CN1569819A - Process for synthesizing paracetamol - Google Patents
Process for synthesizing paracetamol Download PDFInfo
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- CN1569819A CN1569819A CN 200410019103 CN200410019103A CN1569819A CN 1569819 A CN1569819 A CN 1569819A CN 200410019103 CN200410019103 CN 200410019103 CN 200410019103 A CN200410019103 A CN 200410019103A CN 1569819 A CN1569819 A CN 1569819A
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- mirbane
- paracetamol
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Abstract
The invention relates to a process for synthesizing paracetamol by catalysis, hydrogenation and acylation in acid medium, wherein nitrobenzene is used as raw material, load type metal platinum is used as the catalyst, and para amino phenol is obtained through nitrobenzene hydrogenation in boron trifluoride ether and aqueous solution, the APAP is prepared through rearrangement reaction synthesis and acetylation.
Description
Technical field
The present invention relates to a kind of synthesis technique of paracetamol, is raw material with oil of mirbane particularly, in acid medium through shortening again acidylate prepare the processing method of paracetamol (be called for short APAP).
Background technology
Paracetamol (being called for short APAP) is a kind of antipyretic-antalgic class medicine, has become one of most widely used medicine in the whole world, is No.1 antipyretic and analgesic on the world market, also is one of kind of output maximum in China's raw material simultaneously.In recent years, its domestic and international market continues good, and both production and marketing thrive.In addition, APAP also can be used for making azoic dyestuff, photosensitive medicine etc.
The synthetic method of paracetamol is a lot, is generally made through acidylate with acetic acid or acid anhydrides by p-aminophenol (being called for short PAP).Whether the production of paracetamol independently carries out being divided into single stage method and two-step approach according to the preparation of PAP and APAP.Two-step approach is meant that the preparation of PAP and APAP independently carries out respectively, but since PAP in production, transportation and storage process than easy oxidation discoloration, therefore after must making with extra care before use for the producer of outsourcing PAP production APAP, just can be used for the synthetic former medicine of APAP that meets standards of pharmacopoeia, this causes complex technical process, total recovery to reduce, energy consumption is big, and production cost height and quantity of three wastes are big, and economic benefit is not good enough.And the synthetic APAP of single stage method, the acidylate synthetic and subsequently that is about to PAP prepares the APAP two-step reaction and is arranged in the same technological process, and then newly-generated PAP acidylate immediately is APAP, has avoided the problem of oxidation in transportation, the storage process, has simplified technological process.
Single stage method prepares APAP can use p-nitrophenol; paranitrophenol sodium salt; para-nitrochloro-benzene is a starting raw material; but it is starting raw material one-step synthesis APAP that most literature concentrates on the p-nitrophenol; CN1434026A is raw material with the p-nitrophenol; in medium acetic acid/aqueous acetic acid; with the p-nitrophenol catalytic hydrogenating reduction is PAP; behind the reduzate leaching catalyzer; under 100～150 ℃, utilize the acetic acid acidylate in the medium earlier; the p-aminophenol transformation efficiency is 30～80%; add excessive acetic anhydride at 50～100 ℃ then; make the complete acidylate of PAP; through separating; after refining; the APAP total recovery is more than 85%, but the shortcoming of this method is that raw material p-nitrophenol cost is higher relatively, and is uneconomical economically.
Oil of mirbane is large industrial chemicals, compare with p-nitrophenol, paranitrophenol sodium salt, para-nitrochloro-benzene, cost is relatively low, therefore synthesize the hot topic that PAP is present domestic and international exploitation with oil of mirbane for the catalytic material hydrogenation, this technology many with dilute sulphuric acid as reaction medium, with precious metals pt or Pd is that catalyzer prepares PAP, and be that raw material one-step synthesis APAP does not still have the industrialization report at home with oil of mirbane, US5155269 is raw material with oil of mirbane, is that catalyzer carries out shortening with Pt/C in 10% dilute sulphuric acid.PH to 4.5～5.0 with strong aqua conditioned reaction liquid; with toluene extraction impurity such as aniline wherein; with regulating PH to 6.6～7.0 behind the activated carbon decolorizing; carry out reextraction to remove aniline wherein with toluene again; obtain purified PAP suspension; regulate PH to 7.0～7.2 with a spot of ammoniacal liquor, PAP is separated out fully, add acetic anhydride again and carry out acidylate and obtain APAP.But this method will be used a large amount of ammoniacal liquor, and sulfuric acid amine and Ammoniom-Acetate that by-product is a large amount of have increased difficulty to the disposal of three wastes, before acidylate reaction solution are carried out twice extraction in addition, cause complex technical process.
Summary of the invention
The present invention mainly solves the problems such as by-product thiamines, Ammoniom-Acetate, production cost height and complex technical process that exist in the prior art; thereby provide a kind of p-aminophenol method of in the boron trifluoride diethyl etherate aqueous solution, synthesizing; compare with prior art; shortening synthesizes PAP and is that medium is compared with sulfuric acid in the boron trifluoride diethyl etherate aqueous solution; selectivity to PAP is higher; and in follow-up acylation process; do not use a large amount of ammoniacal liquor; under sour environment, just can carry out acylation reaction, so this method has been simplified the technology of producing APAP.
Technical solution of the present invention is as follows: the metal platinum with loading type is a catalyzer, oil of mirbane in the boron trifluoride diethyl etherate aqueous solution in through the synthetic p-aminophenol of hydrogenation, rearrangement reaction, prepare APAP with the acetic anhydride acidylate again, its processing step is as follows:
(1) is medium with the boron trifluoride diethyl etherate aqueous solution, oil of mirbane and catalyzer, tensio-active agent are put into the four-hole bottle that has condenser, thermometer, inlet pipe;
(2) be heated to temperature when being 40～100 ℃, feed N
2After 8～10 minutes, logical H
2Reacted 3～8 hours, and made oil of mirbane be converted into p-aminophenol;
(3) after reaction finishes,, leach catalyzer, extract unreacted oil of mirbane and aniline with hot toluene while hot with reacting liquid filtering;
(4) reaction solution after will extracting joins in the four-hole bottle that has condenser, thermometer, constant pressure funnel, oxidized in reaction process for preventing PAP, in reaction solution, add a certain amount of sodium bisulfite, add a certain amount of acid binding agent again, in constant pressure funnel, add a certain amount of acetic anhydride, when being heated to 20～100 ℃, drip acetic anhydride continuously, reacted 2～10 hours;
(5) after reaction finishes, the reaction solution underpressure distillation is concentrated, again crystallisation by cooling.
The present invention compares with prior art has following effect:
(1) the present invention is the synthetic APAP of raw material with oil of mirbane, has reduced the cost of raw material;
(2) the present invention, and compares with sulfuric acid medium for adding hydrogen medium with the boron trifluoride diethyl etherate aqueous solution, and is higher to the selectivity of PAP;
(3) the present invention can carry out acidylate under the tart environment, has avoided using a large amount of ammoniacal liquor, has reduced the generation of the three wastes.
(4) the present invention is when carrying out underpressure distillation with reaction solution, can the recovery part acid solution, and can in hydrogenation technique, apply mechanically, this has also reduced the generation of the three wastes.
Description of drawings
There is not figure
Embodiment
The synthesis technique of this paracetamol comprises the steps:
(1) is medium with the boron trifluoride diethyl etherate aqueous solution, oil of mirbane and catalyzer, tensio-active agent are put into the four-hole bottle that has condenser, thermometer, inlet pipe;
(2) be heated to temperature when being 40～100 ℃, feed N
2After about 10 minutes, logical H
2Reacted 3～8 hours, and made oil of mirbane be converted into p-aminophenol;
(3) after reaction finishes,, leach catalyzer, extract unreacted oil of mirbane and aniline with hot toluene while hot with reacting liquid filtering;
(4) reaction solution after will extracting joins in the four-hole bottle that has condenser, thermometer, constant pressure funnel, oxidized in reaction process for preventing PAP, in reaction solution, add a certain amount of sodium bisulfite, add a certain amount of acid binding agent again, in constant pressure funnel, add a certain amount of acetic anhydride, when being heated to 20～100 ℃, drip acetic anhydride continuously, reacted 2～10 hours;
(5) after reaction finishes, the reaction solution underpressure distillation is concentrated, again crystallisation by cooling.
The volume ratio of employed water of step (1) and boron trifluoride diethyl etherate is 20: 1～5: 1, and volume ratio is 15: 1～10: 1 preferably.
The mass ratio of employed oil of mirbane of step (1) and catalyzer is 40: 1～10: 1, and the preferable quality ratio is 30: 1～20: 1.
The employed catalyzer of step (1) is that the metal platinum of loading type is a catalyzer, and carrier is a kind of in aluminium sesquioxide, gac, silicon oxide, the sial composite oxides; The charge capacity of metal platinum is 0.5%～10%, and charge capacity is 2%～5% preferably.
The volume ratio of employed boron trifluoride diethyl etherate of step (1) and oil of mirbane is 5: 1～1: 1.
The employed tensio-active agent of step (1) is a kind of in dodecyl trimethylammonium amine bromide, hexadecyl trimethyl ammonium bromide, dodecyl trimethylammonium ammonia chloride, dodecyl dimethyl vitriol, the Sodium dodecylbenzene sulfonate, with the mass ratio of oil of mirbane be 1: 150～1: 50.
The employed acid binding agent of step (4) is a kind of in quadrol, triethylamine, trolamine, tripropyl amine, dimethylamine, the pyridine, with the volume ratio of boron trifluoride diethyl etherate be 1: 5～1: 10.
Step (4) the mol ratio of the acetic anhydride that uses and oil of mirbane be 1: 1～4: 1, ratio is 1.5: 1～3: 1 preferably.
The mass ratio of used sodium bisulfite of step (4) and oil of mirbane is 0.05: 1～0.3: 1.
Step (2) temperature of reaction preferably is 60～90 ℃, and the reaction times is 5～7 hours preferably.
Step (4) temperature of reaction preferably is 70～100 ℃, and the reaction times is 5～8 hours preferably.
Further specify the present invention with specific examples below:
Example 1
(1) with 5ml oil of mirbane, the 10ml boron trifluoride diethyl etherate, 100ml water, 0.15gPt/C catalyzer (Pt charge capacity 2%),, the 0.01g four butyl bromation amine drops in the four-hole bottle;
(2) be heated to 50 ℃, logical N
2After about 10 minutes, feed H
2, reacted 7 hours;
(3) after reaction finishes, while hot with reacting liquid filtering, leach catalyzer, filtrate extracts unreacted oil of mirbane and aniline with hot toluene, and the filtrate after the extraction is joined in the four-hole bottle, add the 0.05g sodium bisulfite, the 2ml quadrol adds the 5ml acetic anhydride, after the temperature of question response liquid rises to 50 ℃ in constant pressure funnel, drip acetic anhydride, reaction 7h;
(4) reaction solution is carried out underpressure distillation, crystallisation by cooling gets crude product again;
(5) crude product is analyzed with liquid chromatography, purity is more than 90%, and the yield of APAP is 55%.
Example 2
(1) with 5ml oil of mirbane, the 20ml boron trifluoride diethyl etherate, 100ml water, 0.15gPt/C catalyzer (Pt charge capacity 2%),, the 0.01g four butyl bromation amine drops in the four-hole bottle;
(2) be heated to 50 ℃, logical N
2After about 10 minutes, feed H
2, reacted 7 hours;
(3) after reaction finishes, while hot with reacting liquid filtering, leach catalyzer, filtrate extracts unreacted oil of mirbane and aniline with hot toluene, and the filtrate after the extraction is joined in the four-hole bottle, add the 0.05g sodium bisulfite, the 2ml quadrol adds the 5ml acetic anhydride, after the temperature of question response liquid rises to 50 ℃ in constant pressure funnel, drip acetic anhydride, reaction 7h;
(4) reaction solution is carried out underpressure distillation, crystallisation by cooling gets crude product again;
(5) crude product is analyzed with liquid chromatography, purity is more than 90%, and the yield of APAP is 45%.
Example 3
(1) with 5ml oil of mirbane, the 10ml boron trifluoride diethyl etherate, 100ml water, 0.15gPt/C catalyzer (Pt charge capacity 2%),, the 0.01g four butyl bromation amine drops in the four-hole bottle;
(2) be heated to 90 ℃, logical N
2After about 10 minutes, feed H
2, reacted 4 hours;
(3) after reaction finishes, while hot with reacting liquid filtering, leach catalyzer, filtrate extracts unreacted oil of mirbane and aniline with hot toluene, and the filtrate after the extraction is joined in the four-hole bottle, add the 0.05g sodium bisulfite, the 2ml quadrol adds the 5ml acetic anhydride, after the temperature of question response liquid rises to 90 ℃ in constant pressure funnel, drip acetic anhydride, reaction 3h;
(4) reaction solution is carried out underpressure distillation, crystallisation by cooling gets crude product again;
(5) crude product is analyzed with liquid chromatography, purity is more than 90%, and the yield of APAP is 65%.
Example 4
(1) with 5ml oil of mirbane, the 10ml boron trifluoride diethyl etherate, 100ml water, 0.3gPt/C catalyzer (Pt charge capacity 2%),, the 0.01g four butyl bromation amine drops in the four-hole bottle;
(2) be heated to 90 ℃, logical N
2After about 10 minutes, feed H
2, reacted 5 hours;
(3) after reaction finishes, while hot with reacting liquid filtering, leach catalyzer, filtrate extracts unreacted oil of mirbane and aniline with hot toluene, and the filtrate after the extraction is joined in the four-hole bottle, add the 0.05g sodium bisulfite, the 3ml quadrol adds the 5ml acetic anhydride, after the temperature of question response liquid rises to 90 ℃ in constant pressure funnel, drip acetic anhydride, reaction 3h;
(4) reaction solution is carried out underpressure distillation, crystallisation by cooling gets crude product again;
(5) crude product is analyzed with liquid chromatography, purity is more than 95%, and the yield of APAP is 50%.
Example 5
(1) with 5ml oil of mirbane, the 10ml boron trifluoride diethyl etherate, 100ml water, 0.15gPt/C catalyzer (Pt charge capacity 2%),, the 0.01g four butyl bromation amine drops in the four-hole bottle;
(2) be heated to 90 ℃, logical N
2After about 10 minutes, feed H
2, reacted 5 hours;
(3) after reaction finishes, while hot with reacting liquid filtering, leach catalyzer, filtrate extracts unreacted oil of mirbane and aniline with hot toluene, and the filtrate after the extraction is joined in the four-hole bottle, add the 0.05g sodium bisulfite, the 3ml quadrol adds the 7ml acetic anhydride, after the temperature of question response liquid rises to 90 ℃ in constant pressure funnel, drip acetic anhydride, reaction 3h;
(4) reaction solution is carried out underpressure distillation, crystallisation by cooling gets crude product again;
(5) crude product is analyzed with liquid chromatography, purity is more than 90%, and the yield of APAP is 55%.
Claims (9)
1. the synthesis technique of a paracetamol is characterized in that this technology comprises the steps:
(1) is medium with the boron trifluoride diethyl etherate aqueous solution, oil of mirbane and catalyzer, tensio-active agent are put into the four-hole bottle that has condenser, thermometer, inlet pipe;
(2) be heated to temperature when being 40～100 ℃, feed N
2After 8～12 minutes, logical H
2Reacted 3～8 hours, and made oil of mirbane be converted into p-aminophenol;
(3) after reaction finishes,, leach catalyzer, extract unreacted oil of mirbane and aniline with hot toluene while hot with reacting liquid filtering;
(4) reaction solution after will extracting joins in the four-hole bottle that has condenser, thermometer, constant pressure funnel, add sodium bisulfite, acid binding agent, in constant pressure funnel, add acetic anhydride, when being heated to 40～100 ℃, drip acetic anhydride continuously, reacted 2～10 hours;
(5) after reaction finishes, the reaction solution underpressure distillation is concentrated, again crystallisation by cooling.
2. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the volume ratio of employed water of step (1) and boron trifluoride diethyl etherate is 20: 1～5: 1.
3. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the employed oil of mirbane of step (1) is 40: 1～10: 1 with the ratio of the quality of catalyzer.
4. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the employed catalyzer of step (1) is that the metal platinum of loading type is a catalyzer, and carrier is a kind of in aluminium sesquioxide, gac, silicon oxide, the sial composite oxides; The charge capacity of metal platinum is 0.5%～10%.
5. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the volume ratio of employed boron trifluoride diethyl etherate of step (1) and oil of mirbane is 5: 1～1: 1.
6. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the employed tensio-active agent of step (1) is a kind of in dodecyl trimethylammonium amine bromide, hexadecyl trimethyl ammonium bromide, dodecyl trimethylammonium ammonia chloride, dodecyl dimethyl vitriol, the Sodium dodecylbenzene sulfonate, with the ratio of the quality of oil of mirbane be 1: 150～1: 50.
7. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the employed acid binding agent of step (4) is a kind of in quadrol, triethylamine, trolamine, tripropyl amine, dimethylamine, the pyridine, with the volume ratio of boron trifluoride diethyl etherate be 1: 5～1: 10.
8. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the mass ratio of used sodium bisulfite of step (4) and oil of mirbane is 0.05: 1～0.3: 1.
9. according to the synthesis technique of the said paracetamol of claim 1, it is characterized in that: the mol ratio of employed acetic anhydride of step (4) and oil of mirbane is 1: 1～4: 1.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101624352B (en) * | 2009-07-30 | 2011-07-13 | 浙江康乐药业股份有限公司 | Method for processing acetaminophen refined mother liquid |
| CN102408351A (en) * | 2011-09-26 | 2012-04-11 | 河北冀衡（集团）药业有限公司 | Crystallization treatment process of paracetamol acylation material liquid |
| RU2495865C1 (en) * | 2012-07-10 | 2013-10-20 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Уральский федеральный университет имени первого Президента России Б.Н. Ельцина" | METHOD OF PRODUCING n-ACETYLAMINOPHENOL |
| CN104628592A (en) * | 2015-03-02 | 2015-05-20 | 河北工业大学 | Method for directly synthesizing acetaminophen from nitrobenzene in acetic acid solution at one step |
| RU2574733C1 (en) * | 2014-12-26 | 2016-02-10 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Уральский федеральный университет имени первого Президента России Б.Н. Ельцина" | Method for producing paracetamol |
| CN115636758A (en) * | 2022-10-18 | 2023-01-24 | 海南新澜科技有限公司 | Preparation method of p-aminophenol |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113254B (en) * | 2013-03-11 | 2014-04-16 | 河北工业大学 | Technology for directly synthesizing acetaminophen from nitrobenzene |
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2004
- 2004-04-30 CN CN 200410019103 patent/CN1285567C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101624352B (en) * | 2009-07-30 | 2011-07-13 | 浙江康乐药业股份有限公司 | Method for processing acetaminophen refined mother liquid |
| CN102408351A (en) * | 2011-09-26 | 2012-04-11 | 河北冀衡（集团）药业有限公司 | Crystallization treatment process of paracetamol acylation material liquid |
| RU2495865C1 (en) * | 2012-07-10 | 2013-10-20 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Уральский федеральный университет имени первого Президента России Б.Н. Ельцина" | METHOD OF PRODUCING n-ACETYLAMINOPHENOL |
| RU2574733C1 (en) * | 2014-12-26 | 2016-02-10 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Уральский федеральный университет имени первого Президента России Б.Н. Ельцина" | Method for producing paracetamol |
| CN104628592A (en) * | 2015-03-02 | 2015-05-20 | 河北工业大学 | Method for directly synthesizing acetaminophen from nitrobenzene in acetic acid solution at one step |
| CN115636758A (en) * | 2022-10-18 | 2023-01-24 | 海南新澜科技有限公司 | Preparation method of p-aminophenol |
| CN115636758B (en) * | 2022-10-18 | 2024-06-04 | 海南新澜科技有限公司 | Preparation method of p-aminophenol |
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| CN1285567C (en) | 2006-11-22 |
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