AU2002336593A1 - Processes for the preparation of 1,5-diaryl-3-substituted-pyrazoles - Google Patents
Processes for the preparation of 1,5-diaryl-3-substituted-pyrazolesInfo
- Publication number
- AU2002336593A1 AU2002336593A1 AU2002336593A AU2002336593A AU2002336593A1 AU 2002336593 A1 AU2002336593 A1 AU 2002336593A1 AU 2002336593 A AU2002336593 A AU 2002336593A AU 2002336593 A AU2002336593 A AU 2002336593A AU 2002336593 A1 AU2002336593 A1 AU 2002336593A1
- Authority
- AU
- Australia
- Prior art keywords
- formula
- group
- compound
- substituted
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims description 69
- 238000002360 preparation method Methods 0.000 title description 22
- -1 sulfa yl Chemical group 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 39
- 150000001345 alkine derivatives Chemical class 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 150000002576 ketones Chemical class 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 5
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000000394 phosphonato group Chemical group [O-]P([O-])(*)=O 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- AJPXTSMULZANCB-UHFFFAOYSA-N chlorohydroquinone Chemical compound OC1=CC=C(O)C(Cl)=C1 AJPXTSMULZANCB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 3
- 125000000335 thiazolyl group Chemical group 0.000 claims 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- IKEURONJLPUALY-UHFFFAOYSA-N 4-hydrazinylbenzenesulfonamide;hydron;chloride Chemical compound [Cl-].NS(=O)(=O)C1=CC=C(N[NH3+])C=C1 IKEURONJLPUALY-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 4
- JFGWPXKGINUNDH-UHFFFAOYSA-N methyl 3-phenylprop-2-ynoate Chemical compound COC(=O)C#CC1=CC=CC=C1 JFGWPXKGINUNDH-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 3
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 2
- FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical compound CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 description 2
- UKKALSJSKAHGTL-UHFFFAOYSA-N 2,2,2-trifluoro-n-phenylethanimidoyl chloride Chemical compound FC(F)(F)C(Cl)=NC1=CC=CC=C1 UKKALSJSKAHGTL-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- UEXCJVNBTNXOEH-UHFFFAOYSA-N Ethynylbenzene Chemical group C#CC1=CC=CC=C1 UEXCJVNBTNXOEH-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 2
- 238000005575 aldol reaction Methods 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 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
- 230000000694 effects Effects 0.000 description 2
- 238000007337 electrophilic addition reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical group CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000001119 stannous chloride Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DGBHRXLUVJFCMS-UHFFFAOYSA-N 4-(3-methyl-5-phenylpyrazol-1-yl)benzenesulfonamide Chemical compound C=1C=C(S(N)(=O)=O)C=CC=1N1N=C(C)C=C1C1=CC=CC=C1 DGBHRXLUVJFCMS-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- YKYIFUROKBDHCY-UHFFFAOYSA-N 4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical compound CCOC=CC(=O)C(F)(F)F YKYIFUROKBDHCY-UHFFFAOYSA-N 0.000 description 1
- UPEUQDJSUFHFQP-UHFFFAOYSA-N 4-phenylbut-3-yn-2-one Chemical compound CC(=O)C#CC1=CC=CC=C1 UPEUQDJSUFHFQP-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 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 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Description
Processes For The Preparation Of l,5-Diaryl-3-Substituted-Pyrazoles
This application claims the benefit of United States Patent Application No. 60/323,479, filed September 18, 2001, the disclosure of which is herein incorporated by reference as if fully set forth herein. The present invention relates to processes for the preparation of l,5-diaryl-3- substituted-pyrazoles, and chemical intermediates that serve as useful intermediates in the preparation of l,5-diaryl-3-substituted-pyrazoles. l,5-diaryl-3-substituted-pyrazoles are particularly useful in the treatment of inflammation and inflammation-related disorders, including arthritis. Selective inhibitors of cyclooxygenase-2 (COX-2) have demonstrated effective anti-inflammatory activity with reduced gastrointestinal side effects, as compared to other antiinflammatory agents, e.g., NSAIDs, that inhibit both the constitutive form of cyclooxygenase (COX-1), and the inducible form of the enzyme, COX-2. A particularly effective structural class of selective COX-2 inhibitors are the l,5-diaryl-3-substituted- pyrazoles. For example, the compound, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH- pyrazol-l-yl]benzenesulfonamide (celecoxib®) has been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis and osteo arthritis.
Penning et al. (J. Med. Chem. 1991, 40, 1347-1365) discloses that 1,5- diarylpyrazoles can be prepared by condensation of 1,3-dicarbonyl adducts with aryl hydrazines. The 1,3-dicarbonyl adducts can be prepared by Claisen condensations of aryl methyl ketones with carboxylic acid esters. In an alternate preparation, the 1,5- diaryl-3-substituted-pyrazoles can be synthesized by epoxidation of β-aryl- ,β- unsaturated ketones, followed by condensation of the resulting epoxides with arylhydrazines.
Summary of the Invention
In one embodiment, the invention relates to a process for preparing a compound of the formula I
wherein X is selected from the group consisting of C Cδ trihalomethyl, preferably trifluoromethyl; C^Ce alkyl; and an optionally substituted or di-substituted phenyl group of formula II:
wherein R3 and R4 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C^Ce alkyl, preferably Cχ-C3 alkyl; Ci-Cg alkoxy, preferably Cι-C3 alkoxy; carboxy; Cj-Ce trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; cyano; alkylsulfonyl, sulfamyl, phosphonato, and hydroxyalkyl; and Y and Z are independently selected from the group consisting of substituted and unsubstituted aryl.
The process includes the step of condensing an alkyne of formula III
with an aryl hydrazine of the formula Y-NHNH2 (IN) or a salt thereof. In some embodiments of the process, preferred aryl groups Y and Z include phenyl and heteroaryL which maybe substituted or unsubstituted. By "substituted" is meant any level of substitution, although mono- di- and tri-substitution are preferred.
The substituents are independently selected. The substituents are preferably selected from the group consisting of halogen, particularly chlorine, fluorine and bromine; hydroxyl; nitro; Ci-C6 alkyl, preferably C^d alkyl, most preferably methyl; Ci-Cβ alkoxy, preferably d-C3 alkoxy, most preferably methoxy; carboxy; Ci-Cβ trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; cyano and a group of the formula
— SO2R5 wherein R5 is Cι-C6 alkyl or amino. Although mono-, di- and tri-substitution is preferred, full substitution, particularly when the aryl group is phenyl, is possible. According to another embodiment of the process, Y is substituted or unsubstituted heteroaryL Such heteroaryl radicals include, for example, pyridyl,
particularly 2-, 3- and 4-pyridyl; thienyl, particularly 2- and 3-thienyl; furyl, particularly 2- and 3-furyl; indolyl, particularly 3-, 4-, 5-, 6- and 7-indolyl; benzothienyl, particularly 3-, 4-, 5-, 6-, and 7-benzothienyl; benzofuryl, particularly 3-, 4-, 5-, 6-, and 7-benzofuryl; imidazolyl, particularly 2- and 5-imidazolyl; pyrazolyl, particularly 3- and 5-pyrazolyl; 2-thiazolyl; 2-benzothiazolyl; quinolinyl, particularly 2-, 3- and 4-quinolinyl; and 4-(2- benzyloxazolyl).
In another embodiment of the process, Y is selected from the group consisting of unsubstituted phenyl, mono-, di-, and trisubstituted phenyl. Preferred radicals wherein Y is substituted phenyl include one or more of halogen, hydroxyl, nitro, C Cδ alkyl, Ci-Cβ alkoxy, carboxy, C Ce trihaloalkyl, cyano, or a group of the formula
— SO2R5, wherein R5 is C^Ce alkyl or amino. In a preferred embodiment, Y is a group of the formula
particularly where R is amino.
According to another embodiment of the process, Z is substituted or unsubstituted heteroaryL Such heteroaryl radicals include, for example, pyridyl, particularly 2-, 3- and 4-pyridyl; thienyl, particularly 2- and 3-thienyl; furyl, particularly 2- and 3-furyl; indolyl, particularly 3-, 4-, 5-, 6- and 7~indolyl; benzothienyl, particularly 3-, 4-, 5-, 6- and 7-benzothienyl; benzofuryl, particularly 3-, 4-, 5-, 6- and 7- benzofuryl; imidazolyl, particularly 2- and 5-imidazolyl; pyrazolyl, particularly 3- and 5- pyrazolyl; 2-thiazolyl; 2-benzothiazolyl; quinolinyl, particularly 2-, 3- and 4-quinolinyl; and 4-(2-benzyloxazolyl). In a preferred embodiment Z is 3-indolyl. Representative preferred substituted heteroaryl groups include 6-methyl-2-pyridyl, 5-halo-2-thienyl, 5- methyl-2-thienyl, 5-halo-2-furyl, 5-halo-3-mryl, 2,5-dimethyl-3-thienyl and 2,5- dimethy 1-3 -furyl.
In another embodiment of the process, Z is selected from the group consisting of unsubstituted phenyl, mono-, di-, and trisubstituted phenyl. Preferred radicals wherein Z is substituted phenyl include, for example, one or more of halogen, hydroxyl, nitro, Ci- C6 alkyl, Ci-C6 alkoxy, carboxy, Cι-C6 trihaloalkyl and cyano.
In a preferred embodiment of the process, X is trifluoromethyl; Y is 4-sulfamyl; and Z is substituted phenyl, preferably p-methyl.
In other embodiments of process, the alkyne of the formula III
is prepared by:
(i) adding bromine to an α,β-unsaturated ketone of formula N
O
2 X(V) wherein X and Z are as defined above; and (ii) contacting the product of step (i) with a base. In embodiments of the process wherein X is trifluoromethyl, the α,β-unsaturated ketone of formula N can be prepared by treating a compound of the formula IX
with trimethyl(trifluoromethyl)silane in the presence of a cesium fluoride.
In an another embodiment the compound of the formula III can be prepared by condensing a methyl ketone of the formula X
I (X) wherein X is Ci-Cβ trihalomethyl, preferably trifluoromethyl; Cι-C6 alkyl; or an optionally substituted or di-substituted phenyl group of formula II; with an aryl aldehyde of the formula XII Z-CHO (XII).
In another embodiment, the compound of the formula III can be prepared by contacting an aryl acetylene of the formula NIII
z (vm) with a strong base, and reacting the resulting aryl acetylide with an acylating agent of the formula XIII
O QAχ (XIII) wherein X is Ci-Cβ trihalomethyl, preferably trifluoromethyl; Ci-Cδ alkyl; or an optionally substituted or di-substituted phenyl group of formula II; and Q is a leaving group, to give the compound of formula III. In embodiments of the process wherein X is trifluoromethyl, the compound of the formula III can also be prepared by (i) contacting an aryl acetylene of the formula NIII
with carbon monoxide, oxygen, and methanol, in the presence of a palladium (II) catalyst to provide a propargylic ester of the formula NI
(ii) treating the propargylic ester of the formula NI with trimethyl(trifluoromethyl)silane in the presence of cesium fluoride to give the compound of formula III.
In another aspect, the invention relates to certain compounds, that among other things, are useful as intermediates for the preparation of the compound of the formula I. For example, the invention provides an alkyne having the formula III
wherein Z is selected from the group consisting of substituted and unsubstituted aryl. Examples of representative Z groups for the alkyne of the formula III are as discussed above for the process aspect of the invention. Preferred Z groups for the alkyne of the formula III are 3 -indolyl and p-methyl.
In another aspect, the invention relates to a compound of the formula I
wherein X is trifluoromethyl, Y is sulfamyl, and Z is 3 -indolyl or substituted 3 -indolyl. In a preferred embodiment of the compound of the formula I, Z is 3-indolyl.
Detailed Description of the Invention
The following terms shall have, for the purposes of this application, the respective meanings set forth below.
"aryl" alone or in combination, includes carbocylic aromatic systems or a heterocyclic aromatic systems (also known as heteroaryl). The systems may contain one, two or three rings wherein such ring may be attached together in a pendent manner or may be fused. "inert organic solvent" means any organic solvent or combination of solvents that is unreactive in the reaction being conducted, and is a solvent for the reactants. Examples of such solvents used in the various reactions of this invention are identified in the discussion of the reaction schemes and in the examples, "lower alkoxy" shall include linear or branched C\ to C6 alkoxy groups, unless otherwise specified.
"lower alkyl" alone or in combintion shall include linear or branched Ci to Cg alkyl groups, unless otherwise specified, "strong base" means a non aqueous base such as sodium-, potassium-, lithium hexamethyldisilazide, lithium diisopropyl amide, and the like.
In accordance with the present invention, novel processes and synthetic intermediates for the preparation of l,5-diaryl-3-substituted-pyrazoles are provided. The processes of the invention have been developed from readily available and inexpensive starting materials. Furthermore, the processes provide high yields of l,5-diaryl-3- substituted-pyrazoles, and simplify isolation and purification steps.
Scheme 1
One embodiment of the invention is depicted in Scheme 1, wherein X, Y and Z are as described above for the compound of formula I. An aryl alkyne of the formula III, is condensed with an aryl hydrazine of the formula IN to provide a l,5-diaryl-3-
substituted-pyrazole compound having the formula I. Preferably, the aryl hydrazine of the formula IN is provided as a salt, e.g., a hydro chloride salt. The reaction can be completed in a protic solvent such as ethanol, n-propanol, isopropanol, butanol or acetic acid at an elevated temperature, e.g., ethanol at reflux. Typically, a slight excess of the aryl hydrazine is used, such as from about 1.05 to about 1.3 molar equivalents. The reaction provides high regio selectivity with respect to the ratio of products obtained of the 1,5-diaryl type (i.e., compound of the formula I) to the 1,3-diaryl type (not shown). Typically, the ratio of the desired 1,5-diaryl pyrazole to the undesired 1,3-isomer is greater than 9 to 1. Purification of the compound of formula I can be conveniently carried out by recrystallization from alcohol solvents, e.g., ethanol.
Various acid addition salts of the compound of the formula I can be prepared by treatment with an organic or inorganic acid. Preferably, the acid addition salts formed are pharmaceutically acceptable salts, such as those described in US Patent No. 5,563, 165, the disclosure of which is herein incorporated by reference. Suitable base addition salts of the compound of formula I, wherein the phenyl group at the 5-position of the pyrazole ring incorporates a carboxy or hydroxyl substituent. Base addition salts include metallic addition salts, e.g, sodium, potassium, and organic base addition salts, e.g, organic amines. Other pharmaceutically acceptable acid addition salts are detailed in US Patent No. 5,563,165. The aryl hydrazine compound of the formula IV can be prepared by treating substituted aryl amines of the formula XI
Z-NH2 (XI) with nitrous acid (e.g., formed from hydrochloric acid and sodium nitrite) to provide a diazonium salt. Typically the reaction is carried out as an aqueous mixture at temperatures below about 5 °C. The resulting diazonium salt is treated with a reducing agent, e.g., stannous chloride, to provide the substituted aryl hydrazine of the formula IN. It will be appreciated by those of ordinary skill in the art that alternative well-known preparations of aryl hydrazine compounds can also be used, for example, through nucleophilic displacement with hydrazine of aryl compounds of the formula Nil Z'Q' (Nil) wherein Q' is a leaving group, e.g., halides.
Preparation of the Alkyne of the Formula III (General Methods) The alkyne of the formula III
wherein X is trihalomethyl, Cι-C6 alkyl or a group of the formula II
can be prepared from an ,β-unsaturated ketone of the formula N
O Z^^^X (N). The ,β-unsaturated ketone of formula N, for example, is first treated with bromine in a suitable inert organic solvent, e.g. chloroform, at room temperature for a sufficient amount of time to form an α,β-dibromo intermediate. The intermediate is subsequently treated with a base such as an alkali metal hydroxide, e.g., potassium, sodium, or lithium hydroxide, to effect elimination of FfBr and provide the alkyne of formula III. The alkyne of the formula III can be further purified by, for example, recrystallization from suitable solvents, e.g., alcohols, when the compound is a solid. Alternatively, the compound of the formula III can be purified by other techniques such as chromatography or distillation (in the case of liquids).
Scheme 2
The α, β-unsaturated ketone of the formula N can be obtained by well-known aldol condensations of aryl aldehydes of the formula Z-CHO (XII) with a methyl ketone of the formula X
l oo
wherein X is trihalomethyl, C\ to C6 alkyl or a group of the formula II as depicted in Scheme 2. Typically, the reaction is carried out using a base such as an alkali metal base (e.g., sodium, potassium or lithium hydroxide). The reaction can be accomplished, for example, without added solvent, or in an alcohol solvent, e.g., ethanol. The reaction can be carried out at about room temperature, although in some condensations elevated temperatures are preferably used to promote faster reaction times. After aqueous workup, the α,β-unsaturated ketones can be isolated and purified by suitable techniques such as distillation, chromatography or recrystallization.
In those embodiments wherein the methyl ketone of the formula X contains additional enolizable protons a to the carbonyl group in addition to the methyl moiety (e.g., wherein the compound of the formula X is 2-pentanone) modification of the aldol reaction conditions can be used. For example, low temperature reaction conditions using a strong base, e.g, lithium diisopropylamide, in an inert organic solvent, e.g., tetrahydrofuran, can be used to generate the corresponding kinetic enolate of the methyl ketone of the formula X, which is then reacted with the aldehyde of the formula XII.
Other techniques for promoting the regioselectivity of the aldol reaction will be apparent to those of ordinary skill in the art.
In another embodiment, the propargylic ester of the formula III, can be obtained by formation of the corresponding aryl acetylide from the aryl alkyne having the formula NIII
z (Niπλ with a strong base, e.g., n-butyllithium, lithium diisopropylamide, followed by addition of the acetylide to an acylating agent having the formula XIII
O
QAχ (XIII) wherein X is as defined above and Q is a leaving group. Examples of acylating agents include anhydrides, acid chlorides, activated esters and the like. The reaction is typically carried out in an ether solvent, e.g., tetrahydrofuran, methyl t-butyl ether or in dichloromethane or dimethylformamide.
Processes for the Preparation of the Alkyne of the Formula III wherein the Radical X is Trihalomethyl
In addition to the general procedures described above for the alkyne of formula III, there are alternative procedures that are useful in instances where the radical X is trihalomethyl in the alkyne of formula III. For example, the alkyne of formula III wherein the radical X is trihalomethyl, can be prepared from the α,β-unsaturated ketone of the formula N
O
Z"^^X (N).
The α,β-unsaturated ketone of the formula N wherein the radical X is trihalomethyl, can be prepared from a dialkyl methylphosphonate, an Ν-phenyltrihaloacetamidoyl chloride and an aryl aldehyde of the formula Z-CHO (XII). An intermediate is formed from the reaction of dialkyl methylphosphonate, Ν-phenyltrihaloacetamidoyl chloride and a strong base (e.g., lithium diisopropylamide) that is condensed with the aryl aldehyde of the formula XII to form the α,β-unsaturated ketone of the formula N. The bromination/elimination procedure described above can then be used to convert the α,β,- unsaturated ketone of the formula N to the alkyne of the formula IΪI.
Preparation of the Alkyne of the Formula III wherein X is trifluoromethyl
In addition to preparations described above for the general preparation of the alkyne of the formula III and the preparations wherein the radical X is trihalomethyl, there are specific processes that are useful for the preparation of the alkyne of the formula III, where the radical X is trifluoromethyl. Some of these processes are depicted in Schemes 3-5, and are also described below.
Scheme 3
wherein X is CF3
In some embodiments of the process, wherein the radical X is trifluoromethyl, the alkyne of the formula III is obtained from the α,β-unsaturated ketone of the formula N using the bromination/elimination procedure described above. The α,β-unsaturated ketone of the formula N is obtained by electrophilic addition of the vinylogous ester, 4- ethoxy-l3l,l-trifluoro-3-buten-2-one, to an aryl compound of the formula Z, wherein Z is as defined above (Scheme 3). For example, toluene can be treated with an equimolar amount of 4-ethoxy- 1,1,1 -trifluoro-3-buten-2-one in a suitable inert solvent, e.g., dichloromethane, to provide l,l,l-trifluoro-4-(4-methylphenyl)-3-buten-2-one. Typically, a catalytic amount, e.g., <10 mole %, of a Lewis acid, e.g., zinc chloride, is added to the reaction mixture to catalyze the addition.
Scheme 4
Z # \ ^^ 1 CF3Si(CH3)3 /^ X ι. OCH3 Z'^^" >CH3 CsF Z^ ^"~^ X
V" IX ^ V wherein X is CF3
In other embodiments of the process, wherein the radical X is trifluoromethyl, the α,β, -unsaturated ketone of the formula N is obtained by treatment of an α,β -unsaturated ester of the formula IX with trimethyl(l,l,l-trifiuoromethyl)silane and cesium fluoride (Scheme 4). The reaction is carried out neat, or in an inert organic solvent, e.g, dichloromethane, tetrahydrofuran, at a temperature of about 15 to about 30 °C. The α,β- unsaturated acid ester of the formula IX can be obtained from a Heck coupling of a halo aryl compound of the formula Nil (wherein Q' is a leaving group, preferably Cl, Br, or I, more preferably Br or I) with methyl acrylate. The reaction mixture includes a base, e.g., potassium carbonate, and a palladium catalyst. Palladium catalysts for the Heck reaction are well-known and include palladium(II) acetate. A stabilizing ligand for the palladium such as triphenylphosphine can be included in the reaction mixture. A preferred catalyst is Pd-Cu-Mont. K-10 (clay). The reaction is typically carried out in a dipolar aprotic solvent, e.g., dimethylformamide, at temperatures of about 100 to about 160 °C. The Heck procedure permits regioselective coupling of the methyl acrylate group on to the aryl ring. This procedure is particularly advantageous for compounds
wherein the electrophilic addition of the vinylogous ester to the aryl precursors Z described above leads to unfavorable mixtures of regioisomers in the product.
Scheme 5
wherein X is CF3
In another embodiment of the process, the alkyne of the formula III, wherein the radical X is trifluoromethyl is obtained by treatment of a propargylic ester of the formula NI, with trimethyl( 1,1,1 -trifluoromethyl) silane and cesium fluoride (Scheme 5). Here again, the reaction is carried out neat, or in an inert organic solvent, e.g, dichloromethane, tetrahydrofuran, at a temperature of about 15 to about 30 °C.
The propargylic ester of the formula NI can be obtained from an aryl acetylene having the formula NIII. The reaction is catalyzed by a palladium (II) catalyst, e.g., palladium (II) acetate, in methanol at a temperature of about 15 °C to about 40 °C. Preferably, the reaction catalyzed by a catalyst mixture having palladium (II) (e.g., palladium (II) acetate), molybdovanadophosphate (ΝPMoV), and chlorohydroquinone (HQ-C1).
In embodiments of the processes wherein the aryl groups Y and Z, or a group of the formula II
bear substituents such as hydroxyl or carboxy that may interfere or decrease the yield of certain synthetic steps, suitable protecting groups for these substituents that are well known in the art, can be used. The protecting groups can be then removed at appropriate points in the synthetic sequence by known methods. Thus, for example, a hydroxyl moiety can be protected as a methyl or silyl ether. Similarly, a carboxy moiety can be protected as an ester if necessary, which can be hydrolyzed in a later synthetic step.
The following examples further illustrate the present invention, but of course, should not be construed as in any way limiting its scope.
Example 1 - Synthesis of 4-[5-(4-methylphenylV3 -(trifluoromethyl)- lH-pyrazol-1- yLJbenzenesulfonamide (Compound of the Formula I. X=CF3, Y=sulfamyL Z=p- methylphenyiY
Preparation of l.l-Trifluoro-4-(4-methylphenyl)-3-buten-2-one (o β, -Unsaturated Ketone of the Formula V. X=CF1V.
To a solution of toluene (10 mmol) and 4-ethoxy-l,l,l-trifluoro-3-buten-2-one (10 mmol) in dichloromethane (10 mL) is added zinc chloride (0.015 g, 1.5 mol%). The reaction mixture is stirred for 3 h at 22 °C. The resulting precipitate is filtered, washed with dichloromethane (2 x 15 mL) and dried.
Preparation of l,l.l-Trifluoro-4-(4-methylphenyl)-3-butyn-2-one (Aryl Alkyne of the Formula III. X=CF3. Z=4-methylphenyl :
To a stirred solution of l,l,l-trifluoro-4-(4-methylphenyl)-3-buten-2-one (10 mmol) in chloroform (100 mL), a solution of bromine (10 mmol) in chloroform (50 mL) is added dropwise at room temperature. The solution is stirred for an additional 30 min
to complete of the reaction. The solvent is then removed under vacuum to obtain the dibromo compound.
The dibromo compound is added in portions to a solution of ethanolic (200 mL) potassium hydroxide (10 mmol) over a period of 30 min. After the addition is complete, the reaction mixture is refluxed for 3 h, cooled and poured onto ice cold water. The precipitated l,l,l-trifluoro-4-(methylphenyl)-3-butyn-2-one is separated by filtration and recrystallized.
Preparation of 4-Sulfamylphenyl hydrazine Hydrochloride (Aryl Hydrazine of the Formula IN. Y 4-sulfamvD:
(A procedure is described inJ. Med Chem. 1979, 22, 321-325.) A cold stirred mixture of sulfanilamide (34.2 g, 0.2 mol), hydrochloric acid (100 mL) and crushed ice (200 g) is diazotized by dropwise addition of sodium nitrite (14 g, 0.2 mol) in water (25 mL) over 30 min. The cold diazonium salt thus formed is rapidly added to a well-cooled solution of stannous chloride (100 g) in hydrochloric acid (150 mL) with vigorous stirring, and the resulting mixture is left in the refrigerator overnight. The precipitated 4- sulfamylphenyl hydrazine hydrochloride is collected at pump and dried.
Preparation of 4- [5 -(4-methylphenyl)-3 -(trifluoromethyl)- 1 H-pyrazol- 1 - yl]benzenesulfonamide (Compound of the Formula I)
A solution of l,l,l-trifluoro-4-(methylphenyl)-3-butyn-2-one (10 mmol) in ethanol (100 mL) is refluxed with 4-sulfamylphenyl hydrazine hydrochloride (12 mmol) for 4 h. The reaction mixture is cooled and diluted with water. The precipitated crude 4- [5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide is filtered and recrystallized.
Example 2 : Prep aration of 4-(5 -Phenyl-3 -methyl- 1 H-pyrazol- 1 -yl)b enzenesulfonamide (Compound of the Formula I, X=GHh. Y=4-sulfamyl. Z=phenyl)
A solution of 4-phenyl-3-butyn-2-one (10 mmol) in ethanol (100 mL) was refluxed with 4-sulfamylphenyl hydrazine hydrochloride (12 mmol) for 4 h. The reaction mixture was cooled and diluted with water. The precipitated crude 4-(5-phenyl- 3 -methyl- lH-pyrazol-l-yl)benzenesulfonamide was filtered and recrystallized from ethanol to provide the purified product: m.p. 212-213 °C (74% yield). 1HNMR (DMSO-dg) δ 2.3 (2, 3H), 6.2 (s, 2H), 6.5 (s, 1H), 7.2-7.3 (m, 2H), 7.38-7.48 (m, 4H), 7.75-7.82 (d, 2H).
Example 3 : Preparation of 1.1.1 -Trifluoro-4-Phenyl-3 -Butyn-2-one (Compound of the
Formula III. Z=phenvL X=CFa
Preparation of Methyl phenylpropiolate (Propargyhc Ester of the Formula NI. Z=phenyl)
A solution of phenylacetylene (2 mmol), chlorohydroquinone(HQ-Cl) (0.4 mmol), molybdovanadophosphate (ΝPMoN) (35 mg) and palladium (II) acetate (50 mg) in methanol (10 mL) is stirred under CO/O2 (10 atm/ 0.5 atm) at 25 °C for 15 h. The reaction is then quenched with wet ether and the product is extracted with n-hexane. After removal of the solvent under reduced pressure, the product is isolated by column
chromatography over silica gel (hexane: ethyl acetate 5:1) to give pure methyl phenylpropiolate.
Conversion of Methyl Phenylpropiolate to 1.1. l-Trifluoro-4-Phenyl-3-Butyn-2-one (Alkyne of the Formula III. Z=Phenyl. X is CFf)
At room temperature, CsF (0.15 g, 1 mmol) is added to a mixture of methyl phenylpropiolate (1.62 g, 10 mmol) and TMS-CF3 (1.46 g, 10.25 mol, Lancaster). After completion of the reaction (3 h), hydrolysis is carried over 3 h by using 4 N HC1 (4 mL). The resulting product is extracted with ether (30 mL). After removing the ether, the trifluoromethylated ketone is obtained.
Example 4: Synthesis of trans- 1.1.1 -trifluoro-4-aryl-3-buten-2-one (α.β -Unsaturated
Ketone of formula V (X=CFV)
O Z^^"^CF3 To a solution of 10% sodium hydroxide in ethanol (25 mL), 1,1,1- trifluoroacetone (10 mmol) is added and stirred at 15-20 °C. To this a solution of the appropriate aryl aldehyde (10 mmol)
Z-CHO (XII) where Z is defined as above, is added and stirred vigorously for 4 hrs. The temperature of the reaction is maintained at 15-20 °C throughout the reaction. The solution is then poured into ice water and acidified with concentrated hydrochloric acid. The resulting separated trαrø-l,l,l-trifluoro-4-aryl-3-buten-2-one of formula V (X=CF3) is extracted with ether and dried over anhydrous MgSO . Evaporation of the dried ethereal layer yields the tra«s-l,l,l-trifluoro-4-aryl-3-buten-2-one which is purified by recrystallization.
The appropriate 1,1,1-trihaloacetone can be substituted for 1,1,1-trifluoroacetone in this procedure to provide other trans- 1, 1, l-trihalo-4-aryl-3-buten-2-one intermediate.
Alternative synthesis of trans- 1.1.1 -trifluoro-4-aryl-3-buten-2-one intermediate (X=CFV) To a cooled solution of (-70 °C) lithium diisopropylamide (10 mmol), diethyl methylphosphonate (5 mmol) is added. After the mixture is stirred for 30 minutes at -
70°C, N-phenyltrifluoroacetimidoyl chloride (5 mmol) is gradually added and stirring is continued at -70 °C for 1 hour. The appropriate araldehyde (5 mmol)
Z-CHO (XII) where Z is defined as above is added dropwise for 10 minutes. The resulting mixture is warmed to room temperature over 2 hours and then stirred overnight. Then 20 mL of dilute hydrochloric acid is added and stirred at room temperature for 4 hours. The solution is extracted thrice with diethyl ether (20 mL each time) and washed successively with 5% sodium bicarbonate and brine until the pH of the solution is 6. The ethereal layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude trans- 1, 1,1 -trifluoromethyl-4-aryl-3-buten-2-one. The product is purified either by column chromatography or by recrystallization.
Similarly, other N-phenyltrihaloacetimidoyl chlorides can be substituted for N- phenyltrifluoroacetimidoyl chloride in this procedure to produce other trans-1, 1, 1- trihalo-4-aryl-3 -buten-2-one intermediates.
Example 5: Synthesis of trans-1 -(alkyl or optionally substituted aryl)-3-aryl-2-propen-l- one intermediate
O Z"^^X To a solution of 10% sodium hydroxide in ethanol (25 mL), a ketone of the formula
H3C^X o (X) wherein X is Cι-C6 alkyl (20 mmol), or a radical of formula II
wherein R3 and R are defined as above (10 mmol), is added and stirred at 15-20 °C. To this a solution of the appropriate aryl aldehyde
Z-CHO (XII)
(10 mmol) where Z is defined as above, is added and stirred vigorously for 4 hours.
The temperature of the reaction is maintained at 15-20 °C throughout the reaction. The solution is then poured into ice water and acidified with concentrated hydrochloric
acid. The resulting separated trans-l -(alkyl or optionally substituted aryl)-3-aryl-2- propen- 1 -one of formula N (X = d-Cβ alkyl, or radical of formula II) is extracted with ether dried over anhydrous MgSO . Evaporation of the dried ethereal layer yields the trans-1 -(alkyl or optionally substituted aryl)-3-aryl-2-propen-l-one, which is purified by distillation or recrystallization.
While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations in the preferred devices and methods may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the claims that follow.
Claims (35)
1. A process for preparing a compound of the formula I
Ϋ (I) wherein
X is selected from the group consisting of trihalomethyl, Cι-C6 alkyl, and a group of the formula II
wherein
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, Ci-Cδ alkyl, Ci-C6 alkoxy, carboxy, Ci-Cβ trihaloalkyl, cyano, alkylsulfonyl, sulfa yl, phosphonato, and hydroxyalkyl; and Y and Z are independently selected from the group consisting of substituted and unsubstituted aryl; the process comprising: condensing an alkyne of formula III
with an aryl hydrazine of the formula Y-NHNH2 (IN) or a salt thereof.
2. The process of claim 1, wherein Y is substituted or unsubstituted heteroaryl.
3. The process of claim 2, wherein Y is selected from the group consisting of substituted and unsubstituted indolyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, imidazolyl, pyrazolyl, thiazolyl, benzothiazolyl, quinolinyl, and 4-(2-benzyloxazolyl).
4. The process of claim 1, wherein Y is selected from the group consistmg of unsubstituted phenyl, mono-, di-, and trisubstituted phenyl.
5. The process of claim 4, wherein Y is phenyl substituted with one or more of halogen, hydroxyl, nitro, C1-C6 alkyl, Ci-Cβ alkoxy, carboxy, Ci-Cβ trihaloalkyl, cyano, or a group of the formula
— SO2R5, wherein R5 is Ci-Cβ alkyl or amino.
6. The process of claim 5, wherein Y is the group
7. The process of claim 6, wherein R5 is amino.
8. The process of claim 1, wherein Z is substituted or unsubstituted heteroaryl.
9. The process of claim 8, wherein Z is selected from the group consisting of substituted and unsubstituted indolyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, imidazolyl, pyrazolyl, thiazolyl, benzothiazolyl, quinolinyl, and 4-(2-benzyloxazolyl).
10. The process of claim 9, wherein Z is 3 -indolyl.
11. The process of claim 1, wherein Z is selected from the group consisting of unsubstituted phenyl, mono-, di-, and trisubstituted phenyl.
12. The process of claim 11, wherein Z is phenyl substituted with one or more of halogen, hydroxyl, nitro, Ci-C6 alkyl, Cι-C6 alkoxy, carboxy, C Ce trihaloalkyl and cyano.
13. The process of claim 1, wherein the alkyne of formula III is prepared by a process comprising:
(i) adding bromine to an ,β -unsaturated ketone of formula N
O z ^ x (N); and (ii) contacting the product of step (i) with a base.
14. The process of claim 13, wherein the base used in step (ii) is an alkali metal hydroxide.
15. The process of claim 1, wherein X is trifluoromethyl.
16. The process of claim 13, wherein X is trifluoromethyl.
17. The process of claim 16, wherein the ,β-unsaturated ketone of formula N is prepared by a process comprising: treating a compound of the formula IX
O
Z OCH3(IX) with trimethyl(trifluoromethyl)silane in the presence of a cesium fluoride.
18. The process of claim 15, wherein the alkyne of formula III is prepared by a process comprising:
(i) contacting an aryl acetylene of the formula NIII
Z (NIII) with carbon monoxide, oxygen, and methanol, in the presence of a palladium (II) catalyst to provide a propargylic ester of the formula Nt
(ii) treating the propargylic ester of the formula NI with trimethyl(trifluoromethyl)silane in the presence of cesium fluoride to give the compound of formula III.
19. The process of claim 18, wherein the contacting of step (i) further comprises contacting with chlorohydroquinone phosphomolybdate and molybdovanadophosphate.
20. The process of claim 18, wherein the palladium (II) catalyst in step (i) is palladium (II) acetate.
21. The process of claim 1, wherein X is selected from the group consisting of Ci-Ce alkyl and a group of the formula II wherein R3 and R4 are independently selected from the group consisting of halogen, hydroxyl, nitro, Ci-Cβ alkyl, C Ce alkoxy, carboxy, Ci- Cs trihaloalkyl, cyano, alkylsulfonyl, sulfamyl, phosphonato, and hydroxyalkyl.
22. The process of claim 13, wherein X is selected from the group consisting of Cι-C6 alkyl and a group of the formula II wherein R3 and R4 are independently selected from the group consisting of halogen, hydroxyl, nitro, Ci-Cβ alkyl, Cι-C6 alkoxy, carboxy, Ci- Ce trihaloalkyl, cyano, alkylsulfonyl, sulfamyl, phosphonato, and hydroxyalkyl.
23. The process of claim 22, wherein the compound of the formula N is prepared by a process comprising: condensing a methyl ketone of the formula X
H3C X
T oo with an aryl aldehyde of the formula XII
Z-CHO (XII).
24. The process of claim 1, wherein the alkyne of the formula III is prepared by a process comprising: contacting an aryl acetylene of the formula NIII
X^ Z (VIII) with a strong base and reacting the resulting aryl acetylide with an acylating agent of the formula XIII O QAχ (XIII) wherein Q is a leaving group to give the compound of formula III.
25. The process of claim 1, wherein X is trifluoromethyl, Y is 4-sulfamyl and Z is substituted phenyl.
26. The process of claim 25, wherein Z is p-methylphenyl.
27. A compound of the formula III
wherein Z is selected from the group consisting of substituted and unsubstituted aryl.
28. The compound of claim 27, wherein Z is substituted or unsubstituted heteroaryl.
29. The compound of claim 28, wherein Z is selected from the group consisting of substituted and unsubstituted indolyl, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, imidazolyl, pyrazolyl, thiazolyl, benzothiazolyl, quinohnyl, and 4-(2-benzyloxazolyl).
30. The compound of claim 29, wherein Z is 3-indolyl.
31. The compound of claim 27, wherein Z is selected from the group consisting of unsubstituted phenyl, mono-, di-, and trisubstituted phenyl.
32. The compound of claim 31, wherein Z is phenyl substituted with one or more of halogen, hydroxyl, nitro, Ci-Cβ alkyl, Ci-Cβ alkoxy, carboxy, Cι-C6 trihaloalkyl and cyano.
33. The compound of claim 32, wherein Z is p-methylphenyl.
34. A compound of the formula I
wherein
X is trifluoromethyl,
Y is 4-sulfamylphenyl, and
Z is 3 -indolyl or substituted 3 -indolyl.
35. The compound of claim 34, wherein Z is 3 -indolyl.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/323,479 | 2001-09-18 |
Publications (1)
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AU2002336593A1 true AU2002336593A1 (en) | 2003-04-01 |
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