CN103524416A - Novel crystal form A of celecoxib and preparation method thereof - Google Patents
Novel crystal form A of celecoxib and preparation method thereof Download PDFInfo
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- CN103524416A CN103524416A CN201310520234.4A CN201310520234A CN103524416A CN 103524416 A CN103524416 A CN 103524416A CN 201310520234 A CN201310520234 A CN 201310520234A CN 103524416 A CN103524416 A CN 103524416A
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- 229960000590 celecoxib Drugs 0.000 title claims abstract description 50
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 239000013078 crystal Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000001816 cooling Methods 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000002425 crystallisation Methods 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- 238000001228 spectrum Methods 0.000 claims abstract description 3
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 23
- 238000010792 warming Methods 0.000 claims description 20
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 9
- 239000012670 alkaline solution Substances 0.000 claims description 8
- 235000019628 coolness Nutrition 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 238000003512 Claisen condensation reaction Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000007704 transition Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 10
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- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 5
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- 238000001514 detection method Methods 0.000 description 5
- 238000009413 insulation Methods 0.000 description 5
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
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- 230000006907 apoptotic process Effects 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 208000037062 Polyps Diseases 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
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- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a novel crystal form A of celecoxib and a preparation method thereof. The novel crystal form of celecoxib is prepared by using isopropanol as a solvent system, subjecting a reaction solution to rapid cooling and crystallization and carrying out filtering and drying. The X-ray powder diffraction spectrum of the crystal form has characteristic diffraction peaks at positions where 2theta (DEG, +/- 0.2) is 5.42, 10.80, 13.10, 14.92, 16.18, 19.73, 21.60, 22.28, 27.06 and 29.68. The crystal form A has the advantages of good stability, convenience in production, transportation and storage, capability of meeting requirements for a preparation raw material, etc.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly, relate to celecoxib new crystal A and preparation method thereof.
Background technology
Celecoxib, trade(brand)name celecoxib (Celecoxib), it is II type cyclooxygenase (COX-2) inhibitor of first listing, by U.S. Searle company, developed, the listing of the 1999 Nian U.S., be used for the treatment of the diseases associated with inflammation such as osteoarthritis and rheumatoid arthritis, there is the advantages such as gi tract and Toxicity of Kidney are little.Because it can optionally suppress COX-2, COX-1, without obvious restraining effect, is had to the curative effect of remarkable anti-inflammatory antipyretic-antalgic, but digestive tube damage can not occur, be a kind of good anti-inflammation analgesis medicament.
On the other hand, COX-2 (COX-2) suppresses and promotes the aspects such as vasculogenesis to play an important role at tumorigenesis, transfer, apoptosis, has become the novel targets for the treatment of and prevention of tumour.U.S. FDA approval celecoxibs in 1999 are used for the assisting therapy of familial intestinal cancer polyp, and this indicates that cox 2 inhibitor is formally for tumor prevention.Research shows, and has suitable COX-2 and suppresses active Compound Phase ratio, and the activity of celecoxib inducing apoptosis of tumour cell is stronger.Therefore, celecoxib is carried out to Anticancer Effect and Mechanism is inquired into and the research of composition optimizes is increasing.
Celecoxib chemical name is 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, structural formula is as follows:
Listing preparation only has celecoxib capsule at present, yet celecoxib bulk drug is water-soluble very poor, affects in body and absorbs, and as such medicine with remarkable clinical efficacy, it is also the emphasis that everybody pays close attention to that its crystal formation is studied.
That report the earliest celecoxib crystal formation is the former world patent WO2001042222<POLYMORPHIC CRYSTALLINE FORMS OF CELECOXIB that grinds drug company application>, it prepares celecoxib polycrystalline, wherein, first use ethyl acetate-heptane solvent, then adopt DMA, DMF solvate, milling to transform obtains crystalline form III; Tianjin Inst. of Materia Medica is studied celecoxib crystal formation, apply for 4 Chinese patent CN102838542, CN102838543, CN102838544, CN102838545, open 4 kinds of crystalline form Is of celecoxib, II, III, IV, adopt respectively ethyl acetate, ethanol, methyl alcohol, tetrahydrofuran (THF) as solvent system.
The present invention finds by research, adopt different solvents system and crystallization method, obtain being different from the celecoxib new crystal A of prior art, this crystal formation shows good physico-chemical property, solvent reclaims economical, stable crystal form, is convenient to produce, transports and stores, and can meet the advantages such as requirement of preparation raw material.
Summary of the invention
The object of this invention is to provide a kind of stable crystal form, be easy to the new crystal A of the celecoxib of commercial scale production.
The present invention also provides the method for preparing celecoxib new crystal A.
The new crystal A of celecoxib of the present invention can adopt following method preparation, but this product never only limits to this preparation method:
(1) Claisen condensation reaction: add alkaline solution and Virahol in p-methyl aceto phenone and trifluoroacetic acid alkyl ester, be warming up to 45～65 ℃, react 2～10h, keep in as reaction solution a;
(2) in another reactor, by Virahol, diazanyl benzsulfamide hydrochloride and trifluoroacetic acid are warming up to 45～55 ℃, add reaction solution a, continue reaction 0.5～2h;
(3) add water, be heated to 60～80 ℃ complete molten, make in reaction solution without solid;
(4) control rate of temperature fall, make system fast cooling, crystallization;
(5) suction filtration, by crystallization drying under reduced pressure 4～10h, obtain celecoxib new crystal A.
Wherein, alkali in described alkaline solution is at least one being selected from sodium methylate, sodium ethylate, n-propyl alcohol sodium, sodium isopropylate, prepare the needed solvent of this solution and include but not limited to methyl alcohol, ethanol, n-propyl alcohol, Virahol, described alkaline solution particular methanol sodium/methanol solution.
The mass concentration of described alkaline solution is 25～35%, preferably 28～30%.
According to embodiments of the invention, Claisen condensation reaction in step (1), p-methyl aceto phenone and trifluoroacetic acid alkyl ester be take mol ratio and are fed intake as 1:1.0～1:1.4, the amount that adds Virahol can be 2～6 volumes (in p-methyl aceto phenone), temperature reaction temperature is 45～70 ℃, and the reaction times is 2～10h.According to a particular embodiment of the invention, in above-mentioned step (1), the alkyl in described trifluoroacetic acid alkyl ester is for being selected from C1-C4 alkyl, being preferably at least one being selected from methyl or ethyl.
According to embodiments of the invention, in step (2), to the mol ratio of diazanyl benzsulfamide hydrochloride and p-methyl aceto phenone, can be 1:0.8～1:1.2, the mol ratio of trifluoroacetic acid and p-methyl aceto phenone can be 1:0.02～1:0.07, be warming up to 45～55 ℃, add and continue reaction 0.5～2h after reaction solution a.In this process, add recrystallisation solvent Virahol, it measures 5～12 times for p-methyl aceto phenone volume.
According to a particular embodiment of the invention, the amount that adds water in step (3) is determined according to reaction system state, make system be heated to 60～80 ℃ complete molten.
According to embodiments of the invention, in step (4), crystallization can be controlled by temperature fast, and reaction system, with the speed of 5～20 ℃ of coolings per hour, is finally cooled to 15～25 ℃, is preferably 6～10 ℃ of coolings per hour.In addition, found through experiments, adopt 0.5～1 ℃ of left and right of cooling per hour to carry out slow crystallization, can obtain the former celecoxib III crystal formation that grinds.
According to embodiments of the invention, in step (5), drying under reduced pressure temperature can be 45～65 ℃, and be 4～10 hours time of drying, can obtain celecoxib new crystal A.
New crystal A of the present invention has good quality, and purity is at least 99.5%.Have and synthesize on a large scale or be mixed with the required performance of therapeutic preparation, to light, wet, thermally-stabilised, be convenient to produce, store and transport.
Gained celecoxib crystal form A of the present invention, its recrystallisation solvent is Virahol, it uses Cu-Ka radiation, to spend the X-ray powder diffraction spectrum that 2 θ represent, 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,27.06 and 29.68, has peak.Its DSC endothermic transition is at 161.3-163.1 ℃.
The testing method of crystal form A provided by the invention is as follows:
1, X-ray powder diffraction
Data are by methods known in the art, utilize senior powder diffractometer to obtain:
Instrument: German Brukrt AXS D8-FOCUS
Model: D8-FOCUS
Condition determination: CuK alpha-ray, Ni filtering, 40KV, 40mA, LynxEye192 bit array detector, 0.01 ° of 2theta of scanning step (Increment), the every step of speed (scanspeed) 0.05sec/step, 4.0Soller slit
2, dsc (DSC)
Instrument: the resistance to STA449F that speeds of Germany
Instrument parameter: temperature accuracy: ± 0.1 ℃;
Temperature rise rate: 0.1～50 ℃/per minute; Top temperature: 1500 ℃; Hot analytical balance range 0.001mg～50g.
Condition determination: starting temperature: 30 ℃, 10 ℃/per minute of temperature rise rate.
The stability of celecoxib crystal form A
Get celecoxib crystal form A in weighing bottle, respectively at 60 ℃, 4500 ± 500LX illumination, and place under 75% relative humidity, in sampling in 5 days, 10 days, HPLC method was measured related substance, and result is as table 1.
Table 1 celecoxib crystal form A factors affecting stability measurement result
| Placement condition | ? | Celecoxib powder | Crystal form A |
| ? | Time | Total impurities (%) | Total impurities (%) |
| ? | 0 day | Do not detect | Do not detect |
| 60 |
5 days | 0.06 | 0.05 |
| 60 |
10 days | 0.07 | 0.05 |
| Illumination (4500Lux) | 5 days | 0.06 | 0.04 |
| Illumination (4500Lux) | 10 days | 0.10 | 0.06 |
| 75% relative humidity (25 ℃) | 5 days | 0.08 | 0.06 |
| 75% relative humidity (25 ℃) | 10 days | 0.10 | 0.07 |
Can find that celecoxib new crystal A places 10 days, related substance is showed no obvious increase.
Pharmaceutical composition provided by the invention contains celecoxib crystal form A and pharmaceutically acceptable carrier.
Celecoxib crystal form A of the present invention, because it has good quality and stability, is suitable for oral Preparation, as tablet comprises fast-release tablet, chewable tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet, enteric coated tablet etc.; Capsule comprises hard capsule, soft capsule, slow releasing capsule, controlled release capsule, enteric coated capsule etc.; Granule comprises mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules, controlled release granule etc.; Oral solution; Oral suspensions; Syrup etc.While preparing oral solid formulation, can or pack gelatine capsule into or suppress in flakes celecoxib and the pack of suitable pharmaceutical excipient granulation.
Accompanying drawing explanation
The X-ray powder diffraction spectrogram of Fig. 1 celecoxib crystal form A;
The differential thermogram of Fig. 2 celecoxib crystal form A;
The collection of illustrative plates of Fig. 3 celecoxib crystal form A purity detecting;
The X-ray powder diffraction spectrogram of Fig. 4 celecoxib crystalline form III.
Embodiment
Describe embodiments of the invention below in detail, it should be noted that the embodiment the following describes is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.In addition, if do not clearly not stated, all reagent of adopting are in the following embodiments can be buied on market, or can be synthetic according to text or known method, for the reaction conditions of not listing, be also that those skilled in the art easily obtain.
In tri-mouthfuls of vials of a 250mL, add p-methyl aceto phenone (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester (13.7g, 0.096mol), add 18.2g methanol solution of sodium methylate (mass concentration is 25%) and 20mL Virahol, be warming up to 50 ℃, after insulation 4h, keep in as reaction solution a.
Get tri-mouthfuls of vials of another one 500mL, add 50mL Virahol, to diazanyl benzsulfamide hydrochloride (17.4g, 0.078mol) and trifluoroacetic acid (0.42g, 0.0037mol), while being warming up to 55 ℃, add reaction solution a, reaction 1h after, add after 50mL water, be warming up to 65 ℃ complete molten, 10 ℃ of coolings per hour, be down to 15 ℃, suction filtration, 45 ℃ of drying under reduced pressure obtain celecoxib A crystal formation 24.06g, yield is that 85%, HPLC detection purity is 99.7%.
The XRD figure of celecoxib crystal form A is at Degree(2 θ) there is charateristic avsorption band on 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,27.06,29.68.
Embodiment 2
In tri-mouthfuls of vials of a 250mL, add p-methyl aceto phenone (10g, 0.075mol) and trifluoro-acetate (13.4g, 0.105mol), add 20g methanol solution of sodium methylate (mass concentration is 28%) and 40mL Virahol, be warming up to 45 ℃, after insulation 2h, keep in as reaction solution a.
Get tri-mouthfuls of vials of another one 500mL, add 100mL Virahol, to diazanyl benzsulfamide hydrochloride (13.4g, 0.06mol) and trifluoroacetic acid (0.6g, 0.005mol), while being warming up to 45 ℃, add reaction solution a, reaction 0.5h after, add after 80mL water, be warming up to 60 ℃ complete molten, 20 ℃ of coolings per hour, be down to 25 ℃, suction filtration, 60 ℃ of drying under reduced pressure obtain celecoxib A crystal formation 22.64g, yield is that 80%, HPLC detection purity is 99.5%.
Embodiment 3
In tri-mouthfuls of vials of a 250mL, add p-methyl aceto phenone (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester (10.7g, 0.075mol), add 30g alcohol sodium alcohol solution (mass concentration is 30%) and 50mL Virahol, be warming up to 65 ℃, after insulation 10h, keep in as reaction solution a.
Get tri-mouthfuls of vials of another one 500mL, add 50mL Virahol, to diazanyl benzsulfamide hydrochloride (20g, 0.09mol) and trifluoroacetic acid (0.6g, 0.005mol), while being warming up to 55 ℃, add reaction solution a, reaction 1h after, add after 100mL water, be warming up to 80 ℃ complete molten, 20 ℃ of coolings per hour, be down to 15 ℃, suction filtration, 65 ℃ of drying under reduced pressure obtain celecoxib A crystal formation 24.1g, yield is that 85%, HPLC detection purity is 99.8%.
In tri-mouthfuls of vials of a 250mL, add p-methyl aceto phenone (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester (13.85g, 0.0975mol), add 40g methanol solution of sodium methylate (mass concentration is 35%) and 60mL Virahol, be warming up to 50 ℃, after insulation 2h, keep in as reaction solution a.
Get tri-mouthfuls of vials of another one 500mL, add 50mL Virahol, to diazanyl benzsulfamide hydrochloride (19.3g, 0.086mol) and trifluoroacetic acid (0.42g, 0.0037mol), while being warming up to 55 ℃, add reaction solution a, reaction 1h after, add after 120mL water, be warming up to 70 ℃ complete molten, 6 ℃ of coolings per hour, be down to 20 ℃, suction filtration, 45 ℃ of drying under reduced pressure obtain celecoxib A crystal formation 23.49g, yield is that 83%, HPLC detection purity is 99.5%.
Comparative example 5
In tri-mouthfuls of vials of a 250mL, add p-methyl aceto phenone (10g, 0.075mol) and Trifluoroacetic Acid Ethyl Ester (13.85g, 0.0975mol), add 40g methanol solution of sodium methylate (mass concentration is 35%) and 60mL Virahol, be warming up to 50 ℃, after insulation 2h, keep in as reaction solution a.
Get tri-mouthfuls of vials of another one 500mL, add 50mL Virahol, to diazanyl benzsulfamide hydrochloride (19.3g, 0.086mol) and trifluoroacetic acid (0.42g, 0.0037mol), while being warming up to 55 ℃, add reaction solution a, reaction 1h after, add after 120mL water, be warming up to 70 ℃ complete molten, 1 ℃ of cooling per hour, be down to 20 ℃, suction filtration, 45 ℃ of drying under reduced pressure obtain celecoxib III crystal formation 21.22g, yield is that 75%, HPLC detection purity is 99.8%.
The XRD figure of celecoxib crystalline form III is at Degree(2 θ) there is charateristic avsorption band on 5.56,11.22,13.24,15.06,1631,18.16,18.63,18.93,19.86,20.72,21.71,22.61,23.67,24.80,25.22,25.60,27.19,27.92,28.47,29.72,30.21.
Although illustrated and described embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention in the situation that not departing from principle of the present invention and aim, modification, replacement and modification.
Claims (10)
1. a celecoxib crystal form A, it is characterized in that, described celecoxib crystal form A is used Cu-Ka radiation, to spend the X-ray powder diffraction spectrum that 2 θ represent, 5.42,10.80,13.10,14.92,16.18,19.73,21.60,22.28,27.06 and 29.68, has peak.
2. celecoxib crystal form A as claimed in claim 1, is characterized in that, DSC endothermic transition is at 161.3-163.1 ℃.
3. a method of preparing the celecoxib crystal form A described in claim 1 or 2, is characterized in that, adopts following steps,
(1) Claisen condensation reaction: add alkaline solution and Virahol in p-methyl aceto phenone and trifluoroacetic acid alkyl ester, be warming up to 45～65 ℃, react 2～10h, keep in as reaction solution a;
(2) in another reactor, by Virahol, diazanyl benzsulfamide hydrochloride and trifluoroacetic acid are warming up to 45～55 ℃, add reaction solution a, continue reaction 0.5～2h;
(3) add water, be heated to 60～80 ℃ complete molten, make in reaction solution without solid;
(4) control rate of temperature fall, make system fast cooling, crystallization;
(5) suction filtration, by crystallization drying under reduced pressure 4～10h, obtain celecoxib new crystal A.
4. preparation method as claimed in claim 3, it is characterized in that, the molar ratio of p-methyl aceto phenone and trifluoroacetic acid alkyl ester is 1:1.0～1:1.4, to the mol ratio of diazanyl benzsulfamide hydrochloride and p-methyl aceto phenone, be 1:0.8～1:1.2, the mol ratio of trifluoroacetic acid and p-methyl aceto phenone is 1:0.02～1:0.07.
5. preparation method as claimed in claim 3, it is characterized in that, alkali in alkaline solution described in step (1) is at least one being selected from sodium methylate, sodium ethylate, n-propyl alcohol sodium, sodium isopropylate, prepare the needed solvent of this solution and include but not limited to methyl alcohol, ethanol, n-propyl alcohol, Virahol, described alkaline solution particular methanol sodium/methanol solution.
6. preparation method as claimed in claim 5, is characterized in that, the mass concentration of described alkaline solution is 25～35%, preferably 28～30%.
7. preparation method as claimed in claim 3, it is characterized in that, in step (1), the amount of Virahol is 2～6 volumes (in p-methyl aceto phenone), and in step (2), Virahol is recrystallisation solvent, and its amount is 5～12 times of volumes (in p-methyl aceto phenone).
8. preparation method as claimed in claim 3, is characterized in that, step (1) temperature of reaction is 45～65 ℃, reacts 2～10h; Step (2) temperature of reaction is 45～55 ℃, reacts 0.5～2h.
9. preparation method as claimed in claim 3, is characterized in that, described fast cooling, and its cooling rate is 5～20 ℃ of coolings per hour, is finally cooled to 15～25 ℃.
10. preparation method as claimed in claim 9, is characterized in that, described fast cooling, and its cooling rate is 6～10 ℃ of coolings per hour.
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| CN105130901A (en) * | 2015-08-06 | 2015-12-09 | 苏州二叶制药有限公司 | Celecoxib preparation method |
| CN116425679A (en) * | 2023-03-20 | 2023-07-14 | 山东省药学科学院 | Preparation method of celecoxib III crystal form |
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