1 synthesis method
Methods p-nitrophenol was used as raw material.
Using p-nitrophenol as raw material, reducing with iron powder, filtering out iron sludge, cooling the filtrate for crystallization, recrystallization, drying and other steps to make finished paper, then adjusting the pH to 5 with ammonia water in the aqueous solution containing p-aminophenol sulfate and aniline sulfate, distilling to remove aniline, acylating with acetic anhydride at 20℃, and maintaining the pH to 5 with ammonia water to obtain 95% APAP. It is reported in the literature that using ethyl acetate or acetic acid instead of water medium can increase the acylation rate to 92.2%, and the solvent is easy to recover, which reduces the pollution of wastewater.
Advantages and disadvantages: The method is simple and mature, but the yield is low, the product quality is unstable, and a large amount of iron sludge and wastewater are produced, which seriously pollutes the environment. Many foreign countries have eliminated this method.
Method 2[3]: Use phenol as raw material.
The derivation of OH takes phenol as raw material, polyphosphoric acid as catalyst, glacial acetic acid and NH as catalysts.
2
After the reaction at 80℃, the product or salt is treated with ice water, and then the pH value is adjusted to 4 with 10%NaOH. After reflux, cooling and extraction, APAP was obtained with a purity of 98%. The reaction formula is:
Method 3[3]: PNP was used as raw material.
Using p-nitrophenol as raw material, in the mixed solution of acetic acid and acetic anhydride, with 5%Pd/C as catalyst, APAP was synthesized by catalytic hydrogenation and acetylation in one step with an overall yield of 80%. The U.S. patent uses 5%Pd/C catalyst to reduce PNP by half, and then adds acetic anhydride to make hydrogenation and acylation simultaneously. The total yield was 8 1.2%. The reaction formula is:
The optimum technological conditions for one-step catalytic hydrogenation of Pd-La/C are as follows: temperature 65438 0 40℃,
Pressure 0.7Mpa, time 2 hours, yield 97%.
Method 4[4]: P-hydroxyacetophenone was used as raw material.
In the presence of potassium iodide and acetate, APAP was obtained by Beckmann rearrangement of p-hydroxyacetophenone. In Beckmann rearrangement reaction, the commonly used catalysts are thionyl chloride, phosphorus oxychloride, methanesulfonic acid, sulfuric acid and phosphorus pentachloride. It is reported that thionyl chloride is used as the catalyst of hydroxyacetophenone in liquid sulfur dioxide, and the yield is 88.7%, but at the low temperature of -50℃. Using thionyl chloride, nitrogen is introduced under reflux for rearrangement, and a small amount of potassium iodide is added to prevent the formation of by-product 3- chloro -4- hydroxyacetanilide. The yield is 99%.
Advantages and disadvantages: the reaction conditions are very harsh, the low temperature is -50℃, but the yield is high.
If p-aminophenol acetate is heated to 65438 000℃ in the presence of sec-butanol, phosphoric acid and acetic acid, and the solvent is evaporated in vacuum after a period of reaction, the crude APAP with a content of 95% can be obtained.
Method 5[5]: Biochemical synthesis.
Biochemical synthesis is to use bioengineering technology to study the production of APAP. By expressing the fusion gene in Saccharomyces cerevisiae, a fusion enzyme composed of mouse hepatocyte cytochrome P450 and NADPH- cytochrome P450 reductase gene can be produced. This enzyme has the ability of oxidation and reduction, and can provide a more effective electron transfer system than cytochrome P450 alone. Acetanilide can be para-hydroxylated by transgenic yeast with a yield of 33 nmol mL-1.
Advantages and disadvantages: Biochemical synthesis has little environmental pollution and high selectivity, but the yield is low, and it is still in the research stage.
Method 6[3]: Nitrobenzene was used as raw material.
Nitrobenzene was reduced to p-aminophenol in dilute sulfuric acid with aluminum powder or magnesium powder as catalyst. Zinc powder can also be used as a catalyst. The main reaction mechanism of this method is that nitrobenzene is hydrogenated to produce phenylhydroxylamine, and then PAP is prepared by Bamberg er rearrangement reaction. PAP was dissolved in 10% acetic acid, Na2S2O4 was added at 85 ~ 90℃, and acetic anhydride was added for a certain period of time, and then acylated at 85℃ to obtain APAP with purity >: 99%.
Advantages and disadvantages: This method is a research hotspot in recent years because of its simple process, easily available raw materials, many technical approaches and great potential for reducing costs. However, it is difficult to produce on a large scale because of its large metal consumption and post-treatment problems such as recycling.
Method 7[6]: p-nitrophenol was used as raw material.
Acetaminophen was synthesized from p-nitrophenol by catalytic hydrogenation and acidification. In this method, Pt/C and Pd/C are used as catalysts, and p-nitrophenol is hydrogenated and reduced at about 0.2 ~ 0.5 MPa and 70 ~ 90℃ to prepare the crude product of p-aminophenol. It is reported abroad that PNP is hydrogenated and reduced with Ni-Al-Pd-Zn composite catalyst, and the yield is 90% ~ 95%. The activity of the catalyst is stable and there is no regeneration after running for 500 hours.
Advantages and disadvantages: the catalyst is expensive, and the catalyst prepared by this method is complicated, and the loss rate is as high as 0. 8 1 ~ 1g/kg hydrogenation product. But the yield is higher.
Method 8[7]: Sulfonated azophenol was used as raw material.
Using sulfoazophenol as raw material, dilute ferrous sulfate solution and ammonia water were added to the suspension of I (sulfonic acid group can also be in meta position) at 60~80℃, and then the product was treated with acetic anhydride. At the same time, at 50~60℃, o-sulfonic acid phenylazo-p-phenol I was alternately added to the suspension containing iron powder and hydrochloric acid under stirring, and then the mixture was treated with acetic anhydride to carry out the above reaction to obtain N-(4- hydroxyphenyl) acetamide solution, which can be salted out with sodium chloride or crystallized from concentrated solution.
Advantages and disadvantages: the reaction conditions are friendly and the yield is acceptable.
Method 9[8]: p-nitrophenol and isopropanol were used as raw materials.
220g of p-nitrophenol, 80g of isopropanol, 140g of water and 0.22 G3% Pb/C were mixed.
The catalyst mixture was hot-pressed at the pressure of 585kPa and the temperature of 1 10℃ for 8min, then 180g acetic anhydride was added within 59min, and then hot-pressed at the pressure of 585kPa and the temperature of1/0℃ for 53 min to obtain the product with a yield of 90%.
Methods 10[8]: p-nitrosophenol was used as raw material.
P-nitrosophenol was reduced by sodium sulfide and the obtained p-aminophenol was acetylated. Treating the crude product with aqueous oxidant solution (such as concentrated nitric acid), adding activated carbon and stirring, and removing the activated carbon with iron oxide. 85-95% N-(4- hydroxyphenyl) acetamide is obtained from the decolorized filtrate, which is the product.
Advantages and disadvantages: mild reaction conditions and high product yield.
Methods 1 1[2]: p-hydroxyacetophenone was used as raw material.
P-hydroxyacetophenone (2.72g, 0.02mol), hydroxylamine hydrochloride (1.53g, 0.022mol), triethylamine (2. 26g, 0.022mol) and ethanol (40ml) were added to the reaction bottle, refluxed for 2 hours, then evaporated and ethyl acetate (40) was added. The white granular crystal was obtained by recrystallization of ethyl acetate, mp 143~ 145℃. Add crude product 2( 1.0g, 0.0067mol) and ethyl acetate (10ml) into the reaction flask, and add them into the reaction flask.
At 50 ~ 60℃, the ethyl acetate solution of phosphorus oxychloride (1.2g, 0.0082mol) was added dropwise, 2. 5h, cooling to room temperature, then adding ethyl acetate (50ml), washing with water (50ml), and evaporating the crude product 1(0.93%, 93%) to dryness.
Advantages and disadvantages: the product yield is relatively high, but the operation is complicated.
Methods 12[7]: Nitrobenzene was used as raw material.
Using nitrobenzene as raw material, 250ml distilled water was added into a three-necked bottle, and then 36g concentrated sulfuric acid, 60g nitrobenzene, 0.6g cetyltrimethyl ammonium chloride and catalyst (3%Pt/C catalyst made by ourselves) were added. Introduce nitrogen to replace air for three times, then introduce hydrogen to replace nitrogen for three times, then continue to introduce hydrogen, raise the temperature to 90℃, and accelerate the stirring to 300 rpm. Record the hydrogen flow and tail gas flow respectively, and calculate the hydrogen absorption. After about 3 hours of reaction, 56 grams of nitrobenzene was added, cooled to room temperature, and left to stand for stratification. Adjust the pH of the water layer to 4~4.5, extract with 30ml toluene-aniline (1: 1) solution for three times, and combine the organic layers. Adjust the pH value of the mother liquor to 7. 5. Add Na2SO3s for precipitation, distill the remaining impurities such as nitrobenzene and aniline by steam distillation, add 25g acetic anhydride-acetic acid (2B 1) while it is hot, and react at 100℃ for 3h. Cooling crystallization, filtering to obtain crude product, refining and drying to obtain 48.6 g product, melting point 168~ 170℃, and recovery rate of 64.3%.
Advantages and disadvantages: the method is complicated and the yield is relatively low.
Methods 13[3]: hydroquinone and acetamide were used as raw materials.
Using hydroquinone and acetamide as raw materials, under the catalysis of ZSM5 molecular sieve, APAP can be obtained by condensation at 300℃ for 65438 0 h in a vacuum tube, with a conversion of 93.6% and a molar selectivity of 45.9%. If titanium silicate is used as catalyst, the molar selectivity is 67.5% and the conversion rate is 90.8%.
Advantages and disadvantages: friendly reaction conditions and high yield.
The reaction formula is:
Methods 14[7]: p-aminophenol was prepared from phenol.
P-aminophenol was prepared from phenol, then the material (P-aminophenol B acetic anhydride = 1: 1.3) was put into a three-necked flask in proportion, and the reaction was stirred under reflux, and the temperature was raised to 120~ 140℃, and the temperature was kept for 15 minutes, then the mixture was cooled and crystallized.
The optimum technological conditions of this experiment are as follows:
( 1):nano 2 = 1.0: 1.36，t=-3℃。 pH= 1.5~0.3。
(2) Nitrosophenol: Na2S = 1.0: 1.22, t = 45℃, and pH after neutralization is 9.
(3) p-aminophenol: acetic anhydride = 1: 1.3, t = 130 ~ 140℃.
Advantages and disadvantages: According to the optimum technological conditions of this experiment, the product has high yield and purity, and has high practical value.
2 The main methods currently used in industry
It is produced by iron powder reduction method. P-nitrochlorobenzene is used as raw material to prepare p-aminophenol through hydrolysis, acidification and reduction, and then acetaminophen is prepared through acylation. Although the iron powder reduction technology is mature and simple, the product yield is low, the quality is poor, the toxicity is high and the cost is high. What's more, a lot of iron-containing sludge and sewage containing phenolamine will be produced in the production process, which is seriously polluted. Therefore, there is an urgent need for technical improvement.
Three methods that China may adopt in the future
Hydrogenation process is used instead of iron filings reduction. Especially, the method of one-step synthesis of acetaminophen with P-nitrophenol as raw material and Pd/C catalyst has the characteristics of less production processes, high product yield, energy saving, greatly reduced waste liquid, less environmental pollution and low production cost. Moreover, aiming at the existing equipment of China manufacturers, the equipment investment is less, and the technical transformation can be greatly reduced.
Expenses. If this method can realize industrial production, it will be of positive significance to increase the economic benefits of enterprises and effectively reduce the pollution of three wastes in chemical plants, and will certainly further promote the development of fine chemical production.
4 references
Liu, Hu Ailin, Wang Hongying. Study on the synthesis of p-aminophenol [J]. Industrial catalysis, 1999, (2):11-6.
Xie Jianhua, Li Guanghua, Lu Sheng. Another synthetic route of paracetamol [J]. China Journal of Medicine, 1999(7).
Yan Huanxin, Xu Danqian, Huai Zheming, et al. Study on the synthesis technology of acetaminophen [J]. China Journal of Modern Applied Medicine, 2000, 17( 1):32-33.
Wei, Fan and Chen Zicheng. Study on the new synthetic route of paracetamol ⅰ. Study on the Synthesis of Hydroxyacetophenone Oxime [J]. journal of anqing teachers (Natural Science Edition),1997,3 (3): 42-43.
Zhao Hai, Wang Jikang. Progress in synthesis of acetaminophen [J]. Chemical Technology and Development, 2004( 1)
Fang,,, et al. One-step synthesis of acetaminophen by hydrogenation and acylation catalyzed by PD-La/C. Modern Chemical Industry, 2000,20 (8): 37-39.
Guan Yanqiong, Yang,, et al. Study on the synthesis technology of acetaminophen [J]. Journal of Guangdong University of Technology, 1997(2).
Chen, Chen, Progress in the synthesis of acetaminophen [J]. Southwest Defence Force Medical Journal, 2007,17 (1):114-117.
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Synthesis method of acetaminophen
Synthesis method of acetaminophen
1 synthesis method
Methods p-nitrophenol was used as raw material.
Using p-nitrophenol as raw material, reducing with iron powder, filtering out iron sludge, cooling the filtrate for crystallization, recrystallization, drying and other steps to make finished paper, then adjusting the pH to 5 with ammonia water in the aqueous solution containing p-aminophenol sulfate and aniline sulfate, distilling to remove aniline, acylating with acetic anhydride at 20℃, and maintaining the pH to 5 with ammonia water to obtain 95% APAP. It is reported in the literature that using ethyl acetate or acetic acid instead of water medium can increase the acylation rate to 92.2%, and the solvent is easy to recover, which reduces the pollution of wastewater.
Advantages and disadvantages: The method is simple and mature, but the yield is low, the product quality is unstable, and a large amount of iron sludge and wastewater are produced, which seriously pollutes the environment. Many foreign countries have eliminated this method.
Page 1
Method 2[3]: Use phenol as raw material.
The derivation of OH takes phenol as raw material, polyphosphoric acid as catalyst, glacial acetic acid and NH as catalysts.
2
After the reaction at 80℃, the product or salt is treated with ice water, and then the pH value is adjusted to 4 with 10%NaOH. After reflux, cooling and extraction, APAP was obtained with a purity of 98%. The reaction formula is: