CN102850206A - Refinement method for ibuprofen - Google Patents
Refinement method for ibuprofen Download PDFInfo
- Publication number
- CN102850206A CN102850206A CN2012103286603A CN201210328660A CN102850206A CN 102850206 A CN102850206 A CN 102850206A CN 2012103286603 A CN2012103286603 A CN 2012103286603A CN 201210328660 A CN201210328660 A CN 201210328660A CN 102850206 A CN102850206 A CN 102850206A
- Authority
- CN
- China
- Prior art keywords
- ibuprofen
- organic solvent
- recrystallization
- sherwood oil
- filter cake
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a refinement method for ibuprofen. The refinement method comprises the following steps: adding an ibuprofen crude product to an organic solvent, heating, cooling to a room temperature, carrying out cold preservation crystallization, and repeating the previous steps 2-5 times. With the method of the present invention, the high purity refinement product can be prepared, cost is low, purity of the prepared ibuprofen is more than 99.5% so as to extremely effectively improve the purity of the ibuprofen, and a high purity injection class ibuprofen compound is finally obtained so as to provide an injection raw material with high safety.
Description
Technical field
The present invention relates to the synthetic field of chemical drug, be specifically related to a kind of process for purification of Ibuprofen BP/EP.
Background technology
Ibuprofen BP/EP (Ibuprofen) is Non-steroidanalgetic drug.Its anti-inflammatory, analgesia, refrigeration function are respond well, and untoward reaction is less.Its chemical name is: 2-(4-isobutylphenyl) propionic acid, molecular formula is C
13H
18O
2, molecular weight is 206.28, has following chemical structural formula:
At present, Ibuprofen BP/EP is widespread use in the world, becomes one of global best-selling nonprescription drugs, and acetylsalicylic acid, Paracetamol are listed as antipyretic and analgesic three large pillar products together.Except Chinese Pharmacopoeia records, also by the multinational pharmacopeia income such as American and Britain, day.
Ibuprofen BP/EP goes on the market in Britain early than nineteen sixty-eight, and the manufacturer is Britain the Boots Co. PLC, and commodity are called Brufen.Because it has rheumatism and analgesic analgesic curative effect concurrently, and toxicity is low, all is better than acetylsalicylic acid and Paracetamol at aspects such as curative effect and side effects, thereby market enlarges rapidly.Ibuprofen BP/EP has its oneself characteristic in clinical application, lighter to GI side effect, and easily tolerance is that gastrointestinal irritation is lower in the non-steroidal anti-inflammatory drugs class medicine, but still idol has the gastrointestinal irritation report.
At present, most ibuprofen pharmaceutical is oral dosage form on the market, and when the patient can not take oral preparations, injection gave Ibuprofen BP/EP and just seems particularly important.For the gastrointestinal irritation that lowers Ibuprofen BP/EP and the demand that satisfies the clinical injection Ibuprofen BP/EP, synthetic and the purification of Ibuprofen BP/EP injection stage raw material just seems most important, because Ibuprofen BP/EP oral preparations raw material is now only arranged on the market, without the injection stage raw material, can not satisfy the demand of preparation injection, therefore preparing injection stage Ibuprofen BP/EP raw material is a problem demanding prompt solution.
The synthetic of Ibuprofen BP/EP has several different methods, but the more main method of domestic industry application is at present:
1, classical Ibuprofen BP/EP synthetic route (Boots method)
The method is take isobutyl-benzene as raw material, generate p-Isobutylphenyl methyl ketone through Friedel-Crafts reaction, generate 1-(4-isobutyl phenenyl) propionic aldehyde through reaching village's condensation (Darzens condensation) again, get Ibuprofen BP/EP at last or through oxidation, or by oximation reaction, make Ibuprofen BP/EP through hydrolysis again.
Pharmaceutical factory, China Changzhou and Xinhua pharmaceutical factory produced Ibuprofen BP/EP with above-mentioned route respectively.
But this synthetic route complex steps, raw material availability is low, power consumption is large.In addition, have a large amount of inorganic salt to produce, making with extra care of finished product is also very numerous and diverse, and production cost is high, pollutes more serious.
2, the synthetic Ibuprofen BP/EP of 1-(4-isobutyl phenenyl) ethanol carbonyl process (BHC method)
The method is to produce BHC technique by the Ibuprofen BP/EP that U.S. Hoechst-Celanese company and Boots company develop jointly; be described as the successful model in this process; and the change synthetic route that therefore obtains the 1997 annual U.S. " presidential Green Chemistry Challenge Awards " is encouraged; the method makes Ibuprofen BP/EP take Isobuytel Benzene as raw material through Fu Ke acidylate, catalytic hydrogenating reduction and catalyzed carbonylation three-step reaction with Acetyl Chloride 98Min..
Other synthetic method has carbonylation of olefin method, halohydrocarbon carbonylation method, hydrogenation of olefins method, propylene oxide rearrangement method, enzyme process etc., and this several method is used seldom in the actual industrial production at home.
The Ibuprofen BP/EP that above-mentioned synthetic method obtains is oral level, and purity is lower, is not suitable as the injection raw material, is an importance that guarantees the injection security and effectively reduce foreign matter content in the preparation of injection.
CN201110386935.4 discloses a kind of method for making of Sodium ibuprofen compound: 1, and raw material Sodium ibuprofen compound is soluble in water, add solvent and extract, then separate the organic phase that contains impurity, obtain water; 2, the alkoxide that adds sodium to above-mentioned aqueous phase is processed, the optional heating in treating processes, and then cooling is filtered, and obtains filtrate;
3, the described Sodium ibuprofen aqueous solution is carried out the negative pressure crystallization,, under the temperature of negative pressure and rising, concentrate first for this reason, then reduce temperature, add Sodium ibuprofen compound crystal seed, when tiny crystal grain occurring, keep temperature until obtain desirable crystal, afterwards the crystal of separating out is separated, washing, drying obtains refining Sodium ibuprofen compound.Described organic solvent is one or more in ethyl acetate, ether, the hexanaphthene.
CN200910096554.5 discloses a kind of preparation method of highly purified aminoprofen, may further comprise the steps: (1) acyl chloride reaction: suc as formula the Ibuprofen BP/EP shown in (II) in solvent toluene, take dimethyl formamide as catalyzer, with SOCl
260～90 ℃ of lower stirring reactions 4～10 hours, underpressure distillation desolventizing toluene got Ibuprofen BP/EP acyl chlorides crude product; (2) amidate action: with Ibuprofen BP/EP acyl chlorides crude product CH
2Cl
2Dissolving under ice bath, slowly splashes into and is dissolved with thanomin and K
2CO
3CH
2Cl
2Suspension liquid in, then reacted under the room temperature 6～24 hours, after reaction finished, the reaction solution separating treatment obtained suc as formula the aminoprofen shown in (I).This patent is Ibuprofen BP/EP and other solvent reactions, and then separates, and finally obtains aminoprofen.
Therefore, make with extra care and purifying on original oral level Ibuprofen BP/EP raw material basis, prepare a kind of highly purified injection stage Ibuprofen BP/EP raw material and have higher technology content and marketable value.
Summary of the invention
An object of the present invention is to provide a kind of process for purification of Ibuprofen BP/EP.
The process for purification of Ibuprofen BP/EP provided by the invention may further comprise the steps: the Ibuprofen BP/EP crude product, add organic solvent, and heating is cooled to room temperature, the refrigeration crystallization, then suction filtration repeats step 2-5 time of front.
In the aforesaid method:
Described Ibuprofen BP/EP crude product is the Ibuprofen BP/EP of the oral level of Ibuprofen BP/EP, and wherein the content of Ibuprofen BP/EP is more than 98.5%;
Described organic solvent is hexanaphthene, normal heptane, vinyl acetic monomer, chloroform, benzene, ether or sherwood oil, is preferably sherwood oil;
The consumption of described organic solvent, the envelope-bulk to weight ratio of organic solvent and Ibuprofen BP/EP crude product is 3-8: 1 (ml: g); Be preferably 5: 1;
Described Heating temperature is 50-80 ℃, is preferably 70 ℃;
The temperature of described refrigeration crystallization is-10-0 ℃, be preferably-5--1 ℃;
How many number of times of described recrystallization carries out according to foreign matter content in the Ibuprofen BP/EP, and foreign matter content is many, can carry out repeatedly, is preferably 2-5 time, more preferably 3 times, gets final product.
Concrete, the process for purification of Ibuprofen BP/EP provided by the invention may further comprise the steps:
1) recrystallization first
The Ibuprofen BP/EP crude product is joined in the organic solvent, be heated to 50-80 ℃, stirring and dissolving is to homogeneous phase, after leaving standstill 0.3-2h, naturally cool to room temperature, reaction mixture is placed-10-0 ℃ crystallization, filter, under the ice bath state, use the organic solvent washing solid, suction filtration is drained, reclaim filtrate, filter cake is air-dry;
2) secondary recrystallization
With the product behind recrystallization, and after organic solvent mixed, secondary recrystallization was carried out in heating, and operation is with 1), filter cake is air-dry;
3) three recrystallizations
With the product behind the secondary recrystallization, and carry out recrystallization three times after the organic solvent mixing, operate same step 1), after draining, filtrate recovery, filter cake namely get highly purified Ibuprofen BP/EP after vacuum-drying.
Described step 1) in:
During with the organic solvent washing solid, described organic solvent is hexanaphthene, normal heptane, vinyl acetic monomer, chloroform, benzene, ether or sherwood oil, be preferably sherwood oil, 60-90 ℃ sherwood oil more preferably, sherwood oil is distinguished according to boiling point, and it is the interior sherwood oil of this boiling spread that the present invention has the sherwood oil of choosing most; Consumption is that the envelope-bulk to weight ratio of described organic solvent and Ibuprofen BP/EP crude product is 3-8: 1 (ml: g), can be identical with the organic solvent of front, also can be different;
Speed during suction filtration is about 100ml/min.
Preferably, the process for purification of Ibuprofen BP/EP provided by the invention may further comprise the steps:
1) recrystallization first
The oral raw material of Ibuprofen BP/EP is slowly joined in the sherwood oil, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, after leaving standstill 0.5h, naturally cool to room temperature, reaction mixture is placed-5--1 ℃ crystallization 1.5h, namely the adularescent solid is separated out, filter, use the petroleum ether solid, slow suction filtration is after draining, reclaim filtrate, filter cake is air-dry;
2) secondary recrystallization
With the product behind recrystallization, and sherwood oil carries out secondary recrystallization after mixing, and operation is with 1), filter cake is air-dry;
(3) three recrystallizations
With the product behind the secondary recrystallization, and carry out recrystallization three times after the sherwood oil mixing, operation is with (1), and after draining, filtrate recovery, filter cake namely get highly purified Ibuprofen BP/EP after vacuum-drying.
In step 3) in, if obvious insolubles is arranged when being heated to 70 ℃, carry out heat filtering when being cooled to 30-40 ℃, physical impurity is removed;
After the filtrate of three recrystallizations can merge, decompression steamed organic solvent (40 ℃ steam), and the gained organic solvent can reuse; To the gained solid still can polyploid long-pending organic solvent, make with extra care according to above-mentioned recrystallizing technology, can meet the sterling of injection requirement behind three recrystallizations.
The process for purification of Ibuprofen BP/EP provided by the invention has the following advantages:
1, it is recyclable that the solvent that uses in the method provided by the invention is preferably sherwood oil, and recycling, can reduce to greatest extent the production cost of enterprise, and can reduce the pollution to environment.Be dissolved in the Ibuprofen BP/EP raw material in the filtrate, can again again put in the next treating process after organic solvent reclaims, recycle can improve the refining yield of Ibuprofen BP/EP, also can reduce the production cost of manufacturing enterprise simultaneously.
Now extract the solvent sherwood oil and mainly be divided into three kinds according to its boiling range: sherwood oil (30-60 ℃), sherwood oil (60-90 ℃), sherwood oil (90-120 ℃), process for purification need be heated to 70 ℃ among the present invention, sherwood oil (30-60 ℃) is 30-60 ℃ because of its boiling range, in the time of 70 ℃, volatilized, be not suitable for using, and its boiling range of sherwood oil (90-120 ℃) is higher, in the time of 70 ℃, its extraction efficiency is not high, but its boiling range of sherwood oil (60-90 ℃) is 60-90 ℃, is in gas 70 ℃ of fashion, the liquid criticality, at this moment, its extraction efficiency is relatively high, so the used extraction solvent of the present invention is preferably sherwood oil (60-90 ℃).
Method provided by the invention, after the recycle, whole technological process total recovery surpasses 80%.Method provided by the invention can make highly purified highly finished product, and with low cost, the Ibuprofen BP/EP purity that makes reaches more than 99.5%, very effectively improved Ibuprofen BP/EP purity, finally obtained a kind of Ibuprofen BP/EP compound of high purity injection stage, thereby safe injection raw material is provided.
2, simple, the easy handling of the inventive method, but raw material and the utilization of solvent recirculation are suitable for large-scale industrial production.
3, need to prove, when if process for refining provided by the invention does not meet the requirements of situation at three recrystallization rear impurities of production appearance, may what be relevant with foreign matter content in the Ibuprofen BP/EP starting raw material, can increase recrystallization number of times 1-2 time to conforming with the impurity requirement.Frontly carry out impurity after refining twice and detect, whenever refining one-time detection is once later on.If the initial impurity of raw material is less, may need the number of times made with extra care also less.
4, CN201010235320.7 discloses a kind of process for purification of ibuprofen for injection, after oral level Ibuprofen BP/EP usefulness solvent heating for dissolving, filtered while hot after the adding charcoal absorption, after the filtrate cooling, crystallization under-20-30 ℃ environment, collect filter cake after again filtering, use the warm water washing post-drying, namely get ibuprofen for injection.This method has lowered raw material availability greatly owing to use charcoal absorption, has reduced total recovery; Finished product with warm water washing after again the oven dry, increased the content of moisture content in the finished product; Oven dry, easily bring degraded product to finished product, and the inventive method is all used volatile organic solvent in the whole technological process, be difficult for residuing in the finished product, and need not water flushing, oven dry, greatly reduce moisture content and the possibility of bringing impurity because of process for refining in producing eventually, and the present invention's charcoal absorption, improved raw material availability, and whole technique Raw and recycled solvent when having reduced environmental pollution, have also improved the utilization ratio of raw material.
Description of drawings
Fig. 1: Ibuprofen BP/EP highly finished product IR spectrogram;
Fig. 2: Ibuprofen BP/EP highly finished product H-NMR (CDCl
3) figure;
Fig. 3: Ibuprofen BP/EP highly finished product MS figure;
Fig. 4: Ibuprofen BP/EP highly finished product purity detecting HPLC color atlas.
Embodiment
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.
Embodiment 1: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) Ibuprofen BP/EP meal 1000g (content is 98.80%) is slowly joined (60-90 ℃ of the sherwood oil of 5L, the classification of the sherwood oil just distinguished according to boiling point) in, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, after leaving standstill 0.5h, naturally cool to room temperature, reaction mixture is placed-5--1 ℃ crystallization 1.5h, be that the adularescent solid is separated out, filter that the sherwood oil (60-90 ℃) of crossing with ice bath washs solid, slow suction filtration (the about 100ml/min of speed), after draining, obtain filter cake, reclaim filtrate;
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the sherwood oil (60-90 ℃) of 5L) twice of operation;
After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 458.8g after vacuum-drying, and yield is 45.88%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2010).Chromatographic condition and system suitability: be weighting agent (4.6 * 250mm, 5 μ m) with octadecylsilane chemically bonded silica, take the 1% Mono Chloro Acetic Acid aqueous solution (regulating pH value to 3.0 with ammoniacal liquor): acetonitrile (40: 60) is as moving phase; The detection wavelength is 254nm; Flow velocity is per minute 2ml.It is an amount of, accurately weighed to get Ibuprofen BP/EP related substance C reference substance, adds acetonitrile and makes every 1ml each contains the solution of 0.15mg approximately, as related substance C reference substance stock solution.Get need testing solution 5ml, add related substance C reference substance stock solution 0.1ml, shake up, get 10 μ l injection liquid chromatographies, the record color atlas.The relative retention time of Ibuprofen BP/EP related substance C is about 1.68; Each peak tailing factor should be not more than 2.5, and number of theoretical plate calculates by the Ibuprofen BP/EP peak and is not less than 2500.
Assay method: precision takes by weighing the about 30mg of Ibuprofen BP/EP highly finished product, puts in the 10ml measuring bottle, adds moving phase and makes in right amount dissolving and be diluted to scale, shakes up, as to need testing solution; Precision is measured related substance C reference substance stock solution 2ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, in contrast product solution.Precision is measured 10 μ l injection liquid chromatographies, the record color atlas.Desolventize outside the peak, calculate maximum single impurity by area normalization method and must not cross 0.1%, always must not mix 0.5%.
Final detection result shows that the content of the Ibuprofen BP/EP that embodiment 1 provides is 99.86%, maximum single impurity only 0.1%, total assorted only 0.5%;
Embodiment 2: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) the oral raw material 1000g of Ibuprofen BP/EP (content is 98.80%) is slowly joined in the normal heptane of 5L, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, leave standstill 0.5h after, naturally cool to room temperature, reaction mixture is placed-5--1 ℃, crystallization 1.5h, namely the adularescent solid is separated out, filter, slow suction filtration (the about 100ml/min of speed) behind the normal heptane washing solid of crossing with ice bath, after draining, recovery filtrate.
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the normal heptane of 5 times (envelope-bulk to weight ratios)) twice of operation.After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 399.9g after vacuum-drying, and yield is 39.99%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is with embodiment 1, and final detection result shows that the content of the Ibuprofen BP/EP that embodiment 2 provides is 99.81%, maximum single impurity only 0.1%, total assorted only 0.5%.
Embodiment 3: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) the oral raw material 1000g of Ibuprofen BP/EP (content is 98.80%) is slowly joined in the sherwood oil (60-90 ℃) of 3L, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, after leaving standstill 0.5h, naturally cool to room temperature, reaction mixture is placed-5--1 ℃ crystallization 1.5h, namely the adularescent solid is separated out, filter, with sherwood oil (60-90 ℃) the washing solid that ice bath is crossed, slow suction filtration (the about 100ml/min of speed) is after draining, obtain filter cake, reclaim filtrate;
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the sherwood oil (60-90 ℃) of 3L) twice of operation.
After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 408.6g after vacuum-drying, and yield is 40.86%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is with embodiment 1, and final detection result shows that the content of the Ibuprofen BP/EP that embodiment 3 provides is 99.64%, maximum single impurity only 0.1%, total assorted only 0.5%.
Embodiment 4: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) the oral raw material 1000g of Ibuprofen BP/EP (content is 98.80%) is slowly joined in the sherwood oil (60-90 ℃) of 8L, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, leave standstill 0.5h after, naturally cool to room temperature, reaction mixture is placed-5--1 ℃ crystallization 1.5h, be that the adularescent solid is separated out, filter, slow suction filtration (the about 100ml/min of speed) behind sherwood oil (60-90 ℃) the washing solid of crossing with ice bath, after draining, reclaim filtrate.
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the sherwood oil (60-90 ℃) of 8 times (envelope-bulk to weight ratios)) twice of operation.After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 396.4g after vacuum-drying, and yield is 39.64%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is with embodiment 1, and final detection result shows that the content of the Ibuprofen BP/EP that embodiment 4 provides is 99.72%, maximum single impurity only 0.1%, total assorted only 0.5%.
Embodiment 5: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) the oral raw material 1000g of Ibuprofen BP/EP (content is 98.80%) is slowly joined in the sherwood oil (60-90 ℃) of 5L, be heated to 50 ℃, stirring and dissolving is to homogeneous phase, leave standstill 0.5h after, naturally cool to room temperature, reaction mixture is placed-5--1 ℃ crystallization 1.5h, be that the adularescent solid is separated out, filter, with ice bath cross sherwood oil (60-90 ℃) washing solid after slow suction filtration (the about 100ml/min of speed), after draining, reclaim filtrate.
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the sherwood oil (60-90 ℃) of 5 times (envelope-bulk to weight ratios)) twice of operation.
After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 414.7g after vacuum-drying, and yield is 41.47%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is with embodiment 1, and final detection result shows that the content of the Ibuprofen BP/EP that embodiment 5 provides is 99.69%, maximum single impurity only 0.1%, total assorted only 0.5%.
Embodiment 6: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) the oral raw material 1000g of Ibuprofen BP/EP (content is 98.80%) is slowly joined in the sherwood oil (60-90 ℃) of 5L, be heated to 80 ℃, stirring and dissolving is to homogeneous phase, leave standstill 0.5h after, naturally cool to room temperature, reaction mixture is placed-5--1 ℃ crystallization 1.5h, be that the adularescent solid is separated out, filter, slow suction filtration (the about 100ml/min of speed) behind sherwood oil (60-90 ℃) the washing solid of crossing with ice bath, after draining, reclaim filtrate.
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the sherwood oil (60-90 ℃) of 5 times (envelope-bulk to weight ratios)) twice of operation.
After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 417.5g after vacuum-drying, and yield is 41.75%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is with embodiment 1, and final detection result shows that the content of the Ibuprofen BP/EP that embodiment 6 provides is 99.67%, maximum single impurity only 0.1%, total assorted only 0.5%.
Embodiment 7: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) the oral raw material 1000g of Ibuprofen BP/EP (content is 98.80%) is slowly joined in the sherwood oil (60-90 ℃) of 5L, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, leave standstill 0.5h after, naturally cool to room temperature, reaction mixture is placed-1-0 ℃ crystallization 1.5h, be that the adularescent solid is separated out, filter, slow suction filtration (the about 100ml/min of speed) behind sherwood oil (60-90 ℃) the washing solid of crossing with ice bath, after draining, reclaim filtrate.
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the sherwood oil (60-90 ℃) of 5 times (envelope-bulk to weight ratios)) twice of operation.
After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 402.6g after vacuum-drying, and yield is 40.26%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is with embodiment 1, and final detection result shows that the content of the Ibuprofen BP/EP that embodiment 7 provides is 99.77%, maximum single impurity only 0.1%, total assorted only 0.5%.
Embodiment 8: the process for purification of Ibuprofen BP/EP
1, process for purification:
1) the oral raw material 1000g of Ibuprofen BP/EP (content is 98.80%) is slowly joined in the sherwood oil (60-90 ℃) of 5L, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, leave standstill 0.5h after, naturally cool to room temperature, reaction mixture is placed-10--5 ℃ crystallization 1.5h, be that the adularescent solid is separated out, filter, slow suction filtration (the about 100ml/min of speed) behind sherwood oil (60-90 ℃) the washing solid of crossing with ice bath, after draining, reclaim filtrate.
2) filter cake carries out recrystallization, repeating step 1 after again mixing with the sherwood oil (60-90 ℃) of 5 times (envelope-bulk to weight ratios)) twice of operation.
After three crystallizations, filter cake namely gets highly purified Ibuprofen BP/EP highly finished product 400.7g after vacuum-drying, and yield is 40.07%.
2, the detection of Ibuprofen BP/EP purity:
Detection method is with embodiment 1, and final detection result shows that the content of the Ibuprofen BP/EP that embodiment 8 provides is 99.82%, maximum single impurity only 0.1%, total assorted only 0.5%.
Experimental example: the structural identification of Ibuprofen BP/EP highly finished product
Ibuprofen BP/EP highly finished product to embodiment 1 preparation carry out respectively the analyses of ultimate analysis, the discriminating of IR spectrum, H-NMR hydrogen spectrum analysis, interpretation of mass spectra and high performance liquid chromatography (HPLC), data are as follows, and the discriminating of IR spectrum, H-NMR hydrogen spectrum analysis, MS and HPLC collection of illustrative plates are seen accompanying drawing 1-4.
Ultimate analysis: theoretical value C:75.69%, H:8.80%;
Experimental value C:75.75%, H:8.85%.
IR(KBr)cm
-1：2966，1720，1509，1452，1366，1329，1202，1169，780。H-NMR (CDCl
3) δ: 0.9 (s, 6H, CH (CH
3)
2); 1.50 (d, 3H, CH
3CH); 1.83 (m, 1H, (CH
3)
2CH); 2.5 (d, 2H, CH
2CH); 3.7 (q, 1H, CH
3CH); (7.0-7.3 dd, 4H are four hydrogen on the phenyl ring).
MS (m/z): 206 is molecular ion peak, and 163,161,119,107,91,77,43 grades all can obtain reasonably cracking parsing.
According to Ibuprofen BP/EP highly finished product structural identification Fig. 1-3, can find out, gained Ibuprofen BP/EP highly finished product infrared spectrogram of the present invention concentrates each peak of Ibuprofen BP/EP infrared spectrogram corresponding with Chinese medicine infrared spectra, the result is corresponding with the Ibuprofen BP/EP structural formula for H-NMR hydrogen spectrum analysis, fragment ion peak is all rationally resolved in the mass spectroscopy, having proved conclusively products therefrom is Ibuprofen BP/EP, and in treating process, the Ibuprofen BP/EP chemical structure does not change.In addition, can find out that by refined products HPLC collection of illustrative plates products therefrom purity of the present invention is higher, the area normalization method integration data shows, the main peak area accounts for 99.86% in the embodiment 1 product HPLC color atlas, and the expression embodiment of the invention 1 gained Ibuprofen BP/EP highly finished product purity is 99.86%.
Equally, the Ibuprofen BP/EP that all the other embodiment are provided carries out structural identification, and the result is with embodiment 1.
Although, above used general explanation, embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. the process for purification of an Ibuprofen BP/EP is characterized in that, this process for purification may further comprise the steps: the Ibuprofen BP/EP crude product, add organic solvent, and heating is cooled to room temperature, the refrigeration crystallization, then suction filtration repeats step 2-5 time of front.
2. process for purification according to claim 1 is characterized in that, described Ibuprofen BP/EP crude product is the Ibuprofen BP/EP of the oral level of Ibuprofen BP/EP, and wherein the content of Ibuprofen BP/EP is more than 98.5%.
3. process for purification according to claim 1 is characterized in that, described organic solvent is hexanaphthene, normal heptane, vinyl acetic monomer, chloroform, benzene, ether or sherwood oil.
4. process for purification according to claim 3 is characterized in that, described organic solvent is sherwood oil.
5. process for purification according to claim 1 is characterized in that, the envelope-bulk to weight ratio of described organic solvent and Ibuprofen BP/EP crude product is 3-8: 1.
6. process for purification according to claim 5 is characterized in that, the envelope-bulk to weight ratio of described organic solvent and Ibuprofen BP/EP crude product is 5: 1.
7. process for purification according to claim 1 is characterized in that, described Heating temperature is 50-80 ℃, is preferably 70 ℃.
8. process for purification according to claim 1 is characterized in that, the temperature of described refrigeration crystallization is-10-0 ℃, is preferably-5--1 ℃.
9. each described process for purification according to claim 1-8 is characterized in that the method may further comprise the steps:
1) recrystallization first
The Ibuprofen BP/EP crude product is joined in the organic solvent, be heated to 50-80 ℃, stirring and dissolving is to homogeneous phase, after leaving standstill 0.3-2h, naturally cool to room temperature, reaction mixture is placed-10-0 ℃ crystallization, filter, under the ice bath state, use the organic solvent washing solid, suction filtration is drained, reclaim filtrate, filter cake is air-dry;
2) secondary recrystallization
With the product behind recrystallization, and after organic solvent mixed, secondary recrystallization was carried out in heating, and operation is with 1), filter cake is air-dry;
3) three recrystallizations
With the product behind the secondary recrystallization, and carry out recrystallization three times after the organic solvent mixing, operate same step 1), after draining, filtrate is reclaimed, and filter cake namely gets highly purified Ibuprofen BP/EP after vacuum-drying.
10. process for purification according to claim 9 is characterized in that, the method may further comprise the steps:
1) recrystallization first
The oral raw material of Ibuprofen BP/EP is slowly joined in the sherwood oil, be heated to 70 ℃, stirring and dissolving is to homogeneous phase, leave standstill 0.5h, naturally cool to room temperature, reaction mixture is placed-5-1 ℃ of crystallization 1.5h, namely the adularescent solid is separated out, filter, use the petroleum ether solid, suction filtration is after draining, reclaim filtrate, filter cake is air-dry;
2) secondary recrystallization
With the product behind recrystallization, and sherwood oil carries out secondary recrystallization after mixing, and operation is with 1), filter cake is air-dry;
3) three recrystallizations
With the product behind the secondary recrystallization, and carry out recrystallization three times after the sherwood oil mixing, operation is with (1), and after draining, filtrate recovery, filter cake namely get highly purified Ibuprofen BP/EP after vacuum-drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103286603A CN102850206A (en) | 2012-09-07 | 2012-09-07 | Refinement method for ibuprofen |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012103286603A CN102850206A (en) | 2012-09-07 | 2012-09-07 | Refinement method for ibuprofen |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102850206A true CN102850206A (en) | 2013-01-02 |
Family
ID=47397245
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012103286603A Pending CN102850206A (en) | 2012-09-07 | 2012-09-07 | Refinement method for ibuprofen |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102850206A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319327A (en) * | 2013-07-12 | 2013-09-25 | 四川省惠达药业有限公司 | Ibuprofen compound, and pharmaceutical composition and preparation method thereof |
| CN114195633A (en) * | 2021-12-24 | 2022-03-18 | 浙江新和成股份有限公司 | Synthesis method of ibuprofen impurity F |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031939C (en) * | 1992-08-14 | 1996-06-05 | 山东新华制药厂 | Process to prepare brufen by rearranging molecular under catalysis |
| CN101885680A (en) * | 2010-07-26 | 2010-11-17 | 石家庄中硕药业集团有限公司 | Method for refining ibuprofen for injection |
| CN102557918A (en) * | 2011-11-28 | 2012-07-11 | 海南永田药物研究院有限公司 | Ibuprofen sodium compound and new preparation method thereof |
-
2012
- 2012-09-07 CN CN2012103286603A patent/CN102850206A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031939C (en) * | 1992-08-14 | 1996-06-05 | 山东新华制药厂 | Process to prepare brufen by rearranging molecular under catalysis |
| CN101885680A (en) * | 2010-07-26 | 2010-11-17 | 石家庄中硕药业集团有限公司 | Method for refining ibuprofen for injection |
| CN102557918A (en) * | 2011-11-28 | 2012-07-11 | 海南永田药物研究院有限公司 | Ibuprofen sodium compound and new preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 山东新华制药厂: "消炎镇痛药布洛芬的合成", 《医药工业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319327A (en) * | 2013-07-12 | 2013-09-25 | 四川省惠达药业有限公司 | Ibuprofen compound, and pharmaceutical composition and preparation method thereof |
| CN114195633A (en) * | 2021-12-24 | 2022-03-18 | 浙江新和成股份有限公司 | Synthesis method of ibuprofen impurity F |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106896164A (en) | A kind of razaxaban and the assay method about material | |
| CN108017583A (en) | A kind of preparation method for winning U.S. | |
| Ma et al. | Process intensification and waste minimization for ibuprofen synthesis process | |
| CN109293574A (en) | A kind of dehydroabietic acid aryl amine benzimidizole derivatives with anti-tumor activity and its preparation method and application | |
| CN105085373A (en) | Purification method for Apremilast products | |
| CN104892614B (en) | A kind of synthetic method of 6H iso-indoles simultaneously ketone derivatives of [2,1 α] indoles 6 | |
| CN102367236A (en) | Synthesizing technology of donepezil hydrochloride | |
| CN102850206A (en) | Refinement method for ibuprofen | |
| CN105949118A (en) | Preparation method of 2-aryl quinoline derivatives | |
| CN102432516B (en) | Method for refining oxiracetam | |
| CN104327067A (en) | Preparation method of amorphous dasatinib | |
| CN107382875A (en) | A kind of synthetic method of rosuvastain calcium chiral isomer impurity | |
| CN112047942B (en) | Synthesis method of 7-fluoroimidazo [1,2-A ] pyridine | |
| CN102924255A (en) | Method for preparing 9-fluorenone through liquid-phase oxidation | |
| CN109694311B (en) | Method for synthesizing isoliquiritigenin | |
| CN111892488A (en) | Method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone | |
| CN113527064A (en) | Preparation method of phloroglucinol | |
| CN105949146A (en) | Pleuromutilin-tizoxanide hybrid drug and preparation method thereof | |
| CN102206185B (en) | Process for refining bendazac lysine and analogs thereof | |
| CN107089912B (en) | Method for selectively catalyzing and synthesizing mandelate compound by metallocene complex | |
| CN101792451A (en) | Full synthesis method of 4'',5''-dihydroxyl-5-methoxyl-[6'',6''-dimethyl pyran (2'',3'':7,8)] Hirtellanine A | |
| CN102558189B (en) | Refining method of methyhaaltrexone bromide | |
| CN103755617A (en) | Method for preparing key impurity of ezetimibe | |
| CN104230882B (en) | A kind of preparation method of duloxetine hydrochloride impurity | |
| CN110256387B (en) | Preparation method of medical intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130102 |