CN109574919A - A kind of purifying and preparation method of Etoricoxib - Google Patents
A kind of purifying and preparation method of Etoricoxib Download PDFInfo
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- CN109574919A CN109574919A CN201910047064.XA CN201910047064A CN109574919A CN 109574919 A CN109574919 A CN 109574919A CN 201910047064 A CN201910047064 A CN 201910047064A CN 109574919 A CN109574919 A CN 109574919A
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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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Abstract
The present invention relates to a kind of purification process of Etoricoxib, including following operation: making Etoricoxib bulk pharmaceutical chemicals and reducing agent to be purified that reduction reaction occur in a solvent.Further relate to a kind of method for preparing Etoricoxib.It is greater than 99.9% using the Etoricoxib finished product purity that preparation method of the present invention obtains, less than 0.001%, impurity M is not detected the total content of impurity F, impurity 20 and impurity 21.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a method of purifying Etoricoxib further relates to a kind of prepare
The method of Etoricoxib.
Background technique
Etoricoxib (etoricoxib) is a kind of highly selective Transitional cell carcinomas (COX-2) inhibitor, has anti-inflammatory, town
Pain and refrigeration function are listed in 84, whole world countries and regions at present by MSD Corp.'s research and development, production.Etoricoxib is logical
Inhibition COX-2 is crossed, prostaglandin is reduced and thromboxane generates and plays antipyretic-antalgic anti-inflammatory effect, there is rapid-action, analgesia by force,
The advantages that long half time, light gastrointestinal reaction, clinical efficacy increase compared with traditional NSAIDs (NSAIDs), simultaneously
The adverse reaction rates such as gastrointestinal tract can be reduced, are the effective former times dry goods medicines for the treatment of acute gouty arthritis having confirmed
Object.
In bulk pharmaceutical chemicals, the substance of any influence drug purity is referred to as impurity." technology of chemicals impurity research refers to
Lead principle " it the formulation of the limit of impurities is proposed clearly requires.Meanwhile (human drugs registration technology requires international association in ICH
Adjust meeting) in guide, for the qualitative of the impurity in the impurity and Q3B (R2) novel formulation in Q3A (R2) new raw material medicine and control
It is described in detail.Have in impurity one kind be genotoxicity impurity (or for genetoxic impurity, Genotoxic
Impurity, GTI), refer to the direct or indirect damaging cells DNA of compound itself, generates gene mutation or mutagenesis in vivo, have
It is carcinogenic or to be inclined to.Its main feature is that the damage of human genetic material can be caused in very low concentrations, and then lead to gene
It is mutated and tumour may be promoted.
Currently, the method for synthesis Etoricoxib be mainly use Merck & Co., Inc to report method (referring to CN 1306425A,
Embodiment 2), this method is using AYTKX01 and AYTKX02 as raw material, by one pot process Etoricoxib, not separation of intermediates
AYTKX04.The product purity obtained with this method is lower, is not easy to crystallize, and impurity is more, and especially impurity M, content are greater than
0.1%, since its physicochemical property is close with raw material, be not easy to remove, need to by repeatedly purification could control limit 0.1% with
Under, yield losses are larger.
In Etoricoxib synthesis process, pyridine nitric oxide impurity F is also inevitably generated, it is also possible to generate miscellaneous
Matter 20 and impurity 21.Wherein pyridine nitric oxide belongs to potential genotoxicity impurity.
The ICH M7 of control requirement according to to(for) genotoxicity impurity, when calculating acceptable intake according to TTC, a tool
Have the impurity of mutagenicity daily everyone when taking in 1.5 μ g its risk be considered negligible (theoretical under lifelong exposure
Suffer from cancer risk less than ten a ten thousandths).Since impurity F, impurity 20 and impurity 21 belong to same class impurity, total amount should be by
It is controlled according to 1.5 μ g/ days.Currently, Etoricoxib preparation maximum specification is 120mg, calculate, in Etoricoxib preparation
The content limit of impurity F, impurity 20 and impurity 21 should be 0.00125%.
The impurity content how being further reduced in Etoricoxib bulk pharmaceutical chemicals is that those skilled in the art unanimously endeavour to solve
The problem of.
Summary of the invention
The present invention relates to a kind of purification process of Etoricoxib, including following operation:
Make Etoricoxib bulk pharmaceutical chemicals and reducing agent to be purified that reduction reaction occur in a solvent.
In certain embodiments, purification process of the present invention, wherein the reducing agent be reducing metal or
Phosphorus trihalide.
In certain embodiments, purification process of the present invention, wherein the reducing agent is reducing metal, institute
It states reduction reaction and carries out Etoricoxib bulk pharmaceutical chemicals to be purified in the presence of acid.Preferably, the reaction temperature of the reduction reaction
Degree is 50-65 DEG C, more preferably 60-65 DEG C.Preferably, the reaction time of the reduction reaction is 2-4 hours, more preferably 2-
3 hours.Preferably, the dosage molar ratio of reducing agent and Etoricoxib bulk pharmaceutical chemicals is (0.1-1.0): 1.Preferably, acid and support
The dosage molar ratio for examining former times bulk pharmaceutical chemicals is (0.05-1.0): 1.
In certain embodiments, purification process of the present invention, wherein the acid be selected from acetic acid, hydrochloric acid, sulfuric acid,
Ammonium chloride etc., preferably ammonium chloride or acetic acid.
In certain embodiments, purification process of the present invention, wherein the reducing metal is zinc or iron.
In certain embodiments, purification process of the present invention, wherein reducing agent is zinc, zinc and Etoricoxib raw material
The molar ratio of medicine is (0.1-1.0): 1 (such as 0.2:1,0.3:1,0.4:1 or 0.5:1), the use of acid and Etoricoxib bulk pharmaceutical chemicals
Amount molar ratio is (0.05-1.0): 1 (such as 0.15:1,0.2:1,0.3:1,0.4:1 or 0.5:1)；
In certain embodiments, purification process of the present invention, wherein reducing agent is iron, iron and Etoricoxib raw material
The molar ratio of medicine is (0.1-1.0): 1 (such as 0.2:1,0.3:1,0.4:1,0.5:1,0.6:1,0.7:1,0.8:1 or 0.9:
1), the dosage molar ratio of acid and Etoricoxib bulk pharmaceutical chemicals is (0.05-1.0): 1 (such as 0.15:1,0.2:1,0.3:1,0.4:1
Or 0.5:1).
In certain embodiments, purification process of the present invention, wherein the phosphorus trihalide be phosphorus trichloride or
Phosphorus tribromide, preferably phosphorus trichloride；Preferably, the reaction temperature of the reduction reaction is 20-65 DEG C, more preferably 20-25
℃；Preferably, the reaction time of the reduction reaction is 0.25-2 hours, and the more preferable reaction time is 0.25-0.5 hours；It is excellent
The dosage molar ratio of selection of land, phosphorus trihalide and Etoricoxib bulk pharmaceutical chemicals is (0.05-0.15): 1, more preferable dosage is (0.06-
0.1): 1.
In certain embodiments, purification process of the present invention, wherein the solvent is tetrahydrofuran.
In certain embodiments, purification process of the present invention further include: the step of crystallization, in certain embodiments
In, the crystallization includes:
After reaction, reaction solution filters, and into filtrate plus water precipitates crystal；
Gained crystal is washed with the mixed solution of tetrahydrofuran and water, it is dry.
In certain embodiments, the crystallization includes:
After reaction, it is 9-10 that alkali (such as sodium hydroxide) is added into reaction solution and adjusts pH value, and water is added to precipitate crystal；
Gained crystal is washed with the mixed solution of tetrahydrofuran and water, it is dry.
In certain embodiments, purification process of the present invention include thes steps that turning crystalline substance,
In certain embodiments, described turn of crystalline substance includes:
1) it will be dissolved in isopropyl acetate wait turn brilliant crystal, cool down crystallization；
2) crystal being precipitated optionally, is again dissolved in isopropyl acetate, control temperature in 60~70 DEG C of addition crystal seeds,
Heat preservation 2~3 hours, cool down crystallization.
The invention further relates to a kind of methods for preparing Etoricoxib, including following operation:
1) Etoricoxib bulk pharmaceutical chemicals are obtained,
2) Etoricoxib bulk pharmaceutical chemicals are purified using purification process of the present invention.
In certain embodiments, the method for acquisition Etoricoxib bulk pharmaceutical chemicals includes:
Make compound AYTKX04 that ring-closure reaction occur, obtains Etoricoxib bulk pharmaceutical chemicals (AYTKX05)
In certain embodiments, the ring-closure reaction carries out in organic solvent and in the presence of base,
Preferably, the organic solvent is tetrahydrofuran,
Preferably, the alkali is concentrated ammonia liquor,
Preferably, the reaction temperature of the ring-closure reaction is 60-65 DEG C,
Preferably, the reaction time of the ring-closure reaction is 3-4 hours,
Preferably, after the ring-closure reaction, sodium bicarbonate is added into organic phase for liquid separation, and solid is precipitated.
In certain embodiments, the preparation method of compound AYTKX04 of the present invention includes:
Make compound AYTKX01 and compound AYTKX02 that condensation reaction occur, obtain compound AYTKX04,
In certain embodiments, the condensation reaction in organic solvent, in the presence of condensing agent, and in nitrogen
Protection is lower to be carried out,
Preferably, the organic solvent is tetrahydrofuran；
Preferably, the condensing agent is potassium tert-butoxide；
Preferably, the condensation reaction includes: that compound AYTKX01 is added in organic solvent, and nitrogen protection adds
Enter potassium tert-butoxide, reacted 10~20 minutes in 15-20 DEG C, compound AYTKX02 is added, it is small in 30-35 DEG C of reaction 0.8~1.5
When, reaction solution is poured into acetic acid, is reacted 0.8~1.5 hour in 30~40 DEG C, yellow solid is precipitated, normal heptane, cooling is added
It is stirred to 5-10 DEG C, filters, obtain compound AYTKX04.Preferably, by filter cake THF/ normal heptane (such as 1:1 after suction filtration
(v/v)) mixed solution washs, and obtains compound AYTKX04.
In certain embodiments, the preparation method of compound AYTKX01 of the present invention includes:
Make compound AYTKX17 and oxidant that oxidation reaction occur, obtain compound AYTKX01,
Preferably, the oxidation reaction in organic solvent, carries out in the presence of a catalyst；
Preferably, the organic solvent is methanol；
Preferably, the catalyst is sodium tungstate；
Preferably, the oxidant is hydrogen peroxide；
Preferably, the concentration of the hydrogen peroxide be 5%-30%, preferably 10%；
Preferably, hydrogen peroxide and compound AYTKX17 dosage molar ratio are (2.2-3.5): 1, preferably 2.2:1；
Preferably, the oxidation reaction includes: that compound AYTKX17 is added in methanol, adds sodium tungstate, stirring,
Hydrogen peroxide is slowly added dropwise, reaction is added dropwise 1.5~2.5 hours, sodium sulfite solution is added, stirring is cooled to 5-10 DEG C and stirs
It mixes 0.8~1.2 hour, filters, faint yellow solid is added in the mixed solution of acetonitrile and water by dry faint yellow solid,
Stirring, crystallization.
Advantageous effects of the invention
Purification process provided by the invention can effectively remove genotoxicity impurity F in Etoricoxib, impurity 20 and miscellaneous
Matter 21.Etoricoxib bulk pharmaceutical chemicals are purified using purification process provided by the invention, obtain Etoricoxib lmpurities
F, less than 0.001%, impurity M is not detected the total content of impurity 20 and impurity 21, and product purity is greater than 99.9%.
In addition, the method provided by the invention for preparing Etoricoxib, is preparing Etoricoxib with AYTKX01 and AYTKX02
During, do not use one kettle way to operate, but intermediate A YTKX04 is separated, be then allowed to that ring-closure reaction occurs, obtain according to
Support examines former times.This method can effectively improve product purity, controls impurity M content, can't detect impurity M in final finished.
Specific embodiment
Essentiality content of the invention is further illustrated below with reference to specific embodiments of the present invention, it should be appreciated that following
Embodiment is merely to illustrate the present invention, but is not limited the scope of protection of the present invention with this.Tool is not specified in following example
Concrete conditions in the establishment of a specific crime person, according to normal conditions or manufacturer suggest progress.Production firm person is not specified in drug or reagent used, and being can
With conventional products that are commercially available.
Although many materials used in following embodiment and operating method be it is known in the art that still the present invention still
So it is described in detail as far as possible herein.It will be apparent to those skilled in the art that if not specified, material used in following example
Material and operating method are well known in the art.
In an embodiment of the present invention, the preparation flow of Etoricoxib is as follows:
In an embodiment of the present invention, compound AYTKX17 (is purchased from Guangdong Raffles, Thomas Stamford Pharmaceutical Technology Inc., chemistry
Entitled 1- (6- methyl -3- pyridine) -2- [4- (first sulfydryl) phenyl]-ethyl ketone, lot number ET04-170112-13)
In an embodiment of the present invention, compound AYTKX02 (is purchased from Guangdong Raffles, Thomas Stamford Pharmaceutical Technology Inc., chemistry
Three methylene hexafluorophosphate of entitled chloro- 1, the 3- of 2- bis- (dimethylaminos), lot number ET11-170526-01)
In an embodiment of the present invention, using the content of the impurity M in high performance liquid chromatography test sample, detection method
It is as follows:
1, chromatographic condition
High performance liquid chromatograph: waters e2695-2489
Detector: ultraviolet
Chromatographic column: Inertsil ODS-3V, 4.6 × 250mm, 3 μm
The preparation of 2% phosphoric acid solution: phosphoric acid 2ml is measured, 100ml is added water to, shakes up spare.
The preparation of 0.02M sodium dihydrogen phosphate (pH2.95 ± 0.05): taking biphosphate sodium-hydrate about 2.76g,
It is accurately weighed, add water 1000ml to dissolve, mix, adjusts pH to 2.95 with 2% phosphoric acid solution, filtered with 0.45 μm of filter membrane, it is spare.
The preparation of mobile phase: measuring 0.02M sodium dihydrogen phosphate (pH2.95 ± 0.05) 740ml, acetonitrile 260ml, mixes
It is even, 3~5min of ultrasound.
Column temperature: 35 DEG C
Flow velocity: 1.0ml/min
Sample volume: 50 μ l
Detection wavelength: 235nm
2, solution is prepared
Blank solution is prepared: taking mobile phase appropriate, as blank solution.
The preparation of Etoricoxib reference substance stock solution I: taking Etoricoxib reference substance about 5mg, accurately weighed, sets 100ml amount
Bottle, add acetonitrile-water (1:1 (v/v)) dissolve and be diluted to scale, shake up to get.
The preparation of impurity M reference substance stock solution I: taking impurity M reference substance about 5mg, accurately weighed, is respectively placed in different
100ml measuring bottle, add acetonitrile-water (1:1 (v/v)) dissolve and be diluted to scale, shake up to get.
The preparation of Etoricoxib reference substance stock solution II: precision measures Etoricoxib reference substance stock solution I 1.0ml, is placed in
10ml measuring bottle, add acetonitrile-water (1:1 (v/v)) be diluted to scale to get.
The preparation of impurity M reference substance stock solution II: precision measures impurity M reference substance stock solution I 1.0ml, is placed in 10ml amount
Bottle, add acetonitrile-water (1:1) to be diluted to scale, shake up to get.
Mixed reference substance solution is prepared: precision measures Etoricoxib reference substance stock solution II 1.0ml and impurity M reference substance
Stock solution II 1.0ml is placed in same 50ml measuring bottle, mobile phase is added to be diluted to scale, shake up to get.
The preparation of system suitability solution: taking Etoricoxib reference substance about 5mg, accurately weighed, is placed in 50ml measuring bottle, then essence
Close measurement impurity M reference substance stock solution II 1.0ml, sets same 50ml measuring bottle, adds flowing phased soln and is diluted to scale, shakes up,
As system suitability solution.
The preparation of test solution: taking test sample about 10mg, accurately weighed, is placed in 100ml measuring bottle, adds flowing phased soln simultaneously
It is diluted to scale, is shaken up, as test solution.
3, system suitability
Precision measures 50 μ l of system suitability solution, injects liquid chromatograph, records chromatogram.Theoretical cam curve is by support
5000 should be not less than by examining former times peak and calculating, and the separating degree between Etoricoxib peak and the peak impurity M should be not less than 2.0.
4, it measures
Precision measures mixed reference substance solution, test solution and each 50 μ l of blank solution, is injected separately into liquid chromatograph,
Detection sensitivity is adjusted, makes to mix the peak height of principal component chromatographic peak in reference substance to be about the 10~20% of recorder full scale, note
Chromatogram is recorded to 2 times of principal component peak retention time.
In the chromatogram of blank solution, peak position and each impurity peak position are noiseless.Mixed reference substance solution continuously into
In the chromatogram of 6 needle of sample, main peak and each impurity peak area RSD should be not more than 10%, the chromatography of each Quality Control mixed reference substance solution
Main peak and each impurity peak area RSD are not greater than 15% in figure.
5, result calculates
Use external standard method with calculated by peak area, formula is as follows:
In formula:
AIt is miscellaneousThe peak area of single known impurities in=test solution
AIt is miscellaneous rightImpurity peak area in=mixed reference substance solution
CFor=test solution concentration
CIt is miscellaneous rightThe concentration of impurity reference substance in=mixed reference substance solution
PIt is miscellaneous right=impurity reference substance purity
In an embodiment of the present invention, using impurity F, impurity 20 and the impurity 21 in high performance liquid chromatography test sample
Content, detection method is as follows:
1, chromatographic condition
High performance liquid chromatograph: waters e2695-2489
Detector: ultraviolet
Chromatographic column: Inertsil ODS-3V, 4.6 × 250mm, 3 μm
The preparation of 2% phosphoric acid solution: phosphoric acid 2ml is measured, 100ml is added water to, shakes up spare.
The preparation of 0.02M sodium dihydrogen phosphate (pH=2.95 ± 0.05): biphosphate sodium-hydrate is taken about
5.52g, it is accurately weighed, add water 2000ml to make to dissolve, mix, adjusts pH to 2.95 with 2% phosphoric acid solution, filtered with 0.45 μm of filter membrane
It crosses, it is spare.
The preparation of mobile phase A: measuring 0.02M sodium dihydrogen phosphate (pH=2.95 ± 0.05) 900ml, acetonitrile 100ml,
It mixes, 3~5min of ultrasound.
The preparation of Mobile phase B: measuring 0.02M sodium dihydrogen phosphate (pH=2.95 ± 0.05) 200ml, acetonitrile 800ml,
It mixes, 3~5min of ultrasound.
According to the form below carries out gradient elution:
Column temperature: 35 DEG C
Flow velocity: 1.0ml/min
Sample volume: 50 μ l
Detection wavelength: 235nm
2, solution is prepared
Solvent is prepared: being measured 0.02M sodium dihydrogen phosphate (pH=2.95 ± 0.05) 740ml, acetonitrile 260ml, is mixed.
Mixed reference substance solution prepare: take impurity 21, impurity F reference substance respectively about 5mg (due to 20 appearance of impurity F and impurity
Time consistency, therefore only weigh impurity F and the progress of impurity 21 sample preparation), it is accurately weighed, it is placed in different 100ml measuring bottles, adds second
Nitrile-water (1:1 (v/v)) dissolves and is diluted to scale, shakes up, as each impurity reference substance stock solution I.It is accurate respectively to measure impurity
21 and impurity F reference substance stock solution I 1.0ml, is placed in different 100ml measuring bottles, and acetonitrile-water (1:1 (v/v)) is added to be diluted to quarter
Degree, shakes up, as impurity 21 and impurity F reference substance stock solution II.It is accurate respectively again to measure impurity 21 and impurity F reference substance reserve
Each 1.0ml of liquid II, sets same 50ml measuring bottle, solubilizer is diluted to scale, shakes up, as mixed reference substance solution.
Test solution is prepared: test sample about 10mg is taken, it is accurately weighed, and it is placed in 10ml measuring bottle, solubilizer is dissolved and diluted
It to scale, shakes up, as test solution.
3, it measures
Precision measures mixed reference substance solution, test solution and each 50 μ l of blank solvent, is injected separately into liquid chromatograph,
Record chromatogram.In blank solvent, each impurity peak position is noiseless.Each impurity peak area RSD of 6 needle of mixed reference substance solution must not
Greater than 10%, each each impurity peak area RSD of Quality Control mixed reference substance solution is not greater than 15%.
4, result calculates
It is calculated using external standard method, formula is as follows:
In formula:
AIt is miscellaneousThe peak area of single impurity in=test solution
AIt is miscellaneous rightImpurity peak area in=mixed reference substance solution
CFor=test solution concentration
CIt is miscellaneous rightThe concentration of impurity reference substance in=mixed reference substance solution
PIt is right=impurity reference substance purity
Result under loss on drying %=loss on drying item
Reference examples 1 synthesize AYTKX05 using the method for CN 1306425A report
Compound AYTKX01 is added into 100mL there-necked flask, and (2.0g, 6.91mmol are purchased from Chengdu gram Lay Mongolia Medicine science and technology
Co., Ltd, lot number 20160401) and super dry tetrahydrofuran (THF, 15ml), stirred under nitrogen atmosphere, 0-10 DEG C of temperature control, point
Potassium tert-butoxide (0.85g, 7.60mmol) is added in batch, then 10-20 DEG C of reaction 15min of temperature control is added at one time compound
AYTKX02 (2.23g, 7.26mmol are purchased from Chengdu Ke Lai Mongolia Medicine Science and Technology Ltd., lot number 20160301), adds 5ml
Super dry tetrahydrofuran, 20-25 DEG C of reaction 1h of temperature control, reaction solution is poured into acetic acid (2.90g, 48.37mmol), keeps the temperature 20-25
DEG C reaction 1.5h, is added dropwise concentrated ammonia liquor (2.66g, 76.01mmol), 60-65 DEG C of reaction 2-3h is heated to after being added dropwise, TLC is shown
Show that fundamental reaction is complete, stand liquid separation, organic phase is added dropwise 120ml saturated sodium bicarbonate aqueous solution, has solid precipitation, cooling is stirred
It mixes, in 5-10 DEG C of stirring 1h or so.It filters, with 5ml THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C of vacuum are dry
It is dry to constant weight, obtain 2.09g yellow solid, as Etoricoxib (compound AYTKX05), yield 84.4%.Through detecting,
The content of impurity M is 0.50% in AYTKX05, purity 96.36%.
Embodiment 1
1) preparation of Etoricoxib (compound AYTKX05)
1.1) into the reaction kettle of 20L be added compound AYTKX17 (800.0g, 3.109mol), methanol (7200ml) and
Sodium tungstate (20.51g, 0.062mol), stirring, obtain yellow suspension, be slowly added dropwise 10% hydrogen peroxide (2325.9g,
6.840mol), for control temperature at 50 DEG C hereinafter, reacting 2h after being added dropwise between 40-50 DEG C of temperature control, TLC display reaction is basic
Completely, sodium sulfite (78.4g, the 0.622mol) solution for being dissolved in 800ml water is added, stirs 20min, then be cooled to 5-10 DEG C and stir
1h to be mixed, is filtered, filter cake is washed with purified water 500ml × 2, and 45-55 DEG C of forced air drying to constant weight obtains faint yellow solid 827.1g,
Yield is 92.0%.Faint yellow solid (825.0g) obtained by step 1.1) is added in 10L there-necked flask, is added acetonitrile (3300ml)
With purified water (2475ml), it is heated to return stirring 0.5h, solution is suspension, and cool down crystallization, 5-10 DEG C of temperature control stirring
1h is filtered, and filter cake is washed with 900ml acetonitrile/water (1:2 (v/v)) mixed liquor, and 45-55 DEG C of forced air drying to constant weight obtains 706.0g
Faint yellow solid, as compound AYTKX01, yield 78.5%.
1.2) compound AYTKX01 (703.0g, 2.430mol) and super dry tetrahydrofuran are added into 20L reaction kettle
10-15 DEG C of temperature control, potassium tert-butoxide (313.5g, 2.794mol) is added in batches in (THF, 6300ml), stirred under nitrogen atmosphere,
15-20 DEG C of reaction 15min of temperature control, is then added at one time compound AYTKX02 (782.2g, 2.551mol), 30-35 DEG C of temperature control
1h is reacted, reaction solution is poured into acetic acid (1021.3g, 17.010mol), 30-40 DEG C of reaction 1h is kept the temperature, there is yellow solid analysis
Out, normal heptane (2109ml) is added, is cooled to 5-10 DEG C or so stirring 30min, filter, filter cake 1500ml THF/ normal heptane
The washing of (1:1 (v/v)) mixed solution, obtains yellow solid compound AYTKX04, direct plunges into next step.
1.3) compound AYTKX04 obtained by step 1.2) is fitted into 20L reaction kettle, 2812ml THF is added, be added dropwise dense
Ammonium hydroxide (1158.5g, 17.01mol) is heated to 60-65 DEG C of reaction 3-4h after being added dropwise, TLC shows that fundamental reaction is complete, quiet
Liquid separation is set, 3% sodium bicarbonate aqueous solution of 5600ml is added dropwise in organic phase, there is solid precipitation, cooling stirring, in 5-10 DEG C of stirring 1h
Left and right.It filters, with 1000ml THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C is dried under vacuum to constant weight, obtains
629.0 yellow solids, as Etoricoxib (compound AYTKX05), yield 72.1%.It is impurity F in AYTKX05, miscellaneous through detecting
The total content of matter 20 and impurity 21 is 0.0072%, and the content of impurity M is 0.0107%.
2) purifying of Etoricoxib (compound AYTKX05)
2.1) AYTKX05 (627.7g, 1.750mol) and THF (2510ml) obtained by step 1) is added into 5L there-necked flask,
Stirring is added zinc powder (22.8g, 0.350mol), is dissolved in ammonium chloride (14.0g, 0.260mol) solution of 63ml purified water, heats
2h is reacted to 60 DEG C or more, is filtered, 5020ml purified water is added in filtrate, there is solid precipitation, cooling stirring, 5-10 DEG C of stirring 1h
Left and right filters, filter cake 1200ml THF/H2The washing of O (1:2) mixed solution, 40-45 DEG C is dried under vacuum to constant weight, obtains
614.4g yellow solid AYTKX06, yield 97.9%.Through detecting, impurity F, impurity 20 and 21 total amount of impurity are less than in AYTKX06
0.001%, impurity M is not detected.
2.2) AYTKX06 (593.0g, 1.653mol) is added into 5L there-necked flask, isopropyl acetate (2370ml), water-bath
Active carbon stir about 1h is added in heating and refluxing to dissolve after clarification, filter, and filtrate cooling crystallization is down to 5-10 DEG C of stirring 1-2h, is taken out
Filter, filter cake are washed with 300ml isopropyl acetate, and 45-55 DEG C of forced air drying to constant weight obtains 501.4g off-white powder AYTKX07,
Yield 84.6%.
2.3) AYTKX07 (500.0g, 1.394mol) is added in 5L there-necked flask, isopropyl acetate (2250ml), water-bath
Heating stirring to the dissolution that flows back, 65 ± 2 DEG C of addition crystal seeds of temperature control observe that crystal seed is insoluble, keep the temperature crystallization 2-3h, start gradient
Cooling is kept for per half an hour drop 5 DEG C of rate, 1-2h is stirred after being cooled to 5-10 DEG C, is filtered, filter cake 300ml acetic acid isopropyl
Ester washing, 45-55 DEG C of forced air drying to constant weight obtain 435.7g off-white powder, as the finished product AYTKX0 of Etoricoxib, receive
Rate 87.1%.Through detecting, the purity of the finished product AYTKX0 of Etoricoxib is 99.93%, wherein impurity F, impurity 20 and impurity
Less than 0.001%, impurity M is not detected 21 total amounts.
Embodiment 2:
1) preparation of Etoricoxib (compound AYTKX05)
1.1) compound AYTKX17 (20.0g, 77.72mmol) is added into 500mL reaction kettle, 180ml methanol and wolframic acid
Sodium (0.51g, 1.55mmol), stirring, obtains yellow suspension, 30% hydrogen peroxide (26.44g, 233.15mol) is slowly added dropwise,
Temperature is controlled at 60 DEG C hereinafter, temperature control reacts 1h between 55-60 DEG C after being added dropwise, TLC display reaction substantially completely, cools down
It to 5-10 DEG C of stirring 1h, filters, filter cake is washed with purified water 30ml × 2, and it is yellowish to obtain 17.5g for 45-55 DEG C of forced air drying to constant weight
Color solid.Faint yellow solid (17.5g) obtained by being added in 500mL there-necked flask, is added acetonitrile (106ml) and purified water
(210ml) is heated to return stirring 0.5h, and solution is suspension, and cool down crystallization, and 5-10 DEG C of stirring 1h of temperature control is filtered, filter
Cake is washed with 20ml acetonitrile/water (1:2 (v/v)) mixed liquor, and 45-55 DEG C of forced air drying to constant weight obtains 16.22g faint yellow solid,
As compound AYTKX01, yield 72.1%.
1.2) AYTKX01 (15.0g, 51.84mmol) He Chaogan THF (165ml) is added into 500mL reaction kettle, nitrogen
The lower stirring of protection, 10-15 DEG C of temperature control, is added potassium tert-butoxide (6.69g, 59.62mmol) in batches, 15-20 DEG C of temperature control reaction
Then 15min is added at one time compound AYTKX02 (16.69g, 54.43mmol), 30-35 DEG C of reaction 1h of temperature control will react
Liquid pours into acetic acid (21.79g, 362.88mmol), keeps the temperature 30-40 DEG C of reaction 1h, there is yellow solid precipitation, and normal heptane is added
(60mL) is cooled to 5-10 DEG C or so stirring 30min, filters, and filter cake is mixed molten with 30ml THF/ normal heptane (2.5:1 (v/v))
Liquid washing, obtains yellow solid compound AYTKX04, direct plunges into next step.
1.3) compound AYTKX04 obtained by step 1.2) is fitted into 500mL reaction kettle, 75mL THF is added, be added dropwise
25% concentrated ammonia liquor (24.72g, 362.88mmol) is heated to 60-65 DEG C of reaction 3-4h, TLC and shows fundamental reaction after being added dropwise
Completely, liquid separation is stood, 3% sodium bicarbonate aqueous solution of 150mL is added dropwise in organic phase, there is solid precipitation, cooling stirring, at 5-10 DEG C
Stir 1h or so.It filters, with 20mlL THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C is dried under vacuum to constant weight,
Obtain 12.25g yellow solid, as Etoricoxib (compound AYTKX05), yield 65.9%.Through detecting, impurity in AYTKX05
F, the total content of impurity 20 is 0.01%.
2) purifying of Etoricoxib (compound AYTKX05)
AYTKX05 (2.0g, 5.57mmol) and THF (8ml) obtained by step 1) is added into 100mL there-necked flask, stirring adds
Ammonium chloride (0.119g, the 2.23mmol) solution for entering iron powder (0.125g, 2.23mmol) and 0.5ml purified water, is heated to 60 DEG C
The above reaction 2h, filters, 16ml purified water is added in filtrate, there is solid precipitation, cooling stirring, and 5-10 DEG C of stirring 1h or so takes out
Filter, filter cake 4ml THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C is dried under vacuum to constant weight, and it is light red to obtain 1.74g
Color solid AYTKX06, yield 87.0%.Through detecting, the total content of impurity F, impurity 20 is less than 0.001% in AYTKX06.
Embodiment 3:
1) preparation of Etoricoxib (compound AYTKX05)
1.1) AYTKX17 (20.0g, 77.72mmol) is added into 500mL reaction kettle, 200ml methanol and sodium tungstate
(0.51g, 1.55mmol), stirring, obtains yellow suspension, is slowly added dropwise 30% hydrogen peroxide (26.44g, 233.15mol), controls
For temperature processed at 60 DEG C hereinafter, reacting 2h after being added dropwise between 55-60 DEG C of temperature control, TLC display reaction substantially completely, is cooled to 5-
10 DEG C of stirring 1h are filtered, and filter cake is washed with purified water 30ml × 2, and it is faint yellow to obtain 19.22g for 45-55 DEG C of forced air drying to constant weight
Solid, yield 85.46%.In 500mL there-necked flask be added obtained by faint yellow solid (18.5g), be added acetonitrile (130ml) and
Purified water (220ml) is heated to return stirring 0.5h, and solution is suspension, and cool down crystallization, 5-10 DEG C of stirring 1h of temperature control,
It filters, filter cake is washed with 20ml acetonitrile/water (1:2 (v/v)) mixed liquor, and it is yellowish to obtain 16.7g for 45-55 DEG C of forced air drying to constant weight
Color solid AYTKX01, yield 90.3%.
1.2) AYTKX01 (15.2g, 52.53mmol) and the super dry THF of 167ml are added into 500mL reaction kettle, nitrogen is protected
The lower stirring of shield, 10-15 DEG C of temperature control, is added potassium tert-butoxide (6.79g, 60.41mmol) in batches, 15-20 DEG C of temperature control reaction
Then 15min is added at one time compound AYTKX02 (16.91g, 55.16mmol), 30-35 DEG C of reaction 1h of temperature control will react
Liquid pours into acetic acid (22.08g, 367.71mmol), keeps the temperature 30-40 DEG C of reaction 1h, there is yellow solid precipitation, and normal heptane is added
(61mL) is cooled to 5-10 DEG C or so stirring 30min, filters, and filter cake is mixed molten with 30ml THF/ normal heptane (2.5:1 (v/v))
Liquid washing, obtains yellow solid compound AYTKX04, direct plunges into next step.
1.3) compound AYTKX04 obtained by step 1.2) is fitted into 500mL reaction kettle, 76mL THF is added, be added dropwise
25% concentrated ammonia liquor (25.05g, 367.71mmol) is heated to 60-65 DEG C of reaction 3-4h, TLC and shows fundamental reaction after being added dropwise
Completely, liquid separation is stood, 3% sodium bicarbonate aqueous solution of 150mL is added dropwise in organic phase, there is solid precipitation, cooling stirring, at 5-10 DEG C
Stir 1h or so.It filters, with 20mlL THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C is dried under vacuum to constant weight,
Obtain 10.2g yellow solid, as Etoricoxib (compound AYTKX05), yield 54.2%.Through detecting, impurity F in AYTKX05,
The total content of impurity 20 is 0.0054%.
2) purifying of Etoricoxib (compound AYTKX05)
AYTKX05 (1.0g, 2.78mmol) and THF (6ml) obtained by step 1) is added in 100mL there-necked flask, stirs, is added
Iron powder (0.16g, 2.86mmol), purified water (2ml) and acetic acid (0.093g, 1.55mmol), are heated to 60 DEG C or more and react 3h,
It filters, 10ml purified water is added in filtrate, there is solid precipitation, cooling stirring, 10-15 DEG C of stirring 1h or so is filtered, and filter cake is used
10ml THF/H2The washing of O (1:2) mixed solution, 40-45 DEG C is dried under vacuum to constant weight, obtains 0.76g beige solid, yield
76.0%.Through detecting, the total content of impurity F, impurity 20 is less than 0.001% in AYTKX06.
Embodiment 4:
1) preparation of Etoricoxib (compound AYTKX05)
1.1) AYTKX17 (1000g, 3.886mol) is added into 20L reaction kettle, 9000ml methanol and sodium tungstate
(25.64g, 0.078mol), stirring, obtains yellow suspension, is slowly added dropwise 10% hydrogen peroxide (2907.4g, 8.549mol), controls
For temperature processed at 60 DEG C hereinafter, reacting 2h after being added dropwise between 55-60 DEG C of temperature control, TLC display reaction substantially completely, is cooled to 5-
10 DEG C of stirring 1h are filtered, and filter cake is washed with purified water 1000mL × 2, and it is faint yellow to obtain 1008g for 45-55 DEG C of forced air drying to constant weight
Solid, yield 90.0%.Faint yellow solid (1000g) obtained by being added in 20L reaction kettle, is added acetonitrile (4000ml) and pure
Change water (3000ml), be heated to return stirring 0.5h, solution is suspension, and cool down crystallization, and 5-10 DEG C of stirring 1h of temperature control takes out
Filter, filter cake are washed with 1500ml acetonitrile/water (1:2 (v/v)) mixed liquor, and it is yellowish to obtain 890.0g for 45-55 DEG C of forced air drying to constant weight
Color solid, as compound AYTKX01, yield 89.0%.
1.2) AYTKX01 (860.0g, 2.972mol) and the super dry THF of 8600ml, nitrogen protection are added into 20L reaction kettle
10-15 DEG C of temperature control, potassium tert-butoxide (383.55g, 3.418mol) is added in batches in lower stirring, 15-20 DEG C of reaction 15min of temperature control,
Then it is added at one time AYTKX02 (956.9g, 3.121mol), reaction solution is poured into acetic acid by 30-35 DEG C of reaction 1h of temperature control
In (1249.3g, 20.81mol), 30-40 DEG C of reaction 1h is kept the temperature, there is yellow solid precipitation, is added normal heptane (3440mL), cooling
It to 5-10 DEG C or so stirring 30min, filters, filter cake is washed, obtained with 2.1L THF/ normal heptane (2.5:1 (v/v)) mixed solution
Yellow solid AYTKX04 is direct plungeed into next step.
1.3) AYTKX04 obtained by step 1.2) is fitted into 20L reaction kettle, 4300mL THF is added, 25% dense ammonia is added dropwise
Water (1417.2g, 20.81mol) is heated to 60-65 DEG C of reaction 3-4h, TLC and shows that fundamental reaction is complete after being added dropwise, standing
3% sodium bicarbonate aqueous solution of 8600mL is added dropwise in liquid separation, organic phase, there is solid precipitation, and cooling stirring is left in 5-10 DEG C of stirring 1h
It is right.It filters, with 1200mlL THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C is dried under vacuum to constant weight, obtains
698.0g yellow solid, as Etoricoxib (compound AYTKX05), yield 65.5%.Through detecting, impurity F in AYTKX05,
The total content of impurity 20 is 0.01%.
2) purifying of Etoricoxib (compound AYTKX05)
AYTKX05 (3.0g, 8.36mmol) obtained by step 1), THF (9ml) are added into 100ml there-necked flask, stirring adds
Enter phosphorus trichloride (0.073ml, 0.836mmol), keep the temperature 20-25 DEG C of reaction 1h, be added 1mol/L NaOH aqueous solution (4ml), adjusts
Section pH is 9-10, adds 14ml purified water crystallization, is cooled to 5-10 DEG C of stirring 1h, is filtered, filter cake 5ml THF/H2O(1:2
(v/v)) mixed solution washs, and 40-45 DEG C is dried under vacuum to constant weight, obtains 2.86g faint yellow solid AYTKX06, yield 95.3%.
Through detecting, the total content of impurity F, impurity 20 is less than 0.001% in AYTKX06.
Embodiment 5:
1) preparation of Etoricoxib (compound AYTKX05) is the same as embodiment 3.
2) purifying of Etoricoxib (compound AYTKX05)
AYTKX05 (3.0g, 8.36mmol) and THF (9ml, 3V) are added into 100ml there-necked flask, trichlorine is added in stirring
Change phosphorus (0.073ml, 0.836mmol), keep the temperature 20-25 DEG C of reaction 2h, be added 1mol/L NaOH aqueous solution (4ml), adjusting pH is
9-10 adds 14ml purified water crystallization, is cooled to 5-10 DEG C of stirring 1h, filters, filter cake 5ml THF/H2O(1:2(v/v))
Mixed solution washing, 40-45 DEG C is dried under vacuum to constant weight, obtains 3.02g faint yellow solid, yield 100%.Impurity in AYTKX06
F, the total content of impurity 20 is less than 0.001%.
Embodiment 6:
1) preparation of Etoricoxib (compound AYTKX05) is the same as embodiment 3.
2) purifying of Etoricoxib (compound AYTKX05)
AYTKX05 (3.0g, 8.36mmol) is added into 100ml there-necked flask, tri-chlorination is added in THF (9ml, 3V), stirring
Phosphorus (0.073ml, 0.836mmol) keeps the temperature 60-65 DEG C of back flow reaction 0.5h, is cooled to 30 DEG C or so rear addition 1mol/L NaOH
Aqueous solution (4ml), adjusting pH are 9-10, add 14ml purified water crystallization, are cooled to 5-10 DEG C of stirring 1h, are filtered, and filter cake is used
5ml THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C is dried under vacuum to constant weight, obtains 2.81g faint yellow solid
AYTKX06, yield 93.7%.Through detecting, the total content of impurity F, impurity 20 is less than 0.001% in AYTKX06.
Embodiment 7
1) preparation of Etoricoxib (compound AYTKX05)
1.1) addition AYTKX17 (100g, 0.389mol) into 2L there-necked flask, 900ml methanol and sodium tungstate (2.64g,
0.008mol), it stirs, obtains yellow suspension, be slowly added dropwise 10% hydrogen peroxide (291.0g, 0.856mol), control temperature exists
50 DEG C are reacted 2h hereinafter, being added dropwise between 40-50 DEG C of rear temperature control, and substantially completely, addition is dissolved in 100ml water for TLC display reaction
Sodium sulfite (9.8g, 0.078mol) solution, stir 20min, be cooled to 5-10 DEG C of stirring 1h, suction filtration, filter cake purified water
100mL × 2 is washed, and obtains 138.2g faint yellow solid.Faint yellow solid (138.0g) obtained by being added in 2L there-necked flask, is added second
Nitrile (400ml) and purified water (300ml), are heated to return stirring 1h, and solution is suspension, and cool down crystallization overnight, next day
It filters, filter cake is dried under vacuum to constant weight at 40-45 DEG C, obtains 86.2g faint yellow solid, and as compound AYTKX01, yield is
76.8%.
1.2) AYTKX01 (86.0g, 0.297mol) and the super dry THF of 774ml are added into 2L there-necked flask, under nitrogen protection
15-20 DEG C of temperature control, potassium tert-butoxide (38.36g, 0.342mol) is added in batches in stirring, 15-20 DEG C of reaction 15min of temperature control, so
After be added at one time AYTKX02 (95.69g, 0.312mol), rinse bottle wall with the super dry THF of 86ml, 30-35 DEG C of reaction 1h of temperature control,
Reaction solution is poured into acetic acid (124.94g, 2.081mol), 30-40 DEG C of reaction 1h is kept the temperature, there is yellow solid precipitation, is added just
Heptane (258mL) is cooled to 5-10 DEG C or so stirring 30min, filters, and filter cake is with 200ml THF/ normal heptane (2.5:1 (v/v))
Mixed solution washing, obtains yellow solid AYTKX04, direct plunges into next step.
1.3) AYTKX04 obtained by step 1.2) is fitted into 2L there-necked flask, 344mL THF is added, 25% concentrated ammonia liquor is added dropwise
(141.73g, 2.081mol) is heated to 60-65 DEG C of reaction 3-4h, TLC and shows that fundamental reaction is complete after being added dropwise, standing point
2% sodium bicarbonate aqueous solution of 690mL is added dropwise in liquid, organic phase, there is solid precipitation, cooling stirring, in 5-10 DEG C of stirring 1-2h.It takes out
Filter, with 150mlL THF/H2The washing of O (1:2 (v/v)) mixed solution, 40-45 DEG C is dried under vacuum to constant weight, obtains 79.65g yellow
Solid, as Etoricoxib (compound AYTKX05), yield 74.7%.Through detecting, impurity F in AYTKX05, impurity 20 it is total
Content is 0.0084%.
2) purifying of Etoricoxib (compound AYTKX05)
AYTKX05 (10.0g, 27.86mmol), THF (30ml) obtained by step 1) are added into 100ml there-necked flask, stirs,
It is added phosphorus trichloride (0.195ml, 2.23mmol), keeps the temperature 20-25 DEG C of reaction 15min, 1mol/L NaOH aqueous solution is added
(12.1ml), adjusting pH are 9-10, add 45ml purified water crystallization, are cooled to 5-10 DEG C of stirring 1h, are filtered, filter cake is in 40-
45 DEG C are dried under vacuum to constant weight, obtain 9.70g faint yellow solid AYTKX06, yield 97.0%.Through detecting, impurity F in AYTKX06,
The total content of impurity 20 is less than 0.001%.
Finally it should be noted that: the above embodiments are merely illustrative of the technical scheme of the present invention and are not intended to be limiting thereof；To the greatest extent
The present invention is described in detail with reference to preferred embodiments for pipe, it should be understood by those ordinary skilled in the art that: still
It can modify to a specific embodiment of the invention or some technical features can be equivalently replaced；Without departing from this hair
The spirit of bright technical solution should all cover within the scope of the technical scheme claimed by the invention.
Claims (19)
1. a kind of purification process of Etoricoxib, including following operation:
Make Etoricoxib bulk pharmaceutical chemicals and reducing agent to be purified that reduction reaction occur in a solvent.
2. purification process described in claim 1, wherein the reducing agent is reducing metal or phosphorus trihalide.
3. purification process described in claim 1, in which:
The reducing agent is reducing metal, and the reduction reaction carries out Etoricoxib raw material to be purified in the presence of acid
Medicine,
Preferably, the acid is selected from acetic acid, hydrochloric acid, sulfuric acid, ammonium chloride etc., preferably ammonium chloride or acetic acid.
4. purification process described in claim 2 or 3, wherein the reducing metal is zinc or iron.
5. purification process as claimed in claim 2, wherein the phosphorus trihalide is phosphorus trichloride or phosphorus tribromide, preferably three
Phosphorus chloride.
6. purification process described in any one of claim 1 to 5, wherein the solvent is tetrahydrofuran.
7. purification process as claimed in claim 3, in which:
The reaction temperature of the reduction reaction is 50-65 DEG C, more preferably 60-65 DEG C；
Preferably, the reaction time of the reduction reaction is 2-4 hours, more preferably 2-3 hours.
8. purification process described in claim 3 or 7, in which:
The dosage molar ratio of reducing agent and Etoricoxib bulk pharmaceutical chemicals is (0.1-1.0): 1,
Preferably, the dosage molar ratio of acid and Etoricoxib bulk pharmaceutical chemicals is (0.05-1.0): 1；
Preferably, reducing agent is zinc, and the molar ratio of zinc and Etoricoxib bulk pharmaceutical chemicals is (0.1-1.0): 1 (such as 0.2:1,0.3:
1,0.4:1 or 0.5:1), the dosage molar ratio of acid and Etoricoxib bulk pharmaceutical chemicals is (0.05-1.0): 1 (such as 0.15:1,0.2:
1,0.3:1,0.4:1 or 0.5:1)；
Preferably, reducing agent is iron, and the molar ratio of iron and Etoricoxib bulk pharmaceutical chemicals is (0.1-1.0): 1 (such as 0.2:1,0.3:
1,0.4:1,0.5:1,0.6:1,0.7:1,0.8:1 or 0.9:1), the dosage molar ratio of acid and Etoricoxib bulk pharmaceutical chemicals is
(0.05-1.0): 1 (such as 0.15:1,0.2:1,0.3:1,0.4:1 or 0.5:1).
9. purification process described in claim 3 or 7, further includes: the step of crystallization,
Preferably, the crystallization includes:
After reaction, reaction solution filters, and into filtrate plus water precipitates crystal；
Gained crystal is washed with the mixed solution of tetrahydrofuran and water, it is dry.
10. purification process described in claim 5, in which:
The reaction temperature of the reduction reaction is 20-65 DEG C, more preferably 20-25 DEG C；
Preferably, the reaction time of the reduction reaction is 0.25-2 hours, and the more preferable reaction time is 0.25-0.5 hours；
Preferably, the dosage molar ratio of phosphorus trihalide and Etoricoxib bulk pharmaceutical chemicals is (0.05-0.15): 1, more preferable dosage is
(0.06-0.1): 1.
11. purification process described in any one of claim 10, further includes: the step of crystallization,
Preferably, the crystallization includes:
After reaction, it is 9-10 that alkali (such as sodium hydroxide) is added into reaction solution and adjusts pH value, and water is added to precipitate crystal；
Gained crystal is washed with the mixed solution of tetrahydrofuran and water, it is dry.
12. purification process described in claim 9 or 11 include thes steps that turning crystalline substance,
Preferably, described turn of crystalline substance includes:
1) it will be dissolved in isopropyl acetate wait turn brilliant crystal, cool down crystallization；
2) crystal being precipitated optionally, is again dissolved in isopropyl acetate, control temperature is in 60~70 DEG C of addition crystal seeds, heat preservation
2~3 hours, cooled down crystallization.
13. a kind of method for preparing Etoricoxib, including following operation:
1) Etoricoxib bulk pharmaceutical chemicals are obtained,
2) Etoricoxib bulk pharmaceutical chemicals are purified using claim 1 to 12 described in any item purification process.
14. a kind of method for preparing Etoricoxib bulk pharmaceutical chemicals, comprising:
Make compound AYTKX04 that ring-closure reaction occur, obtains Etoricoxib bulk pharmaceutical chemicals (AYTKX05)
15. preparation method described in claim 14, wherein the ring-closure reaction is in organic solvent and in the presence of base
It carries out,
Preferably, the organic solvent is tetrahydrofuran,
Preferably, the alkali is concentrated ammonia liquor,
Preferably, the reaction temperature of the ring-closure reaction is 60-65 DEG C,
Preferably, the reaction time of the ring-closure reaction is 3-4 hours,
Preferably, after the ring-closure reaction, sodium bicarbonate is added into organic phase for liquid separation, and solid is precipitated.
16. preparation method described in claim 13 or 14, wherein the preparation method of compound AYTKX04 includes:
Make compound AYTKX01 and compound AYTKX02 that condensation reaction occur, obtain compound AYTKX04,
17. preparation method described in claim 16, wherein the condensation reaction is in organic solvent, in the presence of condensing agent
Under, and carry out under nitrogen protection,
Preferably, the organic solvent is tetrahydrofuran；
Preferably, the condensing agent is potassium tert-butoxide；
Preferably, the condensation reaction includes: that compound AYTKX01 is added in organic solvent, nitrogen protection, and uncle is added
Butanol potassium reacts 10~20 minutes in 15-20 DEG C, and compound AYTKX02 is added, and reacts 0.8~1.5 hour in 30-35 DEG C, will
Reaction solution pours into acetic acid, reacts 0.8~1.5 hour in 30~40 DEG C, and yellow solid is precipitated, and normal heptane is added, is cooled to 5-
10 DEG C of stirrings, filter, obtain compound AYTKX04, it is preferable that by filter cake with THF/ normal heptane (such as 1:1 (v/v)) after suction filtration
Mixed solution washing, obtains compound AYTKX04.
18. preparation method described in claim 16, wherein the preparation method of compound AYTKX01 includes:
Make compound AYTKX17 and oxidant that oxidation reaction occur, obtain compound AYTKX01,
Preferably, the oxidation reaction in organic solvent, carries out in the presence of a catalyst；
Preferably, the organic solvent is methanol；
Preferably, the catalyst is sodium tungstate；
Preferably, the oxidant is hydrogen peroxide；
Preferably, the concentration of the hydrogen peroxide be 5%-30%, more preferable 10%；
Preferably, hydrogen peroxide and compound AYTKX17 dosage molar ratio be (2.2-3.5): 1, more preferable 2.2:1；
Preferably, reaction temperature is 35-65 DEG C, more preferable 40-50 DEG C.
Preferably, the oxidation reaction includes: that compound AYTKX17 is added in methanol, adds sodium tungstate, stirring, slowly
Hydrogen peroxide is added dropwise, reaction is added dropwise 1.5~2.5 hours, sodium sulfite solution is added, stirring is cooled to 5-10 DEG C of stirring 0.8
It~1.2 hours, filtering, faint yellow solid is added in the mixed solution of acetonitrile and water by dry faint yellow solid, it stirs,
Crystallization.
19. preparation method described in claim 13, wherein obtaining the method such as claim 14 to 18 of Etoricoxib bulk pharmaceutical chemicals
Described in any one.
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| CN114989071A (en) * | 2021-12-24 | 2022-09-02 | 四川青木制药有限公司 | Etoricoxib impurity as well as preparation method and detection method thereof |
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| CN113264873A (en) | 2021-08-17 |
| CN113264873B (en) | 2022-11-04 |
| CN109574919B (en) | 2021-06-29 |
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