CN110041191A - A kind of purification process of pelubiprofen - Google Patents
A kind of purification process of pelubiprofen Download PDFInfo
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- CN110041191A CN110041191A CN201910331050.0A CN201910331050A CN110041191A CN 110041191 A CN110041191 A CN 110041191A CN 201910331050 A CN201910331050 A CN 201910331050A CN 110041191 A CN110041191 A CN 110041191A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
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Abstract
This application discloses a kind of purification process of pelubiprofen comprising mixed solvent is added in pelubiprofen crude product, by stirring, crystallization, the pelubiprofen for filtering and being dried to obtain purifying.Mixed solvent is made of intensive polar solvent, weak polar solvent, atent solvent.The purification process of the pelubiprofen of the application, the technological gap of current pelubiprofen purification art is filled up, solves the not no issues of purification of the pelubiprofen of reported literature for a long time, and by using three kinds of solvent collocation mixing, it disposably solves the problems, such as to remove highly polar impurity, low pole impurity in pelubiprofen production, improve pelubiprofen yield, and have found an equalization point between purity is high and high income.
Description
Technical field
The invention belongs to chemical pharmacy fields, and in particular to a kind of purification process of pelubiprofen and its application.
Background technique
Pelubiprofen (Pelubiprofen) also has title training Shandong than ibuprofen, and structural formula I is shown below.
Chemical name are as follows: (±)-(E) -2- [4- (2- (oxo-cyclohex fork ylmethyl)-phenyl] propionic acid, pelubiprofen are
Non-steroidal analgesia and anti-inflammatory agent (NSAIDs), are to be derived by 2- phenylpropionic acid intermediate, therefore are 2- arylpropionic acid men
The member of race is also a kind of racemic prodrug, has analgesia, anti-inflammatory effect.It is reported that pelubiprofen is than other non-steroidals
Class anti-inflammatory and antalgic alexipyretic such as loxoprofen, Ketoprofen, brufen and naproxen have higher pharmacological action and tolerance.Training
Than the III clinical trial phase result table compared with the efficacy and saferry of ibuprofen and celecoxib in patient with rheumatoid arthritis
Bright, pelubiprofen is suitable with celecoxib effect in mitigation pain and the alleviation stiff aspect of patient with rheumatoid arthritis.
Pelubiprofen is a kind of non-steroid anti-inflammatory drug (NSAIDs), is the prodrug of 2- arylpropionic acid, to cyclooxygenase-2
Activity has the function of relative selectivity.In the macrophage of LPS induction and the acute inflammation rat model of carrageenan induction
Inflammatory mediator Study on Molecular Mechanism show pelubiprofen participate in COX activity and TAK1-IKK-NF-kB approach dual suppression
System, discloses the molecular basis of the anti-inflammatory property of pelubiprofen.
4 kinds of metabolins of pelubiprofen include saturated ketone (M-A), unsaturated alcohol (M-B), cis-alcohol (M-C) and trans- alcohol (M-
D).Major metabolite in human plasma is M-B, M-C and M-D, and half-life period (t1/2) is respectively 0.9,2.6 and 1.2h.Urine
Overall recovery be dosage 26%, but within 48 hours the variation of CS-670 less than 2%.In addition, with chiral reagent derivatization
Afterwards, the absolute configuration of metabolin is detected by HPLC, the results showed that pelubiprofen is easy to the chirality by 2- arylpropionic acid part
The Stereoselective reduction of α in conversion and human body, alpha, beta-unsaturated ketone part carry out bioconversion.
In the clinical test of Human Osteoarthritis, (in March, 2005, six South Korea cured pelubiprofen to during in April, 2006
Institute has carried out III clinical trial phase, 228 Human Osteoarthritis) data show that the drug is safe and effective, with Diclofenac
Sodium has similar feature, and hemorrhage of gastrointestinal tract side effect is low, and symptom can be significantly relieved pain in clinical test.Pei Biluo
III clinical trial phase compared with the fragrant efficacy and saferry with celecoxib in patient with rheumatoid arthritis the result shows that,
Pelubiprofen is suitable with celecoxib effect in mitigation pain and the alleviation stiff aspect of patient with rheumatoid arthritis, but Pei Biluo
Sweet smell group adverse drug reaction is higher than celecoxib group.
Pelubiprofen compound is first disclosed as (the Japanese patent application No. 1977- of Japanese patent registration number 1167548
98121) and in Japanese patent registration number 1637767 (Japanese patent application No. 1984-142567).The conjunction of pelubiprofen compound
It is many at route document report, but the purification process about pelubiprofen obtains the product of high-purity then without relevant report.
United States Patent (USP) US4673761 is disclosed by 1- morpholine cyclohexene with 2-(to Fonnylphenyl) propionic acid reacts, pass through ethyl acetate
It is recrystallized with n-hexane, yield 81% does not report purity；United States Patent (USP) US4365076 discloses cyclohexanone and ethyl 2-(to first
Aminosulfonylphenyl) propionic ester reaction, then sour water solution, column chromatographic purifying, also have no that purity is reported.The public affairs such as Atsusuke Terada
" the Synthesis and Antiinflammatory Activity of [(Cycloalky lmethyl) for the document opened
Phenyl] acetic Acids and Related Compounds " (" J. Med. Chem. " 1984,27,212), is introduced
By 1- morpholine cyclohexene with ethyl 2-(to Fonnylphenyl) propionic ester reacts the route for generating pelubiprofen.
Chinese patent application CN201310727477.5 discloses a kind of refining methd of (S)-ibuprofen comprising have by
(S)-ibuprofen crude product is dissolved in organic solvent 1, heats most 30~60 DEG C, stirring, until system clarification dropwise addition sodium hydroxide is molten
Liquid tune pH is 9~10, and drop finishes, and being cooled to T2 is -10~10 DEG C, and stirring and crystallizing 1~4 hour, (S)-ibuprofen sodium is obtained by filtration
Salt；Then gained (S)-ibuprofen sodium salt is dissolved in pure water by it, addition organic solvent 2, and the lower dropwise addition hydrochloric acid tune pH to 1 of stirring~
2；Liquid separation takes organic phase to be evaporated under reduced pressure, and obtaining solid is (S)-ibuprofen sterling；Organic solvent 1 is ethyl alcohol, methanol and third
At least one of ketone solvent；Concentration is 0.1~1g/ml；Organic solvent 2 is in ethyl acetate, methylene chloride and n-hexane
At least one solvent.But the object of its application is brufen, chemical structure has larger with the pelubiprofen that we uses
Difference, and it has an addition basic solvent, i.e., dropwise addition sodium hydroxide the step of, be that can not be applicable in the invention of this point at this end
's.
Preparation (Chinese Journal of Pharmaceuticals, the Dong Xueling of document L- essence aminoprofen;Xu Yanke;Li Zhenzhi, 2002.33(2)
Version) one kind is disclosed using brufen and L-arginine as raw material, 95% ethyl alcohol is reaction dissolvent, and after the completion of reaction with third
Ketone crystallization obtains L- essence aminoprofen, and yield is up to 90% or more.Its purification process is equally to use organic solvent, but it is answered
It is brufen with object, and there is operating procedure complexity, can only solves the problems, such as that brufen purifies one defect.
As a kind of arylprop acids drug, the methyl introduced limits rotating freely for carboxyl, makes it pelubiprofen
It keeps being suitble to the conformation in conjunction with receptor or enzyme, improves antiinflammation, and toxicity also decreases.And pelubiprofen has itself
Unique hexatomic ring, high temperature, concentration is big, have alkali under conditions of, hexatomic ring is easy to that ring-opening reaction occurs, so that Pei Biluo
It reacts to each other between fragrant molecule and molecule, to generate impurity.Based on above-mentioned feature, the purifying crude of pelubiprofen is always
A technological difficulties in the industry.
For pelubiprofen, the purity for the pelubiprofen crude product that existing synthetic technology is synthesized about all exists
90% or so, but to reach the other words of pharmaceutical grade, there is quality standard regulation to have to purity and reach 99% or more, it is single it is miscellaneous 0.5% with
Under.Therefore, the pelubiprofen that crude product is worked it out, which has to purified step, can meet related medicinal and quality standard.
And the method purified is similar, principle is also more similar, and solvent type used by key is and quality proportioning can
The optimum efficiency reached.Purifying about pelubiprofen this kind there are no specific detailed description in existing document, also not
Seeing has the related specific data purified to disclose.
Therefore, in the case where not having document and patent to introduce pelubiprofen purifying crude now, developing one kind can
Purifying crude product pelubiprofen and meet toxicity it is low, it is at low cost, can effectively clean, high income, environmental pollution is small and is suitable for
The method of industrialized production is very significant.
Summary of the invention
The main purpose of the application is to provide purification process and its application of a kind of pelubiprofen.
To achieve the goals above and solve the problems, such as pelubiprofen industrialized production when, the application use with
Lower technical solution:
A kind of purification process of pelubiprofen comprising following steps: mixed solvent is added in pelubiprofen crude product, by stirring,
Crystallization, the pelubiprofen for filtering and being dried to obtain purifying.
Preferably, mixed solvent is made of intensive polar solvent, weak polar solvent, atent solvent.
Preferably, intensive polar solvent is selected from dimethyl sulfoxide, ethylene glycol, methanol, dimethylformamide, acetonitrile, acetone, pyrrole
One of pyridine, 2- butanone, chloroform, ethyl acetate, isopropanol, tetrahydrofuran.
Preferably, weak polar solvent is selected from chlorobenzene, isobutanol, methylene chloride, n-butanol, methyl tertiary butyl ether(MTBE), acetic acid fourth
One of ester, normal propyl alcohol, propyl alcohol.
Preferably, atent solvent is selected from pentamethylene, thiacyclohexane, trimethylpentane, isooctane, normal hexane, petroleum ether, isoamyl
One of alkane, pentane.
Preferably, the temperature of stirring is at 5~50 DEG C, and crystallization temperature is -15~10 DEG C, and drying temperature is 10~80 DEG C.
We the principle of technical solution is, be utilized inside organic chemistry similar mixes and dissimilar immiscible original
Reason.Contain impurity in pelubiprofen crude product, impurity may be that pelubiprofen is mutual between open loop, self-molecules present at high temperature
Reaction and the impurity formed, it is also possible to during synthesis step, other impurities of introducing, but in general, can with compared with
Highly polar impurity is in the majority.Therefore, our technical solution uses intensive polar solvent, removes with the similar principles of chemistry to mix
Highly polar impurity in pelubiprofen crude product, with the low pole impurity in weak polar solvent removal pelubiprofen crude product.
And dissimilar immiscible principle has been used, it goes to train using atent solvent and be forced out than pelubiprofen product and crystallization comes out.
But in the actual production process, there is also the technologies how deployed the quality proportioning of three kinds of solvents and reach optimum efficiency to ask
Topic.For the similar theory to mix, the mass fraction that intensive polar solvent is added in pelubiprofen crude product is more, then its phase
Molten effect is better, and the effect for removing highly polar impurity is stronger, and the pelubiprofen purity of raising is higher, for low pole impurity
For and same reason.But it joined under the yield that excessive strong, weak polar solvent will lead to pelubiprofen entirety
Drop, therefore to the higher of purity requirement, yield is lower.And what atent solvent used is dissimilar immiscible principle, is added
The purpose for entering atent solvent is exactly to force out the pelubiprofen of purifying and crystallization from solution, and the purpose being added is exactly to mention
High whole yield.But its addition is more, yield mentions higher, strong, the low pole impurity being mingled in pelubiprofen
It is removed by strong, weak polar solvent fewer, and will lead to and the problem of purity decline occur.Therefore, our technical staff needs
An equalization point is found in solution between yield and purity, to reach existing higher purity, and has higher yield.
Our technical staff has found the mixed solvent proportion that can obtain higher yields and higher degree by experiment:
In parts by weight, the parts by weight of pelubiprofen crude product are 1,
The parts by weight of its intensive polar solvent being added are 0.1~5, most preferably 1；
The parts by weight of weak polar solvent are 0.1~5, most preferably 2；
The parts by weight of atent solvent are 1~20, most preferably 2.
From the point of view of the resultant effect of experiment, when intensive polar solvent selects acetone, weak polar solvent selects methyl tertbutyl
Ether, when atent solvent selects normal hexane, effect is best, and specific technical solution is as follows:
A kind of purification process of pelubiprofen is added in 1 part of pelubiprofen crude product by acetone, methyl- tert in parts by weight
The mixed solvent of butyl ether, normal hexane composition, by stirring, crystallization, the pelubiprofen for filtering and being dried to obtain purifying, wherein plus
The parts by weight for entering acetone are 1, and the parts by weight of methyl tertiary butyl ether(MTBE) are 2, and the parts by weight of normal hexane are 2.
The application further comprises the pelubiprofen being prepared according to the purification process of above-mentioned pelubiprofen.
The purification process of the application further comprises application of this purification process in medicine preparation.
Due to using the technology described above, the beneficial effects of the present application are as follows:
(1) purification process for the pelubiprofen that we applies, has filled up the technological gap of current pelubiprofen purification art, solves
The not no issues of purification of the pelubiprofen of reported literature for a long time.
(2) our creative mix three kinds of organic solvents combines, for the unique chemical structure of pelubiprofen
And property, the combination of three kinds of organic solvents and the optimal combination of quality proportioning has been found through experiments that, has disposably solved training
Than removing highly polar impurity in ibuprofen production, low pole impurity, improving the problem of pelubiprofen yield, and in purity is high and yield
An equalization point is had found between height.
(3) quality of the product of pelubiprofen obtained by our purification process is more preferable, purity can be up to 99.5% with
On, related substance, which can be effectively controlled, to be limited in range, meet the other requirement of pharmaceutical grade, and yield is able to maintain 80% or more,
Economy with higher and medical value.
Detailed description of the invention
Fig. 1 is our chromatogram that pelubiprofen crude product measures before purification of embodiment 1.
Fig. 2 is our chromatogram that pelubiprofen finished product measures after purification of embodiment 1.
Specific embodiment
The application is described in further detail below by specific embodiments and the drawings.Following embodiment is only to the application
It is further described, should not be construed as the limitation to the application.
Embodiment 1
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds acetone 3.8kg, methyl tertiary butyl ether(MTBE) 7.6kg and is warming up to
Then n-hexane 7.6kg is added in 30 DEG C of stirring 4h, stir 12h in 0 DEG C of crystallization, filtering obtains faint yellow in 30 DEG C of vacuum drying
Crystalline powder 3.05kg, yield are about 80.47%.
The test map (see Detailed description of the invention Fig. 1) of pelubiprofen crude product in the present embodiment 1 and process are obtained after purification
Pelubiprofen finished product (see Detailed description of the invention Fig. 2) is compared, it is clear that the impurity before main peak passes through after purification almost
It is completely removed, the impurity after main peak has also lacked much in amount and type, and purity has reached 99.5% or more, meets this field
To the medicinal requirements of high-purity pelubiprofen drug.
This experiment is repeated 5 times, the experimental results are shown inthe following table:
| It tests for the first time | Second of experiment | Third time is tested | 4th experiment | 5th experiment | |
| Mixed solvent combination | Acetone+methyl tertiary butyl ether(MTBE)+n-hexane | Acetone+methyl tertiary butyl ether(MTBE)+n-hexane | Acetone+methyl tertiary butyl ether(MTBE)+n-hexane | Acetone+methyl tertiary butyl ether(MTBE)+n-hexane | Acetone+methyl tertiary butyl ether(MTBE)+n-hexane |
| Purity before refining | 92.02% | 91.99% | 92.11% | 92.17% | 92.09% |
| Purity after purification | 99.57% | 99.51% | 99.55% | 99.52% | 99.50% |
| Whipping temp | 30℃ | 30℃ | 30℃ | 30℃ | 30℃ |
| Crystallization temperature | 0℃ | 0℃ | 0℃ | 0℃ | 0℃ |
| Drying temperature | 30℃ | 30℃ | 30℃ | 30℃ | 30℃ |
| Yield | 80.47% | 80.33% | 81.00% | 80.66% | 80.52% |
The above the results show, this purification process repeatability is good, meets the needs of large scale purification.
Embodiment 2
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds ethyl acetate 3.8kg, methyl tertiary butyl ether(MTBE) 7.6kg simultaneously rises
Then to 30 DEG C of stirring 4h n-hexane 7.6kg is added, 0 DEG C of crystallization stirs 12h, and filtering obtains yellowish in 30 DEG C of vacuum drying in temperature
Color crystalline powder 3.15kg, yield 83.12%.
Embodiment 3
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds acetonitrile 3.8kg, methylene chloride 3.8kg is simultaneously warming up to 30 DEG C
3h is stirred, n-hexane 7.6kg is then added, 0 DEG C of crystallization stirs 12h, filtering, and 30 DEG C of vacuum drying obtain pale yellow crystals powder
Last 3.08kg, yield 81.26%.
Embodiment 4
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds tetrahydrofuran 3.8kg, methyl tertiary butyl ether(MTBE) 3.8kg simultaneously rises
Then to 30 DEG C of stirring 4h n-hexane 7.6kg is added, 0 DEG C of crystallization stirs 12h, filtering, and 30 DEG C of vacuum drying obtain faint yellow in temperature
Crystalline powder 3.07kg, yield 81.00%.
Embodiment 5
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds chloroform 3.8kg, methyl tertiary butyl ether(MTBE) 3.8kg is simultaneously warming up to
Then n-hexane 9.5kg is added in 30 DEG C of stirring 3h, -5 DEG C of crystallizations stir 12h, filtering, and 30 DEG C of vacuum drying obtain faint yellow knot
Crystalline substance powder 3.10kg, yield 81.79%.
Embodiment 6
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds chloroform 3.8kg, methyl tertiary butyl ether(MTBE) 3.8kg is simultaneously warming up to
Then petroleum ether 9.5kg is added in 30 DEG C of stirring 4h, crystallization stirs 12h, filtering at -10 DEG C, and 30 DEG C of vacuum drying obtain faint yellow
Crystalline powder 3.06kg, yield 80.73%.
Embodiment 7
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds acetone 3.8kg, methyl tertiary butyl ether(MTBE) 3.8kg is simultaneously warming up to
Then petroleum ether 7.6kg is added in 30 DEG C of stirring 4h, crystallization stirs 12h, filtering at -10 DEG C, and 30 DEG C of vacuum drying obtain faint yellow
Crystalline powder 3.05kg, yield 80.47%.
Embodiment 8
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds methanol 3.8kg, methylene chloride 3.8kg is simultaneously warming up to 30 DEG C
4h is stirred, petroleum ether 9.5kg is then added, crystallization stirs 12h, filtering at -5 DEG C, and 30 DEG C of vacuum drying obtain pale yellow crystals
Property powder 3.07kg, yield 81.00%.
Embodiment 9
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds acetone 3.8kg, methylene chloride 3.8kg is simultaneously warming up to 30 DEG C
4h is stirred, normal hexane 30.5kg is then added, crystallization stirs 12h, filtering at -5 DEG C, and 30 DEG C of vacuum drying obtain pale yellow crystals
Property powder 3.07kg, yield 81.00%.
Embodiment 10
Pelubiprofen crude product 3.8kg is added into reaction kettle, adds acetone 3.8kg, methylene chloride 3.8kg is simultaneously warming up to 30 DEG C
4h is stirred, petroleum ether 50.5kg is then added, crystallization stirs 12h, filtering at -5 DEG C, and 30 DEG C of vacuum drying obtain pale yellow crystals
Property powder 3.07kg, yield 81.00%.
The foregoing is a further detailed description of the present application in conjunction with specific implementation manners, and it cannot be said that this Shen
Specific implementation please is only limited to these instructions.For those of ordinary skill in the art to which this application belongs, it is not taking off
Under the premise of from the application design, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to the protection of the application
Range.
Claims (10)
1. a kind of purification process of pelubiprofen, which comprises the following steps: it is molten that mixing is added in pelubiprofen crude product
Agent, by stirring, crystallization, the pelubiprofen for filtering and being dried to obtain purifying.
2. purification process as described in claim 1, which is characterized in that the mixed solvent is molten by intensive polar solvent, low pole
Agent, atent solvent composition.
3. purification process as claimed in claim 2, which is characterized in that the intensive polar solvent be selected from dimethyl sulfoxide, ethylene glycol,
Methanol, dimethylformamide, acetonitrile, acetone, pyridine, 2- butanone, chloroform, ethyl acetate, isopropanol, one in tetrahydrofuran
Kind.
4. purification process as claimed in claim 2, which is characterized in that the weak polar solvent is selected from chlorobenzene, isobutanol, dichloro
One of methane, n-butanol, methyl tertiary butyl ether(MTBE), butyl acetate, normal propyl alcohol, propyl alcohol.
5. purification process as claimed in claim 2, which is characterized in that the atent solvent is selected from pentamethylene, thiacyclohexane, front three
One of base pentane, isooctane, normal hexane, petroleum ether, isopentane, pentane.
6. purification process as claimed in claim 2, which is characterized in that the weight of intensive polar solvent is pelubiprofen crude product weight
0.1~5 times, the weight of weak polar solvent is 0.1~5 times of pelubiprofen crude product weight, and the weight of atent solvent is training ratio
1~20 times of ibuprofen crude product weight.
7. purification process as described in claim 1, which is characterized in that the temperature of stirring is at 5~50 DEG C, crystallization temperature is-
15~10 DEG C, drying temperature is 10~80 DEG C.
8. a kind of purification process of pelubiprofen, which comprises the following steps:
In parts by weight, the mixing being made of acetone, methyl tertiary butyl ether(MTBE), normal hexane is added in 1 part of pelubiprofen crude product
Solvent, by stirring, crystallization, the pelubiprofen for filtering and being dried to obtain purifying, wherein the parts by weight that acetone is added are 1, first
The parts by weight of base tertbutyl ether are 2, and the parts by weight of normal hexane are 2.
9. the pelubiprofen that purification process as described in any one of claims 1 to 8 is prepared.
10. application of the purification process as described in any one of claims 1 to 8 in medicine preparation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111153791A (en) * | 2019-12-26 | 2020-05-15 | 湖南九典制药股份有限公司 | Preparation method of pelubiprofen with different particle sizes |
| WO2021129651A1 (en) * | 2019-12-26 | 2021-07-01 | 湖南九典制药股份有限公司 | 2-[4-[(e)-(2-ketocyclohexenyl)methyl]phenyl]propionic acid crystal form and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111153791A (en) * | 2019-12-26 | 2020-05-15 | 湖南九典制药股份有限公司 | Preparation method of pelubiprofen with different particle sizes |
| WO2021129651A1 (en) * | 2019-12-26 | 2021-07-01 | 湖南九典制药股份有限公司 | 2-[4-[(e)-(2-ketocyclohexenyl)methyl]phenyl]propionic acid crystal form and preparation method therefor |
| CN111153791B (en) * | 2019-12-26 | 2023-03-03 | 湖南九典制药股份有限公司 | Preparation method of pelubiprofen with different particle sizes |
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