JP5127460B2 - 化学的方法 - Google Patents
化学的方法 Download PDFInfo
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- JP5127460B2 JP5127460B2 JP2007547647A JP2007547647A JP5127460B2 JP 5127460 B2 JP5127460 B2 JP 5127460B2 JP 2007547647 A JP2007547647 A JP 2007547647A JP 2007547647 A JP2007547647 A JP 2007547647A JP 5127460 B2 JP5127460 B2 JP 5127460B2
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- compound
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- fluorophenyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 45
- 239000000126 substance Substances 0.000 title description 5
- 125000006239 protecting group Chemical group 0.000 claims description 129
- 150000001875 compounds Chemical class 0.000 claims description 112
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 67
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- 238000002360 preparation method Methods 0.000 claims description 33
- -1 N- (methyl) methylsulfonylamino Chemical group 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000003054 catalyst Substances 0.000 claims description 25
- 229910052763 palladium Inorganic materials 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 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 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 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 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 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
- 239000004202 carbamide Substances 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 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
- 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
- RAYLUPYCGGKXQO-UHFFFAOYSA-N n,n-dimethylacetamide;hydrate Chemical compound O.CN(C)C(C)=O RAYLUPYCGGKXQO-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
- 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
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims 2
- 230000003796 beauty Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 34
- 125000000217 alkyl group Chemical group 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- 239000002585 base Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 125000003118 aryl group Chemical group 0.000 description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 125000003107 substituted aryl group Chemical group 0.000 description 14
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 235000019439 ethyl acetate Nutrition 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
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 10
- 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 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 8
- 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 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 229960000672 rosuvastatin Drugs 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical group CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 239000007858 starting material 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
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229960004796 rosuvastatin calcium Drugs 0.000 description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 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 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 238000007341 Heck reaction Methods 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- SFFYOOJRHFHVCM-LDCPCGJSSA-L calcium (3R,5S)-3,5-dihydroxyhept-6-enoate Chemical compound [Ca+2].O[C@@H](CC(=O)[O-])C[C@@H](C=C)O.O[C@@H](CC(=O)[O-])C[C@@H](C=C)O SFFYOOJRHFHVCM-LDCPCGJSSA-L 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
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- UHNHTTIUNATJKL-UHFFFAOYSA-N n-methylmethanesulfonamide Chemical compound CNS(C)(=O)=O UHNHTTIUNATJKL-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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 3
- 230000009466 transformation Effects 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
- 0 CC(C)C1=*C(*)(C2)C2CC(c(cc2)ccc2N)=C1I Chemical compound CC(C)C1=*C(*)(C2)C2CC(c(cc2)ccc2N)=C1I 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
- 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 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 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
- 150000001721 carbon Chemical group 0.000 description 2
- 238000001311 chemical methods and process Methods 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
- 125000004185 ester group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000003956 methylamines Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 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
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 2
- 238000000844 transformation Methods 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
- 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
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- CMIZNKUKVPDSEI-UHFFFAOYSA-N N-(5-formylpyrimidin-2-yl)-N-methylmethanesulfonamide Chemical compound CN(c1ncc(C=O)cn1)S(C)(=O)=O CMIZNKUKVPDSEI-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 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 description 1
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- 238000010533 azeotropic distillation Methods 0.000 description 1
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- 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
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- 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
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 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
- 229940066901 crestor Drugs 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
- 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
- 125000004356 hydroxy functional group Chemical group O* 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
- 238000007273 lactonization reaction Methods 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
- 159000000003 magnesium salts Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- LKFANOWXMJEZDI-AREMUKBSSA-N methyl (3r)-3-[tert-butyl(dimethyl)silyl]oxy-5-oxo-6-(triphenyl-$l^{5}-phosphanylidene)hexanoate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)C[C@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C)C1=CC=CC=C1 LKFANOWXMJEZDI-AREMUKBSSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 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
- WOCOTUDOVSLFOB-UHFFFAOYSA-N n-[4-(4-fluorophenyl)-5-formyl-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)=C1C=O WOCOTUDOVSLFOB-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- 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 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen 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
- 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
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 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
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 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
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 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)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 (3)
| Publication Number | Publication Date |
|---|---|
| JP2008525407A JP2008525407A (ja) | 2008-07-17 |
| JP2008525407A5 JP2008525407A5 (https=) | 2008-12-18 |
| JP5127460B2 true JP5127460B2 (ja) | 2013-01-23 |
Family
ID=34130901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007547647A Expired - Fee Related JP5127460B2 (ja) | 2004-12-24 | 2005-12-22 | 化学的方法 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US8034932B2 (https=) |
| EP (2) | EP1871747A2 (https=) |
| JP (1) | JP5127460B2 (https=) |
| KR (1) | KR20070092307A (https=) |
| CN (1) | CN101084197B (https=) |
| AU (1) | AU2005317880B2 (https=) |
| BR (1) | BRPI0518647A2 (https=) |
| CA (1) | CA2589775A1 (https=) |
| GB (1) | GB0428328D0 (https=) |
| IL (1) | IL183528A (https=) |
| MX (1) | MX2007007777A (https=) |
| NO (1) | NO20072872L (https=) |
| NZ (1) | NZ555769A (https=) |
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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 |
| ES2335279T3 (es) | 2002-12-16 | 2010-03-24 | Astrazeneca Uk Limited | Procedimiento para la preparacion de compuestos de pirimidina. |
| 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 |
| EP1601658A1 (en) | 2003-11-24 | 2005-12-07 | Teva Pharmaceutical Industries Limited | 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 |
| KR101020024B1 (ko) | 2005-02-22 | 2011-03-09 | 테바 파마슈티컬 인더스트리즈 리미티드 | 로수바스타틴 알킬에테르를 함유하지 않는 로수바스타틴 및이의 염 및 이의 제조 방법 |
| GB0514078D0 (en) * | 2005-07-08 | 2005-08-17 | Astrazeneca Uk Ltd | Chemical process |
| EP1948618A1 (en) * | 2006-09-18 | 2008-07-30 | Teva Pharmaceutical Industries Ltd. | Crystalline rosuvastatin calcium |
| TW200831469A (en) * | 2006-12-01 | 2008-08-01 | Astrazeneca Uk Ltd | Chemical process |
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| 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 |
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| 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 |
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| TW200831469A (en) | 2006-12-01 | 2008-08-01 | Astrazeneca Uk Ltd | Chemical process |
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- 2005-12-22 EP EP05820940A patent/EP1871747A2/en not_active Withdrawn
- 2005-12-22 MX MX2007007777A patent/MX2007007777A/es unknown
- 2005-12-22 EP EP11162467A patent/EP2361906A1/en not_active Withdrawn
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2589775A1 (en) | 2006-06-29 |
| IL183528A0 (en) | 2007-09-20 |
| WO2006067456A3 (en) | 2006-09-21 |
| WO2006067456A2 (en) | 2006-06-29 |
| NO20072872L (no) | 2007-09-17 |
| AU2005317880A1 (en) | 2006-06-29 |
| BRPI0518647A2 (pt) | 2008-12-02 |
| CN101084197A (zh) | 2007-12-05 |
| MX2007007777A (es) | 2007-08-14 |
| KR20070092307A (ko) | 2007-09-12 |
| AU2005317880B2 (en) | 2009-05-28 |
| EP1871747A2 (en) | 2008-01-02 |
| CN101084197B (zh) | 2012-06-13 |
| US20080207903A1 (en) | 2008-08-28 |
| JP2008525407A (ja) | 2008-07-17 |
| ZA200704535B (en) | 2008-11-26 |
| GB0428328D0 (en) | 2005-02-02 |
| NZ555769A (en) | 2010-01-29 |
| US8034932B2 (en) | 2011-10-11 |
| IL183528A (en) | 2012-02-29 |
| EP2361906A1 (en) | 2011-08-31 |
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