CN104817473A - Application of 1-dimethylamino-3-dimethylimino-2-chloropropene perchlorate in preparation of Etocoxib - Google Patents
Application of 1-dimethylamino-3-dimethylimino-2-chloropropene perchlorate in preparation of Etocoxib Download PDFInfo
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- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 27
- 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 claims description 22
- 229960004945 etoricoxib Drugs 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000005457 ice water Substances 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000010792 warming Methods 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 claims description 10
- 229910001488 sodium perchlorate Inorganic materials 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 9
- -1 1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl Chemical group 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 239000012465 retentate Substances 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000007797 corrosion Effects 0.000 description 3
- 238000005260 corrosion Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- OBCUTHMOOONNBS-UHFFFAOYSA-N phosphorus pentafluoride Chemical compound FP(F)(F)(F)F OBCUTHMOOONNBS-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention relates to a preparation method of 1-dimethylamino-3-dimethylimino-2-chloropropene perchlorate (4), and a method for preparing Etocoxib from the compound 4.
Description
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to a kind of Etoricoxib intermediate and use this intermediate to carry out the method for Etoricoxib synthesis.
Background technology
Etoricoxib (Etoricoxib, compound 1) be a kind of highly selective Transitional cell carcinomas (COX-2) Depressant, its chemical name is: [the chloro-2-of 5-(6-picoline-3-base)-3-(4-sulfonyloxy methyl phenyl) pyridine].This compound obtains listing, is mainly used in treating osteoarthritis, rheumatoid arthritis and acute gouty arthritis (Niu Xiaofang, Etoricoxib progress, " medical Leader " 2010 (29), 221-223).
Its chemosynthesis is mainly by following scheme:
Compound 2 and compound 3 obtain Etoricoxib (Etoricoxib, compound 1) under a series of operation.
Wherein, in the building-up process of compound 3, need to use that higher, the toxicity of price is comparatively large, Potassium Hexafluorophosphate that solubleness is lower (this compound in aqueous, hydrogen fluoride gas or the hydrogen fluoride solution of severe toxicity may be generated, glass reaction still required for the reaction of meeting heavy corrosion), this just makes the preparation cost of Etoricoxib high and friendly not to environment.
Summary of the invention
The present invention seeks to for above-mentioned weak point, have employed the sodium perchlorate of price less than Potassium Hexafluorophosphate 1/3rd, synthesized compound 4.As everyone knows, the compound containing polyfluoro has larger toxicity usually, and the aqueous solution of Potassium Hexafluorophosphate has the possibility being decomposed into phosphorus pentafluoride and Potassium monofluoride.In relatively acid system, may be toxic comparatively large and may the hydrogen fluoride of heavy corrosion glass reaction still, this is very disadvantageous.And the generation of above-mentioned situation can be avoided completely with sodium perchlorate, and synthesize Etoricoxib by this compound 4.
Technical scheme
There is a synthetic method for structural compounds shown in formula 4, it is characterized by: after Mono Chloro Acetic Acid and DMF and phosphorus oxychloride reaction, then react obtained with sodium perchlorate solution.
Further, temperature of reaction when Mono Chloro Acetic Acid and DMF and phosphorus oxychloride reaction is progressively warming up to 100 DEG C by 10 DEG C.
Further, step is as follows:
(1) join in DMF by Mono Chloro Acetic Acid, ice-water bath is cooled to 10 DEG C, drip phosphorus oxychloride, after dropwising, be warmed up to 75 DEG C gradually and be incubated 2hr, then be warmed up to 85 DEG C and be incubated 2hr, be finally warming up to 100 DEG C and be incubated 2hr acquisition reaction solution;
(2) reaction solution that step (1) finally obtains is cooled to room temperature, lower the temperature with ice-water bath after dilute with water, dripping while ice-water bath cooling keeps pH value at about 4-5 containing the aqueous solution of sodium perchlorate and NaOH solution, vigorous stirring 2hr, filter, filter cake is through frozen water, cold washing with alcohol, and vacuum-drying, obtains solid;
(3) get the solid that step (2) finally obtains to join in ethanol, then add gac, stir and be warmed up to backflow, after backflow 20min, filter, filtrate is cooled to room temperature, has a large amount of solid to separate out; After treating that solid is separated out completely, filter, namely washing with alcohol filter retentate obtains the compound of structure shown in formula 4.
Further, step is as follows:
(1) Mono Chloro Acetic Acid of 10.0g is joined the N of 60mL, in dinethylformamide, ice-water bath is cooled to 10 DEG C, drip 19mL phosphorus oxychloride, after dropwising, be warmed up to 75 DEG C gradually and be incubated 2hr, be then warmed up to 85 DEG C and be incubated 2hr, be finally warming up to 100 DEG C and be incubated 2hr acquisition reaction solution;
(2) reaction solution that step (1) finally obtains is cooled to room temperature, lower the temperature with ice-water bath with after the dilution of 70mL water, dripping while ice-water bath cooling keeps pH value at about 4-5 containing the 15mL aqueous solution of 20g sodium perchlorate and 1N NaOH solution, vigorous stirring 2hr, filter, filter cake through frozen water, cold washing with alcohol, vacuum-drying, obtain 19.5g solid, yield 70.6%;
(3) get the solid 15.0g that step (2) finally obtains to join in 150mL ethanol, then add 0.2g gac, stir and be warmed up to backflow, after backflow 20min, filter, filtrate is cooled to room temperature, has a large amount of solid to separate out; After treating that solid is separated out completely, filter, namely washing with alcohol filter retentate obtains the compound of structure shown in formula 4.
A kind of method preparing Etoricoxib: 1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl ketone and the compound with structure shown in formula 4 according to claim 1 react.
Further, step is as follows:
Under ice-water bath, 1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl ketone is dissolved in tetrahydrofuran (THF), adds potassium tert.-butoxide in batches; After finishing, be warmed up to room temperature, reaction 1hr; Then add compound 1-dimethylamino-3-dimethyleneimine base-2-propenyl chloride perchlorate, after room temperature reaction 1hr, successively drip Glacial acetic acid and the tetrahydrofuran solution containing trifluoroacetic acid; After dropwising, reaction 1hr; In reaction solution, add ammoniacal liquor again, be warming up to backflow, back flow reaction 3hr, cool to room temperature; Add ethyl acetate again, stir and separatory, reclaim organic phase through concentrating under reduced pressure, the residue by silicagel column chromatography obtained obtains Etoricoxib.
Further, step is as follows:
Under ice-water bath, 1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl ketone of 7.2g is dissolved in 60mL tetrahydrofuran (THF), adds 3.0g potassium tert.-butoxide in batches; After finishing, be warmed up to room temperature, reaction 1hr; Then add 7.0g compound 1-dimethylamino-3-dimethyleneimine base-2-propenyl chloride perchlorate, after room temperature reaction 1hr, successively drip the Glacial acetic acid of 10.5g and the 25mL tetrahydrofuran solution containing 2.3g trifluoroacetic acid; After dropwising, reaction 1hr; In reaction solution, add 15mL ammoniacal liquor again, be warming up to backflow, back flow reaction 3hr, cool to room temperature; Add 100mL ethyl acetate again, stir and separatory, reclaim organic phase through concentrating under reduced pressure, the residue by silicagel column chromatography obtained obtains Etoricoxib.
Beneficial effect
The aqueous solution of Potassium Hexafluorophosphate has the possibility being decomposed into phosphorus pentafluoride and Potassium monofluoride, in relatively acid system, and may be toxic comparatively large and may the hydrogen fluoride of heavy corrosion glass reaction still.The generation of above-mentioned situation can be avoided with sodium perchlorate completely, and synthesized Etoricoxib by this compound 4.This product economy, nontoxic.
Embodiment
Below by embodiment, technical scheme of the present invention is described in further detail.Without specified otherwise, the reagent used by the embodiment of the present invention is commercially available analytical pure.
The synthesis of embodiment 1:1-dimethylamino-3-dimethyleneimine base-2-propenyl chloride perchlorate (compound 4)
Joined by the Mono Chloro Acetic Acid of 10.0g in the DMF (DMF) of 60mL, ice-water bath is cooled to 10 DEG C, drip 19mL phosphorus oxychloride, after dropwising, be warmed up to 75 DEG C gradually and be incubated 2hr, then be warmed up to 85 DEG C and be incubated 2hr, be finally warming up to 100 DEG C and be incubated 2hr.Reaction solution is cooled to room temperature, lower the temperature with ice-water bath with after the dilution of 70mL water, dripping while ice-water bath cooling keeps pH value at about 4-5 containing the 15mL aqueous solution of 20g sodium perchlorate and 1N NaOH solution, vigorous stirring 2hr, filter, filter cake through frozen water, cold washing with alcohol, vacuum-drying, obtain 19.5g solid, yield 70.6%.Get above-mentioned solid 15.0g to join in 150mL ethanol, then add 0.2g gac, stir and be warmed up to backflow, after backflow 20min, filter, filtrate is cooled to room temperature, has a large amount of solid to separate out.After treating that solid is separated out completely, filter, washing with alcohol trapped substance, obtains 12.6g solid, yield 84.0%.Physico-chemical property test result: Mp125-127 DEG C; Ultimate analysis (%) is C
7h
14cl
2n
2o
4, observed value (calculated value): C 31.9 (32.2), H 5.37 (5.4), Cl 27.2 (27.16), N 10.77 (10.73).Be accredited as: 1-dimethylamino-3-dimethyleneimine base-2-propenyl chloride perchlorate (compound 4).
Embodiment 2: the synthesis of Etoricoxib (Etoricoxib, compound 1)
Under ice-water bath, 7.2g compound 2 (1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl ketone) is dissolved in 60mL tetrahydrofuran (THF) (THF), adds 3.0g potassium tert.-butoxide in batches.After finishing, be warmed up to room temperature, reaction 1hr.Then add 7.0g compound 4 (1-dimethylamino-3-dimethyleneimine base-2-propenyl chloride perchlorate), after room temperature reaction 1hr, successively drip the Glacial acetic acid of 10.5g and 25mL tetrahydrofuran (THF) (THF) solution containing 2.3g trifluoroacetic acid.After dropwising, reaction 1hr.In reaction solution, add 15mL ammoniacal liquor again, be warming up to backflow, back flow reaction 3hr, cool to room temperature.Add 100mL ethyl acetate again, stir and separatory, reclaim organic phase through concentrating under reduced pressure, the residue by silicagel column chromatography (hexane/ethyl acetate is gradient elution from 6:1 to 2:1) obtained, Rf0.5), after the composition about (silica GF254, developping agent: isopropanol/hexane/triethylamine=6/30/1), decompression steams solvent, obtain 8.3g Etoricoxib (compound 1).
Spectroscopy result is as follows:
1H NMR(400MHz,CDCl
3),δ8.69(d,1H,J 2.3Hz),8.36(3,1H,J2.2Hz),7.89(d,2H,J 8.4Hz),7,71(d,1H,J 2.3Hz),7.52(dd,1H,J 8Hz,2.3Hz),7.36(d,2H,J 8.5Hz),7.05(d,1H,J 8Hz),3.08(s,3H),2.52(s,3H)。
13C NMR(100MHz,CDCl
3),δ158.4,152,3,149.9,148.4,143.7,140.1,137.7,135.2,131.1,130,130.3,127.8,122.7,44.4,24.3。
Claims (7)
1. there is a synthetic method for structural compounds shown in formula 4, it is characterized by: after Mono Chloro Acetic Acid and DMF and phosphorus oxychloride reaction, then react obtained with sodium perchlorate solution.
2. the synthetic method of a kind of compound as claimed in claim 1, is characterized by: temperature of reaction when Mono Chloro Acetic Acid and DMF and phosphorus oxychloride reaction is progressively warming up to 100 DEG C by 10 DEG C.
3. the synthetic method of a kind of compound as claimed in claim 1, is characterized by step as follows:
(1) join in DMF by Mono Chloro Acetic Acid, ice-water bath is cooled to 10 DEG C, drip phosphorus oxychloride, after dropwising, be warmed up to 75 DEG C gradually and be incubated 2hr, then be warmed up to 85 DEG C and be incubated 2hr, be finally warming up to 100 DEG C and be incubated 2hr acquisition reaction solution;
(2) reaction solution that step (1) finally obtains is cooled to room temperature, lower the temperature with ice-water bath after dilute with water, dripping while ice-water bath cooling keeps pH value at about 4-5 containing the aqueous solution of sodium perchlorate and NaOH solution, vigorous stirring 2hr, filter, filter cake is through frozen water, cold washing with alcohol, and vacuum-drying, obtains solid;
(3) get the solid that step (2) finally obtains to join in ethanol, then add gac, stir and be warmed up to backflow, after backflow 20min, filter, filtrate is cooled to room temperature, has a large amount of solid to separate out; After treating that solid is separated out completely, filter, namely washing with alcohol filter retentate obtains the compound of structure shown in formula 4.
4. the synthetic method of a kind of compound as claimed in claim 3, is characterized by step as follows:
(1) Mono Chloro Acetic Acid of 10.0g is joined the N of 60mL, in dinethylformamide, ice-water bath is cooled to 10 DEG C, drip 19mL phosphorus oxychloride, after dropwising, be warmed up to 75 DEG C gradually and be incubated 2hr, be then warmed up to 85 DEG C and be incubated 2hr, be finally warming up to 100 DEG C and be incubated 2hr acquisition reaction solution;
(2) reaction solution that step (1) finally obtains is cooled to room temperature, lower the temperature with ice-water bath with after the dilution of 70mL water, dripping while ice-water bath cooling keeps pH value at about 4-5 containing the 15mL aqueous solution of 20g sodium perchlorate and 1N NaOH solution, vigorous stirring 2hr, filter, filter cake through frozen water, cold washing with alcohol, vacuum-drying, obtain 19.5g solid, yield 70.6%;
(3) get the solid 15.0g that step (2) finally obtains to join in 150mL ethanol, then add 0.2g gac, stir and be warmed up to backflow, after backflow 20min, filter, filtrate is cooled to room temperature, has a large amount of solid to separate out; After treating that solid is separated out completely, filter, namely washing with alcohol filter retentate obtains the compound of structure shown in formula 4.
5. prepare a method for Etoricoxib, it is characterized by: 1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl ketone and the compound with structure shown in formula 4 according to claim 1 react.
6. a kind of method preparing Etoricoxib as claimed in claim 5, is characterized by step as follows:
Under ice-water bath, 1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl ketone is dissolved in tetrahydrofuran (THF), adds potassium tert.-butoxide in batches; After finishing, be warmed up to room temperature, reaction 1hr; Then add compound 1-dimethylamino-3-dimethyleneimine base-2-propenyl chloride perchlorate, after room temperature reaction 1hr, successively drip Glacial acetic acid and the tetrahydrofuran solution containing trifluoroacetic acid; After dropwising, reaction 1hr; In reaction solution, add ammoniacal liquor again, be warming up to backflow, back flow reaction 3hr, cool to room temperature; Add ethyl acetate again, stir and separatory, reclaim organic phase through concentrating under reduced pressure, the residue by silicagel column chromatography obtained obtains Etoricoxib.
7. a kind of method preparing Etoricoxib as claimed in claim 6, is characterized by step as follows:
Under ice-water bath, 1-(6-methyl-3-pyridyl)-2-[4-(methyl sulphonyl) phenyl] ethyl ketone of 7.2g is dissolved in 60mL tetrahydrofuran (THF), adds 3.0g potassium tert.-butoxide in batches; After finishing, be warmed up to room temperature, reaction 1hr; Then add 7.0g compound 1-dimethylamino-3-dimethyleneimine base-2-propenyl chloride perchlorate, after room temperature reaction 1hr, successively drip the Glacial acetic acid of 10.5g and the 25mL tetrahydrofuran solution containing 2.3g trifluoroacetic acid; After dropwising, reaction 1hr; In reaction solution, add 15mL ammoniacal liquor again, be warming up to backflow, back flow reaction 3hr, cool to room temperature; Add 100mL ethyl acetate again, stir and separatory, reclaim organic phase through concentrating under reduced pressure, the residue by silicagel column chromatography obtained obtains Etoricoxib.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113264873A (en) * | 2019-01-18 | 2021-08-17 | 华润双鹤药业股份有限公司 | Etoricoxib purification and preparation method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1306425A (en) * | 1998-04-24 | 2001-08-01 | 麦克公司 | Process for synthesizing Cox-2 inhibitors |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1306425A (en) * | 1998-04-24 | 2001-08-01 | 麦克公司 | Process for synthesizing Cox-2 inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| ARNOLD, Z. ET AL.: "Note on the Formylation of chloro- and bromoacetic acid", 《COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS》 * |
| 董兆恒 等: "2-(4-正戊氧基苯基)-5-氯-嘧啶的合成", 《合成化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113264873A (en) * | 2019-01-18 | 2021-08-17 | 华润双鹤药业股份有限公司 | Etoricoxib purification and preparation method |
| CN113264873B (en) * | 2019-01-18 | 2022-11-04 | 华润双鹤药业股份有限公司 | Etoricoxib purification and preparation method |
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Application publication date: 20150805 |