CN105130901A - Celecoxib preparation method - Google Patents
Celecoxib preparation method Download PDFInfo
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- CN105130901A CN105130901A CN201510473450.7A CN201510473450A CN105130901A CN 105130901 A CN105130901 A CN 105130901A CN 201510473450 A CN201510473450 A CN 201510473450A CN 105130901 A CN105130901 A CN 105130901A
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- celecoxib
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- ethanol
- benzsulfamide
- amido
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- 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 58
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 49
- 239000013078 crystal Substances 0.000 claims abstract description 13
- 238000002425 crystallisation Methods 0.000 claims abstract description 13
- 230000008025 crystallization Effects 0.000 claims abstract description 12
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000003512 Claisen condensation reaction Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- 239000012043 crude product Substances 0.000 claims description 19
- 229960004756 ethanol Drugs 0.000 claims description 19
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 125000003368 amide group Chemical group 0.000 claims description 16
- 235000010288 sodium nitrite Nutrition 0.000 claims description 12
- VNQMMBHDIDLJEZ-UHFFFAOYSA-N 2-hydrazinylbenzenesulfonamide;hydrochloride Chemical compound Cl.NNC1=CC=CC=C1S(N)(=O)=O VNQMMBHDIDLJEZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010792 warming Methods 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 210000002706 plastid Anatomy 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 4
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003729 cation exchange resin Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 230000003292 diminished effect Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 229960001413 acetanilide Drugs 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000007670 refining Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- IKEURONJLPUALY-UHFFFAOYSA-N 4-hydrazinylbenzenesulfonamide;hydron;chloride Chemical compound [Cl-].NS(=O)(=O)C1=CC=C(N[NH3+])C=C1 IKEURONJLPUALY-UHFFFAOYSA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000010419 fine particle Substances 0.000 abstract 1
- 238000009827 uniform distribution Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000005457 optimization Methods 0.000 description 4
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- ZPNWNLNPDRYULE-UHFFFAOYSA-N 2-iodobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1I ZPNWNLNPDRYULE-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- CEDKAUHEEJPZMM-UHFFFAOYSA-N ethyl acetate;octane Chemical compound CCOC(C)=O.CCCCCCCC CEDKAUHEEJPZMM-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a celecoxib preparation method, wherein 4'-methylacetophenone and ethyl trifluoroacetate are adopted as raw materials, Claisen condensation is performed to obtain a beta-diketone intermediate, the beta-diketone intermediate and p-hydrazinobenzenesulfonamide hydrochloride are subjected to condensation cyclization in ethanol to obtain celecoxib, and refining and crystallization are performed to obtain the celecoxib crystal. According to the present invention, with the preparation method, the celecoxib can be obtained in the high yield manner, the purity of the obtained product is high, the single impurity can be controlled to be less than or equal to 0.5%, and the obtained celecoxib crystal has characteristics of fine particle size and uniform distribution, and is suitable for bulk drug production.
Description
Technical field
The present invention relates to the synthetic method of celecoxib, belong to pharmaceutical synthesis field.
Background technology
Celecoxib (celecoxib) is first specificity COX-2 (COX-2) inhibitor of Xi Er company of U.S. exploitation, for the treatment of osteoarthritis and rheumatoid arthritis.
The principal synthetic routes of existing celecoxib is as follows:
Route one:
Under the effect of 25% sodium methylate-methyl alcohol, carry out Claisen condensation with p-methyl aceto phenone and Trifluoroacetic Acid Ethyl Ester and obtain beta-diketon intermediate, this intermediate is without separation and purification, directly with to Hydrazinobenzenesulfonamide hydrochloride condensation and cyclization in ethanol, obtain, total recovery 46% through ethyl acetate-octane recrystallization again.The shortcoming of the method is: yield is low, and the reaction times is longer; Because intermediate does not carry out separation and purification, impurity is more.
Route two:
This route with to iodobenzenesulfonyl chloride for starting raw material, obtain celecoxib through four-step reaction, overall yield of reaction 30 ~ 40%, this process costs is higher, and total recovery is low, is not suitable for commercially producing.
route three:
This route is starting raw material with sulfanilic amide, and obtain celecoxib through two-step reaction, overall yield of reaction is low, and this process costs is higher, raw material be difficult to buy and expensive, be not suitable for commercially producing.
Summary of the invention
The problem of the low and purity difference of ubiquitous yield in preparation method for existing celecoxib, the invention provides the preparation method of a kind of high yield and highly purified celecoxib:
Step (1): with p-methyl aceto phenone and Trifluoroacetic Acid Ethyl Ester for raw material, obtain fluoro-1, the 3-dimethyl diketone of 1-(4-aminomethyl phenyl)-4,4,4-tri-through Claisen condensation;
Fluoro-1, the 3-dimethyl diketone of step (2): 1-(4-aminomethyl phenyl)-4,4,4-tri-with celecoxib crude product is obtained to the cyclization of Hydrazinobenzenesulfonamide hydrochloride;
Step (3): celecoxib crude product is used dissolve with ethanol at normal temperatures, activated carbon decolorizing, cross filtering gac, filtrate under agitation drips water, separates out celecoxib crystal.
Described step (1) take sodium ethylate as catalyzer, and ethanol is solvent, and temperature of reaction is 48-52 DEG C, preferably 50 DEG C, and the reaction times is 2-3 hour;
Described step (2) is catalyzer with trifluoroacetic acid, take ethanol/water as mixed solvent, first at 48-52 DEG C (preferably 50 DEG C) reaction 30-40 minute, then adds water and is warming up to 63-67 DEG C of (preferably 65 DEG C) stirring reaction 30-40 minute.
Celecoxib crude product in described step (3) is 1:3-5g/mL with the plastid ratio of ethanol, and celecoxib crude product is 1:3.5 ~ 4.5g/mL with the plastid ratio of water, and recrystallization temperature is 25 DEG C, stirs 2 ~ 3 hours.
The preparation method to Hydrazinobenzenesulfonamide hydrochloride described in step (2) is:
To be dissolved in (hydrochloric acid: water=2:3w/w) in aqueous hydrochloric acid to amido benzsulfamide, and be cooled to-4 ~-10 DEG C, drip sodium nitrite in aqueous solution (Sodium Nitrite: water=1:2 ~ 3w/w), hierarchy of control temperature is-4 ~-10 DEG C, drips after finishing, stirs 10 minutes.The sodium sulfite aqueous solution (S-WAT: water=1:2 ~ 3w/w) of above-mentioned reaction solution with-5 DEG C is mixed, stirs 10 minutes.Be warming up to 75 ~ 80 DEG C, add concentrated hydrochloric acid, insulated and stirred 60 minutes, filter, leave standstill, Temperature fall to room temperature, crystallization 2-3 hour, filters, the cold absolute ethanol washing of filter cake, 70 ~ 75 DEG C of vacuum-drying 12 hours.
The add-on of described aqueous hydrochloric acid is 4-5 times to amido benzsulfamide weight;
The add-on of described sodium nitrite in aqueous solution is 1.5-2 times to amido benzsulfamide weight;
The add-on of described sodium sulfite aqueous solution is 6-7 times to amido benzsulfamide weight;
The add-on of described concentrated hydrochloric acid is 4-5 times to amido benzsulfamide weight.
The preparation method of the Trifluoroacetic Acid Ethyl Ester described in step (1) is:
Take dehydrated alcohol as solvent, mixed with the D072 storng-acid cation exchange resin as catalyzer by trifluoroacetic acid (resin is 1:3g/mL with the plastid ratio of trifluoroacetic acid), heated and stirred back flow reaction 8h, filtration under diminished pressure falls resin, rectifying obtains Trifluoroacetic Acid Ethyl Ester, and yield is 93.7%.
To the synthetic method of amido benzsulfamide be:
Acetanilide and chlorsulfonic acid react to obtain para-acetylaminobenzene sulfonyl chloride, then react acetamido benzsulfamide with ammoniacal liquor, after be hydrolyzed in sodium bicarbonate aqueous solution and obtain amido benzsulfamide.
Adopt preparation method of the present invention can high yield prepare celecoxib, products obtained therefrom purity is high, single assorted controls below 0.5%, and the fine size of the celecoxib crystal obtained, and distributes homogeneous, is very applicable to production of raw medicine.
Accompanying drawing explanation
Fig. 1, process flow sheet to Hydrazinobenzenesulfonamide hydrochloride
The process flow sheet of Fig. 2, celecoxib crude product
The process flow sheet that Fig. 3, celecoxib are refining
Embodiment
The preparation of embodiment 1 Trifluoroacetic Acid Ethyl Ester
In 1.4L dehydrated alcohol, add 300mL trifluoroacetic acid in batches, then add 100gD072 storng-acid cation exchange resin and make catalyzer, heated and stirred back flow reaction 8h, filtration under diminished pressure falls resin, rectifying obtains Trifluoroacetic Acid Ethyl Ester 340mL, boiling point 60 ~ 62 DEG C, and yield is 94.2%.
The preparation of embodiment 2 pairs of Hydrazinobenzenesulfonamide hydrochlorides
First with Sodium Nitrite, diazonium salt is obtained by reacting to amido benzsulfamide, is then obtained hydrazine by Sodium Nitrite reduction.
Table 1, prepare feeding intake and proportioning to Hydrazinobenzenesulfonamide hydrochloride
operating process:
A, 200L(208#) drop into (41kg hydrochloric acid and 60kg purified water) mixed solution in retort, stir lower input 20kg to amido benzsulfamide, cool to less than-4 ~-10 DEG C.For subsequent use.
B, in 50L bucket, take 8.84kg Sodium Nitrite, add 24.8kg purified water, be stirred to entirely molten.
C, sodium nitrite solution is instilled 208# retort, temperature-4 ~-10 DEG C in control process, drip after finishing, stir 10 minutes.
D, at 500L(204#) add 96.8kg purified water in retort, add 37.68kg S-WAT under stirring, cooling, is chilled to less than-5 DEG C.208# reaction solution is incorporated to.Purify after washing 208# retort etc. with 4kg and add in the lump.Finish stirring 10 minutes.
Be warming up to 75 ~ 80 DEG C under E, stirring, add 95kg hydrochloric acid, insulated and stirred 60 minutes, filtrate is filtered to 202#, standing, Temperature fall to 25 ± 2 DEG C, crystallization 2-3 hour.Filter, crystalline substance washed by the dehydrated alcohol that filter cake 20kg is cold, dry 12 hours of 70 ~ 75 DEG C of vacuum (vacuum tightness >=0.085Mpa).
F, must to Hydrazinobenzenesulfonamide hydrochloride 20.3kg, purity 98.4%, yield 78.16%.
the optimization of reaction conditions:
Table 2, the research of diazotization reaction condition
According to above-mentioned analysis, we tentatively determine that the temperature of diazotization reaction is-10 ~-4 DEG C, and the reaction times is 10 minutes.
Table 3, Sodium Nitrite and S-WAT quantity research
We have studied the Sodium Nitrite of 1.0,1.1,1.2 equivalents, experimental result draws, 1.1,1.2 equivalents experiment yields basically identical, impurity situation is more stable, the maximum list of 1.0 equivalent mix bigger than normal, yield is on the low side.In order to ensure to react completely, the throwing amount of Sodium Nitrite is decided to be 1.1 equivalents by us.
We are studied the consumption of S-WAT simultaneously, find that S-WAT consumption does not significantly affect on the output of Hydrazinobenzenesulfonamide hydrochloride and yield, in order to ensure that reduction completely, we determine that the consumption of S-WAT is 2.5 times of sulfanilic amide molar weight.
Table 4, reduction reaction temperature are studied
Can be found by upper table, when being added in S-WAT by diazonium salt, temperature must control below-4 DEG C, otherwise diazonium salt decomposes too fast, and by product is more, and yield is lower.
The preparation of fluoro-1, the 3-dimethyl diketone of embodiment 31-(4-aminomethyl phenyl)-4,4,4-tri-
Feeding intake and proportioning of table 5, fluoro-1, the 3-dimethyl diketone of preparation 1-(4-aminomethyl phenyl)-4,4,4-tri-
operating process:
Drop into dehydrated alcohol 47.6kg in A, 208# retort (needing drying), add sodium ethylate 7.62kg, be stirred to entirely molten.
B, temperature control less than 40 DEG C, adds Trifluoroacetic Acid Ethyl Ester 16.1kg, stirs 5 minutes.Add p-methyl aceto phenone 11.42kg, be warming up to 50 ± 2 DEG C, insulated and stirred 2 hours.For subsequent use.
the optimization of reaction conditions:
The reaction conditions research of table 6, fluoro-1, the 3-dimethyl diketone of preparation 1-(4-aminomethyl phenyl)-4,4,4-tri-
Drawn by analytical results, temperature of reaction is lower than 40 DEG C, and raw material reaction is not complete, temperature of reaction high with 60 DEG C, by product is more, reacts more applicable between 50 ± 2 DEG C.
The preparation of embodiment 4 celecoxib crude product
Table 7, prepare feeding intake and proportioning of celecoxib crude product
operating process:
Drop in A, 204# retort Hydrazinobenzenesulfonamide hydrochloride: 20kg, dehydrated alcohol 44.3kg, purified water 31.7kg, under stirring, add trifluoroacetic acid 10.2kg, be warming up to 50 DEG C ± 2 DEG C.
B, slowly add 208# reaction solution, finish insulation reaction 30 minutes.
C, be warming up to 65 ± 2 DEG C, drip 78.6kg purified water.Insulated and stirred 30 minutes.Standing, Temperature fall to 25 ± 2 DEG C, crystallization 2-3 hour.
D, filtration, wash brilliant secondary with 50% ethanol.
E, crude product were in 70-75 DEG C of vacuum (vacuum tightness >=0.085Mpa) drying 15 hours.
F, celecoxib crude product 25.87kg, purity 99.64%, yield 75.93%.
the optimization of reaction conditions:
Table 8, prepare the research of celecoxib reaction conditions
Drawn by interpretation of result, dropping temperature is comparatively suitable at 50 ± 2 DEG C.
Refining of embodiment 5 celecoxib
purification operations:
Drop into crude product 25.5kg in A, 204# retort, dehydrated alcohol 82kg, stir, water-bath 80 DEG C, after entirely molten, add 1kg gac, backflow 15-20 minute.
B, filtration carbon removal.
C, filtrate move in the 402# retort of clean area, add thermosol clear, slowly drip purified water 95kg.Gradually separate out solid, finish, stir Temperature fall to 25 ± 2 DEG C, crystallization 2-3 hour.
D, filtration, wash crystalline substance with 50% ethanol, moved to by filter cake in drying under reduced pressure case, dry 15 hours of 70-75 DEG C of vacuum (vacuum tightness >=0.085Mpa).
E, celecoxib finished product 23.46kg, yield 92%.
Table 9, celecoxib crude product and celecoxib highly finished product HPLC spectrogram contrast
Detect in celecoxib crude product one be greater than 0.05% impurity, in highly finished product without be greater than 0.05% impurity.
the optimization of reaction conditions:
According to the Crystallization method of crude product, the consumption of ethanol and water is we have studied in refining, when ethanol is 3 times amount of crude product plastid ratio, product dissolves completely and does not separate out in filtration procedure, 2.4 times of filtrations can be separated out, we adopt the ethanol of 3.0 ~ 5.0 times amount, by activated carbon decolorizing, filter and remove charcoal.The ethanolic soln of crude product under agitation drips elutriation crystalline substance, and we are by research, and the amount of water can obtain target crystal formation product and yield is higher in 3.5 ~ 4.5 times amount.
The preparation of embodiment 6 celecoxib crystal
(1) research of recrystallization temperature
Taking celecoxib three parts of each 3.0g puts in 3 reaction flasks, and 1., 2., 3. numbering, adds ethanol 12ml respectively, stir lower heating for dissolving, until completely dissolved, respectively to 1., 2., 3. in drip 11ml water, drip and finish, under stirring, be cooled to 25 DEG C, 15 DEG C, 5 DEG C crystallizatioies 3 hours respectively; Suction filtration, is placed in decompression baking oven, 70 ± 5 DEG C of drying under reduced pressure by filter cake.
By the X-ray collection of illustrative plates of comparative analysis products obtained therefrom, be not difficult to find out, their crystal formation is all crystalline form III, and therefore we draw: celecoxib in ethanol water between 5 ~ 25 DEG C the stirring and crystallizing crystal formation of 3 hours be consistent, crystal formation is all crystalline form III.
(2) research of crystallization time
Taking celecoxib 6.0g puts in reaction flask, adds ethanol 24ml, stirs lower heating for dissolving, until completely dissolved, drips 22ml water, drip and finish, stir borehole cooling to 20 ± 5 DEG C crystallization; Start timing when temperature drops to 25 DEG C, get the crystallization sample of 0,2,4,6,8,10,12 hours respectively, suction filtration, filter cake is placed in decompression baking oven, 70 ± 5 DEG C of drying under reduced pressure; Products obtained therefrom be numbered A, B, C, D, E, F, G.
Contrast finds, their X-ray collection of illustrative plates is identical, is all crystalline form III.Therefore, we take this crystal formation, simple to operate, controlled.
Crystallization condition is decided to be 25 ± 2 DEG C the most at last, crystallization 2-3 hour, obtains crystalline form III.2 θ (°) data of its X-ray are mainly: 5.2,10.5,14.6,15.9,19.5,21.3,22.0,26.8,29.4.
After testing, product granularity is all comparatively thin, and the size-grade distribution of each batch of product is consistent, and the D10 of lab scale three batches and pilot scale three batches of products is all in the scope of 3.5 μm ~ 4.5 μm, and D50 is all in the scope of 12 μm ~ 15 μm, and D90 is all in the scope of 35 μm ~ 42 μm.
Adopt preparation method of the present invention can high yield prepare celecoxib, products obtained therefrom purity is high, single assorted controls below 0.5%, and the fine size of the celecoxib crystal obtained, and distributes homogeneous, is very applicable to production of raw medicine.
Claims (10)
1. a preparation method for celecoxib, it comprises the steps:
Step (1): with p-methyl aceto phenone and Trifluoroacetic Acid Ethyl Ester for raw material, obtain fluoro-1, the 3-dimethyl diketone of 1-(4-aminomethyl phenyl)-4,4,4-tri-through Claisen condensation;
Fluoro-1, the 3-dimethyl diketone of step (2): 1-(4-aminomethyl phenyl)-4,4,4-tri-with celecoxib crude product is obtained to the cyclization of Hydrazinobenzenesulfonamide hydrochloride;
Step (3): celecoxib crude product is used dissolve with ethanol at normal temperatures, activated carbon decolorizing, cross filtering gac, filtrate under agitation drips water, separates out celecoxib.
2. the preparation method of celecoxib according to claim 1, is characterized in that: described step (1) take sodium ethylate as catalyzer, and ethanol is solvent, and temperature of reaction is 48-52 DEG C, and the reaction times is 2-3 hour.
3. the preparation method of celecoxib according to claim 1, it is characterized in that: described step (2) take trifluoroacetic acid as catalyzer, take ethanol/water as mixed solvent, first at 48-52 DEG C of reaction 30-40 minute, then add water and be warming up to 63-67 DEG C of stirring reaction 30-40 minute.
4. the preparation method of celecoxib according to claim 1, it is characterized in that: the celecoxib crude product in described step (3) is 1:3-5g/mL with the plastid ratio of ethanol, celecoxib crude product is 1:3.5 ~ 4.5g/mL with the plastid ratio of water, and recrystallization temperature is 25 DEG C, stirs 2 ~ 3 hours.
5. the preparation method of celecoxib according to claim 1, is characterized in that: the preparation method to Hydrazinobenzenesulfonamide hydrochloride described in step (2) is:
To be dissolved in aqueous hydrochloric acid to amido benzsulfamide, and be cooled to-4 ~-10 DEG C, drip sodium nitrite in aqueous solution, hierarchy of control temperature is-4 ~-10 DEG C, drips after finishing, stirs 10 minutes; The sodium sulfite aqueous solution of above-mentioned reaction solution with-5 DEG C is mixed, stirs 10 minutes; Be warming up to 75 ~ 80 DEG C, add concentrated hydrochloric acid, insulated and stirred 60 minutes, filter, leave standstill, Temperature fall is to room temperature, and crystallization 2-3 hour, filters, the cold absolute ethanol washing of filter cake, 70 ~ 75 DEG C of vacuum-drying 12 hours.
6. the preparation method of celecoxib according to claim 5, is characterized in that: in described aqueous hydrochloric acid, the mass ratio of hydrochloric acid and water is 2:3; Mass ratio=1:2 ~ 3 of described sodium sulfite aqueous solution sulfite sodium and water; The add-on of described aqueous hydrochloric acid is 4-5 times to amido benzsulfamide weight; The add-on of described sodium nitrite in aqueous solution is 1.5-2 times to amido benzsulfamide weight; The add-on of described sodium sulfite aqueous solution is 6-7 times to amido benzsulfamide weight; The add-on of described concentrated hydrochloric acid is 4-5 times to amido benzsulfamide weight.
7. the preparation method of celecoxib according to claim 1, is characterized in that: the preparation method of the Trifluoroacetic Acid Ethyl Ester described in step (1) is:
Take dehydrated alcohol as solvent, trifluoroacetic acid is mixed with the D072 storng-acid cation exchange resin as catalyzer, described D072 storng-acid cation exchange resin is 1:3g/mL with the plastid ratio of trifluoroacetic acid, heated and stirred back flow reaction 8h, filtration under diminished pressure falls resin, and rectifying obtains Trifluoroacetic Acid Ethyl Ester.
8. the preparation method of celecoxib according to claim 5, is characterized in that: the described synthetic method to amido benzsulfamide is:
Acetanilide and chlorsulfonic acid react to obtain para-acetylaminobenzene sulfonyl chloride, then react acetamido benzsulfamide with ammoniacal liquor, after be hydrolyzed in sodium bicarbonate aqueous solution and obtain amido benzsulfamide.
9. the preparation method of celecoxib according to claim 1, it is characterized in that: by the celecoxib ethanol heating for dissolving obtained in step (3), the mass volume ratio of celecoxib and ethanol is 1:4g/mL, then the water with ethanol equivalent is dripped, stir borehole cooling to 5-25 DEG C, crystallization 2-3 hour, suction filtration, 70 ± 5 DEG C of drying under reduced pressure, obtain celecoxib crystal.
10. the preparation method of celecoxib according to claim 9, is characterized in that: the X-ray diffraction spectrogram of described celecoxib crystal has the characteristic peak that diffraction angle 2 θ is 5.2 °, 10.5 °, 14.6 °, 15.9 °, 19.5 °, 21.3 °, 22.0 °, 26.8 °, 29.4 °.
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| CN116606231A (en) * | 2023-05-22 | 2023-08-18 | 河北冀衡药业股份有限公司 | P-sulfonamide phenylhydrazine hydrochloride and preparation method thereof |
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