WO2001040164A1 - A multistage process for the preparation of highly pure deferoxamine mesylate salt - Google Patents
A multistage process for the preparation of highly pure deferoxamine mesylate salt Download PDFInfo
- Publication number
- WO2001040164A1 WO2001040164A1 PCT/US2000/032574 US0032574W WO0140164A1 WO 2001040164 A1 WO2001040164 A1 WO 2001040164A1 US 0032574 W US0032574 W US 0032574W WO 0140164 A1 WO0140164 A1 WO 0140164A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- deferoxamine
- eluent
- mesylate
- acetonitrile
- solvent
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 69
- IDDIJAWJANBQLJ-UHFFFAOYSA-N desferrioxamine B mesylate Chemical class [H+].CS([O-])(=O)=O.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN IDDIJAWJANBQLJ-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims abstract description 177
- 239000012458 free base Substances 0.000 claims abstract description 57
- 239000003480 eluent Substances 0.000 claims abstract description 53
- 229920005989 resin Polymers 0.000 claims abstract description 46
- 239000011347 resin Substances 0.000 claims abstract description 46
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000000203 mixture Substances 0.000 claims abstract description 39
- 238000001556 precipitation Methods 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 16
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 90
- 239000000243 solution Substances 0.000 claims description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- 239000012296 anti-solvent Substances 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000000725 suspension Substances 0.000 claims description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical group [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003456 ion exchange resin Substances 0.000 claims description 12
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000012670 alkaline solution Substances 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 6
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
- -1 aliphatic alcohols Chemical class 0.000 claims description 5
- 239000012156 elution solvent Substances 0.000 claims description 5
- 238000010979 pH adjustment Methods 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000002906 microbiologic effect Effects 0.000 claims description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 3
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 230000036961 partial effect Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 abstract description 13
- 229960000958 deferoxamine Drugs 0.000 abstract description 10
- 238000000354 decomposition reaction Methods 0.000 abstract description 6
- 244000005700 microbiome Species 0.000 abstract description 3
- 238000001179 sorption measurement Methods 0.000 abstract 3
- 238000003795 desorption Methods 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 17
- 229920001429 chelating resin Polymers 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 14
- 238000000855 fermentation Methods 0.000 description 14
- 230000004151 fermentation Effects 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical class [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 229910052742 iron Inorganic materials 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000003957 anion exchange resin Substances 0.000 description 5
- 229960001425 deferoxamine mesylate Drugs 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003463 adsorbent Substances 0.000 description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 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 3
- 241001137868 Streptomyces pilosus Species 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- KCRQZLMAZHZDCL-UHFFFAOYSA-N n-[5-[[4-[5-[acetyl(hydroxy)amino]pentylamino]-4-oxobutanoyl]-hydroxyamino]pentyl]-n'-(5-aminopentyl)-n'-hydroxybutanediamide;hydrochloride Chemical compound Cl.CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN KCRQZLMAZHZDCL-UHFFFAOYSA-N 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical group CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Chemical group CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 206010065973 Iron Overload Diseases 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- GPEHQHXBPDGGDP-UHFFFAOYSA-N acetonitrile;propan-2-one Chemical compound CC#N.CC(C)=O GPEHQHXBPDGGDP-UHFFFAOYSA-N 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical group CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical group CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000391 magnesium silicate Substances 0.000 description 2
- 235000012243 magnesium silicates Nutrition 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910019670 (NH4)H2PO4 Inorganic materials 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 1
- 241000209290 Hemigellius pilosus Species 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical group CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 208000002903 Thalassemia Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- FKCBLVCOSCZFHV-UHFFFAOYSA-N acetonitrile;ethanol Chemical compound CCO.CC#N FKCBLVCOSCZFHV-UHFFFAOYSA-N 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 1
- 238000007705 chemical test Methods 0.000 description 1
- 150000003841 chloride salts Chemical class 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000010440 gypsum Substances 0.000 description 1
- 229910052602 gypsum Inorganic materials 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940075525 iron chelating agent Drugs 0.000 description 1
- 239000000797 iron chelating agent Substances 0.000 description 1
- 150000004698 iron complex Chemical class 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
Definitions
- This invention relates to a process for preparing highly pure deferoxamine B mesylate.
- BACKGROUND OF THE INVENTION Deferoxamine B represented by formula I, is a polyhydroxamate iron chelator that is useful for reducing iron concentration in human blood plasma.
- deferoxamine B also known as deferriferrioxamine B
- deferriferrioxamine B N'-[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-l,4- dioxobutyl]hydroxyamino]pentyl]-N-(5-aminopentyl)-N-hydroxy-butanediamide.
- Deferoxamine B is indicated for treatment of acute iron intoxication and chronic iron overload due to transfusion dependant anemias. It promotes iron excretion in patients with secondary iron overload from multiple transfusions, as may occur with treatment of some chronic anemias such as thalassemia. Long term therapy slows accumulation of hepatic iron and retards or eliminates progression of hepatic fibrosis. Physicians Desk Reference 2010 (54th ed. 1999). Deferoxamine B is not well-absorbed orally; it must be administered parenterally.
- Deferoxamine B is typically isolated from the fermentation broth as its hydrochloride salt.
- the hydrochloride salt is not pharmaceutically acceptable for parenteral administration to humans. Therefore, it must be converted into a pharmaceutically acceptable salt.
- the mesylate salt is the FDA approved deferoxamine salt.
- the U.S. Pharmacopeia & National Formulary directs that pharmaceutical grade deferoxamine B mesylate contain not more than 120 ppm chloride. USP/NF 24/19, pp. 499-500 (1999). This has proven to be a challenging standard to meet and there remains a need for an improved process for transforming deferoxamine B produced by fermentation into a pharmaceutically acceptable pure mesylate salt for administration to patients.
- Belgian patent 619.532 discloses purification of deferoxamine B obtained via fermentation using adso ⁇ tion chromatography.
- Activated carbon, activated diatomaceous earth (e.g. fuller's earth) or ion-exchange resin (Asmit) are recommended adsorbents.
- Alternative adsorbents are said to include aluminum oxide, magnesium silicates, silica gel, gypsum and ion-exchange resins.
- deferoxamine B may be eluted using a mobile phase of methanol-water, pyridine-water or acetic acid- methanol.
- deferoxamine B mesylate salt can be obtained from the deferoxamine B hydrochloride salt by passing an aqueous solution of deferoxamine hydrochloride over Dowex-1, X-16 anion exchange resin (in OH " form), adding methanesulfonic acid in equivalent quantity to the resulting deferoxamine base in aqueous solution, then evaporating the water and, lastly, purifying the deferoxamine mesylate salt by recrystallization from aqueous alcohol or a mixture of water-methanol- acetone.
- Dowex-1, X-16 anion exchange resin in OH " form
- 5,374,771 describes purification of crude deferoxamine B hydrochloride by ion-exchange chromatography and multiple recrystallizations.
- the mesylate salt is prepared directly from the purified deferoxamine B hydrochloride by contacting with an anion exchange resin having mesylate counter-ion.
- Deferoxamine B mesylate is obtained from the aqueous solution by lyophilization.
- Bickel, H. et al., Helvetica Chimica Ada, 1385-1389 (1963) describes purification of deferoxamine B base by multiple recrystallizations from a water-alcohol mixture.
- the deferoxamine B base is prepared by anion exchange, evaporation to dryness, and multiple recrystallizations.
- the deferoxamine B base is then suspended in a water-methanol mixture and a mineral acid salt prepared. Subsequently the deferoxamine B solution is evaporated and the residue is recrystallized from
- Removal of chloride ion from an aqueous solution of deferoxamine B is one of the steps in each of the methods described above for purifying deferoxamine B from a fermentation broth.
- the chloride ion is removed using an anion exchange resin.
- ion-exchange resins alone are not effective for isolating deferoxamine B mesylate free of chloride ion as is required in order to achieve a pharmaceutically acceptable state of purity.
- an extract from a deferoxamine-producing fermentation broth contains, relative to the deferoxamine B content, approximately 6 to 20 mole % polyhydroxamate compounds that are structurally related to deferoxamine B.
- Such compounds include other deferoxamines, such as deferoxamine A, C, D,, D 2 , E. F and G. Since deferoxamine B and the other deferoxamines have similar chemical properties, none of the known purification processes or combinations thereof have been able to reduce the quantity of the impurities below about 2.5%.
- the USP/NF specifies that a deferoxamine B injection solution contain between 90.0 and 110 % of the labeled concentration.
- the assay for determining concentration specified by the USP/NF is a photometric absorbence intensity measurement of the iron complex at 485 run. Id.
- the structurally related impurities also form complexes which absorb in the 485 nm range, leading to an overestimation of the deferoxamine B content.
- decomposition products are formed if deferoxamine B is evaporated to dryness.
- Deferoxamine B is a reasonably stable solid, but it is prone to decomposition in concentrated solution.
- the solution concentration rises, which causes decomposition and a solidified product of low purity.
- this decomposition can be minimized by concentration- and pH-adjustment of the eluent from the adso ⁇ tion resin within certain parameters and then direct precipitation of deferoxamine B free base from the eluent.
- the present invention provides a purification process for production of highly pure deferoxamine B mesylate from a source material containing deferoxamine B produced by a microbiological process.
- the purification process is feasible on an industrial scale and is highly economical compared to other known purification processes.
- Microbiological processes for producing deferoxamine B are known in the art, such as the method described in U.S. Patent No. 3,158,552, which is herein inco ⁇ orated by reference in its entirety.
- Streptomyces pilosus is cultivated in a submersion medium with a low iron content to stimulate production of deferoxamines which the microorganism uses to extract iron from its environment.
- deferoxamine B is freed from complexation with Fe 3 " ions in the culture medium by addition of a competitive iron chelating agent, 8-hydroxyquinoline.
- the broth is then filtered to remove cell mass and an aqueous solution containing deferoxamine B is obtained.
- deferoxamine B hydrochloride in mixture with other deferoxamines, is precipitated from aqueous solution.
- the process of the present invention may be applied to a source material obtained from a fermentation broth after processing such as concentration or extraction as described in the '552 patent or after processing as described in U.S. Patent No. 5,374,771.
- an evaporated fermentation broth extract containing deferoxamine B may be taken up in either aqueous or organic solvent and used as source material for deferoxamine B.
- the source material of deferoxamine B is an aqueous solution with a deferoxamine B concentration of from about 5 to about 70 g L "1 , more preferably from about 10 to about 30 g L "1 .
- the purification process is further described as it is applied to such an aqueous solution of deferoxamine B (hereafter "the crude deferoxamine B solution").
- the purification process of the present invention comprises three stages. First, impurities chemically unrelated to deferoxamine B and related substances with significantly different polarity are removed by chromatography over an adso ⁇ tion resin.
- deferoxamine B is separated from chloride anion and other polyhydroxamates by precipitation of the deferoxamine B as its free base.
- the deferoxamine B, in free base form is suspended in a mixed solvent, treated with methanesulfonic acid to dissolve the free base and crystallized as its mesylate salt.
- compounds that are chemically dissimilar to deferoxamine B and related substances with significantly different polarity are substantially separated by contacting the deferoxamine B source material with a bed of adso ⁇ tion resin and collecting deferoxamine B in solution as an eluent from the bed.
- Preferred adso ⁇ tion resins are unsubstituted and substituted aromatic type resins, aromatic resins with hydrophobic groups, acrylic and methacrylic resins.
- Especially preferred adso ⁇ tion resins include Diaion ® resins of the FP, HP, SP and HPMG series (Mitsubishi Chemical Co ⁇ .) and Amberlite ® resins of the XAD series (Rohm & Haas), the most preferred being Diaion ® SP 207 and Amberlite ® XAD 1 180.
- Deferoxamine B can be eluted from these resins with a mixture of water and a water-soluble organic solvent such as methanol, ethanol, acetonitrile and tetrahydrofuran.
- a preferred chromatographic procedure uses a pre-column and a main column containing separate beds of adso ⁇ tion resin.
- the crude deferoxamine B solution is first eluted through the pre-column which contains a small amount of adso ⁇ tion resin, i.e. about 2 to 6 one hundredths of the volume of the crude deferoxamine B solution.
- the pre-column may be mounted atop the main column and the crude deferoxamine B solution may be allowed to pass through the pre-column without eluting with solvent because only a minor portion of the deferoxamine B is adsorbed on the pre-column.
- the pre-column may be eluted with solvent.
- the eluent may be a mixture of water and a water-soluble organic solvent as described above, but preferably, for improved retention of deferoxamine B on the main column, the elution solvent, if used, is salt water as described below.
- a pre-column may result in a small reduction in yield of deferoxamine B mesylate at the end of the process but its use has the advantage of higher ultimate purity and the economic advantage of greater ease of regeneration of the adso ⁇ tion resin of the main column.
- the solution is preferably treated with an inorganic salt to enhance adso ⁇ tion of deferoxamine B on the main column.
- Chloride salts and sulfate salts are preferred inorganic salts, the most preferred being ammonium chloride and ammonium sulfate.
- the inorganic salt should be added in amount of about 2 to about 15 g L "1 of solution, more preferably about 5-10 g L "1 .
- the crude deferoxamine B solution is then loaded onto a main column containing a bed of abso ⁇ tion resin whose volume is from about l/20th the volume of the crude deferoxamine B solution to about the same volume as that of the crude deferoxamine B solution.
- the volume of the bed of abso ⁇ tion resin is from about 1/4 to about 3/4 the volume of the crude deferoxamine B solution.
- a more highly concentrated crude deferoxamine B solution generally requires less resin than does a more dilute solution
- the deferoxamine B adsorbs onto the resin and the aqueous solution depleted of deferoxamine B is either allowed to drain from the bed or is driven from the bed with a solution of the inorganic salt.
- Partially purified deferoxamine B is then recovered from the adso ⁇ tion resin by eluting with a mixture of water and a water-soluble organic solvent such as methanol, ethanol, acetonitrile or tetrahydrofuran, most preferably acetonitrile.
- a water-soluble organic solvent such as methanol, ethanol, acetonitrile or tetrahydrofuran, most preferably acetonitrile.
- the proportion of organic solvent in the mixture should be from about 1% to about 70% (v/v) , preferably about 1% to about 50% (v/v), depending on the resin.
- an 88:12:3 water:acetonitrile:methanol mixture is a very good solvent mixture for eluting deferoxamine B from Amberlite ® XAD 1180 resin.
- Gradient elution may also be advantageously used to elute deferoxamine B from any of the suitable resins.
- One such generally applicable gradient method involves eluting first with salt water, then with water containing an organic elution solvent. Eluting first with water, then with either a water-acetonitrile or water-methanol mixture, optionally followed by elution with a water-ethanol or water-acetone, gives good results.
- a particularly preferred gradient method for eluting deferoxamine B from Amberlite ® XAD 1 180 resin is to elute first with salt water, then with a 90:10 mixture of water-acetonitrile, and then gradually increasing the acetonitrile content to an 80:20 water-acetonitrile mixture.
- deferoxamine B will be collected from the main column dissolved in aqueous organic eluent contained in one or more fractions cut from the eluent stream.
- the deferoxamine B-containing eluent may optionally be decolorized such as by treatment with activated carbon or a cationic exchange resin like Amberlite ® IRC 50, Duolite ® C467 and Lewatit ® CNP 80 according to methods known in the art.
- the deferoxamine B is collected in three or more fractions-an early eluting fraction, one or more middle eluting fractions, and a late eluting fraction-then the middle fraction(s) containing deferoxamine B will typically be colorless. Only the early eluting and late eluting fractions are likely to have coloration. Accordingly, the desirability of a decolorizing treatment will depend on how the fractions are cut. If both early eluting and late eluting fractions are collected and combined with the middle fraction(s), it is desirable to use both activated carbon and a cation exchange resin to decolorize since the early- eluting and late-eluting fractions respond differently to different decolorizing methods.
- deferoxamine B free base is precipitated out of the eluent from the adso ⁇ tion resin.
- the deferoxamine B concentration in the eluent may vary greatly depending upon the solvent mixture(s) used to elute deferoxamine B from the resin, it is not necessary to evaporate the eluent to dryness in order to establish an appropriate concentration and solvent composition for precipitating the base. Evaporation of the eluent to dryness is, in fact, disadvantageous because of the instability of the hydroxamate groups of deferoxamine B toward high solution concentration and applied heat. Rather, the eluent may be prepared for precipitation of the free base in high yield and high purity by the following the procedure.
- the eluent should be evaporated under mild conditions to a deferoxamine B concentration of about 50 g L "1 to about 150 g L "1 , preferably about 80 g L '1 to about 100 g L "1 and most preferably about 90 g L "1 .
- the preferred organic elution solvents listed above are lower boiling than water and in some cases azeotrope with a minor amount of water, so the proportion of water in the solvent mixture increases upon concentration.
- the concentrated eluent is then diluted with acetonitrile in an amount of from about 0.5 to about 1.5 times the volume of the concentrated eluent. Addition of acetonitrile at this stage was found to prevent precipitation of deferoxamine B hydrochloride (or sulfate, as the case may be depending upon the inorganic salt used).
- the concentration-adjusted eluent containing deferoxamine B in water and acetonitrile (and optionally another organic elution solvent) is then pH-adjusted to between about 8.6 and 10.5, more preferably between about 9.4 and about 10.0 pH.
- the pH can be adjusted using either a basic ion exchange resin or by addition of an aqueous alkaline solution or both.
- Suitable basic ion exchange resins include Amberlite ® resins of the IRA series and Diaion ® resins of the WK series, the most preferred being Amberlite ® IRA 67 in OH " form.
- Suitable alkaline solutions are solutions of NaOH, KOH, ammonia or an amine, the most preferred being concentrated aqueous ammonia.
- the pH of the concentration- adjusted eluent is first tested. If it is below pH 8.0, the pH is adjusted to between about 8.0 and 9.3 with a basic ion exchange resin such as Amberlite ® IRA 67 in OH " form. The resin is then separated and aqueous ammonia is added until the concentration-adjusted eluent reaches a pH of between about 9.4 and 10.0.
- a basic ion exchange resin such as Amberlite ® IRA 67 in OH " form.
- deferoxamine B free base anti-solvent such as acetonitrile, ethanol, methanol, or acetone.
- Preferred deferoxamine B free base anti-solvents are acetonitrile and acetonitrile-acetone mixtures.
- anti-solvent means a liquid in which a compound is poorly soluble. Thus the term anti-solvent relates to the solubility of a particular compound in that liquid.
- the present invention uses two classes of anti- solvent: deferoxamine B free base anti-solvents and deferoxamine B mesylate anti- solvents.
- the rate of addition of deferoxamine B free base anti-solvent to the pH-adjusted eluent is not critical, but a slower addition rate tends to produce larger crystals and a purer crystalline deferoxamine B free base.
- a practical rate of addition is about 0.5 to about 2 times the volume of pH-adjusted eluent per hour, though increased crystal size and higher purity may be realized with a slower addition rate.
- the total amount of added deferoxamine B free base anti-solvent is preferably about 1.5 to 10 times, more preferably about 2 to 8 times and most preferably about 2.5 to 5 times the volume of the pH-adjusted eluent.
- the temperature of the solution may be maintained at anywhere from about -20 °C to about 40 °C during the crystallization, although preferably the temperature is maintained at between about 0°C and about 20 °C.
- the deferoxamine B free base crystals may be isolated by any conventional means, such as filtration or decantation.
- the crystals of the free base may be further purified by recrystallization. Acetonitrile- water mixtures are also good solvent systems for recrystallization.
- the crystallized free base is suspended in a mixed solvent.
- Methanesulfonic acid is then added to the suspension which causes the deferoxamine B free base to go into solution.
- methanesulfonic acid is continued until the solution reaches a pH of about 3 to about 6, more preferably about 3.5-4.5.
- Deferoxamine B mesylate is then allowed to precipitate.
- Suitable mixed solvents for suspending the deferoxamine B free base are mixtures of a deferoxamine B mesylate solvent, either water or methanol, and a deferoxamine B mesylate anti-solvent.
- Deferoxamine B mesylate anti-solvents include C,-C 7 aliphatic alcohols, acetone, methyl formate, methyl acetate, ethyl acetate, hexane, toluene, tetrahydrofuran and acetonitrile.
- the polar, solvent component of the mixed solvent i.e.
- the methanol or the water is preferably mixed in a ratio of about 1 : 1 to about 1 : 10 with the anti-solvent component, more preferably in a ratio of about 1 :5.
- Preferred mixed solvents are water-ethanol mixtures, water-acetonitrile mixtures, methanol-ethanol mixtures and methanol-acetonitrile mixtures, the most preferred being 1 :5 water-ethanol mixtures and 1 :3 methanol-ethanol mixtures.
- the volume of mixed solvent that should be used to suspend the free base is from about 5 to about 20 L per kilogram of deferoxamine B free base, more preferably from about 7 to about 15 L per kilogram. After forming the suspension, methanesulfonic acid is added to the suspension.
- the amount of methanesulfonic acid that is required can be approximated by calculating the amount required to provide one equivalent of the acid to the base. Alternatively, the amount of methanesulfonic acid necessary to provide one equivalent may be accurately gauged by observing the amount of undissolved free base that remains suspended during addition of the acid. The methanesulfonic acid should be added slowly for this pu ⁇ ose since the rate at which the suspended base can react with the acid is rate limited by the surface area of the crystals. After the all of the deferoxamine B free base has dissolved, the pH of the solution should be monitored, while additional methanesulfonic acid is added to bring the pH of the solution to between about 3 and about 6, preferably about 3.5-4.5. After the desired pH is reached, deferoxamine B mesylate crystals are allowed to precipitate.
- the solution may be cooled to about -20 to about 10°C.
- precipitation may be accelerated by adding more deferoxamine B mesylate anti- solvent to the mixture, i.e. by adding a C r C 7 aliphatic alcohol, acetone, methyl formate, methyl acetate, ethyl acetate, hexane, toluene, tetrahydrofuran or acetonitrile.
- deferoxamine B mesylate is isolated by conventional means such as filtration or decantation.
- the solution was then loaded onto a column containing Amberlite ® XAD 1180 adso ⁇ tion resin (132 L) (Rohm & Haas) and driven into the bed with salt water.
- the column was eluted with 10% acetonitrile- water and then 20% acetonitrile-water at a flow rate of 14 L h "1 .
- the eluent was collected in fractions.
- the main fraction yielded deferoxamine hydrochloride solution containing 4.53 kg of deferoxamine B.
- the main fraction was then decolorized over activated carbon (45 g) and Duolite ® C 467 (Rohm and Haas) ion exchange resin in H + form yielding deferoxamine hydrochloride solution containing 4.03 kg of deferoxamine B.
- the decolorized eluent was evaporated to a deferoxamine B concentration of 90 g L " '.
- a volume of acetonitrile equal to that of the concentrated eluent was then added and the basicity was adjusted by addition of Amberlite ® IRA 67 (Rohm and Haas) in OH " form to a pH between 8.0-9.3.
- the pH was raised to between 9.4 and 10.0 with aqueous ammonia.
- Deferoxamine free base was then precipitated by adding two volumes of acetonitrile to the solution and cooling to -5°C. Crystallization was complete after several hours.
- the precipitated deferoxamine B free base was found to have a chloride content of less than 60 ppm. USP/NF 24/19, pp. 1857-1858 (1999)
- the deferoxamine free base was suspended in a 14:3 mixture of ethanol and water (42.5 L). Dilute methanesulfonic acid was slowly added to the suspension until the free base dissolved and the solution attained a pH of between 3.7 and 5. Ethanol (200 L) was added to the solution to precipitate the mesylate salt and the resulting suspension was cooled to -10°C and maintained at -10°C for several hours. The resulting crystals were isolated by filtration, washed with ethanol (50 L) and dried under vacuum to yield 3.4 kg of deferoxamine mesylate. HPLC chromatography showed that the mesylate contained 1.84 weight % impurities. The moisture content as determined by Karl-Fischer Analysis was 0.2 mole %.
- the eluent was then loaded onto a bed of Amberlite ® XAD 1180 adso ⁇ tion resin (7.2 L) in a chromatography column.
- the bed was eluted at a flow rate of 0.7 L h "1 , first with 5.6 L of a 10 g L "1 solution of ammonium chloride in water and then with a 1 :4 methanol- water mixture.
- Deferoxamine B (432 g) was collected in a single fraction. This fraction was decolorized by stirring over activated charcoal (40 g) and filtered. The decolorized eluent was evaporated to a deferoxamine B concentration of 60 g L "1 .
- deferoxamine B base was then suspended in a mixture of ethanol (3.1 L) and water (0.46 L). Methanesulfonic acid was slowly added until the deferoxamine B base dissolved and the solution reached a pH of 3.5. Another 30 L of ethanol was added to the solution to precipitate deferoxamine B mesylate. The resulting suspension was then cooled to between -5°C and 0°C and maintained at reduced temperature for 24h. The crystals were isolated by filtration, washed with ethanol and dried under vacuum to yield deferoxamine B mesylate (299 g) with a purity of 98 % (w/w) as determined by HPLC analysis.
- the solution was loaded onto a bed of Amberlite ® XAD 1 180 adso ⁇ tion resin (7.2 L) in a chromatography column and eluted with 25% acetonitrile-water.
- the deferoxamine B (320 g) was obtained in a single fraction.
- the deferoxamine B-containing eluent was decolorized over activated charcoal (10 g). After filtration, the decolorized eluent containing 305 g of deferoxamine B was concentrated to about 1 10 g L " '.
- An equal volume of acetonitrile then was added to the solution.
- the pH of the solution was then adjusted to between 8.6 and 9.0 by adding Amberlite ® IRA 67 anion exchange resin in OH " form.
- Aqueous ammonia was added to the solution to precipitate deferoxamine B free base. The addition was continued until the suspension reached pH 9.8. The suspension was then cooled to -4°C and maintained at reduced temperature for several hours. Crystals were then isolated by filtration and suspended in a 1 :1 mixture of acetonitrile-water, filtered again and then dried under reduced pressure. The dried deferoxamine B free base was then powdered before being used to prepare the mesylate salt as described in Example 1 , last paragraph. The powdered free base was found to be 97.8 % (w/w) pure by HPLC analysis. The mesylate salt obtained using this material contained 0.96 % impurity (w/w) by HPLC analysis and had a chloride content of less than 60 ppm.
- EXAMPLE 4 Deferoxamine B mesylate was isolated from crude deferoxamine B according to the process of Example 2, except that deferoxamine B hydrochloride was eluted from the bed of Amberlite ® XAD 1 180 adso ⁇ tion resin using 15% ethanol-water followed by 25% THF- water. The deferoxamine mesylate (238 g) so obtained was found to have an impurity content of 1.73% (w/w) by HPLC analysis.
- Precipitation was completed by addition of triple the portion volume of a 1 : 1 acetonitrile-anti-solvent mixture to each portion, i.e. either acetonitrile-methanol, acetonitrile-ethanol or acetonitrile- acetone.
- the suspensions were then cooled to -20 to -5°C and deferoxamine B free base was isolated from each suspension by filtration. The crystals were then washed as described in Example 1.
- deferoxamine B mesylate is obtained in amounts of from 24-28 g. starting from 40 g of crude deferoxamine B.
- the impurity content of the so-obtained deferoxamine B mesylate was between 1.1 and 1.5% (w/w).
- Example 6 The process of Example 2 was followed, except that the crude deferoxamine B contained sulfate anion and the Amberlite ® XAD 1180 resin was washed with aqueous ammonium sulfate instead of aqueous ammonium chloride and then eluted with 10% acetonitrile-water instead of a 1 :4 methanol-water mixture.
- the so-obtained deferoxamine B mesylate salt (261 g) had an impurity content of 1.4% (w/w) measured by HPLC.
- EXAMPLE 7 A suspension of deferoxamine B free base was prepared according to the procedure of Example 2 and cooled as described to 4°C.
- a one tenth portion of the suspension containing 34.1 g of deferoxamine B free base was heated to 36°C and stirred at elevated temperature for 1 hour and then filtered to recover the free base.
- the recovered crystals were then dried and converted to the deferoxamine B mesylate as described in Example 2.
- the product (27 g) had an impurity content of 1.4% (w/w) as determined by HPLC analysis.
- EXAMPLE 8 The process of Example 2, paragraphs 1 and 2, was followed, except that a portion of the eluent containing 43.2 g of deferoxamine B was not decolorized. The free base was twice precipitated from this portion of the eluent. The deferoxamine B was first precipitated as described in Example 2, paragraph 2. Then the once-precipitated deferoxamine B base was suspended in a 1 : 1 acetonitrile-water mixture at a concentration of 40-50 g L " ' . One molar hydrochloric acid was then slowly added to the suspension until the deferoxamine B dissolved.
- the deferoxamine B free base was then re-precipitated from the solution by following the procedure of Example 2, paragraph 2, and was transformed into the mesylate salt as described in Example 2, paragraph 3, to yield 27 g of deferoxamine B mesylate.
- Product coloration was indistinguishable from that of the product of Example 2.
- the impurity content as measured by HPLC is 1.4% (w/w).
- EXAMPLE 9 Following the procedure of Example 1, crude deferoxamine B was chromatographed and the eluent containing deferoxamine B (45.3 g) was decolorized. The decolorized solution was concentrated to 90 g L "1 and passed through a bed of Diaion ® SP 207 adso ⁇ tion resin. Proceeding with the procedure for precipitating the free base and converting it to the mesylate salt as described in the second and third paragraphs of Example 1, as much as 31.5 g of the mesylate can be obtained and with only 1.46% (w/w) impurity according to HPLC analysis.
- Example 10 The procedure of Example 1 was followed except that 200 L of acetonitrile was substituted for 200 L of ethanol to induce precipitation of deferoxamine mesylate. Deferoxamine B mesylate was obtained in 94.7 % yield. Following the procedure of Example 1, but substituting propanol, butanol, amyl alcohol, hexanol and heptanol for ethanol to induce precipitation of the deferoxamine B mesylate, the mesylate is obtained in yields ranging from 83.1 to 89.1%.
- deferoxamine B mesylate is obtained in yields ranging from 88.1 to 93.1 %.
- impurity was present in less than 2.5% (w/w) as determined by HPLC.
- EXAMPLE 11 Deferoxamine mesylate prepared according to Example 1 was recrystallized from methanol and mixtures of methanol and other solvents in yields ranging from 81.3 to 93.7%. Recrystallization was performed by dissolving deferoxamine B mesylate in 8.5 volumes of methanol at 35 °C and then adding one of the following solvents at room temperature: methanol, ethanol, propanol, butanol, ethyl formate, ethyl acetate, butyl acetate, hexane, toluene, THF or acetonitrile.
- the recrystallized deferoxamine B mesylate typical had 1.2-1.6 % (w/w) impurity, lower than the 1.84% (w/w) impurity level of the material before recrystallization.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA02005377A MXPA02005377A (en) | 1999-12-01 | 2000-11-30 | A multistage process for the preparation of highly pure deferoxamine mesylate salt. |
KR1020027007014A KR20020067044A (en) | 1999-12-01 | 2000-11-30 | A multistage process for the preparation of highly pure deferoxamine mesylate salt |
AU19351/01A AU1935101A (en) | 1999-12-01 | 2000-11-30 | A multistage process for the preparation of highly pure deferoxamine mesylate salt |
JP2001541852A JP2003515579A (en) | 1999-12-01 | 2000-11-30 | Multi-step process for the production of high purity deferoxamine mesylate salt |
SK747-2002A SK7472002A3 (en) | 1999-12-01 | 2000-11-30 | A multistage process for the preparation of highly pure deferoxamine mesylate salt |
EP00982299A EP1235791A4 (en) | 1999-12-01 | 2000-11-30 | A multistage process for the preparation of highly pure deferoxamine mesylate salt |
CA002392925A CA2392925A1 (en) | 1999-12-01 | 2000-11-30 | A multistage process for the preparation of highly pure deferoxamine mesylate salt |
US10/168,042 US6858414B2 (en) | 1999-12-01 | 2000-11-30 | Multistage process for the preparation of highly pure deferoxamine mesylate salt |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9904454A HU227315B1 (en) | 1999-12-01 | 1999-12-01 | Process having several steps for producing deferoxamine mesilate of high purity |
HUP9904454 | 1999-12-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001040164A1 true WO2001040164A1 (en) | 2001-06-07 |
Family
ID=90000087
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/032574 WO2001040164A1 (en) | 1999-12-01 | 2000-11-30 | A multistage process for the preparation of highly pure deferoxamine mesylate salt |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP1235791A4 (en) |
JP (1) | JP2003515579A (en) |
KR (1) | KR20020067044A (en) |
CN (1) | CN1433399A (en) |
AU (1) | AU1935101A (en) |
CA (1) | CA2392925A1 (en) |
CZ (1) | CZ20021823A3 (en) |
HU (1) | HU227315B1 (en) |
MX (1) | MXPA02005377A (en) |
PL (1) | PL355328A1 (en) |
RU (1) | RU2002114073A (en) |
SK (1) | SK7472002A3 (en) |
WO (1) | WO2001040164A1 (en) |
YU (1) | YU39602A (en) |
ZA (1) | ZA200204030B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111544374A (en) * | 2020-05-13 | 2020-08-18 | 中国人民解放军总医院第四医学中心 | Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3153621A (en) * | 1959-09-25 | 1964-10-20 | Ciba Geigy Corp | Process for producing ferrioxamines |
WO1993003045A1 (en) * | 1991-08-09 | 1993-02-18 | The Regents Of The University Of California | Process for purer organic metal ion chelate complexes |
US5254724A (en) * | 1991-10-30 | 1993-10-19 | University Of Florida Research Foundation, Inc. | Method for synthesis of desferrioxamine B, analogs and homologs thereof |
US5374771A (en) * | 1992-06-01 | 1994-12-20 | Biogal Gyogyszergyar Rt. | Process for the preparation of high-purity deferoxamine salts |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1898M (en) * | 1961-04-07 | 1963-07-08 | Ciba Geigy | New substance usable in therapy. |
-
1999
- 1999-12-01 HU HU9904454A patent/HU227315B1/en not_active IP Right Cessation
-
2000
- 2000-11-30 CN CN00818750A patent/CN1433399A/en active Pending
- 2000-11-30 PL PL00355328A patent/PL355328A1/en unknown
- 2000-11-30 SK SK747-2002A patent/SK7472002A3/en not_active Application Discontinuation
- 2000-11-30 YU YU39602A patent/YU39602A/en unknown
- 2000-11-30 KR KR1020027007014A patent/KR20020067044A/en not_active Application Discontinuation
- 2000-11-30 JP JP2001541852A patent/JP2003515579A/en active Pending
- 2000-11-30 RU RU2002114073/04A patent/RU2002114073A/en unknown
- 2000-11-30 EP EP00982299A patent/EP1235791A4/en not_active Withdrawn
- 2000-11-30 CZ CZ20021823A patent/CZ20021823A3/en unknown
- 2000-11-30 MX MXPA02005377A patent/MXPA02005377A/en unknown
- 2000-11-30 WO PCT/US2000/032574 patent/WO2001040164A1/en not_active Application Discontinuation
- 2000-11-30 AU AU19351/01A patent/AU1935101A/en not_active Abandoned
- 2000-11-30 CA CA002392925A patent/CA2392925A1/en not_active Abandoned
-
2002
- 2002-05-21 ZA ZA200204030A patent/ZA200204030B/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3153621A (en) * | 1959-09-25 | 1964-10-20 | Ciba Geigy Corp | Process for producing ferrioxamines |
US3247197A (en) * | 1959-09-25 | 1966-04-19 | Ciba Geigy Corp | Tetrahydro-3:6-diodo-1:2-oxazines |
WO1993003045A1 (en) * | 1991-08-09 | 1993-02-18 | The Regents Of The University Of California | Process for purer organic metal ion chelate complexes |
US5254724A (en) * | 1991-10-30 | 1993-10-19 | University Of Florida Research Foundation, Inc. | Method for synthesis of desferrioxamine B, analogs and homologs thereof |
US5374771A (en) * | 1992-06-01 | 1994-12-20 | Biogal Gyogyszergyar Rt. | Process for the preparation of high-purity deferoxamine salts |
Non-Patent Citations (1)
Title |
---|
See also references of EP1235791A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111544374A (en) * | 2020-05-13 | 2020-08-18 | 中国人民解放军总医院第四医学中心 | Application of deferoxamine mesylate for injection in treating age-increasing bone loss and bone marrow stem cell senescence |
Also Published As
Publication number | Publication date |
---|---|
HU227315B1 (en) | 2011-03-28 |
EP1235791A4 (en) | 2006-03-08 |
CA2392925A1 (en) | 2001-06-07 |
CN1433399A (en) | 2003-07-30 |
MXPA02005377A (en) | 2002-12-05 |
ZA200204030B (en) | 2003-05-21 |
HUP9904454A2 (en) | 2001-08-28 |
CZ20021823A3 (en) | 2003-02-12 |
YU39602A (en) | 2005-07-19 |
SK7472002A3 (en) | 2003-03-04 |
PL355328A1 (en) | 2004-04-19 |
EP1235791A1 (en) | 2002-09-04 |
JP2003515579A (en) | 2003-05-07 |
HU9904454D0 (en) | 2000-02-28 |
RU2002114073A (en) | 2004-01-20 |
AU1935101A (en) | 2001-06-12 |
KR20020067044A (en) | 2002-08-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9499849B2 (en) | Processes for preparing tubulysins | |
CA2055912C (en) | Novel erythromycin derivatives, their preparation process, the new intermediated obtained and their application as drugs | |
SI9200139A (en) | New inclusion complex of clavulanic acid with hydrophylyc and hydropholyc beta-cyclodextrin derivates for production of them | |
CA2164798C (en) | Novel erythromycin derivatives, process for preparing the same and their use as drugs | |
EP1612216B1 (en) | Process of purifying vancomycin hydrochloride | |
JP4729047B2 (en) | Pure vancomycin hydrochloride | |
US6858414B2 (en) | Multistage process for the preparation of highly pure deferoxamine mesylate salt | |
EP1734042B1 (en) | Acid cefotetan totally solvent free and method for obtaining same | |
SK302003A3 (en) | Stable gabapentin having pH within a controlled range | |
JPH0689038B2 (en) | Vancomycin improved purification method and its product | |
EP1235791A1 (en) | A multistage process for the preparation of highly pure deferoxamine mesylate salt | |
US6861412B2 (en) | Diphosphate salt of A 4″-substituted-9-deoxo-9A-AZA-9A-homoerythromycin derivative and its pharmaceutical composition | |
CN111087410A (en) | Preparation method of amoxicillin impurity G | |
US6767998B2 (en) | Method for preparing purified erythromycin | |
EP0467280B1 (en) | Novel spergualin-related compound and use thereof | |
US20070021359A1 (en) | Addition salts of azithromycin and citric acid and process for preparing them | |
JPH05178743A (en) | Inhibitor of aids virus infection | |
JPH0737434B2 (en) | Method for collecting 7-dimethylamino-6-demethyl-6-deoxytetracycline | |
JP2003201235A (en) | Medicine containing neuraminic acid compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: P-396/02 Country of ref document: YU |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002/04030 Country of ref document: ZA Ref document number: 200204030 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV2002-1823 Country of ref document: CZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 7472002 Country of ref document: SK |
|
ENP | Entry into the national phase |
Ref document number: 2001 541852 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2002/005377 Country of ref document: MX Ref document number: 2392925 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020027007014 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10168042 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2002 2002114073 Country of ref document: RU Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000982299 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 008187509 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 1020027007014 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2000982299 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: PV2002-1823 Country of ref document: CZ |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2000982299 Country of ref document: EP |