CN108069896A - A kind of preparation method of Etoricoxib crystal form - Google Patents
A kind of preparation method of Etoricoxib crystal form Download PDFInfo
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- CN108069896A CN108069896A CN201610992825.5A CN201610992825A CN108069896A CN 108069896 A CN108069896 A CN 108069896A CN 201610992825 A CN201610992825 A CN 201610992825A CN 108069896 A CN108069896 A CN 108069896A
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- etoricoxib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to the preparation method of Etoricoxib V-type crystal form, the described method includes：Etoricoxib is added in organic solvent, heating makes solid entirely molten, adds in the V Form seeds that Etoricoxib weight percent in solution is not higher than 10%, insulated and stirred, and be slowly dropped to room temperature by not higher than 20 DEG C of the rate of cooling down per hour, stir and filtering crystals to obtain the final product.The method prepares Etoricoxib V crystalline substances, high income, and process stabilizing, favorable reproducibility, while can remove impurity E T IMP 409 to greatest extent in crystallization process, and material purity is higher, and other purification step is not required.
Description
Technical field
The invention belongs to drug fields, are related to a kind of preparation method of Etoricoxib V crystalline substances.
Background technology
Etoricoxib（Etoricoxib）, chemical name：The chloro- 3- of 5-（4- methanesulfonylphenYls）- 6- methyl-[2,3] join
Pyridine, structural formula are as follows：
Etoricoxib is highly selective Arcoxia, by inhibiting COX, reduces prostaglandin（PG）With thromboxane generation and
Play antipyretic-antalgic anti-inflammatory effect.Available for rheumatoid arthritis, OA chronic low back pains, post-operative dental pain, have and relieve pain
And antiphlogistic effects, and cause the adverse reactions such as gastrointestinal reaction without non-selective COX-1.
For Etoricoxib in 2002 most early in Mexico, Britain, Brazil's listing, the countries and regions then listed include Europe
Alliance, Asia-Pacific, Australia and Latin America etc., by the end of the year 2013, in global 97 granted listings of country, extensive use
In osteoarthritis (osteoarthritis, OA), rheumatoid arthritis, ankylosing spondylitis, chronic lower pain in back and loin, acute
The treatment of multiple diseases such as urarthritis, primary dysmenorrhea and postoperative pain.
Etoricoxib pharmaceutical dosage form are thin membrane coated tablet, belong to solid tablet.It is well known that the crystal form of drug is to medicine
The solid pharmaceutical preparation of object has a great impact, and WO2001092230 discloses Etoricoxib, and there are five kinds of polymorphics（I, II, III,
IV, V-type）, a kind of amorphous and two kinds of hydrated forms.Wherein V crystal forms are the medicinal crystal-form of Etoricoxib drug, but at this specially
In the preparation method of V crystal forms Etoricoxib disclosed in profit, Etoricoxib with isopropyl acetate is mixed, is heated to below about 75 DEG C
High temperature, and be subsequently cooled to low temperature to produce V-type polymorph, this method has following deficiency：The stabilization of experimental result
Property there are it is larger the problem of, V crystal forms can not be obtained in this way or V crystal forms can only be obtained once in a while, so that the system of crystal form
Standby technique is highly unstable；In addition, crystallization yield is not also high, after multiple batches of experiment is carried out, highest yield is left for 80%
The right side, production loss is very big, is not suitable for industrial large-scale production；3rd, this method for crystallising has a problem that, i.e., after crystallisation
It cannot effectively remove there are one specific impurities ET-IMP-409, since the physicochemical property of the impurity is close with raw material, be crystallized with this
Method cannot be removed once, behind also need to purification process, so technical process is longer, be not suitable for big production.
The content of the invention
The stable preparation process of V crystal form Etoricoxibs is poor, and yield is low, and purity is low etc. is prepared in the prior art in order to overcome
Shortcoming, it is an object of the invention to provide it is a kind of it is reproducible, stablize, and high income and the high suitable industrialization amplification life of purity
The Etoricoxib V crystal form preparation methods of production.
To achieve these goals, the present invention has carried out substantial amounts of experiment, replaces recrystallisation solvent, heating temperature etc., but right
Its crystallization yield is undesirable, finally introduces crystal seed in the solvent of Etoricoxib, so as to obtain V crystalline substance, although can obtain according to
The V that support examines former times is brilliant, but really there are ET-IMP-409 impurity in its crystallization, and need to remove this impurity by purifying process below
It removes, since this impurity is close with finished product liquid phase appearance time, property is close, causes the two principal component loss in crystallization larger,
And impurity is not easy to remove, while repeatedly refined causes product yield relatively low.The reaction principle of ET-IMP-409 impurity is as follows：
ET-IMP-409 impurity is close with finished product in chromatograms, and illustrative is close, is not easy in the purification process in later stage
Removal.
Once accidental it was found that, the amount for adding in crystal seed can obtain the level of ET-IMP-409 impurity in finished product
Difference, i.e., different Seed charges, the level that can cause ET-IMP-409 impurity in finished product are different, it was surprisingly found now that
The addition of crystal seed is controlled, desired crystal form can be not only obtained, can more control the purity of product, in other words, crystallizing
The amount of crystal seed is added in journey possibly through control, while reaches yield and the preferable finished product of purity, purifying again is reduced and brings
Loss.
The addition of crystal seed is further screened, while the temperature of crystallization is investigated.
It is below the investigation to Seed charge, rate of temperature fall is unified for 10 DEG C/h, as a result as follows：
It can be seen that Seed charge influences yield little, stable yield, purity and specific impurities ET- for finished product
IMP-409 is affected, and finished product is lower with Seed charge, and finished product purity improves, and reach national requirements is less than 0.1%
Limit, and the process that the later stage need not purify.
Different rate of temperature fall is investigated simultaneously, Seed charge is unified for 5%, as a result as follows：
Different rate of temperature fall can obtain the finished product of stable yield, but purity and impurity E T- for finished product after addition crystal seed
IMP-409 contents have large effect.When rate of temperature fall is 25 DEG C/h, impurity level is exceeded, and when rate of temperature fall drops to 20
DEG C/h, the content of impurity E T-IMP-409 declines to a great extent, and as rate of temperature fall declines, the purity of sample is further higher.
A kind of preparation method of Etoricoxib V crystal forms is we provided on the basis of many experiments, step is, will
Etoricoxib is added in organic solvent, and heating makes solid entirely molten, is added in Etoricoxib weight percent in solution and is not higher than 10%
V Form seeds, insulated and stirred, and be slowly dropped to room temperature by not higher than 20 DEG C of the rate of cooling down per hour stirs and filters crystalline substance
Body to obtain the final product.This technique can make one step of finished product obtain V crystal forms, and yield reaches more than 90%, and ET-IMP-409 be down to 0.1% with
Under, exempt purifying process below.
The application method is that one kind is markedly improved compared with method disclosed in the prior art：
(1) in terms of with regard to the stability of technique, the more difficult repetition of crystal form preparation method that patent WO2001092230 is reported or again
Renaturation is poor, stability there are it is larger the problem of, the present invention can be stably obtained V crystal form Etoricoxibs.
(2) with regard in terms of yield, the method yield that patent WO2001092230 is reported only has 80%, and the yield of this method
93% can be reached, greatly reduce raw material unit price.
(3) with regard in terms of Etoricoxib product quality, this method can reach the high purity product that HPLC detects more than 99.8%,
It is down to for specific impurities ET-IMP-409 below limit, great convenience is brought to industrialization.
The crystallization processes of the present invention can be solved two problems with a step, technique favorable reproducibility and high income, specific impurities ET-
IMP-409 is removed by one step of crystallization processes, the technique that subsequent purification is not required.
Description of the drawings
Fig. 1 is 1 finished product impurity determination result of embodiment；
Fig. 2 is 2 impurity determination result of embodiment；
Fig. 3 is 2 finished product crystal form diffraction pattern of embodiment.
Specific embodiment
It to make the object, technical solutions and advantages of the present invention clearer, in the following, will be to the specific embodiment of the present invention
It is described in detail.Obviously, described embodiment is only part of the embodiment of the present invention, instead of all the embodiments.
Embodiment 1：Comparing embodiment is added without seeded crystallization situation
5g Etoricoxibs and 15ml isopropyl acetates are added in there-necked flask, 75 DEG C is heated to, makes solid entirely molten, in this temperature
Under（75℃）, insulated and stirred 1h, rear slow cooling to room temperature stirs 2h, and filtering, 60 DEG C of forced air drying 12h of obtained solid obtain
V crystal form Etoricoxib 4.04g, purity：99.0%, yield 80.8%, specific impurities ET-IMP-409 is 0.199%.Finished product liquid phase is surveyed
Determine collection of illustrative plates and see attached drawing 1.
Embodiment 2：The preparation of V crystal form Etoricoxibs
5g Etoricoxibs and 15ml isopropyl acetates are added in there-necked flask, 75 DEG C is heated to, makes solid entirely molten, in this temperature
Under（75℃）Add in 0.25g（5%）Etoricoxib V Form seeds, insulated and stirred 1h are cooled to room by 10 DEG C/h of rate of temperature fall afterwards
Temperature, stirs 2h, filtering, and 60 DEG C of forced air drying 12h of obtained solid obtain V crystal form Etoricoxib 4.64g, purity：99.86%, it receives
Rate 92.8%, specific impurities ET-IMP-409 are 0.063%, and finished product purity liquid phase measurement collection of illustrative plates is shown in attached drawing 2, finished product crystal form diffraction pattern
Spectrum is shown in attached drawing 3.
Embodiment 3：The preparation of V crystal form Etoricoxibs
5g Etoricoxibs and 15ml isopropyl acetates are added in there-necked flask, 75 DEG C is heated to, makes solid entirely molten, in this temperature
Under（75℃）Add in 0.15g（3%）Etoricoxib V Form seeds, insulated and stirred 1h are cooled to room by 20 DEG C/h of rate of temperature fall afterwards
Temperature, stirs 2h, filtering, and 60 DEG C of forced air drying 12h of obtained solid obtain V crystal form Etoricoxib 4.61g, purity：99.95%, it receives
Rate 92.2%.
Embodiment 3：The preparation of V crystal form Etoricoxibs
5g Etoricoxibs and 15ml isopropyl acetates are added in there-necked flask, 75 DEG C is heated to, makes solid entirely molten, at 72 DEG C
Add in 0.15g（3%）Etoricoxib V Form seeds, insulated and stirred 1h are cooled to room temperature by 5 DEG C/h of rate of temperature fall afterwards, stir
2h, filtering, 60 DEG C of forced air drying 12h of obtained solid obtain V crystal form Etoricoxib 4.73g, purity：99.94%, yield 91.8%,
Specific impurities ET-IMP-409 is 0.053%.
Embodiment 4：The preparation of V crystal form Etoricoxibs
5g Etoricoxibs and 10ml ethyl acetate are added in there-necked flask, 75 DEG C is heated to, makes solid entirely molten, add at 61 DEG C
Enter 0.5g（10%）Etoricoxib V Form seeds, insulated and stirred 1h is rear to be cooled to room temperature by 5 DEG C/h of rate of temperature fall, stirs 2h,
Filtering, 60 DEG C of forced air drying 12h of obtained solid obtain V crystal form Etoricoxib 4.63g, purity：99.90%, yield 92.6% is special
Impurity E T-IMP-409 is determined for 0.066%.
Embodiment 5：The preparation of V crystal form Etoricoxibs
5g Etoricoxibs and 10ml acetone are added in there-necked flask, is heated to flowing back, makes solid entirely molten, added at 50 DEG C
0.15g（3%）Etoricoxib V Form seeds, insulated and stirred 1h is rear to be cooled to room temperature by 5 DEG C/h of rate of temperature fall, stirs 2h, mistake
Filter, 60 DEG C of forced air drying 12h of obtained solid obtain V crystal form Etoricoxib 4.56g, purity：99.84%, yield 91.2% is specific
Impurity E T-IMP-409 is 0.071%.
Etoricoxib is dissolved in solvent by this patent, and heating makes solid entirely molten, adds in Etoricoxib weight hundred in solution
Divide than the V Form seeds not higher than 10%, insulated and stirred, and room temperature be slowly dropped to by the rate not higher than 20 DEG C of cooling per hour,
It is to obtain the final product, easy to operate to stir simultaneously filtering crystals, and yield and purity improve, and purifying process is subsequently not required, and are suitble to industry metaplasia
Production.
Claims (7)
1. a kind of preparation method of V-type Etoricoxib, Etoricoxib is added in organic solvent, heating makes solid entirely molten, adds
Enter the V Form seeds that Etoricoxib weight percent in solution is not higher than 10%, insulated and stirred, and press not higher than 20 DEG C per hour
Rate of temperature fall be slowly dropped to room temperature, stir and filtering crystals to obtain the final product.
2. preparation method according to claim 1, which is characterized in that it is not high to add in Etoricoxib weight percent in solution
In 5% V Form seeds.
3. preparation method according to claim 2, which is characterized in that it is not high to add in Etoricoxib weight percent in solution
In 3% V Form seeds.
4. preparation method according to claim 1, which is characterized in that after adding in crystal seed, by not higher than cooling down 10 per hour
DEG C rate be slowly dropped to room temperature.
5. preparation method according to claim 4, which is characterized in that after adding in crystal seed, by not higher than 5 DEG C of cooling per hour
Rate be slowly dropped to room temperature.
6. preparation method according to claim 1, which is characterized in that organic solvent is isopropyl acetate, ethyl acetate, third
Arbitrary mixed solvent in any one of ketone solvent or three kinds.
7. preparation method according to claim 6, which is characterized in that organic solvent is isopropyl acetate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610992825.5A CN108069896B (en) | 2016-11-11 | 2016-11-11 | Preparation method of etoricoxib crystal form |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610992825.5A CN108069896B (en) | 2016-11-11 | 2016-11-11 | Preparation method of etoricoxib crystal form |
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| CN108069896A true CN108069896A (en) | 2018-05-25 |
| CN108069896B CN108069896B (en) | 2022-08-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107417599A (en) * | 2017-06-21 | 2017-12-01 | 四川尚锐生物医药有限公司 | A kind of preparation method of Etoricoxib crystal formation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| WO2013105106A1 (en) * | 2011-11-03 | 2013-07-18 | Cadila Healthcare Limited | An improved process for the preparation of etoricoxib and polymorphs thereof |
| WO2014041558A2 (en) * | 2012-08-27 | 2014-03-20 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of crystalline etoricoxib |
| CN104418799A (en) * | 2013-09-03 | 2015-03-18 | 天津药物研究院 | Etoricoxib crystal as well as preparation method and application thereof |
-
2016
- 2016-11-11 CN CN201610992825.5A patent/CN108069896B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| WO2013105106A1 (en) * | 2011-11-03 | 2013-07-18 | Cadila Healthcare Limited | An improved process for the preparation of etoricoxib and polymorphs thereof |
| WO2014041558A2 (en) * | 2012-08-27 | 2014-03-20 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for preparation of crystalline etoricoxib |
| CN104418799A (en) * | 2013-09-03 | 2015-03-18 | 天津药物研究院 | Etoricoxib crystal as well as preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107417599A (en) * | 2017-06-21 | 2017-12-01 | 四川尚锐生物医药有限公司 | A kind of preparation method of Etoricoxib crystal formation |
| CN107417599B (en) * | 2017-06-21 | 2020-06-09 | 四川尚锐生物医药有限公司 | Preparation method of etoricoxib crystal form |
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| CN108069896B (en) | 2022-08-12 |
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