CN1315769C - Environment-friendly synthesis process for 1- chloroethane-4-butylrubberbenzophenone - Google Patents
Environment-friendly synthesis process for 1- chloroethane-4-butylrubberbenzophenone Download PDFInfo
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- CN1315769C CN1315769C CNB2005102000401A CN200510200040A CN1315769C CN 1315769 C CN1315769 C CN 1315769C CN B2005102000401 A CNB2005102000401 A CN B2005102000401A CN 200510200040 A CN200510200040 A CN 200510200040A CN 1315769 C CN1315769 C CN 1315769C
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Abstract
The present invention provides a synthesis technology for 1-chloroethyl-4-isobutyl benzophenone as an ibuprofen intermediate, which comprises the following concrete synthesizing steps: firstly, reacting anhydrous alchlorwith alpha-chloropropionyl chloride; secondly, adding isobutyl benzene for reaction; thirdly, adding and stirring petroleum ether for hydrolysis reaction; fourthly, using petroleum ether to extract reacted mother liquid; fifthly, washing combined extracted liquid and reaction material in water. The synthesis technology is carried out in room temperature and only requires common circulating water or well water, which reduces corrosion to equipment and realizes clean production. The present invention has the advantages of energy saving and high environmental protection benefit.
Description
Technical field
The present invention relates to chemosynthesis preparation technology, particularly the green synthesis process of anti-inflammatory analgesic Ibuprofen BP/EP intermediate 1-chloroethyl-4-Isobuytel Benzene acetone.
Background technology
Ibuprofen BP/EP is a kind of non-steroid antiinflammatory drug, and its anti-inflammatory analgesic, refrigeration function are stronger 16～32 times than acetylsalicylic acid.Compare with general anti-inflammatory analgesic, its effect is strong and side effect is little, and particularly little to GI side effect to liver, kidney and hemopoietic system non-evident effect, the patient that can not tolerate medicines such as acetylsalicylic acid, phenylbutazone, INDOMETHACIN can take this product.Be applicable to treatment rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, neuritis, pharyngolaryngitis and bronchitis etc.
Last century, the eighties domesticly began to have the people to synthesize Ibuprofen BP/EP.Generally adopting the glycidyl ester route at that time is that Isobuytel Benzene and Acetyl Chloride 98Min. get the Isobuytel Benzene ethyl ketone through friedel-crafts reaction (Friedel-Craftskeactln); Make the Isobuytel Benzene propionic aldehyde through condensation, hydrolysis, decarboxylation again, after oxidation gets Ibuprofen BP/EP.This processing technology routine is long, and is raw materials used many, and total recovery low (only 58%) just was eliminated after 10 years.Though its first step friedel-crafts reaction temperature of reaction moderate (18 ℃) has adopted a large amount of sherwood oil (1: 7) to make solvent.Throughput is little on the one hand, and the solvent waste is big; On the other hand, sherwood oil is a mixture, and its contained aromatic hydroxy compound competition friedel-crafts reaction causes that intermediate is of poor quality, finished product related substance height.
Present domestic Ibuprofen BP/EP production generally adopts 1,2-transposition technology.Be that Isobuytel Benzene and α-chlorpromazine chloride get 1-chloroethyl-4-isobutyl benzophenone through friedel-crafts reaction, get Ibuprofen BP/EP through condensation, rearrangement, hydrolysis.This technology is easy, and the raw material of usefulness is few, and the yield height increases substantially domestic Ibuprofen BP/EP production level.The synthetic Fu Shi acylation reaction that is similarly of first intermediate Zhao of this technology 1-chloroethyl-4-isobutyl benzophenone; In this reaction, adopted ethylene dichloride to make solvent (sherwood oil of employing 1: 7 is also arranged, but its final product quality being poor), temperature is being carried out below-5 ℃.Adopted the very big kind solvent Zhao 1 of toxicity in the reaction on the one hand, the 2-ethylene dichloride has limited the development of product in Europe, the United States market; On the other hand, to temperature requirement harshness (must adopt the hypothermic saline below-18 ℃ to lower the temperature), the energy consumption height makes the cost pressure of product big.
Summary of the invention
Technical problem to be solved by this invention provides the green synthesis process of a kind of 1-chloroethyl that does not adopt ethylene dichloride to make solvent-4-isobutyl benzophenone.
The green synthesis process of Ibuprofen BP/EP intermediate 1-chloroethyl-4-isobutyl benzophenone, it is characterized in that it being by aluminum trichloride (anhydrous) and α-chlorpromazine chloride reaction, with the Isobuytel Benzene reaction, reaction solution carries out hydrolysis reaction after adopting petroleum ether dissolution to extract, and separates purification at last again.
Aluminum trichloride (anhydrous) and α-chlorpromazine chloride reaction can be that aluminum trichloride (anhydrous) slowly adds to α-chlorpromazine chloride, also can be that α-chlorpromazine chloride drips in aluminum trichloride (anhydrous).Can avoid thermopositive reaction too fierce like this.
Aluminum trichloride (anhydrous) is as catalyzer in the chemical reaction provided by the invention.Need not any solvent in the reaction of the Aluminum chloride anhydrous in the synthesis technique, α-chlorpromazine chloride, Isobuytel Benzene.
In above-mentioned reaction, aluminum trichloride (anhydrous) and α-chlorpromazine chloride temperature of reaction is 35～40 ℃, after reacting completely again with Isobuytel Benzene reaction, with the temperature of reaction of Isobuytel Benzene be 15～30 ℃, the temperature of hydrolysis reaction is 25～35 ℃.
Owing to need to make the band aqua in the following operation of Ibuprofen BP/EP production, therefore added sherwood oil in advance in the hydrolysis reaction in the present invention with sherwood oil.
After reaction was finished, separating and purifying method is: the reaction solution behind the hydrolysis reaction left standstill, layering obtains mother liquor and feed liquid, the mother liquor Petroleum ether extraction, and extracting solution and feed liquid wash with water promptly after merging.
The contrast of the present invention and prior art:
1. select for use ethylene dichloride to make solvent in the prior art, ethylene dichloride is a class solvent, has limited the sale of product in Europe, the U.S.; The present invention is without ethylene dichloride.
2. select for use ethylene dichloride to make solvent in the prior art, add solvent in initial reaction stage, hydrolysis steams it complex operation after finishing again; Steam and cooling water have been wasted; More than consumed the solvent ethylene dichloride; The present invention only adds the band aqua sherwood oil of subsequent processing when hydrolysis in advance, and is energy-saving and cost-reducing, realized cleaner production.
3. because ethylene dichloride has 1 ‰ solubleness in water, also must bring part 1-chloroethyl-4-isobutyl benzophenone into simultaneously and dissolve in hydrolysis and the washing water, influence the yield of 1-chloroethyl-4-isobutyl benzophenone, and cause efflux wastewater COD higher; And the present invention is all water insoluble owing to sherwood oil, 1-chloroethyl-4-isobutyl benzophenone, thereby, washing water are being reduced under 50% the situation, still keep efflux wastewater COD to reduce significantly and (reduce to 4800mg/L by 5600mg/L, amplitude reaches 54%), have very high environmental benefit
4. prior art adopts the not too friendly low-temp reaction of environment, and the cooling medium temperature will be with subzero icy salt solution below 18 ℃, and energy consumption is very big, is unfavorable for operating; The present invention at room temperature carries out, and only needs common recirculated water or well water to get final product.
5. prior art is lowered the temperature with icy salt solution, and is big to equipment corrosion, and water of condensation is more in the environment, is unfavorable for this anhydrous response; The present invention does not have these shortcomings.
Embodiment
Drop into the aluminum trichloride (anhydrous) of dosage in drying, clean 250ml reaction flask, 20～35 ℃ drip α-chlorpromazine chlorides, add 35～40 ℃ of reactions in back 20 minutes; 15～30 ℃ drip Isobuytel Benzene, react 60 minutes under this temperature after adding.The mol ratio of aluminum trichloride (anhydrous), α-chlorpromazine chloride, Isobuytel Benzene is: 1.19: 1.05: 1.Add sherwood oil 34ml to reaction flask, stirring and dissolving 20～30 minutes adds reaction solution in the 120 gram frozen water, and 25～35 ℃ of controlled temperature stirred 30 minutes.Leave standstill layering, mother liquor Petroleum ether extraction.After petroleum ether extract and feed liquid merged, water was given a baby a bath on the third day after its birth inferior, and GC analyzes chlorine ketone content and quality.Operation is down handed in qualified back.
Claims (5)
1. the green synthesis process of Ibuprofen BP/EP intermediate 1-chloroethyl-4-isobutyl benzophenone, it is characterized in that it being by aluminum trichloride (anhydrous) and α-chlorpromazine chloride reaction, with the Isobuytel Benzene reaction, reaction solution carries out hydrolysis reaction after adopting petroleum ether dissolution to extract, and separates purification at last again.
2. synthesis technique according to claim 1 is characterized in that aluminum trichloride (anhydrous) and α-chlorpromazine chloride reaction is slowly to be added to α-chlorpromazine chloride by aluminum trichloride (anhydrous), or is dripped in aluminum trichloride (anhydrous) by α-chlorpromazine chloride.
3. synthesis technique according to claim 1 is characterized in that aluminum trichloride (anhydrous) and α-chlorpromazine chloride temperature of reaction is 35～40 ℃, with the temperature of reaction of Isobuytel Benzene be 15～30 ℃.
4. synthesis technique according to claim 1, the temperature that it is characterized in that hydrolysis reaction is 25～35 ℃.
5. synthesis technique according to claim 1, it is characterized in that described separating and purifying method is: the reaction solution behind the hydrolysis reaction leaves standstill, layering obtains mother liquor and feed liquid, the mother liquor Petroleum ether extraction, extracting solution and feed liquid wash with water promptly after merging.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005102000401A CN1315769C (en) | 2005-01-18 | 2005-01-18 | Environment-friendly synthesis process for 1- chloroethane-4-butylrubberbenzophenone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005102000401A CN1315769C (en) | 2005-01-18 | 2005-01-18 | Environment-friendly synthesis process for 1- chloroethane-4-butylrubberbenzophenone |
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| CN1807383A CN1807383A (en) | 2006-07-26 |
| CN1315769C true CN1315769C (en) | 2007-05-16 |
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| CNB2005102000401A Active CN1315769C (en) | 2005-01-18 | 2005-01-18 | Environment-friendly synthesis process for 1- chloroethane-4-butylrubberbenzophenone |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105439849A (en) * | 2014-09-02 | 2016-03-30 | 襄阳新叶生物科技有限公司 | Ibuprofen preparation method adopting solid catalyst |
| CN106496001A (en) * | 2016-08-31 | 2017-03-15 | 山东新华制药股份有限公司 | Prepare method and its micro passage reaction of brufen intermediate |
| CN115466170A (en) * | 2022-08-25 | 2022-12-13 | 浙江新和成股份有限公司 | Preparation method and device of ibuprofen Friedel-crafts intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5118860A (en) * | 1990-11-27 | 1992-06-02 | Hoechst Celanese Corporation | Bf3 catalyzed acylation of aromatic compounds |
| CN1082022A (en) * | 1992-08-14 | 1994-02-16 | 山东新华制药厂 | Molecular transposition prepares the technology of Ibuprofen BP/EP under the catalysis |
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- 2005-01-18 CN CNB2005102000401A patent/CN1315769C/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5118860A (en) * | 1990-11-27 | 1992-06-02 | Hoechst Celanese Corporation | Bf3 catalyzed acylation of aromatic compounds |
| CN1082022A (en) * | 1992-08-14 | 1994-02-16 | 山东新华制药厂 | Molecular transposition prepares the technology of Ibuprofen BP/EP under the catalysis |
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