CN1821242B - Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor - Google Patents
Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title description 19
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title description 19
- 239000002253 acid Substances 0.000 title description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 19
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000006165 cyclic alkyl group Chemical group 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- -1 3-hydroxy-3-methyl glutaryl Chemical group 0.000 description 7
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229960004844 lovastatin Drugs 0.000 description 7
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 7
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 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 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960003765 fluvastatin Drugs 0.000 description 4
- 229960002965 pravastatin Drugs 0.000 description 4
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 4
- 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 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 3
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229960005370 atorvastatin Drugs 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 229960000672 rosuvastatin Drugs 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229960005110 cerivastatin Drugs 0.000 description 2
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 2
- 229950009116 mevastatin Drugs 0.000 description 2
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 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 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- JYVXNLLUYHCIIH-UHFFFAOYSA-N (+/-)-mevalonolactone Natural products CC1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-UHFFFAOYSA-N 0.000 description 1
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- TUZYXOIXSAXUGO-JFBQIPGGSA-N (3r,5r)-7-[(2s,6s,8s,8ar)-6-hydroxy-2-methyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C1=C[C@H](C)C(CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-JFBQIPGGSA-N 0.000 description 1
- WTXXSZUATXIAJO-OWBHPGMISA-N (Z)-14-methylpentadec-2-enoic acid Chemical compound CC(CCCCCCCCCC\C=C/C(=O)O)C WTXXSZUATXIAJO-OWBHPGMISA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- VZTXNOOWMMDDLR-UHFFFAOYSA-N CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1C Chemical compound CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c(cc2)ccc2F)c1C VZTXNOOWMMDDLR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- JYVXNLLUYHCIIH-ZCFIWIBFSA-N R-mevalonolactone, (-)- Chemical compound C[C@@]1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-ZCFIWIBFSA-N 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229940043430 calcium compound Drugs 0.000 description 1
- 150000001674 calcium compounds Chemical class 0.000 description 1
- MMCOUVMKNAHQOY-UHFFFAOYSA-N carbonoperoxoic acid Chemical class OOC(O)=O MMCOUVMKNAHQOY-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002475 indoles Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940057061 mevalonolactone Drugs 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 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 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- RHGYHLPFVJEAOC-FFNUKLMVSA-L pitavastatin calcium Chemical compound [Ca+2].[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1.[O-]C(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 RHGYHLPFVJEAOC-FFNUKLMVSA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 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
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供制备式(I)的方法，Ra为氢，烷基，优选烷基，Rb Rc代表C1～C4的烷基或C3～C6环状烷基，R如说明书定义。 The present invention provides a method for preparing formula (I), Ra is hydrogen, an alkyl group, preferably an alkyl group, R b Rc represents a C1-C4 alkyl group or a C3-C6 cyclic alkyl group, and R is as defined in the specification.
Description
Technical field:
The present invention relates to a kind of novel method for preparing dihydroxy acid HMG CoA reductase inhibitor.
Background technology:
Dihydroxy acid HMG CoA reductase inhibitor is also referred to as: 3-hydroxy-3-methyl glutaryl coenzyme reductase inhibitor A (3-hydroxy-3-methylglutaryl-coenzymeA; HMG-CoA); Being one type of novel blood lipid-lowering medicine, is clinical prevention atherosclerosis drug of first choice at present.
Since first statins mevastatin (mevastatin) in 1976 came out, statins had been developed to the third generation.Statins commonly used in the world at present has 5 kinds (by the appearance sequencing): lovastatin (lovastatin), pravastatin (pravastatin), SV (simvastatin), fluvastatin (fluvastatin) and atorvastatin (atorvastatin).And the accent fat effect of not long ago also using in the international market is powerful, the taking dose Cerivastatin of Gamma Magnitude (cerivastatin) only; Cause rhabdomyolysis to cause dead severely adverse event to take place again and again because of share with the fibrate lipid-lowering medicine, some countries and China stop using in succession in the world.(rosuvastatin's rosuvastatin of new statins--Astrazeneca company ZD4522) also goes on the market, and its effect for reducing fat is powerful, uses separately to surpass every other statins, is known as " super he spit of fland ".Japan development she he cuts down his spit of fland (itavastatin also is a kind of efficient lipid lowerers NK-104), mainly with the original shape metabolism, does not still go public.Statins is efficient, safety, is the choice drug in the fat-reducing medicament.
First statins lovastatin is separated from the mould culture, and pravastatin and SV are the improvement of the chemical structure of lovastatin.The active structure that Hydroxymethylglutaryl is all arranged in the statins structure, just existence form is different.Lovastatin and SV are inactive lactone form medicines, and they must be metabolized to its corresponding open loop alcohol acid form could suppress the HMG-CoA reductase enzyme.Pravastatin exists to have active open hydrochlorate structure; Water-soluble big, mainly act on liver, it is high 400～1200 times to suppress liver SUV synthetic ability force rate surrounding tissue; Therefore do not have the effect that obviously suppresses peripheral tissues's synthetic cholesterol, thereby untoward reaction is few.The structure of lovastatin, SV, pravastatin and relative molecular mass are very approaching, and curative effect, untoward reaction, tolerance etc. are variant slightly on the degree.Fluvastatin is first complete synthesis HMG-CoA reductase inhibitor, and it is obviously different that structure and above 3 kinds of his spit of fland medicines have, and it is the verivate with the mevalonolactone of fluorobenzene substituted indole ring, need not metabolic conversion and just has pharmacologically active.The same fluorobenzene ring and the nitrogen heterocyclic of all containing with fluvastatin of atorvastatin is the 2nd statins of total man worker's synthetic.The two is compared with lovastatin with SV, water-soluble increase, and fat-soluble reduction all shows dose-effect relationship.
Statins has many compound methods because complex structure is synthetic relatively more difficult in the prior art; But all exist yield low, step is long, and cost is high; Defectives such as operational difficulty, the present invention provides a kind of novel method for preparing dihydroxy acid HMG CoA reductase inhibitor, solves these problems.
Summary of the invention:
The present invention provides a kind of novel method for preparing dihydroxy acid HMG CoA reductase inhibitor, and this method is through the important midbody of preparation, and compound in structural formula I realizes.
Therefore, the present invention provides a kind of useful as intermediates, the formula I compound that structure is following
Wherein: R is:
Ra representative: hydrogen, the alkyl of C1～C6 such as methyl, ethyl, propyl group, butyl, sec.-propyl, cyclopropyl, isobutyl-, the tertiary butyl etc., preferable methyl, ethyl, the tertiary butyl, the most preferably tertiary butyl.
Rb, Rc represent hydrogen respectively, the alkyl of C1～C4 or C3～C6 cyclic alkyl, preferable methyl, ethyl or cyclopropyl, cyclohexyl, most preferable.
Formula I compound obtains the end product dihydroxy acid HMG CoA reductase inhibitor through the reactions step of step 3 of the present invention.
Dihydroxy acid HMG CoA reductase inhibitor according to the invention comprises their ester, salt, acid, free acid etc.
For this reason, the present invention provides formula I the preparation method of compound, and this method may further comprise the steps:
Step 1:
With precursor compound R-CH
2OH through oxidizing reaction obtain compound R-CH (=O),
Wherein the R representative is the same.
Said precursor compound R-CH
2OH is a known compound, can prepare through technology among the US5260440.
The reaction conditions of said oxidizing reaction is: the oxygenant of employing is pyridinium chloro-chromate (PCC), and reaction substrate and oxygenant mole proportioning are chosen between 1: 1 to 1: 1.5, between 0～50 ℃ of the temperature of reaction, and preferred 0～25 ℃.This is reflected in hydro carbons or the halogenated hydrocarbon solvent and carries out, like benzene, and toluene, methylene dichloride, trichloromethane etc., here our preferred methylene dichloride.
Step 2:
With gained compound R-CH (=O) with formula (II) compound prepared in reaction formula (I),
Wherein the R representative is the same,
Ra, Rb, the Rc representative is the same.
R
1, R
2The alkyl of C1-C7 or aryl such as the phenyl of C6～C12, tolyl, xylyl, the biphenylyl etc. represented independent of each other.Methyl preferably, ethyl, phenyl, tolyl, most preferred is methyl.
Reaction conditions does, adopted LiCl and organic bases such as triethylamine, temperature of reaction-10～30 ℃, and this is reflected in ether solvent or the halogenated hydrocarbon solvent and carries out, THF for example, methylene dichloride, trichloromethane etc., our preferred methylene dichloride.Aldehyde and organophosphate mole proportioning are chosen between 1: 1 to 1: 2.
Its Chinese style (II) compound is through (R by formula (III) compound
1O) (R
2O) the P processing obtains
X wherein
1Represent halogen atom, like F, Cl, Br, I,
R
1, R
2, represent the same.
Here we obtain formula (II) with two kinds of raw materials at varsol such as reflux in toluene reaction.
Formula (III) compound is a known compound, can obtain by the method for setting forth in the U.S. Pat 5278313, like following method:
With the described compound of formula (IV) is that starting raw material is reduced to the described compound of formula V:
The described compound of formula V is obtained the described compound of formula (III) with (Va) or (Vb) or (Vc) reaction under acidic conditions:
X
1Be halogen atom, Ra is a hydrogen, alkyl or aryl, preferred alkyl, the for example tertiary butyl.R
bR
cBe hydrogen, alkyl or cyclic alkyl, R
5, R
6Be alkyl.
Step 3:
Formula (I) compound obtains following useful dihydroxy acid HMG CoA reductase inhibitor by known method
A obtains following formula dihydroxy carboxylic acids ester with s.t.:
B obtains acceptable salt on the following formula drug effect with alkaline purification, dihydroxy carboxylic acids salt:
C obtains the following formula dihydroxylated acid with s.t.:
D obtains the saturated free acid of following formula with free acid hydrogenation:
Said known method can reference WO01/60804, WO01/49014, or realize according to the method in the embodiment of the invention.
Above step prepares the method for formula (I) compound can be through the reaction formula explanation in more detail in addition of following preparation rosuvastain calcium (ZD-4522).
Rosuvastain calcium (ZD-4522)
Method of the present invention, compared with prior art, advantage is that yield is high, and is easy to operate, mild condition, high chiral purity is synthetic to obtain title product, and environmental pollution is little, and reactions step is few, and cost is low, can scale operation.
Embodiment
Below further specify the present invention through embodiment, but not as limitation of the present invention.
With preparation rosuvastain calcium (ZD-4522) compound (H) is instance.
Embodiment 1: the preparation of compound (B) 4-(4-fluorobenzene)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamido)-5-pyrimidine formaldehyde:
Add pyridinium chloro-chromate (PCC) 28.0g to exsiccant methylene dichloride 300ml, anhydrous sodium acetate 24.6g stirs; 20 ℃ of solution that drip the preparation of compound (A) [4-(4-fluorobenzene)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamido) pyrimidine-5-yl] methyl alcohol 35.3g and 200ml methylene dichloride down stir 1h, filter; Filtrating 1N hydrochloric acid 500ml, 1N NaOH500ml, saturated aqueous common salt 500ml washing; Anhydrous magnesium sulfate drying, decompression removes methylene dichloride, resistates column chromatography; The eluent methylene dichloride gets crystallization title product 29.1g (yield: 82.9%).
Embodiment 2: the preparation of compound (D):
Toluene 200ml adds trimethyl phosphite 13.0g, is warming up to backflow, dropping compound (C) 2-[(4R, 6S)-6-brooethyl-2; 2-dimethyl--1,3-dioxy-4-yl] solution of tert.-butyl acetate 32.3g and toluene 200ml preparation, back flow reaction 3h, decompression removes toluene; Add entry 500ml, chloroform 200ml * 3 extractions, anhydrous magnesium sulfate drying, decompression removes chloroform; The resistates column chromatography, eluent ETHYLE ACETATE gets title product 31.7g (yield: 90.1%).
Embodiment 3: the preparation of compound (E)
Add LiCl15.3g to exsiccant methylene dichloride 300ml under the argon shield, compound (D) 42.2g stirs; 0 ℃ drips triethylamine 12.2g, drips to finish the solution that then drips compound (B) 35.1g and methylene dichloride 200ml preparation, and 20 ℃ are stirred 1h; In reaction solution, add saturated ammonium chloride solution 300ml, layering, extract water methylene dichloride 200ml * 2; Merge organic phase, anhydrous magnesium sulfate drying, decompression removes methylene dichloride; The resistates column chromatography, eluent (normal hexane: ETHYLE ACETATE=5: 1), get title product 40.7g (yield: 70.5%).
Embodiment 4: the preparation of compound (F)
80% aqueous acetic acid 2500ml adding compound (E) 57.8g, stirring at room 20h gets settled solution, and decompression removes solvent to doing, and residual solvent is removed with toluene 250ml * 3 azeotropic, gets white powder shape solid 53.7g (yield: 100.0%).
Embodiment 5: the preparation of rosuvastain calcium-compound (H)
Under the argon shield, acetonitrile 700m adds compound (F) 53.7g, adds 1N NaOH1000ml, room temperature reaction 1h, and decompression removes acetonitrile, and resistates adds entry 3000ml dilution, drips 1M CaCl under the room temperature
2Solution 900ml stirs 2h, suction filtration, and vacuum-drying gets white object product compound (H) 40.3g (yield: 80.7%).
Claims (6)
1. the preparation method of formula (I) compound that structure is following,
Wherein R is:
The Ra representative: the alkyl of hydrogen, C1～C6,
Rb, Rc represent alkyl or the C3～C6 cyclic alkyl of hydrogen, C1～C4 respectively, it is characterized in that: the process following steps:
Step 1:
With precursor compound R-CH
2OH through oxidizing reaction obtain compound R-CH (=O),
Step 2:
With gained compound R-CH (=O) with formula (II) compound prepared in reaction formula (I),
Its Chinese style (II) compound is through P (OCH by formula (III) compound
3)
3Processing obtains
X wherein
1Represent halogen atom,
R
1, R
2The CH that represents independent of each other
3
2. the preparation method of claim 1 is characterized in that:
The reaction conditions of step 1 is: the oxygenant of employing is a pyridinium chloro-chromate, and reaction substrate and oxygenant mole proportioning are between 1: 1 to 1: 1.5, and temperature of reaction is between 0～50 ℃, and this is reflected in hydro carbons or the halogenated hydrocarbon solvent and carries out;
The reaction conditions of step 2 does, adopts LiCl and organic bases, temperature of reaction-10～30 ℃, and this is reflected in ether solvent or the halogenated hydrocarbon solvent and carries out, and aldehyde and Organophosphonate mole proportioning are between 1: 1 to 1: 2.
3. the preparation method of claim 1 is characterized in that:
Reaction conditions is the formula that obtains (II) that two kinds of raw materials are refluxed in varsol.
4. the preparation method of claim 1 is characterized in that:
Wherein
Ra representative: hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl, the isobutyl-or the tertiary butyl;
Rb, Rc represent hydrogen, methyl, ethyl, cyclopropyl or cyclohexyl respectively separately.
5. the preparation method of claim 4 is characterized in that: wherein
Ra represents the tertiary butyl; Rb, the Rc difference is represent methylidene separately.
6. the preparation method of claim 2 is characterized in that:
The reaction conditions of step 1 is: the oxygenant of employing is a pyridinium chloro-chromate, reaction substrate and oxygenant mole proportioning between 1: 1 to 1: 1.5,0～25 ℃ of temperature of reaction, this is reflected in the dichloromethane solvent and carries out;
The reaction conditions of step 2 does, adopts LiCl and triethylamine, temperature of reaction-10～30 ℃, and this is reflected in the dichloromethane solvent and carries out, and aldehyde and Organophosphonate mole proportioning are between 1: 1 to 1: 2.
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| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| WO2007099561A1 (en) * | 2006-02-27 | 2007-09-07 | Cadila Healthcare Limited | Process for preparing rosuvastatin calcium |
| US8455640B2 (en) * | 2006-05-03 | 2013-06-04 | Msn Laboratories Limited | Process for statins and its pharmaceutically acceptable salts thereof |
| KR20080060284A (en) | 2006-09-18 | 2008-07-01 | 테바 파마슈티컬 인더스트리즈 리미티드 | Crystalline rosuvastatin calcium |
| HUE028475T2 (en) | 2006-10-09 | 2016-12-28 | Msn Laboratories Private Ltd | Novel process for the preparation of statins and their pharmaceutically acceptable salts thereof |
| EP2172471B1 (en) | 2007-04-18 | 2013-03-27 | Teva Pharmaceutical Industries, Ltd. | A process for preparing intermediates of HMG-CoA reductase inhibitors |
| WO2009009153A1 (en) | 2007-07-12 | 2009-01-15 | Teva Pharmaceutical Industries Ltd. | Purification of rosuvastatin intermediate by thin film evaporation and chemical method |
| SI2752407T1 (en) | 2009-01-14 | 2016-07-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Crystalline rosuvastatin calcium trihydrate |
| EP2387561A4 (en) | 2009-01-19 | 2012-07-25 | Msn Lab Ltd | Improved process for the preparation of highly pure (3r,5s)-7-ý2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl¨-3,5-dihydroxy-6(e)-heptenoic acid and pharmaceutically acceptable salts thereof |
| US8987444B2 (en) | 2010-01-18 | 2015-03-24 | Msn Laboratories Private Limited | Process for the preparation of amide intermediates and their use thereof |
| CN102219780B (en) * | 2010-04-14 | 2014-08-06 | 上海京新生物医药有限公司 | Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid |
| CN102153463A (en) * | 2011-03-03 | 2011-08-17 | 上海应用技术学院 | 4-subsititued 3,5-dihydroxy carboxylic acid compound and preparation method thereof |
| CN102816152B (en) * | 2011-06-09 | 2015-09-09 | 上海京新生物医药有限公司 | A kind of preparation method of Rosuvastatine intermediate |
| CN102617481A (en) * | 2012-03-16 | 2012-08-01 | 湖南欧亚生物有限公司 | Preparation method of rosuvastatin calcium |
| CN104788387A (en) * | 2015-04-17 | 2015-07-22 | 浙江海森药业有限公司 | Preparation method for high-purity rosuvastatin calcium |
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Application publication date: 20060823 Assignee: Jiangsu Yabang Shengyuan Medicine Co., Ltd. Assignor: Yabang Chemical Group Co. Ltd.|Changzhou kingyo Chemical Co. Ltd. Contract record no.: 2012320000932 Denomination of invention: Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor Granted publication date: 20120307 License type: Exclusive License Record date: 20120816 |
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