1 Synthesis method
Method 1[1]: using p-nitrophenol as raw material
Taking p-nitrophenol as raw material, reducing with iron powder, filtering out the iron sludge, and the filtrate is cooled and crystallized, and then the finished product PAP is made by recrystallization and drying, then in the aqueous solution containing p-aminophenol sulphate and aniline sulphate, adjusting the ammonia The pH was adjusted to 5, the aniline was removed by distillation and then acylated with acetic anhydride at 20°C, while maintaining the pH at 5 with ammonia to obtain APAP with a content of 95%.It is reported in the literature that replacing the aqueous medium with ethyl acetate or acetic acid improves the rate of acylation to 92.2% and the solvent is easy to be recycled and the pollution of wastewater is reduced.
Advantages and disadvantages: this method is simple, mature technology, but the yield is low, product quality is not stable, produce a large number of waste iron sludge and wastewater, serious pollution of the environment, many foreign countries have been eliminated this method.
Method 2[3]: Derivation of phenol as raw material
OH Derivation of phenol as raw material, polyphosphoric acid as a catalyst, with glacial acetic acid and NH
2
Substance or salt, the reaction at 80 ℃ and then treated with iced water, and then adjusted the pH value to 4 with 10% NaOH, refluxed, cooled, and extracted to get the APAP, the purity of up to 98%. The reaction formula is:
Method 3[3]: Using PNP as raw material
Taking PNP as raw material, in the mixture of acetic acid and acetic anhydride, using 5% Pd/C as a catalyst, catalytic hydrogenation followed by acetylation, one-step synthesis of APAP, the total yield is 80%. The U.S. patent used 5% Pd/C catalyst to reduce PNP by half and then added acetic anhydride, so that hydrogenation and acylation were carried out at the same time, with a total yield of 81.2%. The reaction formula is:
The optimal process conditions for one-step synthesis using Pd-La/C catalytic hydrogenation are: temperature 140℃,
pressure 0.7Mpa, time 2h, yield 97%.
Method 4[4]: p-Hydroxyacetophenone as raw material
APAPAP can be obtained by Beckmann rearrangement of p-Hydroxyacetophenone as a raw material in the presence of KI and acetate.To carry out the Beckmann rearrangement reaction, sulfinyl chloride, phosphorus trichloride, methanesulfonic acid, sulfuric acid and phosphorus pentachloride are commonly used as catalysts.Literature reported that p-Hydroxyacetophenone in liquid Sulfur dioxide in liquid sulfur dioxide with sulfoxide chloride as catalyst, yield 88.7%, but need -50 ℃ low temperature. Rearrangement was carried out with sulfoxide chloride under reflux by passing nitrogen, and a small amount of potassium iodide was added to prevent the generation of 3-chloro-4-hydroxyacetanilide by-products, with a yield of 99%.
Advantages and disadvantages: reaction conditions are very harsh need, -50 ℃ low temperature, but the yield is higher.
If p-aminophenol acetate in the presence of sec-butanol, phosphoric acid, acetic acid heated to 100 ° C, the reaction for a certain period of time, vacuum evaporation of the solvent can be obtained with a content of 95% of the crude APAP.
Method 5 [5]: biochemical synthesis
Biochemical synthesis is the use of bio-engineering technology for the production of APAP research. By expressing a fusion gene in Saccharomyces cerevisiae, a fusion enzyme consisting of murine liver cytochrome P450 and NADPH-cytochrome P450 reductase genes can be produced. The enzyme possesses both oxidizing and reducing abilities and can provide a more efficient electron transfer system than a single cytochrome P450. Acetanilide can be para-hydroxylated with the help of transgenic yeast in a yield of 33 nmol-mL-1.
Pros and cons: The biochemical synthesis method is less polluting to the environment and has high selectivity, but the yield is low and is still in the research stage.
Method 6[3]: using nitrobenzene as raw material
Taking nitrobenzene as raw material, in dilute sulfuric acid, aluminum powder or magnesium powder as catalyst to reduce nitrobenzene in one step to PAP. zinc powder can also be used as catalyst. The main reaction mechanism of this method is that nitrobenzene is hydrogenated to generate phenyl hydroxylamine, and then Bamberg er rearrangement to produce PAP. dissolve PAP in 10% acetic acid, at 85 ~ 90 ℃, add Na2S2O4, add acetic anhydride in a certain period of time, acylation at 85 ℃ can be obtained at a purity of >99% of APAP.
Prongs and weaknesses: the process is simple, raw materials are easy to obtain, and there are many ways to do it. Raw materials are easy to obtain, the process pathway, the potential for cost reduction is greater, is the hot spot of research in recent years, but the metal consumption is large, and there are recycling and other post-processing problems, so it is difficult to large-scale production.
Method 7[6]: p-Ethylphthalamidophenol was synthesized by catalytic hydrogenation and acidification using p-nitrophenol as raw material
P-Ethylphthalamidophenol was synthesized by catalytic hydrogenation and acidification using p-nitrophenol as raw material. The method generally uses Pt/C and Pd/C as catalysts, and the crude PAP was prepared by hydrogenation and reduction of PNP at about 0.2~0.5MPa,70~90℃. It has been reported that PNP is reduced by Ni-Al-Pd-Zn composite catalyst, and the yield reaches 90%~95%. The catalyst activity is stable, running for 500h without regeneration.
Advantages and disadvantages: the catalyst is expensive, and the method of catalyst preparation is complex and the loss rate is as high as 0. 81 ~ 1g/kg hydrogenation product. But the yield is higher.
Method 8 [7]: sulfonated azophenol as raw material
The product was obtained by simultaneously adding a dilute solution of ferrous sulfate and ammonia to a suspension of Ⅰ (sulfonate group can also be in the interstitial position) at 60~80°C, and then treating it with acetic anhydride. At the same time, alternately, o-sulfobenzene azo-p-phenol I is added in batches while stirring to a suspension containing powdered iron and hydrochloric acid at 50~60°C, and then the above mixture is treated with acetic anhydride, and the reaction is carried out as above to obtain N-(4-hydroxyphenyl)acetamide solution, which can be used to precipitate with sodium chloride salts or to crystallize the present product Ⅱ from the concentrated solution.
Advantages and disadvantages: friendly reaction conditions, the yield is still acceptable.
Method 9 [8]: p-nitrophenol, isopropanol as raw materials
The mixture of 220g of p-nitrophenol, 80g of isopropanol, 140g of water, and 0.22g of 3% of Pb/C
catalyst was hot-pressurized at a pressure of 585kPa and a temperature of 110°C for 8min and 180g of acetic anhydride was added in 59min, then Then keep the pressure 585kPa and temperature 110°C for 53 min to get the product with 90% yield.
Method 10 [8]: using p-nitrosophenol as raw material
Taking p-nitrosophenol as raw material, p-nitrosophenol was reduced with sodium sulfide, and the resulting p-aminophenol was acetylated, and the resulting crude was treated with an aqueous solution of an oxidizing agent (e.g., concentrated HNO3), and stirred with activated charcoal, and the activated charcoal was removed with iron oxide. From the decolorized filtrate, 85-95% of N-(4-hydroxyphenyl)acetamide, the present product, was obtained.
Advantages and disadvantages: mild reaction conditions, high product yield.
Method 11[2]: using p-hydroxyacetophenone as raw material
Taking p-hydroxyacetophenone as raw material, in a reaction flask, adding p-hydroxyacetophenone (2.72g,0.02mol), hydroxylamine hydrochloride (1.53g,0.022mol), triethylamine (2. 26g,0.022mol), and ethanol (20 ml), and then refluxing for 2h. It was evaporated to dryness, dissolved by adding ethyl acetate (40 ml), washed with water (20 ml), and evaporated to dryness to give white solid 2 (2.85 g,87.4%). Ethyl acetate was recrystallized to obtain white granular crystals, mp143~145°C. The product was extracted from the reaction flask. Add crude 2(1.0g,0.0067mol), ethyl acetate(10ml) in a reaction flask at
50~60℃, dropwise add the ethyl acetate solution of phosphorus triclosan(1.2g,0.0082mol),2. 5h, then cooled to room temperature, add ethyl acetate(50ml), washed with water(50ml), evaporated to obtain crude 1(0.93,. 93%), recrystallized with anhydrous ethanol to obtain white crystal 1 (0.75g, 80.6%),mp166~168°C.
Advantages and disadvantages: the product yield is relatively high, but the operation is cumbersome.
Method 12[7]: with nitrobenzene as raw material
With nitrobenzene as raw material, in a three-mouth bottle, add 250 ml of distilled water, add 36 g of concentrated sulfuric acid, 60 g of nitrobenzene, cetyltrimethylammonium chloride 0.6 g, and a catalyst (homemade 3% Pt/C catalyst) in sequence. Pass nitrogen to replace air for 3 times, then pass hydrogen to replace nitrogen for 3 times, then pass hydrogen continuously, warm up to 90℃, stirring accelerated to 300r/min, respectively, record the flow rate of hydrogen and the flow rate of the exhaust gas to calculate the amount of hydrogen absorption. The reaction was finished about 3h, then 56 g of nitrobenzene was added, cooled to room temperature, and left to stratify. The aqueous layer was adjusted to pH 4~4.5, extracted with 30 ml of toluene-aniline (1:1) solution in 3 times, and the organic layers were combined. Adjust the mother liquor pH=7. 5, add Na2SO3s precipitation, with water vapor distillation to evaporate the remaining nitrobenzene, aniline and other impurities, while hot, add ethanoic anhydride-acetic acid (2B1) solution 25g, at 100 ℃ reaction for 3h. Cooling crystallization, filtration of the crude product, refined and dried to obtain the product of 48.6g, melting point of 168~170 ℃, recovery rate of 64.3%.
Advantages and disadvantages: the formula should be cumbersome operation, and the yield is relatively low.
Method 13[3]: hydroquinone and acetamide as raw materials
Hydroquinone and acetamide as raw materials, catalyzed by ZSM5 molecular sieve, in a vacuum Carius tube, 300 ℃ reaction for 1h can be condensed to obtain APAP, the conversion rate of 93.6%, molar selectivity of 45.9%. If titanium silicate is used as catalyst, the molar selectivity is 67.5% and the conversion is 90.8%.
Advantages and disadvantages: more friendly reaction conditions, higher yield.
The reaction formula is:
Method 14 [7]: p-aminophenol was prepared from phenol
P-aminophenol was prepared from phenol, and then the material was added in a three-necked flask according to the ratio (p-aminophenol B acetic anhydride=1:1.3), and the reaction was carried out under reflux stirring, and the temperature was raised to 120~140°C, kept warm for 15min, cooled to crystallize, and then pumped, and rinsed with A little ice water rinse, white crystals, paracetamol. The yield was 87%. Equation:
The best process conditions in this experiment are:
(1):NaNO2=1.0:1.36,t=-3℃. pH=1.5~0.3.
(2)Nitrosophenol:Na2S=1.0:1.22,t=45℃, pH 9 after neutralization.
(3)p-aminophenol:acetic anhydride =1:1.3,t=130~140℃.
Advantages and disadvantages: the best process conditions according to this experiment for the test, the obtained product yield is high, the purity is also high, has a high practical value.
2 Currently the main methods used in the industry
Produced by iron powder reduction method, which is based on p-nitrochlorobenzene as a raw material, hydrolysis, acidification, reduction of p-aminophenol, and then acylated to obtain acetaminophen. Although the iron powder reduction method is technically mature and the process is simple, the product yield is low, the quality is poor, the toxicity is high, the cost is high, and what's more serious is that the production process produces a large amount of phenol-containing, amine-containing iron sludge and sewage, which is seriously polluted. Therefore, there is an urgent need for technical improvement.
3 Methods that may be adopted in the future in China
The hydrogenation process is used instead of iron scrap reduction. In particular, the method of one-step synthesis of acetaminophen using Pd/C catalyst and p-nitrophen as raw material has the features of fewer production processes, high product yield, energy saving, greatly reduced waste liquid, less environmental pollution and low production cost. And for our manufacturers existing equipment, equipment investment is small, can greatly reduce the cost of technological transformation
. If we can realize the industrial production of this method, to increase the economic benefits of enterprises, and effectively reduce the three wastes of chemical plant pollution are of positive significance, and will further promote the development of fine chemical production.
4References
[1]Liu Zhuqing, Hu Ailin, Wang Gongying. Synthesis of p-aminophenol[J]. Industrial Catalysis,1999,(2):11-16.
[2]Xie Jianhua, Li Guanghua, Lu Sheng. Another synthetic route to paracetamol[J]. Chinese Journal of Pharmaceutical Industry, 1999(7).
[3]Yan Huanxin, Xu Danqian, Huai Zheming, et al. Research on the synthesis process of paracetamol[J]. Chinese Journal of Modern Applied Medicine,2000,17(1):32-33.
[4]WEI Zhaoyun, FAN Mingyue, CHEN Zicheng. Studies on a new route for synthesizing paracetamol Ⅰ. Synthesis study of p-hydroxyacetophenone oxime[J]. Journal of Anqing Normal College (Natural Science Edition), 1997,3(3):42-43.
[5]ZHAO H, WANG Jikang. Progress in the synthesis of p-acetamidophenol[J]. Chemical Technology and Development,2004(1)
[6]Fang Yanxiong, Zhang Weigang, Liu Chunying et al. One-step synthesis of paracetamol by Pd-La/C-catalyzed hydroacylation[J]. Modern Chemical Industry,2000,20(8):37-39.
[7]Guan Yanqiong, Yang Huirong, Chen Wenqing et al. Study on the synthesis process of paracetamol[J]. Journal of Guangdong University of Technology, 1997(2).
[8]Chen Guangyong, Chen Xubing, Liu Guangming. Progress in the synthesis of acetaminophen[J]. Southwest National Defense Medicine, 2007, 17(1):114-117.
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Synthesis of Acetaminophen
Synthesis of Acetaminophen
1 Synthesis method
Method 1[1]: p-nitrophenol as raw material
Taking p-nitrophenol as raw material, reducing it with iron powder, filtering to remove the iron sludge, and the filtrate is cooled and crystallized, and then the finished product PAP is made by steps of recrystallization, drying, etc., and then, in the aqueous solution containing p-aminophenol sulphate and aniline sulphate, adjusting the pH to 5 with ammonia, and then after the removal of aniline by distillation, the PAP is made by acetic Acylation with acetic anhydride while maintaining the pH at 5 with ammonia gives APAP with 95% content. literature reports that using ethyl acetate or acetic acid instead of aqueous medium improves the acylation rate to 92.2%, and the solvent is easy to recycle and the wastewater pollution is reduced.
Advantages and disadvantages: this method is simple, mature technology, but the yield is low, product quality is not stable, produce a large number of waste iron sludge and wastewater, serious pollution of the environment, many foreign countries have eliminated this method.
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Method 2[3]: Derivation of phenol as raw material
OH Derivation of phenol as raw material, polyphosphoric acid as a catalyst, with glacial acetic acid and NH
2
substances or salts, at 80 ℃ after the reaction with iced water, and then adjusted the pH value of 10% NaOH to 4, refluxing, cooling, extraction, and other steps get APAP, the purity can be up to 98%. The reaction formula is: