WO2024189550A1 - Process for the preparation of isavuconazonium sulfate and its crystalline forms - Google Patents
Process for the preparation of isavuconazonium sulfate and its crystalline forms Download PDFInfo
- Publication number
- WO2024189550A1 WO2024189550A1 PCT/IB2024/052413 IB2024052413W WO2024189550A1 WO 2024189550 A1 WO2024189550 A1 WO 2024189550A1 IB 2024052413 W IB2024052413 W IB 2024052413W WO 2024189550 A1 WO2024189550 A1 WO 2024189550A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- sulfate
- isavuconazonium
- isavuconazonium sulfate
- compound
- Prior art date
Links
- LWXUIUUOMSMZKJ-KLFWAVJMSA-M isavuconazonium sulfate Chemical compound OS([O-])(=O)=O.CNCC(=O)OCC1=CC=CN=C1N(C)C(=O)OC(C)[N+]1=CN(C[C@@](O)([C@@H](C)C=2SC=C(N=2)C=2C=CC(=CC=2)C#N)C=2C(=CC=C(F)C=2)F)N=C1 LWXUIUUOMSMZKJ-KLFWAVJMSA-M 0.000 title claims abstract description 136
- 229960003384 isavuconazonium sulfate Drugs 0.000 title claims abstract description 136
- 238000000034 method Methods 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- 238000005580 one pot reaction Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 60
- 238000006243 chemical reaction Methods 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- YRXIMPFOTQVOHG-UHFFFAOYSA-N 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]acetic acid Chemical compound OC(=O)CN(C)C(=O)OC(C)(C)C YRXIMPFOTQVOHG-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 229960000788 isavuconazole Drugs 0.000 claims description 6
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 5
- 150000008045 alkali metal halides Chemical class 0.000 claims description 5
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229960004132 diethyl ether Drugs 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003957 anion exchange resin Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 3
- 238000010899 nucleation Methods 0.000 claims description 3
- 229940078552 o-xylene Drugs 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- LNWWQYYLZVZXKS-UHFFFAOYSA-N 1-pyrrolidin-1-ylethanone Chemical compound CC(=O)N1CCCC1 LNWWQYYLZVZXKS-UHFFFAOYSA-N 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- QLSYIEGOUWSMMQ-UHFFFAOYSA-N acetonitrile;ethyl acetate Chemical compound CC#N.CC#N.CCOC(C)=O QLSYIEGOUWSMMQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-UHFFFAOYSA-M 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- -1 N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2-yl]carbamic acid 1-chloroethyl ester compound Chemical class 0.000 abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 8
- 229960004922 isavuconazonium Drugs 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- RSWOJTICKMKTER-QXLBVTBOSA-N isavuconazonium Chemical class CNCC(=O)OCC1=CC=CN=C1N(C)C(=O)OC(C)[N+]1=CN(C[C@@](O)([C@@H](C)C=2SC=C(N=2)C=2C=CC(=CC=2)C#N)C=2C(=CC=C(F)C=2)F)N=C1 RSWOJTICKMKTER-QXLBVTBOSA-N 0.000 description 6
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 238000001757 thermogravimetry curve Methods 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- VYPMWCUNCNMNOM-UHFFFAOYSA-N [2-(methylamino)pyridin-3-yl]methanol Chemical compound CNC1=NC=CC=C1CO VYPMWCUNCNMNOM-UHFFFAOYSA-N 0.000 description 4
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 241001214789 Basilea Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- AOGQPLXWSUTHQB-UHFFFAOYSA-N hexyl acetate Chemical compound CCCCCCOC(C)=O AOGQPLXWSUTHQB-UHFFFAOYSA-N 0.000 description 2
- MLFHJEHSLIIPHL-UHFFFAOYSA-N isoamyl acetate Chemical compound CC(C)CCOC(C)=O MLFHJEHSLIIPHL-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- DWKNOLCXIFYNFV-HSZRJFAPSA-N 2-[[(2r)-1-[1-[(4-chloro-3-methylphenyl)methyl]piperidin-4-yl]-5-oxopyrrolidine-2-carbonyl]amino]-n,n,6-trimethylpyridine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC(C)=NC(NC(=O)[C@@H]2N(C(=O)CC2)C2CCN(CC=3C=C(C)C(Cl)=CC=3)CC2)=C1 DWKNOLCXIFYNFV-HSZRJFAPSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- UXHQLGLGLZKHTC-CUNXSJBXSA-N 4-[(3s,3ar)-3-cyclopentyl-7-(4-hydroxypiperidine-1-carbonyl)-3,3a,4,5-tetrahydropyrazolo[3,4-f]quinolin-2-yl]-2-chlorobenzonitrile Chemical compound C1CC(O)CCN1C(=O)C1=CC=C(C=2[C@@H]([C@H](C3CCCC3)N(N=2)C=2C=C(Cl)C(C#N)=CC=2)CC2)C2=N1 UXHQLGLGLZKHTC-CUNXSJBXSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- MWHHJYUHCZWSLS-UHFFFAOYSA-N FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F Chemical compound FC=1C=C(C=CC1C1=C2CNC(C2=C(C=C1)C=1NC(=CN1)C)=O)NC(=O)NC1=C(C=C(C=C1F)F)F MWHHJYUHCZWSLS-UHFFFAOYSA-N 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 230000006179 O-acylation Effects 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010061418 Zygomycosis Diseases 0.000 description 1
- MCRWZBYTLVCCJJ-DKALBXGISA-N [(1s,3r)-3-[[(3s,4s)-3-methoxyoxan-4-yl]amino]-1-propan-2-ylcyclopentyl]-[(1s,4s)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]methanone Chemical compound C([C@]1(N(C[C@]2([H])C1)C(=O)[C@@]1(C[C@@H](CC1)N[C@@H]1[C@@H](COCC1)OC)C(C)C)[H])N2C1=CC(C(F)(F)F)=NC=N1 MCRWZBYTLVCCJJ-DKALBXGISA-N 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical group 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 201000009085 invasive aspergillosis Diseases 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 201000007524 mucormycosis Diseases 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- VOVZXURTCKPRDQ-CQSZACIVSA-N n-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide Chemical compound C1[C@H](O)CCN1C1=NC=C(C(=O)NC=2C=CC(OC(F)(F)Cl)=CC=2)C=C1C1=CC=NN1 VOVZXURTCKPRDQ-CQSZACIVSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 1
- 229960000280 phenindione Drugs 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Definitions
- the present invention provides novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, a process for the preparation thereof and a pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
- the present invention relates to a process for the preparation of [N-methyl-N-(3-[((N- tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2-yl]carbamic acid 1- chloroethyl ester compound of Formula (I).
- the compound of Formula (I) is a key intermediate in the preparation of
- Isavuconazonium sulfate of Formula (II) The present invention also relates to one-pot process for the preparation of Isavuconazonium sulfate of Formula (II).
- Isavuconazonium sulfate is the prodrug of Isavuconazole, and it is an azole antifungal agent used for the treatment of invasive aspergillosis and invasive mucormycosis.
- Isavuconazonium Sulfate is very soluble in water and over the pH range 1-7. Isavuconazonium sulfate is being marketed in the US under the brand name Cresemba®.
- Isavuconazonium sulfate is disclosed in US 6,812,238 of Basilea.
- the disadvantage of the above process is the compound Formula VIII contains more number of impurities and it needs multiple purifications for their elimination. Due to sensitivity to moisture, Isavuconazonium salts such as the commercial product Isavuconazonium sulfate, are difficult to purify from crude material in high yield and purity.
- US ‘238 discloses a process for the preparation of compound of Formula (I) by the reaction of 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) with 1- Chloroethyl chloroformate in presence of diisopropylamine in dichloromethane, followed by adding Boc-sarcosine in the presence of DMAP and in diethylether to produce [N-methyl-N-3-((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridin-2- yl]carbamic acid 1 -chloro-ethyl ester of Formula (I).
- CN 106565699 discloses a process for the preparation of crystal form of Isavuconazonium sulfate by dissolving Isavuconazole hydrochloride in water, adjusting the pH to neutral using a base at a low temperature, adding an organic solvent A for extraction, drying and concentrating and then dissolving in an organic solvent B, adding concentrated sulfuric acid and hydrogen peroxide at a low temperature, stirring, and concentrating;
- an organic solvent C heating to dissolve, stirring and cooling to crystallize, and performing suction filtration to produce a crystal.
- CN 106467534 discloses a process for the preparation of crystal form of Isavuconazonium sulfate by dissolving the crude Isavuconazonium sulfate in a mixed solution of water, an organic solvent A and an organic solvent B, then adding an organic solvent C to the Isavuconazonium sulfate solution obtained above; followed by stirring and separation to produce crystalline Isavuconazonium sulfate.
- US 20210323959 discloses a process for the purification of Isavuconazonium sulfate, by dissolving the Isavuconazonium sulfate in an aliphatic alcohol and water, wherein the pH of the mixture is in the range of about pH 1 to about pH 6; allowing a first portion of Isavuconazonium sulfate to crystalize from the mixture; and adding an aprotic organic solvent to the mixture and allowing an additional portion of Isavuconazonium sulfate to precipitate from the mixture to produce crystalline form.
- the present invention is to resolve the above problems, surprisingly found that the compound of Formula (III) is reacted with Boc-sarcosine in presence of a base and an amide solvent to provide compound of Formula (IV) in pure form without forming by-products, which is further reacted with chloroethyl chloroformate in presence of a base and a solvent followed by separating layers using an acid to produce compound of Formula (I) with high purity and yield and removes unreacted compound of Formula (IV).
- the compound of formula (I) is involved in the one-pot process of Isavuconazonium sulfate, which is commercially feasible provides high yield and having purity >99.5% (HPLC). Surprisingly resulted in novel crystalline forms of Isavuconazonium sulfate.
- the main object of the present invention is to provide novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5% by HPLC.
- Another object of the present invention is to provide a process of the preparation of novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5% by HPLC.
- Another object of the present invention is to provide a pharmaceutical composition comprising the novel crystalline forms Isavuconazonium sulfate having purity greater than 99.5% by HPLC.
- Another object of the present invention is to provide a process for the preparation of N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2- yl]carbamic acid 1 -chloroethyl ester compound of Formula (I) in high yield with purity and without forming by-products.
- Another object of the present invention is to provide a one -pot process for the preparation of Isavuconazonium sulfate of Formula (II).
- the main embodiment of the present invention is to provide novel crystalline forms Isavuconazonium sulfate.
- Another embodiment of the present invention is to provide a process for the preparation of crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, which comprises:
- the present invention provides a crystalline form of Isavuconazonium sulfate (Form ISA-1), which is characterized by
- Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-2), which is characterized by
- Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-3), which is characterized by
- Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-4), which is characterized by
- Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-5), which is characterized by
- Another embodiment of the present invention is to provide a process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5), which comprises, exposing a crystalline form of Isavuconazonium sulfate to humidity to obtain crystalline form of Isavuconazonium sulfate (Form ISA-5).
- Another embodiment of the present invention is to provide a process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.
- Another embodiment of the present invention is to provide a process for the preparation of compound of Formula (I) with high purity, which comprises:
- Another embodiment of the present invention is to provide a one -pot process for the preparation of Isavuconazonium sulfate of Formula (II) having purity > 99%, which comprises:
- Figure 1 Illustrates the X-ray powder diffraction pattern of Form ISA-1.
- Figure 2 Illustrates the X-ray powder diffraction pattern of Form ISA-2.
- Figure 3 Illustrates the X-ray powder diffraction pattern of Form ISA-3.
- Figure 4 Illustrates the X-ray powder diffraction pattern of Form ISA-4.
- Figure 5 Illustrates the X-ray powder diffraction pattern of Form ISA-5.
- Figure 6 Illustrates the DSC of Form ISA-1.
- Figure 7 Illustrates the DSC of Form ISA-2.
- Figure 8 Illustrates the DSC of Form ISA-3.
- Figure 9 Illustrates the DSC of Form ISA-4.
- Figure 10 Illustrates the DSC of Form ISA-5.
- Figure 11 Illustrates the TGA of Form ISA-1.
- Figure 12 Illustrates the TGA of Form ISA-2.
- Figure 13 Illustrates the TGA of Form ISA-3.
- Figure 14 Illustrates the TGA of Form ISA-4.
- Figure 15 Illustrates the TGA of Form ISA-5. DETAILED DESCRIPTION OF THE INVENTION
- the main embodiment of the present invention is to provide novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, a process for the preparation thereof and a pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
- the crystalline forms may be substantially hydrates, which may be monohydrate, dihydrate or a trihydrate, which are stable.
- Scan type Continuous scan
- Scan range: 2-40°;
- Step size 0.05°
- Another embodiment of the present invention is to provide a process for the preparation of crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, which comprises, Isavuconazonium sulfate is dissolved in water and a solvent; The reaction mass is cooled and stirred. If the solid is not isolated, then seeding with crystalline form of Isavuconazonium sulfate. The obtained solid is filtered and dried, if required slurried in a solvent, then filtered and dried to obtain crystalline form of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
- the solvent used in the above process comprises water, acetonitrile, ethanenitrile, propionitrile, butyronitrile, isobutyronitrile, ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec -butyl acetate, isopentyl acetate, hexyl acetate, n-hexane, heptane or mixtures thereof.
- the suitable temperature of the above process comprises dissolution temperature ranges from 25°C to 30°C; the cooling temperature ranges from -10°C to 5°C and the drying temperature ranges from 25°C to 40°C.
- the crystalline form of Isavuconazonium sulfate produced by the above process comprises Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 or Form ISA-5.
- the crystalline form of Isavuconazonium sulfate (Form ISA-1) of the present invention is characterized by:
- the crystalline form of Isavuconazonium sulfate (Form ISA-2) of the present invention is characterized by:
- the crystalline form of Isavuconazonium sulfate (Form ISA-3) of the present invention is characterized by:
- the crystalline form of Isavuconazonium sulfate (Form ISA-4) of the present invention is characterized by:
- the crystalline form of Isavuconazonium sulfate (Form ISA-5) of the present invention is characterized by:
- the present invention provides a process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5) which comprises exposing crystalline form of Isavuconazonium sulfate (Form ISA-4) to a humidity between 20-80% RH at room temperature.
- the present invention provides a process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.
- the crystalline Isavuconazonium sulfate used in the preparation of amorphous Isavuconazonium sulfate could be any of the crystalline form such as Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 and Form ISA-5.
- the present invention provides a pharmaceutical composition comprising the crystalline hydrated forms of Isavuconazonium sulfate.
- Isavuconazonium sulfate used in the present invention is prepared according to the process disclosed in the literature.
- the Isavuconazonium sulfate used in the present invention comprising in the form of amorphous or crystalline form produced by priorart procedures.
- the present invention provides a process for the preparation of the compound of Formula (I), in high yield and purity without forming by-products.
- the process comprises, reacting compound of formula (III) with Boc-sarcosine in the presence of a base, a coupling agent in an amide solvent to provide compound of formula (IV).
- the compound of Formula (IV) is reacted with chloroethyl chloroformate in the presence of a base and a solvent to produce a reaction mixture, followed by separating the layers, adding an acid to the organic layer for removing unreacted intermediate compound of Formula (IV) and the compound of Formula (I) is isolated with high purity and yield.
- the base as used in the above reaction comprising an organic base comprises pyridine, piperidine, dimethylaminopyridine, picolines, diisopropyl ethylamine, triethyl amine and the like or mixtures thereof or an inorganic base comprises NaHCO 3 , LiOH, NaOH, KOH, KHCO3, LiHCO 3 , Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , CaCO 3 , MgCO 3 , sodium hydride, potassium tert- butoxide, sodium tert-butoxide, magnesium hydroxide and the like or mixtures thereof.
- the amide solvent used in the above reaction comprises N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethyl phosphoramide, and N-acetyl pyrrolidine and the like or mixtures thereof.
- the coupling agent is selected from carbodiimides or salt thereof such as N,N'- dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC); imidazoliums or salt thereof; such as l,T-carbonyldiimidazole (CDI), l,T-carbonyl-di-(l,2,4-triazole) (CDT); uronium or guanidinium salts such as O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), and
- the solvent used in the above reaction comprises an ether such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.
- an ether such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or
- a one-pot process for the preparation of Isavuconazonium sulfate comprises, the reaction of Isavuconazole of formula (V) with the compound formula (I) in a solvent, in the presence of a catalyst and alkali metal halide to give formula (VI), which is treated with trifluoroacetic acid in a solvent to give compound of formula (VII) which is salt exchanged by an anion exchange resin to give Isavuconazonium sulfate (II) with high purity i.e > 99% (HPLC).
- the alkali metal halide used in the coupling comprises lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide.
- the catalyst used in the coupling comprises tetrabutylammonium bromide (TBAB), tetrabutylammonium hydroxide, triethylbenzylammonium chloride, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, or hexadecyl trimethyl ammonium bromide.
- TBAB tetrabutylammonium bromide
- tetrabutylammonium hydroxide triethylbenzylammonium chloride
- tricaprylylmethylammonium chloride tridecyl sulfate sodium salt
- dodecyl sulfate sodium salt tetrabutylammonium hydrogensulfate
- the solvent used in the above reaction comprises tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; butyronitrile, propionitrile, ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.
- the anion exchange resin used for salt exchange comprises a strong base anion (SBA) resin.
- Example- 1 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-1):
- Isavuconazonium, sulfate (1: 1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-1).
- Example-2 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-2)
- Isavuconazonium, sulfate (1: 1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s. Further material was dried at 35 ⁇ 5°C under vacuum for 3-4hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-2).
- Example-3 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-3)
- Isavuconazonium, sulfate (1: 1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s. Further material was slurried in ethyl acetate 10.0ml at 20°C for 2-3hr’s. Solid was filtered and washed with ethyl acetate 1.0ml followed by suck dried under nitrogen atmosphere for 5min’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-3).
- Example-4 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
- Isavuconazonium, sulfate (1: 1) 0.5gm was dissolved in DM water (1.0ml) at room temperature and acetonitrile (25ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-24hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0ml) followed by suck dried for 5min’s. Further material was dried at 30 ⁇ 5°C under vacuum for 2-3hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ⁇ 99.36%.
- Example-5 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
- Isavuconazonium sulfate (1: 1) 0.5gm was dissolved in DM water (2.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass cooled to -10°C and stirred reaction mass for 45-50 hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed acetonitrile (5.0ml) followed by suck dried for 5min’s. Further material was dried at 30 ⁇ 5°C under vacuum for 2-3hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ⁇ 99.62%.
- Example-6 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
- Isavuconazonium sulfate (1:1) l.Ogm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 20-24hr’s at -10°C and 1% seed was added to above reaction mass. Stirred the reaction mass for 20-24hr’s at -10°C. The temperature was slowly raised up to 0-5 °C and stirred for l-2hr’s. Obtained solid was filtered and washed acetonitrile (20.0ml) followed by suck dried for 5min’s. Further material was dried at 30 ⁇ 5°C under vacuum for 3-5hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ⁇ 99.41%.
- Example-7 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
- Isavuconazonium sulfate (1: 1) 4.0gm was dissolved in DM water (8.0ml) at room temperature and acetonitrile (200ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 44-48hr’s at -10°C and 1% seed was added to above reaction mass. Stirred the reaction mass for 20-24hr’s at -10°C solid was isolated. The temperature was slowly raised up to 0-5°C and stirred for 1- 2hr’s. Obtained solid was filtered and washed acetonitrile (20.0ml) followed by suck dried for 5min’s. Further material was dried at 30 ⁇ 5°C under vacuum for 3-5hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ⁇ 99.16%.
- Example-8 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5)
- Isavuconazonium Sulfate 25g was dissolved in purified water (50 ml) at 20-30°C under nitrogen atmosphere. Reaction mixture was stirred at 20-30°C for 15-20 minutes. Acetonitrile was slowly added (1250 ml) to the above clear solution at 20- 30°C in 45-60 minutes. Reaction mixture was cooled to -10°C to -15°C. The reaction mixture was seeded with Isavuconazonium Sulfate API (0.25g) at -10°C to -15°C. The above solution was maintained at -10° to -15°C for 20-24hr, temperature was slowly raised to 0-5 °C for l-2hr.
- Example-9 Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5)
- Isavuconazonium sulfate (1:1) was exposed to humidity 40% RH or 60% RH at room temperature for 5 days to afford crystalline form of Isavuconazonium sulfate (Form ISA-5).
- Example-10 Preparation of amorphous form of Isavuconazonium sulfate:
- Isavuconazonium sulfate crystalline form (100 g) was dissolved in purified water (500 ml), the solution was stirred for 10 to 15 min at 20-30°C. The above solution was loaded into lyophilizer and lyophilized under optimized recipe to give amorphous material, the material was unloaded under nitrogen atmosphere and the moisture content was checked which is NMT 2.0%.
- EDC.HC1 (84.24 g) was added at 0-5°C and the reaction mixture was maintained at 0-5°C for 2-4 h and monitored the reaction for unreacted 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III).
- 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) In a separate round bottom flask water (3500 mL) was taken to cooled to 0-5°C and the reaction mass was added over a period of ⁇ 30 min then allowed the reaction temperature to reach 20-30°C. The reaction was maintained at this temperature for 2- 3h. The reaction mass was filtered over Buchner funnel under vaccum at 20- 30°C, then continued to suck dry. The wet cake was washed with isopropyl alcohol and dried at 20-30°C for 10-12 h.
- reaction mass was filtered and washed with DCM (100 mL). To the filtrate sodium bicarbonate solution (prepared from 54.0 g NaHCCh + DM water 1000 mL) was added and stirred for 15-30 min at 20-30°C. The layers were separated and the organic layer was collected. Charged organic layer and 10% Aq. Phosphorous acid solution (400 mL) into the above RBF and stirred for 10 ⁇ 5 min and then layers were separated and collected the organic layer. The organic layer was concentrated under reduced pressure below 40°C to obtain the compound of Formula (I) as pale yellow color liquid.
- the MDC layer contains Formula (VII, ⁇ 200g, Isavuconazonium TFA Salt) was Concentrated and dissolved in purified water (400 ml).
- the aqueous solution contains Formula-(VII) was passed through Indion GS 300 Resin to exchange from Isavuconazonium TFA salt to Isavuconazonium Sulfate at 20-30°C.
- acetonitrile (12500 ml) was added at 20-30°C and cooled to -10 to - 15°C.
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Abstract
The present invention provides novel, pure and stable crystalline forms of Isavuconazonium sulfate, a process for the preparation thereof and a pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate. The present invention further provides a process for the preparation of N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2-yl]carbamic acid 1-chloroethyl ester compound of Formula (I), and one pot process for the preparation of Isavuconazonium sulfate, which is obtained in high yield and purity without forming bi-products.
Description
PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM SULFATE AND ITS CRYSTALLINE FORMS
FIELD OF INVENTION
The present invention provides novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, a process for the preparation thereof and a pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
The present invention relates to a process for the preparation of [N-methyl-N-(3-[((N- tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2-yl]carbamic acid 1- chloroethyl ester compound of Formula (I).
The compound of Formula (I) is a key intermediate in the preparation of
Isavuconazonium sulfate of Formula (II).
The present invention also relates to one-pot process for the preparation of Isavuconazonium sulfate of Formula (II).
BACKGROUND OF THE INVENTION
Isavuconazonium sulfate, is the prodrug of Isavuconazole, and it is an azole antifungal agent used for the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazonium Sulfate is very soluble in water and over the pH range 1-7. Isavuconazonium sulfate is being marketed in the US under the brand name Cresemba®.
The structure of Isavuconazonium sulfate is shown as follows:
Isavuconazonium sulfate is disclosed in US 6,812,238 of Basilea.
US 6,812,238 of Basilea discloses a process for the preparation of Isavuconazonium salts including sulfate salt by reacting Isavuconazole compound of formula (V) with compound of formula (I) in acetonitrile and in the presence of Nal to give compound of formula (VIII) which is treated with mineral acid to give Isavuconazonium sulfate Formula II.
The disadvantage of the above process is the compound Formula VIII contains more number of impurities and it needs multiple purifications for their elimination. Due to sensitivity to moisture, Isavuconazonium salts such as the commercial product Isavuconazonium sulfate, are difficult to purify from crude material in high yield and purity.
US ‘238 discloses a process for the preparation of compound of Formula (I) by the reaction of 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) with 1- Chloroethyl chloroformate in presence of diisopropylamine in dichloromethane, followed by adding Boc-sarcosine in the presence of DMAP and in diethylether to produce [N-methyl-N-3-((tert-butoxycarbonylmethylamino)acetoxymethyl)pyridin-2- yl]carbamic acid 1 -chloro-ethyl ester of Formula (I).
The process is as shown in scheme-I below:
The disadvantage of the above processes is due to the strong acylation ability of the acid chloride, both N-acylation and O-acylation can occur, even if the reaction is carried out at a low temperature, the following by-product is unavoidable.
by-product (n)
CN 106565699 discloses a process for the preparation of crystal form of Isavuconazonium sulfate by dissolving Isavuconazole hydrochloride in water, adjusting the pH to neutral using a base at a low temperature, adding an organic solvent A for extraction, drying and concentrating and then dissolving in an organic solvent B, adding concentrated sulfuric acid and hydrogen peroxide at a low temperature, stirring, and concentrating; Followed by adding the obtained concentrate to an organic solvent C, heating to dissolve, stirring and cooling to crystallize, and performing suction filtration to produce a crystal.
The disadvantage of this method is the said process is not suitable for commercial scale-up due to the use of hydrogen peroxide leads to significant degradation of the product. The yield is 62 % and purity is 97.7%.
CN 106467534 discloses a process for the preparation of crystal form of Isavuconazonium sulfate by dissolving the crude Isavuconazonium sulfate in a mixed solution of water, an organic solvent A and an organic solvent B, then adding an organic solvent C to the Isavuconazonium sulfate solution obtained above; followed by stirring and separation to produce crystalline Isavuconazonium sulfate.
The disadvantage of this method is the results in low yield and purity.
US 20210323959 discloses a process for the purification of Isavuconazonium sulfate, by dissolving the Isavuconazonium sulfate in an aliphatic alcohol and water, wherein
the pH of the mixture is in the range of about pH 1 to about pH 6; allowing a first portion of Isavuconazonium sulfate to crystalize from the mixture; and adding an aprotic organic solvent to the mixture and allowing an additional portion of Isavuconazonium sulfate to precipitate from the mixture to produce crystalline form.
The main disadvantage of this method, which produces unwanted impurities and results the product in low yield and low purity.
CN 110551064 discloses a process for the preparation of compound of Formula (I) by the reaction of 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) with Boc-sarcosine in presence of THF, DMAP and DCM to produce 3-(tert- butoxycarbonylmethylamino)acetoxymethyl)-2-methyl aminopyridine of Formula (IV), which is further reacted with 1 -chloroethyl chloroformate in presence of Na2CO3 and DCM.
The process is as shown in scheme- II below:
The disadvantage of the above processes is as it was aforementioned the problem of di-acylation already, even this methodology would furnish the di-acylation and therefore, the following impurities formation is quite inevitable.
by-product (a) by-product (b)
Therefore, there is always a need for the alternative preparative route, which provides the desired compound of Formula (I) in high yield with high purity and without forming by-products and completing isolation of desired compound of Formula (I).
The present invention is to resolve the above problems, surprisingly found that the compound of Formula (III) is reacted with Boc-sarcosine in presence of a base and an amide solvent to provide compound of Formula (IV) in pure form without forming by-products, which is further reacted with chloroethyl chloroformate in presence of a base and a solvent followed by separating layers using an acid to produce compound of Formula (I) with high purity and yield and removes unreacted compound of Formula (IV). The compound of formula (I) is involved in the one-pot process of Isavuconazonium sulfate, which is commercially feasible provides high yield and having purity >99.5% (HPLC). Surprisingly resulted in novel crystalline forms of Isavuconazonium sulfate.
OBJECTIVE OF INVENTION
The main object of the present invention is to provide novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5% by HPLC.
Another object of the present invention is to provide a process of the preparation of novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5% by HPLC.
Another object of the present invention is to provide a pharmaceutical composition comprising the novel crystalline forms Isavuconazonium sulfate having purity greater than 99.5% by HPLC.
Another object of the present invention is to provide a process for the preparation of N-methyl-N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl)pyridin-2- yl]carbamic acid 1 -chloroethyl ester compound of Formula (I) in high yield with purity and without forming by-products.
Another object of the present invention is to provide a one -pot process for the
preparation of Isavuconazonium sulfate of Formula (II).
SUMMARY OF THE INVENTION
The main embodiment of the present invention is to provide novel crystalline forms Isavuconazonium sulfate.
Another embodiment of the present invention is to provide a process for the preparation of crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, which comprises:
(i) dissolving Isavuconazonium sulfate in water and a solvent;
(ii) cooling;
(iii) stirring;
(iv) optionally seeding with crystalline form of Isavuconazonium sulfate,
(v) filtering;
(vi) drying; and
(vii) isolating crystalline form of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
In an embodiment, the present invention provides a crystalline form of Isavuconazonium sulfate (Form ISA-1), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 6.3, 7.9, 9.3, 10.5,
13.9, 15.6, 17.8 and 25.4 ± 0.2° 20;
• DSC as shown in Figure 6;
• TGA as shown in Figure 11.
Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-2), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.2, 6.3, 8.0, 9.7,
11.2, 12.6, 13.7, 17.1, 17.5 and 19.6 ± 0.2° 20 ;
• DSC as shown in Figure 7 ;
• TGA as shown in Figure 12.
Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-3), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.1, 6.3, 8.0, 9.6,
11.0, 12.9, 13.7, 14.6, 17.5 and 20.5 ± 0.2° 20;
• DSC as shown in Figure 8;
• TGA as shown in Figure 13.
Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-4), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.2, 5.7, 6.5, 9.2,
10.2, 14.5, 16.0, 16.6, 18.6 and 20.6 ± 0.2° 20.
• DSC as shown in Figure 9;
• TGA as shown in Figure 14.
Another embodiment of the present invention is to provide a crystalline form of Isavuconazonium sulfate (Form ISA-5), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.6, 6.5, 8.4, 9.2,
10.2, 14.5, 16.1, 16.8, 18.5, and 23.1 ± 0.220.
• DSC as shown in Figure 10;
• TGA as shown in Figure 15.
Another embodiment of the present invention is to provide a process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5), which comprises, exposing a crystalline form of Isavuconazonium sulfate to humidity to obtain crystalline form of Isavuconazonium sulfate (Form ISA-5).
Another embodiment of the present invention is to provide a process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.
Another embodiment of the present invention is to provide a process for the preparation of compound of Formula (I) with high purity,
which comprises:
(i) reacting of compound of Formula (III);
Formula (III)
with Boc-sarcosine or a salt thereof; in presence of a base and in an amide solvent to produce compound of Formula (IV);
(ii) separating the layers,
(iii) reacting compound of Formula (IV) with chloroethyl chloroformate in the presence of a base and a solvent to produce reaction mass; (iv) adding an acid for removing unreacted intermediate compound of formula (IV);
(v) isolating the compound of Formula (I) in pure form.
Another embodiment of the present invention is to provide a one -pot process for the preparation of Isavuconazonium sulfate of Formula (II) having purity > 99%,
which comprises:
(i) reacting Isavuconazole of formula (V);
with a compound of formula (I);
in a solvent, in the presence of an alkali metal halide to give compound of formula (VI);
wherein X is Cl, Br or I;
(ii) reacting the compound of formula (VI) with trifluoroacetic acid to give compound of formula (VII);
(iii) converting the compound of formula (VII) to Isavuconazonium sulfate of Formula (II) having purity > 99%.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 Illustrates the X-ray powder diffraction pattern of Form ISA-1.
Figure 2 Illustrates the X-ray powder diffraction pattern of Form ISA-2.
Figure 3 Illustrates the X-ray powder diffraction pattern of Form ISA-3.
Figure 4 Illustrates the X-ray powder diffraction pattern of Form ISA-4.
Figure 5 Illustrates the X-ray powder diffraction pattern of Form ISA-5.
Figure 6 Illustrates the DSC of Form ISA-1.
Figure 7 Illustrates the DSC of Form ISA-2.
Figure 8 Illustrates the DSC of Form ISA-3.
Figure 9 Illustrates the DSC of Form ISA-4.
Figure 10 Illustrates the DSC of Form ISA-5.
Figure 11 Illustrates the TGA of Form ISA-1.
Figure 12 Illustrates the TGA of Form ISA-2.
Figure 13 Illustrates the TGA of Form ISA-3.
Figure 14 Illustrates the TGA of Form ISA-4.
Figure 15 Illustrates the TGA of Form ISA-5.
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide novel crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, a process for the preparation thereof and a pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
In a preferred embodiment, the crystalline forms may be substantially hydrates, which may be monohydrate, dihydrate or a trihydrate, which are stable.
The novel crystalline forms can be characterized by X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray powder diffraction pattern was measured on Bruker D8 advance-Eco with lynex detector equipped with Cu source (X=1.58A) or any equivalent X-ray powder diffractometer instrument.
Scanning parameters:
Scan type: Continuous scan;
Scan range: 2-40°;
Time/step: 0.8 sec;
Step size: 0.05°;
Divergence slit: V20;
Rotation: 30 rpm.
Another embodiment of the present invention is to provide a process for the preparation of crystalline forms of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC, which comprises, Isavuconazonium sulfate is dissolved in water and a solvent; The reaction mass is cooled and stirred. If the solid is not isolated, then seeding with crystalline form of Isavuconazonium sulfate. The obtained solid is filtered and dried, if required slurried in a solvent, then filtered and dried to obtain crystalline form of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
The solvent used in the above process comprises water, acetonitrile, ethanenitrile, propionitrile, butyronitrile, isobutyronitrile, ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, sec -butyl acetate, isopentyl acetate, hexyl acetate, n-hexane, heptane or mixtures thereof.
The suitable temperature of the above process comprises dissolution temperature ranges from 25°C to 30°C; the cooling temperature ranges from -10°C to 5°C and the drying temperature ranges from 25°C to 40°C.
The crystalline form of Isavuconazonium sulfate produced by the above process comprises Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 or Form ISA-5.
In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-1) of the present invention is characterized by:
• an X-ray powder diffraction pattern profile substantially as shown in Figure 1 which has peaks at 6.3, 7.9, 9.3, 10.5, 13.9, 15.6, 17.7 and 25.4 ± 0.2° 20;
• DSC thermogram having broad endothermic peak at about 62.33 °C, 82.50°C and 87.00°C; and
• TGA thermogram having a weight loss of about 7.5%.
In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-2) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.2, 6.3, 8.0, 9.7, 11.2, 12.6, 13.7, 17.1, 17.5 and 19.6 ± 0.2° 20;
• DSC thermogram having broad endothermic peak at about 70.56°C, 115.05°C and 141.38°C; and
• TGA thermogram having a weight loss of about 4.2%.
In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-3) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.1, 6.3, 8.0, 9.6, 11.0, 12.9, 13.7, 14.6, 17.5 and 20.5 ± 0.2° 20;
• DSC thermogram having broad endothermic peak at about 81.34°C, 119.52° and 141.35°C; and
• TGA thermogram having a weight loss of about 4.2%.
In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-4) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.2, 5.7, 6.5, 9.2, 10.2, 14.5, 16.0, 16.6, 18.6 and 20.6 ± 0.2° 20;
• DSC thermogram having endothermic peaks at about 96.98°C; 138.15°C and
150.63°C; and
• TGA thermogram having a weight loss of about 4.7%.
In a preferred embodiment, the crystalline form of Isavuconazonium sulfate (Form ISA-5) of the present invention is characterized by:
• X-ray powder diffraction pattern profile substantially as shown in Figure 2 which has peaks at 4.6, 6.5, 8.4, 9.2, 10.2, 14.5, 16.1, 16.8, 18.5, and 23.1 ± 0.2 20;
• DSC thermogram having broad endothermic peak at about 61.42°C, 83.95°C and 150.85°C; and
• TGA thermogram having a weight loss of about 3.6%.
In yet another preferred embodiment, the present invention provides a process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5) which
comprises exposing crystalline form of Isavuconazonium sulfate (Form ISA-4) to a humidity between 20-80% RH at room temperature.
In yet another preferred embodiment, the present invention provides a process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.
The crystalline Isavuconazonium sulfate used in the preparation of amorphous Isavuconazonium sulfate could be any of the crystalline form such as Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 and Form ISA-5.
In yet another preferred embodiment, the present invention provides a pharmaceutical composition comprising the crystalline hydrated forms of Isavuconazonium sulfate.
Isavuconazonium sulfate used in the present invention is prepared according to the process disclosed in the literature. The Isavuconazonium sulfate used in the present invention comprising in the form of amorphous or crystalline form produced by priorart procedures.
In yet another preferred embodiment, the present invention provides a process for the preparation of the compound of Formula (I), in high yield and purity without forming by-products.
The process comprises, reacting compound of formula (III) with Boc-sarcosine in the presence of a base, a coupling agent in an amide solvent to provide compound of formula (IV). The compound of Formula (IV) is reacted with chloroethyl chloroformate in the presence of a base and a solvent to produce a reaction mixture, followed by separating the layers, adding an acid to the organic layer for removing unreacted intermediate compound of Formula (IV) and the compound of Formula (I) is isolated with high purity and yield.
The base as used in the above reaction comprising an organic base comprises pyridine, piperidine, dimethylaminopyridine, picolines, diisopropyl ethylamine, triethyl amine and the like or mixtures thereof or an inorganic base comprises NaHCO3, LiOH, NaOH, KOH, KHCO3, LiHCO3, Na2CO3, K2CO3, Li2CO3, CaCO3, MgCO3, sodium hydride, potassium tert- butoxide, sodium tert-butoxide, magnesium hydroxide and the like or mixtures thereof.
The amide solvent used in the above reaction comprises N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethyl phosphoramide, and N-acetyl pyrrolidine and the like or mixtures thereof.
The coupling agent is selected from carbodiimides or salt thereof such as N,N'- dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC); imidazoliums or salt thereof; such as l,T-carbonyldiimidazole (CDI), l,T-carbonyl-di-(l,2,4-triazole) (CDT); uronium or guanidinium salts such as O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), and O-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU); phosphonium salts such as benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP or Castro's reagent), (benzotriazol- 1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), 7-azabenxotriazol-l- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP); alkyl phosphonic acid anhydrides such as T3P etc.
The solvent used in the above reaction comprises an ether such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.
The acid used in the above reaction comprises inorganic acid selected from the group consisting of sulfuric acid, nitric acid or hydrochloric acid, phosphorus acid, phosphoric acid or mixtures thereof. In yet another embodiment of the present invention, a one-pot process for the preparation of Isavuconazonium sulfate comprises, the reaction of Isavuconazole of formula (V) with the compound formula (I) in a solvent, in the presence of a catalyst and alkali metal halide to give formula (VI), which is treated with trifluoroacetic acid in a solvent to give compound of formula (VII) which is salt exchanged by an anion exchange resin to give Isavuconazonium sulfate (II) with high purity i.e > 99% (HPLC).
The process of the present invention is depicted below scheme:
The alkali metal halide used in the coupling comprises lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide.
The catalyst used in the coupling comprises tetrabutylammonium bromide (TBAB), tetrabutylammonium hydroxide, triethylbenzylammonium chloride, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, or hexadecyl trimethyl ammonium bromide.
The solvent used in the above reaction comprises tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; butyronitrile, propionitrile, ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.
The anion exchange resin used for salt exchange comprises a strong base anion (SBA) resin.
The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
Example- 1: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-1):
Isavuconazonium, sulfate (1: 1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-1).
Example-2: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-2)
Isavuconazonium, sulfate (1: 1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s. Further material was dried at 35±5°C under vacuum for 3-4hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-2).
Example-3: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-3)
Isavuconazonium, sulfate (1: 1) 2.0gm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-22hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0 ml) followed by suck dried for 5min’s. Further material was slurried in ethyl acetate 10.0ml at 20°C for 2-3hr’s. Solid was filtered and washed with ethyl acetate 1.0ml followed by suck dried under nitrogen atmosphere for 5min’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-3).
Example-4: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium, sulfate (1: 1) 0.5gm was dissolved in DM water (1.0ml) at room temperature and acetonitrile (25ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 18-24hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed with acetonitrile (5.0ml) followed by suck dried for 5min’s.
Further material was dried at 30±5°C under vacuum for 2-3hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.36%.
Example-5: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium sulfate (1: 1) 0.5gm was dissolved in DM water (2.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass cooled to -10°C and stirred reaction mass for 45-50 hr’s at -10°C. The temperature was slowly raised up to 0-5°C and stirred for l-2hr’s. Obtained solid was filtered and washed acetonitrile (5.0ml) followed by suck dried for 5min’s. Further material was dried at 30±5°C under vacuum for 2-3hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.62%.
Example-6: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium sulfate (1:1) l.Ogm was dissolved in DM water (4.0ml) at room temperature and acetonitrile (100ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 20-24hr’s at -10°C and 1% seed was added to above reaction mass. Stirred the reaction mass for 20-24hr’s at -10°C. The temperature was slowly raised up to 0-5 °C and stirred for l-2hr’s. Obtained solid was filtered and washed acetonitrile (20.0ml) followed by suck dried for 5min’s. Further material was dried at 30±5°C under vacuum for 3-5hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.41%.
Example-7: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-4)
Isavuconazonium sulfate (1: 1) 4.0gm was dissolved in DM water (8.0ml) at room temperature and acetonitrile (200ml) was added at room temperature. Reaction mass was cooled to -10°C and stirred reaction mass for 44-48hr’s at -10°C and 1% seed was added to above reaction mass. Stirred the reaction mass for 20-24hr’s at -10°C
solid was isolated. The temperature was slowly raised up to 0-5°C and stirred for 1- 2hr’s. Obtained solid was filtered and washed acetonitrile (20.0ml) followed by suck dried for 5min’s. Further material was dried at 30±5°C under vacuum for 3-5hr’s to afford crystalline form of Isavuconazonium sulfate (Form ISA-4). HPLC purity ~ 99.16%.
Example-8: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5)
Isavuconazonium Sulfate (25g) was dissolved in purified water (50 ml) at 20-30°C under nitrogen atmosphere. Reaction mixture was stirred at 20-30°C for 15-20 minutes. Acetonitrile was slowly added (1250 ml) to the above clear solution at 20- 30°C in 45-60 minutes. Reaction mixture was cooled to -10°C to -15°C. The reaction mixture was seeded with Isavuconazonium Sulfate API (0.25g) at -10°C to -15°C. The above solution was maintained at -10° to -15°C for 20-24hr, temperature was slowly raised to 0-5 °C for l-2hr. The compound was filtered at 0-5 °C and washed with pre-cooled acetonitrile (0-5 °C, 250 ml) and suck dried. Further, wet material was dried the under vacuum at 30±5°C for 03 hr. to afford crystalline form of Isavuconazonium sulfate (Form ISA-5). HPLC purity -99.57%.
Example-9: Preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5)
Isavuconazonium sulfate (1:1) was exposed to humidity 40% RH or 60% RH at room temperature for 5 days to afford crystalline form of Isavuconazonium sulfate (Form ISA-5).
Example-10: Preparation of amorphous form of Isavuconazonium sulfate:
Isavuconazonium sulfate crystalline form (100 g) was dissolved in purified water (500 ml), the solution was stirred for 10 to 15 min at 20-30°C. The above solution was loaded into lyophilizer and lyophilized under optimized recipe to give
amorphous material, the material was unloaded under nitrogen atmosphere and the moisture content was checked which is NMT 2.0%.
Example-11: preparation of compound of formula (IV):
In a RBF, 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III) (50.0 g) and DMF (100 mL) were charged at 20-30°C. The above reaction mixture was stirred for 5 min at 20-30 C, then cooled to 0-5°C. A solution of N-Boc-sarcosine (102.68 g) & DMAP (13.26g) in DMF (150 mL) were dissolved at 0-5°C. The above reaction mixture was stirred for 10 min at 0-5°C. EDC.HC1 (84.24 g) was added at 0-5°C and the reaction mixture was maintained at 0-5°C for 2-4 h and monitored the reaction for unreacted 2-(N-methylamino)-3-hydroxymethylpyridine of Formula (III). In a separate round bottom flask water (3500 mL) was taken to cooled to 0-5°C and the reaction mass was added over a period of ~30 min then allowed the reaction temperature to reach 20-30°C. The reaction was maintained at this temperature for 2- 3h. The reaction mass was filtered over Buchner funnel under vaccum at 20- 30°C, then continued to suck dry. The wet cake was washed with isopropyl alcohol and dried at 20-30°C for 10-12 h.
Yield: -80-90% (85-95 g) and progress of the reaction was monitored on HPLC purity (Limit: NLT 99.0, 0.97 RRT -NLT 0.5%; 1.08 RRT NLT 0.1% and 1.3 RRT 0.5%).
Example-12: preparation of compound of formula (I):
In a RBF, 3-(tert-butoxycarbonylmethylamino)acetoxymethyl)-2-methyl aminopyridine of compound of Formula (IV also referred as DES-CECF) (50.0 g) at 20-30°C and MDC (400 mL) was charged and the resulting mixture was stirred for 10±5 min at 20-30°C then cooled to 0- 5°C. Sodium carbonate (50 g) was added and stirred for 5-10 min at 0-5°C.l -Chloroethyl chloroformate (24.0 g) was added to reaction mass over a period of 10-20 min and stirred the reaction mass for 8 h at 0- 5 °C, then monitored the reaction for unreacted compound of Formula (IV). It should
be less than 25%. The reaction mass was filtered and washed with DCM (100 mL). To the filtrate sodium bicarbonate solution (prepared from 54.0 g NaHCCh + DM water 1000 mL) was added and stirred for 15-30 min at 20-30°C. The layers were separated and the organic layer was collected. Charged organic layer and 10% Aq. Phosphorous acid solution (400 mL) into the above RBF and stirred for 10±5 min and then layers were separated and collected the organic layer. The organic layer was concentrated under reduced pressure below 40°C to obtain the compound of Formula (I) as pale yellow color liquid.
Yield: ~ 40g and HPLC purity: > 99.0 %
Example-13: Preparation of compound of formula (I):
In a RBF, 3-(tert-butoxycarbonylmethylamino)acetoxymethyl)-2-methyl aminopyridine of compound of Formula (IV) (50.0 g) at 20-30°C and MDC (400 mL) was charged and the resulting mixture was stirred for 10±5 min at 20-30°C then cooled the reaction mixture to 0- 5°C. Pyridine (56 g) was added at 0-5°C and stirred for 5-10 min at 0-5°C. 1 -Chloroethyl chloroformate (24.0 g) was added to reaction mass at 0-5°C over a period of 10-20 min and stirred for 8 h at 0-5°C, the reaction was monitored for unreacted compound of Formula (IV). It should be less than 25%. Reaction mass was filtered and residue was washed with of DCM (100 mL). To the filtrate, sodium bicarbonate solution (prepared from 54.0 g NaHCCh + DM water 1000 mL) was added, stirred for 15-30 min at 20-30°C. Settled for 10±5 min at 20- 30°C, layers were separated. Organic layer was added with 10% Aq. phosphorous acid solution (400 mL), stirred for 10±5 min, layers were separated and organic layer was collected. Concentrated the above organic layer under reduced pressure below 40°C to obtain the compound of Formula (I) as pale yellow color liquid.
Yield: ~55g and HPLC purity: > 99.0 %.
Example-14: preparation of Isavuconazonium sulfate of formula (II)
A. Preparation of compound of formula (VI)
Compound of Formula I (190 g) was added to acetonitrile (500 ml) at 20-30°C under nitrogen atmosphere. The reaction mixture was stirred for 10-15 minutes to give a clear solution. Compound of Formula V (100 g), sodium bromide (70.63g) and TBAB (7.37 g) were added to the reaction mixture. Temperature was raised to 45- 55 °C and maintained for 20 hours. Reaction mixture was filtered on Hyflow and washed the bed with acetonitrile (200 ml). The reaction mass was distilled, MDC (1000 ml) was added to the concentrated mass and stirred for 15-20 min. Reaction mass was washed with purified water (2x1500 ml) and 10% sodium chloride solution (2x1000 ml). Organic layer was treated with carbon to give a wet material (VI) and it is used as such in the next step for the preparation of Formula (VII).
B. Preparation of compound of formula (VII)
Purified water (500 ml) was added to the MDC solution containing Formula (VI) (~200g) at 20-30°C. The mixture was cooled to 0-10°C. Trifluoroacetic acid (1000 ml) was added at 0-10°C. Reaction mass temperature was raised to 20-30°C and maintained for 3 hrs. After completion of the reaction, the reaction mass was washed with water (2x3000 ml) at 20-30°C. The organic layer was treated with carbon to give Formula VII (Isavuconazonium TFA Salt), which is used as such in the preparation of Formula (II).
C. Preparation of compound of formula (II)
The MDC layer contains Formula (VII, ~200g, Isavuconazonium TFA Salt) was Concentrated and dissolved in purified water (400 ml). The aqueous solution contains Formula-(VII) was passed through Indion GS 300 Resin to exchange from Isavuconazonium TFA salt to Isavuconazonium Sulfate at 20-30°C. To the obtained aqueous solution, acetonitrile (12500 ml) was added at 20-30°C and cooled to -10 to - 15°C. Added seed material of Isavuconazonium Sulfate (1.0g) at -10 to -15°C and continued stirring for 30 hours. Raised the temperature to 0-5 °C. Filtered and dried the product to afford crystalline Isavuconazonium Sulfate of compound of Formula (II) having HPLC Purity >99%.
Claims
1. A crystalline form of Isavuconazonium sulfate (Form ISA-1), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 6.3, 7.9, 9.3, 10.5,
13.9, 15.6, 17.8 and 25.4 ± 0.2° 20;
• DSC as shown in Figure 6;
• TGA as shown in Figure 10.
2. A crystalline form of Isavuconazonium sulfate (Form ISA-2), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.2, 6.3, 8.0, 9.7,
11.2, 12.6, 13.7, 17.1, 17.5 and 19.6 ± 0.2° 20;
• DSC as shown in Figure 7 ;
• TGA as shown in Figure 12.
3. A crystalline form of Isavuconazonium sulfate (Form ISA-3), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.1, 6.3, 8.0, 9.6,
11.0, 12.9, 13.7, 14.6, 17.5 and 20.5 ± 0.2° 20;
• DSC as shown in Figure 8;
• TGA as shown in Figure 13.
4. A crystalline form of Isavuconazonium sulfate (Form ISA-4), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.2, 5.7, 6.5, 9.2,
10.2, 14.5, 16.0, 16.6, 18.6 and 20.6 ± 0.2° 20;
• DSC as shown in Figure 9;
• TGA as shown in Figure 14.
5. A crystalline form of Isavuconazonium sulfate (Form ISA-5), which is characterized by
• X-ray powder diffraction pattern having 20 peaks at 4.6, 6.5, 8.4, 9.2,
10.2, 14.5, 16.1, 16.8, 18.5, and 23.1 ± 0.2° 20;
• DSC as shown in Figure 10;
• TGA as shown in Figure 15.
6. A crystallization process of Isavuconazonium sulfate, which comprises,
(i) dissolving Isavuconazonium sulfate in a water and a solvent;
(ii) cooling;
(iii) stirring; or vice -versa
(iv) optionally seeding with crystalline form of Isavuconazonium sulfate,
(v) filtering;
(vi) drying; and
(vii) isolating crystalline form of Isavuconazonium sulfate having purity greater than 99.5 % by HPLC.
7. The process as claimed in claim 6, wherein the crystalline form of Isavuconazonium sulfate comprises Form ISA-1, Form ISA-2, Form ISA-3, Form ISA-4 or Form ISA-5.
8. A process for the preparation of crystalline form of Isavuconazonium sulfate (Form ISA-5), which comprises, exposing crystalline form of Isavuconazonium sulfate to humidity to obtain crystalline form of Isavuconazonium sulfate (Form ISA-5).
9. A process for the preparation of amorphous Isavuconazonium sulfate, which comprises lyophilization of crystalline Isavuconazonium sulfate.
10. A process for the preparation of compound of Formula (I) with high purity, which is an intermediate of Isavuconazonium sulfate (II);
which comprises:
(i) reacting a compound of Formula (III);
Formula (III)
with Boc-sarcosine or a salt thereof; in presence of a base and an amide solvent to produce compound of Formula (IV);
(ii) reacting compound of Formula (IV) with chloroethyl chloroformate in presence of a base and a solvent to produce a reaction mass;
(iii) adding an acid for removing unreacted intermediate compound (IV);
(iv) isolating the compound of Formula (I) in pure form.
11. The process as claimed in claim 10, wherein the base comprises organic base such as pyridine, piperidine, dimethylaminopyridine, picolines, diisopropyl ethylamine, triethyl amine and the like or mixtures thereof; or an inorganic base such as NaHCO3, LiOH, NaOH, KOH, KHCO3, LiHCO3, Na2CO3, K2CO3,
Li2CC>3, CaCCh, MgCCh, sodium hydride, potassium tert-butoxide, sodium tert- butoxide, magnesium hydroxide and the like or mixtures thereof.
12. The process as claimed in claim 10, wherein the amide solvent comprises N,N- dimethyl formamide (DMF), N,N-dimethyl acetamide, N-methyl-2-pyrrolidone, hexamethyl phosphoramide, and N-acetyl pyrrolidine and the like or mixtures thereof.
13. The process as claimed in claim 10, wherein the solvent comprises an ether selected from tetrahydrofuran, dioxane, diisopropylether, diethylether, 2- methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert -butyl ether, diglyme or monoglyme; methanol, ethanol, isopropyl alcohol, toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; hexane, heptane, cyclohexane or mixture thereof.
14. The process as claimed in claim 10, wherein the acid comprises sulfuric acid, nitric acid or hydrochloric acid, phosphorus acid, phosphoric acid or mixtures thereof.
15. A one -pot process for the preparation of Isavuconazonium sulfate of Formula (II),
which comprises:
(i) reacting Isavuconazole of formula (V);
with compound of formula (I);
in a solvent, in the presence of alkali metal halide to give compound of formula (VI);
wherein X is Cl, Br or I;
(ii) reacting the compound of formula (VI) with trifluoroacetic acid to give compound of formula (VII);
(iii) converting compound of formula (VII) to Isavuconazonium sulfate of
Formula (II).
16. The process as claimed in claim 15, wherein the alkali metal halide comprises lithium chloride, sodium chloride, potassium chloride, lithium bromide, sodium bromide, potassium bromide.
17. The process as claimed in claim 15, wherein step-(i) is carried out in the presence or absence of a catalyst comprises tetrabutylammonium bromide (TBAB), tetrabutylammonium hydroxide, triethylbenzylammonium chloride, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, or hexadecyl trimethyl ammonium bromide.
18. The process as claimed in claim 15, wherein the compound of formula (VII) is salt exchanged by an anion exchange resin to give Isavuconazonium sulfate (II) with high purity i.e > 99% (HPLC).
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|---|---|---|---|---|
| CN1185230C (en) * | 1999-11-02 | 2005-01-19 | 巴斯利尔药物股份公司 | N-substd. carbamoyloxyalkyl-azolium derivs. |
| WO2016016766A2 (en) * | 2014-07-26 | 2016-02-04 | Wockhardt Limited | A process for the preparation of isavuconazonium or its salt thereof |
| CN106565699A (en) * | 2015-10-10 | 2017-04-19 | 江苏正大丰海制药有限公司 | Isavuconazole sulfate crystal and preparation method thereof |
| CN110551064A (en) * | 2018-06-01 | 2019-12-10 | 北京莱瑞森医药科技有限公司 | Preparation method of isavuconazole sulfate and intermediate thereof |
| WO2021037597A1 (en) * | 2019-08-26 | 2021-03-04 | Synthon B.V. | Isavuconazonium salts and process for preparing thereof |
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2024
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| CN1185230C (en) * | 1999-11-02 | 2005-01-19 | 巴斯利尔药物股份公司 | N-substd. carbamoyloxyalkyl-azolium derivs. |
| WO2016016766A2 (en) * | 2014-07-26 | 2016-02-04 | Wockhardt Limited | A process for the preparation of isavuconazonium or its salt thereof |
| CN106565699A (en) * | 2015-10-10 | 2017-04-19 | 江苏正大丰海制药有限公司 | Isavuconazole sulfate crystal and preparation method thereof |
| CN110551064A (en) * | 2018-06-01 | 2019-12-10 | 北京莱瑞森医药科技有限公司 | Preparation method of isavuconazole sulfate and intermediate thereof |
| WO2021037597A1 (en) * | 2019-08-26 | 2021-03-04 | Synthon B.V. | Isavuconazonium salts and process for preparing thereof |
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| HUANG LEI, ZHANG YI, CHEN HUA, WANG WEI-WEI, LI JIAN-QI, LIU YU: "A Novel and Practical Synthesis of Isavuconazonium Sulfate via Anion Exchange Resin", PHARMACEUTICAL FRONTS, vol. 04, no. 02, 1 June 2022 (2022-06-01), pages e71 - e77, XP093213284, ISSN: 2628-5088, DOI: 10.1055/s-0042-1747641 * |
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