CN1742000A - 制备若舒伐他汀的方法 - Google Patents
制备若舒伐他汀的方法 Download PDFInfo
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- CN1742000A CN1742000A CNA028301951A CN02830195A CN1742000A CN 1742000 A CN1742000 A CN 1742000A CN A028301951 A CNA028301951 A CN A028301951A CN 02830195 A CN02830195 A CN 02830195A CN 1742000 A CN1742000 A CN 1742000A
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- 238000000034 method Methods 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 229960000672 rosuvastatin Drugs 0.000 title description 3
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 title description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 22
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 19
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000007859 condensation product Substances 0.000 claims description 15
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 11
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- -1 diethyl methoxyl group Chemical group 0.000 claims description 7
- 150000002596 lactones Chemical group 0.000 claims description 7
- 150000003839 salts Chemical group 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 229910000085 borane Inorganic materials 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 239000003791 organic solvent mixture Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 3
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- 230000032050 esterification Effects 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 claims 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 abstract description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 abstract description 4
- 229960004796 rosuvastatin calcium Drugs 0.000 abstract 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 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 5
- 238000005520 cutting process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 159000000007 calcium salts Chemical group 0.000 description 4
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 159000000000 sodium salts Chemical group 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 230000002040 relaxant effect Effects 0.000 description 2
- VPXDEUFAXJFWBG-MCBHFWOFSA-N (4r,6s)-6-[(e)-2-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C=1C=C(F)C=CC=1C=1C2=CC=CC=C2N(C(C)C)C=1\C=C\[C@@H]1C[C@@H](O)CC(=O)O1 VPXDEUFAXJFWBG-MCBHFWOFSA-N 0.000 description 1
- 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 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 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 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- SOKKGFZWZZLHEK-UHFFFAOYSA-N butoxy(dimethyl)silane Chemical group CCCCO[SiH](C)C SOKKGFZWZZLHEK-UHFFFAOYSA-N 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 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 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- NUKZAGXMHTUAFE-UHFFFAOYSA-N hexanoic acid methyl ester Natural products CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- VBQCHPIMZGQLAZ-UHFFFAOYSA-N phosphorane Chemical group [PH5] VBQCHPIMZGQLAZ-UHFFFAOYSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 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 1
- 239000000955 prescription drug Substances 0.000 description 1
- CCOXWRVWKFVFDG-UHFFFAOYSA-N pyrimidine-2-carbaldehyde Chemical compound O=CC1=NC=CC=N1 CCOXWRVWKFVFDG-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000012266 salt solution Substances 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 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 1
- 238000010626 work up procedure 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
- C07D239/42—One nitrogen atom
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及一种制备若舒伐他汀钙的方法,若舒伐他汀钙是一种具有潜在价值的新型HMG-CoA还原酶抑制剂。
Description
技术领域
本发明涉及制备若舒伐他汀(rosuvastatin)的方法,若舒伐他汀是一种具有潜在价值的新型HMG-CoA还原酶抑制剂。
背景技术
HMG-CoA还原酶抑制剂,通常称为他汀(statins),是最广泛使用的降脂处方药物。
化学合成的若舒伐他汀是具有结构式I的(+)-(3R,5S)7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰氨基)-嘧啶-5-基]3,5-二羟基-6(E)-庚烯酸钙盐(2∶1)。
式I
若舒伐他汀是用于治疗动脉粥样硬化的抗高胆固醇血症药物。
目前,高胆固醇血症已经被公认为冠心病的主要危险因素。对降脂制剂的临床研究已经确定,使升高的血清胆固醇水平降低,可以降低心血管的死亡率。最近发现,在临床前和临床试验中,若舒伐他汀钙与其它目前市售的他汀药物(阿伐他汀、斯伐他汀和普伐他汀)相比,总是表现出更强的药效。
若舒伐他汀及其制备方法揭示于美国专利5,260,440中。其中揭示的方法包括4个不同的化学步骤:(1)将(3R)-3[(叔丁基二甲基甲硅烷基)氧基]-5-氧代-6-三苯基正膦亚基己酸甲酯((3R)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-triphenylphosphoranyli-dene hexanoate)与4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰氨基)-5-嘧啶甲醛(4-(4-fluorophenyl)-6-i sopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinecarboxaldehyde)进行缩合;(2)对3-羟基基团进行去保护,从而产生酮醇;(3)对5-氧代基进行还原,从而产生手性的二羟基庚烯酸酯(或盐);和(4)对二羟基庚烯酸酯(或盐)进行水解。
正膦侧链的产生需要8个合成步骤并且涉及昂贵的制剂。该方法不仅不经济而且很费时间,因此不适用于商业化生产。
因此,希望提供有效地制备若舒伐他汀的方法,该方法采用较不昂贵的制剂来改善经济效益并且生产效率更高。
发明概述
本发明提供了若舒伐他汀、其盐类、酯类、或对应的环状内酯形式物质的制备方法以及新型中间产物。该方法明显有利于经济效益的提高并且可在商业化规模上方便地进行操作。
发明详述
本发明提供了制备如流程I中结构式I所示的若舒伐他汀或对应的闭环内酯形式物质的方法,它方法包括:
(a)将结构式II的1-氰基(2S)-2-[(叔丁基二甲基甲硅烷基)氧基]-4-氧代-5-三苯基正膦亚基戊烷与结构式III的4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰氨基)-5-嘧啶甲醛(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinecarbaldehyde)缩合,形成结构式IV的缩合产物,
(b)对缩合产物的叔丁基二甲基甲硅烷基去保护,得到结构式V的氰基酮醇,
(c)还原氰基酮醇,形成结构式VI的氰二醇(cyanodiol),和
(d)水解结构式VI的氰二醇,产生以游离酸形式、或其酯或内酯形式、或盐形式存在的结构式I化合物。
流程I
步骤(a)中的缩合反应在有机溶剂,尤其例如甲苯、苯、环己烷、庚烷、乙腈、四氢呋喃、二噁烷和乙酸乙酯等存在下进行。该反应持续约1至100小时。
步骤(b)中对叔丁基二甲基甲硅烷基团的去保护,是在有机溶剂中和酸或氟化四丁基铵存在下进行,从而形成式V的氰基酮醇。
有机溶剂选自诸如噻吩烷、二噁烷、二甲基噻吩烷、二甲基乙酰胺、N-甲基吡咯烷酮、乙腈、乙醚、四氢呋喃、二甲基甲酰胺之类的溶剂,和诸如甲醇、乙醇、丙醇之类的低级醇。
用于去保护的酸选自磺酸(如甲磺酸、三氟甲磺酸)、无机酸(如盐酸、硫酸、硝酸、磷酸)和有机酸(如甲酸、三氟乙酸、乙酸)。
用二乙基甲氧基硼烷和硼氢化钠还原步骤(b)中得到的式V氰基酮醇。该还原反应在含醇和非醇类溶剂的有机溶剂混合物中进行。反应完成后,反应物经处理(work up),得到式VI的氰二醇。
有机溶剂混合物包括醇,如甲醇、乙醇、丙醇和丁醇。非醇类有机溶剂包括诸如乙腈、乙醚、四氢呋喃和二甲基甲酰胺等溶剂。
步骤(c)的反应是在冷却下,在约-100℃至约20℃的温度下,例如在约-80℃至约-70℃的条件下,进行大约10分钟至20小时,例如约30分钟至约10小时。
在步骤(d)中,用酸对式VI的氰二醇进行水解,形成式VII的内酯。可以使用的酸包括无机酸,如盐酸、硫酸等。式VI的氰二醇可以直接转化成式VIII的钠盐形式。
步骤(d)中得到的内酯可转化成式VIII的钠盐形式,再用乙酸钙处理而转化成式I的若舒伐他汀的半钙盐形式。
在本发明的另一个方面,若舒伐他汀的制备方法包括:用醇(如甲醇、乙醇、丙醇等)和酸(如盐酸)处理结构式IV的缩合产物,从而得到式IX的酯。
式IX
该酯再经还原而形成式X的化合物,
式X
然后,再用流程I中步骤(c)和(d)所述的方法,对式X化合物进行水解,从而得到若舒伐他汀。
式III的起始材料可以用例如美国专利5,260,440中所述的方法进行制备。
可以将本领域已知的方法用于本发明的方法,以改善本发明方法的任何方面。得到的产物可以进一步用本领域技术人员已知的任何技术进行纯化,例如,结晶、柱层析、制备性高压液相色谱、制备性薄层层析、溶液中的萃取洗涤或这些步骤的组合。
在以下实施例中,仅以阐明本发明方法的方式给出本发明的优选实施例。然而,这些实施例不以任何方式限制本发明的范围。
实施例
制备若舒伐他汀(+)-(3R,5S)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰氨基)-嘧啶-5-基]-3,5-二羟基-6(E)-庚烯酸钙盐(2∶1)。
实施例1
步骤A
制备缩合产物N-[5-[-(叔丁基-二甲基-甲硅烷基氧基)-6-氰基-3-氧代-己-1-烯基]-4-(4-氟苯基)-6-异丙基-嘧啶-2-基]-N-甲基-甲磺酰胺(缩合产物,式IV)
将式II的1-氰基(2S)-2-[(叔丁基二甲基甲硅烷基)氧基]-5-氧代-6-三苯基正膦亚基己腈,加入式III的嘧啶醛(1.0克)的甲苯(20ml)溶液中,然后反应混合物回流约24小时。浓缩反应混合物,并将残留物与环己烷(50ml)一起捣碎(titurate)。浓缩环己烷层得到残留物,该残留物用硅胶层析进行纯化,并用甲苯洗脱,得到1.60克厚油状的浓缩产物。
步骤B
制备氰基酮醇N-[5-(6-氰基-5-羟基-3-氧代-己-1-烯基)-4-(4-氟苯基)-6-异丙基-嘧啶-2-基]-N-甲基-甲磺酰胺(氰基酮醇,式V)
在10-15℃下,将0.8ml甲磺酸水溶液(4.6%w/w)滴加到浓缩产物(1.0克)的甲醇(10ml)溶液中。在室温下搅拌反应混合物24小时,浓缩并将残留物溶解在二氯甲烷(10ml)中。用1%的碳酸氢钠洗涤,然后用盐水洗涤。浓缩有机层,得到的残留物。该残留物用硅胶柱层析进行纯化,用甲苯洗脱,得到0.65克的氰基酮醇,为固体。
步骤C
制备氰二醇N-[5-(6-氰基-3,5-二羟基-己-1-烯基)-4-(4-氟苯基)-6-异丙基-嘧啶-2-基]-N-甲基-甲磺酰胺(氰二醇,式VI)
向氰基酮醇(1.0g)的四氢呋喃(THF,25ml)溶液中,加入甲醇(7ml),并将溶液冷却至-78℃。在-76℃至-78℃,在反应混合物中加入二乙基甲氧基硼烷(2.3ml)的THF溶液(1M)。搅拌反应混合物30分钟,并加入硼氢化钠(0.10克)。在相同的温度下进一步搅拌该反应混合物3小时,并且让温度在45分钟内升高至25℃。加入乙酸(1.4ml)并且搅拌10分钟。在真空下蒸发溶剂,然后再加入甲醇(10ml),加入的甲醇也同样被蒸发。加入乙酸乙酯(10ml),并用碳酸氢钠的水溶液(3ml)洗涤该溶液。用盐水(5ml)洗涤有机层,然后再用硫酸钠进行干燥。减压浓缩溶液,形成油状的氰二醇(0.8克)。
步骤D
制备若舒伐他汀
将浓盐酸(2.5ml)加入氰二醇(0.5克)中,并在室温下搅拌该反应混合物12小时。得到的溶液用水(2.5ml)进行稀释,冷却至5℃,再用1%碳酸氢钠水溶液中和。用乙酸乙酯(10ml)萃取得到的混合物。浓缩乙酸乙酯层,并将得到的残留物溶解于甲苯(10ml)中。回流甲苯溶液2小时,并使溶剂蒸发而形成若舒伐他汀内酯。在残留物中加入乙醇(7ml),并且搅拌60分钟,接着加入0.1N NaOH水溶液(11ml)。在真空条件下,将乙醇蒸发掉,然后滴加乙酸钙溶液。搅拌2小时后,产物经过过滤、洗涤并干燥,得到若舒伐他汀的半钙盐(0.26g)。
实施例2
用式IX的甲酯制备若舒伐他汀
在-40℃至-20℃的条件下,将HCl气体通入式IV浓缩产物(1.0克)的甲醇(10ml)悬浮液中,持续2.5小时。得到的溶液在0℃下搅拌15小时,然后去除溶剂。将残留物保留于乙酸乙酯中,并用水(10ml)进行洗涤。用碳酸氢钠水溶液将有机层的pH调至4.5。分离乙酸乙酯层,用水洗涤,再用盐水洗涤。浓缩有机层,得到的残留物。该残留物用硅胶柱层析进行纯化,得到0.8克式IX的甲酯。
用实施例1中步骤(c)所述的方法还原上述所得的甲酯。接着按照实施例1中步骤(d)所述的方法,水解成酸,形成钠盐,并且进一步转化为钙盐,从而形成若舒伐他汀的半钙盐(0.5g)。
尽管本发明用特定的实施例进行了阐述,然而一些改动及等价形式对于本领域的技术人员是显而易见的,并且也包括在本发明的范围内。
Claims (33)
2、如权利要求1所述的方法,其特征在于,所述的步骤(a)在有机溶剂中进行。
3、如权利要求2所述的方法,其特征在于,所述的有机溶剂选自:甲苯、苯、环己烷、庚烷或其混合物。
4、如权利要求3所述的方法,其特征在于,所述的有机溶剂是甲苯。
5、如权利要求1所述的方法,其特征在于,所述的步骤(b)在有机溶剂中进行。
6、如权利要求5所述的方法,其特征在于,所述的有机溶剂选自:噻吩烷、二噁烷、二甲基噻吩烷、二甲基乙酰胺、N-甲基吡咯烷酮、乙腈、乙醚、四氢呋喃、二甲基甲酰胺、甲醇、乙醇、丙醇,及其混合物。
7、如权利要求6所述的方法,其特征在于,所述的有机溶剂为甲醇。
8、如权利要求1所述的方法,其特征在于,所述的步骤(b)中通过用酸或氟化四丁基铵处理进行去保护。
9、如权利要求8所述的方法,其特征在于,所述的酸是磺酸、无机酸或有机酸。
10、如权利要求9所述的方法,其特征在于,所述的酸选自下组:甲磺酸、三氟甲磺酸、盐酸、硫酸、硝酸、磷酸、甲酸、三氟乙酸和乙酸。
11、如权利要求10所述的方法,其特征在于,所述的酸是甲磺酸。
12、如权利要求1所述的方法,其特征在于,所述的步骤(c)中的还原反应在二乙基甲氧基硼烷和硼氢化钠存在下进行。
13、如权利要求12所述的方法,其特征在于,所述的还原反应在含醇和非醇类溶剂的有机溶剂混合物中进行。
14、如权利要求13所述的方法,其特征在于,所述的醇选自:甲醇、乙醇、丙醇和丁醇。
15、如权利要求13所述的方法,其特征在于,所述的醇是甲醇。
16、如权利要求13所述的方法,其特征在于,所述的非醇类有机溶剂选自:乙腈、乙醚、四氢呋喃和二甲基甲酰胺。
17、如权利要求16所述的方法,其特征在于,所述的非醇类溶剂是四氢呋喃。
18、如权利要求1所述的方法,其特征在于,所述步骤(d)中的水解反应是在步骤(c)的反应完成后再进行的。
26、如权利要求25所述的方法,其特征在于,所述的步骤(a)在有机溶剂中进行。
27、如权利要求26所述的方法,其特征在于,所述的有机溶剂选自:甲苯、苯、环己烷、庚烷或其混合物。
28、如权利要求27所述的方法,其特征在于,所述的有机溶剂是甲苯。
29、如权利要求25所述的方法,其特征在于,所述的步骤(b)是在盐酸存在下用甲醇进行处理。
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EP2336116A1 (en) | 2009-12-16 | 2011-06-22 | LEK Pharmaceuticals d.d. | Process for the preparation of key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof |
WO2012011129A2 (en) * | 2010-07-22 | 2012-01-26 | Msn Laboratories Limited | Novel polymorph of bis[(e)-7-[4-(4-fluorophenyl)-6-iso-propyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid] calcium salt |
HU230987B1 (hu) | 2010-11-29 | 2019-08-28 | Egis Gyógyszergyár Nyrt. | Eljárás nagy tisztaságú gyógyszeripari intermedierek előállítására |
CN107252420A (zh) * | 2011-05-20 | 2017-10-17 | 阿斯利康(英国)有限公司 | 罗苏伐他汀钙的药物组合物 |
US9850213B2 (en) * | 2013-11-25 | 2017-12-26 | Jiangxi Boya Seehot Pharmaceutical Co., Ltd. | Method for preparing rosuvastatin sodium |
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JP2648897B2 (ja) | 1991-07-01 | 1997-09-03 | 塩野義製薬株式会社 | ピリミジン誘導体 |
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- 2002-12-10 CN CNA028301951A patent/CN1742000A/zh active Pending
- 2002-12-10 DE DE60239428T patent/DE60239428D1/de not_active Expired - Lifetime
- 2002-12-10 AT AT02781613T patent/ATE501126T1/de active
- 2002-12-10 WO PCT/IB2002/005213 patent/WO2004052867A1/en not_active Application Discontinuation
- 2002-12-10 US US10/537,859 patent/US7566782B2/en not_active Expired - Fee Related
- 2002-12-10 CA CA002509619A patent/CA2509619A1/en not_active Abandoned
- 2002-12-10 HU HU0500851A patent/HUP0500851A3/hu unknown
- 2002-12-10 SI SI200230942T patent/SI1578733T1/sl unknown
- 2002-12-10 AU AU2002348881A patent/AU2002348881A1/en not_active Abandoned
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Cited By (9)
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CN105153010A (zh) * | 2010-07-01 | 2015-12-16 | 柳韩洋行 | HMG-CoA还原酶抑制剂及其中间体的制备方法 |
CN105153010B (zh) * | 2010-07-01 | 2018-06-08 | 柳韩洋行 | HMG-CoA还原酶抑制剂及其中间体的制备方法 |
CN102358747A (zh) * | 2011-08-30 | 2012-02-22 | 浙江宏元药业有限公司 | 瑞舒伐他汀钙中间体及制备瑞舒伐他汀钙中间体和瑞舒伐他汀钙的方法 |
CN102358747B (zh) * | 2011-08-30 | 2012-09-19 | 浙江宏元药业有限公司 | 瑞舒伐他汀钙中间体及制备瑞舒伐他汀钙中间体和瑞舒伐他汀钙的方法 |
CN103601687A (zh) * | 2013-11-25 | 2014-02-26 | 复旦大学 | 一种瑞舒伐他汀钠的制备方法 |
CN104230990A (zh) * | 2014-08-15 | 2014-12-24 | 新发药业有限公司 | 2-((4r,6s)-6-三苯基膦烯甲叉基-2,2-二取代基-1,3-二氧六环-4-基)乙酸酯及其制备方法与应用 |
CN104230990B (zh) * | 2014-08-15 | 2016-05-11 | 新发药业有限公司 | 2-((4r,6s)-6-三苯基膦烯甲叉基-2,2-二取代基-1,3-二氧六环-4-基)乙酸酯及其制备方法与应用 |
CN104630297A (zh) * | 2014-12-10 | 2015-05-20 | 江南大学 | 一种酶法非水相催化合成(r)-3-tbdmso戊二酸甲单酯及其衍生物 |
CN104630297B (zh) * | 2014-12-10 | 2018-07-06 | 江南大学 | 一种酶法非水相催化合成(r)-3-tbdmso戊二酸甲单酯及其衍生物 |
Also Published As
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HUP0500851A2 (en) | 2007-08-28 |
US20060149065A1 (en) | 2006-07-06 |
DK1578733T3 (da) | 2011-06-14 |
WO2004052867A1 (en) | 2004-06-24 |
US7566782B2 (en) | 2009-07-28 |
EP1578733A1 (en) | 2005-09-28 |
AU2002348881A1 (en) | 2004-06-30 |
DE60239428D1 (zh) | 2011-04-21 |
SI1578733T1 (sl) | 2011-07-29 |
EP1578733B1 (en) | 2011-03-09 |
ATE501126T1 (de) | 2011-03-15 |
CA2509619A1 (en) | 2004-06-24 |
HUP0500851A3 (en) | 2008-02-28 |
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