DK2401253T3 - Fremgangsmåde til fremstilling af etoricoxib - Google Patents
Fremgangsmåde til fremstilling af etoricoxib Download PDFInfo
- Publication number
- DK2401253T3 DK2401253T3 DK10719784.0T DK10719784T DK2401253T3 DK 2401253 T3 DK2401253 T3 DK 2401253T3 DK 10719784 T DK10719784 T DK 10719784T DK 2401253 T3 DK2401253 T3 DK 2401253T3
- Authority
- DK
- Denmark
- Prior art keywords
- formula
- compound
- salt
- reaction mixture
- etoricoxib
- Prior art date
Links
- 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 description 84
- 229960004945 etoricoxib Drugs 0.000 title claims description 73
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- -1 chloroacetyl halide Chemical class 0.000 claims description 130
- 239000011541 reaction mixture Substances 0.000 claims description 94
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 62
- 229910019142 PO4 Inorganic materials 0.000 claims description 51
- 239000010452 phosphate Substances 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000003386 piperidinyl group Chemical group 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 44
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 150000001298 alcohols Chemical class 0.000 claims description 12
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 12
- 229940106681 chloroacetic acid Drugs 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 claims description 7
- 150000004820 halides Chemical class 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 5
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 claims description 2
- 235000010259 potassium hydrogen sulphite Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 238000001144 powder X-ray diffraction data Methods 0.000 claims 2
- QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 claims 1
- 229940099427 potassium bisulfite Drugs 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 239000010454 slate Substances 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 239000000243 solution Substances 0.000 description 50
- 235000021317 phosphate Nutrition 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000002360 preparation method Methods 0.000 description 43
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- 238000000746 purification Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 13
- YBFHILNBYXCJKD-UHFFFAOYSA-N 1-(6-methylpyridin-3-yl)-2-(4-methylsulfonylphenyl)ethanone Chemical compound C1=NC(C)=CC=C1C(=O)CC1=CC=C(S(C)(=O)=O)C=C1 YBFHILNBYXCJKD-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 10
- 125000005936 piperidyl group Chemical group 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 235000011054 acetic acid Nutrition 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 7
- 229910019398 NaPF6 Inorganic materials 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 125000002757 morpholinyl group Chemical group 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229940111134 coxibs Drugs 0.000 description 3
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 2
- 150000003930 2-aminopyridines Chemical class 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- KEEKMOIRJUWKNK-CABZTGNLSA-N (2S)-2-[[2-[(4R)-4-(difluoromethyl)-2-oxo-1,3-thiazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide Chemical compound FC([C@H]1N(C(SC1)=O)C=1N=C2N(CCOC3=C2C=CC(=C3)N[C@H](C(=O)N)C)C=1)F KEEKMOIRJUWKNK-CABZTGNLSA-N 0.000 description 1
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- IVUHTLFKBDDICS-UHFFFAOYSA-N (4-methylsulfanylphenyl)boronic acid Chemical compound CSC1=CC=C(B(O)O)C=C1 IVUHTLFKBDDICS-UHFFFAOYSA-N 0.000 description 1
- LCFFREMLXLZNHE-GBOLQPHISA-N (e)-2-[(3r)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile Chemical compound C12=C(N)N=CN=C2N([C@@H]2CCCN(C2)C(=O)C(/C#N)=C/C(C)(C)N2CCN(CC2)C2COC2)N=C1C(C(=C1)F)=CC=C1OC1=CC=CC=C1 LCFFREMLXLZNHE-GBOLQPHISA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- KOMRHPHTMKCPCD-UHFFFAOYSA-N 1,2-dimethoxyethanol Chemical compound COCC(O)OC KOMRHPHTMKCPCD-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KJUCPVIVNLPLEE-UHFFFAOYSA-N 2,6-difluoro-n-[2-fluoro-5-[5-[2-[(6-morpholin-4-ylpyridin-3-yl)amino]pyrimidin-4-yl]-2-propan-2-yl-1,3-thiazol-4-yl]phenyl]benzenesulfonamide Chemical compound S1C(C(C)C)=NC(C=2C=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C(F)=CC=2)=C1C(N=1)=CC=NC=1NC(C=N1)=CC=C1N1CCOCC1 KJUCPVIVNLPLEE-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- SSORSZACHCNXSJ-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NCC(C)O SSORSZACHCNXSJ-UHFFFAOYSA-N 0.000 description 1
- KDDPNNXAZURUGP-UHFFFAOYSA-N 2-[2-(3,4-dichlorophenyl)-3-[2-(piperidin-3-ylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound ClC=1C=C(C=CC=1Cl)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CNCCC1 KDDPNNXAZURUGP-UHFFFAOYSA-N 0.000 description 1
- BWSQKOKULIALEW-UHFFFAOYSA-N 2-[2-[4-fluoro-3-(trifluoromethyl)phenyl]-3-[2-(piperidin-3-ylamino)pyrimidin-4-yl]imidazol-4-yl]acetonitrile Chemical compound FC1=C(C=C(C=C1)C=1N(C(=CN=1)CC#N)C1=NC(=NC=C1)NC1CNCCC1)C(F)(F)F BWSQKOKULIALEW-UHFFFAOYSA-N 0.000 description 1
- DILISPNYIVRDBP-UHFFFAOYSA-N 2-[3-[2-(2-hydroxypropylamino)pyrimidin-4-yl]-2-naphthalen-2-ylimidazol-4-yl]acetonitrile Chemical compound OC(CNC1=NC=CC(=N1)N1C(=NC=C1CC#N)C1=CC2=CC=CC=C2C=C1)C DILISPNYIVRDBP-UHFFFAOYSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- BVGDAZBTIVRTGO-UONOGXRCSA-N 3-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-methoxy-6-[(2s)-2-methylpiperazin-1-yl]pyridin-3-yl]pyridin-2-amine Chemical compound C1([C@@H](C)OC=2C(N)=NC=C(C=2)C2=CN=C(C=C2OC)N2[C@H](CNCC2)C)=C(Cl)C=CC(F)=C1Cl BVGDAZBTIVRTGO-UONOGXRCSA-N 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- ONPGOSVDVDPBCY-CQSZACIVSA-N 6-amino-5-[(1r)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-n-[4-(4-methylpiperazine-1-carbonyl)phenyl]pyridazine-3-carboxamide Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NN=1)N)=CC=1C(=O)NC(C=C1)=CC=C1C(=O)N1CCN(C)CC1 ONPGOSVDVDPBCY-CQSZACIVSA-N 0.000 description 1
- BWJHJLINOYAPEG-HOTGVXAUSA-N 8-chloro-6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclopentyl]-7-methyl-2H-1,3-benzoxazin-4-one Chemical compound ClC1=C(C(=CC=2C(N(COC=21)[C@@H]1[C@H](CCC1)O)=O)CC=1C=NC(=CC=1)Cl)C BWJHJLINOYAPEG-HOTGVXAUSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- LRULVYSBRWUVGR-FCHUYYIVSA-N GSK2879552 Chemical compound C1=CC(C(=O)O)=CC=C1CN1CCC(CN[C@H]2[C@@H](C2)C=2C=CC=CC=2)CC1 LRULVYSBRWUVGR-FCHUYYIVSA-N 0.000 description 1
- 229910004713 HPF6 Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- UQONAEXHTGDOIH-AWEZNQCLSA-N O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 Chemical compound O=C(N1CC[C@@H](C1)N1CCCC1=O)C1=CC2=C(NC3(CC3)CCO2)N=C1 UQONAEXHTGDOIH-AWEZNQCLSA-N 0.000 description 1
- GZMYLSJUNSCMTD-MOPGFXCFSA-N OC[C@@H](C)NC1=NC(=CC(=C1)C=1C=C(C=CC=1C)NC(=O)N1C[C@@H](CC1)CC(F)(F)F)N1CCOCC1 Chemical compound OC[C@@H](C)NC1=NC(=CC(=C1)C=1C=C(C=CC=1C)NC(=O)N1C[C@@H](CC1)CC(F)(F)F)N1CCOCC1 GZMYLSJUNSCMTD-MOPGFXCFSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- ODUIXUGXPFKQLG-QWRGUYRKSA-N [2-(4-chloro-2-fluoroanilino)-5-methyl-1,3-thiazol-4-yl]-[(2s,3s)-2,3-dimethylpiperidin-1-yl]methanone Chemical compound C[C@H]1[C@@H](C)CCCN1C(=O)C1=C(C)SC(NC=2C(=CC(Cl)=CC=2)F)=N1 ODUIXUGXPFKQLG-QWRGUYRKSA-N 0.000 description 1
- PIUHAULDXSPPQV-UHFFFAOYSA-N [2-chloro-3-(dimethylamino)prop-2-enylidene]-dimethylazanium;hexafluorophosphate Chemical class F[P-](F)(F)(F)(F)F.CN(C)\C=C(/Cl)C=[N+](C)C PIUHAULDXSPPQV-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000001626 borono group Chemical group [H]OB([*])O[H] 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VZUGBLTVBZJZOE-KRWDZBQOSA-N n-[3-[(4s)-2-amino-1,4-dimethyl-6-oxo-5h-pyrimidin-4-yl]phenyl]-5-chloropyrimidine-2-carboxamide Chemical compound N1=C(N)N(C)C(=O)C[C@@]1(C)C1=CC=CC(NC(=O)C=2N=CC(Cl)=CN=2)=C1 VZUGBLTVBZJZOE-KRWDZBQOSA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- OEBIHOVSAMBXIB-SJKOYZFVSA-N selitrectinib Chemical compound C[C@@H]1CCC2=NC=C(F)C=C2[C@H]2CCCN2C2=NC3=C(C=NN3C=C2)C(=O)N1 OEBIHOVSAMBXIB-SJKOYZFVSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical group 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Claims (22)
1. Fremgangsmåde til fremstilling af Etoricoxib med formlen (I), hvilken fremgangsmåde omfatter
(a) omsætning af en forbindelse med formlen (IV) med egnet chloracetylhalogenid eller chloreddikesyre og phosphoroxychlorid for at opnå forbindelsen med formlen (IIld) og endvidere omdannelse af forbindelsen med formlen (llld) til dens egnede salt for at opnå forbindelsen med formlen (lllb),
hvor
'æsenterer en cyklisk gruppe, eventuelt indeholdende ét eller flere heteroatomer udvalgt fra N, O eller S, og X’ repræsenterer et egnet mod ion. (b) omsætning af forbindelsen med formlen (lllb) med forbindelsen med formlen (II) i nærvær af en egnet base og et egnet opløsningsmiddel for at opnå Etoricoxib med formlen (I)
2. Fremgangsmåde ifølge krav 1, hvor
*er udvalgt fra en morpholidinyl-, piperidinyl- og pyrolidinylgruppe.
3. Fremgangsmåde ifølge krav 1, hvor det egnede salt af forbindelsen med formlen (IMb) fremstilles ved omsætning af forbindelsen med formlen (llld) med et egnet salt af en syre for at opnå det tilsvarende slat af forbindelsen med formlen (Mlb).
4. Fremgangsmåde ifølge krav 3, hvor det egnede salt af en syre er udvalgt fra gruppen bestående af phosphat, sulfat, acetater, perchlorat, borater, antimonit, halogenider, benzoat, napsylat, hexafluorphosphat, tetrafluorborat, chlorid, bromid, fluorid, iodid, benzoat og carbonat.
5. Fremgangsmåde ifølge krav 4, hvor det egnede salt af syre er hexafluorphosphat.
6. Fremgangsmåde ifølge krav 1 i trin (b), hvor det egnede opløsningsmiddel er udvalgt fra Ci-C6-alkoholer, carbonhydrider udvalgt fra benzen, toluen og xylen; halocarbonopløsningsmidler udvalgt fra mono- eller di-halo Ci-C4-alkyler, nitrogenholdige opløsningsmidler udvalgt fra DMF, dimethylacetamid, N-ethylpyrrolidinon, N-methylpyrrolidinon og acetonitril og dioxan og dimethylsulfoxid.
7. Fremgangsmåde ifølge krav 6, hvor opløsningsmidlerne er udvalgt fra Cr C6-alkohol, THF, DMF, dioxan og dimethylsulfoxid.
8. Fremgangsmåde ifølge krav 1, trin (b), hvor den egnede anvendte base er udvalgt fra organiske eller uorganiske baser, hvor de uorganiske baser er udvalgt fra alkalimetal eller jordalkalimetalhydroxider, alkalimetal eller jordalkalimetalcarbonater, såsom NaHC03, Na2C03, K2C03, alkalimetalhydrider, alkalimetalalkoxider.
9. Fremgangsmåde til fremstilling af forbindelsen med formlen (IIIb), hvor
repræsenterer en cycloalkylgruppe, eventuelt indeholdende et ekstra heteroatom udvalgt fra N, O eller S, og X' repræsenterer det egnede modion, ifølge krav 1, omfattende
Formel lllb omsætning af en forbindelse med formlen (IV) med egnet chloracetylhalogenid eller chloreddikesyre og phosphoroxychlorid ved at kombinere chloracetylhalogenid eller chloreddikesyre og phosphoroxychlorid ved stuetemperatur eller under, og tilsætning af forbindelsen med formlen (IV) til kombinationen for at opnå forbindelsen med formlen (llld) og endvidere omdannelse af forbindelsen med formlen (llld) til dens egnede salt med formlen (lllb),
10. Fremgangsmåde ifølge krav 9, hvor temperaturen er mindre end 30 °C.
11. Fremgangsmåde ifølge krav 9, hvor reaktionsblandingen, efter tilsætning af reaktanterne, opvarmes til en temperatur på 50° til 150 °C, mere fortrinsvis 75 °C til 120 °C og mest fortrinsvis, 90 °C til 100 °C, for at opnå forbindelsen med formlen (lllb).
12. Fremgangsmåde ifølge krav 9, hvor reaktionen udføres i 3 timer til 25 timer, fortrinsvis i6 til 8 timer.
13. Fremgangsmåde ifølge krav 9, hvor forbindelsen med formlen (llld) omdannes til dens egnede salt med formlen (lllb) ved omsætning af den med saltet af tilsvarende syrer.
14. Fremgangsmåde ifølge krav 13 hvor, det egnede salt af syre er udvalgt fra gruppen bestående af phosphat, sulphat, acetater, perchlorat, borater, antimonit, halogenider, benzoat, napsylat, såsom hexafluorphosphat, tetrafluorborat, chlorid, bromid, fluorid, iodid, benzoat, carbonat, hexafluorantimonat.
15. Fremgangsmåde ifølge krav 14, hvor det egnede salt af syre er hexafluorphosphat.
16. Fremgangsmåde ifølge krav 9, hvor forbindelsen med formlen (IMb) endvidere opløses ved i) opløsning af forbindelsen med formlen (Mlb) i CrCs-alkoholer eller estere deraf, eventuelt med vand og efterfølgende isolering af forbindelsen med formlen (Mlb); ii) behandling af forbindelsen med formlen (Mlb) med egnet alkalisk bisulfit eller metabisulfit, i CrCs-alkoholer eller estere deraf og efterfølgende isolering af den rene forbindelse med formlen (lllb).
17. Fremgangsmåde ifølge krav 16, hvor alkalimetalbisulfit eller -metabisulfit er udvalgt fra natrium eller kaliumbisulfit eller -metabisulfit.
18. Fremgangsmåde ifølge krav 16, hvor saltet med formlen (lllb) opnås med mindst 99 % renhed ved FIPLC.
19. Forbindelse med den strukturelle formel (lllc), hvor X' repræsenterer et egnet modion.
Formel lllc
20. Polymorf form I af 2-chlor 1,3-(bispiperidinyl) trimethiniumhexafluorphosphat, kendetegnet ved et PXRD-mønster med spidsværdier ved 9,06, 11,60, 12,06, 12,89, 13,64, 14,38, 16,02, 16,98, 17,56, 18,16, 19,43, 20,16, 20,46, 21,04, 21,48, 21,98, 22,25, 22,68, 23,35, 23,76, 24.24, 24,64, 25,92, 26,75, 27,42, 28,03, 28,55, 29,04, 29,68, 30,06, 30,52, 31.25, 31,96, 32,36, 33,31, 33,94, 34,30, 35,16, 35,80, 38,14, 39,47 ° ± 0,2 0 grader (2Θ).
21.
Polymorf form II af 2-chlor 1,3-(bispiperidinyl) trimethiniumhexafluorphosphat, kendetegnet ved et PXRD-mønster med spidsværdier ved 9,14, 10,142, 12,12, 12,96, 13,71, 17,06, 17,64, 18,24, 19,49, 20,520, 21,10, 21,56, 22,32, 22,74, 23,42, 24,32, 24,72, 26,05, 27,48, 28,10, 29,14, 29,79, 30,12, 30,61, 31,30, 32,06, 32,43, 33,36, 34,02, 34,38 ° ± 0,2 ° grader (2Θ).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN441MU2009 | 2009-02-27 | ||
| PCT/IN2010/000045 WO2010097802A2 (en) | 2009-02-27 | 2010-01-25 | A process for the preparation of etoricoxib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2401253T3 true DK2401253T3 (da) | 2016-04-18 |
Family
ID=42290121
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK12162558.6T DK2479166T3 (da) | 2009-02-27 | 2010-01-25 | Fremgangsmåde til fremstilling af etoricoxib |
| DK10719784.0T DK2401253T3 (da) | 2009-02-27 | 2010-01-25 | Fremgangsmåde til fremstilling af etoricoxib |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK12162558.6T DK2479166T3 (da) | 2009-02-27 | 2010-01-25 | Fremgangsmåde til fremstilling af etoricoxib |
Country Status (10)
| Country | Link |
|---|---|
| EP (2) | EP2401253B1 (da) |
| AR (1) | AR075441A1 (da) |
| BR (1) | BRPI1006374A2 (da) |
| DK (2) | DK2479166T3 (da) |
| ES (2) | ES2562981T3 (da) |
| HU (1) | HUE028730T2 (da) |
| MY (1) | MY163020A (da) |
| PL (2) | PL2479166T3 (da) |
| PT (1) | PT2479166E (da) |
| WO (1) | WO2010097802A2 (da) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2591848C2 (ru) | 2010-11-15 | 2016-07-20 | Вирдев Интермидиетс Пвт. Лтд. | Способ получения селективного ингибитора циклооксигеназы-2 |
| WO2012163839A1 (en) | 2011-05-27 | 2012-12-06 | Farma Grs, D.O.O. | A process for the preparation of polymorphic form i of etoricoxib |
| EP2773618A1 (en) | 2011-11-03 | 2014-09-10 | Cadila Healthcare Limited | An improved process for the preparation of etoricoxib and polymorphs thereof |
| GR1007973B (el) * | 2012-06-26 | 2013-09-12 | Φαρματεν Αβεε, | Νεα ν-οξοιμινο παραγωγα ως ενδιαμεσα μιας βελτιωμενης μεθοδου παρασκευης 2,3-διαρυλο-5-υποκατεστημενων πυριδινων |
| WO2014114352A1 (en) * | 2013-01-25 | 2014-07-31 | Synthon Bv | Process for making etoricoxib |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5593994A (en) | 1994-09-29 | 1997-01-14 | The Dupont Merck Pharmaceutical Company | Prostaglandin synthase inhibitors |
| US5739166A (en) | 1994-11-29 | 1998-04-14 | G.D. Searle & Co. | Substituted terphenyl compounds for the treatment of inflammation |
| SI0912518T1 (en) | 1996-07-18 | 2003-12-31 | Merck Frosst Canada & Co. | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| US5861419A (en) | 1996-07-18 | 1999-01-19 | Merck Frosst Canad, Inc. | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| UA57143C2 (uk) | 1998-04-24 | 2003-06-16 | Мерк Енд Ко., Інк. | Спосіб синтезу інгібіторів сох-2 (циклооксигенази-2) та проміжні сполуки для їх одержання |
| CA2391650C (en) | 1999-11-29 | 2011-01-25 | Merck & Co., Inc. | Polymorphic, amorphous and hydrated forms of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl |
| PH12001001175B1 (en) | 2000-05-26 | 2006-08-10 | Merck Sharp & Dohme | 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl- (2,3')bipyridinyl in pure crystalline form and process for synthesis |
| US6521642B2 (en) | 2000-05-26 | 2003-02-18 | Merck & Co., Inc. | 5-chloro-3-(4-methanesulfonylphenyl)-6′-methyl-[2,3′]bipyridinyl in pure crystalline form and process for synthesis |
| JP2003160563A (ja) * | 2001-11-29 | 2003-06-03 | Sankio Chemical Co Ltd | 新規な３−アミノ−２−プロペニリデンアンモニウム誘導体・ｂｆ４塩 |
| WO2005085199A1 (en) | 2004-01-14 | 2005-09-15 | Cadila Healthcare Limited | Novel polymorphs of etoricoxib |
-
2010
- 2010-01-25 HU HUE10719784A patent/HUE028730T2/en unknown
- 2010-01-25 EP EP10719784.0A patent/EP2401253B1/en active Active
- 2010-01-25 BR BRPI1006374A patent/BRPI1006374A2/pt not_active IP Right Cessation
- 2010-01-25 EP EP12162558.6A patent/EP2479166B1/en not_active Not-in-force
- 2010-01-25 ES ES10719784.0T patent/ES2562981T3/es active Active
- 2010-01-25 PL PL12162558T patent/PL2479166T3/pl unknown
- 2010-01-25 PL PL10719784T patent/PL2401253T3/pl unknown
- 2010-01-25 WO PCT/IN2010/000045 patent/WO2010097802A2/en not_active Ceased
- 2010-01-25 PT PT121625586T patent/PT2479166E/pt unknown
- 2010-01-25 ES ES12162558.6T patent/ES2496465T3/es active Active
- 2010-01-25 DK DK12162558.6T patent/DK2479166T3/da active
- 2010-01-25 MY MYPI2011003123A patent/MY163020A/en unknown
- 2010-01-25 DK DK10719784.0T patent/DK2401253T3/da active
- 2010-02-16 AR ARP100100449A patent/AR075441A1/es not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ES2496465T3 (es) | 2014-09-19 |
| MY163020A (en) | 2017-07-31 |
| PL2479166T3 (pl) | 2014-11-28 |
| PT2479166E (pt) | 2014-11-28 |
| EP2479166B1 (en) | 2014-08-20 |
| EP2479166A1 (en) | 2012-07-25 |
| PL2401253T3 (pl) | 2016-05-31 |
| EP2401253B1 (en) | 2016-01-13 |
| DK2479166T3 (da) | 2014-09-01 |
| ES2562981T3 (es) | 2016-03-09 |
| BRPI1006374A2 (pt) | 2019-09-24 |
| EP2401253A2 (en) | 2012-01-04 |
| WO2010097802A3 (en) | 2010-12-23 |
| WO2010097802A2 (en) | 2010-09-02 |
| AR075441A1 (es) | 2011-03-30 |
| HUE028730T2 (en) | 2017-01-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3812366B1 (en) | A preparation method for m-diamide compounds | |
| JP5656952B2 (ja) | ピペラジン誘導体蓚酸塩結晶 | |
| WO2016102438A1 (en) | Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidine analogues | |
| IL278533B1 (en) | Process for the preparation of 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid | |
| CN117736152A (zh) | 一种双重内皮素受体拮抗剂阿普昔腾坦的合成方法 | |
| IL197954A (en) | A process for preparing imatinib, its intermediates and a process for making these intermediates | |
| JP6068569B2 (ja) | シロドシンの製造方法および中間体 | |
| EP2401253B1 (en) | A process for the preparation of etoricoxib | |
| DK2948441T3 (da) | Fremgangsmåde til fremstilling af 1-(4-(4-(3,4-dichlor-2-fluorphenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-on | |
| US9663490B2 (en) | Process for making reverse transcriptase inhibitors | |
| KR101855334B1 (ko) | 옥사졸리디논 유도체의 중간체 제조방법 | |
| AU745355B2 (en) | Process for producing substituted alkylamines or salts thereof | |
| JPH0550514B2 (da) | ||
| KR102441327B1 (ko) | 다이아미노피리미딘 유도체 또는 이의 산부가염의 신규의 제조방법 | |
| KR102702677B1 (ko) | 피마살탄 및 그의 제조 중간체의 제조방법 | |
| KR100839322B1 (ko) | Ｂ형 간염 치료제 클레부딘의 개선된 제조방법 | |
| CZ2004423A3 (cs) | Způsob výroby }@@nitrofenylB acetonitrilových derivátů a meziprodukt použitý pro tuto syntézu | |
| WO2003097603A1 (en) | Process for the preparation of highly pure torsemide | |
| MXPA02007060A (es) | Procedimiento para la obtencion de compuestos heterociclicos. | |
| KR101628946B1 (ko) | 실로도신의 개선된 제조방법 | |
| JP2004075616A (ja) | ４−ハロゲノ−２−（４−フルオロフェニルアミノ）−５，６−ジメチルピリミジンの製造方法 | |
| EP0066442B1 (en) | Chemical process | |
| CN119431186A (zh) | 一种n-烷胺基取代苯甲腈类化合物的制备方法 | |
| KR100580940B1 (ko) | 2-아미노-4-클로로-5-니트로-6(1ｈ)-피리미디논의 제조방법 | |
| JPWO2010029756A1 (ja) | ５−［２−（メチルチオ）エトキシ］ピリミジン−２−アミンの製造方法 |