CN101218210A - 罗苏伐他汀的制备方法和中间体 - Google Patents
罗苏伐他汀的制备方法和中间体 Download PDFInfo
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- CN101218210A CN101218210A CNA2006800247173A CN200680024717A CN101218210A CN 101218210 A CN101218210 A CN 101218210A CN A2006800247173 A CNA2006800247173 A CN A2006800247173A CN 200680024717 A CN200680024717 A CN 200680024717A CN 101218210 A CN101218210 A CN 101218210A
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- Prior art keywords
- compound
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- fluorophenyl
- alkyl
- Prior art date
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Links
- 238000000034 method Methods 0.000 title claims abstract description 37
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 4
- 229960000672 rosuvastatin Drugs 0.000 title abstract description 5
- 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 abstract description 5
- 239000000543 intermediate Substances 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 238000006243 chemical reaction Methods 0.000 claims description 27
- -1 halide salts Chemical class 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000002585 base Substances 0.000 claims description 21
- 150000001412 amines Chemical class 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 159000000007 calcium salts Chemical class 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 6
- 150000008045 alkali metal halides Chemical class 0.000 claims description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical group CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- LCKIEQZJEYYRIY-UHFFFAOYSA-N Titanium ion Chemical compound [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000000468 ketone group Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229920002554 vinyl polymer Polymers 0.000 claims description 4
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims 1
- 238000005575 aldol reaction Methods 0.000 abstract 1
- 230000000707 stereoselective effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 229910000085 borane Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- NFHAVJAHHJJXJL-UHFFFAOYSA-M CC(C)O[Ti](OC(C)C)Oc1ccc2ccccc2c1 Chemical compound CC(C)O[Ti](OC(C)C)Oc1ccc2ccccc2c1 NFHAVJAHHJJXJL-UHFFFAOYSA-M 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 3
- 239000010936 titanium Substances 0.000 description 3
- 229910052719 titanium Inorganic materials 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- UWNADWZGEHDQAB-UHFFFAOYSA-N 2,5-dimethylhexane Chemical group CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 2
- KCHQXPGUJBVNTN-UHFFFAOYSA-N 4,4-diphenylbut-3-en-2-one Chemical compound C=1C=CC=CC=1C(=CC(=O)C)C1=CC=CC=C1 KCHQXPGUJBVNTN-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-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
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229960002797 pitavastatin Drugs 0.000 description 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- SMDGVPQREIZILS-UHFFFAOYSA-N $l^{1}-oxidanylmethylbenzene Chemical compound [O]CC1=CC=CC=C1 SMDGVPQREIZILS-UHFFFAOYSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical class C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 1
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 1
- AXZHQYSKPYLONQ-UHFFFAOYSA-N C=C.[B] Chemical class C=C.[B] AXZHQYSKPYLONQ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- FBHSUABQCRNUDW-UHFFFAOYSA-N [K].CCCCCCCCC Chemical compound [K].CCCCCCCCC FBHSUABQCRNUDW-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 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
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940066901 crestor Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- QVQGTNFYPJQJNM-UHFFFAOYSA-N dicyclohexylmethanamine Chemical compound C1CCCCC1C(N)C1CCCCC1 QVQGTNFYPJQJNM-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- YFXCNIVBAVFOBX-UHFFFAOYSA-N ethenylboronic acid Chemical compound OB(O)C=C YFXCNIVBAVFOBX-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000002223 garnet Substances 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- FYFFGSSZFBZTAH-UHFFFAOYSA-N methylaminomethanetriol Chemical compound CNC(O)(O)O FYFFGSSZFBZTAH-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- UHNHTTIUNATJKL-UHFFFAOYSA-N n-methylmethanesulfonamide Chemical compound CNS(C)(=O)=O UHNHTTIUNATJKL-UHFFFAOYSA-N 0.000 description 1
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- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 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 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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- 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
- C07D239/30—Halogen atoms or nitro radicals
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- 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
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Abstract
本文描述了一种通过立体选择性醛醇反应来制备式(V)化合物的方法,所述化合物可用于制备罗苏伐他汀。本文还描述了制备它们的新中间体和方法。
Description
本发明涉及一种新的化学方法,更具体而言,它涉及一种制备罗苏伐他汀及其可药用盐、尤其是罗苏伐他汀钙盐的新化学方法、以及在所述方法中使用的新中间体和该新中间体的制备方法。
罗苏伐他汀及其可药用盐为HMG CoA还原酶抑制剂,尤其在治疗高胆固醇血症和混合型血脂障碍中有应用。罗苏伐他汀钙盐(式(A))以商标CRESTORTM出售。欧洲专利申请公开号(EPA)0521471公开了(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基](3R,5S)-3,5-二羟基庚-6-烯酸(罗苏伐他汀)及其钠盐和钙盐(罗苏伐他汀钙盐,如下所示)以及它们的制备方法。
其中罗苏伐他汀及其可药用盐由(3R)-3-[(叔丁基二甲基甲硅烷基)氧基]-5-氧代-6-三苯基亚膦基(phosphoranylidene)己酸甲酯与4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲烷磺酰基氨基)-5-嘧啶-羧甲醛缩合、之后经脱去3-羟基保护基、5-氧代基团的不对称还原和水解获得。
制备罗苏伐他汀及其可药用盐的其它方法描述于WO 00/49014和WO 04/52867中。在WO 00/49104中该化合物及其可药用盐通过二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基甲基]氧化膦与2-[(4R,6S)-6-甲酰基-2,2-二甲基-1,3-二烷-4-基]乙酸叔丁酯在碱的存在下反应、之后除去保护基而获得。WO 04/52867公开了1-氰基-(2S)-2-[(叔丁基二甲基甲硅烷基)氧基-4-氧代-5-三苯基亚膦基戊烷与4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲烷磺酰基氨基)-5-嘧啶-甲醛缩合、之后脱保护、不对称还原4-氧代基团和水解。
然而仍需要发现另外的制备罗苏伐他汀及其可药用盐的方法。例如,这种方法,与先前已知的方法相比,更便于应用,更适合大规模生产,得到更高收率的产物,减少所涉及的步骤,使用更容易分离的中间体,要求较不复杂的纯化技术,使用价格较低廉的试剂和/或对环境更无害。
WO 03/064382描述了他汀化合物如尤其是匹伐他汀和罗苏伐他汀的制备方法,其是利用手性钛催化剂基于不对称的醛醇反应制备。WO03/42180描述了合成匹伐他汀的类似方法。
现在我们已经发现了一种采用WO 03/064382中的方法的变化形式制备罗苏伐他汀及其可药用盐特别有用的方法,我们已经发现其在产物收率和/或对映体过量方面特别有利。
根据本发明的第一方面,本发明提供一种式(I)化合物
或其可药用盐的制备方法,包括
a)使式(II)化合物
其中每个R1独立选自(1-6C)烷基,且R选自(1-6C)烷基、(3-6C)环烷基或芳基(1-6C)烷基;
与式(III)化合物
在式(IV)的钛(IV)催化剂
(其中每个R2独立选自(1-6C)烷基且联萘部分为S-构型)、碱金属卤化物盐和胺的存在下,在惰性溶剂中反应,得到式(V)化合物;
b)将式(V)化合物的酮基还原得到式(VI)化合物;
和
c)脱除R基团得到式(I)化合物或其盐;
任选地接着形成可药用盐。
该反应的适宜条件描述如下。
步骤a)
使用碱金属卤化物和胺被认为对与式(III)化合物的该反应获得良好的收率和对映体过量是必不可少的。
最初存在于反应混合物中的式(III)醛和式(II)化合物的摩尔比适宜在1∶1和1∶6之间,如1∶1至1∶4,适宜在1∶1.5和1∶3之间,如1∶2。
最初存在于反应混合物中的式(IV)的钛(IV)催化剂与式(III)醛的摩尔比适宜在0.01∶1和0.15∶1之间,如在0.01∶1和0.05∶1之间。
最初存在于反应混合物中的碱金属卤化物与式(III)醛的摩尔比适宜在0.03∶1和1∶1之间,尤其是在0.1∶1和0.4∶1之间。技术人员将会理解所用碱金属卤化物的精确数量取决于使用哪一种胺和/或所用钛催化剂的量和/或反应溶液的浓度。当碱金属卤化物为氯化锂时上面给出的量尤其合适。
最初存在于反应混合物中的胺与式(III)醛的摩尔比适宜在0.015∶1和2∶1之间,尤其是在0.5∶1和1.5∶1之间,优选约1∶1。技术人员将会理解所用胺的精确数量取决于使用哪一种胺和/或所用钛催化剂的量和/或所用金属盐的量和/或反应溶液的浓度。当胺为TMEDA时上面给出的量尤其合适。
反应可在极性非质子溶剂如四氢呋喃、二乙醚或二甲氧基乙烷、优选四氢呋喃中进行。也可以使用溶剂的组合。
反应可在约0℃至约70℃、如约10℃至约60℃和优选约15℃至约30℃的温度下进行。
优选的碱金属卤化物为氯化锂。
优选的胺为N,N,N,N-四甲基乙二胺(TMEDA)。可供选择的胺包括DABCO(1,4-二氮杂双环[2.2.2]辛烷)、吗啉和N,N-二甲基哌嗪。一方面优选的胺为二齿螯合物。
(1-6C)烷基的实例包括甲基、乙基、丙基、异丙基和叔丁基。(3-6C)环烷基的实例包括环丙基、环丁基、环戊基和环己基。芳基(1-6C)烷基的实例包括苄基。
适宜地每个R1基团为甲基。适宜地R选自(1-6C)烷基,尤其R为乙基。
式(II)化合物可按照WO03/064382和WO03/42180中、和J.Am.Chem.Soc.1993,第830页中描述的步骤制备。
式(IV)化合物可按照WO03/064382和WO03/42180中描述的步骤制备。
式(III)化合物可通过以下步骤方式制备,在所附实施例中举例说明并如下面的流程图1所示。
流程图1
应当理解本发明包括使用通过任何适宜的方法制备的式(III)化合物并不局限于上述流程图所示的方法。不过流程图1所示的路线被认为是新的,且作为本发明的其它独立的方面被提供。
在本发明的其它方面中,本发明提供一种式(III)化合物的制备方法,包括:
i)由式(X)化合物生成式(XI)化合物;和
ii)将式(X)化合物转化为式(III)化合物。
适宜地式(XI)化合物可通过使式(X)化合物与丙烯腈在过渡金属催化剂如钯催化剂、如Pd[P(tBu)3]2[由例如双(二苯亚甲基丙酮)钯(0)(Pd(dba)2)或三(二苯亚甲基丙酮)二钯(0)(Pd2(dba)3)和tBu3PH·BF4预先制备或就地产生]的存在下反应。可以使用相转移催化剂,如溴化四丁铵。
适宜地,式(XI)化合物转化为式(III)化合物可通过用DIBAL(二异丁基铝氢化物)还原来进行。其它适宜的还原剂包括下列物质及其络合物:阮内镍(与H2源一起)、氯化锡(II)、三乙基氢硼化锂、9-仲-戊基9-borata双环[3.3.1]壬烷钾、二异丙基氢化铝、三乙氧基氢化铝锂、二乙氧基氢化铝锂、二乙基氢化铝钠、氢化铝锂、三(二烷基氨基)氢化铝锂和在适宜的路易斯酸的存在下的三烷基硅烷。
更适宜地,式(XI)化合物转化为式(III)化合物可通过用DIBAL还原、例如在甲苯中在<0℃还原来进行。
这类反应其它适宜的条件可见于所附的实施例,或为本领域公知。
式(III)化合物,即反式-N-(4-(4-氟苯基)-6-异丙基-5-(3-氧代丙-1-烯基)嘧啶-2-基)-N-甲基甲烷磺酰胺被认为是新的并作为本发明的其它方面被提供。
式(VII)化合物,即4-(4-氟苯基)-6-异丙基嘧啶-2-醇被认为是新的并作为本发明的其它方面被提供。
式(VIII)化合物,即5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-醇被认为是新的并作为本发明的其它方面被提供。
式(IX)化合物,即5-溴-2-氯-4-(4-氟苯基)-6-异丙基嘧啶被认为是新的并作为本发明的其它方面被提供。
式(X)化合物,即N-(5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺被认为是新的并作为本发明的其它方面被提供。
式(XI)化合物,即反式-N-(5-(2-氰基乙烯基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺被认为是新的并作为本发明的其它方面被提供。
制备式(III)化合物另一种方法是使式(X)化合物与适宜的乙烯硼类反应。
因此按照本发明的其它方面,本发明提供一种形成式(III)化合物(如上文中定义)的方法,包括:
A)使式(X)化合物(如上文中定义)与式(XII)的乙烯基硼酸酯(vinylboronate)反应
其中BYx选自B(OH)2,B(OH)3 -,B(OH)2F-,BX3 -(其中X=卤素),B(OR5)2,B(OR5)2F-,B(OR5)2(OH)-,B(OR6)(OR7),B(OR6)(OR7)(OH)-,B(OR6)(OR7)F-,BR5 2,BR5 2OH-和BR5F-;
R5选自(1-6C)烷基、(3-6C)环烷基和芳基(1-6C)烷基;
R6和R7一起在它们所连的两个氧之间形成两个或三个碳亚烷基桥连,任选地被1、2、3或4个甲基或苯基取代;
或R6和R7一起形成苯环:
且R3为保护基;
接着脱除保护基得到式(XIII)化合物:
和
B)将式(XIII)化合物氧化得到式(III)化合物。
R3的适宜值包括公知的羟基保护基团,例如包括Si(R4)3(其中每个R4独立地选自(1-6C)烷基)、四氢吡喃基、苄基、对甲氧苄基、甲氧基甲基(MOM)和苄基氧基甲基(BOM)。优选地OR3不是酯基。
一方面,R3为Si(R4)3(例如三甲基甲硅烷基或叔丁基二甲基甲硅烷基)。另一方面R3为四氢吡喃基。
适宜地BYx为B(OR6)(OR7)。
B(OR6)(OR7)的实例包括:
一方面,B(OR6)(OR7)为:
适宜地(XII)与(X)的反应可在钯催化剂如(1,1′-双(二叔丁基膦基)二茂铁)钯(II)氯化物的存在下进行。该反应可在碱如碳酸钾的存在下在乙腈和水中进行。作为选择,该反应可在氟化物的存在下进行,例如参见J.Org.Chem.1994,59,6095-6097。
应当理解对于一些R3的值(例如当R3为Si(R4)3时,甲硅烷基可在步骤A中就地脱除)。当R3为四氢吡喃基时,要求一个单独的步骤脱保护中间体烯丙基醚以得到醇(XIII);这可例如通过用盐酸水溶液水解来进行。该脱保护步骤可不分离中间体烯丙基醚而进行,如在所附实施例中举例说明。当R3为对甲氧苄基基团时,可在氧化条件下脱除,同时氧化羟基得到式(III)的醛。
适宜地氧化(XIII)得到(III)(步骤B)可使用二氧化锰来进行,例如在甲苯中进行。也可以采用本领域公知的其它氧化条件,例如在Swern氧化中的变化形式,如采用氯和二甲硫醚将达到目的。
这类反应其它适宜的条件可见于所附的实施例。
式(XIII)化合物,即反式-N-(4-(4-氟苯基)-5-(3-羟基丙-1-烯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺被认为是新的并构成本发明的其它方面。
步骤b)
式(V)化合物中的酮基的还原可在二(低级烷基)甲氧硼烷、如二乙基甲氧硼烷或二丁基甲氧硼烷的存在下进行。适宜地使用二乙基甲氧硼烷。该反应通常在极性溶剂中进行,极性溶剂如四氢呋喃或醇如甲醇或乙醇,或这类溶剂的混合物,例如四氢呋喃和甲醇的混合物。
还原剂适宜地为氢化物试剂如硼氢化钠或硼氢化锂,尤其是硼氢化钠。
该反应可低温下进行,如在约-20℃至约-100℃、尤其约-50℃至约-80℃下进行。
类似的手性还原描述于EP0521471。
步骤c)
式(VI)化合物中的R基团可通过在本领域公知的条件下水解而脱除,形成式(I)化合物或其盐。这类盐可以是可药用盐或可以转化为可药用盐。例如,R可用氢氧化钠水溶液处理而水解形成(I)的钠盐。
适宜的可药用盐包括,例如,碱金属盐,例如钠盐或钾盐,碱土金属盐,例如,钙盐或镁盐,铵盐或与提供生理学可接受的阳离子的有机碱成的盐,有机碱例如甲胺、乙胺、二甲胺、三甲胺、吗啉、二乙醇胺、三(2-羟乙基)胺和三(羟甲基)甲胺。
式(I)化合物以上文中描述的其钙盐形式出售。该钙盐可以以脱除R基团的反应产物形式直接形成(例如通过用氢氧化钙水溶液处理式(VI)化合物,参见专利申请US 2003/0114685)或通过用适宜的钙源水溶液处理式(I)化合物的另一种盐如钠盐而形成。适宜的钙源包括氯化钙和乙酸钙。这如流程图2所示:
流程图2
钠盐转化为钙盐的适宜条件描述于EP0521471。应当理解如果需要所得钙盐可以通过本领域已知的方法(例如参见国际专利申请WO00/42024和WO2005/023779)再处理以得到不同的粒度、或不同的物理形式(如无定形vs晶体)。
在本发明的其它方面中,提供一种式(VI)化合物的制备方法
包括:
a)使式(II)化合物
其中每个R1独立选自(1-6C)烷基,且R选自(1-6C)烷基、(3-6C)环烷基或芳基(1-6C)烷基;
与式(III)化合物
在式(IV)的钛(IV)催化剂
(其中R2为(1-6C)烷基且联萘部分为S-构型)、碱金属卤化物盐和胺的存在下,在惰性溶剂中反应,得到式(V)化合物;
和
b)将式(V)化合物的酮基还原得到式(VI)化合物。
步骤a)和b)的适宜条件如上文中描述。
在本发明的其它方面中,提供一种式(V)化合物的制备方法
包括
使式(II)化合物
其中每个R1独立选自(1-6C)烷基,且R选自(1-6C)烷基、(3-6C)环烷基或芳基(1-6C)烷基;
与式(III)化合物
在式(IV)的钛(IV)催化剂
(其中R2为(1-6C)烷基且联萘部分为S-构型)、碱金属卤化物盐和胺的存在下,在惰性溶剂中反应。
该反应的适宜条件如上文方法a)中的描述。
在本发明的其它方面中,提供一种式(VI)化合物的制备方法,包括
a)按照在上文中的描述形成形成式(V)化合物;和进一步包括
b)将式(V)化合物的酮基还原得到式(VI)化合物。
按照本发明的其它方面,本发明提供一种形成式(I)化合物或其可药用盐的方法,包括
a)形成式(V)化合物和b)形成如上文中描述的式(VI)化合物;和进一步包括
c)脱除R基团得到式(I)化合物或其盐;
任选地接着形成可药用盐。
在一定条件下,如所附实施例中举例说明,可进行化合物(V)还原为化合物(VI)和随后转化为化合物(I)或其盐,而不分离中间化合物(VI)。用这种方法将两步反应并缩为一步,将被预期是有效的和经济合算的,所提供的产品质量不会有损害。
按照本发明的其它方面,提供一种式(I)化合物或其盐的形成方法,其中步骤b)和c)在不分离式(VI)的中间化合物的情况下进行。
实施例
在下面的非限制性实施例中,除非另有说明:
(i)蒸发通过在真空中旋转蒸发进行和后处理步骤在除去残留的固体物如干燥剂之后通过过滤进行;
(ii)操作在室温下即在18-25℃的范围内和在惰性气体如氩气或氮气下进行;
(iii)收率仅供说明之用而给出,不一定是能达到的最大值;
(iv)式(I)终产物的结构由核(通常为质子)磁共振(NMR)证实;质子核磁共振化学位移值以Δ度量(相对于四甲基硅烷)进行测量,峰的多重性显示如下:s,单峰;d,双峰;t,三重峰;m,多重峰;br,宽峰;q,四重峰,quin,五重峰;
(v)中间体不一定完全地表征,纯度通过薄层色谱法(TLC)、熔点(Mp)、高效液相色谱(HPLC)、红外(IR)或NMR分析来评价;
(vi)色谱提纯一般指在二氧化硅上的快速柱色谱分离,除非另有说明。柱色谱分离通常采用预先装入的二氧化硅盒体(4g直至400g)如Biotage(Biotage UK Ltd,Hertford,Herts,UK)、采用泵和级分收集器系统洗脱来进行。
(vii)高分辨率质谱(HRMS)数据利用Micromass LCT飞行时间质谱仪产生。
(viii)熔点数据通常使用Perkin Elmer Pyris 1采用差示扫描量热法(DSC)测量。所引用的值为开始的温度。
本发明将以下列实施例说明,其中使用下列缩写:
DIBAL 二异丁基氢化铝
DCM 二氯甲烷
EtOAc 乙酸乙酯
CDCl3 氘氯仿
DMF 二甲基甲酰胺
MTBE 甲基叔丁基醚
实施例1:(3R,5S)-反式-7-(4-(4-氟苯基)-6-异丙基-2-(N-甲基甲基亚磺酰氨)嘧啶-5-基)-3,5-二羟基庚-6-烯酸钙盐
在氮气氛下,将(S)-反式-7-(4-(4-氟苯基)-6-异丙基-2-(N-甲基甲基亚磺酰氨)嘧啶-5-基)-5-羟基-3-氧代庚-6-烯酸乙酯(200mg,0.39mmol)和甲醇(0.67ml)溶于5mL四氢呋喃中并冷却至-70℃。向该溶液中通过注射器(syrine)在25分钟内滴加二乙基甲氧硼烷(1M,在四氢呋喃中,430μL,0.43mmol)。将产生的浅黄色溶液在-78℃下搅拌30分钟,然后加入硼氢化钠(16.3mg,0.43mmol)。将混合物在-78°下搅拌两小时,然后用乙酸(86mg,1.44mmol)中止反应并使其温热至室温。向其中加入2ml的1M NaOH水溶液,并将所得溶液搅拌90分钟。然后将其用5mL水和5mL甲苯稀释、搅拌30分钟、分离,并将水溶液在真空中浓缩得到浅白色油。将该油状物溶于5mL水中,加热至40℃,然后通过注射器滴加氯化钙水溶液(0.93M,300μL,0.28mmol)。将产生的浆液在60分钟内冷却至室温,然后通过用1mL水洗过滤收集固体物。将收集的固体物在真空下干燥过夜产生白色结晶固体(3R,5S)-反式-7-(4-(4-氟苯基)-6-异丙基-2-(N-甲基甲基亚磺酰氨)嘧啶-5-基)-3,5-二羟基庚-6-烯酸钙盐(122.6g,62%收率)。物理数据与现有标准及其公开的说明完全相同。
(3R,5S)-反式-7-(4-(4-氟苯基)-6-异丙基-2-(N-甲基甲基亚磺酰氨)嘧啶-5-基)-3,5-二羟基庚-6-烯酸乙酯
在氮气氛下,将(S)-反式-7-(4-(4-氟苯基)-6-异丙基-2-(N-甲基甲基亚磺酰氨)嘧啶-5-基)-5-羟基-3-氧代庚-6-烯酸乙酯(506mg,1.00mmol)和甲醇(1.7mL)溶于10mL四氢呋喃中并冷却至-76℃。在30分钟内通过注射器向该溶液中加入二乙基甲氧硼烷(1.0M,在四氢呋喃中,1.15mL,1.15mmol)。将产生的浅黄色溶液在-75℃下搅拌30分钟,然后加入硼氢化钠(43.5mg,1.15mmol)。将反应物在-65℃下搅拌两小时,然后用乙酸(224μL,3.75mmol)中止反应并使其温热至室温。将其用100mL的甲基叔丁基醚和20mL水稀释,剧烈搅拌10分钟,然后分离。上层有机相用20mL水、20mL饱和NaHCO3水溶液洗涤,然后用20mL水洗涤,然后在真空中浓缩得到浅白色油,经Biotage色谱纯化(50∶50 EtOAc/己烷)产生白色固体的标题产物(182mg,36%收率)。1HNMR(400MHz)(CDCl3)δ:1.27(6H,d),1.28(3H,t),2.45(1H,s),2.47(1H,d),3.37(1H,m),3.52(3H,s),3.57(3H,s),3.58(1H,br.s),3.74(1H,br.s.),4.19(2H,q),4.22(1H,m),4.46(1H,m),5.46(1H,dd),6.64(1H,dd),7.09(2H,dd),7.65(2H,dd)。Mp:92-94℃。对C24H32FN3O6S计算的HRMS为509.1996,实测值509.1999。
(S)-反式-7-(4-(4-氟苯基)-6-异丙基-2-(N-甲基甲基亚磺酰氨)嘧啶-5-基)-5-羟基-3-氧代庚-6-烯酸乙酯
在氮气氛下,将反式-N-(4-(4-氟苯基)-6-异丙基-5-(3-氧代丙-1-烯基)嘧啶-2-基)-N-甲基甲基磺酰胺(1.00g,2.65mmol)、(S)-(-)-1,1′-双(2-萘氧基)(二异丙氧基)钛(41.8mg,0.093mmol)和氯化锂(40.2mg,0.94mmol)在室温下溶于四氢呋喃(15mL)中。将溶液搅拌10分钟,然后通过注射器加入N,N,N′N′-四甲基乙二胺(397μL,2.51mmol),导致该溶液由红色变为橙色。通过注射泵在1小时内向该溶液中加入1,3-双(三甲基甲硅烷氧基)-1-乙氧丁-1,3-二烯(1.45g,5.30mmol)。将该反应混合物在室温下搅拌过夜,然后在0℃下用20%三氟醋酸水溶液(2.5mL)中止并使其在1小时内温热至室温。将混合物冷却至0℃,然后加入25%磷酸水溶液(4mL)并使反应物温热至室温。将其搅拌1小时,然后用甲基叔丁基醚(50mL)稀释。让混合物分离,并将水层用甲基叔丁基醚(2×50mL)萃取。将合并的有机级分用水(2×100mL)洗涤,干燥(MgSO4),并在真空中浓缩得到淡黄色油状物。经色谱纯化(Biotage盒体,40∶60 EtOAc/己烷)得到99.3%对映体过量的浅白色油状标题化合物(1.221g,91%收率)。
1H NMR(400MHz;CDCl3)δ:1.26(6H,d),1.28(3H,t),2.65(1H,d),2.66(1H,s),2.89(1H,br.s), 3.34(1H,m),3.44(2H,s),3.51(3H,s),3.57(3H,s),4.21(2H,q),4.65(1H,m),5.45(1H,dd),6.67(1H,dd),7.11(2H,dd),7.63(2H,dd)。
对C24H30FN3O6S计算的HRMS为507.1839,实测值507.1870。
(S)-(-)1,1′-双(2-萘氧基)(二异丙氧基)钛
在氮气氛下,将(S)-(-)-1,1′-双(2-萘酚)(500mg,1.74mmol)、四异丙醇钛(500μL,1.69mmol)和粉末4分子筛(500mg)悬浮于二氯甲烷(25mL)中并在室温下搅拌一小时。滤去固体物,并将滤液在真空中浓缩得到暗红色粉末(S)-(-)-1,1′-双(2-萘氧基)(二异丙氧基)钛(980mg,126%收率),其不经进一步纯化用于随后的反应。
4-(4-氟苯基)-6-异丙基嘧啶-2-醇
在使用之前,将用于该试验的反应器通过甲苯蒸馏充分干燥。将新鲜的甲苯(100mL)和叔丁醇钾(7.50g,64.8mmol)装入容器中并搅拌形成浆液。将混合物冷却至-9℃并加入3-甲基-2-丁酮(3.63g,41.7mmol)。将反应混合物温热至-5℃并搅拌30分钟。将4-氟苯甲酸乙酯(6.25g,36.8mmol)溶于甲苯(4mL)中并通过注射器加入,之后用少量的甲苯(1ml)线洗涤。将混合物在0℃下搅拌10分钟,温热至10℃,然后在此温度下搅拌过夜。将流动的浆液温热至25℃并加入乙酸(4.4mL),之后加入水(37.5mL)。将混合物充分搅拌5分钟然后让其静置。放出下层相并弃去。将5%碳酸氢钠溶液(16mL)加到上层相中,搅拌5分钟然后让其静置。放出下面的水层并将上层有机相用水(5mL)洗涤两次。
剩下的甲苯溶液通过共沸蒸馏干燥(用Dean Stark分离器就地回流)并将溶液冷却至60℃。加入尿素(5.1g,84.9mmol)和异丙醇(20mL)并在加入盐酸(5-6M,在异丙醇中,32.3mL,183mmol)过程中剧烈搅拌。将溶液加热至80℃并在加入更多的异丙醇中的盐酸(2mL,11mmol)之前搅拌48.5小时。在80℃总共112小时之后,将混合物冷却至60℃并加入水(50mL)。在搅拌15分钟之后,让混合物静置然后放出下面的水相并保留。搅拌水相分批加入碳酸氢钠(6.9g)直至pH=7。使产物从溶液中结晶然后冷却至20℃。滤出固体并用水(20mL)洗涤两次然后在50℃下在真空烘箱中干燥过夜。分离出4-(4-氟苯基)-6-异丙基嘧啶-2-醇(4.92g),为白色粉末,总收率56%;
1H NMR(400MHz;CDCl3)δ:1.41(6H,d),3.08(1H,m),6.69(1H,s),7.17(2H,dd),8.14(2H,dd),13.57(1H,br.s).Mp:215-217℃.对C13H13N2OF计算的HRMS为232.1012,实测值232.0963;不经进一步纯化用于随后的反应。
5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-醇
将4-(4-氟苯基)-6-异丙基嘧啶-2-醇(8.00g,34.1mmol)加到反应器中,接着加入DMF(100mL)中。搅拌混悬液,冷却至-3℃并加入N-溴代琥珀酰亚胺(6.25g,34.8mmol)。将反应混合物温热至20℃并搅拌过夜。将水(100mL)加到反应混合物中并在滤出之前将晶体混合物搅拌1小时。将分离出的固体用水(25mL)洗涤两次并将固体在真空烘箱中在50℃下干燥。得到白色固体5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-醇(10.45g,97%收率);
1H NMR(400MHz;CDCl3)δ:1.39(6H,d),3.57(1H,m),7.16(2H,dd),7.66(2H,dd)。
Mp:在199℃分解。对C13H12N2OFBr计算的HRMS为310.0117,实测值310.0116;不经进一步纯化用于随后的反应。
5-溴-2-氯-4-(4-氟苯基)-6-异丙基嘧啶
将磷酰氯(5.00mL,53.8mmol)加入到5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-醇(5.027g,15.28mmol)中并将反应混合物加热至内部温度90℃。然后将混合物在此温度下搅拌150分钟,然后让其冷却至25℃。通过将反应混合物滴加(用30mL的EtOAc冲洗)到搅拌过的冰(60g)、水(40mL)和碳酸氢钠(10g)的混合物里使其中止反应。加入完毕,加入碳酸氢钠(13g)到确保中性。然后将混合物用乙酸乙酯(4×70mL)萃取。将有机相合并用无水硫酸镁干燥。将溶液通过硅藻土垫过滤、并在真空中浓缩得到标题化合物(4.98g,99%收率)。
1H NMR(400MHz;CDCl3)δ:1.34(6H,d),3.64(1H,m),7.17(2H,dd),7.73(2H,dd)。
Mp:99-101℃.对C13H11N2FClBr计算的HRMS为327.9778,实测值327.9752;不经进一步纯化用于随后的反应。
N-(5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺
将氢化钠(1.20g,30.0mmol,60%在矿物油中的混悬液)用己烷(2×10mL)洗涤,然后加入DMF(50mL),接着加入5-溴-2-氯-4-(4-氟苯基)-6-异丙基嘧啶(4.944g,15.0mmol)。将产生的混悬液冷却至-7℃并加入N-甲基甲烷磺酰胺(2.585g,22.5mmol),用DMF(10mL)洗涤。将混合物搅拌17.5小时,然后用乙酸乙酯(80mL)、甲苯(100mL)和水(120mL)稀释。分离出有机相,并将水相用乙酸乙酯(20mL)和甲苯(30mL)的混合物萃取。将有机相合并,用水(2×40mL)洗涤然后用盐水(20mL)洗涤,并经无水硫酸镁干燥。将溶液在真空中浓缩(用2×20mL己烷共沸混合物)得到该标题化合物(5.50g,91%收率)。
1H NMR(400MHz;CDCl3)δ:1.32(6H,d),3.49(3H,s),3.55(3H,s),3.63(1H,m),7.16(2H,dd),7.77(2H,dd).Mp:122-125℃.对C13H17N3O2FSBr计算的HRMS为401.0209,实测值401.0225;不经进一步纯化用于随后的反应。
反式-N-(5-(2-氰基乙烯基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺
将N-(5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺(20.0g,49.72mmol)、四N-丁基溴化铵(3.24g,10mmol)和双(三叔丁基膦)钯(0)(1.48g,2.89mmol)加到500ml圆底烧瓶中。将烧瓶用氮气冲洗5分钟,然后通过注射器加入甲苯(200mL)、二环己基甲基胺(31.6mL,147mmol)、丙烯腈(3.60mL,54.67mmol)并搅拌反应物。将产生的琥珀色溶液在50℃下油浴加热7小时,期间米色沉淀开始形成。让反应物冷却至室温,用异己烷(200mL)稀释,然后进一步冷却至-8℃。通过过滤收集沉淀物并用异己烷(4×100mL)洗涤得到大致由85%反式异构体组成的粗制品(31g,湿的)。向该粗制品中加入甲醇(130mL)并将所得混悬液在室温下搅拌30分钟,然后冷却至-8℃。通过过滤收集白色结晶固体并在真空烘箱中干燥过夜得到白色结晶固体的标题化合物(13.1g,70%收率)。
1H NMR(400MHz;CDCl3)δ:1.32(6H,d),3.29(1H,m),3.51(3H,s),3.58(3H,s),5.31(1H,d),7.18(2H,dd),7.49(1H,d),7.58(2H,dd);Mp:134.5℃。
对C18H19FN4O2S计算的HRMS为374.1213,实测值374.1210。
反式-N-(4-(4-氟苯基)-6-异丙基-5-(3-氧代丙-1-烯基)嘧啶-2-基)-N-甲基甲烷磺酰胺
将反式-N-(5-(2-氰基乙烯基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺(12.83g,34.27mmol)溶于甲苯(750mL)中并冷却至-9℃。向该溶液中通过注射泵在45分钟内加入DIBAL(20%的甲苯溶液,34mL,41.1mmol),保持内部温度在-6℃以下。加入完毕,使反应物慢慢温热至室温过夜然后用甲醇(3mL)继之以1M HCl(41.1mL)中止反应。将产生的混悬液过滤并滤液的下水层分离。滤液有机层用1M HCl(100mL)处理,并将产生的混悬液过滤。让各层分离,有机层用盐水(125mL)、饱和NaHCO3水溶液(125mL)和水(125mL)洗涤,然后用MgSO4和Novit SX 1G碳处理,过滤并在真空中浓缩得到12g黄色油。将该产物通过色谱纯化(Biotage盒体,100%DCM)得到浅黄色无定形固体标题化合物(9.7g,76%收率)。
1H NMR(400MHz;CDCl3)δ:1.32(6H,d),3.39(1H,m),3.53(3H,s),3.60(3H,s),6.22(1H,dd),7.15(2H,dd),7.52(1H,d),7.59(2H,dd),9.61(1H,d);Mp:86.5℃.对C18H20FN3O3S计算的HRMS为377.1209,实测值377.1196。
反式-N-(4-(4-氟苯基)-5-(3-羟基丙-1-烯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺
向(1,1′-双(二叔丁基膦基)二茂铁)钯(II)氯化物(162mg,0.249mmol)和碳酸钾(10.3g,74.6mmol)在乙腈(40mL)和水(40mL)的室温溶液中加入乙腈(35mL)中溶液形式的反式-4,4,5,5-四甲基-2-(3-(四氢-2H-吡喃-2-基氧基)丙-1-烯基)-1,3,2-二氧杂戊硼烷(dioxaborolane)(参见Synthesis,2004,第1814-1820页;11.9g(70%浓度),31.1mmol)并用水冲冼(12.5mL)。将混合物搅拌5分钟,然后加入白色固体N-(5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺(10.0g,24.9mmol)接着加入水(12.5mL)。将反应物加热至回流(77℃的内部温度)5小时,然后让其冷却至室温。将其用MTBE(150mL)和水(150mL)稀释,分离并将有机层用水(50mL)洗涤两次然后在真空中浓缩,得到16g的棕色油。将该物质在室温下溶于150mL乙腈中,并加入10M盐酸水溶液(3.0mL,30mmol)。将所得混合物在室温下搅拌45分钟,然后用碳酸氢钠(2.52g,30mmol)中止反应。将混合物用甲苯(150mL)和水(150mL)稀释、分离,并将有机层用水(40mL)洗涤两次。将有机层经硫酸钠干燥,在真空中浓缩,并经色谱纯化(1∶1异己烷/EtOAc,450g硅胶)得到淡黄色油状的标题化合物(8.29g,72%收率)。1H NMR(400MHz)(CDCl3)δ:1.27(6H,d),3.38(1H,m),3.51(3H,s),3.57(3H,s),4.20(2H,d),5.65(1H,ddd),6.58(1H,ddd),7.09(2H,dd),7.59(2H,dd)。对C18H22FN3O3S计算的HRMS为379.1366,实测值379.1392。
反式-N-(4-(4-氟苯基)-6-异丙基-5-(3-氧代丙-1-烯基)嘧啶-2-基)-N-甲基甲烷磺酰胺
向反式-N-(4-(4-氟苯基)-5-(3-羟基丙-1-烯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺(1.81g(95%浓度),4.53mmol)在25mL甲苯中的室温溶液中加入二氧化锰(10g(85%浓度),97.77mmol)。将产生的混悬液搅拌18小时,然后通过C盐垫以甲苯冲冼过滤。在真空中从滤液中除去溶剂得到黄色油状的标题化合物(1.33g,75%收率),其迅速变为结晶固体。1H NMR(400MHz)(CDCl3)δ:1.32(6H,d),3.39(1H,m),3.53(3H,s),3.60(3H,s),6.22(1H,dd),7.15(2H,dd),7.52(1H,d),7.59(2H,dd),9.61(1H,d)。Mp:86.5℃。对C18H20FN3O3S计算的HRMS为377.1209,实测值377.1196。
Claims (22)
3.一种形成式(I)化合物或其可药用盐的方法,包括
a)形成式(V)化合物和b)形成如权利要求2的式(VI)化合物;和进一步包括
c)脱除R基团得到式(I)化合物或其盐;
任选地接着形成可药用盐
4.根据权利要求3的方法,其中步骤b)和c)在不分离式(VI)的中间化合物的情况下进行。
5.根据权利要求1-4任一项的方法,其中碱金属卤化物为氯化锂。
6.根据权利要求1-5任一项的方法,其中胺为N,N,N,N-四甲基乙二胺(TMEDA)。
7.根据权利要求1-5任一项的方法,其中每个R1为甲基。
8.根据前述权利要求任一项的方法,其中R为(1-6C)烷基。
9.根据前述权利要求任一项的方法,其中式(I)化合物以其钙盐的形式分离。
11.根据权利要求10的方法,其中步骤i)通过使化合物(X)与丙烯腈在Pd[P(tBu)3]2的存在下反应来进行。
12.根据权利要求10或权利要求11的方法,其中步骤ii)通过与DIBAL反应来进行。
13.一种形成式(III)化合物(如权利要求1中定义)的方法,包括:
A)使式(X)化合物(如权利要求8中定义)与式(XII)的乙烯基硼酸酯反应
其中BYx选自B(OH)2,B(OH)3 -,B(OH)2F-,BX3 -(其中X=卤素),B(OR5)2,B(OR5)2F-,B(OR5)2(OH)-,B(OR6)(OR7),B(OR6)(OR7)(OH)-,B(OR6)(OR7)F-,BR5 2,BR5 2OH-和BR5F-;
R5选自(1-6C)烷基、(3-6C)环烷基或芳基(1-6C)烷基;
R6和R7一起在它们所连的两个氧之间形成两个或三个碳亚烷基桥连,任选地被1、2、3或4个甲基或苯基取代;
或R6和R7一起形成苯环:
且R3为保护基;
接着脱除保护基得到式(XIII)化合物:
和
B)将式(XIII)化合物氧化得到式(III)化合物。
14.如权利要求13要求保护的方法,其中R3为四氢吡喃基。
15.如权利要求13或权利要求14中要求保护的方法,其中BYx为B(OR6)(OR7)。
16.化合物:反式-N-(4-(4-氟苯基)-6-异丙基-5-(3-氧代丙-1-烯基)嘧啶-2-基)-N-甲基甲烷磺酰胺。
17.化合物:4-(4-氟苯基)-6-异丙基嘧啶-2-醇。
18.化合物:5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-醇。
19.化合物:5-溴-2-氯-4-(4-氟苯基)-6-异丙基嘧啶。
20.化合物:N-(5-溴-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺。
21.化合物:反式-N-(5-(2-氰基乙烯基)-4-(4-氟苯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺。
22.化合物:反式-N-(4-(4-氟苯基)-5-(3-羟基丙-1-烯基)-6-异丙基嘧啶-2-基)-N-甲基甲烷磺酰胺。
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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 |
DE10352659B4 (de) * | 2003-11-11 | 2007-09-13 | Ratiopharm Gmbh | Verfahren zur Herstellung von Statinen und Tetrahydropyranonderivate zur Verwendung in dem Verfahren |
WO2005054207A1 (en) * | 2003-12-04 | 2005-06-16 | Glenmark Pharmaceuticals Limited | Process for the preparation of pyrimidine derivatives |
US7161004B2 (en) * | 2004-06-21 | 2007-01-09 | Dr. Reddy's Laboratories Limited | Processes to produce intermediates for rosuvastatin |
CN1763015B (zh) * | 2004-10-22 | 2011-06-22 | 四川抗菌素工业研究所有限公司 | 一种罗舒伐他汀及其药用盐的制备方法及中间体 |
GB0428328D0 (en) * | 2004-12-24 | 2005-02-02 | Astrazeneca Uk Ltd | Chemical process |
CN100351240C (zh) * | 2005-01-19 | 2007-11-28 | 安徽省庆云医药化工有限公司 | 瑞舒伐他汀钙的合成方法 |
US20090124803A1 (en) * | 2005-03-22 | 2009-05-14 | Pandurang Balwant Deshpande | Process for preparation of rosuvastatin |
TW200831469A (en) * | 2006-12-01 | 2008-08-01 | Astrazeneca Uk Ltd | Chemical process |
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2005
- 2005-07-08 GB GBGB0514078.5A patent/GB0514078D0/en not_active Ceased
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2006
- 2006-07-03 JP JP2008520005A patent/JP2009500388A/ja not_active Withdrawn
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- 2006-07-03 WO PCT/GB2006/003543 patent/WO2007007119A1/en active Application Filing
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- 2006-07-03 BR BRPI0612851-3A patent/BRPI0612851A2/pt not_active IP Right Cessation
- 2006-07-03 US US11/994,925 patent/US20100228028A1/en not_active Abandoned
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- 2006-07-03 CN CN2006800247173A patent/CN101218210B/zh not_active Expired - Fee Related
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2007
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105473542A (zh) * | 2013-08-30 | 2016-04-06 | 日产化学工业株式会社 | 光学活性5-羟基-3-酮酯类的制造方法 |
CN105473542B (zh) * | 2013-08-30 | 2018-12-04 | 日产化学工业株式会社 | 光学活性5-羟基-3-酮酯类的制造方法 |
Also Published As
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AU2006268024B2 (en) | 2010-07-01 |
CA2614281A1 (en) | 2007-01-18 |
IL188201A0 (en) | 2008-03-20 |
WO2007007119A1 (en) | 2007-01-18 |
TW200726754A (en) | 2007-07-16 |
BRPI0612851A2 (pt) | 2011-03-01 |
KR20080024538A (ko) | 2008-03-18 |
ZA200711085B (en) | 2009-09-30 |
NZ564609A (en) | 2010-07-30 |
GB0514078D0 (en) | 2005-08-17 |
CN101218210B (zh) | 2011-08-03 |
US20100228028A1 (en) | 2010-09-09 |
AR054818A1 (es) | 2007-07-18 |
AU2006268024A1 (en) | 2007-01-18 |
EP1904456A1 (en) | 2008-04-02 |
MX2008000362A (es) | 2008-03-07 |
JP2009500388A (ja) | 2009-01-08 |
NO20076660L (no) | 2008-01-09 |
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