 60%, more preferably 40 to 50%.

In the invention, the temperature of the oximation reaction is preferably 5-10 ℃, and the time of the oximation reaction is preferably 3-4 hours.

And after the oximation reaction is finished, carrying out suction filtration on the reaction liquid, washing the solid, and drying to obtain the cyclohexyl-m-trioxime.

After the cyclohexyl-m-trioxime is obtained, the invention mixes the cyclohexyl-m-trioxime and a methylating reagent for methylation reaction under the alkaline condition to obtain the cyclohexyl-m-trimethoxy oxime.

According to the invention, the cyclohexyl-m-trioxime is mixed with an alkaline reagent, and then a methylation reagent is added at a reaction temperature to carry out a methylation reaction, so that the cyclohexyl-m-trimethoxyxime is obtained.

In the present invention, the alkaline agent is preferably sodium hydroxide, potassium hydroxide or the like or an aqueous solution thereof, for example, the mass concentration of the aqueous sodium hydroxide solution is preferably 5 to 20%, more preferably 10 to 15%, and the amount of the alkaline agent used in the present invention is not particularly limited, and the pH of the reaction system may be adjusted to be within a range of 9 to 10.

In the present invention, the methylating agent is preferably dimethyl sulfate or a methyl halide such as methyl chloride, methyl bromide, methyl fluoride; the molar ratio of the methylating agent to the cyclohexane-oxime is (0.3-0.35): 0.1.

The methylation reagent is slowly dripped into the cyclohexane-oxime, the temperature of the methylation reaction is preferably 0-10 ℃, such as 0 ℃, 1 ℃, 2 ℃, 3 ℃, 4 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃ and 10 ℃, and the methylation reagent is preferably in a range value taking any value as an upper limit or a lower limit; the methylation reaction time is preferably 3-4 hours.

The reaction solution obtained in the methylation reaction is directly used for the next step of acidic hydrolysis without separation. Adding an acidic reagent such as sulfuric acid, hydrochloric acid and the like into the reaction liquid obtained by methylation, adjusting the pH value of the reaction liquid to 4-5, and heating for hydrolysis.

In the present invention, the hydrolysis temperature is preferably 80 to 90 ℃, such as 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃ and 90 ℃, and is preferably a range value with any value as an upper limit or a lower limit; the hydrolysis time is preferably 0.5 to 2 hours, and more preferably 1 to 1.5 hours.

Carrying out acid hydrolysis to obtain methoxyamine and phloroglucinol, wherein the methoxyamine and water are subjected to azeotropic distillation, and the methoxyamine can be separated by distillation and simultaneously the balance is promoted to move to the right. And further concentrating and desalting the residual phloroglucinol aqueous solution after distillation separation, and returning to the oximation reaction step.

In the invention, the phloroglucinol aqueous solution is distilled to half of the volume of the raw material, then the distillation is stopped, the solution is cooled to room temperature and then is subjected to suction filtration, the salt obtained by suction filtration is mainly sodium sulfate, the filtrate mainly contains phloroglucinol and a small amount of salt, and the filtrate can be used for a hydroxamation reaction.

The invention provides a method for synthesizing methoxyamine by using phloroglucinol as a platform molecule, which comprises the following steps: A) mixing phloroglucinol and hydroxylamine aqueous solution for oximation reaction to obtain cyclohexyl-m-trioxime; B) performing methylation reaction on the cyclohexane-oxime and a methylation reagent under an alkaline condition to obtain the cyclohexane-oxime; C) adjusting the pH value of the reaction liquid in the step B) to 4-5, and heating for hydrolysis to obtain methoxyamine. The invention takes phloroglucinol as a platform molecule and obtains the methoxyamine through three steps of reactions of oximation, methylation and hydrolysis. The method of the invention not only avoids the defect that a sodium nitrite sulfonation method generates a large amount of waste salt, but also overcomes the defect that the platform molecule can not be directly used when ethyl acetate is used as the platform molecule, thereby achieving the effects of reducing the generation of solid wastes and improving the utilization rate of raw materials. The experimental result shows that the yield of the methoxyamine is 85.3 percent based on the cyclohexane-oxime.

In order to further illustrate the present invention, the method for synthesizing methoxyamine by using phloroglucinol as a platform molecule according to the present invention is described in detail below with reference to the following examples, which should not be construed as limiting the scope of the present invention.

Example 1

Oximation of

81.0g of phloroglucinol dihydrate and 100.0g of 50% hydroxylamine aqueous solution are sequentially added into a reaction bottle, stirred, dissolved and then kept stand for 1hr, then the upper solid layer is smashed and kept stand for 2hr, and the mixture is subjected to suction filtration, water washing and drying to obtain 76.1g of cyclohexane-oxime with the yield of 88.0%.

Methylation of

Under the protection of nitrogen, 51.3g (0.3mol) of the above-obtained cyclohexane-oxime was dissolved in 124.0g (0.6mol) of a 30% aqueous solution of sodium hydroxide, cooled to 10 ℃ or less, and 113.4g (0.9mol) of dimethyl sulfate was slowly added dropwise while maintaining the temperature at less than 10 ℃. After dropping, the cooling bath was removed, and the reaction was continued for 3hr with stirring.

Hydrolysis

Then adding 30% sulfuric acid, adjusting pH to about 5, stirring for reaction for 30min, changing into a distillation device, slowly heating to raise temperature until distillate is distilled off, cooling and collecting to obtain methoxyamine aqueous solution, analyzing its content, and stopping collecting methoxyamine until the content of methoxyamine in distillate is less than 0.3%. The yield of methoxyamine was 85.3% based on cyclohexanetrioxime.

Concentration desalination

The solution is continuously distilled and concentrated, and the obtained fraction is water containing a very small amount of methoxyamine and can be used for preparing 10% sodium hydroxide. Distilling to half of the volume of the raw material, cooling to room temperature, performing suction filtration to obtain salt mainly comprising sodium sulfate, and filtrate mainly comprising phloroglucinol and a small amount of salt, wherein the filtrate can be subjected to a re-oximation reaction.

Example 2

The procedure is as in example 1, 15.7g of methyl chloride are used as methylating agent, the yield of methoxyamine is 82.6%, and the salt removed after concentration is mainly sodium chloride.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.