CN101250131B - Preparation technique of p-acetyl aminophenol - Google Patents
Preparation technique of p-acetyl aminophenol Download PDFInfo
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- CN101250131B CN101250131B CN2008100177985A CN200810017798A CN101250131B CN 101250131 B CN101250131 B CN 101250131B CN 2008100177985 A CN2008100177985 A CN 2008100177985A CN 200810017798 A CN200810017798 A CN 200810017798A CN 101250131 B CN101250131 B CN 101250131B
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Abstract
The invention provides a preparation method of 4 acetamidophenol, which comprises mixing p-aminophenol and acetic acid at the mass ratio of 1:4-1:8, adding zinc powder at 1.0-1.4 wt% of p-aminophenol as catalyst and reducer, controlling the temperature at 130-160DEG C, and reacting for 6-11h at normal pressure and constant temperature, cooling and filtering to remove unreacted zinc powder, depressurizing and distilling the filter liquor to recover acetic acid, and obtaining crude incanus solid product, using deionized water to wash the crude white solid product, filtering and drying to obtain final product. The invention uses p-aminophenol as raw material, uses zinc powder as catalyst and uses acetic acid as acylation agent and reaction solvent, to acylate p-aminophenol in acetic acid to obtain the product, while the left acetic acid after the reaction can be simply treated to be circulated. The invention has simple process, low cost and high yield (90% at most), and the prepared APAP can eliminate complex separation and purification, while the product purity can reach 98% at least.
Description
Technical field
The invention belongs to organic chemistry filed, relate to a kind of preparation technology of pharmaceutical chemicals acetoamidophenol, relating in particular to a kind of is raw material with p-aminophenol, Glacial acetic acid, is catalyzer with the zinc powder, the novel process of preparation acamol.
Background technology
Acamol (APAP), have another name called Paracetamol, because of its antipyretic-antalgic effect better, effect rapidly and lastingly, little to the human body side effect, advantages such as little anaphylaxis just progressively replace in the past antipyretic and analgesic (as acetylsalicylic acid etc.), become the first-selected antipyretic and analgesic of world's medical market.APAP is except being the good antipyretic and analgesic, still the synthetic intermediate of multiple other medicines.As be used for synthesizing new expectorant Ambroxol HCl, anodyne propacetamol etc.
Up to now, the synthetic method of APAP generally is divided into one-step synthesis and two-step synthesis.In two-step synthesis, p-aminophenol acidylate method mostly adopts the aceticanhydride acidylate to make APAP, and what obtain generally all needs through activated carbon decolorizing and pure crystallisation process, and technology is complicated, so its production cost is higher.
Summary of the invention
The purpose of this invention is to provide that a kind of technology is simple, cost is low, the novel process of the purified preparation acamol of product (APAP).
The present invention is to be raw material with p-aminophenol (PAP) and Glacial acetic acid, in the presence of the catalyzer zinc powder, makes p-aminophenol acidylate and making in Glacial acetic acid.Its synthetic route is as follows:
The specific embodiment that the present invention synthesizes acamol (APAP) is: be that p-aminophenol, Glacial acetic acid are mixed with 1: 4～1: 8 mass ratio, the zinc powder that adds p-aminophenol quality 1.0～1.4% is made catalyzer and reductive agent, controlled temperature is at 130 ℃～160 ℃, normal pressure, isothermal reaction 6～11h; Cool off, remove by filter unreacted zinc powder; Glacial acetic acid is reclaimed in the filtrate decompression distillation, get the pale solid crude product; With deionized water wash pale solid crude product, filter, at 30～60 ℃ of following vacuum-dryings APAP that gets product.
Influence below by description of test temperature of reaction, time, zinc powder consumption, raw materials quality comparison APAP product yield.
1, temperature of reaction is to the influence of APAP product yield
Under the identical condition of p-aminophenol and Glacial acetic acid mass ratio, reaction times, zinc powder consumption, the influence that temperature of reaction changes yield sees Table 1.
Table 1 temperature variation is to the influence of yield
| Temperature (℃) | 130? | 140? | 150? | 160? |
| Yield (%) | 75.5? | 82.2? | 88.4? | 60.6? |
As shown in Table 1, temperature yield in the time of 150 ℃ reaches maximum value 88.4%, and this may be because side reaction increase when temperature is too high, and speed of response is slower when temperature is too low, so yield is low during all than 150 ℃.
2, the reaction times is to the influence of APAP product yield
Under the identical condition of p-aminophenol and Glacial acetic acid mass ratio, temperature of reaction, zinc powder consumption, change the reaction times to experimentize, the results are shown in Table 2.
Table 2 time changes the influence to yield
| Time (h) | 6? | 7? | 8? | 9? | 10? | 11? |
| Yield (%) | 70.0? | 75.2? | 80.2? | 88.4? | 88.6? | 88.7? |
As shown in Table 2, in reaction times during greater than 9h, yield tends towards stability with the variation in reaction times, so optimum reacting time is about 9h.
3, p-aminophenol and Glacial acetic acid mass ratio are to the influence of APAP product yield
Under the identical condition of temperature of reaction, reaction times, zinc powder consumption, change p-aminophenol and Glacial acetic acid mass ratio, experimentize, the results are shown in Table shown in 3.
The change of table 3 raw materials quality ratio is to the influence of yield
| The PAP/ Glacial acetic acid | 1∶4? | 1∶6? | 1∶7? | 1∶8? |
| Yield (%) | 88.5? | 88.5? | 80.3? | 75.2? |
As shown in Table 3, product yield reduces and increases with the raw materials quality ratio, and yield reaches maximum value when mass ratio is 1: 6 left and right sides, continue to increase the consumption of Glacial acetic acid, possible side reaction increases, and yield descends to some extent, so PAP and Glacial acetic acid mass ratio are the highest at 1: 6 o'clock yield.
4, the influence of zinc powder consumption
Fixedly amino-phenol and Glacial acetic acid mass ratio, temperature of reaction, reaction times, change the zinc powder consumption and experimentize, the results are shown in Table 4.
Table 4 zinc powder consumption changes the influence to yield
| Zinc powder/PAP (%) | 1.0? | 1.1? | 1.2? | 1.4? |
| Yield (%) | 78.1? | 88.5? | 89.5? | 89.6? |
As shown in Table 4, it is best that the zinc powder consumption accounts for 1.1 of PAP quality～1.2% o'clock yield, when being higher than 1.2%, yield does not have very big variation, may be because reacted completely 1.1～1.2% the time when the zinc powder consumption, and the zinc powder consumption increases and may side reaction increase, so the zinc powder consumption is that 1.1 of PAP quality～1.2% o'clock yield is the highest.
5, optimization Test: the results are shown in Table 5.
Table 5 optimization experiment
| Temperature of reaction (℃) | Reaction times (h) | Zinc powder/PAP (%) | The PAP/ Glacial acetic acid | Yield (%) |
| 150? | 9? | 1.1? | 1∶6? | 88.5? |
| 150? | 9? | 1.1? | 1∶6? | 90.7? |
Show according to The results of univariate logistic analysis and the optimization Test result that further carries out, at PAP and Glacial acetic acid mass ratio at 1: 6, temperature of reaction is 150 ℃, reaction times is 9h, catalyzer (zinc powder) consumption is 1.1 of PAP quality～1.2% o'clock, good repeatability is arranged, and reaction yield is better, is about 90%.
The present invention compared with prior art has the following advantages:
1, the present invention is a raw material with p-aminophenol (PAP), makes catalyzer and reductive agent with zinc powder, is acylating reagent and reaction solvent with the Glacial acetic acid; make p-aminophenol acidylate and directly making in Glacial acetic acid; technology is simple, and the reaction conditions gentleness can suppress the generation of other side reaction effectively.
2, the present invention is acylating reagent with the Glacial acetic acid, and the remaining Glacial acetic acid in reaction back can recycle after simple process, and technology is simple and economical, product yield height (reaching 90%); The APAP that obtains does not need complicated separation and purification process, product purer (purity reaches 98%).
Embodiment
P-aminophenol is mixed with the mass ratio of Glacial acetic acid with 1: 6, and the zinc powder that adds p-aminophenol quality 1.1% is made catalyzer and reductive agent, controlled temperature about 150 ℃, normal pressure, isothermal reaction 9h; Cooling removes by filter unreacted zinc powder; The filtrate decompression distillation to reclaim Glacial acetic acid, is got the pale solid crude product; With the deionized water wash crude product repeatedly, filter, 40 ℃ of following vacuum-dryings, APAP gets product at last.Yield 88.4%, purity 98.5%.
1HMNR(400MHz，d
6-DMSO)δ：9.64(s，1H，NH)，9.14(s，1H，OH)，7.30-7.33(m，1H，Ar-H)，6.64-6.67(m，1H，Ar-H)，1.96(s，3H，CH
3)。
Claims (2)
1. the preparation technology of an acamol, be that p-aminophenol, Glacial acetic acid are mixed with 1: 4～1: 8 mass ratio, the zinc powder that adds p-aminophenol quality 1.0～1.4% is made catalyzer and reductive agent, and controlled temperature is at 130 ℃～160 ℃, normal pressure, isothermal reaction 6～11h; Cool off, remove by filter unreacted zinc powder; Glacial acetic acid is reclaimed in the filtrate decompression distillation, get the pale solid crude product; With deionized water wash pale solid crude product, filter, be drying to obtain the finished product acamol.
2. the preparation technology of acamol according to claim 1, it is characterized in that: described drying is for carrying out vacuum-drying under 30～60 ℃.
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| CN2008100177985A CN101250131B (en) | 2008-03-15 | 2008-03-15 | Preparation technique of p-acetyl aminophenol |
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| CN101250131A CN101250131A (en) | 2008-08-27 |
| CN101250131B true CN101250131B (en) | 2011-02-16 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104557593A (en) * | 2014-12-13 | 2015-04-29 | 常熟华港制药有限公司 | Preparation process of paracetamol |
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| CN102824758B (en) * | 2012-08-24 | 2015-01-07 | 安徽丰原发酵技术工程研究有限公司 | System and method for separating paracetamol by simulated moving bed chromatography |
| CN103508916B (en) * | 2013-10-25 | 2015-03-25 | 山东新华制药股份有限公司 | Preparation technology for paracetamol |
| CN105152956A (en) * | 2015-08-05 | 2015-12-16 | 安丘市鲁安药业有限责任公司 | Process and device for acylation reaction of acetaminophen |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1434026A (en) * | 2003-02-11 | 2003-08-06 | 中国石化集团南京化工厂 | Process for prepraring p-acetpamidophenol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1434026A (en) * | 2003-02-11 | 2003-08-06 | 中国石化集团南京化工厂 | Process for prepraring p-acetpamidophenol |
Non-Patent Citations (4)
| Title |
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| 吴晓云.对乙酰氨基苯酚生产技术.精细石油化工进展3 5.2002,3(5),41-45. |
| 吴晓云.对乙酰氨基苯酚生产技术.精细石油化工进展3 5.2002,3(5),41-45. * |
| 李勤耕.扑热息痛工艺改进.华西药学杂志7 3.1992,7(3),189. |
| 李勤耕.扑热息痛工艺改进.华西药学杂志7 3.1992,7(3),189. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557593A (en) * | 2014-12-13 | 2015-04-29 | 常熟华港制药有限公司 | Preparation process of paracetamol |
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