WO2014086072A1 - Forme cristalline d'un ester de rosuvastatine et son procédé de préparation - Google Patents
Forme cristalline d'un ester de rosuvastatine et son procédé de préparation Download PDFInfo
- Publication number
- WO2014086072A1 WO2014086072A1 PCT/CN2012/087703 CN2012087703W WO2014086072A1 WO 2014086072 A1 WO2014086072 A1 WO 2014086072A1 CN 2012087703 W CN2012087703 W CN 2012087703W WO 2014086072 A1 WO2014086072 A1 WO 2014086072A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- isopropyl
- fluorophenyl
- amino
- dihydroxyhept
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 88
- -1 rosuvastatin ester Chemical class 0.000 title claims description 41
- 229960000672 rosuvastatin Drugs 0.000 title claims description 28
- 238000000034 method Methods 0.000 title abstract description 56
- 239000002904 solvent Substances 0.000 claims abstract description 39
- 238000002425 crystallisation Methods 0.000 claims abstract description 29
- 230000008025 crystallization Effects 0.000 claims abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 155
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 147
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 128
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 99
- 239000000203 mixture Substances 0.000 claims description 83
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 67
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 65
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 32
- 239000003208 petroleum Substances 0.000 claims description 23
- 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 claims description 23
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 17
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 17
- 150000002576 ketones Chemical class 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- MMTXSCWTVRMIIY-UHFFFAOYSA-N 3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)CC(O)CC(O)C=C MMTXSCWTVRMIIY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N p-dimethylbenzene Natural products CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 2
- ZYOZFSCMERENNR-HTQZYQBOSA-N ethyl (3r,5s)-3,5-dihydroxyhept-6-enoate Chemical compound CCOC(=O)C[C@H](O)C[C@H](O)C=C ZYOZFSCMERENNR-HTQZYQBOSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 3
- UHNHTTIUNATJKL-UHFFFAOYSA-N n-methylmethanesulfonamide Chemical compound CNS(C)(=O)=O UHNHTTIUNATJKL-UHFFFAOYSA-N 0.000 abstract 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 34
- MSHKEMUMXTZIIT-MCBHFWOFSA-N ethyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CCOC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 MSHKEMUMXTZIIT-MCBHFWOFSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- IJHZGLLGELSZAF-OKLSWEBGSA-N tert-butyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate 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)OC(C)(C)C IJHZGLLGELSZAF-OKLSWEBGSA-N 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 13
- MMTXSCWTVRMIIY-PHDIDXHHSA-N (3r,5s)-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)C=C MMTXSCWTVRMIIY-PHDIDXHHSA-N 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- VDXAJPMEBTVBFW-UHFFFAOYSA-N 5,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)CCCC(O)(O)C=C VDXAJPMEBTVBFW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 125000004494 ethyl ester group Chemical group 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ODEACPYYVHAIHJ-UHFFFAOYSA-N COC(C(CCCC=C)(O)O)=O Chemical compound COC(C(CCCC=C)(O)O)=O ODEACPYYVHAIHJ-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- SOEGVMSNJOCVHT-VEUZHWNKSA-N Rosuvastatin lactone Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC(N(C)S(C)(=O)=O)=NC=1C1=CC=C(F)C=C1 SOEGVMSNJOCVHT-VEUZHWNKSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001342 alkaline earth metals Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- JUROBSIQARVDNX-UHFFFAOYSA-N ethyl 2,2-dihydroxyhept-6-enoate Chemical compound CCOC(=O)C(O)(O)CCCC=C JUROBSIQARVDNX-UHFFFAOYSA-N 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- SUTPUCLJAVPJRS-NDZBKKTDSA-N methyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 SUTPUCLJAVPJRS-NDZBKKTDSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-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
- 229910052799 carbon Inorganic materials 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
- 238000010828 elution Methods 0.000 description 2
- ZYOZFSCMERENNR-UHFFFAOYSA-N ethyl 3,5-dihydroxyhept-6-enoate Chemical compound CCOC(=O)CC(O)CC(O)C=C ZYOZFSCMERENNR-UHFFFAOYSA-N 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 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 2
- 229960004796 rosuvastatin calcium Drugs 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- ILCHMHPRFFCEHP-UHFFFAOYSA-N 2,4,6,8-tetramethylnonan-5-one Chemical compound CC(C)CC(C)C(=O)C(C)CC(C)C ILCHMHPRFFCEHP-UHFFFAOYSA-N 0.000 description 1
- UUWFCRDPOPYJDH-UHFFFAOYSA-N 2-hydroxyhept-6-enoic acid Chemical compound OC(=O)C(O)CCCC=C UUWFCRDPOPYJDH-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- AOWPVIWVMWUSBD-RNFRBKRXSA-N [(3r)-3-hydroxybutyl] (3r)-3-hydroxybutanoate Chemical compound C[C@@H](O)CCOC(=O)C[C@@H](C)O AOWPVIWVMWUSBD-RNFRBKRXSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- VKXIFZRVLHRJDT-DDVDASKDSA-N butyl (e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CCCCOC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 VKXIFZRVLHRJDT-DDVDASKDSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- JFOXBMYJIWOVOU-UHFFFAOYSA-N ethyl 2-hydroxyhept-6-enoate Chemical compound CCOC(=O)C(O)CCCC=C JFOXBMYJIWOVOU-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- FVPOOSCUAVMUII-LLSOJIOMSA-N n-[5-[(e,3s,5r)-3,5-dihydroxyhept-1-enyl]-4-(4-fluorophenyl)-6-propan-2-ylpyrimidin-2-yl]-n-methylmethanesulfonamide Chemical compound CC[C@@H](O)C[C@H](O)\C=C\C1=C(C(C)C)N=C(N(C)S(C)(=O)=O)N=C1C1=CC=C(F)C=C1 FVPOOSCUAVMUII-LLSOJIOMSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- IJHZGLLGELSZAF-WOJBJXKFSA-N tert-butyl (3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1C=C[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C IJHZGLLGELSZAF-WOJBJXKFSA-N 0.000 description 1
- KFXCYIXTBOEXFF-UHFFFAOYSA-N tert-butyl 2,2-dihydroxyhept-6-enoate Chemical compound C(C)(C)(C)OC(C(CCCC=C)(O)O)=O KFXCYIXTBOEXFF-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
-
- 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
-
- 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
-
- 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
Definitions
- the invention relates to the field of compound preparation, in particular to a novel crystal form of rosuvastatin ester and a preparation method thereof. Background technique
- Rosuvastatin calcium bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 N-methylmethanesulfonylaminopyrimidine)-5-yl] (3R, 5S)-Dihydroxy-(E)-6-heptanoic acid] calcium salt, which has the structure shown in Formula I, is an HMG-CoA reductase inhibitor developed by Shionogi for treatment (especially High cholesterol, hyperlipoproteinemia, and atherosclerosis. Rosuvastatin calcium is a super statin that is more effective than first-generation drugs in lowering LDL-cholesterol and triglycerides.
- Rosuvastatin and the intermediate rosuvastatin esters exist as enantiomers and diastereomers with molecules having two chiral centers at positions 3 and 5.
- the structure of 5-dihydroxyhept-6-enoate is as shown in formula II
- the structure of acyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate is as shown in formula III
- WO 2005/040134 reports reducing rosuvastatin by lactonization or by converting amorphous rosuvastatin and an intermediate into a crystalline rosuvastatin intermediate and subsequent conversion to an amorphous form. The diastereomeric content of the intermediate.
- the present invention provides rosuvastatin ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine- A new crystalline form of 5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate and a process for its preparation.
- the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2 - [A] having an enantiomeric impurity of less than 0.50% and a diastereomeric impurity of less than 0.30%.
- the present invention provides the following technical solutions:
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid ethyl ester having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367 , 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.
- the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.87
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.3, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
- the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S ) -3,5-dihydroxy-hept-6-enoic acid ethyl ester for preparing a crystalline form of rosuvastatin or a pharmaceutically acceptable salt thereof; (E) above - 7 - [4- (4-fluorophenyl) -6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5-dihydroxyhept-6-
- the crystalline X-ray powder diffraction pattern of ethyl enoate has a peak at 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367, 17.8864, 18.
- the present invention also provides the above ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt, according to US Publication No. 2005/080134 get on. This conversion can be carried out by alkaline hydrolysis of the ethyl ester.
- Alkaline hydrolysis of -dihydroxyhept-6-enoic acid ethyl ester can be carried out by one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca(OH) 2 in an organic solvent such as: tetrahydrofuran, ACN (acetonitrile), (1-4C) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.), (3-8C) ketone or (3-8C) ester (acetone, methyl ethyl) Ketone, methyl isopropyl ketone, ethyl acetate).
- the hydrolysis may also be carried out by water or a mixture of the above solvents or
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 1 position, said 2 ⁇ being 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532 .
- the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 0.3 positions, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystalline form of tert-butyl-3,5-dihydroxyhept-6-enoate for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof; (E 7-[4-(4-fluorophenyl)- X-ray powder diffraction pattern of 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S 3,5-dihydroxyhept-6-enoic acid tert-butyl ester There is a peak at 2 ⁇ 1, which is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S
- the crystalline form of tert-butyl-3,5-dihydroxyhept-6-enoate is used to prepare rosuvastatin or a pharmaceutically acceptable salt thereof.
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for crystallizing a crystal form of 5S)-3,5-dihydroxyhept-6-enoate, comprising the steps of:
- Step 1 Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: K3R,5S)- Crude 3,5-dihydroxyhept-6-enoate;
- Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoate crude product is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
- the solvent is d_ 4 alcohols, C 3 _ 8 esters, C 3 _ 8 ketones, C 3 _ 8 ethers, C 6 _ () 1 mixture of the above aromatic hydrocarbons, water, one or both of acetonitrile.
- the solvent in step 2 is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, a mixture of ethanol and water, MEK, 4-methyl-2. a mixture of pentanone and toluene, a mixture of one or more of ethyl acetate and petroleum ether.
- the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentanone, toluene, a mixture of acetone and water, and one or more of a mixture of acetonitrile and water. mixture.
- the crystallization in the step 2 is specifically taking the first solution, heating to 50 ° C or higher, and cooling.
- the cooling temperature is -20 to 40 °C.
- the structure of R3R, 5S)-3,5-dihydroxyhept-6-enoate is as shown in Formula III.
- R is ethyl, propyl, n-butyl or t-butyl.
- (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)- 3,5-Dihydroxyhept-6-enoate is (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine -5-yl: R3R, 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester or (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [Methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester.
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for crystallizing a crystal form of -3,5-dihydroxyhept-6-enoic acid, comprising the steps of:
- Step 1 Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester;
- Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
- the solvent is d_ 4 alcohols, C 3 _ 8 esters, C 3 _ 8 ketones, C 3 _ 8 ethers, C 6 _ () 1 mixture of the above aromatic hydrocarbons, water, one or both of acetonitrile.
- the solvent in step 2 is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, a mixture of ethanol and water, MEK, 4-methyl-2. a mixture of pentanone and toluene, a mixture of one or more of ethyl acetate and petroleum ether.
- CM alcohol C ⁇ ester
- CM ketone CM ether
- CWQ aromatic hydrocarbon ethylene glycol diethyl ether
- water acetonitrile
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-
- the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentanone , toluene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the solvent in step 2 is a mixture of methyl isobutyl ketone and petroleum ether, 4 -methyl-2-pentanone or toluene.
- (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] is in g/mL Pyrimidine-5-yl](3R,5S 3,5-dihydroxyhept-6-enoic acid ethyl ester mixed with methyl isobutyl ketone and petroleum ether
- the mass ratio of the compound, 4-methyl-2-pentanone or toluene is 1:3; wherein the volume ratio of methyl isobutyl ketone to petroleum ether is 1:1.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the solvent is selected from the mixture of acetonitrile and methyl tert-butyl ether, MEK, acetic acid a mixture of ethyl ester and petroleum ether, methanol, a mixture of acetone and water, a mixture of methanol and water, a mixture of ethanol and water, a mixture of acetonitrile and water, a mixture of tetrahydrofuran and petroleum ether.
- volume ratio of acetonitrile to methyl tert-butyl ether is 2:6; the volume ratio of ethyl acetate to petroleum ether is 1:1; the volume ratio of methanol to water is less than 6:1, in some embodiments of the present invention
- the volume ratio of methanol to water is 5:2.
- the volume ratio of methanol to water is 2:1; and the volume ratio of tetrahydrofuran to petroleum ether is 1:1.
- (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] is in g/mL
- the mass to volume ratio of crude pyrimidine-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester to ethylene glycol dimethyl ether is 1:1.5.
- the invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the solvent is MTBE.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the crystallization in step 2 is specifically taking the first solution and heating to 50 ° C or higher. , cool down.
- (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R) is provided by the present invention.
- the cooling temperature is -20 to 40 °C.
- the cooling temperature is -10 to 30 °C.
- the cooling temperature is -5 to 10 °C.
- the filtration in step 2 is vacuum filtration.
- step 2 the drying is carried out under reduced pressure or at elevated temperature.
- the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid ethyl ester having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367 , 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.
- the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.87
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.3, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
- the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
- the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S ) -3,5-dihydroxy-hept-6-enoic acid ethyl ester for preparing a crystalline form of rosuvastatin or a pharmaceutically acceptable salt thereof; (E) above - 7 - [4- (4-fluorophenyl) X-ray powder of -6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester
- the diffraction pattern has a peak at 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367, 17.8864, 18.
- the present invention also provides the above (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt, according to US Publication No. 2005/080134 get on. This conversion can be carried out by alkaline hydrolysis of the ethyl ester.
- Alkaline hydrolysis of -dihydroxyhept-6-enoic acid ethyl ester can be carried out by one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca(OH) 2 in an organic solvent such as: tetrahydrofuran, ACN (acetonitrile), (1-4C) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.), (3-8C) ketone or (3-8C) ester (acetone, methylethyl) Ketone, methyl isopropyl ketone, ethyl acetate).
- the hydrolysis may also be carried out by water or a mixture of the above solvents or
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S a method for crystallizing a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester, comprising the steps of:
- Step 1 Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)- 3,5-dihydroxyhept-6-enoic acid tert-butyl ester;
- Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid crude tert-butyl ester is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
- the solvent is d_ 4 alcohols, C 3 _ 8 esters, C 3 _ 8 ketones, C 3 _ 8 ethers, C 6 _ () 1 mixture of the above aromatic hydrocarbons, water, one or both of acetonitrile.
- the solvent in step 2 is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, a mixture of ethanol and water, MEK, 4-methyl-2. a mixture of pentanone and toluene, a mixture of one or more of ethyl acetate and petroleum ether.
- CM alcohol C ⁇ ester
- CM ketone CM ether
- CWQ aromatic hydrocarbon ethylene glycol diethyl ether
- water acetonitrile
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-
- the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentyl Ketone, toluene, a mixture of acetone and water, in a mixture of acetonitrile and water One or a mixture of two or more.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the solvent in step 2 is 4-methyl-2-pentanone and / Or MTBE.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the second solvent is 4-methyl-2-pentanone and/or MTBE.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the second solvent is methanol, in g/mL
- the mass-to-volume ratio of crude -6-tert-butyl tert-butylate to methanol is 1:1 to 10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the second solvent is a mixture of methanol and water, wherein methanol and water The volume ratio is less than 6:1.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the second solvent is a mixture of acetonitrile and MTBE, wherein acetonitrile and MTBE are The volume ratio is less than 1:10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the second solvent is a mixture of methanol and MTBE, wherein methanol and MTBE are The volume ratio is less than 1:10.
- the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
- the separation in step 2 is filtration.
- the filtration in step 2 is vacuum filtration.
- step 2 the drying is dried under reduced pressure or dried at elevated temperature.
- the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.
- the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 1 position, said 2 ⁇ being 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532 .
- the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
- the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine -5-yl: R3R, 5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystal form, the X-ray powder diffraction pattern has a peak at 2 ⁇ ⁇ 0.8 position, the 2 ⁇ is 17.0352, 18.0864 19.3245, 19.7326, 20.5246 and 21.8532.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 0.3 positions, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystalline form of tert-butyl-3,5-dihydroxyhept-6-enoate for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof; (E 7-[4-(4-fluorophenyl)- X-ray powder diffraction pattern of 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S 3,5-dihydroxyhept-6-enoic acid tert-butyl ester There is a peak at 2 ⁇ 1, which is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
- the present invention also provides the above ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt, according to US Publication No. 2005/ 080134. This conversion can be carried out by alkaline hydrolysis of the ethyl ester.
- Alkaline hydrolysis of -dihydroxyhept-6-enoic acid tert-butyl ester can be carried out by one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca(OH) 2 in an organic solvent such as: tetrahydrofuran, ACN (acetonitrile), (1-4C) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.), (3-8C) ketone or (3-8C) ester (acetone, methyl b) Ketone, methyl isopropyl ketone, ethyl acetate).
- the hydrolysis may also be carried out by water or a mixture of the above solvents or
- the present invention provides rosuvastatin ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]B-pyridine-5- (3R,5S)-3,5-dihydroxyhept-6-enoate and a process for the preparation thereof.
- the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30% by solvent.
- Figure 1 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl prepared in Example 1.
- Figure 2 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl prepared in Example 18.
- the invention discloses rosuvastatin ester and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
- the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
- the reagents used in the rosuvastatin ester provided by the present invention and the preparation method thereof are commercially available.
- the present invention passes a sample in crystalline form on a Siemans single silicon crystal (SSC) wafer back mount and passes the sample invention through a Siemans single silicon crystal (SSC) wafer patch by means of a microscopic slide.
- the sample in crystalline form was placed on the waiter mounts and the sample was coated as a thin layer by means of a microscopic slide to determine the X-ray powder diffraction spectrum.
- the instrument used was a Philips Xper't X-ray diffractometer illuminated with X-rays generated by an elongated focusing copper tube operating at a wavelength of 1.5406 angstroms at 40 kV and 40 mA.
- the sample received 4 seconds of radiation (continuous scan mode) for every 0.02 degrees 2 turns in the ⁇ - ⁇ mode over a range of 2 to 40 degrees 2 ⁇ .
- the running time is 2 hours, 6 minutes and 40 seconds.
- the instrument is equipped with a Philips super detector. Processing data with Highscore software using Philips software
- the invention is not limited, and a suitable temperature range is within the scope of the invention.
- Sample preparation Take a proper amount of the sample and add a mobile phase to make a 0.2 mg/ml solution. Inject 20 ⁇ . 10 g of (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5- Dihydroxyhept-6-enoic acid ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 20 ml of toluene, then cooled to room temperature (30 ° C) and placed in the refrigerator.
- Example 7 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from ethyl acetate: petroleum ether (1:1)
- Example 8 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from 4-methyl-2-pentanone
- Example 12 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from acetonitrile: methyl tert-butyl ether (2:6)
- Example 13 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from a mixture of acetonitrile and water
- Example 14 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from tetrahydrofuran: petroleum ether (volume ratio: 1:1)
- Example 15 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester crystallized from a mixture of acetone and water
- Example 16 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from methyl isobutyl ketone: petroleum ether (volume ratio: 1:1)
- Example 17 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester crystallized from a mixture of methanol and water (2:1 by volume)
- Example 18 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of methanol and water
- Example 19 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of ethanol and water
- Example 20 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of ethanol and water (volume ratio of 2:1)
- Example 21 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of ethanol and water (volume ratio less than 6:1)
- Example 22 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of acetonitrile and methyl tert-butyl ether (2:8 by volume)
- Example 26 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from ethyl acetate: petroleum ether (1:2)
- Example 28 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from methanol
- Example 30 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of methanol and water (volume ratio of 2:1)
- Example 31 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of methanol and water (volume ratio less than 6:1)
- Example 32 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of acetone and water lOg (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5- Dihydroxyhept-6-enoic acid tert-butyl ester (0.52% diastereomer 0.3% enantiomer) was heated to room temperature (15 ° C) with 20 ml of a mixture of acetone and water.
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Abstract
La présente invention appartient au domaine de la préparation des composés. La présente invention concerne une forme cristalline d'un ester de l'acide (E)-7-(4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amine]pyrimidine-5-groupe)(3R,5S)-3,5-dihydroxy-6-hepténoïque et son procédé de préparation. Ledit procédé permet de mettre en œuvre une cristallisation dans un solvant afin d'obtenir une forme cristalline d'un ester de l'acide (E)-7-(4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amine]pyrimidine-5-groupe)(3R,5S)-3,5-dihydroxy-6-hepténoïque dans lequel les puretés énantiomériques sont inférieures à 0,50 % et les puretés diastéréotopes sont inférieures à 0,30 %.
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