CN1031939C - Process to prepare brufen by rearranging molecular under catalysis - Google Patents
Process to prepare brufen by rearranging molecular under catalysis Download PDFInfo
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- CN1031939C CN1031939C CN 92106667 CN92106667A CN1031939C CN 1031939 C CN1031939 C CN 1031939C CN 92106667 CN92106667 CN 92106667 CN 92106667 A CN92106667 A CN 92106667A CN 1031939 C CN1031939 C CN 1031939C
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- ibuprofen
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Abstract
The present invention relates to technology for preparing ibuprofen. Isobutyl phenyl serves as initial raw material, and carries out ketone filtration, ketone concentration and catalysis, the molecules are rearranged, hydrolyzed and acidified, and the intermediate products are not separated. The present invention is characterized in that zinc salt which is used as a catalyst is zinc toluene sulfonic acid or zinc oxide or a mixture of the zinc toluene sulfonic acid or the zinc oxide; solvent with ketone concentration, catalysis and rearrangement reaction is ligarine. Compared with the reaction solvent of the prior art, the present invention has the advantages of simple manufacturing technology, good postprocessing stratification, little waste water amount, and good catalyst with molecular rearrangement. The ibuprofen crude product is red oily matter, the quality is good, and the yield is high.
Description
The present invention relates to organic compound and prepare category, molecular transposition prepares the processing method of Ibuprofen BP/EP under particularly a kind of catalysis.
Aryl alkanoic acid class actasal thing Ibuprofen BP/EP has become one of three the most frequently used big ntipyretic analgesic medicines of the world.Its industrial process, the present domestic glycidic acid route of still continuing to use, low because of its productive rate, cost is high, will be eliminated gradually.US4,623,736 have proposed the novel process that molecular transposition under the catalysis prepares Ibuprofen BP/EP, its productive rate has been had increase substantially.
The technology of United States Patent (USP) is from starting raw material Isobuytel Benzene input, does not separate intermediate, and through chlorine ketone, ketal, molecular transposition, hydrolysis, acidifying under the catalysis are separated until the Ibuprofen BP/EP finished product, wherein:
1. the solvent of chlorine reactive ketone is a methylene dichloride, adds aqueous hydrochloric acid dissolving layering after the reaction, and the water dichloromethane extraction merges organic phase, and with alkali neutralization, washing, recovery alkyl halide, oily chlorine ketone changes down the step over to again.
2. the solvent of ketal reaction is a heptane, and sulfuric acid is made catalyst, reacts complete with the buck neutralization, heptane extraction water, and the organic phase washing gets the yellow oily ketal behind the recovery heptane and changes down the step over to.
3. molecular transposition adopts 2-ethyl acid zinc to make catalyst under the catalysis, almost under the diluent free situation, react, gained dark oil reaction mixture adsorbs catalyst, heptane dilution through flocculating aids, filtering solid, heptane liquid are made with extra care in heptane through circulation decolouring back, hydrolysis, acidifying, thick Ibuprofen BP/EP, in Isobuytel Benzene productive rate 82.8%.
Its weak point is:
1. reaction solvent incompatibility industrial requirement, the methylene dichloride boiling point is low, and only 39～41 ℃, high price and loss are big; The heptane high price.
2. to finish alkali neutralization, washing, wastewater flow rate big in reaction, and solvent loss is big.
3. the condition of molecular transposition is too harsh under the catalysis, is almost reacting under the diluent free situation, and product is the dark oil thing, and is of poor quality.
Purpose of the present invention is to overcome the deficiency of prior art, and it is lower to seek a reaction solvent toxicity, and price is more cheap, quantity of three wastes is few, and quality product is better than prior art, is suitable for industrialized production Ibuprofen BP/EP method.
The objective of the invention is to implement by following technical solution:
Development and design a kind of be starting raw material by Isobuytel Benzene, molecular transposition, hydrolysis, acidifying under chlorine ketone, ketal, catalysis, do not separate intermediate product, make the processing method of Ibuprofen BP/EP, it is characterized in that:
1. the zinc salt as catalyst is tosic acid zinc or zinc oxide or both mixtures,
2. the solvent of ketal, catalytically rearranging reaction is a sherwood oil,
Molecular transposition prepares the processing method of Ibuprofen BP/EP under the above-mentioned catalysis, it is characterized in that the weight ratio of described starting raw material and catalytically rearranging catalyst is:
1∶0.02～0.01。
Molecular transposition prepares the processing method of Ibuprofen BP/EP under the above-mentioned catalysis, and when it is characterized in that described zinc salt catalyst is the mixture of tosic acid zinc and zinc oxide, both weight ratios are:
Tosic acid zinc: zinc oxide-1: 0.5～1.
Molecular transposition prepares the processing method of Ibuprofen BP/EP under the above-mentioned catalysis, it is characterized in that described chlorine reactive ketone after, the layering that is dissolved in water, Petroleum ether extraction get chlorine ketone-sherwood oil liquid, are used for the next step.
Molecular transposition prepares the processing method of Ibuprofen BP/EP under the above-mentioned catalysis, it is characterized in that in the described ketal reaction, adopts sherwood oil to make solvent, and tosic acid or sulfuric acid are made catalyst.
Molecular transposition prepares the processing method of Ibuprofen BP/EP under the above-mentioned catalysis, it is characterized in that the Ibuprofen BP/EP crude product that makes is refining through Ethanol Method.Its reaction process is:
Technology of the present invention has following advantage compared with the prior art:
1. the reaction solvent of molecular transposition under chlorine ketone, ketal and the catalysis adapts to industrial requirement, and price is cheap than prior art.
2. technology is easy to be reasonable, and the aftertreatment layering is good, and wastewater flow rate is little, and solvent loss is few, and cost is low.
3. the catalyst of molecular transposition is selected for use rationally under the catalysis, and the end reaction crude product is a red oil, and quality is good, productive rate is high.
The present invention is further elaborated below in conjunction with embodiment:
[embodiment one]
Preparation chlorine ketone (1-chloroethyl-4-isobutyl benzophenone; 1-Chloroethyl-4-isobutyl-phenyl ketone)
In the reaction flask, adding aluminum chloride 36g and ethylene dichloride 33ml are cooled to-5 ℃ under stirring, and drip chlorpromazine chloride 30g, add the back and stir 15min, drip Isobuytel Benzene 28.8g at 0～-5 ℃, add the back and under this temperature, stir 1h, drip water 150ml dissolving at 0～10 ℃.Tell organic layer, wash twice with water, each 25ml reclaims ethylene dichloride.Merge mother liquor and aqueous extract, with the Petroleum ether extraction twice of 90～120 ℃ of boiling ranges, each 25ml, extracting solution washes twice with water, each 25m1.Extracting solution after the washing is incorporated in the chlorine ketone liquid that reclaims behind the ethylene dichloride, faint yellow chlorine ketone petroleum ether solution, gc analysis chlorine ketone content is amounted to pure chlorine ketone 46.52g, productive rate 96.99%.Water lotion is applied mechanically down and is criticized, and mother liquor reclaims aluminum chloride.
Preparation ketal (the neo-pentyl ketal of 1-chloroethyl-4-isobutyl benzophenone; Neopentyl ketal of thel-chloroethyl-4-isobutylphenyl ketone)
In the reaction flask that the reflux condensation mode water trap is arranged, add above-mentioned chlorine ketone sherwood oil liquid full dose, neopentyl glycol 31.2g, water 4ml, stir adding tosic acid 2.2g down, temperature rising reflux band water 6h, reaction is finished, be chilled to 0～5 ℃, filter, get faint yellow ketal petroleum ether solution, vapor-phase chromatography is surveyed content, amount to pure ketal 62.41g, productive rate 97.00%.
Preparation 3-chloro-2,2-dimethyl propyl ibuprofen ester (3-Chloro-2,2-dimethylpropyl ester ofIbuprofen)
Above-mentioned ketal petroleum ether solution adds tosic acid zinc 2.88g, stirs, and heats up and reclaims solvent, keeps 140～150 ℃ of 2～2.5h, molecular transposition is finished, and reduces to room temperature, adds diatomite 2g and sherwood oil 40ml, absorption 0.5h, filter, with petroleum ether twice, each 15ml must reset liquid.
Hydrolysis, acidifying, refining
Above-mentioned rearrangement petroleum ether solution full dose refluxes and stirs down, adds 50% caustic lye of soda 26g in about 10min, back hydrolysis 40min, add 3ml water,, filter, twice of petroleum ether of filter cake 0～5 ℃ of crystallization, each 15ml gets crude product Ibuprofen BP/EP sodium salt, gets 50g after doing.Add 8 times of hot water dissolvings, Lip river property carbon decoloring 30min filters, and washing, is filtered to PH2.0～5 ℃ crystallisation by cooling with hcl acidifying, gets crude product Ibuprofen BP/EP 40.2g, and content 95% is in Isobuytel Benzene productive rate 86.72%.Add 3～4 times and measure 70% ethanol thermosols, transfer to PH3～4 with phosphoric acid, activated carbon decolorizing filters, and 0～5 ℃ of crystallization is filtered, the distillation washing, the dry Ibuprofen BP/EP elaboration that gets is qualified by the full inspection of pharmacopeia
[embodiment two]
Preparation chlorine ketone is with example one.
Preparation ketal catalyst sulfuric acid 2.2ml, all the other are with example one.
When preparation 3-chloro-2,2-dimethyl propyl ibuprofen ester (rearrangement), catalyst zinc oxide 2.88g, all the other are with example one.Last crude product Ibuprofen BP/EP is in Isobuytel Benzene productive rate 86.07%.
[embodiment three]
Preparation chlorine ketone is with example one.
Preparation ketal catalyst sulfuric acid 2.2ml, all the other are with example one.
When preparation 3-chloro-2,2-dimethyl propyl ibuprofen ester (rearrangement), catalyst zinc oxide 0.72g, tosic acid zinc 1.44g, all the other are with example one.Last crude product Ibuprofen BP/EP is in Isobuytel Benzene productive rate 86.88%.
[embodiment four]
Preparation chlorine ketone is with example one.
Preparation ketal catalyst sulfuric acid 2.2ml, all the other are with example one.
When preparation 3-chloro-2,2-dimethyl propyl ibuprofen ester (rearrangement), catalyst zinc oxide 1.44g, tosic acid zinc 1.44g all the other with example one.Last crude product Ibuprofen BP/EP is in Isobuytel Benzene productive rate 86.03%.
[embodiment five]
Preparation chlorine ketone is with example one.
Preparation ketal catalyst tosic acid 2.2g, when all the other prepare 3-chloro-2,2-dimethyl propyl ibuprofen ester (rearrangement) with example, catalyst tosic acid zinc 0.58g, all the other are with example one.Last crude product Ibuprofen BP/EP is in Isobuytel Benzene productive rate 86.55%.
Claims (6)
1. one kind is starting raw material by Isobuytel Benzene, and molecular transposition, hydrolysis, acidifying under chlorine ketone, ketal, catalysis do not separate intermediate product, makes the processing method of Ibuprofen BP/EP, the invention is characterized in:
1.1. in the catalytically rearranging reaction, the zinc salt that is used as catalyst is tosic acid zinc or zinc oxide or both mixtures,
1.2. the solvent of ketal, catalytically rearranging reaction is a sherwood oil,
2. prepare the processing method of Ibuprofen BP/EP according to molecular transposition under the described catalysis of claim 1, it is characterized in that the weight ratio of described starting raw material and catalytically rearranging catalyst is: 1: 0.02～0.1.
3. the processing method for preparing Ibuprofen BP/EP according to molecular transposition under the described catalysis of claim 1, when it is characterized in that described zinc salt catalyst is the mixture of tosic acid zinc and zinc oxide, both weight ratios are: tosic acid zinc: zinc oxide=1: 0.5～1.
4. the processing method for preparing Ibuprofen BP/EP according to molecular transposition under the described catalysis of claim 1, it is characterized in that described chlorine reactive ketone after, the layering that is dissolved in water, Petroleum ether extraction get chlorine ketone-sherwood oil liquid, are used for the next step.
5. prepare the processing method of Ibuprofen BP/EP according to molecular transposition under the described catalysis of claim 1, it is characterized in that in the described ketal reaction, adopt sherwood oil to make solvent, tosic acid or sulfuric acid are made catalyst.
6. the processing method for preparing Ibuprofen BP/EP according to molecular transposition under the described catalysis of claim 1 is characterized in that the Ibuprofen BP/EP crude product that makes is refining through Ethanol Method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92106667 CN1031939C (en) | 1992-08-14 | 1992-08-14 | Process to prepare brufen by rearranging molecular under catalysis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92106667 CN1031939C (en) | 1992-08-14 | 1992-08-14 | Process to prepare brufen by rearranging molecular under catalysis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1082022A CN1082022A (en) | 1994-02-16 |
| CN1031939C true CN1031939C (en) | 1996-06-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92106667 Expired - Fee Related CN1031939C (en) | 1992-08-14 | 1992-08-14 | Process to prepare brufen by rearranging molecular under catalysis |
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| CN (1) | CN1031939C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850206A (en) * | 2012-09-07 | 2013-01-02 | 蚌埠丰原涂山制药有限公司 | Refinement method for ibuprofen |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315769C (en) * | 2005-01-18 | 2007-05-16 | 山东新华制药股份有限公司 | Environment-friendly synthesis process for 1- chloroethane-4-butylrubberbenzophenone |
| CN103183604B (en) * | 2011-12-28 | 2015-07-29 | 药源药物化学（上海）有限公司 | The preparation method of Vedaprofen |
| CN102701948B (en) * | 2012-06-14 | 2013-12-11 | 山东新华制药股份有限公司 | Refining method for ibuprofen production |
| CN102701949A (en) * | 2012-06-14 | 2012-10-03 | 山东新华制药股份有限公司 | Method for preparing 2-[4-(2-methyl-1-propenyl)phenyl]propionic acid |
| CN103880622B (en) * | 2012-12-19 | 2016-08-17 | 山东新华制药股份有限公司 | A kind of brufen process units and technique |
| 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 |
| CN104926609B (en) * | 2015-04-13 | 2016-08-03 | 青岛科技大学 | The method of neopentyl glycol mother solution and technological process thereof in a kind for the treatment of cloth ibuprofen synthesis procedure |
| CN105037078B (en) * | 2015-06-03 | 2016-09-28 | 青岛科技大学 | A kind of method reclaiming dichloromethane in chlorine ketone mother solution |
| CN107488094A (en) * | 2017-07-18 | 2017-12-19 | 青岛三瑞节能环保技术有限公司 | A kind of ibuprofen sodium salt centrifuge mother liquor petrochina ether recovery process and device |
| CN108285403A (en) * | 2018-03-24 | 2018-07-17 | 青岛科技大学 | Recycling petroleum ether and chlorhydrin energy saving technique in a kind of ibuprofen sodium salt centrifuge mother liquor |
| CN114471519B (en) * | 2022-02-11 | 2023-03-24 | 青岛科技大学 | Active zinc catalyst, preparation method thereof and application of active zinc catalyst in catalyzing ibuprofen rearrangement reaction |
-
1992
- 1992-08-14 CN CN 92106667 patent/CN1031939C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102850206A (en) * | 2012-09-07 | 2013-01-02 | 蚌埠丰原涂山制药有限公司 | Refinement method for ibuprofen |
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| CN1082022A (en) | 1994-02-16 |
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