CN106632003B - A kind of preparation method of Etoricoxib - Google Patents
A kind of preparation method of Etoricoxib Download PDFInfo
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- CN106632003B CN106632003B CN201611153262.7A CN201611153262A CN106632003B CN 106632003 B CN106632003 B CN 106632003B CN 201611153262 A CN201611153262 A CN 201611153262A CN 106632003 B CN106632003 B CN 106632003B
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- etoricoxib
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- acid salt
- solvent
- halogen
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- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 title claims abstract description 184
- 229960004945 etoricoxib Drugs 0.000 title claims abstract description 183
- 238000002360 preparation method Methods 0.000 title claims abstract description 103
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 61
- 239000002253 acid Substances 0.000 claims abstract description 59
- 239000002904 solvent Substances 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 150000002367 halogens Chemical class 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 150000008282 halocarbons Chemical class 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 235000019441 ethanol Nutrition 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 15
- -1 halogen acids Chemical class 0.000 claims description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 150000007529 inorganic bases Chemical class 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 150000001298 alcohols Chemical class 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000012805 post-processing Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 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 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 24
- 238000003756 stirring Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000356 contaminant Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 229950004288 tosilate Drugs 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 201000005569 Gout Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 206010018634 Gouty Arthritis Diseases 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- HGGWOSYNRVOQJH-UHFFFAOYSA-N 2-(4-methylsulfonylphenyl)acetic acid Chemical compound CS(=O)(=O)C1=CC=C(CC(O)=O)C=C1 HGGWOSYNRVOQJH-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- 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
Abstract
The invention discloses a kind of preparation methods of Etoricoxib.The present invention provides the preparation methods of Etoricoxib I a kind of, comprising the following steps: in halogenated hydrocarbon solvent, Etoricoxib I halogen acid salt and alkali is carried out neutralization reaction, obtain Etoricoxib I；Wherein, X is halogen.Preparation method reaction condition of the invention is mild, safety easy to operate, without extraordinary purifier apparatus, avoid and use column chromatography that operation, high income, (purity is greater than 99.5% to Etoricoxib obtained purity is high in last handling process, all impurity are respectively less than 0.10%, can reach bulk pharmaceutical chemicals standard), it is at low cost, be suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of Etoricoxib.
Background technique
Etoricoxib piece (trade name: Ankang letter), is a kind of Selective COX-2 inhibitor, has anti-inflammatory, analgesia and antipyretic
Effect, suitable for treating the sings and symptoms of osteoarthritis acute stage and chronic phase, also can treat acute gouty arthritis.
By MSD Corp.'s research and development, production, listed in 84 countries and regions in the whole world including China at present.Etoricoxib
Recommended the treatment for being used for acute gouty arthritis by American Society of Rheumatism gout diagnosis and treatment guide.China's osteoarthritis diagnosis and treatment
Guide and the Orthopedic Pain of osteology branch of Chinese Medical Association processing expert opinion recommend the patient for having gastrointestinal tract risk to select
Etoricoxib can be used in Selective COX-2 inhibitor.Etoricoxib structure is shown in formula I.
The method that Etoricoxib is synthesized under the conditions of the prior art is reacted by intermediate II and Etoricoxib intermediate III
It obtains, most of document (United States Patent (USP) 6040319, Chinese patent CN1182117C, CN1227233C and CN102898357A
Deng) report the tosilate for needing to be made into Etoricoxib re-refine.The condition that Etoricoxib tosilate is formed
Compare harsh, operating condition is cumbersome, yield relatively low (yield<40%), impurity are difficult to purify (single contaminant>0.15%) more
(see comparative example 1), is unfavorable for industrialized production.It is, thus, sought for a kind of effective preparation method, simplifies purification process
Step improves purity and yield.
Summary of the invention
The technical problem to be solved by the present invention is in order to overcome in the prior art Etoricoxib preparation method it is cumbersome,
The purity difference of low, the obtained product of yield is difficult to purify, high production cost, is not suitable for the defects of industrialized production and provides
A kind of preparation method of Etoricoxib.Preparation method reaction condition of the invention is mild, safety easy to operate, without extraordinary purifying
Equipment avoids that operation, high income, Etoricoxib obtained are used column chromatography in last handling process is with high purity, at low cost, suitable
Together in industrialized production.
The present invention provides the preparation methods of Etoricoxib I a kind of comprising following steps:, will in halogenated hydrocarbon solvent
The halogen acid salt and alkali of Etoricoxib I carries out neutralization reaction, obtains Etoricoxib I；
Wherein, X is halogen (such as chlorine, bromine or iodine).
The preparation method of the Etoricoxib I can be the conventional method of such neutralization reaction in this field, the present invention
In particularly preferably following reaction condition:
In the preparation method of the Etoricoxib I, the preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent；It is described
The preferred methylene chloride of chlorinated hydrocarbon solvent.
In the preparation method of the Etoricoxib I, the hydrogen of the halogenated hydrocarbon solvent and the Etoricoxib I
Volume mass ratio preferred 1mL/g~100mL/g, further preferred 2mL/g~10mL/g, such as the 2mL/g of halate.
In the preparation method of the Etoricoxib I, the preferred Etoricoxib I salt of Etoricoxib I halogen acid salt
One of hydrochlorate, Etoricoxib I hydrobromate and Etoricoxib I hydriodate are a variety of, further preferred Etoricoxib I salt
Hydrochlorate.
In the preparation method of the Etoricoxib I, the preferred inorganic base of the alkali, the preferred carbonic acid of the inorganic base
One of hydrogen sodium, sodium carbonate, potassium carbonate and cesium carbonate are a variety of, in further preferred sodium bicarbonate, sodium carbonate and potassium carbonate
It is one or more.The inorganic base uses preferably in the form of its aqueous solution, and the quality of the inorganic base aqueous solution is dense
Degree preferably 5%~15%, such as 10%, the mass concentration refers to the quality and inorganic base aqueous solution gross mass of inorganic base
Percentage.
In the preparation method of the Etoricoxib I, mole of the alkali and the Etoricoxib I halogen acid salt
Ratio preferably 1~5, further preferred 1.1~3, such as 1.2,1.5 or 1.9.
In the preparation method of the Etoricoxib I, preferably 0~40 DEG C of the temperature of the neutralization reaction, further
It is preferred that 20 DEG C~30 DEG C, such as 10 DEG C~20 DEG C.
In the preparation method of the Etoricoxib I, the process of the neutralization reaction can be using in this field
Routine monitoring method (such as TLC, HPLC or NMR) is monitored, as reaction when generally being disappeared using Etoricoxib I halogen acid salt
Terminal, the time of the neutralization reaction preferably 10 minutes~1 hour, further preferred 30 minutes~1 hour, such as 30 points
Clock.
The preparation method of the Etoricoxib I preferably includes following post-processing step: after neutralization reaction, washing,
Organic phase is dry, filter, obtains Etoricoxib I after removing solvent.Washing, liquid separation, drying, filtering and the removing solvent can
Using the conventional method of the generic operation in this field.The washing preferably uses saturated sodium-chloride water solution to wash；It is described
Number preferably 1~3 time of washing, such as 2 times.Alkane solvents are preferably first added in the organic phase before the drying；Institute
The preferred normal heptane of the alkane solvents stated.The drying preferably uses anhydrous sodium sulfate and/or anhydrous magnesium sulfate.The mistake
Filter preferred silica gel or diatomite filtering.The silica gel preferably 200 mesh~300 mesh silica gel.The filter cake obtained after filtering is preferred
It is eluted.The mixed solvent of solvent preferred chlorinated hydrocarbon solvent and alkane solvents that the elution uses；The chlorine
For the in the mixed solvent of hydrocarbon solvent and alkane solvents, the volume of the chlorinated hydrocarbon solvent and the alkane solvents
Ratio preferred 5:1~1:5, further preferred 1:1~1:2, such as 1:1.The preferred methylene chloride of the chlorinated hydrocarbon solvent, institute
The preferred normal heptane of the alkane solvents stated.The number of the elution preferably 1 time~3 times, such as 2 times.The removing solvent
It is preferred that by the way of being concentrated under reduced pressure, the pressure of the reduced pressure preferably -0.08MPa~0.01MPa；The decompression is dense
Preferably 15 DEG C~40 DEG C of the temperature of contracting.
The Etoricoxib I is preferably further recrystallized to give Etoricoxib I after purification.The recrystallization can be with
For the conventional method of the generic operation in this field.The preferred alcohols solvent of solvent that the recrystallization uses.The alcohols is molten
One of the preferred isopropanol of agent, methanol and ethyl alcohol are a variety of.
The recrystallization preferably uses following steps: the solution that Etoricoxib I and alcohols solvent are formed is cooled to 0
~30 DEG C (preferably 15 DEG C~25 DEG C, such as 17 DEG C~22 DEG C), crystallization obtains Etoricoxib I after purification.The support is examined
The solution that former times I and alcohols solvent are formed, which refers to, is dissolved in Etoricoxib I in alcohols solvent.The temperature of the dissolution preferably 40
DEG C~boiling point of solvent, further preferred 60 DEG C~80 DEG C, such as 60 DEG C~70 DEG C.
The Etoricoxib I HPLC purity after purification is greater than 99.50%, and maximum single contaminant content is less than
0.10%, reach bulk pharmaceutical chemicals standard.
The preparation method of the Etoricoxib I, it is also preferable to include the preparation method of Etoricoxib I halogen acid salt, packets
It includes following steps: in alkyl alcohol solvent, Etoricoxib I crude product and halogen acids being subjected to salt-forming reaction and obtain the Etoricoxib
I halogen acid salt；
Wherein, X is as defined above described.
The preparation method of the Etoricoxib I halogen acid salt can be the routine side of such salt-forming reaction in this field
Method, the present invention in particularly preferably following reaction condition:
In the preparation method of the Etoricoxib I halogen acid salt, the preferred methanol of the alkyl alcohol solvent, ethyl alcohol,
One of isopropanol and the tert-butyl alcohol are a variety of；Further preferred isopropanol.
In the preparation method of the Etoricoxib I halogen acid salt, the alkyl alcohol solvent is examined with the support
Volume mass ratio preferred 1mL/g~6mL/g, further preferred 2mL/g~5mL/g, such as the 2.2mL/g of former times I crude product.
In the preparation method of the Etoricoxib I halogen acid salt, the preferred hydrochloric acid of the halogen acids, hydrobromic acid or hydrogen
Acid iodide.Hydrochloric acid, hydrobromic acid and the hydroiodic acid can be conventional commercial reagent.The molar concentration of the halogen acids is preferred
1mol/L~5mol/L, further preferred 3mol/L~4mol/L, such as 4mol/L.The halogen acids is preferably with its alkylol
The form of solution uses, one of the preferred methanol of the alkylol, ethyl alcohol, isopropanol and tert-butyl alcohol or a variety of.Described
The molar concentration of halogen acids alkyl alcohol solution preferred 1mol/L~5mol/L, further preferred 3mol/L~4mol/L, such as
4mol/L。
In the preparation method of the Etoricoxib I halogen acid salt, the purity of the Etoricoxib I crude product is preferred
80%~99%, the Etoricoxib I crude product may be to be reacted to prepare Etoricoxib I with compound III by compound II
Reaction solution.
In the preparation method of the Etoricoxib I halogen acid salt, the halogen acids and the Etoricoxib I are thick
The molar ratio of product preferably 0.5~3, further preferred 0.9~1.5, such as 0.8 or 0.9.
In the preparation method of the Etoricoxib I halogen acid salt, the temperature of the salt-forming reaction preferably 0~40
DEG C, further preferred 10 DEG C~20 DEG C.
In the preparation method of the Etoricoxib I halogen acid salt, the process of the salt-forming reaction can be using this
Routine monitoring method (such as TLC, HPLC or NMR) in field is monitored, and is anti-when generally being disappeared with Etoricoxib I crude product
The terminal answered, the time of the salt-forming reaction preferably 1 hour~10 hours, further preferred 2 hours~5 hours, such as 2 is small
When.
The preparation method of the Etoricoxib I halogen acid salt preferably uses following steps: to Etoricoxib I crude product and alkane
The alkyl alcohol solution of halogen acids is added in the solution that base alcohol is formed, carries out salt-forming reaction and obtains the Etoricoxib I halogen acids
Salt.The mode of the addition is preferably added dropwise.The speed of the dropwise addition is subject to maintenance system temperature no more than 15 DEG C.
The preparation method of the Etoricoxib I halogen acid salt preferably includes following post-processing step: after reaction, mistake
It filters, wash, being dried to obtain the Etoricoxib I halogen acid salt.Described being filtered, washed and dried can be using in this field
The conventional method of the generic operation.The washing preferably uses alkyl alcohol solvent to wash；The preferred methanol of the alkyl alcohol solvent,
One of ethyl alcohol and isopropanol are a variety of.The number of the washing preferably 1~3 time, such as 2 times.The drying is preferred
Vacuum drying；The vacuum drying pressure preferably -0.08MPa~0.01MPa.The vacuum drying temperature preferably 50
DEG C~60 DEG C, such as 60 DEG C；The vacuum drying time preferably 10 hours~24 hours, further preferred 16 hours~20
Hour, such as 16 hours.
In the preparation method of the Etoricoxib I halogen acid salt, the Etoricoxib intermediate II and support are examined
The method that former times intermediate III can be reported according to patent CN01810137 is made；The Etoricoxib intermediate III can be by
It is made according to method reported in the literature.
The present invention also provides the preparation methods of Etoricoxib I halogen acid salt comprising following steps: alkyl alcohol solvent
In, Etoricoxib I crude product and halogen acids are subjected to salt-forming reaction and obtain Etoricoxib I halogen acid salt；
Wherein, X is halogen (such as chlorine, bromine or iodine).Each reaction condition is as described above.
The present invention also provides Etoricoxib I halogen acid salt, structure is as follows:
Wherein, X is as defined above described.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: preparation method reaction condition of the invention is mild, safety easy to operate, nothing
Extraordinary purifier apparatus is needed, avoids and uses column chromatography operation, high income, Etoricoxib obtained purity is high in last handling process
(purity be greater than 99.5%, all impurity are respectively less than 0.10%, can reach bulk pharmaceutical chemicals standard), it is at low cost, be suitable for industrializing
Production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1: the preparation method (being prepared according to the method for patent CN01810137 description) of Etoricoxib intermediate II
Tetrahydrofuran (6L) is added in 4- mesyl phenylacetic acid (3.0Kg), and the tetrahydro furan of the tert-butyl magnesium chloride of 1M is added dropwise
Mutter solution (40L), heats 70~80 DEG C, tetrahydrofuran (5L) solution of 6- methyinicotinate (1.7kg) is slowly added dropwise, about
It drips off within 2~3 hours.1 hour is maintained the reflux for after adding.20~25 DEG C are cooled to, water is added, is 20% sodium hydroxide with mass concentration
Aqueous solution (mass concentration refers to that the quality of sodium hydroxide accounts for the percentage of sodium hydrate aqueous solution gross mass) is transferred to pH
=7~8, a large amount of solids are precipitated.Centrifugation, filter cake are dried in vacuo 16 hours after being eluted with water at 50 DEG C, and it is solid to obtain about 3.6kg yellow
Body.II among 1.8kg Etoricoxib is recrystallized to give with methylene chloride (20L).
Embodiment 2: the preparation method (being prepared according to the method for patent CN01810137 description) of Etoricoxib intermediate III
N,N-Dimethylformamide (8.8L) is heated to 50~55 DEG C, and 2.0kg chloracetyl chloride is slowly added dropwise, it is warming up to 65~
It 70 DEG C, is added dropwise phosphorus oxychloride (2.8kg), is cooled to 20~30 DEG C after stirring 12 hours at 65~70 DEG C.It is added dropwise to quick stirring
Ice water (40L) in, wherein ice water contain hexafluorophosphoric acid (7.75kg) and sodium hydroxide (1.6kg), with 50% after adding
(wt%) sodium hydrate aqueous solution tune pH=1~2.After stirring 30 minutes, centrifugation, filter cake is eluted with water (2L), 60 DEG C of air blast
It is 12 hours dry, obtain 3.2kg Etoricoxib intermediate III.
Embodiment 3: the preparation method of Etoricoxib I hydrochloride
The dissolution of 4L isopropanol is added in Etoricoxib crude product 2.6Kg (HPLC purity 85.17%).At 15 DEG C or less under stirring
The hydrochloric acid aqueous isopropanol 1.7L of 4mol/L is added dropwise, in 10~20 DEG C of stirrings, 2 hours precipitation hydrochlorides after adding.Filtering, filter cake
Twice with isopropanol (1L) elution, -0.08MPa~0.01MPa, 60 DEG C obtain 2.25kg yellow solid in vacuum drying 16 hours and are
Etoricoxib I hydrochloride.Yield 91.5%.
Embodiment 4: the preparation method of Etoricoxib I
Methylene chloride (4.5L) is added in Etoricoxib I hydrochloride (2.25kg) at 10~20 DEG C, adds mass concentration
For 10% sodium bicarbonate aqueous solution (10Kg), (it is total that the mass concentration refers to that the quality of sodium bicarbonate accounts for sodium bicarbonate aqueous solution
The percentage of quality).Stirring 30 minutes, liquid separation；Organic phase is washed twice with saturated sodium-chloride (6L), liquid separation.It is organic to be added to
Normal heptane (4.5L) is simultaneously dry with anhydrous sodium sulfate (1kg), with silica gel (200~300 mesh；It 2kg) filters, filter cake is with the two of 1:1
The mixed solution (1L) and methylene chloride (1L) of chloromethanes and normal heptane elute twice, merging mother liquor, and -0.08MPa~
0.01MPa, 15~40 DEG C are concentrated to dryness.4L isopropanol is added and being heated to 60 DEG C~70 DEG C dissolves residue.Solution
It is cooled to 17~22 DEG C of precipitation solids under stirring, filters；Filter cake is eluted with isopropanol (1L), and normal heptane (1L) elution, 50 DEG C true
Sky drying 18 hours, obtains 1.95kg Etoricoxib I.Yield 96.5%.LC-MS:m/z=359,361 (M+H)+.HPLC:
99.87%, maximum single contaminant 0.099%.
Embodiment 5: the preparation method of Etoricoxib I hydrochloride
The dissolution of 40mL isopropanol is added in Etoricoxib crude product 26.0g (HPLC purity 87.90%).Under stirring 15 DEG C with
The lower hydrochloric acid aqueous isopropanol 17mL that 4mol/L is added dropwise, in 10~20 DEG C of stirrings, 2 hours precipitation hydrochlorides after adding.Filtering, filter
Cake is eluted twice with isopropanol (10mL), -0.08MPa~0.01MPa, and 60 DEG C obtain 23.1g yellow for vacuum drying 16 hours and consolidate
Body is Etoricoxib I hydrochloride, yield 90.8%.
Embodiment 6: the preparation method of Etoricoxib I
Methylene chloride (45mL) is added in Etoricoxib I hydrochloride (22.1g) at 10~20 DEG C, and adding mass concentration is
(mass concentration refers to that the quality of sodium carbonate accounts for the hundred of aqueous sodium carbonate gross mass to 10% aqueous sodium carbonate (100g)
Divide ratio).Stirring 30 minutes, liquid separation；Organic phase is washed twice with saturated sodium-chloride (60mL), liquid separation.It is organic to be added to normal heptane
It is (45mL) and dry with anhydrous sodium sulfate (10g), with silica gel (200~300 mesh；It 20g) filters, the methylene chloride of filter cake 1:1
It is eluted twice with the mixed solution (10mL) and methylene chloride (10mL) of normal heptane, merging mother liquor, -0.08MPa~0.01MPa,
15~40 DEG C are concentrated to dryness.40mL isopropanol is added and being heated to 60 DEG C~70 DEG C dissolves residue.Under solution stirring
17~22 DEG C of precipitation solids are cooled to, are filtered；Filter cake is eluted with isopropanol (10mL), normal heptane (10mL) elution, 50 DEG C of vacuum
Drying 18 hours, obtains 18.9g Etoricoxib I.Yield 95.2%.HPLC:99.89%, maximum single contaminant 0.053%.
Embodiment 7: the preparation method of Etoricoxib I hydrochloride
The dissolution of 400mL isopropanol is added in Etoricoxib crude product 259g (HPLC purity 88.1%).Under stirring 15 DEG C with
The lower hydrochloric acid aqueous isopropanol 170mL that 4mol/L is added dropwise, in 10~20 DEG C of stirrings, 2 hours precipitation hydrochlorides after adding.Filtering, filter
Cake is eluted twice with isopropanol (100mL), -0.08MPa~0.01MPa, and 60 DEG C obtain 233g yellow for vacuum drying 16 hours and consolidate
Body is Etoricoxib I hydrochloride.Yield 91.7%.
Embodiment 8: the preparation method of Etoricoxib I
Methylene chloride (450mL) is added in Etoricoxib I hydrochloride (223g) at 10~20 DEG C, and adding mass concentration is
(mass concentration refers to that the quality of potassium carbonate accounts for the hundred of wet chemical gross mass to 10% wet chemical (1Kg)
Divide ratio).Stirring 30 minutes, liquid separation；Organic phase is washed twice with saturated sodium-chloride (600mL), liquid separation.It is organic to be added to normal heptane
It is (450mL) and dry with anhydrous sodium sulfate (100g), with silica gel (200~300 mesh；It 200g) filters, the dichloromethane of filter cake 1:1
The mixed solution (100mL) and methylene chloride (100mL) of alkane and normal heptane elute twice, merging mother liquor, and -0.08MPa~
0.01MPa, 15~40 DEG C be concentrated to dryness.400mL isopropanol is added and being heated to 60 DEG C~70 DEG C dissolves residue.It is molten
17~22 DEG C of precipitation solids are cooled under liquid stirring, are filtered；Filter cake is eluted with isopropanol (100mL), normal heptane (100mL) leaching
Wash, 50 DEG C vacuum drying 18 hours, obtain 192.3g Etoricoxib I.Yield 96.0%.HPLC:99.93% is maximum single miscellaneous
Matter 0.034%.
Comparative example 1: the original preparation method of Etoricoxib I
It by Etoricoxib crude product (HPLC purity 85.17%) 21.8g, is added acetone (500mL), stirs lower be added dropwise to toluene
The acetone soln of sulfonic acid (15.8g) stirs 16 hours precipitation tosilate after adding.Filtering, acetone elute twice, and 50 DEG C
It is Etoricoxib tosilate that vacuum drying, which obtains 17.8g yellow solid,.Etoricoxib tosilate (17.8g) adds
Enter methylene chloride (36mL), adds saturated sodium bicarbonate aqueous solution (400mL).Stirring 30 minutes, liquid separation, washing, drying are used
Silica gel (200~300 mesh) filtering, elution, 15~40 DEG C are concentrated to dryness.160mL isopropanol, which is added, and heats makes residue
Dissolution.20 DEG C of precipitation solids are cooled under solution stirring, are filtered；Filter cake is eluted with isopropanol (50mL), normal heptane (50mL) leaching
It washes, 50 DEG C of vacuum dryings obtain 9.6g Etoricoxib I, yield 51.7%.LCMS:m/z=359,361 (M+H)+.HPLC:
99.58%, maximum single contaminant 0.168%.
Claims (46)
1. a kind of preparation method of Etoricoxib I, it is characterised in that it in halogenated hydrocarbon solvent the following steps are included: will rely on
It examines former times I halogen acid salt and alkali carries out neutralization reaction, obtain Etoricoxib I, Etoricoxib I is further recrystallized to give after purification
Etoricoxib I；The solvent used is recrystallized as alcohols solvent；
Wherein, X is chlorine；The alkali is inorganic base, and the inorganic base is sodium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate
One of or it is a variety of；The Etoricoxib I halogen acid salt is Etoricoxib I hydrochloride；The temperature of the neutralization reaction
It is 10 DEG C~20 DEG C；
The preparation method of the Etoricoxib I, it is further comprising the steps of: in alkyl alcohol solvent, by Etoricoxib I crude product and hydrogen
Hydracid carries out salt-forming reaction and obtains the Etoricoxib I halogen acid salt；
2. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that: the halogenated hydrocarbon solvent is chlorine
For hydrocarbon solvent.
3. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
The volume mass ratio of the halogen acid salt of the halogenated hydrocarbon solvent and the Etoricoxib I be 1mL/g~
100mL/g。
4. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that: the alkali is examined with the support
The molar ratio of former times I halogen acid salt is 1~5.
5. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that: the time of the neutralization reaction is
10 minutes~1 hour.
6. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
The preparation method of the Etoricoxib I includes following post-processing step: after neutralization reaction, washing, is organic relevant
Dry, filtering obtains Etoricoxib I after removing solvent.
7. the preparation method of Etoricoxib I as claimed in claim 2, it is characterised in that: in the preparation of the Etoricoxib I
In method, the chlorinated hydrocarbon solvent is methylene chloride.
8. the preparation method of Etoricoxib I as claimed in claim 3, it is characterised in that:
The volume mass ratio of the halogen acid salt of the halogenated hydrocarbon solvent and the Etoricoxib I is 2mL/g~10mL/
g。
9. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that: the inorganic base is with its aqueous solution
Form use.
10. the preparation method of Etoricoxib I as claimed in claim 4, it is characterised in that: the alkali is examined with the support
The molar ratio of former times I halogen acid salt is 1.1~3.
11. the preparation method of Etoricoxib I as claimed in claim 5, it is characterised in that: the time of the neutralization reaction is
30 minutes~1 hour.
12. the preparation method of Etoricoxib I as claimed in claim 6, it is characterised in that: the washing is using saturation food
Salt water washing.
13. the preparation method of Etoricoxib I as claimed in claim 6, it is characterised in that: the number of the washing is 1~3
It is secondary.
14. the preparation method of Etoricoxib I as claimed in claim 6, it is characterised in that: the organic phase is before the drying
Alkane solvents are first added.
15. the preparation method of Etoricoxib I as claimed in claim 6, it is characterised in that: the drying uses anhydrous slufuric acid
Sodium and/or anhydrous magnesium sulfate.
16. the preparation method of Etoricoxib I as claimed in claim 6, it is characterised in that: the filtering using silica gel or
Diatomite filtering.
17. the preparation method of Etoricoxib I as claimed in claim 6, it is characterised in that: the filter cake obtained after filtering is drenched
It washes.
18. the preparation method of Etoricoxib I as claimed in claim 6, it is characterised in that: the removing solvent is using decompression
The mode of concentration.
19. the preparation method of Etoricoxib I as claimed in claim 8, it is characterised in that: the halogenated hydrocarbon solvent and institute
The volume mass ratio of the halogen acid salt of the Etoricoxib I stated is 2mL/g.
20. the preparation method of Etoricoxib I as claimed in claim 9, it is characterised in that:
When the inorganic base in the form of its aqueous solution in use, the mass concentration of the inorganic base aqueous solution be 5%~
15%, the mass concentration refers to the quality of inorganic base and the percentage of inorganic base aqueous solution gross mass.
21. the preparation method of Etoricoxib I as claimed in claim 10, it is characterised in that: the alkali and the support
The molar ratio for examining former times I halogen acid salt is 1.2,1.5 or 1.9.
22. the preparation method of Etoricoxib I as claimed in claim 11, it is characterised in that: in the system of the Etoricoxib I
In Preparation Method, the time of the neutralization reaction is 30 minutes.
23. the preparation method of Etoricoxib I as claimed in claim 14, it is characterised in that: the alkane solvents are positive
Heptane.
24. the preparation method of Etoricoxib I as claimed in claim 16, it is characterised in that: the silica gel be 200 mesh~
300 mesh silica gel.
25. the preparation method of Etoricoxib I as claimed in claim 17, it is characterised in that: the solvent that the elution uses
For the mixed solvent of chlorinated hydrocarbon solvent and alkane solvents.
26. the preparation method of Etoricoxib I as claimed in claim 17, it is characterised in that: the number of the elution is 1 time
~3 times.
27. the preparation method of Etoricoxib I as claimed in claim 18, it is characterised in that: the pressure of the reduced pressure
For -0.08MPa~0.01MPa.
28. the preparation method of Etoricoxib I as claimed in claim 18, it is characterised in that: the temperature of the reduced pressure
It is 15 DEG C~40 DEG C.
29. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that: the alcohols solvent is isopropyl
One of alcohol, methanol and ethyl alcohol are a variety of.
30. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
The recrystallization uses following steps: the solution that Etoricoxib I and alcohols solvent are formed is cooled to 0~30 DEG C, analysis
Crystalline substance obtains Etoricoxib I after purification.
31. the preparation method of Etoricoxib I as claimed in claim 30, it is characterised in that:
In the step of recrystallization uses, the solution that the Etoricoxib I is formed with alcohols solvent, which refers to, examines support
Former times, I was dissolved in alcohols solvent；The temperature of the dissolution is 40 DEG C~80 DEG C.
32. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
In the preparation method of the Etoricoxib I halogen acid salt, the alkyl alcohol solvent is methanol, ethyl alcohol, isopropanol
With one of the tert-butyl alcohol or a variety of.
33. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
In the preparation method of the Etoricoxib I halogen acid salt, the alkyl alcohol solvent and the Etoricoxib I are thick
The volume mass ratio of product is 1mL/g~6mL/g.
34. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
In the preparation method of the Etoricoxib I halogen acid salt, the halogen acids is made in the form of its alkyl alcohol solution
With.
35. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
In the preparation method of the Etoricoxib I halogen acid salt, the purity of the Etoricoxib I crude product is 80%~
99%.
36. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
In the preparation method of the Etoricoxib I halogen acid salt, the halogen acids and the Etoricoxib I crude product
Molar ratio is 0.5~3.
37. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
In the preparation method of the Etoricoxib I halogen acid salt, the temperature of the salt-forming reaction is 0~40 DEG C.
38. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that: in the Etoricoxib I hydrogen halogen
In the preparation method of hydrochlorate, the time of the salt-forming reaction is 1 hour~10 hours.
39. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
The preparation method of the Etoricoxib I halogen acid salt uses following steps: being formed to Etoricoxib I crude product with alkylol
Solution in the alkyl alcohol solution of halogen acids is added, carry out salt-forming reaction and obtain the Etoricoxib I halogen acid salt.
40. the preparation method of Etoricoxib I as described in claim 1, it is characterised in that:
The preparation method of the Etoricoxib I halogen acid salt includes following post-processing step: after reaction, be filtered, washed,
It is dried to obtain the Etoricoxib I halogen acid salt.
41. the preparation method of Etoricoxib I as claimed in claim 33, it is characterised in that: the alkyl alcohol solvent and institute
The volume mass ratio for the Etoricoxib I crude product stated is 2mL/g~5mL/g.
42. the preparation method of Etoricoxib I as claimed in claim 34, it is characterised in that:
When the halogen acids in the form of its alkyl alcohol solution in use, the alkylol as methanol, ethyl alcohol, isopropanol and
One of tert-butyl alcohol is a variety of.
43. the preparation method of Etoricoxib I as claimed in claim 34, it is characterised in that:
When the halogen acids in the form of its alkyl alcohol solution in use, the molar concentration of the halogen acids alkyl alcohol solution
For 1mol/L~5mol/L.
44. the preparation method of Etoricoxib I as claimed in claim 36, it is characterised in that: the halogen acids and described
The molar ratio of Etoricoxib I crude product is 0.9~1.5.
45. the preparation method of Etoricoxib I as claimed in claim 37, it is characterised in that: the temperature of the salt-forming reaction
It is 10 DEG C~20 DEG C.
46. the preparation method of Etoricoxib I as claimed in claim 38, it is characterised in that: the time of the salt-forming reaction
It is 2 hours~5 hours.
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| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| CN1152863C (en) * | 1996-07-18 | 2004-06-09 | 麦克弗罗斯特(加拿大)公司 | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| CN104710349A (en) * | 2014-12-18 | 2015-06-17 | 威海康邦德医药技术开发有限公司 | Method for purifying etoricoxib |
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| WO2012004677A1 (en) * | 2010-07-05 | 2012-01-12 | Actavis Group Ptc Ehf | Solid state forms of etoricoxib salts |
| WO2013105106A1 (en) * | 2011-11-03 | 2013-07-18 | Cadila Healthcare Limited | An improved process for the preparation of etoricoxib and polymorphs thereof |
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| CN1152863C (en) * | 1996-07-18 | 2004-06-09 | 麦克弗罗斯特(加拿大)公司 | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| CN1443168A (en) * | 2000-05-26 | 2003-09-17 | 麦克公司 | 5-chloro-3-(4-methane sulfonylphenyl)-6-methyl-[2,3'] bipyridine and process for synthesis |
| CN104710349A (en) * | 2014-12-18 | 2015-06-17 | 威海康邦德医药技术开发有限公司 | Method for purifying etoricoxib |
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