Preparation method of key intermediate m-dimethylaminophenol of neostigmine methylsulfate

Abstract

The invention discloses a preparation method of a key intermediate m-dimethylaminophenol of neostigmine methylsulfate, which comprises the following specific implementation processes: reacting 3-aminophenol with dimethyl sulfate to generate an intermediate 3-hydroxy-N, N, N-trimethylaniline sulfuric acid monomethyl ester salt, reacting the intermediate in the presence of organic alkali to obtain a crude product of m-dimethylaminophenol, and separating and purifying the crude product of m-dimethylaminophenol to obtain m-dimethylaminophenol. And after the reaction is finished, distilling, neutralizing, crystallizing, filtering and drying to obtain the m-dimethylaminophenol. The method provided by the invention is high in yield, high in purity, simple to operate, low in equipment requirement, green and environment-friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical organic synthesis, and particularly relates to a method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate. Background Art

[0002] Meta-dimethylaminophenol, also known as 3-(dimethylamino)phenol, has the following structural formula:

[0003] It is a pharmaceutical intermediate for drugs such as neostigmine methylsulfate and an intermediate for anthrone dyes.

[0004] The current better preparation methods are summarized as follows: Method 1: Resorcinol is used as a raw material and reacted with dimethylamine aqueous solution under high temperature and high pressure conditions to produce m-dimethylaminophenol. This method requires high temperature and high pressure reaction conditions, has high requirements for reaction equipment, and has a reaction yield of ~40% and a purity of >98.0%.

[0005]

[0006] Method 2: Using m-aminoanisole as raw material, reacting with dimethyl sulfate to obtain m-dimethylaminoanisole, and then using aluminum chloride or hydrogen bromide for demethylation to obtain m-dimethylaminophenol. The yield of this method is ~80%, and the purity is ~99.0%. However, the price of the raw material m-aminoanisole is relatively expensive.

[0007]

[0008] Method 3: Using N,N-dimethylaniline as raw material, first undergo sulfonation, salt formation and hydrolysis to obtain crude m-dimethylaminophenol, and then purify the target product with liquid paraffin. This method has cheap raw materials, but has many steps, poor selectivity, low yield, and uses a large amount of strong acid and strong base, resulting in large pollution of three wastes.

[0009]

[0010] Method 4: Using m-aminophenol as raw material and toluene as solvent, it reacts with dimethyl sulfate to obtain m-dimethylaminophenol. Since the demethylation reaction is not carried out, the yield is only ~33%.

[0011]

[0012] Method 5: Using m-aminophenol as raw material and methyl iodide as methylating agent to prepare m-dimethylaminophenol. The cost of methyl iodide in this method is relatively high, but it can reduce the formation of by-products. After using molecular sieve catalyst, the yield is ~65% and the purity is 98.8%.

[0013]

[0014] Method 6: (Indian patent IN1078MUM2014A) Using m-aminophenol as raw material, water as solvent, sodium bicarbonate as acid binding agent, methylation reaction with dimethyl sulfate, and then demethylation with ethanolamine to obtain m-dimethylaminophenol reaction solution. Toluene is added to the reaction solution and stirred and filtered. The filtrate is washed with sodium hydroxide aqueous solution. After the water layer is neutralized with concentrated hydrochloric acid, m-dimethylaminophenol is filtered to obtain, which is washed with water and dried. This method is complicated to operate, and the yield of the obtained product is ~80%, and the purity is >98.0%, but the final product is dark in color and contains more high-polymer impurities that cannot be detected in the liquid phase, which will seriously affect the subsequent reaction.

[0015] . Summary of the invention

[0016] In view of the above problems, the object of the present invention is to provide a method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate.

[0017] The specific technical solutions are as follows: A method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate, comprises the following steps: 3-aminophenol reacts with dimethyl sulfate to generate an intermediate 3-hydroxy-N,N,N-trimethylaniline monomethyl sulfate salt, the intermediate reacts in the presence of an organic base to obtain m-dimethylaminophenol, and after the reaction is completed, the m-dimethylaminophenol is obtained through distillation, neutralization, crystallization, filtration and drying. The reaction equation is as follows: .

[0018] Furthermore, the organic base is selected from one or more of aniline, ethanolamine, diethanolamine, and isopropanolamine.

[0019] Furthermore, the reaction temperature is 100-150°C.

[0020] Furthermore, the distillation adopts reduced pressure distillation, the distillation temperature is 150-240°C, the vacuum degree is ≤-0.095MPa, room temperature circulating water is used for condensation, and the 100-180°C fraction is collected.

[0021] Furthermore, the collected fractions are diluted with water and then neutralized, and the amount of water used is 2-7 times the amount of 3-aminophenol fed.

[0022] Further, the fraction is neutralized with one or more of hydrochloric acid and sulfuric acid to control the pH to 7-9.

[0023] Furthermore, the crystallization temperature is -5~20°C.

[0024] Furthermore, the temperature of the drying process is 55-75° C., and the vacuum degree is ≤-0.095 MPa.

[0025] The beneficial effects of the present invention are: The method provided by the present invention has simple process, high yield, high purity, low cost, and meets green environmental protection requirements. In particular, the method has low equipment requirements and only requires the use of a simple distillation device for reduced pressure distillation. The obtained fraction is liquid at room temperature and does not require additional insulation measures. The distillation temperature is low and the operation can be easily implemented in industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the purity detection spectrum of m-dimethylaminophenol in Example 1. DETAILED DESCRIPTION

[0027] The present invention is further described below in conjunction with the accompanying drawings and embodiments, but the protection scope of the present invention is not limited thereto.

[0028] Embodiment 1: Add 2.0 kg of sodium bicarbonate, 1.0 kg of 3-aminophenol and 2.7 kg of water to a 20L reaction bottle, cool to an internal temperature of 10°C, slowly drop 3.6 kg of dimethyl sulfate while stirring, and continue to react until complete after the dropwise addition. Add 3.8 kg of diethanolamine and slowly raise the temperature to 120°C until the reaction is complete.

[0029] The reaction liquid was concentrated by vacuum distillation at a distillation temperature of 210°C and a vacuum degree of -0.097MPa until there was basically no liquid outflow, and condensed with room temperature circulating water, and the fractions between 110 and 170°C were collected. 4.0kg of water was added to the fraction. At room temperature, concentrated hydrochloric acid was added dropwise to pH=7.6. The reaction liquid was cooled to 0°C and stirred for crystallization, and 3-dimethylaminophenol was obtained by suction filtration. The reaction flask and the filter cake were washed with water. The obtained filter cake was vacuum dried to dryness at a temperature of 70°C and a vacuum degree of -0.095MPa, and about 1.00kg of dry product was obtained, with a purity of 99.8% and a yield of 79.5%. The appearance is a white solid powder.

[0030] Embodiment 2: Add 1.0 kg of 3-aminophenol and 1.0 kg of water to a 20L reaction bottle, raise the temperature to 40°C, and slowly drop 3.6 kg of dimethyl sulfate and 2.0 kg of saturated sodium carbonate aqueous solution while stirring. After the dropwise addition is complete, continue to react until complete. Add 4.5 kg of isopropanolamine and slowly raise the temperature to 120°C until the reaction is complete.

[0031] The reaction liquid was concentrated by vacuum distillation at a distillation temperature of 200°C and a vacuum degree of -0.096MPa until there was almost no liquid outflow, and condensed with room temperature circulating water, and the fractions between 120 and 180°C were collected. 3.0kg of water was added to the fraction. At room temperature, concentrated hydrochloric acid was added dropwise to pH=8.0. The reaction liquid was cooled to 1°C and stirred for crystallization, and 3-dimethylaminophenol was obtained by suction filtration. The reaction flask and the filter cake were washed with water. The obtained filter cake was vacuum dried to dryness at 70°C and a vacuum degree of -0.095MPa to obtain about 1.02kg of dry product, with a purity of 99.8%, a yield of 81.9%, and an appearance of white solid powder.

[0032] Embodiment 3: Add 1.0 kg of 3-aminophenol and 5.0 kg of toluene to a 20L reaction bottle, raise the temperature to 100°C, slowly drop 4.0 kg of dimethyl sulfate while stirring, and continue to react until complete after the addition is complete. Add 5.0 kg of aniline and slowly raise the temperature to 110°C until the reaction is complete.

[0033] The reaction liquid was concentrated by vacuum distillation at a distillation temperature of 190°C and a vacuum degree of -0.095MPa until there was basically no liquid outflow, and condensed with room temperature circulating water, and the fractions between 120 and 170°C were collected. 6.0kg of water was added to the fractions. At room temperature, concentrated hydrochloric acid was added dropwise to pH=8.4. The reaction liquid was cooled to 5°C and stirred for crystallization, and 3-dimethylaminophenol was obtained by suction filtration. The reaction flask and the filter cake were washed with water. The obtained filter cake was vacuum dried to dryness at 70°C and a vacuum degree of -0.095MPa to obtain about 0.95kg of dry product, with a purity of 99.8% and a yield of 75.5%. The appearance is a white solid powder.

[0034] The above obtained m-dimethylaminophenol purity detection method is specifically shown in Table 1: Table 1 Summary of the detection methods and parameters for the purity of m-dimethylaminophenol

[0035] Example 1 Metadimethylaminophenol Purity Detection Spectrum Figure 1 As shown: from Figure 1 The test results show that the purity of m-dimethylaminophenol is 99.83%, which meets the quality standard requirements for intermediate control.

Claims

1. A method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate, characterized in that: The method comprises the following steps: 3-aminophenol reacts with dimethyl sulfate to generate an intermediate 3-hydroxy-N,N,N-trimethylaniline monomethyl sulfate salt, the intermediate reacts in the presence of an organic base to obtain m-dimethylaminophenol, and after the reaction is completed, the m-dimethylaminophenol is obtained through distillation, neutralization, crystallization, filtration and drying. The reaction equation is as follows: .

2. A method for preparing the key intermediate of neostigmine methylsulfate, m-dimethylaminophenol, as claimed in claim 1, characterized in that: The organic base is selected from one or more of aniline, ethanolamine, diethanolamine and isopropanolamine.

3. A method for preparing the key intermediate of neostigmine methylsulfate, m-dimethylaminophenol, as claimed in claim 1, characterized in that: The reaction temperature is 100-150°C.

4. A method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate, as claimed in claim 1, characterized in that: The distillation adopts reduced pressure distillation, the distillation temperature is 150-240°C, the vacuum degree is ≤-0.095MPa, room temperature circulating water is used for condensation, and the 100-180°C fraction is collected.

5. A method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate, as claimed in claim 4, characterized in that: The collected fractions are diluted with water and then neutralized, wherein the amount of water used is 2-7 times the amount of 3-aminophenol fed.

6. A method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate, as claimed in claim 5, characterized in that: The distillate is neutralized with one or more of hydrochloric acid and sulfuric acid to control the pH to 7-9.

7. A method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate, as claimed in claim 1, characterized in that: The crystallization temperature is -5~20℃.

8. The method for preparing m-dimethylaminophenol, a key intermediate of neostigmine methylsulfate, as claimed in claim 1, characterized in that: The temperature of the drying process is 55-75°C and the vacuum degree is ≤-0.095MPa.

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