NO782945L - PROCEDURE FOR THE PREPARATION OF 4-ARYL-CHINAZOLINONE DERIVATIVES - Google Patents
PROCEDURE FOR THE PREPARATION OF 4-ARYL-CHINAZOLINONE DERIVATIVESInfo
- Publication number
- NO782945L NO782945L NO782945A NO782945A NO782945L NO 782945 L NO782945 L NO 782945L NO 782945 A NO782945 A NO 782945A NO 782945 A NO782945 A NO 782945A NO 782945 L NO782945 L NO 782945L
- Authority
- NO
- Norway
- Prior art keywords
- stated
- alkyl
- chlorine
- fluorine
- bromine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- 239000000460 chlorine Chemical group 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 150000002736 metal compounds Chemical class 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000011593 sulfur Substances 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Chemical group 0.000 claims description 9
- 239000007858 starting material Substances 0.000 claims description 8
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- -1 alkoxy radical Chemical class 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910052976 metal sulfide Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 claims 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- TYNNEEKKMHSZMO-UHFFFAOYSA-N 3,4,4a,5-tetrahydro-1h-quinazolin-2-one Chemical compound C1C=CC=C2NC(=O)NCC21 TYNNEEKKMHSZMO-UHFFFAOYSA-N 0.000 claims 1
- DBXATJCVRRXUTC-UHFFFAOYSA-N 5,6,7,8-tetrahydro-1h-quinazolin-2-one Chemical compound C1CCCC2=NC(O)=NC=C21 DBXATJCVRRXUTC-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 6
- 239000008096 xylene Substances 0.000 description 5
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- ZWOUXWWGKJBAHQ-UHFFFAOYSA-N fluproquazone Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=C(F)C=C1 ZWOUXWWGKJBAHQ-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 3
- JTIGKVIOEQASGT-UHFFFAOYSA-N proquazone Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=CC=C1 JTIGKVIOEQASGT-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011787 zinc oxide Substances 0.000 description 3
- NOJAJMMKDHHEGC-UHFFFAOYSA-N 4-(4-fluorophenyl)-7-methyl-1-propan-2-yl-5,6,7,8-tetrahydroquinazolin-2-one Chemical compound N=1C(=O)N(C(C)C)C=2CC(C)CCC=2C=1C1=CC=C(F)C=C1 NOJAJMMKDHHEGC-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000012485 toluene extract Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 150000003738 xylenes Chemical class 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BNHGVULTSGNVIX-UHFFFAOYSA-N 1-(2-ethoxyethoxy)ethanol Chemical compound CCOCCOC(C)O BNHGVULTSGNVIX-UHFFFAOYSA-N 0.000 description 1
- JAPCFGJAINHVJK-UHFFFAOYSA-N 5,7-dimethyl-4-phenyl-1-propan-2-ylquinazolin-2-one Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC(C)=C2C=1C1=CC=CC=C1 JAPCFGJAINHVJK-UHFFFAOYSA-N 0.000 description 1
- UPFLALOGLUZWRA-UHFFFAOYSA-N 7-methyl-1-propan-2-yl-4-thiophen-2-ylquinazolin-2-one Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=CS1 UPFLALOGLUZWRA-UHFFFAOYSA-N 0.000 description 1
- XLKSQIVWBJAEJN-UHFFFAOYSA-N 7-methyl-4-(4-methylphenyl)-1-propan-2-ylquinazolin-2-one Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=C(C)C=C1 XLKSQIVWBJAEJN-UHFFFAOYSA-N 0.000 description 1
- YKFXBRUJMZNBAN-UHFFFAOYSA-N 7-methyl-4-phenyl-1-propan-2-yl-5,6,7,8-tetrahydroquinazolin-2-one Chemical compound N=1C(=O)N(C(C)C)C=2CC(C)CCC=2C=1C1=CC=CC=C1 YKFXBRUJMZNBAN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229910052787 antimony Inorganic materials 0.000 description 1
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000011133 lead Substances 0.000 description 1
- 229910000464 lead oxide Inorganic materials 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 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
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- HCHKCACWOHOZIP-NJFSPNSNSA-N zinc-67 Chemical compound [67Zn] HCHKCACWOHOZIP-NJFSPNSNSA-N 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
- C07D239/82—Oxygen atoms with an aryl radical attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
Fremgangsmåte for fremstilling av Method of manufacture of
4-aryl-kinazolinon-derivater.4-aryl-quinazolinone derivatives.
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av 4-aryl-kinazolin-2(1H)-on-forbindelser, spesielt en forbindelse med formel I, The present invention relates to a method for the preparation of 4-aryl-quinazolin-2(1H)-one compounds, in particular a compound of formula I,
hvori R, betyr et (C. - C„) hydrokarbonradikal eventuelt mono-, in which R, means a (C. - C. ) hydrocarbon radical optionally mono-,
i lo I laughed
di- eller tri-substituert med fluor, klor eller brom,di- or tri-substituted with fluorine, chlorine or bromine,
betyr monocyklisk aryl, ogmeans monocyclic aryl, and
og R^, som er like eller forskjellige, betyr hvert et hydrogenatom, et (C^- C.j) alkyl- eller alkoksy-radikal, eller fluor, klor, brom eller trifluormetyl, and R₂, which are the same or different, each represents a hydrogen atom, a (C₁-C₆) alkyl or alkoxy radical, or fluorine, chlorine, bromine or trifluoromethyl,
eller R^og R^betyr sammen 6,7-metylendioksy,or R^ and R^ together mean 6,7-methylenedioxy,
ved dehydrogenering av et tilsvarende 4-aryl-5,6,7,8-tetrahydra-2(1H)-kinazolinon, spesielt en forbindelse med formel II by dehydrogenation of a corresponding 4-aryl-5,6,7,8-tetrahydra-2(1H)-quinazolinone, in particular a compound of formula II
hvori R^ , ,,R^°g R^har den ovennevnte betydning, med svovel i et inert organisk løsningsmiddel. Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at dehydrogeneringen gjennom-føres i nærvær av en uorganisk metallforbindelse som er et oksyd, hydroksyd eller salt av et annet metall enn magnesium, aluminium eller et alkalimetall, og som danner et metallsulfid under reaksjonsbetingelsene. wherein R^ , ,,R^°g R^ has the above meaning, with sulfur in an inert organic solvent. The peculiarity of the method according to the invention is that the dehydrogenation is carried out in the presence of an inorganic metal compound which is an oxide, hydroxide or salt of a metal other than magnesium, aluminum or an alkali metal, and which forms a metal sulphide under the reaction conditions.
Fremgangsmåten i henhold til oppfinnelsen gjennomføres passende ved temperaturer i området fra 125 til 250°C, foretrukket 130 The method according to the invention is conveniently carried out at temperatures in the range from 125 to 250°C, preferably 130
til 200°C og spesielt i området 135 til 200°C.to 200°C and especially in the range 135 to 200°C.
Reaksjonen gjennomføres i et organisk løsningsmiddel som er inert under reaksjonsbetingelsene og foretrukne løsningsmidler omfatter etylenglycol, propylenglycol, etoksyetoksyetanol, dioksan, toluen, xylen og p-cymen. Det foretrekkes vanligvis å anvende et løs-ningsmiddel som koker ved den ønskede reaksjonstemperatur for å utnytte tilbakeløpsbetingelser, f.eks. p-cymen under de mer foretrukne temperaturbetingelser. The reaction is carried out in an organic solvent which is inert under the reaction conditions and preferred solvents include ethylene glycol, propylene glycol, ethoxyethoxyethanol, dioxane, toluene, xylene and p-cymene. It is usually preferred to use a solvent which boils at the desired reaction temperature in order to utilize reflux conditions, e.g. p-cymene under the more preferred temperature conditions.
Molforholdet mellom svovel og kinazolinon-utgangsmateriale kan variere innen ganske vide grenser men er passende minst 1,7 : 1. Den øvre grense er ikke spesielt kritisk, men det er unødvendig og virkningsløst å anvende svovelet i en mengde overstigende ét molforhold på 6 : 1. Mer passende vil molforholdet være i området fra 1,9 : 1 til 4:1, foretrukket i området 2 : 1 til 3:1. The molar ratio of sulfur to quinazolinone starting material can vary within fairly wide limits but is suitably at least 1.7 : 1. The upper limit is not particularly critical, but it is unnecessary and ineffective to use the sulfur in an amount exceeding a molar ratio of 6 : 1 More suitably the molar ratio will be in the range of 1.9:1 to 4:1, preferably in the range of 2:1 to 3:1.
Den metallforbindelse som anvendes er som angitt en forbindelse som danner et sulfid under reaksjonsbetingelsene. I tillegg til alkalimetallene og magnesium og aluminium, foretrekkes som en praktisk foranstaltning ikke de sjeldne jordartmetaller og metaller med et atomtall på 84 eller mer. Foretrukne metaller omfatter kalsium, titan, zirkonium, krom, bly, molybden, mangan, jern, tinn, kobolt, nikkel, palladium, kobber, sølv, sink, kadmium, kvikksølv, antimon og bismutt og mer spesielt kalsium, jern eller sink. Metallforbindelsen kan være et salt, f.eks.. The metal compound used is, as indicated, a compound which forms a sulphide under the reaction conditions. In addition to the alkali metals and magnesium and aluminum, as a practical measure, the rare earth metals and metals with an atomic number of 84 or more are not preferred. Preferred metals include calcium, titanium, zirconium, chromium, lead, molybdenum, manganese, iron, tin, cobalt, nickel, palladium, copper, silver, zinc, cadmium, mercury, antimony and bismuth and more particularly calcium, iron or zinc. The metal compound can be a salt, e.g.
et salt av en sterk syre som f.eks. et halogenid som klorid, sulfat eller nitrat, men er foretrukket et oksyd eller.hydroksyd, a salt of a strong acid such as a halide such as chloride, sulfate or nitrate, but is preferably an oxide or hydroxide,
spesielt et oksyd. De foretrukne metallforbindelser inkluderer kalsiumoksyd, sinkoksyd og spesielt ferrioksyd. Et antall av de metallforbindelser som kan anvendes, f.eks. kalsiumklorid, reagerer med hydrogensulfid til å danne et surt medium og de resulterende metallsulfider vil gjerne være ustabile eller opp-løselige i et slikt medium. I slike tilfeller foretrekkes det å inkludere i reaksjonsblandingen en hydroksydbase, f.eks. et alkalimetallhydroksyd eller jordalkalimetallhydroksyd, eller et overskudd av metallforbindelsen når denne er en hydroksydbase. Foretrukket anvendes et alkalimetallhydroksyd, f.eks. kalium-eller natrium-hydroksyd. especially an oxide. The preferred metal compounds include calcium oxide, zinc oxide and especially ferric oxide. A number of the metal compounds that can be used, e.g. calcium chloride, reacts with hydrogen sulphide to form an acidic medium and the resulting metal sulphides will preferably be unstable or soluble in such a medium. In such cases, it is preferred to include in the reaction mixture a hydroxide base, e.g. an alkali metal hydroxide or alkaline earth metal hydroxide, or an excess of the metal compound when this is a hydroxide base. An alkali metal hydroxide is preferably used, e.g. potassium or sodium hydroxide.
Molforholdet mellom metallforbindelse og kinazolinon-utgangsmaterial er passende minst 1:1, foretrukket minst 1,5 : 1. The molar ratio of metal compound to quinazolinone starting material is suitably at least 1:1, preferably at least 1.5:1.
Den øvre grense er ikke kritisk men molforhold på over 10 : 1 frembyr ingen ytterligere fordel. Mer passende bør molforholdet være i området fra 1,8 : 1 til 6:1, foretrukket 2 : 1 til 4 : 1 og helt spesielt i området fra 2,1 : 1 til 3:1. The upper limit is not critical, but molar ratios above 10:1 offer no further advantage. More suitably, the molar ratio should be in the range from 1.8:1 to 6:1, preferably 2:1 to 4:1 and especially in the range from 2.1:1 to 3:1.
Ved eventuell anvendelse av hydroksydbasen er denne passende til-stede i et molforhold i forhold til kinazolinon-utgangsmaterialet på minst 1:1, passende minst 1,5 : 1, foretrukket 1,8 til 6 : 1 og helt spesielt fra 2 : 1 til 3:1. In the event that the hydroxide base is used, this is suitably present in a molar ratio in relation to the quinazolinone starting material of at least 1:1, suitably at least 1.5:1, preferably 1.8 to 6:1 and especially from 2:1 to 3:1.
Fremgangsmåten i henhold til oppfinnelsen kan gjennomføres under under- eller over-atmosfærisk trykk men gjennomføres mest passende under atmosfærisk trykk. Et teppe eller en konstant strøm av en gass som er inert under reaksjonsbetingelsene, f.eks. nitrogen, foretrekkes ledet over reaksjonsblandingen. The method according to the invention can be carried out under sub- or super-atmospheric pressure but is most suitably carried out under atmospheric pressure. A blanket or constant flow of a gas which is inert under the reaction conditions, e.g. nitrogen, is preferably passed over the reaction mixture.
Reaksjonen kan typisk foregå i fra 1 til 15 timer. The reaction can typically take place for from 1 to 15 hours.
Fremgangsmåten i henhold til oppfinnelsen resulterer i vesentlig høyere utbytter enn ved tilsvarende kjente prosesser, som ikke anvender en metallforbindelse, og som vanligvis resulterer i en blanding av det ønskede kinazolin-2(1H)-on og det tilsvarende 3,4-dihydro-derivat. The method according to the invention results in substantially higher yields than in corresponding known processes, which do not use a metal compound, and which usually result in a mixture of the desired quinazolin-2(1H)-one and the corresponding 3,4-dihydro-derivative .
Forbindelsene II er enten kjente i og for seg eller kan fremstilles fra kjente materialer ved kjente metoder beskrevet i litteraturen. The compounds II are either known in and of themselves or can be prepared from known materials by known methods described in the literature.
I forbindelsene med formler I og II kan (C1 . - CoQ)hydrokarbon-radikalet R, f.eks. være (C. - C,) alkyl, (C_ - C„) cykloalkyl, In the compounds of formulas I and II, the (C1 . - CoQ)hydrocarbon radical R, e.g. be (C. - C.) alkyl, (C. - C.) cycloalkyl,
1 lbil1 lcar
(C^- C7) cykloalkylalkyl, med en (C^ - C&) cykloalkyl-del og en (C^ - C^) alkyl-del, fenyl, benzyl eller fenetyl. Eksempler på halogen-substituerte hydrokarbonradikaler for R^omfatter (C1 , - CD,) alkyl, mono-, di- eller tri-substituert med fluor, klor eller brom og fenyl, benzyl eller fenetyl, mono- eller di-substituert med fluor, klor eller brom. Di- eller tri-halogen -substituerte radikaler foretrekkes substituert med de samme halogenatomer. (C 1 - C 7 ) cycloalkylalkyl, having a (C 1 - C 1 ) cycloalkyl moiety and a (C 1 - C 7 ) alkyl moiety, phenyl, benzyl or phenethyl. Examples of halogen-substituted hydrocarbon radicals for R^ include (C1 , - CD, ) alkyl, mono-, di- or tri-substituted with fluorine, chlorine or bromine and phenyl, benzyl or phenethyl, mono- or di-substituted with fluorine, chlorine or bromine. Di- or tri-halogen-substituted radicals are preferably substituted with the same halogen atoms.
I forbindelsene med formler I og II er R2mer foretrukket et radikal med formel III eller IV In the compounds of formulas I and II, R2 is more preferably a radical of formula III or IV
hvor Y og Y 1 er like eller forskjellige og hver betyr et hydrogen-, fluor-, klor- eller brom-atom, et (C^- C^) alkyl-eller alkoksy-radikal, eller en trifluormetylgruppe, med den betingelse at når en av Y og Y.. betyr en trifluormetylgruppe, betyr den annen et hydrogenatom, og where Y and Y 1 are the same or different and each represents a hydrogen, fluorine, chlorine or bromine atom, a (C^-C^) alkyl or alkoxy radical, or a trifluoromethyl group, with the proviso that when one of Y and Y.. represents a trifluoromethyl group, the other represents a hydrogen atom, and
Y2betyr et hydrogen-, fluor-, klor- eller brom-atom, eller etY 2 means a hydrogen, fluorine, chlorine or bromine atom, or a
(C^- C^) alkyl- eller alkoksy-radikal.(C^-C^) alkyl or alkoxy radical.
Forbindelsene med formel I er kjent for sin anti-inflammatoriske virkning og i denne henseende er R., foretrukket (C^ - C^) alkyl eller cyklopropylmetyl, mer foretrukket ( C^ - C^) alkyl og spesielt isopropyl. R2er foretrukket et fenylradikal eventuelt mono-.eller di-substituert som angitt ovenfor, og er mer foretrukket fenyl eller p-fluorfenyl. R^og R4kan hver være hydrogen. Foretrukket er imidlertid minst en av dem 2-alkyl, spesielt metyl, f.eks..i 7-stillingen, eller C^^-alkoksy/ f.eks. metoksy, f.eks. i 6-stillingen. The compounds of formula I are known for their anti-inflammatory action and in this respect R. is preferably (C 1 -C 2 ) alkyl or cyclopropylmethyl, more preferably (C 2 -C 3 ) alkyl and especially isopropyl. R2 is preferably a phenyl radical optionally mono- or di-substituted as indicated above, and is more preferably phenyl or p-fluorophenyl. R 1 and R 4 may each be hydrogen. However, at least one of them is preferably 2-alkyl, especially methyl, e.g. in the 7-position, or C₁-₄-alkoxy/ e.g. methoxy, e.g. in the 6 position.
De forbindelser som helst fremstilles er 7-metyl-l-isopropyl-4-fenyl-2(1H)-kinazolin og l-isopropyl-4-p-fluorfenyl-7-metyl-2(1H)-kinazolinon. The compounds preferably prepared are 7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazoline and 1-isopropyl-4-p-fluorophenyl-7-methyl-2(1H)-quinazolinone.
De følgende eksempler illusterer fremgangsmåten i henhold til oppfinnelsen. The following examples illustrate the method according to the invention.
EKSEMPEL 1: 7- metyl- l- isopropyl- 4- fenyl- 2( 1H)- kinazolinonEXAMPLE 1: 7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone
En blanding av 200 ml p-cymen, 40 g ferrioksyd og 7 g svovel oppvarmes under tilbakeløp (ca. 175°C) og tilsettes dråpevis i løpet av 40 minutter en varm løsning (130°C) av 28,2 g 7-metyl-l-isopropyl-4-fenyl-5,6,7,8-tetrahydro-2(1H)-kinazolinon i 200 ml p-cymen. Den resulterende løsning kokes under til-bakeløp i 3,5 timer hvorunder 1,8 ml vann samles i en Dean-Stark-separator. Reaksjonsløsningen avkjøles så til 28°C og filtreres gjennom en pute av "Celite" som så vaskes fire ganger hver gang med 25 ml toluen. Toluen-vaskeløsningene ekstraheres med 50 ml 4N saltsyre og p-cymenfiltratet ekstraheres med 350 ml 4N saltsyre. Syreekstraktene kombineres og ekstraheres med 100 ml toluen og disse toluenekstrakter kastes. Den sure løsning som er tilbake etter hver toluenekstraksjon behandles ved tilsetning av 350. ml toluen og 110 g 50 % vanndig natriumhydroksydløsning. Fasene separeres og toluenfasen vaskes to ganger hver gang med A mixture of 200 ml of p-cymene, 40 g of ferric oxide and 7 g of sulfur is heated under reflux (approx. 175°C) and a hot solution (130°C) of 28.2 g of 7-methyl is added dropwise over 40 minutes -1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone in 200 ml p-cymene. The resulting solution is refluxed for 3.5 hours during which time 1.8 ml of water is collected in a Dean-Stark separator. The reaction solution is then cooled to 28°C and filtered through a pad of "Celite" which is then washed four times each time with 25 ml of toluene. The toluene washing solutions are extracted with 50 ml of 4N hydrochloric acid and the p-cymene filtrate is extracted with 350 ml of 4N hydrochloric acid. The acid extracts are combined and extracted with 100 ml of toluene and these toluene extracts are discarded. The acidic solution that remains after each toluene extraction is treated by adding 350 ml of toluene and 110 g of 50% aqueous sodium hydroxide solution. The phases are separated and the toluene phase is washed twice each time with
100 ml vann etterfulgt av tørking over natriumsulfat, filtrering og inndamping under vakuum. Den faste rest krystalliseres fra etylacetat til å gi 7-metyl-l-isopropyl-4-fenyl-kinazolin-2(1H)- 100 ml of water followed by drying over sodium sulfate, filtration and evaporation under vacuum. The solid residue is crystallized from ethyl acetate to give 7-methyl-1-isopropyl-4-phenyl-quinazoline-2(1H)-
on med smeltepunkt 139 til 141°C.on with a melting point of 139 to 141°C.
EKSEMPEL 2: l- isopropyl- 4- p- fluorfenyl- 7- metyl- 2( 1H)- kinazolinon EXAMPLE 2: 1-isopropyl-4-p-fluorophenyl-7-methyl-2(1H)-quinazolinone
En blanding av 67 ml xylen, 13,3 g ferrioksyd og 2,5 g svovel oppvarmes under en nitrogenatmosfære under tilbakeløp og tilsettes dråpevis i løpet av 20 minutter en varm løsning (100 - llO^C) av 10 g 7-metyl-l-isopropyl-4-p-fluor-fenyl-5,6,7,8-tetrahydro-2-(1H)-kinazolinon i 100 ml xylen. Den resulterende løsning kokes under tilbakeløp i 10 timer hvorunder vann samles i en Dean-Stark-separator. Reaksjonsblandingen avkjøles så til A mixture of 67 ml of xylene, 13.3 g of ferric oxide and 2.5 g of sulfur is heated under a nitrogen atmosphere under reflux and added dropwise over 20 minutes to a hot solution (100 - 110°C) of 10 g of 7-methyl-l -isopropyl-4-p-fluoro-phenyl-5,6,7,8-tetrahydro-2-(1H)-quinazolinone in 100 ml of xylene. The resulting solution is refluxed for 10 hours during which water is collected in a Dean-Stark separator. The reaction mixture is then cooled to
80°C og filtreres gjennom et lag av "Celite".80°C and filtered through a layer of "Celite".
Filtratet og filterkaken vaskes tre ganger hver gang med 50 ml toluen. Filtratene kombineres og ekstraheres så i rekkefølge med 200, 100 og 50 ml 4N saltsyre. Syreekstraktene kombineres og vaskes med 100 ml toluen, idet toluenekstraktene kastes. The filtrate and the filter cake are washed three times each time with 50 ml of toluene. The filtrates are combined and then extracted in sequence with 200, 100 and 50 ml of 4N hydrochloric acid. The acid extracts are combined and washed with 100 ml of toluene, the toluene extracts being discarded.
Til den sure løsning, som er tilbake etter hver toluenekstraksjon, tilsettes 200 ml toluen og 115 g 50 % vanndig natriumhydroksyd-løsning under omrøring og avkjøling. Fasene separeres og den vandige fase vaskes to ganger hver gang med 100 ml toluen. To the acidic solution, which remains after each toluene extraction, 200 ml of toluene and 115 g of 50% aqueous sodium hydroxide solution are added while stirring and cooling. The phases are separated and the aqueous phase is washed twice each time with 100 ml of toluene.
Toluenfåsene kombineres, vaskes to ganger hver gang med 100 ml vann, etterfulgt av tørking over vannfritt magnesiumsulfat, filtrering gjennom "Celite" og inndamping til å gi 8,8 g (90 %) gule krystaller. Omkrystallisasjon fra etylacetat gir den i overskriften nevnte forbindelse med smeltepunkt 175 - 176,5°C. The toluene phases are combined, washed twice each time with 100 mL of water, followed by drying over anhydrous magnesium sulfate, filtration through "Celite" and evaporation to give 8.8 g (90%) of yellow crystals. Recrystallization from ethyl acetate gives the compound mentioned in the title with a melting point of 175 - 176.5°C.
EKSEMPEL 3: l- isopropyl- 4- fenyl- 7- metyl- 2( 1H)- kinazolinonEXAMPLE 3: 1-isopropyl-4-phenyl-7-methyl-2(1H)-quinazolinone
En blanding av 28,2 g 7-metyl-l-isopropyl-4-fenyl-5,6,7,8-tetrahydro-2(1H)-kinazolinon, 9,6 g svovel, 10 g natriumhydroksyd, 20 g kalsiumklorid og 200 ml karbitol (2-|72-etoksyetoksy]etanol) oppvarmes under et nitrogenteppe ved 150°C i 2 timer. Den resulterende blanding avkjøles så til 65°C, 500 ml benzen tilsettes og blandingen avkjøles under omrøring til 15°C og væske-fasen avhelles. Den organiske fase vaskes med vann og inndampes til å gi en olje som oppløses i en blanding av 100 ml benzen og 100 ml 50 % vanndig saltsyre. Den resulterende blanding omrøres i en time ved romtemperatur, fasene separeres og den sure fase behandles med 50 ml benzen. Den sure fase nøytraliseres med 50 % natriumhydroksydløsning, ekstraheres ved 150 ml benzen og benzenekstraktene vaskes med vann til nøytral reaksjon. Etter tørking over natriumsulfat inndampes benzenløsningen til å gi det rå produkt som omkrystalliseres fra etylacetat til å gi l-isopropyl-4-fenyl-7-metyl-2(1H)-kinazolinon, smeltepunkt 141-142°C. A mixture of 28.2 g of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone, 9.6 g of sulfur, 10 g of sodium hydroxide, 20 g of calcium chloride and 200 ml of carbitol (2-|72-ethoxyethoxy]ethanol) is heated under a blanket of nitrogen at 150°C for 2 hours. The resulting mixture is then cooled to 65°C, 500 ml of benzene is added and the mixture is cooled with stirring to 15°C and the liquid phase is decanted. The organic phase is washed with water and evaporated to give an oil which is dissolved in a mixture of 100 ml of benzene and 100 ml of 50% aqueous hydrochloric acid. The resulting mixture is stirred for one hour at room temperature, the phases are separated and the acidic phase is treated with 50 ml of benzene. The acidic phase is neutralized with 50% sodium hydroxide solution, extracted with 150 ml of benzene and the benzene extracts are washed with water until the reaction is neutral. After drying over sodium sulfate, the benzene solution is evaporated to give the crude product which is recrystallized from ethyl acetate to give 1-isopropyl-4-phenyl-7-methyl-2(1H)-quinazolinone, mp 141-142°C.
EKSEMPEL 4: 7-metyl-l-isopropyl-4-(p-fluorfenyl)-kinazolin-2 ( 1H)- on EXAMPLE 4: 7-methyl-1-isopropyl-4-(p-fluorophenyl)-quinazolin-2(1H)-one
Til en omrørt blanding av 4,3 g svovel, 6,8 g sinkoksyd og 67 ml av en blanding av xylener oppvarmet under tilbakeløp (ca. 138°C) under et nitrogenteppe tilsettes en foroppvarmet (100 -115°C) løsning av 10,0 g 7-metyl-l-isopropyl-4-(p-fluorfenyl)-5,6,7,8-tetrahydro-2(1H)-kinazolinon i 100 ml av en blanding av xylener. Etter tilsetning (ca. 20 minutter) kokes den resulterende blanding under tilbakeløp over natten, avkjøles og filtreres gjennom "Celite". Tørrstoffene vaskes med toluen og filtratet og vaskeløsningene ekstraheres fire ganger med 4N saltsyre og ekstraktene vaskes med 100 ml toluen. Den vanndige fase behandles med 200 ml toluen og behandles porsjonsvis med 115 g 50 % natriumhydroksydløsning i et isbad. Den vandige fase ekstraheres to ganger hver gang med 100 ml toluen og den organiske fase vaskes med vann og tørkes. Det rå gule faststoff oppnådd ved filtrering og inndamping under vakuum oppløses i 100 ml etylacetat, filtreres og konsentreres til et volum på 50 ml og avkjøles til 0°C til å gi et bunnfall som omkrystalliseres fra etylacetat til å gi 7-metyl-l-isopropyl-4-(p-fluorfenyl)-kinazolin-2(1H)-on. To a stirred mixture of 4.3 g of sulphur, 6.8 g of zinc oxide and 67 ml of a mixture of xylenes heated under reflux (about 138°C) under a blanket of nitrogen is added a preheated (100 -115°C) solution of 10 .0 g of 7-methyl-1-isopropyl-4-(p-fluorophenyl)-5,6,7,8-tetrahydro-2(1H)-quinazolinone in 100 ml of a mixture of xylenes. After addition (about 20 minutes), the resulting mixture is refluxed overnight, cooled and filtered through Celite. The dry substances are washed with toluene and the filtrate and the washing solutions are extracted four times with 4N hydrochloric acid and the extracts are washed with 100 ml of toluene. The aqueous phase is treated with 200 ml of toluene and treated in portions with 115 g of 50% sodium hydroxide solution in an ice bath. The aqueous phase is extracted twice each time with 100 ml of toluene and the organic phase is washed with water and dried. The crude yellow solid obtained by filtration and evaporation under vacuum is dissolved in 100 ml of ethyl acetate, filtered and concentrated to a volume of 50 ml and cooled to 0°C to give a precipitate which is recrystallized from ethyl acetate to give 7-methyl-1- isopropyl-4-(p-fluorophenyl)-quinazolin-2(1H)-one.
EKSEMPEL 5:EXAMPLE 5:
Fremgangsmåten i eksempel 4 gjentas under anvendelse av en ekvivalent molar mengde blyoksyd i stedet for sinkoksyd til å The procedure in Example 4 is repeated using an equivalent molar amount of lead oxide instead of zinc oxide to
gi det samme produkt.give the same product.
EKSEMPEL 6:EXAMPLE 6:
På analog måte som hvilke som helst av de foregående eksemplerIn an analogous manner to any of the preceding examples
og under anvendelse av passende utgangsmaterialer i passende ekvivalente mengder ble følgende forbindelser fremstilt: 5,7-dimetyl-l-isopropyl-4-fenyl-kinazolin-2(1H)-on; l-isopropyl-7-metyl-4-(p-metylfenyl)-kinazolin-2(1H)-on; l-isopropyl-7-metyl-4-(2-tienyl)-kinazolin-2(1H)-on; and using appropriate starting materials in appropriate equivalent amounts, the following compounds were prepared: 5,7-dimethyl-1-isopropyl-4-phenyl-quinazolin-2(1H)-one; 1-isopropyl-7-methyl-4-(p-methylphenyl)-quinazolin-2(1H)-one; 1-isopropyl-7-methyl-4-(2-thienyl)-quinazolin-2(1H)-one;
l-.cyklopropylmetyl-6-metoksy-4-f enyl-kinazolih-2 (1H) -on. 1-.Cyclopropylmethyl-6-methoxy-4-phenyl-quinazolin-2(1H)-one.
Claims (20)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US83041177A | 1977-09-06 | 1977-09-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO782945L true NO782945L (en) | 1979-03-07 |
Family
ID=25256956
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO782945A NO782945L (en) | 1977-09-06 | 1978-08-29 | PROCEDURE FOR THE PREPARATION OF 4-ARYL-CHINAZOLINONE DERIVATIVES |
Country Status (28)
Country | Link |
---|---|
JP (1) | JPS5455583A (en) |
AR (1) | AR228235A1 (en) |
AT (1) | AT376211B (en) |
AU (1) | AU523728B2 (en) |
BE (1) | BE870185A (en) |
CA (1) | CA1111847A (en) |
CH (1) | CH642638A5 (en) |
DD (1) | DD138657A5 (en) |
DE (1) | DE2837403A1 (en) |
DK (1) | DK144999C (en) |
ES (1) | ES473103A1 (en) |
FI (1) | FI66362C (en) |
FR (1) | FR2401917A1 (en) |
GB (1) | GB2003873B (en) |
GR (1) | GR73605B (en) |
HU (1) | HU183018B (en) |
IE (1) | IE47184B1 (en) |
IL (1) | IL55492A (en) |
IT (1) | IT1106289B (en) |
NL (1) | NL7808981A (en) |
NO (1) | NO782945L (en) |
NZ (1) | NZ188329A (en) |
PL (1) | PL114207B1 (en) |
PT (1) | PT68505A (en) |
SE (1) | SE7809098L (en) |
SU (1) | SU900810A3 (en) |
YU (1) | YU211078A (en) |
ZA (1) | ZA785061B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH637114A5 (en) * | 1978-08-16 | 1983-07-15 | Sandoz Ag | 2- (N-CARBOALKOXYAMINO) -BENZOPHENONE, THEIR PRODUCTION AND USE. |
CH645362A5 (en) * | 1979-07-05 | 1984-09-28 | Sandoz Ag | METHOD FOR PRODUCING 4-PHENYL-2 (1H) -QUINAZOLINONES. |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE785937A (en) * | 1971-07-08 | 1973-01-08 | Sandoz Sa | NEW DERIVATIVES OF QUINAZOLINE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
-
1978
- 1978-08-25 CH CH904578A patent/CH642638A5/en not_active IP Right Cessation
- 1978-08-28 FI FI782619A patent/FI66362C/en not_active IP Right Cessation
- 1978-08-28 DE DE19782837403 patent/DE2837403A1/en not_active Withdrawn
- 1978-08-29 NO NO782945A patent/NO782945L/en unknown
- 1978-08-29 SE SE7809098A patent/SE7809098L/en unknown
- 1978-08-29 DK DK382078A patent/DK144999C/en not_active IP Right Cessation
- 1978-08-31 FR FR7825162A patent/FR2401917A1/en active Granted
- 1978-08-31 GB GB7835143A patent/GB2003873B/en not_active Expired
- 1978-09-01 NL NL7808981A patent/NL7808981A/en not_active Application Discontinuation
- 1978-09-01 IT IT50936/78A patent/IT1106289B/en active
- 1978-09-04 NZ NZ188329A patent/NZ188329A/en unknown
- 1978-09-04 IE IE1780/78A patent/IE47184B1/en unknown
- 1978-09-04 JP JP10769178A patent/JPS5455583A/en active Pending
- 1978-09-04 PT PT68505A patent/PT68505A/en unknown
- 1978-09-04 IL IL55492A patent/IL55492A/en unknown
- 1978-09-04 BE BE190237A patent/BE870185A/en not_active IP Right Cessation
- 1978-09-05 HU HU78SA3133A patent/HU183018B/en unknown
- 1978-09-05 SU SU782658400A patent/SU900810A3/en active
- 1978-09-05 AU AU39571/78A patent/AU523728B2/en not_active Expired
- 1978-09-05 PL PL1978209423A patent/PL114207B1/en unknown
- 1978-09-05 AT AT0639978A patent/AT376211B/en not_active IP Right Cessation
- 1978-09-05 YU YU02110/78A patent/YU211078A/en unknown
- 1978-09-05 DD DD78207656A patent/DD138657A5/en unknown
- 1978-09-05 CA CA310,645A patent/CA1111847A/en not_active Expired
- 1978-09-05 ES ES473103A patent/ES473103A1/en not_active Expired
- 1978-09-05 AR AR273577A patent/AR228235A1/en active
- 1978-09-06 ZA ZA785061A patent/ZA785061B/en unknown
-
1980
- 1980-01-04 GR GR57147A patent/GR73605B/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR900007624B1 (en) | 9-amino-1,2,3,4-tetrahydroacridin-1-al and their preparation | |
Finnegan et al. | Preparation and isomerization of 5-alkylaminotetrazoles | |
Taylor et al. | The Synthesis of 4-Aminoisoxazolo [5, 4-d] pyrimidines1 | |
US4028373A (en) | Thiophene saccharines | |
NO782945L (en) | PROCEDURE FOR THE PREPARATION OF 4-ARYL-CHINAZOLINONE DERIVATIVES | |
DE2647853A1 (en) | PROCESS FOR THE PREPARATION OF 3,4-DIHYDRO-2-(1H)-QUINAZOLINONES AND 3,4-DIHYDRO-2(1H)-QUINAZOLINTHIONES | |
HU183048B (en) | Process for producing bracket-2s,3r-bracket closed-, bracket-2s,3s-bracket closed-, bracket-2rs,3r-bracket closed- or bracket-2rs,3rs-bracket closed-3-amino-2-hydroxy-propionyl-glycine derivatives | |
US4171441A (en) | Preparation of quinazolin-2(1H)-ones | |
SU507236A3 (en) | The method of obtaining derivatives of 1-thieno / 3,2-s // 1 / benzazepine or their salts | |
JPH0449539B2 (en) | ||
KR820001716B1 (en) | Process for preparing 4-aryl-quinazoline-2(1h)-ones | |
Sundholm et al. | The Reaction of 2, 3-Dichloro-1, 4-naphthoquinone with Salts of Alkyl Substituted and Unsubstituted Dithiocarbamic Acids | |
NL8003153A (en) | PROCESS FOR PREPARING N- (2-AMINO-3,5-DIBROOMBENZYL) -N-METHYLCYCLOHEXYLAMINE ("BROMHEXIN"). | |
NO132800B (en) | ||
Wasfy | Cationic and mesoionic 1, 3‐thiazolo‐[3, 2‐c] quinazoline derivatives | |
Postovskii et al. | Researches on benzodiazines: VI. Synthesis of 2-R-4-hydrazinoquinazolines, 5-R-[3, 4-c]-s-triazolo-and 5-R [1, 5-c] tetrazoloquinazolines | |
Koščík et al. | New Preparation of 2-N-Alkyl (aryl) amino-5-methyl-4H-1, 3-thiazin-4-ones and 3, 4-Dihydro-5-methyl-2, 4-dioxo-2H-1, 3-thiazine | |
CS233736B2 (en) | Processing of derivative of 1,1-dioxid 4-hydroxy-2-methyl-2h-1,2-benzothiazin-3-karboxyl acid | |
NO130276B (en) | ||
Dimant et al. | Preparation of l-xylose | |
JPS5953479A (en) | Pyridazinone derivative | |
SU437284A1 (en) | Method for preparing indeno-pyridine derivatives | |
SU376942A1 (en) | ALL-UNION / | |
DE1932401A1 (en) | Heterocyclic compounds and processes for their preparation | |
SU444367A1 (en) | The method of obtaining 2 (1H) quinazolinone |