CA2589775A1 - Process for preparing rosuvastatin - Google Patents
Process for preparing rosuvastatin Download PDFInfo
- Publication number
- CA2589775A1 CA2589775A1 CA002589775A CA2589775A CA2589775A1 CA 2589775 A1 CA2589775 A1 CA 2589775A1 CA 002589775 A CA002589775 A CA 002589775A CA 2589775 A CA2589775 A CA 2589775A CA 2589775 A1 CA2589775 A1 CA 2589775A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- protecting group
- fluorophenyl
- compound
- hydroxy
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 38
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 title description 10
- 229960000672 rosuvastatin Drugs 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 151
- 238000000034 method Methods 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 125000006239 protecting group Chemical group 0.000 claims description 138
- 238000006243 chemical reaction Methods 0.000 claims description 68
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 65
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 239000003054 catalyst Substances 0.000 claims description 34
- -1 N-(methyl)methylsulfonylamino Chemical group 0.000 claims description 33
- 229910052763 palladium Inorganic materials 0.000 claims description 30
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical group [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 claims description 20
- 125000003107 substituted aryl group Chemical group 0.000 claims description 18
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 13
- QIYZIFYBNWCMIL-UHFFFAOYSA-N 4-(4-fluorophenyl)-6-propan-2-yl-1h-pyrimidin-2-one Chemical compound OC1=NC(C(C)C)=CC(C=2C=CC(F)=CC=2)=N1 QIYZIFYBNWCMIL-UHFFFAOYSA-N 0.000 claims description 11
- YNXIMZNTYYBSME-UHFFFAOYSA-N 5-bromo-4-(4-fluorophenyl)-6-propan-2-yl-1h-pyrimidin-2-one Chemical compound CC(C)C1=NC(O)=NC(C=2C=CC(F)=CC=2)=C1Br YNXIMZNTYYBSME-UHFFFAOYSA-N 0.000 claims description 10
- 230000036571 hydration Effects 0.000 claims description 10
- 238000006703 hydration reaction Methods 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- CULWMSRHPTUCHE-UHFFFAOYSA-N n-[5-bromo-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1Br CULWMSRHPTUCHE-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000004202 carbamide Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- LAOUURGVXFCRDD-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-methylpentane-1,3-dione Chemical compound CC(C)C(=O)CC(=O)C1=CC=C(F)C=C1 LAOUURGVXFCRDD-UHFFFAOYSA-N 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 claims description 4
- GCPRYLDYSIUKIL-UHFFFAOYSA-N 5-bromo-2-chloro-4-(4-fluorophenyl)-6-propan-2-ylpyrimidine Chemical compound CC(C)C1=NC(Cl)=NC(C=2C=CC(F)=CC=2)=C1Br GCPRYLDYSIUKIL-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- UMPRJGKLMUDRHL-UHFFFAOYSA-N ethyl 4-fluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C=C1 UMPRJGKLMUDRHL-UHFFFAOYSA-N 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims description 3
- VFNTUENRFPZOCD-UHFFFAOYSA-N 2,5-dichloro-4-(4-fluorophenyl)-6-propan-2-ylpyrimidine Chemical compound CC(C)C1=NC(Cl)=NC(C=2C=CC(F)=CC=2)=C1Cl VFNTUENRFPZOCD-UHFFFAOYSA-N 0.000 claims description 2
- BHWKKOFPMLXKSF-UHFFFAOYSA-N 2-chloro-4-(4-fluorophenyl)-5-iodo-6-propan-2-ylpyrimidine Chemical compound CC(C)C1=NC(Cl)=NC(C=2C=CC(F)=CC=2)=C1I BHWKKOFPMLXKSF-UHFFFAOYSA-N 0.000 claims description 2
- JOIRMTASGAFDCY-UHFFFAOYSA-N 4-(4-fluorophenyl)-5-iodo-6-propan-2-yl-1h-pyrimidin-2-one Chemical compound CC(C)C1=NC(O)=NC(C=2C=CC(F)=CC=2)=C1I JOIRMTASGAFDCY-UHFFFAOYSA-N 0.000 claims description 2
- AKWUSZQHYAKZIS-UHFFFAOYSA-N 4-(4-fluorophenyl)-5-iodo-6-propan-2-ylpyrimidin-2-amine Chemical compound CC(C)C1=NC(N)=NC(C=2C=CC(F)=CC=2)=C1I AKWUSZQHYAKZIS-UHFFFAOYSA-N 0.000 claims description 2
- VTFNRECTRDUOCH-UHFFFAOYSA-N 5-bromo-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-amine Chemical compound CC(C)C1=NC(N)=NC(C=2C=CC(F)=CC=2)=C1Br VTFNRECTRDUOCH-UHFFFAOYSA-N 0.000 claims description 2
- XCQRGZNVLDSDQT-UHFFFAOYSA-N 5-bromo-4-(4-fluorophenyl)-n-methyl-6-propan-2-ylpyrimidin-2-amine Chemical compound CNC1=NC(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=N1 XCQRGZNVLDSDQT-UHFFFAOYSA-N 0.000 claims description 2
- SVBOEHREPWPHKA-UHFFFAOYSA-N 5-chloro-4-(4-fluorophenyl)-6-propan-2-yl-1h-pyrimidin-2-one Chemical compound CC(C)C1=NC(O)=NC(C=2C=CC(F)=CC=2)=C1Cl SVBOEHREPWPHKA-UHFFFAOYSA-N 0.000 claims description 2
- ZAIRMSSHPAVSDZ-UHFFFAOYSA-N 5-chloro-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-amine Chemical compound CC(C)C1=NC(N)=NC(C=2C=CC(F)=CC=2)=C1Cl ZAIRMSSHPAVSDZ-UHFFFAOYSA-N 0.000 claims description 2
- DJQYAHISGHBRGR-UHFFFAOYSA-N 5-chloro-4-(4-fluorophenyl)-n-methyl-6-propan-2-ylpyrimidin-2-amine Chemical compound CNC1=NC(C(C)C)=C(Cl)C(C=2C=CC(F)=CC=2)=N1 DJQYAHISGHBRGR-UHFFFAOYSA-N 0.000 claims description 2
- KMYMQXJMTPYDMW-UHFFFAOYSA-N [2-amino-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-5-yl] trifluoromethanesulfonate Chemical compound CC(C)C1=NC(N)=NC(C=2C=CC(F)=CC=2)=C1OS(=O)(=O)C(F)(F)F KMYMQXJMTPYDMW-UHFFFAOYSA-N 0.000 claims description 2
- ZBQIGXJQNQOPGV-UHFFFAOYSA-N [2-chloro-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-5-yl] trifluoromethanesulfonate Chemical compound CC(C)C1=NC(Cl)=NC(C=2C=CC(F)=CC=2)=C1OS(=O)(=O)C(F)(F)F ZBQIGXJQNQOPGV-UHFFFAOYSA-N 0.000 claims description 2
- NXNNAFFPYHBDGS-UHFFFAOYSA-N [4-(4-fluorophenyl)-2-(methanesulfonamido)-6-propan-2-ylpyrimidin-5-yl] trifluoromethanesulfonate Chemical compound CC(C)C1=NC(NS(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1OS(=O)(=O)C(F)(F)F NXNNAFFPYHBDGS-UHFFFAOYSA-N 0.000 claims description 2
- VKKFPHWKDSRQQP-UHFFFAOYSA-N [4-(4-fluorophenyl)-2-(methylamino)-6-propan-2-ylpyrimidin-5-yl] trifluoromethanesulfonate Chemical compound CNC1=NC(C(C)C)=C(OS(=O)(=O)C(F)(F)F)C(C=2C=CC(F)=CC=2)=N1 VKKFPHWKDSRQQP-UHFFFAOYSA-N 0.000 claims description 2
- WJWSSCVWXGEMIN-UHFFFAOYSA-N [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl] trifluoromethanesulfonate Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1OS(=O)(=O)C(F)(F)F WJWSSCVWXGEMIN-UHFFFAOYSA-N 0.000 claims description 2
- YBHRXIOFOFRIIL-UHFFFAOYSA-N [4-(4-fluorophenyl)-5-iodo-6-propan-2-ylpyrimidin-2-yl] 4-methylbenzenesulfonate Chemical compound N=1C(C=2C=CC(F)=CC=2)=C(I)C(C(C)C)=NC=1OS(=O)(=O)C1=CC=C(C)C=C1 YBHRXIOFOFRIIL-UHFFFAOYSA-N 0.000 claims description 2
- WTHHJCLGBYOSRS-UHFFFAOYSA-N [4-(4-fluorophenyl)-6-propan-2-yl-5-(trifluoromethylsulfonyloxy)pyrimidin-2-yl] 4-methylbenzenesulfonate Chemical compound N=1C(C=2C=CC(F)=CC=2)=C(OS(=O)(=O)C(F)(F)F)C(C(C)C)=NC=1OS(=O)(=O)C1=CC=C(C)C=C1 WTHHJCLGBYOSRS-UHFFFAOYSA-N 0.000 claims description 2
- LXTQTFHJVDQLQK-UHFFFAOYSA-N [5-bromo-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl] 4-methylbenzenesulfonate Chemical compound N=1C(C=2C=CC(F)=CC=2)=C(Br)C(C(C)C)=NC=1OS(=O)(=O)C1=CC=C(C)C=C1 LXTQTFHJVDQLQK-UHFFFAOYSA-N 0.000 claims description 2
- YRFAHKBRELZEPJ-UHFFFAOYSA-N [5-chloro-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl] 4-methylbenzenesulfonate Chemical compound N=1C(C=2C=CC(F)=CC=2)=C(Cl)C(C(C)C)=NC=1OS(=O)(=O)C1=CC=C(C)C=C1 YRFAHKBRELZEPJ-UHFFFAOYSA-N 0.000 claims description 2
- GFBJWTOVEAKLEF-UHFFFAOYSA-N n-[4-(4-fluorophenyl)-5-iodo-6-propan-2-ylpyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1I GFBJWTOVEAKLEF-UHFFFAOYSA-N 0.000 claims description 2
- CGJKYULSOXQJDU-UHFFFAOYSA-N n-[4-(4-fluorophenyl)-5-iodo-6-propan-2-ylpyrimidin-2-yl]methanesulfonamide Chemical compound CC(C)C1=NC(NS(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1I CGJKYULSOXQJDU-UHFFFAOYSA-N 0.000 claims description 2
- BERBICNGGCBEST-UHFFFAOYSA-N n-[5-bromo-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl]methanesulfonamide Chemical compound CC(C)C1=NC(NS(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1Br BERBICNGGCBEST-UHFFFAOYSA-N 0.000 claims description 2
- KQRDSRFIOVPETP-UHFFFAOYSA-N n-[5-chloro-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1Cl KQRDSRFIOVPETP-UHFFFAOYSA-N 0.000 claims description 2
- DDNYCUNNCZJGHM-UHFFFAOYSA-N n-[5-chloro-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl]methanesulfonamide Chemical compound CC(C)C1=NC(NS(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1Cl DDNYCUNNCZJGHM-UHFFFAOYSA-N 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- TWUDOAUKFBFXDF-UHFFFAOYSA-N 4-(4-fluorophenyl)-5-iodo-n-methyl-6-propan-2-ylpyrimidin-2-amine Chemical compound CNC1=NC(C(C)C)=C(I)C(C=2C=CC(F)=CC=2)=N1 TWUDOAUKFBFXDF-UHFFFAOYSA-N 0.000 claims 1
- IHSQHYFHNZECSW-UHFFFAOYSA-N [4-(4-fluorophenyl)-2-oxo-6-propan-2-yl-1h-pyrimidin-5-yl] trifluoromethanesulfonate Chemical compound CC(C)C1=NC(O)=NC(C=2C=CC(F)=CC=2)=C1OS(=O)(=O)C(F)(F)F IHSQHYFHNZECSW-UHFFFAOYSA-N 0.000 claims 1
- RAYLUPYCGGKXQO-UHFFFAOYSA-N n,n-dimethylacetamide;hydrate Chemical compound O.CN(C)C(C)=O RAYLUPYCGGKXQO-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000007341 Heck reaction Methods 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 39
- 239000000203 mixture Substances 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 26
- 239000002585 base Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 125000003944 tolyl group Chemical group 0.000 description 11
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical group CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 7
- 101150041968 CDC13 gene Proteins 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 229960004796 rosuvastatin calcium Drugs 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 159000000007 calcium salts Chemical class 0.000 description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001311 chemical methods and process Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- HHVIBTZHLRERCL-UHFFFAOYSA-N methylsulphonylmethane Natural products CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 3
- UHNHTTIUNATJKL-UHFFFAOYSA-N n-methylmethanesulfonamide Chemical compound CNS(C)(=O)=O UHNHTTIUNATJKL-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 150000003956 methylamines Chemical class 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- OLRJXMHANKMLTD-UHFFFAOYSA-N silyl Chemical compound [SiH3] OLRJXMHANKMLTD-UHFFFAOYSA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YKPQUSLRUFLVDA-UHFFFAOYSA-N $l^{2}-azanylmethane Chemical compound [NH]C YKPQUSLRUFLVDA-UHFFFAOYSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 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 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- FAVAVMFXAKZTMV-UHFFFAOYSA-N dibutylboranyl trifluoromethanesulfonate Chemical compound CCCCB(CCCC)OS(=O)(=O)C(F)(F)F FAVAVMFXAKZTMV-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- FESAXEDIWWXCNG-UHFFFAOYSA-N diethyl(methoxy)borane Chemical compound CCB(CC)OC FESAXEDIWWXCNG-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WIFPCEOJTKZGSA-UQECUQMJSA-N tert-butyl 2-[(4r,6s)-6-[(e)-2-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound C(\[C@H]1OC(C)(C)O[C@@H](CC(=O)OC(C)(C)C)C1)=C/C=1C(C(C)C)=NC(N(C)S(C)(=O)=O)=NC=1C1=CC=C(F)C=C1 WIFPCEOJTKZGSA-UQECUQMJSA-N 0.000 description 1
- OSNUGXHZKGQAMT-GHMZBOCLSA-N tert-butyl 2-[(4r,6s)-6-ethenyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1C[C@@H](C=C)OC(C)(C)O1 OSNUGXHZKGQAMT-GHMZBOCLSA-N 0.000 description 1
- JEFQIIXBSQLRTF-ZJUUUORDSA-N tert-butyl 2-[(4r,6s)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1 JEFQIIXBSQLRTF-ZJUUUORDSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tri-tert-butylphosphine Substances CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
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Applications Claiming Priority (3)
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| GBGB0428328.9A GB0428328D0 (en) | 2004-12-24 | 2004-12-24 | Chemical process |
| GB0428328.9 | 2004-12-24 | ||
| PCT/GB2005/004999 WO2006067456A2 (en) | 2004-12-24 | 2005-12-22 | Process for preparing rosuvastatin |
Publications (1)
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| CA2589775A1 true CA2589775A1 (en) | 2006-06-29 |
Family
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Family Applications (1)
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| CA002589775A Abandoned CA2589775A1 (en) | 2004-12-24 | 2005-12-22 | Process for preparing rosuvastatin |
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| US (1) | US8034932B2 (enExample) |
| EP (2) | EP2361906A1 (enExample) |
| JP (1) | JP5127460B2 (enExample) |
| KR (1) | KR20070092307A (enExample) |
| CN (1) | CN101084197B (enExample) |
| AU (1) | AU2005317880B2 (enExample) |
| BR (1) | BRPI0518647A2 (enExample) |
| CA (1) | CA2589775A1 (enExample) |
| GB (1) | GB0428328D0 (enExample) |
| IL (1) | IL183528A (enExample) |
| MX (1) | MX2007007777A (enExample) |
| NO (1) | NO20072872L (enExample) |
| NZ (1) | NZ555769A (enExample) |
| WO (1) | WO2006067456A2 (enExample) |
| ZA (1) | ZA200704535B (enExample) |
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| GB0011120D0 (en) | 2000-05-09 | 2000-06-28 | Avecia Ltd | Process |
| NL1015744C2 (nl) | 2000-07-19 | 2002-01-22 | Dsm Nv | Werkwijze voor de bereiding van 2-(6-gesubstitueerde-1,3-dioxan-4-yl) azijnzuurderivaten. |
| IL159741A0 (en) | 2001-07-13 | 2004-06-20 | Astrazeneca Uk Ltd | Preparation of aminopyrimidine compounds |
| EP1323717A1 (en) | 2001-12-27 | 2003-07-02 | Dsm N.V. | Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives |
| EP1375493A1 (en) | 2002-06-17 | 2004-01-02 | Dsm N.V. | Process for the preparation of an dioxane acetic acid ester |
| GB0218781D0 (en) | 2002-08-13 | 2002-09-18 | Astrazeneca Ab | Chemical process |
| BR0317313A (pt) | 2002-12-16 | 2005-11-08 | Astrazeneca Uk Ltd | Processo para a preparação de um composto, e, composto |
| GB0312896D0 (en) | 2003-06-05 | 2003-07-09 | Astrazeneca Ab | Chemical process |
| UY28501A1 (es) * | 2003-09-10 | 2005-04-29 | Astrazeneca Uk Ltd | Compuestos químicos |
| GB0324791D0 (en) | 2003-10-24 | 2003-11-26 | Astrazeneca Ab | Chemical process |
| TW200526596A (en) | 2003-11-24 | 2005-08-16 | Teva Pharma | Crystalline ammonium salts of rosuvastatin |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| GB0428328D0 (en) | 2004-12-24 | 2005-02-02 | Astrazeneca Uk Ltd | Chemical process |
| JP2008526781A (ja) | 2005-02-22 | 2008-07-24 | テバ ファーマシューティカル インダストリーズ リミティド | ロスバスタチンの製造 |
| GB0514078D0 (en) * | 2005-07-08 | 2005-08-17 | Astrazeneca Uk Ltd | Chemical process |
| WO2008036286A1 (en) * | 2006-09-18 | 2008-03-27 | Teva Pharmaceutical Industries Ltd. | Crystalline rosuvastatin calcium |
| TW200831469A (en) * | 2006-12-01 | 2008-08-01 | Astrazeneca Uk Ltd | Chemical process |
| US8183397B2 (en) | 2007-04-03 | 2012-05-22 | Lek Pharmaceuticals D.D. | Synthesis of statins |
| EP1978020A1 (en) * | 2007-04-03 | 2008-10-08 | LEK Pharmaceuticals D.D. | Processes for the preparation of statins, particularly rosuvastatin, and intermediates for the preparation thereof |
| US20110295005A1 (en) * | 2007-08-20 | 2011-12-01 | Ratiopharm Gmbh | Process for preparing pyrimidine derivatives |
| EA201000214A1 (ru) | 2007-08-28 | 2010-10-29 | Рациофарм Гмбх | Способ получения производных пентадикарбоновой кислоты |
| EP2334667A4 (en) * | 2008-09-09 | 2011-10-26 | Biocon Ltd | PROCESS FOR THE PREPARATION OF ACETONIDE ROSUVASTATIN CALCIUM |
| CN105669561B (zh) * | 2014-11-19 | 2018-11-27 | 南京博优康远生物医药科技有限公司 | 一种4-(4-氟苯基)-5-烷氧基羰基-6-异丙基-3,4-二氢嘧啶-2(1h)-酮的制备方法 |
| HUE069744T2 (hu) * | 2015-01-23 | 2025-04-28 | Centrient Pharmaceuticals Netherlands B V | Fejlesztett eljárás a sztatin prekurzor elõállítására |
| KR20160126700A (ko) | 2015-04-24 | 2016-11-02 | 미래파인켐 주식회사 | 스타틴의 중간체, 이의 제조방법 및 이를 이용한 로수바스타틴의 제조방법 |
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| UY28501A1 (es) * | 2003-09-10 | 2005-04-29 | Astrazeneca Uk Ltd | Compuestos químicos |
| GB0321827D0 (en) | 2003-09-18 | 2003-10-15 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0324791D0 (en) | 2003-10-24 | 2003-11-26 | Astrazeneca Ab | Chemical process |
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| GB0428328D0 (en) | 2004-12-24 | 2005-02-02 | Astrazeneca Uk Ltd | Chemical process |
| CA2498978A1 (en) | 2005-02-28 | 2006-08-28 | Apotex Pharmachem Inc. | An improved process for the preparation of atorvastatin and intermediates |
| GB0514078D0 (en) | 2005-07-08 | 2005-08-17 | Astrazeneca Uk Ltd | Chemical process |
| TW200831469A (en) * | 2006-12-01 | 2008-08-01 | Astrazeneca Uk Ltd | Chemical process |
-
2004
- 2004-12-24 GB GBGB0428328.9A patent/GB0428328D0/en not_active Ceased
-
2005
- 2005-12-22 KR KR1020077017101A patent/KR20070092307A/ko not_active Ceased
- 2005-12-22 EP EP11162467A patent/EP2361906A1/en not_active Withdrawn
- 2005-12-22 MX MX2007007777A patent/MX2007007777A/es unknown
- 2005-12-22 AU AU2005317880A patent/AU2005317880B2/en not_active Ceased
- 2005-12-22 CA CA002589775A patent/CA2589775A1/en not_active Abandoned
- 2005-12-22 NZ NZ555769A patent/NZ555769A/en not_active IP Right Cessation
- 2005-12-22 WO PCT/GB2005/004999 patent/WO2006067456A2/en not_active Ceased
- 2005-12-22 BR BRPI0518647-1A patent/BRPI0518647A2/pt not_active IP Right Cessation
- 2005-12-22 CN CN2005800440532A patent/CN101084197B/zh not_active Expired - Lifetime
- 2005-12-22 JP JP2007547647A patent/JP5127460B2/ja not_active Expired - Fee Related
- 2005-12-22 US US11/793,418 patent/US8034932B2/en not_active Expired - Fee Related
- 2005-12-22 EP EP05820940A patent/EP1871747A2/en not_active Withdrawn
-
2007
- 2007-05-29 IL IL183528A patent/IL183528A/en not_active IP Right Cessation
- 2007-05-31 ZA ZA200704535A patent/ZA200704535B/xx unknown
- 2007-06-06 NO NO20072872A patent/NO20072872L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0518647A2 (pt) | 2008-12-02 |
| CN101084197A (zh) | 2007-12-05 |
| GB0428328D0 (en) | 2005-02-02 |
| MX2007007777A (es) | 2007-08-14 |
| IL183528A (en) | 2012-02-29 |
| ZA200704535B (en) | 2008-11-26 |
| EP1871747A2 (en) | 2008-01-02 |
| NO20072872L (no) | 2007-09-17 |
| WO2006067456A3 (en) | 2006-09-21 |
| EP2361906A1 (en) | 2011-08-31 |
| NZ555769A (en) | 2010-01-29 |
| AU2005317880A1 (en) | 2006-06-29 |
| KR20070092307A (ko) | 2007-09-12 |
| JP5127460B2 (ja) | 2013-01-23 |
| JP2008525407A (ja) | 2008-07-17 |
| US8034932B2 (en) | 2011-10-11 |
| US20080207903A1 (en) | 2008-08-28 |
| WO2006067456A2 (en) | 2006-06-29 |
| CN101084197B (zh) | 2012-06-13 |
| AU2005317880B2 (en) | 2009-05-28 |
| IL183528A0 (en) | 2007-09-20 |
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