WO2009047577A1 - Process for preparation of rosuvastatin zinc salt - Google Patents
Process for preparation of rosuvastatin zinc salt Download PDFInfo
- Publication number
- WO2009047577A1 WO2009047577A1 PCT/HU2008/000122 HU2008000122W WO2009047577A1 WO 2009047577 A1 WO2009047577 A1 WO 2009047577A1 HU 2008000122 W HU2008000122 W HU 2008000122W WO 2009047577 A1 WO2009047577 A1 WO 2009047577A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- zinc
- carbon atoms
- formula
- compound
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- KUQHZGJLQWUFPU-BGRFNVSISA-L zinc;(e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical class [Zn+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 KUQHZGJLQWUFPU-BGRFNVSISA-L 0.000 title claims description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 125000004432 carbon atom Chemical group C* 0.000 claims description 106
- 229910052739 hydrogen Inorganic materials 0.000 claims description 89
- 239000001257 hydrogen Substances 0.000 claims description 89
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 86
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 86
- 239000000243 solution Substances 0.000 claims description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 77
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- 239000000047 product Substances 0.000 claims description 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 53
- -1 aliphatic alcohols Chemical class 0.000 claims description 45
- 239000003960 organic solvent Substances 0.000 claims description 40
- 239000011541 reaction mixture Substances 0.000 claims description 40
- 229910052725 zinc Inorganic materials 0.000 claims description 39
- 239000011701 zinc Substances 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 35
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- 125000003342 alkenyl group Chemical group 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical class 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 29
- 150000003751 zinc Chemical class 0.000 claims description 27
- 150000001768 cations Chemical group 0.000 claims description 26
- 229960000672 rosuvastatin Drugs 0.000 claims description 24
- 150000007524 organic acids Chemical class 0.000 claims description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 23
- 150000007522 mineralic acids Chemical class 0.000 claims description 22
- 125000005704 oxymethylene group Chemical group [H]C([H])([*:2])O[*:1] 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 22
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000002585 base Substances 0.000 claims description 17
- 229910001415 sodium ion Inorganic materials 0.000 claims description 17
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 16
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 16
- 239000011734 sodium Substances 0.000 claims description 16
- 229910052708 sodium Inorganic materials 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- NHXVNEDMKGDNPR-UHFFFAOYSA-N zinc;pentane-2,4-dione Chemical compound [Zn+2].CC(=O)[CH-]C(C)=O.CC(=O)[CH-]C(C)=O NHXVNEDMKGDNPR-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- HVTHJRMZXBWFNE-UHFFFAOYSA-J sodium zincate Chemical compound [OH-].[OH-].[OH-].[OH-].[Na+].[Na+].[Zn+2] HVTHJRMZXBWFNE-UHFFFAOYSA-J 0.000 claims description 14
- 229960001763 zinc sulfate Drugs 0.000 claims description 14
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 14
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 12
- 235000010755 mineral Nutrition 0.000 claims description 12
- 239000011707 mineral Substances 0.000 claims description 12
- 150000003752 zinc compounds Chemical class 0.000 claims description 12
- RCQZCHPRZSTYAX-UHFFFAOYSA-N zinc tetrahydrate Chemical compound O.O.O.O.[Zn] RCQZCHPRZSTYAX-UHFFFAOYSA-N 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 239000011592 zinc chloride Substances 0.000 claims description 11
- 235000005074 zinc chloride Nutrition 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 230000001131 transforming effect Effects 0.000 claims description 10
- RGEBGDYYHAFODH-DHMAKVBVSA-M sodium;(e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical class [Na+].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 RGEBGDYYHAFODH-DHMAKVBVSA-M 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 6
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- 239000004246 zinc acetate Substances 0.000 claims description 5
- 239000003125 aqueous solvent Substances 0.000 claims description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 230000009466 transformation Effects 0.000 claims description 3
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- 239000011667 zinc carbonate Substances 0.000 claims description 2
- 235000004416 zinc carbonate Nutrition 0.000 claims description 2
- 229910000010 zinc carbonate Inorganic materials 0.000 claims description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 2
- PKMTWMDBJHRDBM-ODZAUARKSA-N (z)-but-2-enedioic acid;zinc Chemical compound [Zn].OC(=O)\C=C/C(O)=O PKMTWMDBJHRDBM-ODZAUARKSA-N 0.000 claims 1
- CLWNPUARORRDFD-UHFFFAOYSA-N 2-hydroxybutanedioic acid;zinc Chemical compound [Zn].OC(=O)C(O)CC(O)=O CLWNPUARORRDFD-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- CANRESZKMUPMAE-UHFFFAOYSA-L Zinc lactate Chemical compound [Zn+2].CC(O)C([O-])=O.CC(O)C([O-])=O CANRESZKMUPMAE-UHFFFAOYSA-L 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- TVOIPJPTFTYKQM-UHFFFAOYSA-N propanedioic acid;zinc Chemical compound [Zn].OC(=O)CC(O)=O TVOIPJPTFTYKQM-UHFFFAOYSA-N 0.000 claims 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 239000011746 zinc citrate Substances 0.000 claims 1
- 235000006076 zinc citrate Nutrition 0.000 claims 1
- 229940068475 zinc citrate Drugs 0.000 claims 1
- 239000011576 zinc lactate Substances 0.000 claims 1
- 235000000193 zinc lactate Nutrition 0.000 claims 1
- 229940050168 zinc lactate Drugs 0.000 claims 1
- HJSYJHHRQVHHMQ-TYYBGVCCSA-L zinc;(e)-but-2-enedioate Chemical compound [Zn+2].[O-]C(=O)\C=C\C([O-])=O HJSYJHHRQVHHMQ-TYYBGVCCSA-L 0.000 claims 1
- MCOGTQGPHPAUJN-UHFFFAOYSA-L zinc;2-hydroxyacetate Chemical compound [Zn+2].OCC([O-])=O.OCC([O-])=O MCOGTQGPHPAUJN-UHFFFAOYSA-L 0.000 claims 1
- MLYNHXYBUIJTRF-UHFFFAOYSA-L zinc;ethanesulfonate Chemical compound [Zn+2].CCS([O-])(=O)=O.CCS([O-])(=O)=O MLYNHXYBUIJTRF-UHFFFAOYSA-L 0.000 claims 1
- MKRZFOIRSLOYCE-UHFFFAOYSA-L zinc;methanesulfonate Chemical compound [Zn+2].CS([O-])(=O)=O.CS([O-])(=O)=O MKRZFOIRSLOYCE-UHFFFAOYSA-L 0.000 claims 1
- ZPEJZWGMHAKWNL-UHFFFAOYSA-L zinc;oxalate Chemical compound [Zn+2].[O-]C(=O)C([O-])=O ZPEJZWGMHAKWNL-UHFFFAOYSA-L 0.000 claims 1
- XDWXRAYGALQIFG-UHFFFAOYSA-L zinc;propanoate Chemical compound [Zn+2].CCC([O-])=O.CCC([O-])=O XDWXRAYGALQIFG-UHFFFAOYSA-L 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 230000037356 lipid metabolism Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 229940093499 ethyl acetate Drugs 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 229960004132 diethyl ether Drugs 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 229920002554 vinyl polymer Polymers 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229940126601 medicinal product Drugs 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 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 3
- 239000012453 solvate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical group [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229910001424 calcium ion Inorganic materials 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
- 239000002274 desiccant Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229960004796 rosuvastatin calcium Drugs 0.000 description 2
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 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 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- GANYMSDHMBJFIL-UHFFFAOYSA-N acetonitrile;ethoxyethane Chemical compound CC#N.CCOCC GANYMSDHMBJFIL-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- RZLVQBNCHSJZPX-UHFFFAOYSA-L zinc sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Zn+2].[O-]S([O-])(=O)=O RZLVQBNCHSJZPX-UHFFFAOYSA-L 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
Definitions
- the present invention relates to the preparation of the zinc salt of (+)- 7-[4-(4-fluorophenyl)-6-isopro ⁇ yl-2-(methanesulfonyl-methylamino)- pyrimidin-5-yl]-(3i-,5S)-dihydroxy-hept-6-enoic acid of the Formula (II).
- (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- rnethylamino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid of the Formula (II) is a pharmaceutically active ingredient known under the International Non-proprietary Name rosuvastatin. Rosuvastatin exerts its activity by inhibiting 2-hydroxy-2-methyl-glutaryl coenzyme A reductase in the liver, which is a rate-limiting step in the biosynthesis of cholesterol.
- Rosuvastatin of the Formula (II) is generally used therapeutically in form of salts thereof for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
- the object of the present invention is a process for the preparation of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1) of the Formula (I).
- (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)- ⁇ yrimidin-5-yl]-(3i?,5iS)-dihydroxy-hept-6-enoic acid of the Formula (II) is a compound known from the state of the art, which has been disclosed together with some salts thereof in European Patent No. 521471. According to the process disclosed in European Patent No.
- rosuvastatin salts are produced by saponifying an alkyl ester of rosuvastatin and if desired, setting rosuvastatin acid free from the thus obtained salt and converting the rosuvastatin salt or rosuvastatin acid thus obtained into a pharmaceutically acceptable salt, in most cases, into the calcium salt.
- Rosuvastatin zinc salt of the Formula (I) has been disclosed for the first time in Published International Patent Application No. 2007/119085. Rosuvastatin zinc salt of the Formula (I) is especially advantageous since it is stable against heat and light, which is especially favourable during the production and use of medicinal products.
- the quality of the pharmaceutically active ingredients is regulated by strict requirements. Some of these criteria apply to the chemical purity and stability of the active ingredient. Further regulatory requirement pertaining to medicinal products is pharmaceutical quality and stability. These and some other requirements are regulated by and published in official pharmacopoeias. Compliance with the regulations of the health authorities is necessary for obtaining marketing authorization for the medicinal product concerned. In case of rosuvastatin, there exists a demand for the high purity and stability of the active ingredient, and it is advantageous to produce the active ingredient in a form which allows the reproducible manufacture of the medicinal product under industrial circumstances in high quality.
- ,alkyl means a straight or branched chain saturated hydrocarbon chain comprising 1 to 6 carbon atoms, e.g. methyl, ethyl, 1 -propyl, 2-propyl, 1-methylpropyl etc.
- ,alkenyl is a straight or branched hydrocarbon chain comprising 2 to 6 carbon atoms which contain one double bond, e.g. etenyl, 1-propenyl etc.
- T represents hydroxy group or T and Q together represents a single bond or T and R together can form an oxymethylene group substituted by one or two alkyl groups;
- R represent hydrogen or R and T together form an oxymethylene group substituted by one or two alkyl groups
- (+)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methylamino)- pyrimidin-5-yl]-(3/?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1) [rosuvastatin zinc salt] of the Formula (I) is prepared by
- the advantageous starting compounds are those wherein Q represents ethyl, t-butyl, sodium ion, calcium ion or ammonium ion.
- starting compounds of the general Formula (III) are those wherein T and R together represents an oxymethylene group substituted by R 1 and R 2 alkyl groups, thus forming together with the adjoining and inclusive carbon atoms a 2,2-dimethyl-l,3-dioxane ring system as depicted in the partial Formula (IV),
- R 1 and R 2 are independently from each other hydrogen or alkyl group comprising 1 to 6 carbon atoms.
- rosuvastatin zinc salt of the Formula (I) is produced by hydrolyzing a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms, an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl or t-butyl group, the meaning of T is hydroxy group, R represents hydrogen in water, an organic solvent or in the mixture thereof in the presence of a base, subsequently converting the thus obtained rosuvastatin salt of the general Formula (III), wherein Q represents cation, the meaning of T and R is as defined above, by treating with organic or inorganic acid into rosuvastatin free acid (wherein T represents hydroxy, R represents hydrogen), reacting the thus obtained acid with a zinc alcoholate of the general Formula (V)
- Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms,
- a compound of the general Formula (III), wherein R represents hydrogen, T and Q together form a single bond is transformed into a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents hydrogen or cation, preferably sodium ion in aqueous or organic solvent or in a mixture thereof, and the thus obtained product is reacted directly or if desired, after isolation with a zinc salt of an organic or inorganic acid and the obtained rosuvastatin zinc salt of the Formula (I) is isolated.
- a compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, Q represents an alkyl group, preferably ethyl or t-butyl group, is transformed in the presence of an organic or inorganic acid in aqueous or organic solvent or in the mixture thereof into a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents alkyl group, hydrolyzing the thus obtained ester in the presence of a base in aqueous or organic solvent or in a mixture thereof, converting the thus obtained salt of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents cation, preferably sodium ion using organic or inorganic acid into the corresponding carboxylic acid of the general Formula (III), wherein Q represents hydrogen, and reacting the thus obtained acid in an organic solvent, in water or in a mixture thereof with a zinc
- a compound of the general Formula (III), wherein Q represents an alkyl or alkenyl group, preferably ethyl or t-butyl group, T and R together form an oxymethylene group optionally substituted by one or two alkyl groups, preferably by two methyl groups, is hydrolyzed in the presence of a base in an organic solvent or in the mixture of water and an organic solvent into a compound of the general Formula (III), wherein the meaning of Q is cation, T and R together form an oxymethylene group optionally substituted by one or two alkyl groups, preferably by two methyl groups, and if desired, setting the corresponding acid (wherein Q represents hydrogen) free and the thus obtained product is transformed under acidic conditions into a compound of the general Formula (III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is hydrogen, and the thus obtained product is transformed into rosuvastatin zinc salt of the Formula (I) by reacting said compound of the general Formula (I) by reacting said compound of the general
- rosuvastatin zinc salt of the Formula (I) is prepared by transforming a compound of the general Formula (III), wherein the meaning of Q is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups in presence of a mineral acid, in organic solvent or in a mixture of an organic solvent and water into a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents hydrogen and reacting the thus obtained rosuvastatin with a zinc alcoholate of the general Formula (V), zinc acetylacetonate of the Formula (VI), sodium zincate(II) or sodium tetrahydroxo-zincate(II) complex and isolating the rosuvastatin zinc salt of the Formula (III), wherein the meaning of Q is an
- a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents a cation, e.g. sodium or calcium ion, is reacted with an organic or mineral acid yielding a compound of the general Formula (III), wherein the meaning of T and R is the above, Q is hydrogen, and reacting the thus obtained rosuvastatin of the Formula (II) in an organic solvent or in a mixture of an organic solvent and water with a zinc alcoholate of the general Formula (V) or zinc acetylacetonate of the Formula (VI) or sodium zincate or sodium tetrahydroxo-zincate(II) complex and isolating the rosuvastatin zinc salt of the Formula (I).
- rosuvastatin zinc salt of the Formula (I) is produced by dissolving a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q denotes a cation, preferably sodium ion, in water or an organic solvent or in a mixture thereof, and is reacted with a zinc salt of an organic or inorganic acid and subsequently isolating the rosuvastatin zinc salt of the Formula (I).
- a 1.0-1.25 molar equivalent of a base preferably an alkali metal hydroxide, e.g. sodium hydroxide can be used.
- the base can be used in solid form. However, the base is preferably used as an aqueous solution of 0.05-10 mol/dm 3 concentration or as saturated aqueous solution.
- the reaction is carried out at a temperature between room temperature and the boiling temperature or the reaction mixture, preferably between 40 and 65 °C.
- the reaction proceeds rapidly, the reaction time depending on the temperature and the concentration of the base is approximately 0.25-12 hours.
- solvent aliphatic alcohols comprising one to four carbon atoms, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester having 2 to 8 carbon atoms, an ether comprising 4 to 8 carbon atoms can be used.
- the reaction temperature range spans from room temperature to the boiling point of the reaction mixture. The duration of the reaction depending on the reaction temperature is several hours.
- a strong mineral or organic acid such as an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid e.g., benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably aqueous hydrochloric acid solution can be used.
- a strong mineral or organic acid such as an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid e.g., benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably aqueous hydrochloric acid solution
- a strong mineral or organic acid such as an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid e.g.,
- the useful concentration range of the acid is between 0.2-10 mol/dm 3 .
- T and R together form an oxymethylene group substituted by one or two alkyl group(s), preferably by two methyl groups into the compounds of the general Formula (III), wherein Q is hydrogen, an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group containing 2 to 6 carbon atoms, T represents a hydroxy group, R represents hydrogen, the starting substance is reacted with a strong mineral or organic acid in a solvent selected from aliphatic alcohols comprising 1 to 4 carbon atoms, acetonitrile, in an aliphatic ketone comprising 3 to 8 carbon atoms, in an aliphatic ester having 2 to 8 carbon atoms or in an ether comprising 4 to 8 carbon atoms.
- a strong acid a hydrogen halogenide, sulfuric acid or an aromatic or aliphatic sulfonic acid having 1 to 4 carbon atoms can be used.
- hydrochloric acid is used in the form of an aqueous solution.
- the reaction is carried out at a temperature between room temperature and the boiling temperature or the reaction mixture, preferably at a temperature between 50 and 80 °C.
- the reaction time depending on the temperature is several hours.
- the acid can be applied in an equimolar amount, however, preferably a 2.0-40 fold molar excess of the acid is used.
- the zinc salts can be the salts of zinc with inorganic or organic acids or the hydrates thereof.
- Suitable salts in the salts formation are zinc salts formed with formic, acetic, propionic, maleic, fumaric, tartaric, lactic, malic, citric, ascorbic, malonic, oxalic, glycolic, methanesulfonic, ethanesulfonic acids, a salt of zinc with an amino acid, zinc sulfate, zinc chloride, zinc carbonate or zinc nitrate can be used.
- zinc sulfate, zinc chloride or zinc acetate is used.
- the salt formation can be carried out using the alcoholates of zinc of the general Formula (V) prepared with aliphatic alcohols comprising 1 to 4 carbon atoms.
- the organic or inorganic zinc salt or a zinc alcoholate of the general Formula (V) (wherein R 3 represents a straight or branched chain alkyl group comprising 1 to 4 carbon atoms) is applied in 0.4-0.6 molar equivalent amount relative to the molar amount of rosuvastatin or the salt thereof.
- Rosuvastatin zinc salt of the Formula (I) can be prepared starting from complex zinc compounds, e.g. zinc acetylacetonate of the Formula (VI) and complexes formed by treating an inorganic zinc salt by sodium hydroxide, e.g. sodium zincate(II) or sodium tetrahydro- zincate(II) complexes.
- complex zinc compounds e.g. zinc acetylacetonate of the Formula (VI) and complexes formed by treating an inorganic zinc salt by sodium hydroxide, e.g. sodium zincate(II) or sodium tetrahydro- zincate(II) complexes.
- zinc chloride, zinc sulfate and zinc acetate ca n be used for the transformation of rosuvastatin salts into the zinc salt
- zinc alcoholates of the general Formula (V), zinc acetylacetonate of the Formula (VI), sodium zincate(II) and sodium tetrahydo-zincate(II) complexes are useful in the transformation of rosuvastatin free acid into the zinc salt of the Formula (I).
- the amount of the complex zinc compounds used for the preparation of rosuvastatin zinc salt of the Formula (I) is determined as the amount USed contains 0.5-0.6 molar equivalent amount of zinc calculated on the amount of the starting rosuvastatin salt or acid.
- the directly used starting substance in the preparation of rosuvastatin zinc salt of the Formula (I) is the compound of the general Formula (III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is sodium ion.
- the zinc salt can be formed at a temperature between 0 "C and the boiling point of the solvent, preferably between 0 and 50 0 C.
- the reaction can be performed in an aqueous solution, using a water- soluble reagent, e.g. zinc chloride, zinc nitrate, zinc sulfate or zinc acetate.
- a water- soluble reagent e.g. zinc chloride, zinc nitrate, zinc sulfate or zinc acetate.
- the reaction can be carried out in organic solvents as well.
- aliphatic alcohols comprising 1 to 4 carbon atoms
- aliphatic ketones comprising 3 to 8 carbon atoms
- aliphatic nitriles or aliphatic esters comprising 3 to 8 carbon atoms or the mixtures thereof can be used.
- the solution of zinc chloride in an alcohol or in water is used and the reaction is carried out at a temperature between 25 and 50 0 C.
- rosuvastatin sodium salt is reacted with a 0.5 molar equivalent of zinc sulfate in aqueous solution at a temperature between 25 and 40 0 C.
- the rosuvastatin zinc salt of the Formula (I) can be isolated from the reaction mixture by filtering the solid product from the aqueous solution or extracting the product from a non-miscible solvent, separating and evaporating the organic phase and isolating the rosuvastatin zinc salt from the evaporation residue.
- aliphatic esters comprising 2 to 8 carbon atoms, in which rosuvastatin zinc salt has good solubility, can be used with good results.
- esters are ethylformiate, ethylacetate and methylacetate.
- the final product is obtained from the evaporation residue of the extracts by precipitation with an aliphatic ether having 4 to 8 carbon atoms, e.g. diethylether.
- the volume of the aliphatic ether is approximately 2 to 50-fold volume of the evaporation residue.
- the organic phase is concentrated by evaporation and the rosuvastatin zinc salt of the Formula (I) is isolated from the residue by precipitating with an aliphatic ether comprising 4 to 8 carbon atoms.
- an inorganic salt preferably with sodium chloride
- (+)-7-[4-(4-fluoro ⁇ henyl)-6- iso ⁇ ropyl-2-(methanesulfonyl-methylamino)- ⁇ yrimidin-5-yl]-(3i?,5iS)- dihydroxy-hept-6-enoic acid zinc salt (2:1) of the Formula (I) can contain solvent bound in form of solvates in varying amounts, e.g. an alcohol, water, acetonitrile, an aliphatic ketone or an ester. Solvents bound in the form of solvates are solvents present in the final product which can not be removed by drying at the temperature of 105 0 C for 1 hour.
- concentration of the solvate in the rosuvastatin zinc salt of the Formula (I) prepared according to the present invention can vary depending on the method of preparation and drying conditions between 0.01 and 30 weight%.
- the reaction mixture is cooled to room temperature, filtered and the solvent is evaporated.
- the residue is triturated with 50 ml of diethylether.
- the suspension is filtered, dissolved in 50 ml of ethylacetate and stirred with 2.0 g of silicagel for three hours.
- the silicagel is filtered, the reaction mixture is concentrated to one-third volume and the residue is mixed with tenfold volume of diethylether.
- the precipitated zinc salt is filtered, washed with diethylether and dried. Yield, 2,8 g (68 %).
- the product is precipitated by large excess of diethylether from the concentrated acetonitrile solution.
- the upper organic phase is separated, washed twice with 8-8 ml of 10 weight% sodium chloride solution, dried over 8.0 g of anhydrous magnesium sulfate and the drying agent is filtered.
- the product is precipitated from the concentrated acetonitrile solution by addition of a large excess of diethylether.
- the solids are filtered, washed with diethylether and dried in vacuo. Yield, 3.50 g (68 %).
- reaction mixture is filtered using a sintered G4 glass filter and the ethanol is evaporated at the pressure of 20 Hgmm.
- the residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 50 ml of ethanol is evaporated twice and the thus obtained crystalline solid is stirred in 200 ml of diisopropylether and filtered.
- the solution is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm.
- the residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each time.
- the aqueous layer is evaporated at the pressure of 20 Hgmm.
- 50 ml of ethanol is evaporated twice and the crystalline residue is stirred in 200 ml of diisopropylether and filtered. Yield, 43.8 g (97 %).
- reaction mixture in cooled under the temperature of 10 0 C by cooling with an ice- water mixture and 50.0 ml (0.15 mol) of 3.0 M hydrochloric acid solution are added dropwise and stirred for ten minutes.
- 300 ml of 1.0 M (0.30 mol) zinc sulfate solution are added to the reaction mixture dropwise and the mixture is stirred for one and a half hour.
- 500 ml of 10 weight% sodium chloride solution is added to the reaction mixture with stirring and the greatest part of ethanol is evaporated at the temperature of 60 0 C in vacuo using a water bath. The residue is extracted with 300 ml of ethylacetate.
- the organic layer is separated and the aqueous layer is extracted again twice with 100 ml of ethylacetate each time.
- the ethylacetate layers are combined and washed by 300 ml of 300 ml of 10 weight% sodium chloride solution and mixed with 1.0 g of activated carbon and 5.0 g of magnesium sulfate.
- the half volume of the solvent is evaporated and the remaining solution is transferred dropwise into 2000 ml of diethylether.
- the mixture is stirred until a white crystalline solid with good filtration properties is obtained.
- the solids are filtered and washed thoroughly with diethylether.
- the solution is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm.
- the residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each, and the aqueous layer is evaporated at the pressure of 20 Hgmm.
- 50 ml of ethanol is evaporated twice and the crystalline residue is stirred in 200 ml of diisopropylether and filtered. Yield, 43.8 g (97 %).
- the product is identical in all respects with the product of Example 5.
- the solids thus obtained are stirred in 300 ml of ethanol at room temperature for two hours.
- the white suspension is filtered, the filtered solids are washed with 20 ml of ethanol and dried in vacuo at the temperature of 50 0 C, protected from light.
- the solution is stirred at room temperature for two hours. Subsequently the reaction is cooled in ice and 2 M sodium hydroxide solution is added until pH 6 (approx. 36 ml) dropwise in a manner that the temperature could not exceed 15 0 C. Subsequently 150 ml of water are added and the aqueous solution is extracted twice with 75 ml of dichloromethane each. The organic layer is dried over anhydrous sodium sulfate and evaporated at the pressure of20 Hgmm. The pale yellow oily residue is crystallized by addition of diisopropylether (20 ml). The white solid is stirred in diisopropylether, filtered and crystallized from the mixture of water (40 ml) and ethanol (35 ml).
- reaction mixture is stirred at the temperature of 60 °C for 60 minutes. Subsequently the reaction mixture is cooled by using an ice- water mixture to a temperature between 0 and 10 °C and at the same temperature, 5.80 ml (17.44 mmol) of 3.0 M hydrochloric acid solution are added thereto dropwise and the stirring is continued for a further 10 minutes.
- the reaction mixture is evaporated and the residue is extracted with 80 ml of water and 80 ml of ethylacetate. The organic layer is dried over magnesium sulfate, evaporated and the oily residue is dissolved in 250 ml of methanol.
- Rosuvastatin sodium salt (6.65 g; 13.2 mmol) is dissolved in 80 ml of water and the solution is filtered through a G4 sintered glass filter. Into the stirred filtrate, 5.56 ml of 1.0 M zinc sulfate (II) solution (5.56 mmol) is added dropwise at room temperature in 15 minutes. The precipitated white solids are filtered, washed with water and dried at 0.1 Hgmm pressure at room temperature, protected from light. Yield, 5.35 g (94 %).
- reaction mixture is cooled to room temperature and 100 ml of ethylacetate are added.
- organic layer is extracted with 40 ml of water and the organic layer is evaporated.
- the residue is dissolved in 200 ml of water and made acidic by the addition of 1 M hydrochloric acid under cooling.
- the precipitated product is filtered and washed twice with 50 ml of water each.
- Example 15 The quality of the product is identical in all respects with that of the product obtained in Example 1.
- Oils (r ⁇ SUVastatin acid) is dissolved in 70 ml of ethylacetate and mixed with 4.2 ml (4.2 mmol) of freshly prepared 1 M ethanolic sodium ethylate solution at room temperature. While the stirring is continued at the same temperature, the solution of 0.28 g (2.07 mmol) of anhydrous zinc chloride prepared in 10 ml of ethanol is added in 30 minutes. Stirring is continued at the temperature of 50 0 C for further two hours, thereafter the reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated to one-tenth volume and the product is precipitated by the addition of tenfold volume of diethylether. The solids are filtered and dried at 50 0 C. Yield, 1.8 g (85.7 %).
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Abstract
The subject of the present invention is an improved process for the preparation of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1), which allows the reproducible manufacture of said compound on industrial scale in high purity. The compound of the Formula (I) can be used for the treatment of diseases related to lipid metabolism.
Description
Process for preparation of rosuvastatin zinc salt
FIELD OF THE INVENTION
The present invention relates to the preparation of the zinc salt of (+)- 7-[4-(4-fluorophenyl)-6-isoproρyl-2-(methanesulfonyl-methylamino)- pyrimidin-5-yl]-(3i-,5S)-dihydroxy-hept-6-enoic acid of the Formula (II).
(II)
(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- rnethylamino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid of the Formula (II) is a pharmaceutically active ingredient known under the International Non-proprietary Name rosuvastatin. Rosuvastatin exerts its activity by inhibiting 2-hydroxy-2-methyl-glutaryl coenzyme A reductase in the liver, which is a rate-limiting step in the biosynthesis of cholesterol. Rosuvastatin of the Formula (II) is generally used therapeutically in form of salts thereof for the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
The object of the present invention is a process for the preparation of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1) of the Formula (I).
(I)
TECHNICAL BACKGROUND OF THE INVENTION
(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-ρyrimidin-5-yl]-(3i?,5iS)-dihydroxy-hept-6-enoic acid of the Formula (II) is a compound known from the state of the art, which has been disclosed together with some salts thereof in European Patent No. 521471.
According to the process disclosed in European Patent No. 521471, rosuvastatin salts are produced by saponifying an alkyl ester of rosuvastatin and if desired, setting rosuvastatin acid free from the thus obtained salt and converting the rosuvastatin salt or rosuvastatin acid thus obtained into a pharmaceutically acceptable salt, in most cases, into the calcium salt.
Several methods utilizing a wide range of intermediate products have been disclosed in the state of the art for the preparation of rosuvastatin, rosuvastatin esters and the therapeutically most used salt, rosuvastatin calcium. Preparation of rosuvastatin through the ketal ester thereof has been described in Published International Patent Applications No. WO2006/126035 and WO2005/042522. Rosuvastatin ketal salts and rosuvastatin ketal acid have been disclosed in Published International Patent Application No. WO2006/126035. Processes starting from the alkyl esters of rosuvastatin are described in Published International Patent Applications No. WO2003/097614 and WO2005/023778. Rosuvastatin lactone can also be used for the preparation of rosuvastatin calcium, which process has been disclosed in International Patent Applications Nos. WO2005/040134, WO2005/077916 and WO2006/136407.
Rosuvastatin zinc salt of the Formula (I) has been disclosed for the first time in Published International Patent Application No. 2007/119085. Rosuvastatin zinc salt of the Formula (I) is especially advantageous since it is stable against heat and light, which is
especially favourable during the production and use of medicinal products.
SUMMARY OF THE INVENTION
The quality of the pharmaceutically active ingredients is regulated by strict requirements. Some of these criteria apply to the chemical purity and stability of the active ingredient. Further regulatory requirement pertaining to medicinal products is pharmaceutical quality and stability. These and some other requirements are regulated by and published in official pharmacopoeias. Compliance with the regulations of the health authorities is necessary for obtaining marketing authorization for the medicinal product concerned. In case of rosuvastatin, there exists a demand for the high purity and stability of the active ingredient, and it is advantageous to produce the active ingredient in a form which allows the reproducible manufacture of the medicinal product under industrial circumstances in high quality.
During our research-development work we established that using the methods known from the state of the art, it was not possible to produce rosuvastatin zinc salt of the Formula (I) of high purity in reproducible quality on an industrial scale. The objective of our research was to develop a chemical process which allows the production of rosuvastatin zinc salt of the Formula (I) of high purity in reproducible manner on industrial scale.
The above objective is solved by the present invention.
DETAILED DESCRIPTION OF THE INVENTION
According to the first aspect of the present invention, there is provided a process for the preparation of (+)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-(methanesulfonyl-methylamino)-pyrimidin-5 -yl] -(3i-,5S)-dihydroxy- hept-6-enoic acid zinc salt (2:1) of the Formula (I) and hydrates thereof of high purity in a reproducible manner on industrial scale.
Surprisingly we have found that by using the process according to the present invention, is becomes feasible to produce rosuvastatin zinc salt of the Formula (I) in high purity on industrial scale in a reproducible manner.
In the present specification, the expression ,,alkyl" means a straight or branched chain saturated hydrocarbon chain comprising 1 to 6 carbon atoms, e.g. methyl, ethyl, 1 -propyl, 2-propyl, 1-methylpropyl etc.
The meaning of the expression ,,alkenyl" is a straight or branched hydrocarbon chain comprising 2 to 6 carbon atoms which contain one double bond, e.g. etenyl, 1-propenyl etc.
The meaning of the expression ,,cation" is a metal ion, preferably an alkali metal or an alkali earth metal ion or an ammonium ion substituted by one to four alkyl groups.
In the process, a compound of general Formula (III)
(HI) can be used as starting compound, wherein
T represents hydroxy group or T and Q together represents a single bond or T and R together can form an oxymethylene group substituted by one or two alkyl groups;
R represent hydrogen or R and T together form an oxymethylene group substituted by one or two alkyl groups;
Q represent hydrogen, an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, a cation or Q and T together can form a single group.
According to the process of the present invention, (+)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methylamino)- pyrimidin-5-yl]-(3/?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1) [rosuvastatin zinc salt] of the Formula (I) is prepared by
a) transforming a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms by hydrolysis into a compound of the general Formula (III) wherein the meaning of T and R is as defined above, Q represents hydrogen or cation, and the thus obtained product is reacted with an organic or inorganic zinc compound or zinc complex and the rosuvastatin zinc salt of the Formula (T) is isolated, or
b) transforming a compound of the general Formula (III) wherein T and R together represent an oxymethylene group substituted with one or two alkyl groups, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms by hydrolysis into a compound of the general Formula (III), wherein the meaning of T and R is the above, Q represents hydrogen atom or a cation, and reacting the thus obtained product with strong acid to produce a compound of the general Formula (III) wherein T represents hydroxy group, R represents hydrogen, Q represents hydrogen, and
δ
reacting the product with an inorganic or organic zinc compound of zinc complex and isolating the compound of the Formula (I), or
c) reacting a compound of the general Formula (III), wherein T and R together represents an oxymethylene group substituted by one or two alkyl groups with a strong acid, thus obtaining a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents hydrogen, an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, and reacting the thus obtained compound of the general Formula (III), wherein T represents hydroxy, R represent hydrogen, Q represents hydrogen, an alkyl group or an alkenyl group, directly or after converting the Q group into hydrogen or a cation, with an organic or inorganic zinc compound or zinc complex and isolating the compound of the Formula (I), or
d) transforming a compound of the general Formula (III), wherein T and Q together represent a single bond and the meaning of R is hydroxy group, into a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents hydrogen or a cation, reacting the thus obtained product with an organic or inorganic zinc compound and isolating the compound of the Formula (I).
Among the compounds of general Formula (III), the advantageous starting compounds are those wherein Q represents ethyl, t-butyl, sodium ion, calcium ion or ammonium ion. Further preferable starting compounds of the general Formula (III) are those wherein T and R together represents an oxymethylene group substituted by R1 and R2 alkyl groups, thus forming together with the adjoining and inclusive carbon atoms a 2,2-dimethyl-l,3-dioxane ring system as depicted in the partial Formula (IV),
wherein the meaning of R1 and R2 is independently from each other hydrogen or alkyl group comprising 1 to 6 carbon atoms.
According to the first process variant, rosuvastatin zinc salt of the Formula (I) is produced by hydrolyzing a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms, an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl or t-butyl group, the meaning of T is hydroxy group, R represents hydrogen in water, an organic solvent or in the mixture thereof in the presence of a base, subsequently converting the thus obtained rosuvastatin salt of the general Formula (III), wherein Q represents cation, the meaning of T and R is as defined above, by treating with organic or inorganic acid into rosuvastatin free acid
(wherein T represents hydroxy, R represents hydrogen), reacting the thus obtained acid with a zinc alcoholate of the general Formula (V)
R i_O Zn- O— R3
(V)
or a zinc acetylacetonate of the Formula (VI)
(VI)
or with sodium tetrahydroxo-zincate(II) complex and isolating rosuvastatin zinc salt of the Formula (I).
According to the second variant of the process according to the present invention, a compound of general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T represents hydroxy group, R represents hydrogen, is hydrolyzed in the presence of an organic or inorganic acid in aqueous or aqueous-organic solvent and the thus obtained compound of the general Formula (III), wherein Q and R represent hydrogen, T represents hydroxy, is reacted in water or in an organic solvent or in a mixture thereof with a zinc alcoholate of the general Formula (V) or
with zinc acetylacetonate of the Formula (VI) or sodium zincate(II) or sodium tetrahydroxo-zincate(II) complex and the thus obtained rosuvastatin zinc salt of the Formula (I) is isolated.
According to the third variant of the process according to the present invention, a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms, an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t- butyl group, T represents hydroxy group, R represents hydrogen, is hydrolyzed in the presence of a base, and the thus obtained product of the general Formula (III), wherein the meaning of T and R is the above, Q represents a cation, preferably sodium ion, is reacted directly or if desired, after isolation with a zinc salt of an organic or inorganic acid and the thus obtained rosuvastatin zinc salt of the Formula (I) is isolated.
According to the fourth variant of the process according to the present invention, a compound of the general Formula (III), wherein R represents hydrogen, T and Q together form a single bond, is transformed into a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents hydrogen or cation, preferably sodium ion in aqueous or organic solvent or in a mixture thereof, and the thus obtained product is reacted directly or if desired, after isolation with a zinc salt of an organic or inorganic acid and the obtained rosuvastatin zinc salt of the Formula (I) is isolated.
According to the fifth variant of the process according to the present invention, a compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, Q represents an alkyl group, preferably ethyl or t-butyl group, is transformed in the presence of an organic or inorganic acid in aqueous or organic solvent or in the mixture thereof into a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents alkyl group, hydrolyzing the thus obtained ester in the presence of a base in aqueous or organic solvent or in a mixture thereof, converting the thus obtained salt of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents cation, preferably sodium ion using organic or inorganic acid into the corresponding carboxylic acid of the general Formula (III), wherein Q represents hydrogen, and reacting the thus obtained acid in an organic solvent, in water or in a mixture thereof with a zinc alcoholate of the general Formula (VI), wherein the alcoholate anion comprises one to four carbon atoms or with zinc acetylacetonate of the Formula (VI) or with sodium zincate(II) or sodium tetrahydroxo-zincate(II) and isolating the thus obtained rosuvastatin zinc salt.
According to the sixth variant of the process of the present invention, a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups, is converted in the presence
of an organic or inorganic acid in an organic, aqueous or aqueous- organic solvent into a compound of the general Formula (III), wherein T represents a hydroxy group, R represents hydrogen, Q represents alkyl group or alkenyl-group, the thus obtained ester is hydrolyzed in the presence of a base in water, in an organic solvent or in a mixture thereof, and the thus obtained salt of the Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents a cation, preferably sodium ion is reacted with a zinc salt of an organic or inorganic acid in water, in an organic solvent or in mixture thereof, and the thus formed rosuvastatin zinc salt of the Formula (I) is isolated.
According to the seventh process variant of the present invention, a compound of the general Formula (III), wherein Q represents an alkyl or alkenyl group, preferably ethyl or t-butyl group, T and R together form an oxymethylene group optionally substituted by one or two alkyl groups, preferably by two methyl groups, is hydrolyzed in the presence of a base in an organic solvent or in the mixture of water and an organic solvent into a compound of the general Formula (III), wherein the meaning of Q is cation, T and R together form an oxymethylene group optionally substituted by one or two alkyl groups, preferably by two methyl groups, and if desired, setting the corresponding acid (wherein Q represents hydrogen) free and the thus obtained product is transformed under acidic conditions into a compound of the general Formula (III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is hydrogen, and the thus obtained product is transformed into rosuvastatin zinc salt of the Formula (I) by
reacting said compound of the general Formula (III) with a zinc alcoholate of the general Formula (V), zinc acetylacetonate of the Formula (VI), sodium zincate or sodium tetrahydroxo-zincate(II) complex.
According to the eighth process variant of the present invention, rosuvastatin zinc salt of the Formula (I) is prepared by transforming a compound of the general Formula (III), wherein the meaning of Q is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups in presence of a mineral acid, in organic solvent or in a mixture of an organic solvent and water into a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents hydrogen and reacting the thus obtained rosuvastatin with a zinc alcoholate of the general Formula (V), zinc acetylacetonate of the Formula (VI), sodium zincate(II) or sodium tetrahydroxo-zincate(II) complex and isolating the rosuvastatin zinc salt of the Formula (I).
According to the ninth process variant of the present invention, a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen atom, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, is reacted in an organic solvent or an aqueous-organic solvent mixture in the presence
of a zinc salt with sodium hydroxide, and isolating the rosuvastatin zinc salt of the Formula (I).
According to the tenth process variant of the present invention, a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents a cation, e.g. sodium or calcium ion, is reacted with an organic or mineral acid yielding a compound of the general Formula (III), wherein the meaning of T and R is the above, Q is hydrogen, and reacting the thus obtained rosuvastatin of the Formula (II) in an organic solvent or in a mixture of an organic solvent and water with a zinc alcoholate of the general Formula (V) or zinc acetylacetonate of the Formula (VI) or sodium zincate or sodium tetrahydroxo-zincate(II) complex and isolating the rosuvastatin zinc salt of the Formula (I).
According to the eleventh process variant of the present invention, rosuvastatin zinc salt of the Formula (I) is produced by dissolving a compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q denotes a cation, preferably sodium ion, in water or an organic solvent or in a mixture thereof, and is reacted with a zinc salt of an organic or inorganic acid and subsequently isolating the rosuvastatin zinc salt of the Formula (I).
The alkaline hydrolysis of those compounds of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl-group or t-butyl group, is carried out in water or in an inert
organic solvent, preferably in aliphatic alcohols comprising one to four carbon atoms, acetonitrile, in an aliphatic ketone comprising 3 to 8 carbon atoms, in an aliphatic ester having 2 to 8 carbon atoms or in an ether comprising 4 to 8 carbon atoms or in the mixture of the above.
In the reaction, a 1.0-1.25 molar equivalent of a base, preferably an alkali metal hydroxide, e.g. sodium hydroxide can be used. The base can be used in solid form. However, the base is preferably used as an aqueous solution of 0.05-10 mol/dm3 concentration or as saturated aqueous solution.
The reaction is carried out at a temperature between room temperature and the boiling temperature or the reaction mixture, preferably between 40 and 65 °C. The reaction proceeds rapidly, the reaction time depending on the temperature and the concentration of the base is approximately 0.25-12 hours.
The acidic hydrolysis of the compounds of the general Formula (III), wherein Q represents an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms, preferably ethyl-group or t- butyl group, is carried out in an inert organic solvent or in a mixture thereof, which optionally can contain water. As solvent, aliphatic alcohols comprising one to four carbon atoms, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester having 2 to 8 carbon atoms, an ether comprising 4 to 8 carbon atoms can be used.
The reaction temperature range spans from room temperature to the boiling point of the reaction mixture. The duration of the reaction depending on the reaction temperature is several hours.
As an acid, a strong mineral or organic acid, such as an aqueous solution of a hydrogen halogenide, sulfuric acid, an aromatic or aliphatic sulfonic acid e.g., benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, preferably aqueous hydrochloric acid solution can be used.
The useful concentration range of the acid is between 0.2-10 mol/dm3.
In the conversion of the compound of the general Formula (III), wherein the meaning of Q is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl group(s), preferably by two methyl groups into the compounds of the general Formula (III), wherein Q is hydrogen, an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group containing 2 to 6 carbon atoms, T represents a hydroxy group, R represents hydrogen, the starting substance is reacted with a strong mineral or organic acid in a solvent selected from aliphatic alcohols comprising 1 to 4 carbon atoms, acetonitrile, in an aliphatic ketone comprising 3 to 8 carbon atoms, in an aliphatic ester having 2 to 8 carbon atoms or in an ether comprising 4 to 8 carbon atoms.
As a strong acid, a hydrogen halogenide, sulfuric acid or an aromatic or aliphatic sulfonic acid having 1 to 4 carbon atoms can be used. Preferably, hydrochloric acid is used in the form of an aqueous solution.
The reaction is carried out at a temperature between room temperature and the boiling temperature or the reaction mixture, preferably at a temperature between 50 and 80 °C. The reaction time depending on the temperature is several hours.
The acid can be applied in an equimolar amount, however, preferably a 2.0-40 fold molar excess of the acid is used.
During the formation of rosuvastatin zinc salt of the Formula (I), the zinc salts can be the salts of zinc with inorganic or organic acids or the hydrates thereof.
Suitable salts in the salts formation are zinc salts formed with formic, acetic, propionic, maleic, fumaric, tartaric, lactic, malic, citric, ascorbic, malonic, oxalic, glycolic, methanesulfonic, ethanesulfonic acids, a salt of zinc with an amino acid, zinc sulfate, zinc chloride, zinc carbonate or zinc nitrate can be used. Preferably, zinc sulfate, zinc chloride or zinc acetate is used.
Alternatively, the salt formation can be carried out using the alcoholates of zinc of the general Formula (V) prepared with aliphatic alcohols comprising 1 to 4 carbon atoms.
During the salt formation, the organic or inorganic zinc salt or a zinc alcoholate of the general Formula (V) (wherein R3 represents a straight or branched chain alkyl group comprising 1 to 4 carbon atoms) is applied in 0.4-0.6 molar equivalent amount relative to the molar amount of rosuvastatin or the salt thereof.
Rosuvastatin zinc salt of the Formula (I) can be prepared starting from complex zinc compounds, e.g. zinc acetylacetonate of the Formula (VI) and complexes formed by treating an inorganic zinc salt by sodium hydroxide, e.g. sodium zincate(II) or sodium tetrahydro- zincate(II) complexes.
Among the above-mentioned zinc compounds, zinc chloride, zinc sulfate and zinc acetate ca n be used for the transformation of rosuvastatin salts into the zinc salt, while zinc alcoholates of the general Formula (V), zinc acetylacetonate of the Formula (VI), sodium zincate(II) and sodium tetrahydo-zincate(II) complexes are useful in the transformation of rosuvastatin free acid into the zinc salt of the Formula (I).
The amount of the complex zinc compounds used for the preparation of rosuvastatin zinc salt of the Formula (I) is determined as the amount USed contains 0.5-0.6 molar equivalent amount of zinc calculated on the amount of the starting rosuvastatin salt or acid.
According to a preferable embodiment of the invention, the directly used starting substance in the preparation of rosuvastatin zinc salt of the Formula (I) is the compound of the general Formula (III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is sodium ion.
The zinc salt can be formed at a temperature between 0 "C and the boiling point of the solvent, preferably between 0 and 50 0C. The reaction can be performed in an aqueous solution, using a water- soluble reagent, e.g. zinc chloride, zinc nitrate, zinc sulfate or zinc acetate. The reaction can be carried out in organic solvents as well. For example, aliphatic alcohols comprising 1 to 4 carbon atoms, aliphatic ketones comprising 3 to 8 carbon atoms, aliphatic nitriles or aliphatic esters comprising 3 to 8 carbon atoms or the mixtures thereof can be used.
According to a preferable embodiment of the invention, the solution of zinc chloride in an alcohol or in water is used and the reaction is carried out at a temperature between 25 and 50 0C. According to the most preferable embodiment, rosuvastatin sodium salt is reacted with a 0.5 molar equivalent of zinc sulfate in aqueous solution at a temperature between 25 and 40 0C.
The rosuvastatin zinc salt of the Formula (I) can be isolated from the reaction mixture by filtering the solid product from the aqueous solution or extracting the product from a non-miscible solvent, separating and evaporating the organic phase and isolating the rosuvastatin zinc salt from the evaporation residue.
In the case when extraction is used for the isolation of the product, aliphatic esters comprising 2 to 8 carbon atoms, in which rosuvastatin zinc salt has good solubility, can be used with good results. Such esters are ethylformiate, ethylacetate and methylacetate. The final product is obtained from the evaporation residue of the extracts by precipitation with an aliphatic ether having 4 to 8 carbon atoms, e.g. diethylether. The volume of the aliphatic ether is approximately 2 to 50-fold volume of the evaporation residue.
If the reaction mixture is free from water or water is present in small amounts only, the organic phase is concentrated by evaporation and the rosuvastatin zinc salt of the Formula (I) is isolated from the residue by precipitating with an aliphatic ether comprising 4 to 8 carbon atoms.
One can proceed by saturating the reaction mixture comprising water and a water-miscible organic solvent with an inorganic salt, preferably with sodium chloride, thus salting out the organic phase and the isolation of the product is performed using the organic phase thus obtained.
It was found during our experiments that (+)-7-[4-(4-fluoroρhenyl)-6- isoρropyl-2-(methanesulfonyl-methylamino)-ρyrimidin-5-yl]-(3i?,5iS)- dihydroxy-hept-6-enoic acid zinc salt (2:1) of the Formula (I) can contain solvent bound in form of solvates in varying amounts, e.g. an alcohol, water, acetonitrile, an aliphatic ketone or an ester. Solvents
bound in the form of solvates are solvents present in the final product which can not be removed by drying at the temperature of 105 0C for 1 hour.
The concentration of the solvate in the rosuvastatin zinc salt of the Formula (I) prepared according to the present invention can vary depending on the method of preparation and drying conditions between 0.01 and 30 weight%.
Further details of the invention are demonstrated by the following examples without limiting the invention to the examples in any way.
Example 1
7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,5iS)-dihydroxy-hept-6-enoic acid zinc salt
(2:1)
2 g (4.26 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-55»S)-dihydroxy- hept-6-enoate [compound of the general Formula (III), wherein the meaning of T is hydroxy group, R represents hydrogen, Q represents ethyl group] are dissolved in 20 ml of ethanol, and using external cooling with cold water, 2.13 ml of 2.5 M (5.32 mmol) sodium hydroxide solution is added dropwise in 20 minutes, and the reaction mixture is subsequently stirred for 30 minutes at a water bath having the temperature of 60 0C. Thereafter while cooling ice and water mixture, at a temperature between 0 and 10 0C, 1.77 ml (5.32 mmol) of 3.0 M hydrochloric acid solution is added dropwise, and stirred for ten minutes. The reaction mixture is evaporated, the residue is extracted with 20 ml of water and 20 ml of ethylacetate. The organic phase is dried over magnesium sulfate, evaporated and the oily residue is dissolved in 70 ml of methanol. Into this solution, 0.60 g (2.13 mmol) of zinc acetylacetonate monohydrate is added at room temperature and the reaction mixture is stirred for 8 hours at the same temperature. Afterwards 1.0 g of silicagel is added to the reaction mixture, stirred for 30 minutes and filtered. The filtrate is concentrated to one tenth volume and the product is precipitated with twentyfold volume of diethylether. The solids are filtered, washed with diethylether and dried at 40 0C in vacuo.
Yield, 2.05 g (94 %).
Melting point, melting starts from 137 °C.
IR (KBr): 3423, 1546, 1381, 1156 cm"1
1H-NMR (OMSO-dβ, 500 MHz): δ 7.72 (dd, J=7.7, 5.9 Hz, 4H), 7.27 (t, J=8.5 Hz, 4H)5 6.52 (d, J=I 5.9 Hz, 2H)5 5.54 (dd, J=I 5.9 Hz5 5.1 Hz, 2H)5 4.94 (br S5 4H)5 4.21 (m, 2H)5 3.84 (m5 2H), 3.55 (s, 6H)5 3.46 (s, 6H), 3.40 (m, 2H)5 2.26 (d, J=13.7 Hz5 2H), 2.16 (dd, J=14.5, 7.7 Hz5 2H)5 1.52 (m, 2H)5 1.38 (m5 2H)5 1.22 (d, J=6.4 Hz, 12H) ppm.
Example 2
7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt
(2:1)
4 g (8.0 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-555)-dihydroxy- hept-6-enoate [compound of the general Formula (III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is ethyl] are dissolved in 30 ml of ethanol, and during external cold water cooling, 4.00 ml of 2.5 M (10.0 mmol) sodium hydroxide solution are added dropwise in 20 minutes. Thereafter the solution is stirred for 30 minutes at a water bath having the temperature of 60 0C. Subsequently, while applying cooling with ice and water mixture, at a
temperature between 0 and 10 °C 3.33 ml (10.0 mmol) of 3.0 M hydrochloric acid solution is added dropwise and the reaction mixture is stirred for ten minutes. The reaction mixture is evaporated, the residue is extracted with 20 ml of water and 20 ml of ethylacetate. The organic phase is dried over magnesium sulfate, evaporated and the oily residue is dissolved in 40 ml of ethylacetate. Into this solution the solution of 0.62 g (4.0 mmol) of zinc ethylate in 40 ml of ethanol is added, and the mixture is boiled for two hours. The reaction mixture is cooled to room temperature, filtered and the solvent is evaporated. The residue is triturated with 50 ml of diethylether. The suspension is filtered, dissolved in 50 ml of ethylacetate and stirred with 2.0 g of silicagel for three hours. The silicagel is filtered, the reaction mixture is concentrated to one-third volume and the residue is mixed with tenfold volume of diethylether. The precipitated zinc salt is filtered, washed with diethylether and dried. Yield, 2,8 g (68 %).
Analytical results of the product are identical to those obtained in Example 1 in all respects.
Example 3
7-[4-(4-Fluoroρhenyl)-6-isopropyl-2-(methanesulfonyl-methyl- ammo)-pyrimidin-5-yl]-(3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt
(2:1)
4 g (9.54 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methylamino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy-
hept-6-enoate [compound of the general Formula (III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is ethyl group] is added to 33.0 ml of acetonitrile and into this mixture 9.53 ml (9.53 mmol) of 1.0 M sodium hydroxide solution are added. The mixture is stirred for 35 minutes at room temperature. Subsequently 4.3 g solid sodium chloride are added to the reaction mixture and the stirring is continued until the reaction mixture is separated into two layers. The upper organic layer is separated, washed twice with 8 ml of 10 weight% sodium chloride solution each. The thus obtained acetonitrile solution is cooled below the temperature of 10 0C with intense stirring and 4.8 ml (4.8 mmol) of 1.0 M zinc sulfate solution are added dropwise. The mixture is stirred for one hour at 10 0C and for two hours at room temperature and subsequently allowed to stand overnight. The upper organic layer is separated, washed twice with 8 ml of 10 weight% sodium chloride solution each, dried over 8.0 g of anhydrous magnesium sulfate and the drying agent is filtered. Subsequently the product is precipitated by large excess of diethylether from the concentrated acetonitrile solution. The upper organic phase is separated, washed twice with 8-8 ml of 10 weight% sodium chloride solution, dried over 8.0 g of anhydrous magnesium sulfate and the drying agent is filtered. Subsequently the product is precipitated from the concentrated acetonitrile solution by addition of a large excess of diethylether. The solids are filtered, washed with diethylether and dried in vacuo. Yield, 3.50 g (68 %).
Analytical results of the product are identical to those obtained in Example 1 in all respects.
Example 4
7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-555)-dihydroxy-hept-6-enoic acid zinc salt
(2:1)
1.27 g (2.5 mmol) of ethyl-7-[4-(4-fluoroρhenyl)-6-isoproρyl-2-
hept-6-enoate [compound of the general Formula (III), wherein T represents a hydroxy group, R represents hydrogen, Q represents an ethyl group] are stirred in the mixture of 10 ml of acetonitrile and 5.0 ml of hydrochloric acid (1:1 (v/v) dilution) at room temperature for two hours. Subsequently 2.0 g of solid sodium chloride are added to the reaction mixture. The organic layer is separated and washed twice with 10 ml of 10 weight% sodium chloride solution each. Subsequently 1.0 ml of 2.5 M sodium hydroxide (2.5 mmol) solution is added dropwise, while stirring the solution continuously. After 30 minutes, 1.25 ml of 1.0 M zinc sulfate solution (1.25 mmol) are added to the reaction mixture dropwise. After three hours reaction time at room temperature, the reaction mixture is diluted with 10 weight% sodium chloride solution, the separated organic layer is washed twice with 10 ml of 10 weight% sodium chloride solution each and dried over anhydrous magnesium sulfate. The product is precipitated by large excess of diethylether and the thus obtained product is further purified by stirring in the mixture of diethylether-acetonitrile 20:1 (v/v) solvent mixture.
Yield, 0.45 g (35 %).
Analytical results of the product are identical to those obtained in
Example 1 in all respects.
Example 5
7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid zinc salt
(2:1)
A. 7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,5S)-dihydroxy-hept-6-enoic acid sodium salt
45.9 g (90.0 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy- hept-6-enoate [compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents ethyl group] are dissolved in 1000 ml of ethanol at room temperature and 360 ml of 0.25 M sodium hydroxide solution (90.0 mmol) are added dropwise in 20 minutes. After further four hours of reaction time, the reaction mixture is filtered using a sintered G4 glass filter and the ethanol is evaporated at the pressure of 20 Hgmm. The residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 50 ml of ethanol is evaporated twice and
the thus obtained crystalline solid is stirred in 200 ml of diisopropylether and filtered.
Yield, 43,8 g (97 %) of rosuvastatin sodium salt [ compound of the general Formula (III), wherein T represents hydroxy group, R represents hydrogen, Q represents sodium ion] in form of a white solid.
Melting point, starts melting from 130 0C.
IR (KBr): 3419, 2970, 1548, 1383, 1150 cm"1
1H-NMR (DMSO-c?6, 500 MHz): δ 7.72 (dd, J=8.8, 5.9 Hz5 2H)5 7.27 (t, J=8.9 Hz5 2H), 6.52 (dd5 J=15.9, 1.2 Hz, IH), 5.54 (dd, J=16.1 Hz, 5.9 Hz, IH)5 5.11 (br s, IH), 4.41 (br s, IH), 4.21 (m, IH), 3.65 (m, IH), 3.55 (s, 3H), 3.45 (s5 3H)5 3.43 (m, IH)5 3.35 (br s, 2H), 2.04 (dd, J=15.0, 3.8 Hz5 IH)5 1.85 (dd, J=15.0, 8.4 Hz, IH), 1.48 (m, IH), 1.28 (m5 IH)5 1.23 (d5 3H), 1.21 (d, 3H) ppm.
B. 7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3R,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
31.06 g (61.7 mmol) of rosuvastatin sodium salt obtained in the first stage are dissolved in 400 ml of water and the solution is filtered using a G4 sintered glass filter. While stirring, 26.0 ml of 1.0 M zinc sulfate solution (26.0 mmol) are added dropwise to the filtrate in 15 minutes.
The white precipitate is filtered, washed with water and dried at the pressure of 0.1 Hgmm at room temperature, protected from light. Yield, 24.48 g (92 %).
Analytical results of the product are identical to those obtained in Example 1 in all respects.
Example 6
7-[4-(4-florophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
A. 7- [4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,5S)-dihydroxy-hept-6-enoic acid sodium salt
45.9 g (90.0 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,5S)-dihydroxy- hept-6-enoate [compound of the general Formula(III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is ethyl] are dissolved in 1000 ml of ethanol by stirring at room temperature and in 20 minutes, 360 ml of 0.25 M sodium hydroxide solution (90.0 mmol) are added dropwise. After further 4 hours reaction time, the solution is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm. The residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each time. The aqueous layer is evaporated at the pressure of 20 Hgmm. From the
residue, 50 ml of ethanol is evaporated twice and the crystalline residue is stirred in 200 ml of diisopropylether and filtered. Yield, 43.8 g (97 %).
The product is identical in all respects with the product obtained in the process of Example 5.
B . 7- [4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
1.04 g (2.07 mmol) of the product of stage A (rosuvastatin sodium salt) are dissolved in 20 ml of methanol at room temperature and the solution is filtered using a G4 sintered glass filter. Under stirring, 1.0 ml of 1.0 M methanolic zinc chloride(II) solution (1.0 mmol) is added to the filtrate and after stirring the mixture for further 30 minutes, the solution is evaporated. The solid white residue is stirred in 10 ml of water, filtered, washed with water and dried at room temperature, protected from light at the pressure of 0.1 Hgmm. Yield, 0.96 g (94 %).
The product is identical in all respects to the product obtained in Example 1.
Example 7
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-(3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
306.0 g (0.60 mol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy- hept-6-enoate [the compound of the general Formula (III), wherein the meaning of T is hydroxy group, R is hydrogen, Q is ethyl group] are dissolved in 2400 ml of ethanol, and by external cold water cooling, 300 ml of 2.5 M (0.75 mol) of sodium hydroxide solution are added dropwise in 20 minutes and subsequently the mixture is stirred for 30 minutes at a water bath having the temperature of 60 °C. After this period, the reaction mixture in cooled under the temperature of 10 0C by cooling with an ice- water mixture and 50.0 ml (0.15 mol) of 3.0 M hydrochloric acid solution are added dropwise and stirred for ten minutes. At the same temperature, 300 ml of 1.0 M (0.30 mol) zinc sulfate solution are added to the reaction mixture dropwise and the mixture is stirred for one and a half hour. After this period, 500 ml of 10 weight% sodium chloride solution is added to the reaction mixture with stirring and the greatest part of ethanol is evaporated at the temperature of 60 0C in vacuo using a water bath. The residue is extracted with 300 ml of ethylacetate. the organic layer is separated and the aqueous layer is extracted again twice with 100 ml of ethylacetate each time. The ethylacetate layers are combined and washed by 300 ml of 300 ml of 10 weight% sodium chloride solution and mixed with 1.0 g of activated carbon and 5.0 g of magnesium sulfate. The half volume of the solvent is evaporated and the
remaining solution is transferred dropwise into 2000 ml of diethylether. The mixture is stirred until a white crystalline solid with good filtration properties is obtained. The solids are filtered and washed thoroughly with diethylether.
Yield, 216.0 g (70 %)
The product is identical in all respects with that of Example 1.
Example 8
45.9 g (90.0 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,5(S)-dihydroxy- hept-6-enoate [the compound of the general Formula (III), wherein the meaning of T is hydroxy, R is hydrogen, Q is ethyl] are dissolved by stirring in 1000 ml of ethanol at room temperature and in 20 minutes, 360 ml of 0.25 M sodium hydroxide solution (90.0 mmol) are added dropwise. After further four hour reaction time, the solution is filtered through a G4 sintered glass filter and the ethanol is evaporated at the pressure of 20 Hgmm. The residue is mixed with 200 ml of water and extracted three times with 75 ml of ethylacetate each, and the aqueous layer is evaporated at the pressure of 20 Hgmm. From the residue, 50 ml of ethanol is evaporated twice and the crystalline residue is stirred in 200 ml of diisopropylether and filtered.
Yield, 43.8 g (97 %). The product is identical in all respects with the product of Example 5.
The solids thus obtained are stirred in 300 ml of ethanol at room temperature for two hours. The white suspension is filtered, the filtered solids are washed with 20 ml of ethanol and dried in vacuo at the temperature of 50 0C, protected from light.
Yield, 38.63 g (88 %).
Purity (as determined by HPLC) > 99.95 %.
Example 9
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
15.0 g (32.3 mmol) of 4-(4-fluoroρhenyl)-6-isoρropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl-2-(4-hydroxy- 6-oxo-tetrahidro-2H-pirane) [compound of the general Formula (III), wherein T and Q form a single bond, R is hydrogen] are dissolved in the mixture of 150 ml water and 150 ml of ethanol, the solution is made alkaline until pΗ 9 by adding 10 weight% sodium hydroxide solution and stirred for four hours. The ethanol is evaporated in vacuo and the aqueous layer is washed with 100 ml of diethylether. 15 ml of 1 M zinc chloride solution (15.0 mmol) are added to the aqueous layer dropwise in 30 minutes and the precipitated white solids are filtered and dried at room temperature, protected from light in vacuo. Yield, 14.8 g (89 %).
The quality of the product is identical in all respects with that of the product obtained in Example 1.
Example 10
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3.R,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
A. 7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i-s55)-dihydroxy-hept-6-enoic acid tert- butyl-ester
10.0 g (17.3 mmol) of (6-{2-[4-(4-fluorophenyl)-6-isoproρyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5 -yl] -vinyl } -2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid fert-butylester [compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by two methyl groups, Q is t-butyl group] are dissolved at room temperature in 100 ml of tetrahydrofurane and 50 ml of 10 weight% hydrochloric acid solution are added in 30 minutes. The solution is stirred at room temperature for two hours. Subsequently the reaction is cooled in ice and 2 M sodium hydroxide solution is added until pH 6 (approx. 36 ml) dropwise in a manner that the temperature could not exceed 15 0C. Subsequently 150 ml of water are added and the aqueous solution is extracted twice with 75 ml of dichloromethane each. The organic layer is dried over anhydrous sodium sulfate and evaporated at the pressure of20 Hgmm. The pale yellow oily residue is
crystallized by addition of diisopropylether (20 ml). The white solid is stirred in diisopropylether, filtered and crystallized from the mixture of water (40 ml) and ethanol (35 ml).
Yield, 7,54 g (81 %) of 7-[4-(4-fluorophenyl)-6-isopropyl-2-
(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,5S)-dihydroxy- hept-6-enoic acid ført-butyl-ester.
Melting point, 139-140 0C.
IR (KBr): 3375, 2976, 1735, 1606, 1542, 1510, 1381, 1340, 1226, 1149, 964 cm"1.
1H-NMR (CDCl3, 500 MHz): 7.65 (dd, 2H, J = 8.8, 5.5 Hz), 7.09 (t, 2H, J = 8.7 Hz), 6.64 (dd, IH, J = 16.0, 1.4 Hz), 5.46 (dd, IH, J = 16.1, 5.3 Hz), 4.45 (m, IH), 4.17 (m, IH), 3.84 (m, IH), 3.71 (m, IH), 3.57 (s, 3H), 3.52 (s, 3H), 3.38 (m, IH), 2.38 (d, 2H), 1.52 (m, IH), 1.47 (s, 9H), 1.45 (m, IH)5 1.27 (d, 6H) ppm.
13C-NMR (CDCl3, 500 MHz): 174.89, 172.08, 163.42, 163.17 (d, J = 249.5 Hz), 157.23, 139.47, 134.53 (d, J = 3.4 Hz), 132.11 (d, J = 8.3 Hz), 122.50, 121.45, 114.95 (d, J = 21.5 Hz), 81.79, 71.91, 68.58, 42.39, 42.20, 41.87, 33.06, 32.07, 28.06, 21.58, 21.55 ppm.
Elemental analysis:
Calculated: C 58, 08 H 6,75 N 7,82 S 5,96 %.
Measured: C 58, 16 H 6,87 N 7,97 S 5,80 %.
B . 7- [4-(4-fluorophenyl)-6-isopropyl-2-(memanesulfonyl-methyl- amino)-pyrimidin-5-yl]- (S^SSydihydroxy-hept-δ-enoic acid zinc salt (2:1)
7.54 g (13.96 mmol) of 7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy- hept-6-enoic acid tert-butylester [compound of the general Formula (III), wherein the meaning of T is hydroxy, R is hydrogen, Q is t-butyl group] obtained in the previous stage are dissolved in 80 ml of ethanol and into this solution 6.98 ml of 2.5 M (17.44 mmol) of sodium hydroxide solution are added dropwise in 20 minutes. Subsequently the reaction mixture is stirred at the temperature of 60 °C for 60 minutes. Subsequently the reaction mixture is cooled by using an ice- water mixture to a temperature between 0 and 10 °C and at the same temperature, 5.80 ml (17.44 mmol) of 3.0 M hydrochloric acid solution are added thereto dropwise and the stirring is continued for a further 10 minutes. The reaction mixture is evaporated and the residue is extracted with 80 ml of water and 80 ml of ethylacetate. The organic layer is dried over magnesium sulfate, evaporated and the oily residue is dissolved in 250 ml of methanol. Into this solution, 1.97 g (6.98 mmol) of zinc acetylacetonate monohydrate are added and the reaction mixture is stirred at room temperature for four hours. Subsequently 2.0 g of silicagel are added to the solution, stirred for further 30 minutes and filtered. The filtrate is evaporated to one tenth volume of the initial and the product is precipitated by the addition of twentyfold- volume of diethylether. The solids are filtered, washed with diethylether and dried in vacuo at the temperature of 40 0C.
Yield, 6.36 g (89 %).
The product is identical in all respects with that of Example 1.
Example 11
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
A. 7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?, 55) -dihydroxy-hept-6-enoic acid tert- butylester
10.0 g (17.3 mmol) of (6-{2-[4-(4-fluoroρhenyl)-6-isoproρyl-2- (methanesulfonyl-methyl-amino)-pyriniidin-5-yl]-vinyl}-2,2-dimethyl- [l,3]dioxane-4-yl)-acetic acid fer/-butyl ester [the compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by two methyl groups, Q is t-butyl group] are dissolved at room temperature in 100 ml of tetrahydrofurane, and 50 ml of 10 volume% hydrochloric acid solution is added in 30 minutes. The solution is stirred for 2 hours at room temperature. The reaction mixture is cooled with ice and 2 M sodium hydroxide solution is added until pH 6 (approx. 36 ml). During the addition of the sodium hydroxide solution, care is taken to keep the temperature of the reaction mixture below 15 0C. Thereafter 150 ml of water is added to the reaction and extracted twice with 75 ml of dichloromethane each time. The organic layer is dried over sodium sulfate and evaporated at the pressure of 20 Hgmm. The pale yellow oily residue is solidified by
mixing with diisopropylether (20 ml). The white solids are stirred with diisopropylether, filtered and recrystallized from the mixture of water (40 ml) and ethanol (35 ml). Yield, 7.81 g (84 %)
B . 7- [4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]- (3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
7.81 g (14.5 mmol) of 7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,5S)-dihydroxy- hept-6-enoic acid fert-butylester are dissolved in 200 ml of ethanol at room temperature and 58 ml of 0.25 M sodium hydroxide solution (14.5 mmol) are added dropwise in 30 minutes. The reaction mixture is kept at the temperature of 60 °C for 4 hours. Subsequently the solution is filtered on a G4 sintered glass filter and the ethanol is evaporated at 20 Hgmm pressure. The residue is mixed with 40 ml of water and extracted three times with 15 ml of ethylacetate each and the aqueous layer is evaporated. From the residue, 10 ml of ethanol is evaporated twice and the remaining solids are stirred in 40 ml of diisopropylether and filtered. Yield, 6.65 g (91 %)
The quality of the product is identical in all respects with those of the product obtained in Example 5.
Rosuvastatin sodium salt (6.65 g; 13.2 mmol) is dissolved in 80 ml of water and the solution is filtered through a G4 sintered glass filter. Into
the stirred filtrate, 5.56 ml of 1.0 M zinc sulfate (II) solution (5.56 mmol) is added dropwise at room temperature in 15 minutes. The precipitated white solids are filtered, washed with water and dried at 0.1 Hgmm pressure at room temperature, protected from light. Yield, 5.35 g (94 %).
The quality of the product is identical in all respects to that of the product of Example 1.
Example 12
7-[4-(4-fiuorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i?,5iS)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
A. (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-(3i?,5<S)-dihydroxy-hept-6-enoic acid
10.0 g (17.3 mmol) of (6-{2-[4-(4-fluorophenyl)-6-isoρroρyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl- [l,3]dioxane-4-yl)-acetic acid t-butylester [compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by two methyl groups, Q is ^-butyl-group] are dissolved in 100 ml of tetrahydrofurane, and while stirring, 60 ml (60 mmol) of 1 M sodium hydroxide solution is added to the solution and the reaction mixture is boiled for 8 hours. Thereafter the reaction mixture is cooled to room temperature and 100 ml of ethylacetate are added. The organic layer is extracted with 40 ml of water and the organic layer is
evaporated. The residue is dissolved in 200 ml of water and made acidic by the addition of 1 M hydrochloric acid under cooling. The precipitated product is filtered and washed twice with 50 ml of water each. (6- {2- [4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxane-4- yl)-acetic acid thus obtained [compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by two methyl groups, Q is hydrogen] thus obtained are mixed with 250 ml of tetrahydrofurane and 40 ml (40 mmol) of 1 M hydrochloric acid and the mixture is reacted for 30 minutes at the temperature of 80 "C. The reaction mixture is evaporated and the residue is mixed with 100 ml of water and 100 ml of ethylacetate. The organic layer is dried over magnesium sulfate and the solvent is evaporated. Yield, 6.50 g (78 %) (+)-7-[4-(4-fluorophenyl)-6-isoproρyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy- hept-6-enoic acid.
B. 7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]- (3i?,5.S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
2.05 g (4.26 mmol) of rosuvastatin of the Formula (II) obtained in the previous stage are dissolved in 70 ml of methanol and into this solution, 0.60 g (2.13 mmol) of zinc acetylacetonate monohydrate is added. The reaction mixture is stirred for 8 hours at room temperature. Thereafter 1.0 g of silicagel is added to the reaction mixture, stirred for 30 minutes and filtered. The filtrate is evaporated to one tenth
volume and the product is precipitated by the addition of twenty-fold volume of diethylether. The solids are filtered, washed with diethylether and dried in vacuo at the temperature of 40 0C. Yield, 1.98 g (91 %).
The quality of the product is identical in all respects with that of the product obtained in Example 1.
Example 13
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
A. (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-(3/?,5S)-dihydroxy-hept-6-enoic acid
10.0 g (17.3 mmol) of (6-{2-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl- [l,3]dioxan-4-yl)-acetic acid t-butyl ester are mixed with 250 ml of tetrahydrofurane and 40 ml (40 mmol) of 1 M hydrochloric acid and the mixture is reacted at 80 0C for 2 hours. The reaction mixture is evaporated and the residue is mixed with 100 ml water and 100 ml of ethylacetate. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated.
Yield, 6.75 g (81 %) of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy-
hept-6-enoic acid [compound of the general Formula (III), wherein the meaning of T is hydroxy, Q and R are hydrogen].
B. 7-[4-(4-fiuorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl- amino)-pyrimidin-5-yl]-(3i?,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
3.86 g of (8.01 mmol) of rosuvastatin of the Formula (II) obtained in the previous stage are dissolved in 40 ml of ethylacetate. Into this solution the solution of 0.62 g (4.0 mmol) of zinc ethylate in 40 ml of ethanol is added and the thus obtained mixture is boiled for two hours. The reaction mixture is thereafter cooled to room temperature, filtered and the solvent is evaporated. The residue is triturated in 50 ml of diethylether. The suspension is filtered, dissolved in 50 ml of ethylacetate and the solution is stirred with 2.0 g silicagel for three hours. The solution is filtered, the mixture is evaporated to one-third volume and the residue is mixed with tenfold-volume of diethylether. The precipitated zinc salt is filtered, washed with diethylether and dried. Yield, 3.07 g (75 %).
The quality of the product is identical to that of the product obtained in Example 1.
Example 14
(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(iV-niethyl-N-methyl-sulfonyl- amino)-pyrimidin-5-yl]-(3i?,51S)-dihydroxy-(E)-6-heptenoic acid zinc salt (2:1)
3.O g (75 mmol) of sodium hydroxide are dissolved in 30 ml of distilled water and 0.4 ml of ethanol is added to the solution. Subsequently, solution of 2.3 g (8.0 mmol) of zinc sulfate heptahydrate in 8 ml of water is added with intense stirring. The solution thus obtained is heated to 70 0C and at this temperature, 2,0 g (3.9 mmol) of ethyl-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy- hept-6-enoate are introduced into the mixture in portions. After dissolution, the reaction mixture is stirred for 30 minutes at 70 0C, thereafter for 60 minutes at 25 0C. The mixture is cooled to room temperature and extracted twice with 50 ml of ethylacetate each. The ethylacetate solutions are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue is mixed with 100 ml of diethylether, filtered and the crude product is purified by stirring in the mixture of ethylacetate- diethylether 1:1 by volume. Yield, 1.85 g (92 %).
The quality of the product is identical in all respects with that of the product obtained in Example 1.
Example 15
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3J?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
2.08 g (2.07 mmol) of rosuvastatin calcium salt (2:1) [compound of the general Formula (III), wherein the meaning of T is hydroxy, R is hydrogen, Q is 1A calcium] are mixed with 100 ml of water, 100 ml of ethylacetate and 5 ml of 3 M hydrochloric acid solution (15 mmol). After 10 minutes intense stirring, the layers are separated and the ethylacetate layer is dried and evaporated. The remaining colourless
Oils (røSUVastatin acid) is dissolved in 70 ml of ethylacetate and mixed with 4.2 ml (4.2 mmol) of freshly prepared 1 M ethanolic sodium ethylate solution at room temperature. While the stirring is continued at the same temperature, the solution of 0.28 g (2.07 mmol) of anhydrous zinc chloride prepared in 10 ml of ethanol is added in 30 minutes. Stirring is continued at the temperature of 50 0C for further two hours, thereafter the reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated to one-tenth volume and the product is precipitated by the addition of tenfold volume of diethylether. The solids are filtered and dried at 50 0C. Yield, 1.8 g (85.7 %).
The quality of the product is identical in all respects with that of the product obtained in Example 1.
Example 16
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i?,55)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
31.06 g (61.7 mmol) of rosuvastatin sodium salt are dissolved in 400 ml of water and the solution is filtered with a G4 sintered glass filter.
Into the filtrate, 26.0 ml of 1.0 M zinc sulfate solution (26.0 mmol) are added dropwise in 15 minutes. The white precipitate is filtered, washed with water and dried at 0.1 Hgmm pressure, protected from light.
Yield, 24.48 g (92 %).
The quality of the product is identical in all respects with that of the product obtained in Example 1.
Example 17
7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]- (3i?,5S)-dihydroxy-hept-6-enoic acid zinc salt (2:1)
1.04 g (2.07 mmol) of rosuvastatin sodium salt are dissolved in 20 ml of methanol and the solution is filtered thorough a G4 sintered glass filter. Under stirring at room temperature, 1.0 ml of 1.0 M methanolic zinc chloride solution (1.0 mmol) is added dropwise to the filtrate in 30 minutes. After 30 minutes of stirring, the solution is evaporated. The white solid residue is stirred in 10 ml of water, filtered, washed with water and dried at 0.1 Hgmm pressure, protected from light.
Yield, 0.96 g (94 %).
The quality of the product is identical in all respects with that of the product obtained in Example 1.
Claims
1. Process for the preparation of (+)-7-[4-(4-fluorophenyl)-6- isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i?,5.S)- dihydroxy-hept-6-enoic acid zinc salt (2:1) of the Formula (I),
(I)
which comprises
a) transforming a compound of the general Formula (III),
(III) wherein T represents a hydroxy group, R represents hydrogen, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms by hydrolysis into a compound of the general Formula (HI), wherein the meaning of T and R is the above, Q represents hydrogen or a cation, and reacting the thus obtained product with an inorganic or organic zinc compound or a zinc complex and isolating the compound of the Formula (I) thus obtained, or
b) transforming a compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups comprising 1 to 6 carbon atoms, preferably by two methyl group, Q is an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms by hydrolysis into a compound of the general Formula (III), wherein the meaning of T and R is as defined above, Q represents hydrogen or cation and converting the thus obtained product in the presence of a strong acid into a compound of the general Formula (III), wherein the meaning of T is hydroxy, R is hydrogen, Q is hydrogen, reacting the thus obtained product with an inorganic or organic zinc compound or zinc complex and isolating the compound of the Formula (I), or
c) transforming a compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups comprising 1 to 6 carbon atoms, preferably by two methyl groups, Q is an alkyl group comprising 1 to 6 carbon atoms of an alkenyl group comprising 2 to 6 carbon atoms by reacting with a strong acid into a compound of the general Formula (III), wherein the meaning of T is hydroxy, R is hydrogen, Q is hydrogen, an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms and reacting the product thus obtained directly or indirectly after the transformation of Q into a hydrogen or a cation by hydrolysis with an organic or inorganic zinc compound or zinc complex and isolating the product of the Formula (I)5 or
d) transforming a compound of the general Formula (III), wherein T and Q together form a single bond and R represents hydrogen into a compound of the general Formula (III), wherein T is hydroxy, R is hydrogen, the meaning of Q is hydrogen or cation, reacting the thus obtained product with an organic or inorganic zinc compound or zinc complex and isolating the product of the Formula (I).
2. Process for the preparation of rosuvastatin zinc salt of the Formula (I), characterized in that a compound of the general Formula (IH), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl or t-butyl groups, T represents hydroxy, R represents hydrogen, is hydrolysed in water, in an organic solvent or in the mixture thereof in the presence of a base and the thus obtained rosuvastatin salt, wherein the meaning of Q is cation, preferably sodium ion, T means hydroxy, R represents hydrogen, is converted by treatment with a strong acid into rosuvastatin free acid (wherein Q and R represent hydrogen, T represents hydroxy) and reacting the thus obtained acid in water, in an organic solvent or in a mixture thereof with a zinc compound selected from zinc alcoholates of the general Formula (V)
R__o — Zn_0_R3 (V)
corresponding to aliphatic alcohols comprising 1 to 4 carbon atoms, zinc acetylacetonate of the Formula (VI),
(VI) sodium zincate or sodium tetrahydroxo-zincate(II) complex and isolating rosuvastatin zinc salt of the Formula (I).
3. Process for the preparation of rosuvastatin zinc salt of the Formula (I), characterized in that a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl or t-butyl group, T represents hydroxy, R represents hydrogen, is hydrolysed in water, in an organic solvent or in the mixture thereof in the presence of a strong mineral or organic acid, rosuvastatin free acid of the Formula (II)
m thus obtained (wherein Q and R are hydrogen, T represents hydroxy) is reacted in water, in an organic solvent or in the mixture thereof with a zinc alcoholate of the Formula (V), corresponding to aliphatic alcohols comprising 1 to 4 carbon atoms or zinc acetylacetonate of the Formula (VI) or sodium zincate or sodium tetrahydroxo-zincate(II) complex and the product rosuvastatin zinc salt of the Formula (I) is isolated.
4. Process for the preparation of rosuvastatin zinc salt of the Formula (I)5 which comprises hydrolysing a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T represents hydroxy, R represents hydrogen in the presence of a base, reacting the compound of the general Formula (III) thus obtained, wherein the meaning of T and R is as defined above, Q is cation, preferably sodium ion, directly or if desired, after isolation with a zinc salt of an organic or inorganic acid and isolating rosuvastatin zinc salt of the Formula (I).
5. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises converting a compound of the general Formual (III), wherein R represents hydrogen, T and Q together form a single bond, in water, in an organic solvent or in the mixture thereof into a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q represents a cation, preferably a sodium ion, and reacting the product thus obtained directly or after isolation with a zinc salt of an organic or inorganic acid and isolating the rosuvastatin zinc salt of the Formula (I).
6. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises reacting a compound of the general Formula (III), wherein T and R together form an oxymethylene group substituted by one or two alkyl groups comprising 1 to 6 carbon atoms, preferably by two methyl groups, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably methyl group or t-butyl group with an inorganic or organic acid in an organic solvent or in water or in a mixture thereof, hydrolysing the thus obtained ester of the general Formula (III), wherein the meaning of T is hydroxy, R represents hydrogen, Q represents an alkyl group in presence of a base, converting the salt, wherein T is hydroxy, R is hydrogen, Q represents cation, preferably sodium ion by a mineral or organic acid into the corresponding carboxylic acid, and reacting the thus obtained acid in water, in an organic solvent or in the mixture thereof with a zinc alcoholate of the Formula (V), corresponding to aliphatic alcohols comprising 1 to 4 carbon atoms or zinc acetylacetonate of the Formula (VI) or sodium zincate or sodium tetrahydroxo-zincate(II) complex and isolating the product rosuvastatin zinc salt of the Formula (I).
7. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises transforming a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl group(s), preferably by two methyl groups in the presence of an inorganic or organic acid in an organic solvent optionally containing water into a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q represents an alkyl group, hydrolysing the ester of the general Formula (III) thus obtained in presence of a base in water, in an organic solvent or in an aqueous-organic solvent, reacting the salt of the general Formula (III), wherein the meaning of T is hydroxy, R represents hydrogen, Q represents a cation, preferably sodium ion in an organic solvent, in water or in the mixture thereof with a zinc salt of an inorganic or organic acid and isolating rosuvastatin zinc salt of the Formula (I).
8. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises converting a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl groups, preferably by two methyl groups in presence of a base in an organic or aqueous solvent into a compound of the general Formula (III), wherein Q represents a cation, preferably sodium ion, the meaning of T and R is as defined above, optionally setting free the corresponding acid, wherein Q represents hydrogen, and converting said compound under acidic conditions into a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q represents hydrogen and reacting the product in water, in an organic solvent or in the mixture thereof with a zinc alcoholate of the Formula (V), corresponding to aliphatic alcohols comprising 1 to 4 carbon atoms or zinc acetylacetonate of the Formula (VI) or sodium zincate or sodium tetrahydroxo-zincate(II) complex and the product rosuvastatin zinc salt of the Formula (I) is isolated.
9. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises transforming a compound of the general Formula (III), wherein Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t-butyl group, T and R together form an oxymethylene group substituted by one or two alkyl group(s), preferably by two methyl groups in presence of a mineral acid in an organic or in an aqueous-organic solvent into a compound of general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q represents hydrogen, and reacting said compound in water, in an organic solvent or in the mixture thereof with a zinc alcoholate of the Formula (V), corresponding to aliphatic alcohols comprising 1 to 4 carbon atoms or zinc acetylacetonate of the Formula (VI) or sodium zincate or sodium tetrahydroxo-zincate(II) complex and the product rosuvastatin zinc salt of the Formula (I) is isolated.
10. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises reacting a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, preferably ethyl group or t- butyl group in an organic solvent, in water or in a mixture thereof in presence of a zinc salt with sodium hydroxide and isolating rosuvastatin zinc salt of the Formula (I).
11. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises converting a compound of the general Formula (TU), wherein T represents hydroxy, R is hydrogen, Q is a cation, preferably sodium ion by an organic or mineral acid into a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q is hydrogen and reacting the thus obtained rosuvastatin acid in water, in an organic solvent or in the mixture thereof with a zinc alcoholate of the Formula (V), corresponding to aliphatic alcohols comprising 1 to 4 carbon atoms or zinc acetylacetonate of the Formula (VI) or sodium zincate or sodium tetrahydroxo-zincate(π) complex and the product rosuvastatin zinc salt of the Formula (I) is isolated.
12. Process for the preparation of rosuvastatin zinc salt of the Formula (I), which comprises dissolving a compound of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q is a cation, preferable sodium ion, in water or in an organic solvent, reacting said compound with a zinc salt of an organic or inorganic acid and isolating rosuvastatin zinc salt of the Formula (I).
13. Process according to any of claims 1 to 12, characterized in that the solvent is selected from water, aliphatic alcohols comprising 1 to 4 carbon atoms, acetonitrile, an aliphatic ketone comprising 3 to 8 carbon atoms, an aliphatic ester comprising 2 to 8 carbon atoms and an aliphatic ether comprising 4 to 8 carbon atoms or the mixtures thereof.
14. Process according to any of claims 1 to 12, characterized in that the reaction is carried out at a temperature between 0 0C and the boiling temperature of the reaction mixture, preferably between 25 and 80 °C, the most advantageously, between 25 and .50 0C.
15. Process according to any of claims 1, 2, 4 to 8, or 10, characterized in that the hydrolysis is carried out in the presence of 1.0 to 1.25 molar equivalents of base calculated on the molar amount of the starting material.
16. Process according to claim 15, characterized in that as a base, an inorganic or organic base, preferably an alkali metal hydroxide, the most advantageously, sodium hydroxide is used.
17. Process according to claim 15 or 16, characterized in that the base is used in solid form or as a solution having a concentration of 0,05-10 mol/dm3 or as saturated aqueous solution.
18. Process according to claim 3, characterized in that the acidic hydrolysis is carried out in the presence of a strong mineral or organic acid, e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, methansulfonic acid, ethanesulfonic acid, preferably, in the presence of hydrochloric acid.
19. Process according to claim 18, characterized in that the concentration of the strong mineral or organic acid is between 0.2-10,0 mol/dm3.
20. Process according to any of claims 6 to 9, characterized in that for the preparation of those compounds of the general Formula (III), wherein T represents hydroxy, R represents hydrogen, Q represents an alkyl group comprising 1 to 6 carbon atoms or an alkenyl group comprising 2 to 6 carbon atoms, the corresponding compound of the general Formula (III), wherein T and R together corresponds to an oxymethylene group substituted with one or two alkyl groups, preferably by two methyl groups, the meaning of Q is as defined above, is reacted with a strong mineral acid or organic acid, e.g. hydrogen chloride, hydrogen bromide, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid.
21. Process according to claim 20, characterized in that the strong organic or mineral acid is used in 1.0 to 40.0-fold molar equivalent amount of the starting compound.
22. Process according to any of claims 1 to 12, characterized in that for the zinc salt formation, an organic or inorganic zinc salt or hydrates thereof, e.g. zinc formiate, zinc acetate, zinc propionate, zinc maleate, zinc fumarate, zinc tartarate, zinc lactate, zinc malate, zinc citrate, zinc ascorbace, zinc malonate, zinc oxalate, zinc glycolate, zinc methanesulfonate, zinc ethanesulfonate, a salt of zinc with an amino acid, zinc sulfate, zinc chloride, zinc carbonate or zinc nitrate, preferably zinc sulfate, zinc chloride or zinc acetate is used.
23. Process according to any of claims 1 to 12, characterized in that the zinc salt formation is carried out using a zinc alcoholate of the general Formula (V) prepared from an aliphatic alcohol comprising 1 to 4 carbon atoms.
24. Process according to any of claims 1 to 12, characterized in that in the zinc salt formation, a zinc complex, e.g. zinc acetylacetonate of the Formula (VI) or hydrate thereof, sodium zincate or sodium tetrahydro-zincate(II) is used.
25. Process according to any of claims 1 to 12, characterized in that the zinc salt is applied in an amount which contains 0.4-0.6 molar equivalent amount of zinc calculated on the basis of the molar amount of the starting compound.
26. Process according to any of claims 1, 4, 6 to 9 and 12, characterized in that as starting material of zinc salt formation, rosuvastatin sodium salt is used.
27. Process according to any of claims 1 to 12, characterized in that the salt formation is carried out in aqueous solution by reacting rosuvastatin sodium salt and 0.4-0.6 molar equivalent amount of zinc sulfate at a temperature between 0 and 40 °C.
28. Process according to any of claims 1 to 12, characterized in that the rosuvastatin zinc salt of the Formula (I) is isolated by extracting the compound of the Formula (I) with an aliphatic ester comprising 2 to 8 carbon atoms, concentrating the solution and precipitating the rosuvastatin zinc salt by addition of an aliphatic ether comprising 4 to 8 carbon atoms.
29. (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-(3i-,5iS)-dihydroxy-hept-6-enoic acid zinc salt (2:1), containing 0.01-30 weight% amount of solvated water, aliphatic alcohol comprising 1 to 4 carbon atoms, acetonitrile, aliphatic ketone comprising 3 to 8 carbon atoms, aliphatic ester comprising 2 to 8 carbon atoms or aliphatic ether comprising 4 to 8 carbon atoms.
30. High purity (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2- (methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3i-,55)-dihydroxy- hept-6-enoic acid sodium salt (1:1), obtainable by reacting a compound of the general Formula (111), wherein T represents hydroxy, R represents hydrogen, Q represents an alkyl group comprising 1 to 6 carbon atoms, preferably ethyl-group in acetonitrile or in an aliphatic alcohol comprising 1 to 4 carbon atoms with equivalent amount of sodium hydroxide at room temperature, evaporating the solvent, extracting the aqueous residue with an ester-type solvent comprising 2 to 8 carbon atoms, evaporating the aqueous residue and removing the traces of water from said residue, solidifying the residue by stirring in a mixture of an aliphatic alcohol comprising 1 to 4 carbon atoms and an aliphatic ether comprising 2 to 8 carbon atoms and washing the solid product with an aliphatic alcohol comprising 1 to 4 carbon atoms.
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Cited By (3)
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WO2011010174A1 (en) * | 2009-07-24 | 2011-01-27 | Egis Gyógyszergyár Nyilvánosan Működő | Crystalline form i rosuvastatin zinc salt |
WO2012066365A2 (en) | 2010-11-16 | 2012-05-24 | EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság | Crystalline pharmaceutically active ingredients |
WO2012073054A2 (en) | 2010-11-29 | 2012-06-07 | Egis Gyógyszergyár Nyilvánosan Múködó Részvény-Társaság | Method for preparing rosuvastatin salts |
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US9321733B2 (en) | 2010-11-16 | 2016-04-26 | Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag | Crystalline pharmaceutically active ingredients |
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WO2012073054A2 (en) | 2010-11-29 | 2012-06-07 | Egis Gyógyszergyár Nyilvánosan Múködó Részvény-Társaság | Method for preparing rosuvastatin salts |
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