WO2012135686A1 - Methods for synthesizing metal mesoporphyrins - Google Patents
Methods for synthesizing metal mesoporphyrins Download PDFInfo
- Publication number
- WO2012135686A1 WO2012135686A1 PCT/US2012/031557 US2012031557W WO2012135686A1 WO 2012135686 A1 WO2012135686 A1 WO 2012135686A1 US 2012031557 W US2012031557 W US 2012031557W WO 2012135686 A1 WO2012135686 A1 WO 2012135686A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tin
- metal
- mesoporphyrin
- compound
- hemin
- Prior art date
Links
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 137
- 239000002184 metal Substances 0.000 title claims abstract description 137
- 238000000034 method Methods 0.000 title claims abstract description 87
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 22
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims abstract description 88
- -1 mesoporphyrin compound Chemical class 0.000 claims abstract description 73
- NCAJWYASAWUEBY-UHFFFAOYSA-N 3-[20-(2-carboxyethyl)-9,14-diethyl-5,10,15,19-tetramethyl-21,22,23,24-tetraazapentacyclo[16.2.1.1^{3,6}.1^{8,11}.1^{13,16}]tetracosa-1(21),2,4,6(24),7,9,11,13,15,17,19-undecaen-4-yl]propanoic acid Chemical class N1C2=C(C)C(CC)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1CCC(O)=O)=NC1=CC(C(CCC(O)=O)=C1C)=NC1=C2 NCAJWYASAWUEBY-UHFFFAOYSA-N 0.000 claims abstract description 68
- BTIJJDXEELBZFS-QDUVMHSLSA-K hemin Chemical compound CC1=C(CCC(O)=O)C(C=C2C(CCC(O)=O)=C(C)\C(N2[Fe](Cl)N23)=C\4)=N\C1=C/C2=C(C)C(C=C)=C3\C=C/1C(C)=C(C=C)C/4=N\1 BTIJJDXEELBZFS-QDUVMHSLSA-K 0.000 claims abstract description 54
- 229940025294 hemin Drugs 0.000 claims abstract description 54
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 44
- 229950003776 protoporphyrin Drugs 0.000 claims abstract description 30
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 229910052718 tin Inorganic materials 0.000 claims description 82
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 66
- LLDZJTIZVZFNCM-UHFFFAOYSA-J 3-[18-(2-carboxyethyl)-8,13-diethyl-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoic acid;dichlorotin(2+) Chemical compound [H+].[H+].[Cl-].[Cl-].[Sn+4].[N-]1C(C=C2C(=C(C)C(=CC=3C(=C(C)C(=C4)N=3)CC)[N-]2)CCC([O-])=O)=C(CCC([O-])=O)C(C)=C1C=C1C(C)=C(CC)C4=N1 LLDZJTIZVZFNCM-UHFFFAOYSA-J 0.000 claims description 61
- 229950001307 stannsoporfin Drugs 0.000 claims description 44
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 40
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 40
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 37
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 36
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 claims description 28
- 229910001887 tin oxide Inorganic materials 0.000 claims description 28
- 229910052763 palladium Inorganic materials 0.000 claims description 24
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 20
- 235000019253 formic acid Nutrition 0.000 claims description 20
- 229910052742 iron Inorganic materials 0.000 claims description 20
- 229910052759 nickel Inorganic materials 0.000 claims description 18
- 229910052697 platinum Inorganic materials 0.000 claims description 18
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 claims description 18
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 17
- DBOVLDLKDZRBNC-UHFFFAOYSA-J 2,4,6,7,8-pentaoxa-3lambda5,5lambda5-diphospha-1-stannatricyclo[3.1.1.11,3]octane 3,5-dioxide hydrate Chemical compound O.[Sn+4].[O-]P([O-])(=O)OP([O-])([O-])=O DBOVLDLKDZRBNC-UHFFFAOYSA-J 0.000 claims description 16
- PGGZKNHTKRUCJS-UHFFFAOYSA-N methanesulfonic acid;tin Chemical compound [Sn].CS(O)(=O)=O PGGZKNHTKRUCJS-UHFFFAOYSA-N 0.000 claims description 16
- FAKFSJNVVCGEEI-UHFFFAOYSA-J tin(4+);disulfate Chemical compound [Sn+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O FAKFSJNVVCGEEI-UHFFFAOYSA-J 0.000 claims description 16
- LTSUHJWLSNQKIP-UHFFFAOYSA-J tin(iv) bromide Chemical compound Br[Sn](Br)(Br)Br LTSUHJWLSNQKIP-UHFFFAOYSA-J 0.000 claims description 16
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 15
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 15
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 15
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052787 antimony Inorganic materials 0.000 claims description 15
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 claims description 15
- 229910052785 arsenic Inorganic materials 0.000 claims description 15
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 claims description 15
- 229910052793 cadmium Inorganic materials 0.000 claims description 15
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 15
- 229910052804 chromium Inorganic materials 0.000 claims description 15
- 239000011651 chromium Substances 0.000 claims description 15
- 229910017052 cobalt Inorganic materials 0.000 claims description 15
- 239000010941 cobalt Substances 0.000 claims description 15
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 15
- 229910052802 copper Inorganic materials 0.000 claims description 15
- 239000010949 copper Substances 0.000 claims description 15
- 229910052733 gallium Inorganic materials 0.000 claims description 15
- 229910052732 germanium Inorganic materials 0.000 claims description 15
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 claims description 15
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052737 gold Inorganic materials 0.000 claims description 15
- 239000010931 gold Substances 0.000 claims description 15
- 229910052749 magnesium Inorganic materials 0.000 claims description 15
- 239000011777 magnesium Substances 0.000 claims description 15
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 15
- 229910052709 silver Inorganic materials 0.000 claims description 15
- 239000004332 silver Substances 0.000 claims description 15
- 229910052725 zinc Inorganic materials 0.000 claims description 15
- 239000011701 zinc Substances 0.000 claims description 15
- 239000011135 tin Substances 0.000 claims description 14
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 14
- 229920001843 polymethylhydrosiloxane Polymers 0.000 claims description 12
- NGCDGPPKVSZGRR-UHFFFAOYSA-J 1,4,6,9-tetraoxa-5-stannaspiro[4.4]nonane-2,3,7,8-tetrone Chemical compound [Sn+4].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O NGCDGPPKVSZGRR-UHFFFAOYSA-J 0.000 claims 5
- 239000000543 intermediate Substances 0.000 abstract description 51
- 238000003780 insertion Methods 0.000 abstract description 16
- 230000037431 insertion Effects 0.000 abstract description 16
- 238000002955 isolation Methods 0.000 abstract description 8
- 238000006478 transmetalation reaction Methods 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 description 72
- 239000000047 product Substances 0.000 description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 32
- 239000003054 catalyst Substances 0.000 description 31
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 19
- 239000000908 ammonium hydroxide Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000000746 purification Methods 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 239000000463 material Substances 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- QHGNHLZPVBIIPX-UHFFFAOYSA-N tin(ii) oxide Chemical compound [Sn]=O QHGNHLZPVBIIPX-UHFFFAOYSA-N 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- OQBLGYCUQGDOOR-UHFFFAOYSA-L 1,3,2$l^{2}-dioxastannolane-4,5-dione Chemical compound O=C1O[Sn]OC1=O OQBLGYCUQGDOOR-UHFFFAOYSA-L 0.000 description 12
- 239000011790 ferrous sulphate Substances 0.000 description 12
- 235000003891 ferrous sulphate Nutrition 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 238000010949 in-process test method Methods 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 11
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000005909 Kieselgur Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 230000001590 oxidative effect Effects 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- LQBPATQBTSBIIH-UHFFFAOYSA-N methyl 3-[8,13-bis(ethenyl)-18-(3-methoxy-3-oxopropyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoate Chemical compound N1C(C=C2C(=C(C=C)C(=CC=3C(=C(CCC(=O)OC)C(=C4)N=3)C)N2)C)=C(C=C)C(C)=C1C=C1C(C)=C(CCC(=O)OC)C4=N1 LQBPATQBTSBIIH-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical group [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000003610 charcoal Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 5
- 238000010268 HPLC based assay Methods 0.000 description 5
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- SYRHIZPPCHMRIT-UHFFFAOYSA-N tin(4+) Chemical compound [Sn+4] SYRHIZPPCHMRIT-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
- CQKDGYMHYLBWTQ-UHFFFAOYSA-N methyl 3-[8,13-diethyl-18-(3-methoxy-3-oxopropyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoate Chemical compound N1C2=C(C)C(CC)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1CCC(=O)OC)=NC1=CC(C(CCC(=O)OC)=C1C)=NC1=C2 CQKDGYMHYLBWTQ-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- PNOXNTGLSKTMQO-UHFFFAOYSA-L diacetyloxytin Chemical compound CC(=O)O[Sn]OC(C)=O PNOXNTGLSKTMQO-UHFFFAOYSA-L 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
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- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- PLONEVHFXDFSLA-UHFFFAOYSA-N ethyl hexanoate;tin(2+) Chemical compound [Sn+2].CCCCCC(=O)OCC PLONEVHFXDFSLA-UHFFFAOYSA-N 0.000 description 2
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- ZSUXOVNWDZTCFN-UHFFFAOYSA-L tin(ii) bromide Chemical compound Br[Sn]Br ZSUXOVNWDZTCFN-UHFFFAOYSA-L 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- VAJVGAQAYOAJQI-UHFFFAOYSA-N 3-[18-(2-carboxylatoethyl)-3,8,13,17-tetramethyl-22,23-dihydroporphyrin-21,24-diium-2-yl]propanoate Chemical compound N1C(C=C2C(C)=CC(N2)=CC=2C(=C(CCC(O)=O)C(=C3)N=2)C)=CC(C)=C1C=C1C(C)=C(CCC(O)=O)C3=N1 VAJVGAQAYOAJQI-UHFFFAOYSA-N 0.000 description 1
- KFKRXESVMDBTNQ-UHFFFAOYSA-N 3-[18-(2-carboxylatoethyl)-8,13-bis(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-21,24-diium-2-yl]propanoate Chemical class N1C2=C(C)C(C(C)O)=C1C=C(N1)C(C)=C(C(O)C)C1=CC(C(C)=C1CCC(O)=O)=NC1=CC(C(CCC(O)=O)=C1C)=NC1=C2 KFKRXESVMDBTNQ-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101001021103 Homo sapiens Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 241001328813 Methles Species 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102100036201 Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 159000000014 iron salts Chemical class 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- AFNRRBXCCXDRPS-UHFFFAOYSA-N tin(ii) sulfide Chemical compound [Sn]=S AFNRRBXCCXDRPS-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2284—Compounds with one or more Sn-N linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Definitions
- Embodiments described herein are generally directed to methods of synthesizing metal mesoporphyrin compounds.
- a method of synthesizing a metal mesoporphyrin compound comprises transmetallating hemin and hydrogenating the metal protoporphyrin IX.
- the hemin is transmetallated in the presence of ferrous sulfate.
- the metal protoporphyrin IX is hydrogenated using dilute ammonium hydroxide, dimethyl formamide or n-methyl pyrrolidinone.
- the metal mesopo ⁇ hyrin is precipitated using methyl tert-butyl ether (MTBE).
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- tin is the inserted metal.
- tin is inserted into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- a method of synthesizing a metal mesoporphyrin compound comprises forming a protoporphyrin methyl ester from hemin and converting the protoporphyrin methyl ester intermediate to a metal mesoporphyrin compound through metal insertion and hydrogenation.
- metal insertion yields a metal protoporphyrin dimethyl ester intermediate.
- the metal protoporphyrin dimethyl ester is hydrogenated in dichloromethane over palladium catalyst to form a metal mesoporphyrin dimethyl ester.
- the metal mesoporphyrin dimethyl ester is heated in dilute ammonium hydroxide to form the metal mesoporphyrin compound.
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- tin is the inserted metal.
- tin is inserted into mesoporphyrin to make stannsoporfm using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- a method of synthesizing a metal mesoporphyrin compound comprises forming a mesoporphyrin IX intermediate from hemin by a hydrogen-free hydrogenation, inserting a metal into the intermediate, and hydrogenating the metallated intermediate to form the metal mesoporphyrin compound.
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- tin is the inserted metal.
- tin is inserted into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- a method of synthesizing a metal mesoporphyrin compound comprises forming a mesoporphyrin IX dihydrochloride intermediate compound and converting the mesoporphyrin IX intermediate to a metal mesoporphyrin compound through metal insertion.
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- tin is the inserted metal.
- tin is inserted into mesoporphyrin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- the metal mesoporphyrin halide is stannsoporfin.
- a metal mesoporphyrin halide may be formed directly from hemin without isolation of any intermediates.
- a method of synthesizing a metal mesoporphyrin may comprise hydrogenation of hemin and subsequent insertion of metal.
- no intermediate compound is isolated.
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- tin is the inserted metal.
- tin is inserted into mesoporphyrin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- the metal mesoporphyrin halide is stannsoporfin.
- Figure 1 illustrates an exemplary low temperature, oxygen-free synthesis of stannsoporfin and each constituent synthesis.
- Figure 2 illustrates an exemplary oxidative reflux synthesis of stannsoporfin.
- Figure 3 illustrates the structure of stannsoporfin (B992).
- Figure 4 illustrates the structure of mono vinyl intermediates (A) CJ9 and (B)
- Figure 5 illustrates the structure of tin protoporphyrin (CH8).
- the term "about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
- compositions comprising a compound described herein and a pharmaceutically acceptable carrier or diluent, or an effective amount of a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier or diluent.
- Embodiments herein generally relate to novel processes for the preparation of metal mesoporphyrin halides.
- a metal mesoporphyrin compound may be formed by hemin transmetallation and subsequent hydrogenation of the metal protoporphyrin to form a metal mesoporphyrin halide.
- a method of synthesizing a metal mesoporphyrin halide comprises forming a protoporphyrin methyl ester from hemin and converting the ⁇ ⁇ methyl ester intermediate to a metal mesoporphyrin halide through metal insertion and hydrogenation.
- a metal mesoporphyrin halide may be formed from hemin by a hydrogen-free hydrogenation method to form a mesoporphyrin IX intermediate followed by metal insertion into the mesoporphyrin IX intermediate and hydrogenation of the metallated intermediate to form the metal mesoporphyrin halide.
- Tin (IV) mesoporphyrin IX dichloride or stannsoporfm is a chemical compound having the structure indicated in FIG. 3. It has been proposed for use, for example, as medicament in the treatment of various diseases including, for example, psoriasis and infant jaundice. Stannsoporfm may also inhibit heme metabolism in mammals, to control the rate of tryptophan metabolism in mammals, and to increase the rate at which heme is excreted by mammals.
- mesoporphyrin halides for example, but not limited to, mesoporphyrin chlorides of other metals such as, for example, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium and palladium, among others.
- a metal mesoporphyrin compound may be formed by hemin transmetallation and subsequent hydrogenation of the metal protoporphyrin IX to form a metal mesoporphyrin halide.
- hemin is transmetallated with a metal carrier, for example tin to form tin protoporphyrin, followed by hydrogenation in a solvent, such as n-methyl pyrrolidinone, dilute ammonium hydroxide, or dimethyl formamide.
- the hemin may be subjected to transmetallation with or without the addition of ferrous sulfate.
- the transmetallated hemin is treated with charcoal.
- the product is isolated after hydrogenation by the addition of acetic acid or hydrochloric acid.
- the final product is precipitated using MTBE.
- the product is further purified by chromatography.
- a method of synthesizing a metal mesopo ⁇ hyrin halide comprises forming a protoporphyrin methyl ester from hemin and converting the protoporphyrin methyl ester intermediate to a metal mesoporphyrin halide through metal insertion and hydrogenation.
- hemin, pyridine, and dichloromethane may be agitated to form a solution.
- Ferrous sulfate, methanol, dichloromethane, and HC1 gas may then be added to form an exothermic reaction.
- the exothermic reaction may then be held at reflux for a period of about 2 to about 5 hours.
- the reaction may further be washed with water and dilute ammonium hydroxide to form the protoporphyrin methyl ester.
- a metal may be inserted into the protoporphyrin methyl ester.
- tin may be inserted into the protoporphyrin methyl ester using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- the metal protoporphyrin dimethyl ester may be hydrogenated using an appropriate metal catalyst in a hydrogen atmosphere to form a metal mesoporphyrin dimethyl ester.
- tin protoporphyrin dimethyl ester may be hydrogenated to form tin mesoporphyrin dimethyl ester.
- a metal mesoporphyrin halide may be formed by heating the metal mesoporphyrin dimethyl ester in dilute ammonium hydroxide.
- stannsoporfin may be formed from tin mesoporphyrin dimethyl ester by heating the material at about 70°C to about 80°C in dilute ammonium hydroxide.
- stannsoporfin may be formed by heating tin mesoporphyrin dimethyl ester to about 75°C in dilute ammonium hydroxide.
- the product may be further purified by chromatography.
- Some embodiments describe a method of synthesizing a metal mesoporphyrin halide comprising forming a mesoporphyrin IX dihydrochloride intermediate compound and converting the mesoporphyrin IX dihydrochloride intermediate to a metal mesoporphyrin halide through metal insertion.
- hemin is hydrogenated in formic acid, over an appropriate metal catalyst under a hydrogen atmosphere, at about 80°C to about 101°C for about 1 hour to about 3 hours.
- hydrogenation of the hemin may continue for an additional time of about 24 hours to about 36 hours at about 40°C to about 60°C.
- hemin may be hydrogenated at about 85°C to about 90°C at about 60 psi of hydrogen for about 1 hour to about 2 hours followed and then at about 45°C to about 50°C for about 24 hours to about 36 hours.
- the metal catalyst may be palladium, nickel, platinum, palladium on carbon, or the like.
- the reaction may be cooled to about 20°C to about 30°C, or about 20°C to about 25°C, and optionally charged with powdered activated carbon, such as that sold under the trade name Darco KB-G.
- the reaction may be agitated prior to filtration.
- the reaction may be filtered through a metal scavenger such as Hyflo Supercel to remove catalyst.
- the filtrate solution may then be concentrated, for example by vacuum distillation.
- a solution of about IN HCL may then be added over about 1 hour or more to precipitate the intermediate product.
- the product is dried under a stream of nitrogen to yield a mesoporphyrin IX dihydrochloride.
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- the metal carrier is a tin (II) carrier. Tin (II) carriers such as tin (II) halides or tin (II) acetate may be used.
- the tin carrier may be tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- tin (II) oxide powder may be suspended in acetic acid.
- to this suspension may be added a solution of mesoporphyrin IX dihydrochloride in formic acid under a nitrogen atmosphere and warmed to about 60°C to about 65°C.
- water may be added slowly and the reaction mixture may be slowly cooled to about 20°C to about 30°C, or about 20°C to about 25°C, agitated, and filtered.
- the filter cake may be rinsed with water, suspended in IN HC1, and warmed to about 85°C to about 95°C for about 1 hours to about 3 hours.
- the suspension may be cooled to about 20°C to about 30°C, or about 20°C to about 25°C, agitated, and filtered and dried under nitrogen to yield crude tin mesoporphyrin IX dichloride.
- tin (II) oxide (SnO, 1.7 kg) powder may be suspended in about 40.5 L of acetic acid at about 20°C to about 25°C and then warmed to about 60°C to about 65°C under nitrogen.
- the reaction may be carried out under a nitrogen atmosphere at about 60°C to about 65°C for a minimum of about 12 hours.
- the reaction may be monitored by HPLC. Once the reaction is complete, about 17 L of water may be added over about 0.5 hours.
- the reaction mixture is then cooled to about 20°C to about 25°C over about 0.5 hours, agitated for about 1 to about 3 hours and then filtered.
- the filter cake may be rinsed with distilled water (USP), suspended in about IN HC1 and warmed to about 85°C to about 95°C for about 1 to about 3 hours.
- the suspension may then be cooled to about 20°C to about 25°C, agitated for about 0.5 hours, filtered, rinsed with distilled water (USP) and dried under nitrogen to yield about 1.3 to about 1.5 Kg of crude tin mesoporphyrin IX dichloride (stannsoporfin).
- mesoporphyrin IX dihydrochloride may be subjected to heating with a metal carrier in acetic acid, in the presence of an oxidant, at reflux (oxidative reflux process).
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- the metal carrier is a tin (II) carrier. Tin (II) carriers such as tin (II) halides or tin (II) acetate may be used.
- the tin carrier may be tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- the heating is performed with aeration, for example, by an inflow of about 6% oxygen mixed with nitrogen for about 24 hours to about 48 hours. Air inflow may also be used to aerate during heating.
- the reaction may also be carried out in the presence of suitable acetate counter ions include ammonium, sodium or potassium ions. Oxidants such as oxygen from air or in pure form as well as hydrogen peroxide may also be used.
- mesopo ⁇ hyrin IX formate is subjected to heating with tin (II) oxide in acetic acid, buffered with ammonium acetate, and the reaction is conducted with aeration, at reflux. The ammonium acetate can be eliminated.
- the metallated mesoporphyrin may be isolated from the reaction mixture by the addition of water, followed by filtration. In embodiments, prior to drying, the cake may triturated into hot, dilute hydrochloric acid, preferably at concentration of about 0.1N - 6N and at an elevated temperature of about 90°C to about 100°C.
- the reaction yields a crude metal mesoporphyrin IX dichloride. In some embodiments, the reaction yields a crude tin (IV) mesoporphyrin IX dichloride.
- the metal mesoporphyrin dichloride so obtained may be further purified by dissolving the product in an aqueous inorganic base solution, preferably dilute ammonium hydroxide, followed by treatment with charcoal.
- the product may then be re-precipitated by addition to an acid solution, such as acetic acid, hydrochloric acid or a mixture thereof.
- the above dissolving charcoal treatment and re-precipitation steps may be repeated a number of times, typically about 1 to 3 times in order to ensure the desired purity.
- the cake Prior to drying, the cake is triturated in hot, dilute hydrochloric acid of a concentration of about 0.
- the metallated mesoporphyrin chloride product (tin (IV) mesopo ⁇ hyrin IX dichloride or stannsoporfin) is obtained.
- the tin mesopo ⁇ hyrin chloride product (tin (IV) mesoporphyrin IX dichloride or stannsoporfin) is obtained.
- the final product, ex. stannsoporfin is isolated by chromatography.
- crude tin mesoporphyrin IX dichloride (1.7 Kg) may be dissolved in 2% ammonium hydroxide (22 L).
- a pH check may be performed to ensure the pH is > 9.0.
- the solution may be treated with Darco KB-G (0.1 Kg) and Hyflo Supercel (0.2 Kg), agitated for a period of 1 to 2 hours and filtered to remove solids.
- the filtrate may then be added drop wise to acetic acid (44 L) containing hydrochloric acid (31%, 2.7 L), keeping the temperature at 20°C to about 25°C.
- a pH check may again be performed to ensure pH ⁇ 1.0.
- the resultant suspension may be agitated for 1 to 2 hours under nitrogen prior to isolating the product by filtration.
- the wet cake may then be triturated in 3N HC1 (35 L) at 85°C to about 90°C and agitated for about 16 hours to about 18 hours to convert the crystalline form to monomer and remove residual ammonium salts.
- the suspension may be cooled to 20°C to about 25°C and the product isolated by filtration.
- the product cake may be rinsed with 0.3N HC1 (16 L) and dried under a stream of nitrogen to yield about 1.2 to about 1.6 Kg of Stannsoporfin.
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- a halide such as chloride, bromide or iodide of the chosen metal in place of stannous chloride in the process described, in substantially equivalent amounts.
- a metal mesoporphyrin halide may be formed from hemin by a hydrogen-free hydrogenation method to form a mesoporphyrin IX intermediate followed by metal insertion into the mesoporphyrin IX intermediate and hydrogenation of the metallated intermediate to form the metal mesoporphyrin halide.
- Mesoporphyrin may be obtained by reacting hemin with ferrous sulfate, palladium on carbon, and poly(methylhydrosiloxane) (PMHS) in formic acid at reflux and further hydrogenated with PMHS.
- the product may be isolated as mesoporphyrin formate from formic acid and methyl tertbutyl ether.
- the product may then be carried through the dihydrochloride formation process outlined above.
- the hemin was reacted with ferrous sulfate, palladium on carbon, and poly(methylhydrosiloxane) (PMHS) in formic acid and then concentrated by rotary evaporation to remove formic acid.
- the ensuing solids may be isolated by filtration and carried through the standard tin oxide route.
- the resulting filtrate may then be concentrated and dissolved in dilute ammonium hydroxide and precipitated by addition to acetic acid or hydrochloric acid.
- the iron may be removed from hemin using ferrous sulfate prior to the PMHS hydrogenation.
- the product is further purified by chromatography.
- the reactants, intermediates, and/or products can undergo additional steps of purification.
- the additional purification comprises treating the reactant, intermediate, or product with diatomaceous earth and/or activated carbon.
- the treating of the reactant, intermediate, or product with diatomaceous earth and/or activated carbon comprises dissolving or suspending the reactant, intermediate, and/or product in a solvent, adding diatomaceous earth and/or activated carbon, filtering off the diatomaceous earth and/or activated carbon, and recovering the reactant, intermediate, or product from the filtrate.
- the additional purification comprises triturating the reactant, intermediate, or product with hot acid, such as about 0.1 to 6N HC1 in water, preferably about 3N HC1 in water.
- hot acid such as about 0.1 to 6N HC1 in water, preferably about 3N HC1 in water.
- one, two, or three of the steps of treating with diatomaceous earth, treating with activated carbon, and triturating with hot acid are performed sequentially, in any order, and can be repeated as desired.
- a metal mesoporphyrin halide may be formed directly from hemin without isolation of any intermediates.
- metal mesoporphyrin compound is synthesized without isolating a mesoporphyrin formate intermediate or a mesoporphyrin dihydrochloride intermediate.
- the metal mesoporphyrin may be synthesized using any of the above described methods without isolating the mesoporphyrin dihydrochloride intermediate.
- the metal mesoporphyrin may be synthesized using any of the above described methods without isolating an intermediate.
- the metal mesoporphyrin may be synthesized using the standard tin oxide route or the oxidative-refiux process described above without isolating the mesoporphyrin dihydrochloride intermediate. In some embodiments, the metal mesoporphyrin may be synthesized using the standard tin oxide route or the oxidative-reflux process described above without isolating an intermediate. In some embodiments, a method of synthesizing stannsoporfin comprises hydrogenating hemin and heating the reaction in the presence of a metal carrier. In some embodiments, the heating takes place in a nitrogen atmosphere.
- a method of synthesizing stannsoporfin comprises hydrogenating hemin and heating the resulting reaction with a metal carrier in acetic acid, in the presence of an oxidant, at reflux.
- the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
- the metal carrier is a tin (II) carrier. Tin (II) carriers such as tin (II) halides or tin (II) acetate may be used.
- the tin carrier may be tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- hemin is hydrogenated in formic acid, over an appropriate metal catalyst under a hydrogen atmosphere, at about 80°C to about 101°C for about 1 hour to about 3 hours.
- hydrogenation of the hemin may continue for an additional time of about 24 hours to about 36 hours at about 40°C to about 60°C.
- hemin may be hydrogenated at about 85°C to about 90°C at about 60 psi of hydrogen for about 1 hour to about 2 hours followed and then at about 45°C to about 50°C for about 24 hours to about 36 hours.
- the metal catalyst may be palladium, nickel, platinum, palladium on carbon, or the like.
- the reaction may be cooled to about 20°C to about 30°C, or about 20°C to about 25°C, and optionally charged with powdered activated carbon, such as that sold under the trade name Darco KB-G.
- the reaction may be agitated prior to filtration.
- the reaction may be filtered through a metal scavenger such as Hyflo Supercel to remove catalyst.
- the filtrate solution may then be concentrated, for example, by vacuum distillation.
- the reactants, intermediates, and/or products can undergo additional steps of purification.
- the additional purification comprises treating the reactant, intermediate, or product with diatomaceous earth and/or activated carbon.
- the treating of the reactant, intermediate, or product with diatomaceous earth and/or activated carbon comprises dissolving or suspending the reactant, intermediate, and/or product in a solvent, adding diatomaceous earth and/or activated carbon, filtering off the diatomaceous earth and/or activated carbon, and recovering the reactant, intermediate, or product from the filtrate.
- the additional purification comprises triturating the reactant, intermediate, or product with hot acid, such as about 0.1 to about 6N HC1 in water, preferably about 3N HC1 in water.
- hot acid such as about 0.1 to about 6N HC1 in water, preferably about 3N HC1 in water.
- one, two, or three of the steps of treating with diatomaceous earth, treating with activated carbon, and triturating with hot acid are performed sequentially, in any order, and can be repeated as desired.
- a method of making a metal mesoporphyrin halide comprises the steps of: a) exposing a metallic hydrogenation catalyst to a hydrogen atmosphere to form pre-hydrogenated catalyst; and b) contacting hemin with the pre-hydrogenated catalyst and maintaining the hemin and catalyst under one or more cycles having a combination of temperature, hydrogen pressure, and time sufficient to remove iron from the hemin and reduce the vinyl groups of the hemin to ethyl groups, thus forming mesoporphyrin IX.
- a method of making a metal mesoporphyrin halide comprises the steps of: a) exposing a metallic hydrogenation catalyst to a hydrogen atmosphere to form pre-hydrogenated catalyst; b) contacting hemin with the pre-hydrogenated catalyst and maintaining the hemin and catalyst under one or more cycles having a combination of temperature, hydrogen pressure, and time sufficient to remove iron from the hemin and reduce the vinyl groups of the hemin to ethyl groups, thus forming mesoporphyrin IX; and c) reacting mesoporphyrin IX with a metal salt to form a metal mesoporphyrin halide using a controlled rate of oxidation.
- step b) of embodiments herein may be carried out at about 80°C to about 100° C, preferably at about 85°C to about 90°C, with hydrogen pressure at about 50 to about 70 psi, preferably at about 55 to about 60 psi, for about 1 to about 3 hours, preferably about 1 to about 1.5 hours; then at about 40°C to about 60°C, preferably about 45°C to about 50°C, with hydrogen pressure at about 50 to about 70 psi, preferably at about 55 to about 60 psi, for about 18 to about 48 hours, preferably about 24 hours.
- the metallic hydrogenation catalyst comprises palladium, palladium on carbon, platinum, platinum on carbon, nickel, or nickel-aluminum catalyst. In another embodiment, the metallic hydrogenation catalyst is palladium. In another embodiment, the metallic hydrogenation catalyst is palladium on carbon.
- Embodiments herein also include insertion of tin into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- tin is inserted into mesoporphyrin using tin oxide, tin chloride or tin 2-ethylhexanoate.
- the mesoporphyrin IX hydrochloride may be treated with a tin (II) salt in an organic solvent, such as acetic acid, under oxidizing conditions, which yields the desired product, tin (IV) mesoporphyrin IX dichloride (stannsoporfin).
- mesoporphyrin IX dihydrochloride and tin (II) chloride may be placed in a vessel, and acetic acid may be added at about 20°C to about 30°C, preferably at about 20°C to about 25°C.
- the suspended reagents are agitated for at least about 30 minutes. With vigorous agitation, the mixture is warmed under an inert atmosphere (such as nitrogen or argon) to reflux.
- the invention embraces a method of inserting tin into mesoporphyrin IX, comprising reacting the mesoporphyrin IX with a tin salt in the absence of a proton scavenger.
- the invention embraces a method of inserting tin into mesoporphyrin IX, comprising reacting the mesoporphyrin IX with a tin salt at a controlled rate of oxidation.
- the mesoporphyrin IX is reacted with a tin salt in a reaction vessel having a headspace, and the rate of oxidation is controlled by introducing an oxygen-containing gas into the headspace of the reaction vessel.
- the oxygen-containing gas introduced into the headspace of the reaction vessel is about 3% to about 22% oxygen in an inert gas, such as nitrogen.
- the oxygen-containing gas introduced into the headspace of the reaction vessel is air.
- the oxygen-containing gas introduced into the headspace of the reaction vessel is about 4% to about 15% oxygen in an inert gas, such as nitrogen.
- the oxygen-containing gas introduced into the headspace of the reaction vessel is about 5% to about 10% oxygen in an inert gas, such as nitrogen. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is about 6% oxygen in an inert gas, such as nitrogen. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is about 6% oxygen in nitrogen.
- Embodiments herein also include insertion of tin into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
- porphyrin compounds and tetrapyrroles can also be metallated using the procedures described herein, including, but not limited to, porphyrins such as deuteroporphyrins and deuteroporphyrin IX 2,4-bis(ethylene glycol) (8,13-bis(l,2-dihydroxyethyl)-3, 7,12,17- tetramethyl-21H,23H-po ⁇ hine-2,18-dipropionic acid).
- porphyrins such as deuteroporphyrins and deuteroporphyrin IX 2,4-bis(ethylene glycol) (8,13-bis(l,2-dihydroxyethyl)-3, 7,12,17- tetramethyl-21H,23H-po ⁇ hine-2,18-dipropionic acid).
- Additional porphyrin compounds which can be metallated using the procedures described herein include, but are not limited to, coproporphyria, cytoporphyrins, etioporphyrins, hematoporphyrins, mesoporphyrins, phylloporphyrins, protoporphyrins, ⁇ ⁇ , and A comprehensive listing of ⁇ ⁇ compounds is given at World- Wide- Web, chem. qmul.ac.uk/iupac/tetrapyrrole/; the described therein are hereby inco ⁇ orated by reference herein as ⁇ which can be metallated using the procedures described herein.
- Stannsoporfin may be prepared by a reverse route in which hemin is transmetallated with tin oxide to form tin protoporphyrin followed by hydrogenation in either n-methyl pyrrolidinone, dilute ammonium hydroxide, or dimethyl formamide.
- DILUTE AMMONIUM HYDROXIDE A hydrogenation was carried out in dilute ammonium hydroxide over palladium catalyst. The solvent volume and concentration was chosen to match that used in the RPA438-04-EF purification process illustrated in FIG. 1.
- DIMETHYL FORMAMIDE An hydrogenation was carried out using dimethyl formamide (DMF) solvent and palladium on carbon. Both the starting material and product can be dissolved at 50 parts allowing for catalyst removal upon reaction completion. After reacting overnight in process analysis (IPC) analysis showed 35.5% B992, 28 & 11% monovinyl intermediates, and 25.4% of tin ⁇ ⁇ . The DMF solution at the IPC stage was analyzed by liquid chromatography-mass spectrometry (LC/MS) to confirm the identity of each peak in the IPC HPLC.
- LC/MS liquid chromatography-mass spectrometry
- NMP N-METHYL PYRROLIDINONE
- Tin insertion followed by hydrogenation Tin protoporphyrin dimethyl ester was prepared according to the standard tin oxide route, directly substituting protoporphyrin dimethyl ester for mesoporphyrin. The product was obtained in a yield of 77.7%
- Mesoporphyrin was obtained by reacting hemin with ferrous sulfate, palladium on carbon, and poly(methylhydrosiloxane) (PMHS) in formic acid at reflux. The reaction was split. Half was subjected to further hydrogenation with PMHS. The subsequent IPC showed the reaction to be complete.
- the product was isolated as CK1 (structure shown in FIG. 1) from formic acid and methyl tertbutyl ether (1198-CB-004-1). The isolation was very difficult due to solids (both products and wastes) sticking to the walls of the flask. This is likely due to the side product formed from PMHS which is expected to be a silicon grease. The initial reaction yielded 57.5% mesoporphyrin.
- Each tin carrier was evaluated according to an oxidative reflux for making stannsoporfin outlined in FIG. 2 and the low temperature, oxygen-free process outlined in FIG. 1.
- Initial screening reactions were carried out on a 150 mg scale. The results of the initial screening reactions in the oxidative process and in the low temperature, oxygen-free process are summarized in Tables 5 and 6, respectively.
- reaction 1198-CB-092 and 1198-CB-093 were discarded after 96 hours.
- Reactions 1198-CB-091 and 1198-CB-094 were isolated according to procedure. In both cases the observed yield upon drying was 79.7% (4.7g). Both products were then carried through the final purification method (RPA438-04-ES) and the isolated products were analyzed.
- the tin (II) oxide (1198-CB-091) and tin (II) ethylhexanoate salts produced products with purities of 99.2% and 99.4%, respectively (Table 8).
- one third of the reaction mixture was isolated as CK1 through the RPA438-01-ES process, which was then carried through the remainder of the process (1165-CB-155-1).
- the filtrate solution is concentrated by vacuum distillation to a residual volume, and 30 L of methyl tert-butyl ether (MTBE, 120 L) is added to the concentrate over a minimum of 1 hour to precipitate the intermediate product.
- MTBE methyl tert-butyl ether
- the resultant suspension is cooled to -20 to -25°C over 1 hour and agitated for 4 hours prior to filtration.
- the cake is dried under vacuum to remove residual MTBE, yielding 5 to 6 Kg mesoporphyrin IX formate (CK1, 85 to 100% yield).
- the resultant suspension is agitated at 20 to 25°C under nitrogen for 2 hours prior to filtration. After filtration, the product is dried under a stream of nitrogen to yield 3.4 to 4.5 Kg of mesoporphyrin IX dihydrochloride (60 to 80% yield).
- the reaction is carried out under a nitrogen atmosphere at 60 to 65°C for a minimum of 12 hours.
- the reaction is monitored by HPLC. Once the reaction is complete, 17 L of water is added over 0.5 hours.
- the reaction mixture is then cooled to 20 to 25°C over 0.5 hours, agitated for 1 to 3 hours and then filtered.
- the filter cake is rinsed with distilled water (USP), suspended in IN HC1 and warmed to 85 to 95°C for 1 to 3 hours.
- USP distilled water
- each additional isolation decreased the overall yield for the process while increasing the assay and purity of the final product. All three materials passed specifications other than HPLC assay.
- the final purification method may increase the assay of the crude API. As such, each material was subjected to the final purification, RPA438-04-ES, for a second iteration and reanalyzed for HPLC purity and assay (Table 10).
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Abstract
Methods of synthesizing metal mesoporphyrin compounds, wherein the compound may be formed by hemin transmetallation and subsequent hydrogenation of the tin protoporphyrin IX to form a metal mesoporphyrin. A method of synthesizing a metal mesoporphyrin compound comprises forming a protoporphyrin methyl ester from hemin and converting the protoporphyrin methyl ester intermediate to a metal mesoporphyrin compound through metal insertion and hydrogenation. A metal mesoporphyrin compound may be formed from hemin by a hydrogen-free hydrogenation method to form a mesoporphyrin IX intermediate followed by metal insertion and hydrogenation. A method of synthesizing a metal mesoporphyrin compound comprises forming a mesoporphyrin IX dihydrochloride intermediate compound and converting the mesoporphyrin IX intermediate to a metal mesoporphyrin compound through metal insertion. A metal mesoporphyrin compound may be formed directly from hemin without isolation of any intermediates.
Description
A. Title: Methods for Synthesizing Metal Mesoporphyrins
B. Cross-Reference to Related Applications:
[0001] This application claims priority to U.S. Provisional Patent Applications No. 61/469,791 filed on March 30, 2011, No. 61/469,792 filed on March 30, 2011, and No. 61/532,301 filed on September 08, 2011 and each entitled "Methods for Synthesizing Metal Mesoporphyrins," the entire contents of which are hereby incorporated by reference.
C. Government Interests: Not applicable
D. Parties to a Joint Research Agreement: Not applicable
E. Incorporation by Reference of Material submitted on a Compact Disc: Not applicable
F. Background: Not applicable
G. Brief summary of the invention
[0001] Embodiments described herein are generally directed to methods of synthesizing metal mesoporphyrin compounds.
[0002] In some aspects, a method of synthesizing a metal mesoporphyrin compound comprises transmetallating hemin and hydrogenating the metal protoporphyrin IX. In some embodiments, the hemin is transmetallated in the presence of ferrous sulfate. In some embodiments, the metal protoporphyrin IX is hydrogenated using dilute ammonium hydroxide, dimethyl formamide or n-methyl pyrrolidinone. In some embodiments, the metal mesopoφhyrin is precipitated using methyl tert-butyl ether (MTBE). In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, tin is the inserted metal. In embodiments, tin is inserted into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
[0003] In some aspects, a method of synthesizing a metal mesoporphyrin compound comprises forming a protoporphyrin methyl ester from hemin and converting the protoporphyrin methyl ester intermediate to a metal mesoporphyrin compound through metal insertion and hydrogenation. In some embodiments, metal insertion yields a metal protoporphyrin dimethyl ester intermediate. In further embodiments, the metal protoporphyrin dimethyl ester is hydrogenated in dichloromethane over palladium catalyst to form a metal mesoporphyrin dimethyl ester. In embodiments, the metal mesoporphyrin dimethyl ester is heated in dilute ammonium hydroxide to form the metal mesoporphyrin compound. In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like.
In some embodiments, tin is the inserted metal. In embodiments, tin is inserted into mesoporphyrin to make stannsoporfm using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
[0004] In some aspects, a method of synthesizing a metal mesoporphyrin compound comprises forming a mesoporphyrin IX intermediate from hemin by a hydrogen-free hydrogenation, inserting a metal into the intermediate, and hydrogenating the metallated intermediate to form the metal mesoporphyrin compound. In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, tin is the inserted metal. In embodiments, tin is inserted into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
[0005] In embodiments, a method of synthesizing a metal mesoporphyrin compound comprises forming a mesoporphyrin IX dihydrochloride intermediate compound and converting the mesoporphyrin IX intermediate to a metal mesoporphyrin compound through metal insertion. In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, tin is the inserted metal. In embodiments, tin is inserted into mesoporphyrin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate. In some embodiments, the metal mesoporphyrin halide is stannsoporfin.
[0006] In embodiments, a metal mesoporphyrin halide may be formed directly from hemin without isolation of any intermediates. In embodiments, a method of synthesizing a metal mesoporphyrin may comprise hydrogenation of hemin and subsequent insertion of metal. In some embodiments, no intermediate compound is isolated. In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, tin is the inserted metal. In embodiments, tin is inserted into mesoporphyrin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate. In some embodiments, the metal mesoporphyrin halide is stannsoporfin.
H. Description of Drawings
[0007] For a fuller understanding of the nature and advantages of the present invention, reference should be had to the following detailed description taken in connection with the accompanying drawings, in which:
[0008] Figure 1 illustrates an exemplary low temperature, oxygen-free synthesis of stannsoporfin and each constituent synthesis.
[0009] Figure 2 illustrates an exemplary oxidative reflux synthesis of stannsoporfin.
[0010] Figure 3 illustrates the structure of stannsoporfin (B992).
[0011] Figure 4 illustrates the structure of mono vinyl intermediates (A) CJ9 and (B)
CKO.
[0012] Figure 5 illustrates the structure of tin protoporphyrin (CH8).
I. Detailed Description
[0013] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
[0014] It must also be noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a "compound" is a reference to one or more compounds and equivalents thereof known to those skilled in the art, and so forth.
[0015] As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
[0016] By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0017] In some aspects, embodiments are directed to a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier or diluent, or an effective amount of a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier or diluent.
[0018] Embodiments herein generally relate to novel processes for the preparation of metal mesoporphyrin halides. In embodiments, a metal mesoporphyrin compound may be formed by hemin transmetallation and subsequent hydrogenation of the metal protoporphyrin to form a metal mesoporphyrin halide. In other embodiments, a method of synthesizing a metal mesoporphyrin halide comprises forming a protoporphyrin methyl ester from hemin and converting the ρΓθίορο Ιινιτη methyl ester intermediate to a metal mesoporphyrin halide through metal insertion and hydrogenation. In other embodiments, a metal mesoporphyrin halide may be formed from hemin by a hydrogen-free hydrogenation method to form a mesoporphyrin IX intermediate followed by metal insertion into the mesoporphyrin IX intermediate and hydrogenation of the metallated intermediate to form the metal mesoporphyrin halide.
[0019] Tin (IV) mesoporphyrin IX dichloride or stannsoporfm is a chemical compound having the structure indicated in FIG. 3. It has been proposed for use, for example, as medicament in the treatment of various diseases including, for example, psoriasis and infant jaundice. Stannsoporfm may also inhibit heme metabolism in mammals, to control the rate of tryptophan metabolism in mammals, and to increase the rate at which heme is excreted by mammals.
[0020] The insertion of metal into mesoporphyrin IX dihydrochloride to obtain metal mesoporphyrin halide is described above with specific reference to tin, to prepare stannsoporfin, a known pharmaceutical and a specific preferred embodiment of the invention. It is not intended that the scope of the invention should be limited thereto, but is generally applicable to the preparation of mesoporphyrin halides, for example, but not limited to, mesoporphyrin chlorides of other metals such as, for example, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium and palladium, among others.
[0021] In embodiments, a metal mesoporphyrin compound may be formed by hemin transmetallation and subsequent hydrogenation of the metal protoporphyrin IX to form a metal mesoporphyrin halide. In embodiments, hemin is transmetallated with a metal carrier, for example tin to form tin protoporphyrin, followed by hydrogenation in a solvent, such as n-methyl pyrrolidinone, dilute ammonium hydroxide, or dimethyl formamide. In some embodiments, the hemin may be subjected to transmetallation with or without the addition of ferrous sulfate. In
some embodiments, the transmetallated hemin is treated with charcoal. In some embodiments, the product is isolated after hydrogenation by the addition of acetic acid or hydrochloric acid. In some embodiments, the final product is precipitated using MTBE. In some embodiments, the product is further purified by chromatography.
[0022] In other embodiments, a method of synthesizing a metal mesopoφhyrin halide comprises forming a protoporphyrin methyl ester from hemin and converting the protoporphyrin methyl ester intermediate to a metal mesoporphyrin halide through metal insertion and hydrogenation. To form the methyl ester, hemin, pyridine, and dichloromethane may be agitated to form a solution. Ferrous sulfate, methanol, dichloromethane, and HC1 gas may then be added to form an exothermic reaction. In embodiments, the exothermic reaction may then be held at reflux for a period of about 2 to about 5 hours. In embodiments, the reaction may further be washed with water and dilute ammonium hydroxide to form the protoporphyrin methyl ester. In embodiments, a metal may be inserted into the protoporphyrin methyl ester. In some embodiments, tin may be inserted into the protoporphyrin methyl ester using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate. In embodiments, the metal protoporphyrin dimethyl ester may be hydrogenated using an appropriate metal catalyst in a hydrogen atmosphere to form a metal mesoporphyrin dimethyl ester. In some embodiments, tin protoporphyrin dimethyl ester may be hydrogenated to form tin mesoporphyrin dimethyl ester. In embodiments, a metal mesoporphyrin halide may be formed by heating the metal mesoporphyrin dimethyl ester in dilute ammonium hydroxide. In some embodiments, stannsoporfin may be formed from tin mesoporphyrin dimethyl ester by heating the material at about 70°C to about 80°C in dilute ammonium hydroxide. For example, stannsoporfin may be formed by heating tin mesoporphyrin dimethyl ester to about 75°C in dilute ammonium hydroxide. In some embodiments, the product may be further purified by chromatography.
[0023] Some embodiments describe a method of synthesizing a metal mesoporphyrin halide comprising forming a mesoporphyrin IX dihydrochloride intermediate compound and converting the mesoporphyrin IX dihydrochloride intermediate to a metal mesoporphyrin halide through metal insertion. In some embodiments, hemin is hydrogenated in formic acid, over an appropriate metal catalyst under a hydrogen atmosphere, at about 80°C to about 101°C for about 1 hour to about 3 hours. In further embodiments, hydrogenation of the hemin may continue for an additional time of about 24 hours to about 36 hours at about 40°C to about 60°C. For example, hemin may be hydrogenated at about 85°C to about 90°C at about 60 psi of hydrogen for about 1 hour to about 2 hours followed and then at about 45°C to about 50°C for about 24 hours to about
36 hours. In some embodiments, the metal catalyst may be palladium, nickel, platinum, palladium on carbon, or the like. Upon completion of hydrogenation, the reaction may be cooled to about 20°C to about 30°C, or about 20°C to about 25°C, and optionally charged with powdered activated carbon, such as that sold under the trade name Darco KB-G. Optionally, the reaction may be agitated prior to filtration. The reaction may be filtered through a metal scavenger such as Hyflo Supercel to remove catalyst. Optionally, the filtrate solution may then be concentrated, for example by vacuum distillation. A solution of about IN HCL may then be added over about 1 hour or more to precipitate the intermediate product. After filtration, the product is dried under a stream of nitrogen to yield a mesoporphyrin IX dihydrochloride.
[0024] The second stage of the process according to one or more embodiments of the invention is illustrated in FIG. 1 as RPA438-03-ES with reference to tin as the inserted metal (standard tin oxide route). In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, the metal carrier is a tin (II) carrier. Tin (II) carriers such as tin (II) halides or tin (II) acetate may be used. In some embodiments, the tin carrier may be tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate. In the standard tin oxide route, tin (II) oxide powder may be suspended in acetic acid. In embodiments, to this suspension may be added a solution of mesoporphyrin IX dihydrochloride in formic acid under a nitrogen atmosphere and warmed to about 60°C to about 65°C. Once the reaction is complete, water may be added slowly and the reaction mixture may be slowly cooled to about 20°C to about 30°C, or about 20°C to about 25°C, agitated, and filtered. The filter cake may be rinsed with water, suspended in IN HC1, and warmed to about 85°C to about 95°C for about 1 hours to about 3 hours. The suspension may be cooled to about 20°C to about 30°C, or about 20°C to about 25°C, agitated, and filtered and dried under nitrogen to yield crude tin mesoporphyrin IX dichloride.
[0025] In an exemplary embodiment, tin (II) oxide (SnO, 1.7 kg) powder may be suspended in about 40.5 L of acetic acid at about 20°C to about 25°C and then warmed to about 60°C to about 65°C under nitrogen. To this suspension may be added a solution of mesoporphyrin IX dihydrochloride (B991, 2.1 kg) in about 10.5 L formic acid over a period of about 6 hours. The reaction may be carried out under a nitrogen atmosphere at about 60°C to about 65°C for a minimum of about 12 hours. The reaction may be monitored by HPLC. Once the reaction is complete, about 17 L of water may be added over about 0.5 hours. The reaction mixture is then cooled to about 20°C to about 25°C over about 0.5 hours, agitated for about 1 to
about 3 hours and then filtered. The filter cake may be rinsed with distilled water (USP), suspended in about IN HC1 and warmed to about 85°C to about 95°C for about 1 to about 3 hours. The suspension may then be cooled to about 20°C to about 25°C, agitated for about 0.5 hours, filtered, rinsed with distilled water (USP) and dried under nitrogen to yield about 1.3 to about 1.5 Kg of crude tin mesoporphyrin IX dichloride (stannsoporfin).
[0026] In embodiments, mesoporphyrin IX dihydrochloride may be subjected to heating with a metal carrier in acetic acid, in the presence of an oxidant, at reflux (oxidative reflux process). In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. In some embodiments, the metal carrier is a tin (II) carrier. Tin (II) carriers such as tin (II) halides or tin (II) acetate may be used. In some embodiments, the tin carrier may be tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
[0027] In an exemplary embodiment, the heating is performed with aeration, for example, by an inflow of about 6% oxygen mixed with nitrogen for about 24 hours to about 48 hours. Air inflow may also be used to aerate during heating. The reaction may also be carried out in the presence of suitable acetate counter ions include ammonium, sodium or potassium ions. Oxidants such as oxygen from air or in pure form as well as hydrogen peroxide may also be used. In an exemplary embodiment, mesopoφhyrin IX formate is subjected to heating with tin (II) oxide in acetic acid, buffered with ammonium acetate, and the reaction is conducted with aeration, at reflux. The ammonium acetate can be eliminated. The metallated mesoporphyrin may be isolated from the reaction mixture by the addition of water, followed by filtration. In embodiments, prior to drying, the cake may triturated into hot, dilute hydrochloric acid, preferably at concentration of about 0.1N - 6N and at an elevated temperature of about 90°C to about 100°C. In embodiments, the reaction yields a crude metal mesoporphyrin IX dichloride. In some embodiments, the reaction yields a crude tin (IV) mesoporphyrin IX dichloride.
[0028] The metal mesoporphyrin dichloride so obtained may be further purified by dissolving the product in an aqueous inorganic base solution, preferably dilute ammonium hydroxide, followed by treatment with charcoal. In embodiments, the product may then be re-precipitated by addition to an acid solution, such as acetic acid, hydrochloric acid or a mixture thereof. The above dissolving charcoal treatment and re-precipitation steps may be repeated a number of times, typically about 1 to 3 times in order to ensure the desired purity. Prior to drying, the cake is triturated in hot, dilute hydrochloric acid of a concentration of about 0. IN to about 6N, at an elevated temperature of about 90°C to about 100°C, in order to remove any residual
ammonium salts. In embodiments, the metallated mesoporphyrin chloride product (tin (IV) mesopoφhyrin IX dichloride or stannsoporfin) is obtained. In some embodiments, the tin mesopoφhyrin chloride product (tin (IV) mesoporphyrin IX dichloride or stannsoporfin) is obtained. In further embodiments, the final product, ex. stannsoporfin, is isolated by chromatography.
[0029] In an exemplary embodiment using tin mesoporphyrin dichloride, crude tin mesoporphyrin IX dichloride (1.7 Kg) may be dissolved in 2% ammonium hydroxide (22 L). A pH check may be performed to ensure the pH is > 9.0. The solution may be treated with Darco KB-G (0.1 Kg) and Hyflo Supercel (0.2 Kg), agitated for a period of 1 to 2 hours and filtered to remove solids. The filtrate may then be added drop wise to acetic acid (44 L) containing hydrochloric acid (31%, 2.7 L), keeping the temperature at 20°C to about 25°C. A pH check may again be performed to ensure pH < 1.0. The resultant suspension may be agitated for 1 to 2 hours under nitrogen prior to isolating the product by filtration. The wet cake may then be triturated in 3N HC1 (35 L) at 85°C to about 90°C and agitated for about 16 hours to about 18 hours to convert the crystalline form to monomer and remove residual ammonium salts. The suspension may be cooled to 20°C to about 25°C and the product isolated by filtration. The product cake may be rinsed with 0.3N HC1 (16 L) and dried under a stream of nitrogen to yield about 1.2 to about 1.6 Kg of Stannsoporfin.
[0030] In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, palladium, or the like. Preparation of mesoporphyrin halides of these other metals simply entails a substitution of a halide such as chloride, bromide or iodide of the chosen metal in place of stannous chloride in the process described, in substantially equivalent amounts.
[0031] In other embodiments, a metal mesoporphyrin halide may be formed from hemin by a hydrogen-free hydrogenation method to form a mesoporphyrin IX intermediate followed by metal insertion into the mesoporphyrin IX intermediate and hydrogenation of the metallated intermediate to form the metal mesoporphyrin halide. Mesoporphyrin may be obtained by reacting hemin with ferrous sulfate, palladium on carbon, and poly(methylhydrosiloxane) (PMHS) in formic acid at reflux and further hydrogenated with PMHS. The product may be isolated as mesoporphyrin formate from formic acid and methyl tertbutyl ether. The product may then be carried through the dihydrochloride formation process outlined above. In other embodiments, the hemin was reacted with ferrous sulfate, palladium on carbon, and poly(methylhydrosiloxane) (PMHS) in formic acid and then concentrated by rotary evaporation to remove formic acid. The ensuing solids may be isolated by filtration and carried through the
standard tin oxide route. The resulting filtrate may then be concentrated and dissolved in dilute ammonium hydroxide and precipitated by addition to acetic acid or hydrochloric acid. In some embodiments, the iron may be removed from hemin using ferrous sulfate prior to the PMHS hydrogenation. In some embodiments, the product is further purified by chromatography.
[0032] In any of the above embodiments, the reactants, intermediates, and/or products can undergo additional steps of purification. In some embodiments, the additional purification comprises treating the reactant, intermediate, or product with diatomaceous earth and/or activated carbon. In one embodiment, the treating of the reactant, intermediate, or product with diatomaceous earth and/or activated carbon comprises dissolving or suspending the reactant, intermediate, and/or product in a solvent, adding diatomaceous earth and/or activated carbon, filtering off the diatomaceous earth and/or activated carbon, and recovering the reactant, intermediate, or product from the filtrate. In some embodiments, the additional purification comprises triturating the reactant, intermediate, or product with hot acid, such as about 0.1 to 6N HC1 in water, preferably about 3N HC1 in water. In some embodiments, one, two, or three of the steps of treating with diatomaceous earth, treating with activated carbon, and triturating with hot acid are performed sequentially, in any order, and can be repeated as desired.
[0033] In certain embodiments, a metal mesoporphyrin halide may be formed directly from hemin without isolation of any intermediates. In some embodiments, metal mesoporphyrin compound is synthesized without isolating a mesoporphyrin formate intermediate or a mesoporphyrin dihydrochloride intermediate. In some embodiments, the metal mesoporphyrin may be synthesized using any of the above described methods without isolating the mesoporphyrin dihydrochloride intermediate. In some embodiments, the metal mesoporphyrin may be synthesized using any of the above described methods without isolating an intermediate. In some embodiments, the metal mesoporphyrin may be synthesized using the standard tin oxide route or the oxidative-refiux process described above without isolating the mesoporphyrin dihydrochloride intermediate. In some embodiments, the metal mesoporphyrin may be synthesized using the standard tin oxide route or the oxidative-reflux process described above without isolating an intermediate. In some embodiments, a method of synthesizing stannsoporfin comprises hydrogenating hemin and heating the reaction in the presence of a metal carrier. In some embodiments, the heating takes place in a nitrogen atmosphere. In some embodiments, a method of synthesizing stannsoporfin comprises hydrogenating hemin and heating the resulting reaction with a metal carrier in acetic acid, in the presence of an oxidant, at reflux. In embodiments, the metal may comprise tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium,
palladium, or the like. In some embodiments, the metal carrier is a tin (II) carrier. Tin (II) carriers such as tin (II) halides or tin (II) acetate may be used. In some embodiments, the tin carrier may be tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
[0034] In some embodiments, hemin is hydrogenated in formic acid, over an appropriate metal catalyst under a hydrogen atmosphere, at about 80°C to about 101°C for about 1 hour to about 3 hours. In further embodiments, hydrogenation of the hemin may continue for an additional time of about 24 hours to about 36 hours at about 40°C to about 60°C. For example, hemin may be hydrogenated at about 85°C to about 90°C at about 60 psi of hydrogen for about 1 hour to about 2 hours followed and then at about 45°C to about 50°C for about 24 hours to about 36 hours. In some embodiments, the metal catalyst may be palladium, nickel, platinum, palladium on carbon, or the like. Upon completion of hydrogenation, the reaction may be cooled to about 20°C to about 30°C, or about 20°C to about 25°C, and optionally charged with powdered activated carbon, such as that sold under the trade name Darco KB-G. Optionally, the reaction may be agitated prior to filtration. The reaction may be filtered through a metal scavenger such as Hyflo Supercel to remove catalyst. Optionally, the filtrate solution may then be concentrated, for example, by vacuum distillation.
[0035] In any of the above embodiments, the reactants, intermediates, and/or products can undergo additional steps of purification. In some embodiments, the additional purification comprises treating the reactant, intermediate, or product with diatomaceous earth and/or activated carbon. In one embodiment, the treating of the reactant, intermediate, or product with diatomaceous earth and/or activated carbon comprises dissolving or suspending the reactant, intermediate, and/or product in a solvent, adding diatomaceous earth and/or activated carbon, filtering off the diatomaceous earth and/or activated carbon, and recovering the reactant, intermediate, or product from the filtrate. In some embodiments, the additional purification comprises triturating the reactant, intermediate, or product with hot acid, such as about 0.1 to about 6N HC1 in water, preferably about 3N HC1 in water. In some embodiments, one, two, or three of the steps of treating with diatomaceous earth, treating with activated carbon, and triturating with hot acid are performed sequentially, in any order, and can be repeated as desired.
[0036] In another embodiment, a method of making a metal mesoporphyrin halide comprises the steps of: a) exposing a metallic hydrogenation catalyst to a hydrogen atmosphere to form pre-hydrogenated catalyst; and b) contacting hemin with the pre-hydrogenated catalyst and maintaining the hemin and catalyst under one or more cycles having a combination of temperature, hydrogen pressure, and time sufficient to remove iron from the hemin and reduce the
vinyl groups of the hemin to ethyl groups, thus forming mesoporphyrin IX. In another embodiment, a method of making a metal mesoporphyrin halide comprises the steps of: a) exposing a metallic hydrogenation catalyst to a hydrogen atmosphere to form pre-hydrogenated catalyst; b) contacting hemin with the pre-hydrogenated catalyst and maintaining the hemin and catalyst under one or more cycles having a combination of temperature, hydrogen pressure, and time sufficient to remove iron from the hemin and reduce the vinyl groups of the hemin to ethyl groups, thus forming mesoporphyrin IX; and c) reacting mesoporphyrin IX with a metal salt to form a metal mesoporphyrin halide using a controlled rate of oxidation.
[0037] In embodiments, step b) of embodiments herein may be carried out at about 80°C to about 100° C, preferably at about 85°C to about 90°C, with hydrogen pressure at about 50 to about 70 psi, preferably at about 55 to about 60 psi, for about 1 to about 3 hours, preferably about 1 to about 1.5 hours; then at about 40°C to about 60°C, preferably about 45°C to about 50°C, with hydrogen pressure at about 50 to about 70 psi, preferably at about 55 to about 60 psi, for about 18 to about 48 hours, preferably about 24 hours.
[0038] In one embodiment, the metallic hydrogenation catalyst comprises palladium, palladium on carbon, platinum, platinum on carbon, nickel, or nickel-aluminum catalyst. In another embodiment, the metallic hydrogenation catalyst is palladium. In another embodiment, the metallic hydrogenation catalyst is palladium on carbon.
[0039] Embodiments herein also include insertion of tin into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate. In particular embodiments, tin is inserted into mesoporphyrin using tin oxide, tin chloride or tin 2-ethylhexanoate.
[0040] In embodiments, the mesoporphyrin IX hydrochloride may be treated with a tin (II) salt in an organic solvent, such as acetic acid, under oxidizing conditions, which yields the desired product, tin (IV) mesoporphyrin IX dichloride (stannsoporfin). For example, mesoporphyrin IX dihydrochloride and tin (II) chloride may be placed in a vessel, and acetic acid may be added at about 20°C to about 30°C, preferably at about 20°C to about 25°C. The suspended reagents are agitated for at least about 30 minutes. With vigorous agitation, the mixture is warmed under an inert atmosphere (such as nitrogen or argon) to reflux.
[0041] In an embodiment, the invention embraces a method of inserting tin into mesoporphyrin IX, comprising reacting the mesoporphyrin IX with a tin salt in the absence of a proton scavenger.
[0042] In another embodiment, the invention embraces a method of inserting tin into mesoporphyrin IX, comprising reacting the mesoporphyrin IX with a tin salt at a controlled rate of oxidation. In one embodiment, the mesoporphyrin IX is reacted with a tin salt in a reaction vessel having a headspace, and the rate of oxidation is controlled by introducing an oxygen-containing gas into the headspace of the reaction vessel. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is about 3% to about 22% oxygen in an inert gas, such as nitrogen. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is air. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is about 4% to about 15% oxygen in an inert gas, such as nitrogen. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is about 5% to about 10% oxygen in an inert gas, such as nitrogen. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is about 6% oxygen in an inert gas, such as nitrogen. In another embodiment, the oxygen-containing gas introduced into the headspace of the reaction vessel is about 6% oxygen in nitrogen.
[0043] Embodiments herein also include insertion of tin into mesoporphyrin to make stannsoporfin using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
[0044] Other porphyrin compounds and tetrapyrroles can also be metallated using the procedures described herein, including, but not limited to, porphyrins such as deuteroporphyrins and deuteroporphyrin IX 2,4-bis(ethylene glycol) (8,13-bis(l,2-dihydroxyethyl)-3, 7,12,17- tetramethyl-21H,23H-poφhine-2,18-dipropionic acid). Additional porphyrin compounds which can be metallated using the procedures described herein include, but are not limited to, coproporphyria, cytoporphyrins, etioporphyrins, hematoporphyrins, mesoporphyrins, phylloporphyrins, protoporphyrins,
τηοάορο ΙτγΓΪηβ, and
A comprehensive listing of ροφΐτ ιτη compounds is given at World- Wide- Web, chem. qmul.ac.uk/iupac/tetrapyrrole/; the
described therein are hereby incoφorated by reference herein as ροφΙττΐΊηβ which can be metallated using the procedures described herein.
[0045] This invention and embodiments illustrating the method and materials used may be further understood by reference to the following non-limiting examples.
EXAMPLE 1
[0046] Stannsoporfin may be prepared by a reverse route in which hemin is transmetallated with tin oxide to form tin protoporphyrin followed by hydrogenation in either n-methyl pyrrolidinone, dilute ammonium hydroxide, or dimethyl formamide.
[0047] Reactions were carried out wherein hemin was subjected to the RPA438-03-ES tin oxide chemistry (see FIG. 1), with and without the addition of ferrous sulfate. After heating the reaction mixture to 90°C for 2 hours under nitrogen to effect dissolution of the hemin, the reaction was continued at 60°C to about 65°C overnight. HPLC analysis confirmed the reaction complete for the reaction which did not have ferrous sulfate, and 98.4% complete for the reaction which did. Both reactions were isolated by the standard water addition with identical yields of 97.3%.
[0048] Based on the success of these experiments, the reaction without ferrous sulphate was scaled up to 40g to prepare material to study the subsequent transformations. See Table 1 for results.
[0049] DILUTE AMMONIUM HYDROXIDE: A hydrogenation was carried out in dilute ammonium hydroxide over palladium catalyst. The solvent volume and concentration was chosen to match that used in the RPA438-04-EF purification process illustrated in FIG. 1.
[0050] The initial IPC analysis for this reaction seemed to indicate that no reaction had occurred. However, when the product was isolated and analyzed by the final product purity method, it was determined that the solid contained 18.2% stannsoporfin (B992; FIG. 3), 14.7 & 39.5% of the monovinyl intermediates (CJ9/CKO; FIG. 4), and 27.6% of tin protoporphyrin (CH8; FIG. 5).
[0051] The ammonium hydroxide reaction was repeated with a charcoal pre-treatment. The first IPC analysis after reacting overnight showed 83.3% stannsoporfin (B992), 15.9% of the monovinyl intermediates (CJ9/CKO), and 0.7% tin protoporphyrin (CH8). The reaction mixture was filtered and the hydrogenation continued with fresh catalyst to drive the reaction to completion in less than 2 hours. The product was isolated by addition to acetic acid/hydrochloric acid (as with the RPA438-04-EF purification process illustrated in FIG. 1) and triturated in hot IN HC1 for 1 hour. The yield from this transformation was 78%. The product from the reaction
was carried through the purification process with a yield of 91.4%. The overall yield for the process was 65.9% with a purity of 98.8% (See Table 2, Ref: 1 165-CB- 172-1).
[0052] DIMETHYL FORMAMIDE: An hydrogenation was carried out using dimethyl formamide (DMF) solvent and palladium on carbon. Both the starting material and product can be dissolved at 50 parts allowing for catalyst removal upon reaction completion. After reacting overnight in process analysis (IPC) analysis showed 35.5% B992, 28 & 11% monovinyl intermediates, and 25.4% of tin ρΓοίορο Ινγιϊη. The DMF solution at the IPC stage was analyzed by liquid chromatography-mass spectrometry (LC/MS) to confirm the identity of each peak in the IPC HPLC.
[0053] N-METHYL PYRROLIDINONE (NMP): NMP was evaluated as a solvent for the hydrogenation. After reacting overnight at 50°C/60psi, IPC analysis showed 51% stannsoporfin (B992), 20% & 10% monovinyl intermediates (CJ9/CKO), and 18.5% tin protoporphyrin (CH8). During this reaction it was observed that all hydrogen seemed to be taken up within the first 1 to 2 hours of reaction suggesting that the catalyst may have been poisoned. The reaction was then warmed to 90°C/60 psi overnight again. IPC analysis showed that the reaction had proceeded further to 68% stannsoporfin (B992), 21 and 9% monovinyl intermediates (CJ9/CKO), and 2.1% tin protoporphyrin (CH8), suggesting that the catalyst hadn't been completely poisoned.
[0054] Based on the assumption that the catalyst was being poisoned during the reaction, an NMP solution of tin protoporphyrin (CH8) was treated with Darco-KBG activated carbon for 1 hour and filtered prior to charging the catalyst for hydrogenation. After reacting overnight at 50°C/60 psi IPC analysis showed 94.2% stannsoporfin (B992) and 1.7% monovinyl intermediates (CJ9/CKO). This reaction mixture was split into 2 equal parts and added to either 300 parts of water or 300 parts of methyl tert-butyl ether (MTBE) and cooled to about 0°C to about 5°C for about 2 hours. Upon filtration, it was discovered that there was little to no precipitation with water, but MTBE afforded a nice filterable solid with a yield of 90%.
[0055] The NMP hydrogenation with charcoal treatment was scaled up to lOg. The first IPC analysis after reacting at 50°C/60 psi overnight showed 92.5% stannsoporfin (B992), 3.6 and 2.4% monovinyl intermediates (CJ9/CKO), and 0.4% tin protoporphyrin (CH8). The reaction mixture was filtered prior to re-subjecting to hydrogenation with fresh catalyst to drive the reaction to completion after 2 further hours. The product was isolated by addition to a copious quantity of methyl tert-butyl ether in a yield of 119.9% (product contains residual NMP). The product from the reaction was carried through the purification process with a yield of 108.0% (likely due to residual solvents). The purity obtained was 98.2%. (See Table 2, Ref: 1165-CB-171-1).
TABLE 2: ANALYTICAL RESULTS, REVERSE ROUTE
Experiment Description Overall HPLC Purity HPLC
Yield (%) (%a/a) Assay
From (%w/w) Hemin
1165-CB-171- Stannsoporfin 119.9 98.2 47.0 1 Reverse route prep
NMP hydrogenation
1165-CB-172- Stannsoporfin 65.9 80.8 1 Reverse route prep
NH40H
hydrogenation
EXAMPLE 2
[0056] Formation of Protoporphyrin Methyl Ester. A 5L reactor was charged with 20g of hemin, 50 ml pyridine, and 200 ml of dichloromethane and agitated 10 minutes to form a solution. 50g of Ferrous sulfate, 1000 ml of methanol, and 1000 ml of dichloromethane were then added. HCl gas was added slowly. The exothermic reaction eventually reached a reflux temperature of 41°C (note: no heating was applied) and held at reflux for a period of 3 hours. TLC analysis confirmed the reaction was complete. The reaction was quenched with 1000 ml of water, which was followed by additional washes with water and dilute ammonium hydroxide. Then protoporphyrin methyl ester was isolated from dichloromethane/methanol in a yield of 50.4%.
[0057] Tin insertion followed by hydrogenation. Tin protoporphyrin dimethyl ester was prepared according to the standard tin oxide route, directly substituting protoporphyrin dimethyl ester for mesoporphyrin. The product was obtained in a yield of 77.7%
[0058] The tin protoporphyrin dimethyl ester was hydrogenated in dichloromethane over 5% palladium catalyst at 50 psi. After reaction overnight, the product was isolated by concentration by rotary evaporation in 100% yield. NMR analysis of the product suggested there was circa 10% unreacted starting material. However, upon re-subjecting the material to the hydrogenation conditions, no further change was noted and the reaction was carried forward as is.
[0059] Stannsoporfin was formed from the tin mesopoφhyrin dimethyl ester by heating the material to 75°C in dilute ammonium hydroxide. After 18 hours of reaction no further change was noted in the HPLC IPC, even after the addition of further ammonium hydroxide. The product
was isolated from solution by addition into acetic acid/hydrochloric acid, as typically perfected during the purification, in a yield of 72.6%. The crude Stannsoporfin was purified according to the standard method and isolated in a yield of 72.2%. The overall process yield was 23.8% with a purity of 87.4% (See Table 3, Ref.: 1198-CB-003-1).
TABLE 3: ANALYSIS RESULTS, METHL ESTER ROUTE
Overall
Yield (%)
From HPLC Purity HPLC Assay
Experiment Description Hemin (%a/a) (%w/w as is)
87.4
Stannsoporfin
Methyl ester
EXAMPLE 3
[0060] Mesoporphyrin was obtained by reacting hemin with ferrous sulfate, palladium on carbon, and poly(methylhydrosiloxane) (PMHS) in formic acid at reflux. The reaction was split. Half was subjected to further hydrogenation with PMHS. The subsequent IPC showed the reaction to be complete. The product was isolated as CK1 (structure shown in FIG. 1) from formic acid and methyl tertbutyl ether (1198-CB-004-1). The isolation was very difficult due to solids (both products and wastes) sticking to the walls of the flask. This is likely due to the side product formed from PMHS which is expected to be a silicon grease. The initial reaction yielded 57.5% mesoporphyrin.
[0061] On the second half of the reaction, an attempt was made to isolate directly as B991 hydrochloride salt. However after following the standard process, no crystals were found. The solution was concentrated on by rotary evaporation to remove formic acid and the ensuing solids were isolated by filtration in a yield of 42.8%. A second crop of material was obtained from the filtrate the following day for an additional 11.2% yield. The two crops of material were combined and carried through the tin oxide process. After a standard reaction time no further B991 could be detected by HPLC. An attempt was made to isolate the product according to the standard process, however no solids were found. The filtrate was subsequently concentrated by rotary evaporation and the residue dissolved in dilute ammonium hydroxide and precipitated by addition to acetic acid/hydrochloric acid. The crude product was obtained in a yield of 26.6% (Table 4, Ref.: 1198-CB-Ol l-l).
[0062] An attempt was also made to perform the iron removal from hemin using ferrous sulfate prior to the PMHS hydrogenation. This reaction was easier to handle since the iron salts and grease, both of which are insoluble, were not present in the reactor at the same time. The product was isolated in a yield of 62.1%. However, when the B991 (structure shown in FIG. 1) formation was attempted on this material it was found that no solids precipitated when hydrochloric acid was added to the formic acid solution.
[0063] The product from reaction 1198-CB-004-1 was carried through the B991 hydrochloride formation with a yield of 42.5%. The tin oxide process was repeated with this sample but the precipitation was allowed to stir overmght prior to filtration. The product from this reaction was obtained in a yield of 90.3%. The overall yield was 22.1% with 75.1% purity. (Table 4, Ref.: 1198-CB-013-1).
TABLE 4: ANALYSIS RESULTS, HYDROGEN-FREE PREPARATION
Overall
Yield (%) HPLC Purity HPLC Assay
Experiment Description
From (%a/a) (%w/w as is) Hemin
1198-CB-Ol l-l Stannsoporfin 14.4 73.3 25.2%
Hydrogen-free
preparation
1198-CB-013-1 Stannsoporfin 22.1 0.8%
Hydrogen-free
preparation
[0064] Each tin carrier was evaluated according to an oxidative reflux for making stannsoporfin outlined in FIG. 2 and the low temperature, oxygen-free process outlined in FIG. 1. Initial screening reactions were carried out on a 150 mg scale. The results of the initial screening reactions in the oxidative process and in the low temperature, oxygen-free process are summarized in Tables 5 and 6, respectively.
[0065] Based on the relative completeness of the reactions tin (II) bromide, tin (II) oxalate, and tin (II) ethylhexanoate were chosen for further study against a tin (II) oxide control.
The tin insertion reactions were scaled to 5g in order to prepare enough material for full analysis. The reactions were left for 96 hours instead of 48 due to an intervening weekend. Results are presented in Table 7.
[0066] Due to their incompleteness, reactions 1198-CB-092 and 1198-CB-093 were discarded after 96 hours. Reactions 1198-CB-091 and 1198-CB-094 were isolated according to procedure. In both cases the observed yield upon drying was 79.7% (4.7g). Both products were then carried through the final purification method (RPA438-04-ES) and the isolated products were analyzed. The tin (II) oxide (1198-CB-091) and tin (II) ethylhexanoate salts produced products with purities of 99.2% and 99.4%, respectively (Table 8).
[0067] Under RPA438-01-ES process, 5% palladium on carbon (50% wet, 0.6 Kg) is hydrogenated in formic acid (60 L) under an inert atmosphere at 40°C/(60 to 65psi) for a period of 12 hours. Upon cooling, hemin (B990, 6 Kg) is added to the reaction vessel as a slurry in formic acid (60 L). The hemin is then hydrogenated at 85 to 90°C/60 psi for 1 to 2 hours followed by hydrogenation at 45 to 50°C/60 psi for a further 24 to 36 hours. The reaction is monitored by HPLC. Upon completion, the reaction is cooled to 20 to 25°C, charged with Darco KB-G, and filtered through Hyflo Supercel to remove catalyst. After filtration of the palladium catalyst, the reaction mixture was split into three equal portions by mass.
[0068] Referring to FIG. 1, one third of the reaction mixture was isolated as CK1 through the RPA438-01-ES process, which was then carried through the remainder of the process (1165-CB-155-1). The filtrate solution is concentrated by vacuum distillation to a residual volume, and 30 L of methyl tert-butyl ether (MTBE, 120 L) is added to the concentrate over a minimum of 1 hour to precipitate the intermediate product. The resultant suspension is cooled to -20 to -25°C over 1 hour and agitated for 4 hours prior to filtration. The cake is dried under vacuum to remove residual MTBE, yielding 5 to 6 Kg mesoporphyrin IX formate (CK1, 85 to 100% yield).
[0069] One third was isolated directly as B991 through the RPA438-02-ES process and then carried through the remainder of the process (1165-CB-154-1). In the RPA438-02-ES, mesoporphyrin IX formate (CK1, 5 kg as free base) is dissolved in formic acid (22 L) and treated with active charcoal (Darco KB-G, 0.2 Kg) and Hyflo Supercel (0.4 Kg) and agitated for a period of 2 hours at 20 to 25°C prior to filtration to remove solids. The filtrate is concentrated by vacuum distillation to a residual volume of 12L. To this concentrate is added a solution of IN HC1 (13 L) over a minimum of 1 hour to precipitate the intermediate product. The resultant suspension is agitated at 20 to 25°C under nitrogen for 2 hours prior to filtration. After filtration, the product is dried under a stream of nitrogen to yield 3.4 to 4.5 Kg of mesoporphyrin IX dihydrochloride (60 to 80% yield).
[0070] The remaining third of the reaction mixture was carried directly into the tin insertion reaction, RPA438-03-ES, as the filtered formic acid solution to make Stannsoporfin (B992) (1165-CB-153-1). In the RPA438-03-ES process, tin (II) oxide (SnO, 1.7 kg) powder is suspended in 40.5 L of acetic acid at 20 to 25°C and then warmed to 60 to 65°C under nitrogen. To this suspension is added a solution of mesoporphyrin IX dihydrochloride (B991, 2.1kg) in 10.5 L formic acid over a period of 6 hours. The reaction is carried out under a nitrogen
atmosphere at 60 to 65°C for a minimum of 12 hours. The reaction is monitored by HPLC. Once the reaction is complete, 17 L of water is added over 0.5 hours. The reaction mixture is then cooled to 20 to 25°C over 0.5 hours, agitated for 1 to 3 hours and then filtered. The filter cake is rinsed with distilled water (USP), suspended in IN HC1 and warmed to 85 to 95°C for 1 to 3 hours. The suspension is then cooled to 20 to 25°C, agitated for 0.5 hours, filtered, rinsed with distilled water (USP) and dried under nitrogen to yield 1.3 to 1.5 Kg of crude tin mesopo hyrin IX dichloride (StannsoporfinTM, B992) (65 to 75% yield).
[0071] All B992 products obtained were also subjected to the final purification, RPA438-04-ES. Under the RPA438-04-ES process, crude tin mesopoφhyrin IX dichloride (B992, 1.7 Kg) is dissolved in 2% ammonium hydroxide (22 L). A pH check is performed to ensure the pH is 2: 9.0. The solution is treated with Darco KB-G (0.1 Kg) and Hyflo Supercel (0.2 Kg), agitated for a period of 1 to 2 hours and filtered to remove solids. The filtrate is then added drop wise to acetic acid (44 L) containing hydrochloric acid (31%,2.7 L) keeping the temperature at 20 to 25°C. A pH check is again performed to ensure pH < 1.0. The resultant suspension is agitated for 1 to 2 hours under nitrogen prior to isolating the product by filtration. The wet cake is then triturated in 3NHC1 (35 L) at 85 to 90°C and agitated for 16 to 18 hours to convert the crystalline form to monomer. The suspension is cooled to 20 to 25°C and the product is isolated by filtration. The product cake is rinsed with 0.3N HC1 (16 L) and dried under a stream of nitrogen to yield 1.2 to 1.6 kg of Stannsoporfin API (70 to 90% yield). The results are summarized in Table 9.
TABLE 9: ANALYTICAL RESULTS, COMBINATION OF PROCESS STEPS
Test 1165-CB-153-1 1165-CB-154-1 1165-CB-155-1
B991/CK1 isolation
Experiment No isolations B991 isolation
(Control)
Yield (%) 61.9 54.2 48.2
99.3 99.5 99.6
RRt %a/a
0.22 0.06
HPLC Purity (% a/a) 0.67 0.07
0.88 0.09
others <0.05
HPLC Assay (% w/w) 96.8 98.2 99.5
Description Conforms Conforms Conforms
IR Identification Conforms Conforms Conforms
HPLC Identification Conforms Conforms Conforms
KF(%w/w) 1.2 0.4 0.6
Residual Solvents
<500 <500 <500
(Acetone)
Residual Solvents (Acetic &
0.1
Formic)
Iron (ppm) 6.55 2.94 2.84
Palladium (ppm) 6.95 <2 <2
Solubility Soluble Soluble Soluble
Chloride (% w/w) 7.3 9.69 9.97
[0072] As can be seen in the table, each additional isolation decreased the overall yield for the process while increasing the assay and purity of the final product. All three materials passed specifications other than HPLC assay. The final purification method may increase the assay of the crude API. As such, each material was subjected to the final purification, RPA438-04-ES, for a second iteration and reanalyzed for HPLC purity and assay (Table 10).
TABLE 10: ANALYTICAL RESULTS, COMBINATION OF PROCESS STEPS
WITH EXTRA PURIFICATION
1198-CB-022-1
Test 1198-CB-020-1 1198-CB-021-1 (CONTROL)
Starting Material 1165-CB-153-1 1165-CB-154-1 1165-CB-155-1
Yield (%) 92.0 92.0 94.0
RRt %a/a
0.22 0.07
0.39 0.05
0.44 0.05
0.64 0.05
HPLC Assay (% w/w) 98 (as is) 98 (as is) 99 (as is)
[0001] With the exception of tin sulfide, all tin salts screened for use in the tin insertion reaction produced stannsoporfin by both the oxidative and non-oxidative processes. It is believed that higher purity may be achieved for all such tin salts. Using tin ethylhexanoate as the tin
carrier, it was possible to prepare stannsoporfin of a quality equivalent to the product prepared using tin oxide.
[0002] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification.
Claims
1. A method of synthesizing a metal mesoporphyrin compound comprising transmetallating hemin and hydrogenating the metal protoporphyrin IX.
2. The method of claim 1, wherein the metal is selected from tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, and palladium.
3. The method of claim 2, wherein tin is selected from tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, and tin trifiuromethanesulfonate.
4. The method of claim 1 , wherein the metal mesoporphyrin compound is stannsoporfin.
5. A method of synthesizing a metal mesoporphyrin compound comprising forming a protoporphyrin methyl ester and inserting a metal into the protoporphyrin methyl ester and hydrogenating the metal protoporphyrin methyl ester.
6. The method of claim 5, wherein the metal is selected from tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, and palladium.
7. The method of claim 6, wherein tin is selected from tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, and tin trifiuromethanesulfonate.
8. The method of claim 5, wherein the metal mesoporphyrin compound is stannsoporfin.
9. A method of synthesizing a metal mesoporphyrin compound comprises forming a mesoporphyrin IX intermediate by a hydrogen-free hydrogenation, inserting a metal into the intermediate to and hydrogenating to form the metal mesoporphyrin compound.
10. The method of claim 9, wherein the mesoporphyrin IX intermediate is formed by hydrogenation with polymethylhydrosiloxane.
11. The method of claim 10, wherein the metal is selected from tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, and palladium.
12. The method of claim 10, wherein tin is selected from tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, and tin trifluromethanesulfonate.
13. The method of claim 16, wherein the metal mesoporphyrin compound is stannsoporfin.
14. A method of synthesizing a metal mesoporphyrin compound comprising:
hydrogenating hemin to form a mesoporphyrin IX dihydrochloride intermediate compound;
isolating the mesoporphyrin IX dihydrochloride intermediate compound; and inserting a metal into the mesopoφhyrin IX dihydrochloride intermediate.
15. The method of claim 14, wherein the metal may be selected from tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, and palladium.
16. The method of claim 15, wherein the metal is tin.
17. The method of claim 16, wherein the tin is inserted using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
18. The method of claim 14, wherein the metal mesoporphyrin compound is stannsoporfin.
19. A method of synthesizing a metal mesopo hyrin compound comprising:
hydrogenating hemin in formic acid to form a formic acid solution; and
inserting a metal into the formic acid solution, wherein the metal mesoporphyrin compound is synthesized without isolating an intermediate compound.
20. The method of claim 19, wherein the metal may be selected from tin, iron, zinc, chromium, manganese, copper, nickel, magnesium, cobalt, platinum, gold, silver, arsenic, antimony, cadmium, gallium, germanium, and palladium.
21. The method of claim 20, wherein the metal is tin.
22. The method of claim 21, wherein the tin is inserted using tin oxide, tin chloride, tin sulfate, tin bromide, tin oxalate, tin pyrophosphate hydrate, tin 2-ethylhexanoate, tin methanesulfonic acid, or tin trifluromethanesulfonate.
23. The method of claim 19, wherein the metal mesoporphyrin compound is stannsoporfin.
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ES12765367.3T ES2609110T3 (en) | 2011-03-30 | 2012-03-30 | Synthesis procedures of metallic mesoporphyrins |
EP12765367.3A EP2691398B1 (en) | 2011-03-30 | 2012-03-30 | Methods for synthesizing metal mesoporphyrins |
DK12765367.3T DK2691398T3 (en) | 2011-03-30 | 2012-03-30 | Methods for synthesizing metal mesoporphyrins |
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EP (1) | EP2691398B1 (en) |
DK (1) | DK2691398T3 (en) |
ES (1) | ES2609110T3 (en) |
HU (1) | HUE032290T2 (en) |
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JP2023541324A (en) * | 2020-10-02 | 2023-09-29 | アジェロ・バイオファーマシューティカルズ・ホールディングス・インコーポレイテッド | Method for producing nickel (II) ethioporphyrin-I |
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- 2012-03-30 PT PT127653673T patent/PT2691398T/en unknown
- 2012-03-30 DK DK12765367.3T patent/DK2691398T3/en active
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Also Published As
Publication number | Publication date |
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EP2691398A1 (en) | 2014-02-05 |
US20190002481A1 (en) | 2019-01-03 |
DK2691398T3 (en) | 2017-01-16 |
PT2691398T (en) | 2017-01-02 |
HUE032290T2 (en) | 2017-09-28 |
EP2691398B1 (en) | 2016-09-28 |
ES2609110T3 (en) | 2017-04-18 |
US10533024B2 (en) | 2020-01-14 |
US9688705B2 (en) | 2017-06-27 |
PL2691398T3 (en) | 2017-07-31 |
US20160024124A1 (en) | 2016-01-28 |
EP2691398A4 (en) | 2014-10-08 |
US20170260217A1 (en) | 2017-09-14 |
US9181285B2 (en) | 2015-11-10 |
US20120253033A1 (en) | 2012-10-04 |
US20140228560A1 (en) | 2014-08-14 |
US8735574B2 (en) | 2014-05-27 |
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