WO2024022998A1 - Process for preparing daprodustat and cocrystals thereof - Google Patents
Process for preparing daprodustat and cocrystals thereof Download PDFInfo
- Publication number
- WO2024022998A1 WO2024022998A1 PCT/EP2023/070405 EP2023070405W WO2024022998A1 WO 2024022998 A1 WO2024022998 A1 WO 2024022998A1 EP 2023070405 W EP2023070405 W EP 2023070405W WO 2024022998 A1 WO2024022998 A1 WO 2024022998A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- daprodustat
- process according
- crystal form
- compound
- Prior art date
Links
- 229950010337 daprodustat Drugs 0.000 title claims abstract description 396
- RUEYEZADQJCKGV-UHFFFAOYSA-N 2-[(1,3-dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5-carbonyl)amino]acetic acid Chemical compound O=C1N(C2CCCCC2)C(=O)C(C(=O)NCC(=O)O)C(=O)N1C1CCCCC1 RUEYEZADQJCKGV-UHFFFAOYSA-N 0.000 title claims abstract description 375
- 238000004519 manufacturing process Methods 0.000 title claims description 19
- 239000013078 crystal Substances 0.000 claims abstract description 333
- 238000000034 method Methods 0.000 claims abstract description 154
- 230000008569 process Effects 0.000 claims abstract description 137
- 239000002253 acid Substances 0.000 claims abstract description 85
- -1 alkali metal salt Chemical class 0.000 claims abstract description 67
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 238000002360 preparation method Methods 0.000 claims abstract description 46
- 229910052751 metal Inorganic materials 0.000 claims abstract description 40
- 239000002184 metal Substances 0.000 claims abstract description 40
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims description 166
- 150000001875 compounds Chemical class 0.000 claims description 115
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 108
- 239000000203 mixture Substances 0.000 claims description 106
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 105
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 93
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 78
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 66
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 55
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- 239000002585 base Substances 0.000 claims description 50
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- WZWKEEOAUZXNJJ-UHFFFAOYSA-N isocyanato acetate Chemical compound CC(=O)ON=C=O WZWKEEOAUZXNJJ-UHFFFAOYSA-N 0.000 claims description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 38
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 34
- SPGPSFWOMJQSDF-UHFFFAOYSA-N ethyl 4-oxo-6-(trifluoromethyl)-1h-quinoline-3-carboxylate Chemical compound C1=C(C(F)(F)F)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 SPGPSFWOMJQSDF-UHFFFAOYSA-N 0.000 claims description 31
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 claims description 28
- CFCNTIFLYGKEIO-UHFFFAOYSA-N 2-isocyanoacetic acid Chemical compound OC(=O)C[N+]#[C-] CFCNTIFLYGKEIO-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 28
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000000725 suspension Substances 0.000 claims description 25
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 22
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 229910052802 copper Inorganic materials 0.000 claims description 21
- 239000010949 copper Substances 0.000 claims description 21
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 21
- 230000005855 radiation Effects 0.000 claims description 21
- 150000002148 esters Chemical class 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 19
- 150000007529 inorganic bases Chemical class 0.000 claims description 18
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 239000000010 aprotic solvent Substances 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- 238000004821 distillation Methods 0.000 claims description 14
- 238000001704 evaporation Methods 0.000 claims description 14
- 230000008020 evaporation Effects 0.000 claims description 14
- 150000007530 organic bases Chemical class 0.000 claims description 14
- 150000001298 alcohols Chemical class 0.000 claims description 12
- 239000012296 anti-solvent Substances 0.000 claims description 12
- 238000010899 nucleation Methods 0.000 claims description 11
- 150000001340 alkali metals Chemical class 0.000 claims description 10
- 239000000908 ammonium hydroxide Substances 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 10
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 6
- 238000006386 neutralization reaction Methods 0.000 claims description 6
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 5
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 5
- 206010058116 Nephrogenic anaemia Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 4
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 claims description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims 18
- 229940043279 diisopropylamine Drugs 0.000 claims 6
- 159000000000 sodium salts Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 31
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 50
- 239000007787 solid Substances 0.000 description 37
- 239000000523 sample Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- DLRFZUMZEDGKAM-UHFFFAOYSA-N ethyl 2-[(1,3-dicyclohexyl-4-hydroxy-2,6-dioxopyrimidine-5-carbonyl)amino]acetate Chemical compound O=C1N(C2CCCCC2)C(=O)C(C(=O)NCC(=O)OCC)=C(O)N1C1CCCCC1 DLRFZUMZEDGKAM-UHFFFAOYSA-N 0.000 description 25
- 239000012453 solvate Substances 0.000 description 24
- 238000002411 thermogravimetry Methods 0.000 description 23
- 239000007864 aqueous solution Substances 0.000 description 20
- 239000002245 particle Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- 229910052708 sodium Inorganic materials 0.000 description 18
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 17
- 238000002425 crystallisation Methods 0.000 description 17
- 230000008025 crystallization Effects 0.000 description 17
- 229910052700 potassium Inorganic materials 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 16
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 16
- 239000011591 potassium Substances 0.000 description 16
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 15
- 238000005259 measurement Methods 0.000 description 15
- 238000000113 differential scanning calorimetry Methods 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 10
- 229940071870 hydroiodic acid Drugs 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 9
- 229910000000 metal hydroxide Inorganic materials 0.000 description 9
- 150000004692 metal hydroxides Chemical class 0.000 description 9
- 238000005580 one pot reaction Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 238000001757 thermogravimetry curve Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 6
- 229940044613 1-propanol Drugs 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 239000012429 reaction media Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 5
- 239000004210 ether based solvent Substances 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000001000 micrograph Methods 0.000 description 5
- 229920006395 saturated elastomer Chemical group 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001479 atomic absorption spectroscopy Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 238000013480 data collection Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- DUVOZUPPHBRJJO-UHFFFAOYSA-N ethyl 2-isocyanatoacetate Chemical compound CCOC(=O)CN=C=O DUVOZUPPHBRJJO-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 239000013067 intermediate product Substances 0.000 description 4
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 229940078552 o-xylene Drugs 0.000 description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- PRZQJMWBZWAUKW-UHFFFAOYSA-N 1,3-dicyclohexyl-1,3-diazinane-2,4,6-trione Chemical compound O=C1N(C2CCCCC2)C(=O)CC(=O)N1C1CCCCC1 PRZQJMWBZWAUKW-UHFFFAOYSA-N 0.000 description 3
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical group C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
Definitions
- the present invention provides crystal forms of daprodustat, which are cocrystals comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt.
- the invention also refers to processes for the preparation of said cocrystals of daprodustat in good yield and high purity, to pharmaceutical compositions containing them and to their use in therapy.
- the present invention also provides an efficient process for the preparation of daprodustat or a pharmaceutically or veterinary acceptable salt thereof in good yield and high purity suitable for industrial scale applications which involves improved conditions for the preparation of key intermediates.
- N-[(1 ,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine also known as daprodustat, compound of formula (I)
- daprodustat compound of formula (I)
- HIF-PHI oral hypoxia-inducible factor prolyl hydroxylase inhibitor
- Daprodustat and its tautomer N-[(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 ,2,3,4-tetrahydro-5-pyrimidinyl)- carbonyl]glycine were first disclosed in W02007/150011 A2, which describes the preparation of daprodustat by using N, N'-dicyclohexylcarbodiimide (DCC) or N,N'-dicyclohexylurea (DCU) as the starting material.
- DCC N, N'-dicyclohexylcarbodiimide
- DCU N,N'-dicyclohexylurea
- the method involves cyclization of the starting material with malonic acid derivatives to provide 1 ,3-dicyclohexyl barbituric acid, following condensation with ethyl isocyanatoacetate and subsequent ester hydrolysis with aqueous sodium hydroxide in ethanol.
- DCC is an acute skin irritant in susceptible individuals, and due to its low melting point it is difficult to manipulate and consequently not feasible for industrial application.
- DCU is reacted with malonyl chloride, which not only is unstable and corrosive but also is an environmentally unfriendly halogenated reagent.
- Example 18 of W02007/150011 A2 discloses the preparation of daprodustat from the hydrolysis of an advanced ethyl ester intermediate (i.e., ethyl (1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 , 2,3,4- tetrahydropyrimidine-5-carbonyl)glycinate) with aqueous sodium hydroxide in ethanol followed by neutralization with hydrochloric acid. Then, daprodustat is isolated from a mixture of diethyl ether and hexane according to Method 1 of said example 18. Alternatively, daprodustat is isolated from acetic acid with hot filtration to remove a small amount of insoluble material according to Method 2 of said example 18.
- an advanced ethyl ester intermediate i.e., ethyl (1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 , 2,3,4- tetrahydropyrimidine-5
- CN102432549 A discloses the preparation of key intermediate 1 ,3-dicyclohexyl barbituric acid by reacting DCU with malonic acid in the presence of acetic acid and acetic anhydride.
- the 1 ,3-dicyclohexyl barbituric acid is isolated by solvent evaporation with increases the cost of the process at industrial scale.
- Daprodustat is neither disclosed nor prepared.
- WO2019/052133 A1 discloses solid forms of daprodustat named CS1 and CS9 which have higher purity and lower hygroscopicity compared to the prior art solid form of daprodustat obtained by reproducing the above Method 2 (i.e., from recrystallization in acetic acid).
- the solid forms CS1 and CS9 are isolated from slow evaporation, which is not feasible for industrial scale.
- the kinetic solubility in pure water of CS1 is of 0.014 mg/mL and for CS9 is of 0.020 mg/mL, which suggests poor aqueous solubility of either form CS1 or form CS9 of daprodustat.
- W02020/102302 A1 discloses crystalline forms of daprodustat named Form 3 and Form 4.
- Form 3 is prepared by crystallization from ethylbenzene and Form 4 by slurrying daprodustat in diethyl ether.
- Form 3 corresponds to prior art solid form obtained from the above Method 2
- Form 4 corresponds to prior art solid form obtained from the above Method 1 . Therefore, there is a need in developing solid forms of daprodustat with better solubility to increase the bioavailability, which can be easily manufactured at an industrial scale with low energy and costs. Further, it is also desirable to obtain an efficient and safe process for the preparation of daprodustat in high purity and high yield, which can be easily applied at an industrial scale with low energy and costs and good yields.
- Daprodustat is a poorly soluble drug, and for poorly soluble drugs, it is important to increase solubility to increase the bioavailability of the drug, thereby improving the efficacy and safety of daprodustat.
- the present invention refers to crystal forms of daprodustat which are cocrystals comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt.
- a cocrystal comprising daprodustat free acid and daprodustat sodium salt is referred herein as crystal form N2.
- another cocrystal comprising daprodustat free acid and daprodustat sodium salt is referred herein as crystal form N4.
- a cocrystal comprising daprodustat free acid and daprodustat potassium salt is referred herein as crystal form K2.
- crystal form K1 another cocrystal comprising daprodustat free acid and daprodustat potassium salt is referred herein as crystal form K1.
- these cocrystals of daprodustat have improved properties such as solubility, hygroscopicity and stability as well as manufacturing behaviour (compaction, flowability, filterability etc.) thereby resulting beneficial for the development of medicinal products containing daprodustat.
- the first aspect of the present invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt.
- the invention relates to a crystal form N2 of daprodustat having an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.3° ⁇ 0.2°, 7.4° ⁇ 0.2°, 7.6° ⁇ 0.2°, 11.4° ⁇ 0.2° and 16.2° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the invention relates to a crystal form N4 having an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.4° ⁇ 0.2°, 7.4° ⁇ 0.2°, 7.6° ⁇ 0.2°, 13.4° ⁇ 0.2° and 16.7° ⁇ 0.2, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the invention relates to a crystal form K2 having an X-ray powder diffraction pattern comprising peaks at 2theta values of 5.5° ⁇ 0.2°, 6.3° ⁇ 0.2°, 7.0° ⁇ 0.2°, 16.8° ⁇ 0.2° and 18.0° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the invention relates to a crystal form K1 having an X-ray powder diffraction pattern comprising peaks at 2theta values of 5.4° ⁇ 0.2°, 7.9° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2° and 17.5° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the second and third aspects of the invention provide processes for preparing the crystal forms of daprodustat as defined herein.
- a fourth aspect of the invention refers to pharmaceutical compositions comprising crystal forms of daprodustat as defined herein, in particular daprodustat in a crystal form selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 , and a combination thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
- a fifth aspect refers to crystal forms of daprodustat as defined herein for use in therapy, particularly for the treatment of renal anemia.
- This aspect can also be formulated as a method of treatment of renal anemia, which comprises administering to a subject in need thereof, including a human, a crystal form of daprodustat as defined herein and one or more pharmaceutically acceptable carriers, diluents or excipients.
- daprodustat as defined herein for the manufacture of pharmaceutical composition for the treatment of renal anemia.
- the present invention also provides an efficient and environmentally friendly process for manufacturing daprodustat or a salt thereof in good yield and applicable at industrial scale without requiring laborious and unfeasible purification steps, yielding high purity which complies with pharmaceutical standards.
- the present inventors found that the hydrolysis of the ester intermediate, ethyl N-[(1 ,3-dicyclohexyl-6- hydroxy-2,4-dioxo-1 ,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]-glycinate, following the conditions disclosed in example 18 of W02007/150011 A2 (i.e. in the presence of sodium hydroxide in ethanol followed by neutralization with hydrochloric acid) provides daprodustat with significant amounts of inorganic salts such as sodium chloride difficult to separate by conventional purification techniques such as extraction, followed by slurry in water plus an additional crystallization step in acetic acid which requires hot filtration to remove inorganic material.
- inorganic salts such as sodium chloride difficult to separate by conventional purification techniques such as extraction, followed by slurry in water plus an additional crystallization step in acetic acid which requires hot filtration to remove inorganic material.
- the salt formed as byproduct from the reaction of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and an acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic acid (TFA) is soluble in the reaction media which enhances the isolation of final daprodustat without requiring laborious and unfeasible purification steps.
- a sixth aspect of the present invention relates to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, which comprises converting a compound of formula (VI), wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl, into daprodustat of formula (I) by hydrolysis in the presence of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and
- the compound of formula (VI) may be prepared from 1 ,3-dicyclohexyl barbituric acid of formula (V) which can be obtained by reacting dicyclohexylurea (DCU) with malonic acid.
- DCU dicyclohexylurea
- the inventors have found that advantageously, the crystallization of the key intermediate of formula (V) in the presence of an antisolvent, preferably water, avoids the solvent evaporation step for its isolation which increases the cost of the process and the final cost of the medicinal product.
- a seventh aspect of the invention provides a process for preparing key intermediate 1 ,3-dicyclohexyl barbituric acid of formula (V), which comprises the steps of:
- step (ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
- An eighth aspect of the invention refers to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, which comprises: a1) preparing a 1 ,3-dicyclohexyl barbituric acid of formula (V) by a process which comprises the steps of:
- step (ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
- a ninth aspect of the present invention provides a process for preparing a compound of formula (VI), wherein R is (Ci-Cio)alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl, which comprises the steps of: a) converting a formamide of formula (II), into a compound an isocyanoacetate of formula (III), wherein R is as defined above, preferably R is ethyl; b) converting the isocyanoacetate of formula (III) of step (a) into an isocyanatoacetate of formula (IV), wherein R
- a tenth aspect of the invention refers to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, which comprises: b1) converting a formamide of formula (II), into a compound an isocyanoacetate of formula (III), wherein R is as defined above, preferably R is ethyl; b2) converting the isocyanoacetate of formula (III) of step (b1) into an isocyanatoacetate of formula (IV), wherein R is as defined above, preferably R is ethyl; b3) reacting the isocyanatoacetate of formula (IV) obtained in step (b2) with a 1 ,3-dicyclohexyl barbituric acid of formula (V), in the presence of a base and a solvent to provide the compound of formula (VI) wherein R is as defined above, preferably R is ethyl; wherein steps (b2) and (b3) are carried out in a consecutive manner, i.
- the term "about” as used herein refers to a statistically meaningful range of a value. Such a range can lie within experimental error, typical of standard methods used for the measurement and/or determination of a given value or range. In one embodiment, the range is within ⁇ 5% of the indicated value. In another embodiment, the range is within ⁇ 1% of the indicated value. In yet another embodiment, the range is within ⁇ 0.5% of the indicated value.
- alkyl means straight-chain or branched hydrocarbon chain radical containing no unsaturation having from 1 to 10 carbon atoms, represented as (Ci-Cio)alkyl.
- alkyl groups may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight- or branched- pentyl, straight- or branched- hexyl, straight- or branched-heptyl, straight- or branched-nonyl or straight- or branched- decyl.
- cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term “Ca-Cecycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to six carbon atoms. Exemplary "Ca-Cecycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- heterocycloalkyl means a non-aromatic heterocyclic ring containing the specified number of ring atoms, e.g., having 3 to 12 carbon atoms, represented as (C3-C12) heterocycloalkyl, being, saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions independently selected from 0, S and N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s).
- heterocyclic moieties include, but are not limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
- aryl refers to optionally substituted monocyclic and polycarbocyclic unfused or fused groups having 6 to 14 carbon atoms, represented as (Ce-Cujaryl, and having at least one aromatic ring that complies with Huckel's Rule.
- Examples of (Ce-Ci4)aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
- heteroaryl means an optionally substituted aromatic monocyclic ring or polycarbocyclic fused ring system having 5 to 12 carbon atoms, represented as (Cs-C ⁇ heteroaryl, wherein at least one ring complies with Huckel's Rule, has the specified number of ring atoms, and that ring contains at least one heteratom independently selected from N, 0 and S.
- Examples of "(C5-Ci2)heteroaryl” groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxopyridyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl and indazolyl.
- hydrate refers to a crystalline form of a molecule that further comprises water incorporated into the crystalline structure.
- the water molecules in the hydrate may be present in a regular arrangement and/or a non-ordered arrangement.
- the hydrate may comprise either a stoichiometric or nonstoichiometric amount of the water molecules.
- solvate refers to a crystalline form of a molecule that further comprises solvent molecule/s incorporated into the crystalline structure.
- solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
- the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. Solvates can exhibit polymorphism.
- cocrystal also known as "crystalline molecular complex” refers to a crystalline solid made up of two or more unique chemical species in the same crystal lattice, in a defined stoichiometric ratio, and that possesses distinct physical, crystallographic and spectroscopic properties when compared to the chemical species individually.
- Present crystal forms are cocrystals which comprise the daprodustat free acid, compound of formula (I), and a daprodustat pharmaceutically acceptable metal salt, wherein the metal is an alkali metal such as sodium or potassium.
- Cocrystals may be in the form of hydrates or solvates.
- a cocrystal is distinct from a "salt" which comprises charged-balanced charged species.
- the species making up a cocrystal typically are neutral, and are generally held together by weak, freely reversible, non-covalent interactions.
- the weak interaction is defined as neither ionic bond interaction nor covalent bond interaction, and include hydrogen bonding, van der Waals forces, p-p interactions and halogen bond interactions.
- Cocrystals can generally be distinguished from salts by the absence of a proton transfer between the chemical species. So, the cocrystals of the present invention hold together by weak interactions without accompanying proton transfer between daprodustat free acid and daprodustat metal salt.
- particle size refers to the average length of the needles observed in the microscope images measured with an Environmental Scanning Electron Microscope (ESEM).
- solvent refers to water or an organic molecule capable of at least partially dissolving another substance (i.e., the solute).
- Solvents may be liquids at room temperature.
- Organic solvents may be liquids at room temperature.
- Suitable organic solvents may be, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes (C6-Ci4)aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated (Ci-Ci2)hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane,
- the solvent may be formed by the combination of two or more solvents.
- aprotic solvent as used herein means any molecular solvent which cannot donate H + , i.e. a compound not having labile hydrogens.
- Suitable aprotic solvents may be, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, etc.), halogenated hydrocarbon solvents (e.g., 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents (e.g., toluene, o-xylene, m-xylene, and p-xylene, etc), and ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether
- (Ci-C3)alcohols as used herein means methanol, ethanol, isopropanol or 1-propanol.
- one-pot reaction or “consecutive manner” is generally known in the art and refers to a chemical reaction wherein the starting material is converted to the end product of the reaction in a single reaction vessel or container, i.e. there is no intermediary reaction product which is isolated, removed or purified from the reaction vessel.
- a “one-pot” reaction or “consecutive manner” in its broadest meaning still allows the formation of intermediary products which are, however, further converted to the end-product by addition of further reactants (in situ generation of the intermediate).
- a “one-pot” reaction or “consecutive manner” also encompasses a reaction in a single reaction vessel where the starting product is converted to the end product through the formation of one or multiple intermediate products that are formed sequentially, even without further addition of a reagent ("multistep” reaction).
- a “one-pot” or “consecutive manner” process is characterized by at least two reaction steps carried out without isolation and/or purification of the intermediate product or products, and suitably carried out in a single reaction vessel/container.
- hydrochloric acid aka binary acid
- hydrobromic acid a second nonmetallic element such as S, F, Cl, Br or I. More preferably the “hydracid” is selected from the group consisting of hydrochloric acid, hydrobromic acid and hydroiodic acid.
- inorganic base refers to hydroxides of an alkali metal such as sodium or potassium and an alkali earth metal such as calcium or magnesium, and mixtures thereof.
- room temperature in the context of the present invention refers to a temperature from 15°C to 30°C, preferably from 20°C to 25°C.
- solvent extraction refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component and may, therefore, separate said one component from at least a second component which is less miscible than said one component with said solvent.
- filtration refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid.
- the expression filtrate refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size.
- the expression filter cake refers to residual solid material remaining on a feed side of a filtration element.
- evaporation refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor.
- Various solvents may be evaporated during the processes disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and/or temperature.
- distillation refers to the process of separating the component substances from a liquid mixture by selective evaporation and condensation. It may result in essentially complete separation (nearly pure components), or it may be a partial separation that increases the concentration of selected components of the mixture. In either case the process exploits differences in the volatility of mixture's components.
- slurrying refers to any process which employs a solvent to wash, suspend or disperse a crude solid product.
- phase separation refers to a solution or mixture having at least two physically distinct regions.
- crystallization refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound, optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as dissolving the compound in a solvent and precipitating it by addition of an "antisolvent” (i.e., a solvent in which the desired compound has low solubility or insolubility, and can be used to precipitate such compound by adding it to a solution in which the compound is dissolved).
- an antisolvent i.e., a solvent in which the desired compound has low solubility or insolubility, and can be used to precipitate such compound by adding it to a solution in which the compound is dissolved.
- conventional isolation techniques or “purification” as used herein refer to the process of rendering a product clean of foreign elements whereby a purified product can be obtained.
- industrial purification refers to purifications which can be carried out on an industrial scale such
- pharmaceutically acceptable metal salt of daprodustat derived from pharmaceutically acceptable bases include alkali metal such as sodium or potassium.
- compositions for medical use refers to components which are appropriate for use in pharmaceutical technology for the preparation of compositions for medical use. Each component should be “acceptable” in the sense of being compatible with the other ingredients of the composition. When used in contact with the tissue or organ of humans and animals should not have excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts of daprodustat derived from pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, such as alkyl amines, arylalkyl amines and heterocyclic amines.
- FIG. 1 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form N2 of daprodustat.
- FIG. 2 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form N2 of daprodustat.
- DSC Differential Scanning Calorimetry
- TGA Thermal Gravimetric Analysis
- FIG. 3 provides a representative 1 H-RMN plot of crystal form N2 of daprodustat.
- FIG. 4 provides a representative infrared absorption spectrum (IR) of crystal form N2 of daprodustat.
- FIG. 5 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form N4 of daprodustat.
- FIG. 6 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form N4 of daprodustat.
- DSC Differential Scanning Calorimetry
- TGA Thermal Gravimetric Analysis
- FIG. 7 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form K2 of daprodustat.
- FIG. 8 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form K2 of daprodustat.
- DSC Differential Scanning Calorimetry
- TGA Thermal Gravimetric Analysis
- FIG. 9 provides a representative 1 H-RMN plot of crystal form K2 of daprodustat.
- FIG. 10 provides a representative infrared absorption spectrum (IR) of crystal form K2 of daprodustat.
- FIG. 11 provides a representative micrograph of crystal form N2 of daprodustat obtained by optical microscopy.
- FIG. 12 provides a representative micrograph of crystal form K2 of daprodustat obtained by optical microscopy.
- FIG. 13 provides a representative micrograph of crystal form N2 of daprodustat obtained by ESEM.
- FIG. 14 provides a representative micrograph of crystal form K2 of daprodustat obtained by ESEM.
- FIG. 15 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form K1 of daprodustat.
- FIG. 16 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form K1 of daprodustat.
- DSC Differential Scanning Calorimetry
- TGA Thermal Gravimetric Analysis
- the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt.
- the molar ratio of daprodustat free acid to daprodustat metal salt in the cocrystal is of from 1 :3 to 3:1 , preferably from 1 :2 to 2:1, more preferably is about 1 :1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat metal salt in the cocrystal is about 2:1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat metal salt in the cocrystal is about 1 : 1.
- the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat sodium salt.
- the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat sodium salt referred as form N2, which has an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.3° ⁇ 0.2°, 7.4° ⁇ 0.2°, 7.6° ⁇ 0.2°, 11 .4° ⁇ 0.2° and 16.2° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
- the crystal form N2 of daprodustat further comprises peaks at 2theta values of 13.0° ⁇ 0.2°, 13.5° ⁇ 0.2°, 14.5° ⁇ 0.2°, 14.8° ⁇ 0.2° and 15.2° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the crystal form N2 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 6.3, 7.4, 7.6, 11.4, 13.0, 13.5, 14.5, 14.8, 15.2, 16.2 ⁇ 0.2 degrees 2Theta measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the crystal form N2 of daprodustat is characterized by an XRPD pattern which matches the pattern exhibited in FIG. 1 .
- the crystal form N2 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form N2 of daprodustat pattern provided in Table 1.
- the crystal form N2 of daprodustat is characterized by thermal analysis.
- a representative DSC plot for crystal form N2 is shown in FIG. 2.
- the crystal form N2 is characterized by a DSC plot comprising an endothermic event with a first onset temperature at about 115°C.
- the crystal form N2 is characterized by a DSC plot further comprising a second endothermic event with an onset temperature at about 190°C.
- the crystal form N2 is characterized by a DSC plot further comprising a third endothermic event with an onset temperature at about 201 °C.
- the crystal form N2 is characterized by a DSC plot further comprising a fourth endothermic event with an onset temperature at about 228°C.
- a representative TGA plot for crystal form N2 of daprodustat is also shown in FIG. 2.
- the crystal form N2 of daprodustat is characterized by a TGA plot comprising a mass loss of about 4.4%, of the total mass of the sample upon heating from about 35°C to about 150°C.
- the crystal form N2 of daprodustat contains water or other solvent in the crystal lattice.
- the crystal form N2 of daprodustat contains water in the crystal lattice.
- the crystal form N2 of daprodustat contains water in an amount from 0.2% to 10%, preferably from 2% to 8%, more preferably from 4% to 6%, by weight with respect to the total weight of the crystal.
- the crystal form N2 of daprodustat is a hydrate.
- the crystal form N2 of daprodustat is a hydrate which contains an amount of water of about 4.4% as measured by TGA analysis.
- the XRPD pattern of the crystal form N2 of daprodustat is substantially unchanged following the adsorption/desorption analysis.
- the crystal form N2 is stable with respect to humidity.
- the crystal form N2 of daprodustat is slightly hygroscopic according to European Pharmacopoeia 6.0 (5.11).
- the crystal form N2 of daprodustat is characterized by proton nuclear magnetic resonance ( 1 H-NMR) as shown in FIG. 3.
- the crystal form N2 of daprodustat is characterized by having a proton NMR spectrum with signals 5 (ppm) at 10.13, 4.66, 3.96, 2.31, 1.77, 1.57, and 1.20.
- the crystal form N2 of daprodustat is characterized by an infrared absorption spectrum (FTIR) which has a spectrum shown in FIG. 4, and has peaks at the following wavenumbers (cm 1 ): 691 , 761 , 789, 840, 895, 924, 966, 1000, 1024, 1057, 1132, 1178, 1237, 1266, 1306, 1338, 1379, 1420, 1444, 1479, 1522, 1586, 1670, 1716, 2849, 2914, 2930, 2973, 3233, 3522, and 3649.
- the wavenumbers (cm 1 ) may contain an error of ⁇ 0.5% according to the measuring apparatus, measurement conditions, etc., such a level of error is within an acceptable range in the present invention.
- the molar ratio of daprodustat free acid to daprodustat sodium salt in the crystal form N2 is of from 1 :3 to 3:1 , preferably from 1 :2 to 2:1, more preferably is about 1 :1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N2 is about 2: 1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N2 is about 1 :1.
- the crystal form N2 of daprodustat is characterized by its stability profile.
- the crystal form N2 of daprodustat material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon grinding or milling and compression.
- the crystal form N2 of daprodustat keeps its form unchanged in a dry environment at room temperature, at 45°C and at 60°C for at least one month. In certain embodiments, the crystal form N2 of daprodustat keeps its form unchanged under accelerated conditions at 40°C and 75% RH (Relative Humidity) for at least one month or for at least two months.
- RH Relative Humidity
- the crystal form N2 of daprodustat keeps its form unchanged upon slurry in water at room temperature for at least one hour. In other words, the crystal form N2 of daprodustat does not undergo dissociation (i.e., phase separation into their individual constituents) in the presence of water.
- the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat sodium salt referred as form N4 which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2theta values of 6.4° ⁇ 0.2°, 7.4° ⁇ 0.2°, 7.6° ⁇ 0.2°, 13.4° ⁇ 0.2° and 16.7° ⁇ 0.2, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
- XRPD X-ray powder diffraction
- the crystal form N4 of daprodustat further comprises peaks at 2theta values of 15.0° ⁇ 0.2°, 26.9° ⁇ 0.2°, 27.5° ⁇ 0.2°, 27.7° ⁇ 0.2° and 28.2° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the crystal form N4 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 6.4, 7.4, 7.6, 13.4, 15.0, 16.7, 26.9, 27.5, 27.7 and 28.2 ⁇ 0.2 degrees 2Theta.
- the crystal form N4 is characterized by an XRPD pattern which matches the pattern exhibited in FIG.5.
- the crystal form N4 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form N4 of daprodustat pattern provided in Table 2.
- Table 2
- a representative DSC/TGA plots for crystal form N4 is shown in FIG. 6.
- the crystal form N4 of daprodustat is characterized by a DSC plot comprising an endothermic event with a first onset temperature at about 107°C.
- form N4 is characterized by a DSC plot further comprising a second endothermic event with an onset temperature at about 190°C.
- form N4 is characterized by a DSC plot further comprising a third endothermic event with an onset temperature at about 200°C.
- form N4 is characterized by a DSC plot further comprising a fourth endothermic event with an onset temperature at about 228°C.ln certain embodiments, the crystal form N4 of daprodustat is characterized by a TGA plot comprising a mass loss of about 4.0%, of the total mass of the sample upon heating from about 35°C to about 150°C. In certain embodiments, the crystal form N4 of daprodustat contains water or other solvents in the crystal lattice. In certain embodiments, the crystal form N4 of daprodustat contains water in the crystal lattice.
- the crystal form N4 of daprodustat contains water in an amount of from 0.2% to 10%, preferably from 0.2% to 5%, more preferably from 2% to 5%, even more preferably from 3.9% to 4.5% by weight with respect to the total weight of the crystal.
- the crystal form N4 of daprodustat is a hydrate.
- the crystal form N4 of daprodustat is a hydrate which contains an amount of water of about 4.0% as measured by TGA analysis.
- the XRPD pattern of the crystal form N4 of daprodustat is substantially unchanged following the adsorption/desorption analysis.
- the crystal form N4 is stable with respect to humidity.
- the crystal form N4 of daprodustat is slightly hygroscopic according to European Pharmacopoeia 6.0 (5.11).
- the water content in the crystal form N4 of daprodustat is lower than the water content in the crystal form N2 of daprodustat.
- the molar ratio of daprodustat free acid to daprodustat sodium salt in the crystal form N4 is of from 1 :3 to 3:1, preferably from 1 :2 to 2:1 , more preferably is about 1 :1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N4 is about 2: 1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N4 is about 1 :1.
- the crystal form N4 of daprodustat is characterized by its stability profile.
- the crystal form N4 of daprodustat material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon grinding or milling and compression.
- the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat potassium salt.
- the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat potassium salt referred as form K2, which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2theta values of 5.5° ⁇ 0.2°, 6.3° ⁇ 0.2°, 7.0° ⁇ 0.2°, 16.8° ⁇ 0.2° and 18.0° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
- XRPD X-ray powder diffraction
- the crystal form K2 of daprodustat further comprises peaks at 2theta values of 7.8° ⁇ 0.2°, 11.8° ⁇ 0.2°, 12.7° ⁇ 0.2°, 13.7° ⁇ 0.2° and 27.6° ⁇ 0.2°, measured with Ko radiation of copper having an X- ray wavelength of 1 .5406 A at room temperature.
- the crystal form K2 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 5.5, 6.3, 7.0, 7.8, 11.8, 12.7, 13.7, 16.8, 18.0, and 27.6 ⁇ 0.2 degrees 2Theta.
- the crystal form K2 of daprodustat is characterized by an XRPD pattern which matches the pattern exhibited in FIG. 7.
- the crystal form K2 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form K2 of daprodustat pattern provided in Table 3.
- Table 3 Table 3
- the crystal form K2 of daprodustat is characterized by thermal analysis.
- a representative DSC plot for the crystal form K2 is shown in FIG. 8.
- the crystal form K2 is characterized by a DSC plot comprising a first endothermic event with an onset temperature at about 33°C.
- the crystal form K2 is characterized by a DSC plot further comprising a second endothermic event with an onset temperature at about 248°C.
- a representative TGA plot for the crystal form K2 of daprodustat is also shown in FIG. 8.
- the crystal form K2 of daprodustat is characterized by a TGA plot comprising a mass loss of about 5.4%, of the total mass of the sample upon heating from about 30°C to about 130°C.
- the crystal form K2 of daprodustat contains water or other solvent in the crystal lattice.
- the crystal form K2 of daprodustat contains water in the crystal lattice.
- the crystal form K2 of daprodustat contains water in an amount from 0.2% to 10%, preferably from 2% to 8%, more preferably from 4% to 6% by weight with respect to the total weight of the crystal.
- the crystal form K2 of daprodustat is a hydrate. In certain embodiments, the crystal form K2 of daprodustat is a hydrate which contains an amount of water of about 5.4% as measured by TGA analysis. In certain embodiments, the XRPD pattern of the crystal form K2 of daprodustat is substantially unchanged following the adsorption/desorption analysis. In certain embodiments, the crystal form K2 is stable with respect to humidity.
- the crystal form K2 of daprodustat is characterized by proton nuclear magnetic resonance ( 1 H-NMR) as shown in FIG. 9.
- the crystal form K2 of daprodustat is characterized by having a proton NMR spectrum with signals 5 (ppm) at 10.08, 4.65, 3.93, 2.30, 1.77, 1.57, and 1.20.
- the crystal form K2 of daprodustat is characterized by an infrared absorption spectrum (FTIR) which has a spectrum shown in FIG. 10, and has peaks at the following wavenumbers (cm 1 ): 693, 740, 762, 790, 882, 894, 918, 996, 1054, 1134, 1187, 1235, 1258, 1302, 1340, 1378, 1446, 1472, 1506, 1522, 1589, 1669, 2655, 2852, 2935, 2977, 3180, 3477, and 3546.
- the wavenumbers (cm 1 ) may contain an error of ⁇ 0.5% according to the measuring apparatus, measurement conditions, etc., such a level of error is within an acceptable range in the present invention.
- the molar ratio of daprodustat free acid to daprodustat potassium salt in the crystal form K2 is of from 1 :3 to 3: 1 , preferably from 1 :2 to 2: 1 , more preferably is 1 : 1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K2 is about 2: 1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K2 is about 1 :1.
- the crystal form K2 of daprodustat is characterized by its stability profile.
- the crystal form K2 of daprodustat material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon grinding or milling and compression.
- the crystal form K2 of daprodustat keeps its form unchanged in a dry environment at room temperature, at 45°C and at 60°C for at least one month. In certain embodiments, the crystal form K2 of daprodustat keeps its form unchanged under accelerated conditions at 40°C and 75% RH (Relative Humidity) for at least one month or for at least two months.
- RH Relative Humidity
- the crystal form K2 of daprodustat keeps its form unchanged in a dry environment under vacuum at 45°C and at 60°C least 12 hours (i.e., overnight). In certain embodiments, the crystal form K2 of daprodustat keeps its form unchanged upon slurry in water at room temperature for at least one hour. In other words, the crystal form K2 of daprodustat does not undergo dissociation (i.e., phase separation into their individual constituents) in the presence of water.
- a sample of the crystal form N2 of daprodustat comprises particles having needles (acicular) morphology. In certain embodiments, a sample of the crystal form N2 of daprodustat comprises acicular crystals as shown in FIG. 11. In certain embodiments, the particles of the crystal form N2 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns.
- the particles of the crystal form N2 of daprodustat have a size between 100 to 5 microns, between 80 to 5 microns, between 60 to 5 microns, between 40 to 5 microns or between 30 to 5 microns. In certain embodiments, the particles of the crystal form N2 of daprodustat comprises acicular crystals having a size as shown in FIG. 13.
- a sample of the crystal form N4 of daprodustat comprises particles having needles (acicular) morphology.
- the particles of the crystal form N4 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns.
- the particles of the crystal form N4 of daprodustat have a size between 100 to 5 microns, between 80 to 5 microns, between 60 to 5 microns, between 40 to 5 microns, or between 30 to 5 microns.
- a sample of the crystal form K2 of daprodustat comprises particles having needles (acicular) morphology. In certain embodiments, a sample of the crystal form K2 of daprodustat comprises acicular crystals as shown in FIG. 12. In certain embodiments, the particles of the crystal form K2 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns.
- the particles of the crystal form N2 of daprodustat have a size between 120 to 10 microns, between 90 to 10 microns, between 60 to 10 microns, or between 30 to 10 microns.
- the particles of the crystal form K2 of daprodustat comprises acicular crystals having a size as shown in FIG. 14.
- the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat potassium salt referred as form K1 , which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2theta values of 5.4° ⁇ 0.2°, 7.9° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.6° ⁇ 0.2° and 17.5° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
- XRPD X-ray powder diffraction
- the crystal form K1 of daprodustat further comprises peaks at 2theta values of 10.2° ⁇ 0.2°, 11.3° ⁇ 0.2°, 12.1 ° ⁇ 0.2°, 15.8° ⁇ 0.2° and 16.2° ⁇ 0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
- the crystal form K1 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 5.4, 7.9, 10.2, 11.3, 12.1 , 14.6, 15.6, 15.8, 16.2, and 17.5 ⁇ 0.2 degrees 2Theta.
- the crystal form K1 of daprodustat is characterized by an XRPD pattern which matches the pattern exhibited in FIG. 15.
- the crystal form K1 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form K1 of daprodustat pattern provided in Table 4.
- the crystal form K1 of daprodustat is characterized by thermal analysis.
- a representative DSC plot for the crystal form K1 is shown in FIG. 16.
- the crystal form K1 is characterized by a DSC plot comprising a first endothermic event with an onset temperature at about 56°C.
- the crystal form K1 is characterized by a DSC plot further comprising an exothermic event with an onset temperature at about 202°C.
- the crystal form K1 is characterized by a DSC plot further comprising two overlapped endothermic events with onset temperatures at about 251 °C and about 254°C, respectively.
- a representative TGA plot for the crystal form K1 of daprodustat is also shown in FIG. 16.
- the crystal form K1 of daprodustat is characterized by a TGA plot comprising a mass loss of about 13.2%, of the total mass of the sample upon heating from about 40°C to about 130°C.
- the crystal form K1 of daprodustat contains water or other solvent in the crystal lattice.
- the crystal form K1 of daprodustat contains water in the crystal lattice.
- the crystal form K1 of daprodustat is a hydrate.
- the crystal form K1 of daprodustat is a hydrate which contains an amount of water between 10% and 14% as measured by TGA analysis.
- the molar ratio of daprodustat free acid to daprodustat potassium salt in the crystal form KI is of from 1 :3 to 3:1 , preferably from 1 :2 to 2:1, more preferably is about 1 :1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K1 is about 2:1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K1 is about 1 :1.
- a sample of the crystal form K1 of daprodustat comprises particles having needles (acicular) morphology.
- the particles of the crystal form K1 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns.
- the particles of the crystal form K1 of daprodustat have a size between 120 to 10 microns, between 90 to 10 microns, between 60 to 10 microns, or between 30 to 10 microns.
- the invention further encompasses the crystal form N2, the crystal form N4, the crystal form K2 and the crystal form K1 of daprodustat in pure form or when admixed with other materials, for example, other polymorphs, solvates or remaining reaction solvents or side products.
- the invention also refers to mixtures comprising crystal form of N2 with crystal form N4 thereof.
- the invention also refers to mixtures of crystal form of K2 with crystal form K1 thereof.
- the invention provides a process for the preparation of crystal forms of daprodustat as defined above, comprising the following steps: a) providing daprodustat free acid in a solvent or a mixture of solvents, b) optionally, heating the mixture of step (a) at a suitable temperature, preferably from 70°C to 100°C, more preferably from 75°C to 95°C, c) adding a source of a pharmaceutically acceptable metal inorganic base, preferably an alkali metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, more preferably in the form of an alkali metal hydroxide, in an amount of about 0.5 molar equivalents with respect to daprodustat free acid of step (a), d) optionally, cooling the solution resulting from step (c) to room temperature, and e) isolating the crystal form of daprodustat.
- Daprodustat free acid used in (a) may be in solvate, hydrate, anhydrous, crystalline form, or non-crystalline form thereof.
- daprodustat free acid is in crystalline form, even more preferably daprodustat free acid used in step (a) is in anhydrous form.
- Daprodustat solvate used in step (a) may be a diethyl ether solvate as prepared in Ex. 18 Method 1 of W02007/150011 A2.
- daprodustat solvate is methyl tert-butyl ether solvate, dioxane solvate, tetrahydrofuran solvate, methanol solvate, ethanol solvate, isopropanol solvate, tert-butanol solvate, dimethylformamide (DMF) solvate or dimethylsulfoxide (DMSO) solvate, all prepared in Table 5 of example 1.
- Suitable solvent used in step (a) may be selected from the group of (C6-Ci4)aromatic hydrocarbon solvents such as toluene, o-xylene, m-xylene, and p-xylene; halogenated (Ci-Ci2)hydrocarbon solvents such as 1 ,2- dichloroethane, dichloromethane, chloroform; (Ci-Ci2)ether solvents such as diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 ,4-dioxane; (Ci-Ci2)alcohol solvents such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1 -propanol, 1-butanol, 2-butanol, 1- pentanol, 3-methyl-1 -butanol, tert-butanol
- the solvent may be formed by the combination of two or more solvents.
- the solvent used in step (a) is selected from the group consisting of (Ci-Cejalcohol, acetonitrile, dichloromethane (DCM), toluene, tetrahydrofuran, and a combination thereof.
- the solvent used in step (a) is a mixture of water and another solvent selected from the group consisting of (Ci-C6)alcohol, acetonitrile, dichloromethane (DCM), toluene, and tetrahydrofuran.
- the solvent of step (a) is mixture of a (Ci-Ce)alcohol or acetonitrile with water.
- the solvent used in step (a) is a mixture of acetonitrile and water.
- the solvent used in step (a) is a mixture of acetonitrile and water in a ratio from 5: 1 (v/v) to 15:1 (v/v), preferably from 8: 1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v).
- the pharmaceutically acceptable metal inorganic base is an alkali metal inorganic base, selected from a sodium and a potassium inorganic base.
- the source of the pharmaceutically acceptable metal hydroxide of step (b) is in the form of an alkali metal hydroxide.
- the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.
- the pharmaceutically acceptable metal inorganic base is sodium to provide the cocrystal of daprodustat and daprodustat sodium salt.
- the pharmaceutically acceptable metal inorganic base is potassium to provide the cocrystal of daprodustat and daprodustat potassium salt.
- step (b) is carried out to provide a solution.
- step (d) is carried out to induce the crystallization of the crystal form.
- seeding with the desired crystal form of daprodustat is used to control the crystallization before step (d) is carried out.
- steps (b) and (d) are carried out.
- steps (b) and (d) are carried out, and seeding with the desired crystal form of daprodustat is used before step (d) is carried out.
- daprodustat free acid of step (a) is prepared by the process as defined in the sixth aspect, or alternatively by the process as defined in any of the eighth aspect, or alternatively by the process as defined in the tenth aspect.
- the preparation of crystal forms of daprodustat which are cocrystals comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt, comprises the steps of:
- a source of a pharmaceutically acceptable metal inorganic base preferably an alkali metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide-salt, , more preferably in the form of an alkali metal hydroxide, in an amount from 1.0 to 1.2, or alternatively from 1.0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat alkali metal of formula (la), wherein M is an alkali metal such as sodium or potassium, iv.
- step (iii) adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
- an acid preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid
- step (iii) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (I); and step (iv) comprises adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii).
- the process for the preparation of crystal forms of daprodustat as defined herein starting from ester intermediate of formula (VI), wherein R is as defined above is reproducible and does not generate an excess of inorganic base, particularly a pharmaceutically acceptable
- Ester intermediate used in step (i) as starting material may be prepared as described in W02007/150011 A2, particularly compound VI wherein R is ethyl, i.e. N-[(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 , 2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine as prepared in Example 18.
- Suitable solvent used in step (i) may be selected from the group of water, (Ci-Ci2)alcohol solvents such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl- 1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3- methyl-1 -butanol, tert-butanol, 1 -octanol, benzylalcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol; (Ci-Ci2)ether solvents such as diethyl ether, tert-butyldimethyl ether, tetrahydrofuran and dioxane; nitrobenzene; N,N-dimethylformamide; N,N, -dimethylacetamide; N-methyl-2- pyrrolidone; and acetonitrile.
- the solvent may be formed by the combination of two or more solvents.
- the solvent used in step (i) is a (Ci-Ci2)alcohol or acetonitrile.
- the solvent of step (i) is methanol, ethanol, isopropanol, 1-propanol or acetonitrile.
- the solvent of step (i) is a mixture of a (Ci-Ci2)alcohol or acetonitrile with water.
- the (Ci-Ci2)alcohol is selected from methanol, ethanol, isopropanol and 1-propanol.
- the solvent used in step (i) is a mixture of ethanol or acetonitrile with water.
- the solvent used in step (i) is a mixture of ethanol or acetonitrile with water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9: 1 (v/v).
- the pharmaceutically acceptable metal salt of step (iii) is an alkali metal salt selected from a sodium and a potassium salt.
- the source of the pharmaceutically acceptable metal inorganic base, particularly a metal hydroxide, of step (iii) is in the form of an alkali metal hydroxide.
- the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.
- metal hydroxide of step (iii) is added as an aqueous solution.
- the pharmaceutically acceptable metal salt of step (iii) is sodium to provide the cocrystal of daprodustat free acid and daprodustat sodium salt.
- the pharmaceutically acceptable metal salt of step (iii) is potassium to provide the cocrystal of daprodustat free acid and daprodustat potassium salt.
- the step (iii) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (I) by evaporation or distillation, and (iii.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
- the solvent in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (iii.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M is an alkali metal such as sodium or potassium.
- Suitable acid used in step (iv) is an inorganic or an organic acid.
- Suitable acids are those which have a pKa (relative to water) below 5, preferably below 3, more preferably below 1.
- the acid has a pKa (relative to water) from -10 to 5, preferably from -10 to 3, more preferably from -10 to 1 .
- suitable acids include but are not limited to hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, dichloroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid.
- the acid used in step (iv) is a hydracid such as hydrochloric, hydrobromic or hydroiodic acid, which may be present either as gas or as an aqueous solution or generated in situ, for example from an alkylsilyl halogenide in the presence of a protic solvent. More preferably, the acid used in step (iv) is hydrochloric acid in aqueous solution.
- step (ii) is carried out to provide a solution.
- step (v) is carried out to induce the crystallization of the crystal form.
- seeding with the desired crystal form of daprodustat is used to control the crystallization before step (v) is carried out.
- seeding with the desired crystal form of daprodustat is carried out before or during step (iv).
- seeding with the desired crystal form of daprodustat is carried out as many times as necessary to control the desired crystal form of daprodustat.
- steps (ii) and (v) are carried out.
- steps (ii) and (v) are carried out, and seeding with the desired crystal form of daprodustat is used before step (v) is carried out.
- steps (ii) and (v) are carried out, and seeding with the desired crystal form of daprodustat is used before step (v), or before or during step (iv) are carried out.
- hot filtration of the resulting mixture of step (iii) may be carried out to remove any insoluble material.
- the present invention refers to the potassium salt of daprodustat of formula (la) wherein M is potassium.
- the potassium salt of daprodustat of formula (la) wherein M is potassium is in solvate, hydrate, crystalline form, or non-crystalline form thereof.
- the ester intermediate of formula (VI) is prepared by the process as defined in the ninth aspect.
- the preparation of crystal form N2 of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat sodium salt, comprises the steps of: i. providing an ester intermediate of formula (VI), wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (Cs-C ⁇ heteroaryl, preferably R is ethyl, in a solvent or a mixture of solvents, ii.
- R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (C
- step (i) optionally, heating the mixture of step (i) at a suitable temperature, preferably from room temperature to 100°C, more preferably from 30°C to 75°C, iii. adding a source of an alkali metal which is sodium, preferably in the form of an alkali metal hydroxide which is sodium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat sodium salt, iv.
- a suitable temperature preferably from room temperature to 100°C, more preferably from 30°C to 75°C
- adding a source of an alkali metal which is sodium preferably in the form of an alkali metal hydroxide which is sodium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester
- step (iii) adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
- an acid preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid
- step (iii) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (i); and step (iv) comprises adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii).
- a source of a pharmaceutically acceptable metal inorganic base particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an
- steps (ii) and (v) as defined above are carried out.
- seeding with crystal form N2 of daprodustat is used to control the crystallization before step (v) is carried out.
- the step (iii) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (i) by evaporation or distillation, and (iii.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
- the solvent in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (iii.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M is sodium.
- the preparation of crystal form K2 of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat potassium salt, comprises the steps of: i. providing an ester intermediate of formula (VI), wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (Cs-C ⁇ heteroaryl, preferably R is ethyl, in a solvent or a mixture of solvents, ii.
- R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (C
- step (i) optionally, heating the mixture of step (i) at a suitable temperature, preferably from room temperature to 100°C, more preferably from 30°C to 75°C, iii. adding a source of an alkali metal which is potassium, preferably in the form of an alkali metal hydroxide which is potassium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat potassium salt, iv.
- a suitable temperature preferably from room temperature to 100°C, more preferably from 30°C to 75°C
- adding a source of an alkali metal which is potassium preferably in the form of an alkali metal hydroxide which is potassium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester
- an acid preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1.7 molar equivalents to the mixture of step (ill), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
- an acid preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid
- step (ill) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (I); and step (iv) comprises adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (ill).
- a source of a pharmaceutically acceptable metal inorganic base particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1
- steps (II) and (v) as defined above are carried out.
- seeding with crystal form K2 of daprodustat is used to control the crystallization before step (v) is carried out.
- the step (ill) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (I) by evaporation or distillation, and (ill.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
- the solvent in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (ill.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M potassium.
- step (i) adding a source of an alkali metal which is potassium, preferably in the form of an alkali metal hydroxide which is potassium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat potassium salt, iv. adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
- an acid preferably a hydracid such as hydrochloric acid, hydrobromic acid
- step (iii) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (I); and step (iv) comprises adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii).
- a source of a pharmaceutically acceptable metal inorganic base particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an
- steps (ii) and (v) as defined above are carried out.
- seeding with crystal form K1 of daprodustat is used to control the crystallization before step (v) is carried out.
- the step (iii) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (I) by evaporation or distillation, and (iii.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
- the solvent in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (iii.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M potassium.
- a process for the preparation of a crystal form N4 of daprodustat which comprises drying the crystal form N2 of daprodustat under vacuum and isolating the crystal form N4 of daprodustat.
- the process for the preparation of a crystal form N4 comprises drying the crystal form N2 of daprodustat under vacuum (about 12 mbar) at a temperature from room temperature to 75°C, preferably from 45°C to 60°C, for at least 6 hours, preferably for at least 12 hours, and isolating the crystal form N4 of daprodustat.
- the process for the preparation of a crystal form N4 comprises drying the crystal form N2 of daprodustat under vacuum (about 12 mbar) at a temperature from 45°C to 60°C for at least 6 hours, preferably for at least 12 hours, and isolating the crystal form N4 of daprodustat.
- the above processes may further provide the crystal form N2, the crystal form N4, the crystal form K2 and the crystal form K1 of daprodustat in pure form or when admixed with other materials, for example, other polymorphs, solvates or remaining reaction solvents or side products.
- the above processes may provide mixtures comprising crystal form of N2 with crystal form N4 thereof.
- the above processes may provide mixtures of crystal form of K2 with crystal form K1 thereof.
- the pharmaceutical compositions comprising crystal forms of daprodustat selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 , and a combination thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients may further contain disintegrants, glidants, lubricants, binders, colorants, and combinations thereof.
- the pharmaceutical compositions comprising crystal forms of daprodustat selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 may be tablets, dispersible tablets or granules suitable for oral use.
- the crystal forms of daprodustat selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 , and a combination thereof may be particularly indicated for the treatment of symptomatic anaemia associated with chronic kidney disease (CKD), in adults on chronic maintenance dialysis or in adults not in dialysis.
- CKD chronic kidney disease
- a sixth aspect of the present invention relates to a process for preparing daprodustat of formula (I), or a salt thereof which comprises hydrolysing a compound of formula (VI) in the presence of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and a solvent, and optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
- a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH preferably tetramethylammonium hydroxide (TMAH)
- TMAH tetramethylammonium hydroxide
- the amount of the quaternary ammonium hydroxide is in a molar ratio from 1 : 1 to 4: 1 of base to compound of formula (VI), preferably from 2:1 to 3: 1 of base to compound of formula (VI).
- suitable solvents of the sixth aspect are selected from the group consisting of a (Ci- Cajalcohols, preferably methanol, ethanol or isopropanol; water; and mixtures thereof.
- the solvent is a mixture of a (Ci-C3)alcohols, preferably methanol, ethanol or isopropanol, and water in a volume ratio from 10: 1 to 1 :2, preferably from 5:1 to 1 :2, even more preferably from 10: 1 to 5:1.
- a (Ci-C3)alcohols preferably methanol, ethanol or isopropanol
- water in a volume ratio from 10: 1 to 1 :2, preferably from 5:1 to 1 :2, even more preferably from 10: 1 to 5:1.
- the amount of acid preferably trifluoroacetic acid (TFA) is in a molar ratio from 1 : 1 to 4:1 of acid to compound of formula (VI), preferably from 2:1 to 3: 1 of base to compound of formula (VI).
- daprodustat is further purified by slurrying or crystallizing it in an organic solvent selected from alcohols, preferably (Ci-C3)alcohols, more preferably methanol, ethanol or isopropanol, more preferably in ethanol, or an acid solvent such as acetic acid.
- daprodustat is purified by crystallization in acetic acid.
- the compound (VI) is obtained by reacting a compound of formula (V) with an isocyanatoacetate of formula (IV), in the presence of a base and a solvent, wherein the compound of formula (V) is preferably obtained according to the process of the seventh aspect.
- the compound (VI) is obtained from a compound of formula (II), preferably according to the process of the fourth aspect.
- the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the second aspect of the invention.
- the seventh aspect of the invention provides a process for preparing key intermediate 1 ,3-dicyclohexyl barbituric acid of formula (V), which comprises the steps of:
- step (iii) optionally, heating the mixture of step (ii) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
- the compound (V) is further converted into daprodustat by reacting it with an isocyanatoacetate of formula (IV), in the presence of a base and a solvent to provide the compound of formula (VI); and hydrolyzing compound of formula (VI) in the presence of a base and a solvent, preferably according to the process of the sixth aspect, or alternatively using NaOH or KOH instead of a quaternary ammonium hydroxide, followed by neutralization with an acid such as hydrochloric acid.
- the amount of malonic acid in step (i) to dicyclohexylurea (DCU) is in a molar ratio from 2:1 to 1 :1 , preferably from 1.5:1 to 1.1 :1.
- the amount of AC2O used in step (i) to dicyclohexylurea (DCU) is in a molar ratio from 4:1 to 2: 1 , preferably from 3: 1 to 2:1.
- the mixture of step (i) is heated at a temperature from 70°C to 95°C, preferably from 85°C to 90°C.
- the amount of antisolvent, preferably water, of step (ii) is from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V).
- the mixture of compound of formula (V) and the antisolvent, preferably water, of step (ii) is heated at a temperature from 20°C to 85°C, preferably from 20°C to 30°C as the yield increases.
- compound of formula (V) is further purified by crystallization or slurrying it in an organic solvent selected from (Ci-C3)alcohols, preferably methanol, ethanol or isopropanol, more preferably in isopropanol.
- the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the second aspect of the invention.
- a ninth aspect of the present invention provides a process for preparing a compound of formula (VI), wherein R is (Ci-Cio)alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (Cs-C ⁇ heteroaryl, preferably R is ethyl, which comprises the steps of: a) converting a formamide of formula (II), into a compound an isocyanoacetate of formula (III), wherein R is as defined above, preferably R is ethyl; b) converting the isocyanoacetate of formula (III) of step (a) into an isocyanatoacetate of formula (IV), wherein R is
- the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of trimethyl orthoformate or triethyl orthoformate. In an embodiment, the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of methyl formate or ethyl formate and a base, preferably an organic base such as TEA. In an embodiment, the formamide of formula (II) is alternatively prepared from glycine ethyl ester in the presence of methyl formate. In an embodiment, the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of ethyl formate and a base, preferably an organic base such as TEA.
- the reaction mixture may be heated at a temperature from 20°C to 85°C, preferably from 35°C to 85°C, more preferably from 45°C to 85°C, for the time sufficient to complete the reaction (e.g., from 4 to 48 h).
- the organic salt (e.g., triethylamine hydrochlrohide) formed in the preparation of formamide of formula (II) when using methyl formate or ethyl formate and a base, preferably an organic base such as TEA, may be removed by adding an organic solvent, preferably from (C6-Ci4)aromatic hydrocarbon solvent such as toluene.
- an organic solvent preferably from (C6-Ci4)aromatic hydrocarbon solvent such as toluene.
- the formamide of formula (II) is purified by fractioned distillation.
- the formamide of formula (II) is used in the next step without further purification.
- step (a) is carried out in the presence of a dehydrating agent and a base.
- dehydrating agent include but are not limited to phosgene, phosphorus oxychloride (POCh), p-toluensulfonic chloride, triphenylphosphine (PPh3)/iodine (I2), Burgess reagent, Appel reagent, or trifluoromethyl sulfonic acid anhydride.
- the dehydrating agent is POCI3.
- Suitable base may be an organic base selected from ammonia derivatives, such as diethylamine, triethylamine (TEA), N,N- dicyclohexylmethylamine, N,N-dicyclohexylamine, and N, N-diisopropylethylamine (DIPEA), and heterocyclic bases such as pyridine, and diazabicycloundecene (DBU), and mixtures thereof.
- the base is TEA and DIPEA.
- the isocyanoacetate of formula (III) is used in the next step (b) without further purification.
- step (b) is carried out in the presence of dimethylsulfoxide (DMSO) and trifluoroacetic anhydride (TFAA).
- step (b) is carried out using mercuric oxide, lead tetraacetate, ozone, halogen- or acid-catalyzed oxidations by dimethyl sulfoxide (DMSO) and pyridine N-oxide.
- the temperature used in step (b) is from -20°C to -40°C, preferably about -30°C.
- a solution of DMSO in a solvent is added to a solution of compound (III) and trifluoroacetic anhydride in a solvent.
- step (c) the amount of the isocyanatoacetate of formula (IV), preferably wherein R is ethyl, to compound of formula (V) is in a molar ratio from 1 :1 to 2:1 , preferably from 1 :1 to 1.5: 1 , more preferably from 1 :1 to 1.2:1.
- step (c) is carried out in the presence of a base and a solvent to provide the compound of formula (VI).
- a suitable base may be an organic base including ammonia derivatives, such as diethylamine, triethylamine (TEA), N,N-dicyclohexyl-methylamine, N,N-dicyclohexylamine, and N,N- diisopropylethylamine (DIPEA), and heterocyclic bases such as pyridine, diazabicycloundecene (DBU) and mixtures thereof.
- the base used in step (c) is an organic base selected from TEA or DIPEA.
- the amount of base may be from 1 .0 to 3.0, preferably from 1 .1 to 2.5, more preferably from 1 .1 to 1 .5 molar equivalents with respect to compound of formula (V).
- a suitable solvent for steps (a), (b) and (c) may be an aprotic organic solvent.
- the aprotic solvent may be selected from halogenated hydrocarbon solvents (e.g., 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents (e.g., toluene, o-xylene, m-xylene, and p-xylene), and ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.).
- the solvent is dichloromethane, toluene or tetrahydrofuran.
- the 1 ,3-dicyclohexyl barbituric acid of formula (V) is added to the isocyanatoacetate of formula (IV).
- compound of formula (V) is added in solid form or dissolved in solution or suspended in an aprotic solvent with or without the presence of a base.
- a solution of isocyanatoacetate of formula (IV) in solution of an aprotic solvent is added to a solution or a suspension of compound of formula (V) in an aprotic solvent.
- a solution of compound of formula (V) in an aprotic is added to a solution of isocyanatoacetate of formula (IV) in an aprotic solvent.
- the aprotic solvent is as defined above for step (c).
- the aprotic solvent is dichloromethane, toluene or tetrahydrofuran.
- compound (V) is added in solution of an aprotic solvent, preferably DCM, with or without base. Additionally, the reaction medium of compound (IV) is added into another vessel containing compound (V), with or without base and with or without an aprotic solvent.
- an aprotic solvent preferably DCM
- the compound (VI) is further converted into daprodustat by hydrolysis in the presence of a base and a solvent, preferably according to the process of the sixth aspect, or alternatively using NaOH or KOH, instead of a quaternary ammonium hydroxide, followed by neutralization with an acid such as hydrochloric acid.
- the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the third aspect of the invention.
- the invention relates to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, which comprises:
- step (ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
- step (2) reacting the isocyanatoacetate of formula (IV) obtained in step (2) with the 1 ,3-dicyclohexyl barbituric acid of formula (V) obtained in step (3), in the presence of a base and a solvent to provide the compound of formula (VI) wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl; wherein steps (2) and (4) are carried out in a consecutive manner;
- converting a compound of formula (VI) into daprodustat of formula (I) by hydrolysis in the presence of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and a solvent, and optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
- a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH preferably tetramethylammonium hydroxide (TMAH)
- TMAH tetramethylammonium hydroxide
- an acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic acid (TFA), preferably trifluoroacetic acid (TFA) is added.
- daprodustat is further purified by slurrying in an organic solvent selected from alcohols, preferably (Ci-C3)alcohols, more preferably methanol, ethanol or isopropanol, more preferably in ethanol.
- daprodustat is further purified by crystallizing it in an acid solvent, preferably acetic acid.
- the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the second aspect of the invention.
- Sample preparation Approximately 20 mg of non-manipulated sample were prepared in standard sample holders using two foils of polyacetate.
- Powder diffraction pattern was acquired on a Bruker D8 Advance Series 2Theta/Theta powder diffraction system using CuKo 1 -radiation in transmission geometry.
- the system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and a radial seller.
- Measurement conditions The samples were measured at room temperature in a range from 4° to 40° in 20 in a 0.5 hours measurement using an angular step of 0.049° and a time per step of 2787 s.
- powder X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. It is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed and the relative intensity values can e.g., vary by ⁇ 30%. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about ⁇ 0.2 degrees 2Theta, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles.
- crystal forms of the present invention are not limited to the crystalline forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying figures.
- DSC Differential Scanning Calorimetry
- Sample preparation Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 pL aluminium crucibles with a pinhole lid.
- Measurement conditions The samples were heated under dry nitrogen (flow rate: 50 mL/min) at 10 °C/min from 30 to 300 °C.
- Sample preparation Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 L aluminium crucibles with a pinhole lid.
- Measurement conditions The samples were heated under dry nitrogen (flow rate: 10 mL/min) at 10 °C/min from 30 to 300 °C.
- Sample preparation Approximately 2-5 mg of sample were dissolved in 0.7 mL of deuterated solvent (dimethylsulfoxide-d6).
- Measurement conditions The samples were analyzed at room temperature.
- FTIR Fourier Transformed Infrared spectroscopy analysis
- the FTIR spectra were recorded using an Agilent Technologies Cary 630 FTIR spectrometer, equipped with an Agilent Diamond single reflection ATR system, a mid-infrared source as the excitation source and a DTGS detector.
- the spectra were acquired in 32 scans at a resolution of 4 cm 1 in the range of 4000- 650 cm’ 1 .
- Sample preparation Approximately 5-10 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 150 pL platinum crucibles without lid.
- Sample preparation Crystals of the sample were immersed in perfluorinated oil.
- Zeiss Stemi SV 11 stereomicroscope has a variable amplification in the range between 15x and 154x and is equipped with cross coupled polarization filters (Carl Zeiss Pol 45517 and 455174) and a I/2 filter (Carl Zeiss Lambda 455172).
- a transmission cold light source Zeiss KL2500 LCD is used for sample illumination.
- the size of the crystals can be measured using a standard microscale (5+100/100 mm, Carl Zeiss 474026).
- Sample preparation The samples were mounted on an aluminium stub using a double adhesive carbon conductive tab.
- AAS Atomic absorption spectrometry
- Measurement conditions wavelength for sodium: 589,592 nm; wavelength for potassium: 766,490 nm
- Sample preparation 25 mg of a sample, 3 mL of concentrated HNO3 and 1 mL of H2O2 were digested in a digester ultraWAVE Milestone. The temperature was heated at 100°C in 5 min, at 170°C in 10 min, and finally at 240°C in 10 min. The sample was kept at this final temperature for 15 min. Then, the sample was diluted in 25 mL of an aqueous solution of 2% of HNO3 followed by a second dilution of 1 mL in 20 mL of an aqueous solution of 2% of HNO3.
- daprodustat solvates (Form A, Form B, Form C, Form D, Form E, Form F, Form G and Form H) were prepared as shown in Table 5. All solids obtained herein were crystalline solvates of daprodustat as characterized by XRPD and DSC/TGA analysis.
- Cooling crystallization A sample of daprodustat obtained by reproducing the Method 2 of WC2007/150011 A2 (50 mg) was dissolved in the minimum quantity of solvent at 75°C in a solvent and the obtained solution was slowly cooled down to room temperature or 4°C to induce crystallization.
- a sample of daprodustat obtained by reproducing the Method 2 of W02007/150011 A2 (1 g, 2.54 mmol) was suspended in a mixture of acetonitrile and water (9:1 respectively, 55 mL) at 95°C.
- an aqueous solution of sodium hydroxide (1 M, 0.5 equiv., 1.28 mL) was added dropwise, and the obtained suspension was left to cool down to room temperature.
- the resulting solid was filtered off, dried under vacuum (2 mbar, 40°C, 3 hours).
- XRPD Crystalline.
- DSC (FIG. 2): Endothermic peaks with onset temperatures at 115°C (-63 J/g), 190°C (-11 J/g), 202°C (-2 J/g) and 228°C (-39 J/g).
- TGA (FIG. 2): Weight loss of 4.4% between 33 and 150°C (probable loss of water; 2 theoretical equivalents: 4.3%). Decomposition starting at about 230°C.
- FTIR v (cm 1 , FIG. 4): 691 , 761 , 789, 840, 895, 924, 966, 1000, 1024, 1057, 1132, 1178, 1237, 1266, 1306, 1338, 1379, 1420, 1444, 1479, 1522, 1586, 1670, 1716, 2849, 2914, 2930, 2973, 3233, 3522, 3649.
- DVS Weight increase of about 0.4% between 10% and 80% Relative Humidity (slightly hygroscopic). No changes observed in the XRPD before and after the analysis.
- AAS 2.9 % Na (which corresponds to a 1 : 1 molar ratio of daprodustat free acid and daprodustat sodium salt)
- a sample of daprodustat obtained by reproducing the Method 2 of W02007/150011 A2 (1 g, 2.54 mmol) was suspended in a mixture of acetonitrile and water (9:1 respectively, 55 mL) at 95°C.
- an aqueous solution of potassium hydroxide (1 M, 0.5 equiv., 1.28 mL) was added dropwise, and the obtained suspension was left to cool down to room temperature.
- the resulting solid was filtered off, dried under vacuum (2 mbar, 40°C, 3 hours).
- DSC (FIG. 8): Endothermic peaks with onset temperatures at 33°C (-87 J/g) and 248°C (-46 J/g).
- TGA (FIG. 8): Weight loss of 5.4% between 27 and 125°C (probable loss of water; 2.5 theoretical equivalents: 5.2%). Decomposition starting at about 250°C.
- FTIR v (cm 1 , FIG. 10): 693, 740, 762, 790, 882, 894, 918, 996, 1054, 1134, 1187, 1235, 1258, 1302, 1340, 1378, 1446, 1472, 1506, 1522, 1589, 1669, 2655, 2852, 2935, 2977, 3180, 3477, 3546.
- DVS Weight increase of about 3.9% between 10% and 80% Relative Humidity (hygroscopic). No changes observed in the XRPD before and after the analysis.
- AAS 4.6 % K (which corresponds to a 1 :1 molar ratio of daprodustat free acid and daprodustat potassium salt)
- Prior art form CS1, crystal form N2 and crystal form K2 of daprodustat were suspended in the different mediums at 25°C to obtain saturated solutions. The solutions were sampled at fixed time points (1 h, 4 hours and 24 hours). Concentrations values in mg/mL were measured by HPLC. The results are listed in Table 7.
- the crystal form K2 of daprodustat kept its form unchanged by XRPD analysis.
- the crystal form N2 of daprodustat transformed to the crystal form N4 characterized by XRPD, DSC/TGA and DVS analysis as shown below.
- DSC (FIG. 6): Endothermic peaks with onset temperatures at 107°C (-62 J/g), 190°C (-6 J/g), 200°C (-2 J/g) and 229°C (-38 J/g).
- TGA (FIG. 6): Weight loss of 4.0% between 39°C and 141°C (probable loss of water; 2 theoretical equivalents: 4.3%). Decomposition starting at about 220°C.
- DVS Weight increase of about 0.5% between 10% and 80% Relative Humidity (slightly hygroscopic). No changes observed in the XRPD before and after the analysis.
- Crystal form N2 kept its form unchanged as confirmed by XRPD analysis.
- Crystal form K2 kept its form unchanged as confirmed by XRPD analysis.
- Crystal form N2 kept its form unchanged in all experiments as confirmed by XRPD analysis.
- Crystal form K2 kept its form unchanged in all experiments as confirmed by XRPD analysis.
- Ethyl (1 ,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycinate (5.0 g, 11.9 mmol, 1.0 eq.) was suspended in ethanol (20 mL). An 1 M aqueous solution of NaOH (23.8 mL, 23.8 mmol, 2.0 equiv.) was added and stirred at 20-25 °C for 2 h. The solvent was distilled off at reduced pressure at 40 °C. Acetonitrile (25 mL) was added, the medium was heated at 40 °C until a solution was obtained and then the solvent was distilled off at reduced pressure at 40 °C. This operation was repeated once.
- the obtained white solid was suspended in water (100 mL) at 20-25 °C for 1 hour.
- the white suspension was filtered and washed with water (2x25 mL) at reduced pressure.
- the obtained white solid was suspended once again in water (100 mL) at 20-25 °C for 1 hour.
- the white solid was filtered, washed with water (2x25 mL) at reduced pressure and dried at reduced pressure at 40 °C for 4 h (3.3g, 7.8 mmol, Yield: 66%)
- XRPD Crystal form N2 of daprodustat.
- the obtained white solid was suspended in water (100 mL) at 20-25 °C for 1 h.
- the white suspension was filtered and washed with water (2x25 mL) at reduced pressure.
- the obtained white solid was suspended once again in water (100 mL) at 20-25 °C for 1 h.
- the white solid was filtered, washed with water (2x25 mL) at reduced pressure and dried at reduced pressure at 40 °C for 4 h (3.1 g, 7.0 mmol, Yield: 60%).
- XRPD Crystalline crystal form K1 of daprodustat.
- Crystal form K1 of daprodustat obtained above was dried under vacuum at room temperature to provide crystal form K2 of daprodustat.
- the resulting suspension was stirred at 20-25 °C for 16 h.
- the white solid was separated by filtration at reduced pressure at 20-25 °C and washed with a 1 :1 mixture of acetic acid and water (2 x 85 mL), water (175 mL) and isopropanol (175 mL).
- the resulting solid was slurried from isopropanol (1300 mL) at 80 °C and stirred 10 min at this temperature. Then, the mixture was cooled to 20- 25 °C and stirred at this temperature for 16 h and then stirred for 1 h at 0-5 °C.
- the white solid was separated by filtration at reduced pressure at 0-5 °C, washed with ice-cooled isopropanol (2x100 mL) and dried at 40- 45 °C.
- Ethyl glycinate hydrochloride (25.0 g, 179 mmol, 1.0 equiv.) was mixed with ethyl formate (75.0 mL, 69.1 g, 932 mmol, 5.2 equiv.) and triethylamine (26.2 mL, 19,0 g, 188 mmol, 1 ,05 equiv.) at 20-25 °C.
- the resulting white suspension was heated at reflux temperature and stirred at this temperature for 24 h.
- the reaction medium was cooled down to 20-25 °C and the white solid was filtered off and washed with ethyl formate.
- the solvent of the filtrate was distilled at reduced pressure at 40 °C.
- the organic phases were joined and washed with a saturated aqueous solution of sodium bicarbonate (200 mL) and with water (200 mL).
- the solvent of the organic phase was distilled at reduced pressure and swapped with isopropanol (1056 mL) to yield a yellowish suspension, which was heated at reflux temperature to yield a solution that was cooled to 20-25 °C.
- the obtained suspension was stirred at this temperature for 1 h.
- the white solid was separated by filtration at reduced pressure at 20-25 °C and washed with isopropanol (2 x 100 mL).
- the white solid was recrystallized from IPA (1000 mL), filtered off and dried at 40-45 °C.
- the phases were separated, and the aqueous phase was extracted with dichloromethane (70 mL).
- the organic phases were joined and washed with water (70 mL) and a saturated aqueous solution of sodium bicarbonate (70 mL).
- the solvent of the organic phase was distilled at reduced pressure and swapped with isopropanol (700 mL) to yield a yellowish suspension, which was heated at reflux temperature to yield a solution that was cooled to 20-25 °C.
- the obtained suspension was stirred at this temperature for 16 h.
- the white solid was separated by filtration at 20-25 °C and washed with isopropanol (3x35 mL).
- the white solid was recrystallized from IPA (6600 mL), filtered and dried at 40-45 °C.
Abstract
The present invention provides crystal forms of daprodustat, which are cocrystals comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt. The invention also refers to processes for the preparation of said cocrystals of daprodustat in good yield and high purity suitable for industrial scale, to pharmaceutical compositions containing them and to their use in therapy. The present invention also provides an efficient process for the preparation of daprodustat or a pharmaceutically or veterinary acceptable salt thereof in good yield and high purity suitable for industrial scale applications which involves improved conditions for the preparation of key intermediates.
Description
PROCESS FOR PREPARING DAPRODUSTAT AND COCRYSTALS THEREOF
This application claims the priority of the European Patent Application EP22382718.9 filed on 26.07.2022, the European Patent Application EP22383096.9 filed on 14.11.2022, and the European Patent Application EP23382239.4, filed on 14.03.2023.
FIELD OF THE INVENTION
The present invention provides crystal forms of daprodustat, which are cocrystals comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt. The invention also refers to processes for the preparation of said cocrystals of daprodustat in good yield and high purity, to pharmaceutical compositions containing them and to their use in therapy. The present invention also provides an efficient process for the preparation of daprodustat or a pharmaceutically or veterinary acceptable salt thereof in good yield and high purity suitable for industrial scale applications which involves improved conditions for the preparation of key intermediates.
BACKGROUND OF THE INVENTION
N-[(1 ,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl]glycine, also known as daprodustat, compound of formula (I), is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) first approved in Japan under the trade name Duvroq in the form of film coated tablets in 1 , 2, 4 and 6 mg dosage strengths.
Daprodustat and its tautomer N-[(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 ,2,3,4-tetrahydro-5-pyrimidinyl)- carbonyl]glycine were first disclosed in W02007/150011 A2, which describes the preparation of daprodustat by using N, N'-dicyclohexylcarbodiimide (DCC) or N,N'-dicyclohexylurea (DCU) as the starting material. The method involves cyclization of the starting material with malonic acid derivatives to provide 1 ,3-dicyclohexyl barbituric acid, following condensation with ethyl isocyanatoacetate and subsequent ester hydrolysis with aqueous sodium hydroxide in ethanol. DCC is an acute skin irritant in susceptible individuals, and due to its low melting point it is difficult to manipulate and consequently not feasible for industrial application.
Alternatively, DCU is reacted with malonyl chloride, which not only is unstable and corrosive but also is an environmentally unfriendly halogenated reagent.
Example 18 of W02007/150011 A2 discloses the preparation of daprodustat from the hydrolysis of an advanced ethyl ester intermediate (i.e., ethyl (1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 , 2,3,4- tetrahydropyrimidine-5-carbonyl)glycinate) with aqueous sodium hydroxide in ethanol followed by neutralization with hydrochloric acid. Then, daprodustat is isolated from a mixture of diethyl ether and hexane according to Method 1 of said example 18. Alternatively, daprodustat is isolated from acetic acid with hot filtration to remove a small amount of insoluble material according to Method 2 of said example 18. These isolation methods have many disadvantages, for instance, diethyl ether is volatile and explosive, not appropriate for use at industrial scale; hexane is also an inappropriate solvent for use at industrial scale due to its flammability and the safety precautions needed for safe handling; and acetic acid is difficult to remove due to its high boiling point which increases the cost of the process.
CN102432549 A discloses the preparation of key intermediate 1 ,3-dicyclohexyl barbituric acid by reacting DCU with malonic acid in the presence of acetic acid and acetic anhydride. However, the 1 ,3-dicyclohexyl barbituric acid is isolated by solvent evaporation with increases the cost of the process at industrial scale. Daprodustat is neither disclosed nor prepared.
Prior art Annalen der Chemie, Justus Liebigs (1949), 562, 75-136, prepares key ethyl isocyanatoacetate starting from glycine ethyl ester by using phosgene, which is extremely toxic by acute (short-term) inhalation exposure and likely a carcinogen. Daprodustat is neither disclosed nor prepared.
WO2019/052133 A1 discloses solid forms of daprodustat named CS1 and CS9 which have higher purity and lower hygroscopicity compared to the prior art solid form of daprodustat obtained by reproducing the above Method 2 (i.e., from recrystallization in acetic acid). However, the solid forms CS1 and CS9 are isolated from slow evaporation, which is not feasible for industrial scale. According to WO2019/052133 A1 the kinetic solubility in pure water of CS1 is of 0.014 mg/mL and for CS9 is of 0.020 mg/mL, which suggests poor aqueous solubility of either form CS1 or form CS9 of daprodustat.
W02020/102302 A1 discloses crystalline forms of daprodustat named Form 3 and Form 4. Form 3 is prepared by crystallization from ethylbenzene and Form 4 by slurrying daprodustat in diethyl ether. However, it seems that Form 3 corresponds to prior art solid form obtained from the above Method 2, and Form 4 corresponds to prior art solid form obtained from the above Method 1 .
Therefore, there is a need in developing solid forms of daprodustat with better solubility to increase the bioavailability, which can be easily manufactured at an industrial scale with low energy and costs. Further, it is also desirable to obtain an efficient and safe process for the preparation of daprodustat in high purity and high yield, which can be easily applied at an industrial scale with low energy and costs and good yields.
SUMMARY OF THE INVENTION
Daprodustat is a poorly soluble drug, and for poorly soluble drugs, it is important to increase solubility to increase the bioavailability of the drug, thereby improving the efficacy and safety of daprodustat.
The present invention refers to crystal forms of daprodustat which are cocrystals comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt. Particularly, a cocrystal comprising daprodustat free acid and daprodustat sodium salt is referred herein as crystal form N2. Particularly, another cocrystal comprising daprodustat free acid and daprodustat sodium salt is referred herein as crystal form N4. Particularly, a cocrystal comprising daprodustat free acid and daprodustat potassium salt is referred herein as crystal form K2. Particularly, another cocrystal comprising daprodustat free acid and daprodustat potassium salt is referred herein as crystal form K1. Advantageously, these cocrystals of daprodustat have improved properties such as solubility, hygroscopicity and stability as well as manufacturing behaviour (compaction, flowability, filterability etc.) thereby resulting beneficial for the development of medicinal products containing daprodustat.
Thus, the first aspect of the present invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt.
Particularly, the invention relates to a crystal form N2 of daprodustat having an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.3°±0.2°, 7.4°±0.2°, 7.6°±0.2°, 11.4°±0.2° and 16.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
Particularly, the invention relates to a crystal form N4 having an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.4°±0.2°, 7.4°±0.2°, 7.6°±0.2°, 13.4°±0.2° and 16.7°±0.2, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
Particularly, the invention relates to a crystal form K2 having an X-ray powder diffraction pattern comprising peaks at 2theta values of 5.5°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 16.8° ±0.2° and 18.0°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
Particularly, the invention relates to a crystal form K1 having an X-ray powder diffraction pattern comprising peaks at 2theta values of 5.4°±0.2°, 7.9°±0.2°, 14.6°±0.2°, 15.6°±0.2° and 17.5°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
The second and third aspects of the invention provide processes for preparing the crystal forms of daprodustat as defined herein.
A fourth aspect of the invention refers to pharmaceutical compositions comprising crystal forms of daprodustat as defined herein, in particular daprodustat in a crystal form selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 , and a combination thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
A fifth aspect refers to crystal forms of daprodustat as defined herein for use in therapy, particularly for the treatment of renal anemia. This aspect can also be formulated as a method of treatment of renal anemia, which comprises administering to a subject in need thereof, including a human, a crystal form of daprodustat as defined herein and one or more pharmaceutically acceptable carriers, diluents or excipients.
It also forms part of the invention the use of a crystal form of daprodustat as defined herein for the manufacture of pharmaceutical composition for the treatment of renal anemia.
The present invention also provides an efficient and environmentally friendly process for manufacturing daprodustat or a salt thereof in good yield and applicable at industrial scale without requiring laborious and unfeasible purification steps, yielding high purity which complies with pharmaceutical standards.
The present inventors found that the hydrolysis of the ester intermediate, ethyl N-[(1 ,3-dicyclohexyl-6- hydroxy-2,4-dioxo-1 ,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]-glycinate, following the conditions disclosed in example 18 of W02007/150011 A2 (i.e. in the presence of sodium hydroxide in ethanol followed by neutralization with hydrochloric acid) provides daprodustat with significant amounts of inorganic salts such as sodium chloride difficult to separate by conventional purification techniques such as extraction, followed by slurry in water plus an additional crystallization step in acetic acid which requires hot filtration to remove inorganic material.
Advantageously, the salt formed as byproduct from the reaction of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and an acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic acid (TFA) is soluble in the reaction
media which enhances the isolation of final daprodustat without requiring laborious and unfeasible purification steps.
Thus, a sixth aspect of the present invention relates to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, which comprises converting a compound of formula (VI),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl, into daprodustat of formula (I) by hydrolysis in the presence of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and a solvent, and optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
The compound of formula (VI) may be prepared from 1 ,3-dicyclohexyl barbituric acid of formula (V) which can be obtained by reacting dicyclohexylurea (DCU) with malonic acid. The inventors have found that advantageously, the crystallization of the key intermediate of formula (V) in the presence of an antisolvent, preferably water, avoids the solvent evaporation step for its isolation which increases the cost of the process and the final cost of the medicinal product.
Thus, a seventh aspect of the invention provides a process for preparing key intermediate 1 ,3-dicyclohexyl barbituric acid of formula (V),
which comprises the steps of:
(I) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(II) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V).
An eighth aspect of the invention refers to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof, which comprises: a1) preparing a 1 ,3-dicyclohexyl barbituric acid of formula (V)
by a process which comprises the steps of:
(I) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(II) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V); a2) reacting the 1 ,3-dicyclohexyl barbituric acid of formula (V) obtained in step (a1) with an isocyanatoacetate of formula (IV),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and
(C5-Ci2)heteroaryl, preferably R is ethyl, in the presence of a base and a solvent to provide the compound of formula (VI);
wherein R is as defined above, preferably R is ethyl; a3) converting the compound of formula (VI) into daprodustat of formula (I) by hydrolysis in the presence of a base and a solvent; and a4) optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
A ninth aspect of the present invention provides a process for preparing a compound of formula (VI),
wherein R is (Ci-Cio)alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl, which comprises the steps of: a) converting a formamide of formula (II),
into a compound an isocyanoacetate of formula (III),
wherein R is as defined above, preferably R is ethyl; b) converting the isocyanoacetate of formula (III) of step (a) into an isocyanatoacetate of formula (IV),
wherein R is as defined above, preferably R is ethyl; c) reacting the isocyanatoacetate of formula (IV) obtained in step (b) with a 1 ,3-dicyclohexyl barbituric acid of formula (V),
in the presence of a base and a solvent to provide the compound of formula (VI); wherein steps (b) and (c) are carried out in a consecutive manner, i.e. in one-pot manner.
Advantageously, the preparation of key intermediate of formula (VI) following the process according to the ninth aspect, Scheme 1, by reacting 1 ,3-dicyclohexyl barbituric acid of formula (V) with intermediate (IV), which is known to be unstable, in a consecutive manner process (i.e. in a one-pot reaction) starting from intermediate of formula (III) from steps (b) and (c) of the present invention, increases the yield and chemical purity of compound of formula (VI).
Scheme 1
A tenth aspect of the invention refers to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof,
which comprises: b1) converting a formamide of formula (II),
into a compound an isocyanoacetate of formula (III),
wherein R is as defined above, preferably R is ethyl; b2) converting the isocyanoacetate of formula (III) of step (b1) into an isocyanatoacetate of formula (IV),
wherein R is as defined above, preferably R is ethyl; b3) reacting the isocyanatoacetate of formula (IV) obtained in step (b2) with a 1 ,3-dicyclohexyl barbituric acid of formula (V),
in the presence of a base and a solvent to provide the compound of formula (VI)
wherein R is as defined above, preferably R is ethyl; wherein steps (b2) and (b3) are carried out in a consecutive manner, i.e. in one-pot manner; b4) converting the compound of formula (VI) into daprodustat of formula (I) by hydrolysis in the presence of a base and a solvent; and b5) optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
DEFINITIONS
When describing the compounds and methods of the invention, the following terms have the following meanings, unless otherwise indicated.
The term "about” as used herein refers to a statistically meaningful range of a value. Such a range can lie within experimental error, typical of standard methods used for the measurement and/or determination of a given value or range. In one embodiment, the range is within ±5% of the indicated value. In another embodiment, the range is within ±1% of the indicated value. In yet another embodiment, the range is within ±0.5% of the indicated value.
As used herein, "alkyl” means straight-chain or branched hydrocarbon chain radical containing no unsaturation having from 1 to 10 carbon atoms, represented as (Ci-Cio)alkyl. Such alkyl groups may be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight- or branched- pentyl, straight- or branched- hexyl, straight- or branched-heptyl, straight- or branched-nonyl or straight- or branched- decyl.
The term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term "Ca-Cecycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to six carbon atoms. Exemplary "Ca-Cecycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "heterocycloalkyl" means a non-aromatic heterocyclic ring containing the specified number of ring atoms, e.g., having 3 to 12 carbon atoms, represented as (C3-C12) heterocycloalkyl, being, saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions independently selected from 0, S and N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" moieties include, but are not limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
The term "aryl” refers to optionally substituted monocyclic and polycarbocyclic unfused or fused groups having 6 to 14 carbon atoms, represented as (Ce-Cujaryl, and having at least one aromatic ring that complies with Huckel's Rule. Examples of (Ce-Ci4)aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
The term "heteroaryl” means an optionally substituted aromatic monocyclic ring or polycarbocyclic fused ring system having 5 to 12 carbon atoms, represented as (Cs-C^heteroaryl, wherein at least one ring complies with Huckel's Rule, has the specified number of ring atoms, and that ring contains at least one heteratom independently selected from N, 0 and S. Examples of "(C5-Ci2)heteroaryl" groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxopyridyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl and indazolyl.
As used herein, "hydrate” refers to a crystalline form of a molecule that further comprises water incorporated into the crystalline structure. The water molecules in the hydrate may be present in a regular arrangement and/or a non-ordered arrangement. The hydrate may comprise either a stoichiometric or nonstoichiometric amount of the water molecules.
The term "solvate" refers to a crystalline form of a molecule that further comprises solvent molecule/s incorporated into the crystalline structure. When the solvent incorporated in the crystal is water, is called hydrate. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. Solvates can exhibit polymorphism.
As used herein, the term "cocrystal" also known as "crystalline molecular complex” refers to a crystalline solid made up of two or more unique chemical species in the same crystal lattice, in a defined stoichiometric ratio, and that possesses distinct physical, crystallographic and spectroscopic properties when compared to
the chemical species individually. Present crystal forms are cocrystals which comprise the daprodustat free acid, compound of formula (I), and a daprodustat pharmaceutically acceptable metal salt, wherein the metal is an alkali metal such as sodium or potassium. Cocrystals may be in the form of hydrates or solvates.
A cocrystal is distinct from a "salt" which comprises charged-balanced charged species. The species making up a cocrystal typically are neutral, and are generally held together by weak, freely reversible, non-covalent interactions. The weak interaction is defined as neither ionic bond interaction nor covalent bond interaction, and include hydrogen bonding, van der Waals forces, p-p interactions and halogen bond interactions. Cocrystals can generally be distinguished from salts by the absence of a proton transfer between the chemical species. So, the cocrystals of the present invention hold together by weak interactions without accompanying proton transfer between daprodustat free acid and daprodustat metal salt.
The term "particle size” as used herein in relation to the crystal forms of daprodustat in the form of needles (i.e., acicular morphology) refers to the average length of the needles observed in the microscope images measured with an Environmental Scanning Electron Microscope (ESEM).
As used herein the term "solvent” refers to water or an organic molecule capable of at least partially dissolving another substance (i.e., the solute). Solvents may be liquids at room temperature. Organic solvents may be liquids at room temperature. Suitable organic solvents may be, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes (C6-Ci4)aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated (Ci-Ci2)hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone or 2- butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), (Ci-Ci2)ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 ,4-dioxane, etc.), amine solvents (e.g., propyl amine, diethylamine, triethylamine, aniline, pyridine), (Ci-Ci2)alcohol solvents (e.g., methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1 -propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1 -butanol, tert-butanol, 1-octanol, benzylalcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), acid solvents (e.g., acetic acid, hexanoic acid, etc.), carbon disulfide, nitrobenzene, N,N-dimethylformamide, N,N, -dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetonitrile, silicone solvents (e.g., silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the solvent may be formed by the combination of two or more solvents.
The term "aprotic solvent” as used herein means any molecular solvent which cannot donate H+, i.e. a compound not having labile hydrogens. Suitable aprotic solvents may be, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, etc.), halogenated hydrocarbon solvents (e.g., 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents (e.g., toluene, o-xylene, m-xylene, and p-xylene, etc), and ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, etc.), acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone. Preferably, the aprotic solvent is dichloromethane, toluene, or tetrahydrofuran.
The term "(Ci-C3)alcohols” as used herein means methanol, ethanol, isopropanol or 1-propanol.
The term "one-pot" reaction or "consecutive manner” is generally known in the art and refers to a chemical reaction wherein the starting material is converted to the end product of the reaction in a single reaction vessel or container, i.e. there is no intermediary reaction product which is isolated, removed or purified from the reaction vessel. A "one-pot" reaction or "consecutive manner” in its broadest meaning still allows the formation of intermediary products which are, however, further converted to the end-product by addition of further reactants (in situ generation of the intermediate). A "one-pot” reaction or "consecutive manner” also encompasses a reaction in a single reaction vessel where the starting product is converted to the end product through the formation of one or multiple intermediate products that are formed sequentially, even without further addition of a reagent ("multistep" reaction). Thus, a "one-pot" or "consecutive manner” process is characterized by at least two reaction steps carried out without isolation and/or purification of the intermediate product or products, and suitably carried out in a single reaction vessel/container. It will be understood by one of skill in the art that a simple transfer of the whole reaction mass at an intermediate stage, but without isolating and/or purifying the intermediate product, is still a "one-pot" process or "consecutive manner” according to the present invention, not the least because such a process would still achieve the technical advantage associated with a one-pot process in that the intermediate formed in situ does not need to be isolated and/or purified.
The term “hydracid” (aka binary acid) as used herein refers to an inorganic acid in which hydrogen is combined with a second nonmetallic element such as S, F, Cl, Br or I. More preferably the "hydracid” is selected from the group consisting of hydrochloric acid, hydrobromic acid and hydroiodic acid.
The term "inorganic base” refers to hydroxides of an alkali metal such as sodium or potassium and an alkali earth metal such as calcium or magnesium, and mixtures thereof.
The term "room temperature” in the context of the present invention refers to a temperature from 15°C to 30°C, preferably from 20°C to 25°C.
As used herein, the term "solvent extraction” refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component and may, therefore, separate said one component from at least a second component which is less miscible than said one component with said solvent.
The term "filtration” refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression filtrate refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression filter cake refers to residual solid material remaining on a feed side of a filtration element.
The term "evaporation” refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Various solvents may be evaporated during the processes disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and/or temperature.
The term "distillation” refers to the process of separating the component substances from a liquid mixture by selective evaporation and condensation. It may result in essentially complete separation (nearly pure components), or it may be a partial separation that increases the concentration of selected components of the mixture. In either case the process exploits differences in the volatility of mixture's components.
As used herein, the term "slurrying” refers to any process which employs a solvent to wash, suspend or disperse a crude solid product.
The term "phase separation” refers to a solution or mixture having at least two physically distinct regions.
The term "crystallization” refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound, optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as dissolving the compound in a solvent and precipitating it by addition of an "antisolvent” (i.e., a solvent in which the desired compound has low solubility or insolubility, and can be used to precipitate such compound by adding it to a solution in which the compound is dissolved).
The terms "conventional isolation techniques” or "purification” as used herein refer to the process of rendering a product clean of foreign elements whereby a purified product can be obtained. The term industrial purification refers to purifications which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, distillation, centrifugation or crystallization.
The term "pharmaceutically acceptable metal salt” of daprodustat derived from pharmaceutically acceptable bases include alkali metal such as sodium or potassium.
The term "pharmaceutically acceptable" refers to components which are appropriate for use in pharmaceutical technology for the preparation of compositions for medical use. Each component should be "acceptable" in the sense of being compatible with the other ingredients of the composition. When used in contact with the tissue or organ of humans and animals should not have excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically or veterinary acceptable salt” refers to a salt prepared from a base or acid or their respective conjugated acids or bases, which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. Salts of daprodustat derived from pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, such as alkyl amines, arylalkyl amines and heterocyclic amines.
BRIEF DESCRIPTION OF THE FIGURES
Examples of the invention are illustrated with the following drawings:
FIG. 1 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form N2 of daprodustat. FIG. 2 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form N2 of daprodustat.
FIG. 3 provides a representative 1H-RMN plot of crystal form N2 of daprodustat.
FIG. 4 provides a representative infrared absorption spectrum (IR) of crystal form N2 of daprodustat.
FIG. 5 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form N4 of daprodustat. FIG. 6 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form N4 of daprodustat.
FIG. 7 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form K2 of daprodustat. FIG. 8 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form K2 of daprodustat.
FIG. 9 provides a representative 1H-RMN plot of crystal form K2 of daprodustat.
FIG. 10 provides a representative infrared absorption spectrum (IR) of crystal form K2 of daprodustat.
FIG. 11 provides a representative micrograph of crystal form N2 of daprodustat obtained by optical microscopy.
FIG. 12 provides a representative micrograph of crystal form K2 of daprodustat obtained by optical microscopy.
FIG. 13 provides a representative micrograph of crystal form N2 of daprodustat obtained by ESEM.
FIG. 14 provides a representative micrograph of crystal form K2 of daprodustat obtained by ESEM.
FIG. 15 provides a representative X-ray Powder Diffraction (XRPD) pattern of crystal form K1 of daprodustat. FIG. 16 provides a representative Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) plot of crystal form K1 of daprodustat.
Any crystalline forms that provide X-ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.
DETAILED DESCRIPTION OF THE INVENTION
According to the first aspect, the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt.
In certain embodiments, the molar ratio of daprodustat free acid to daprodustat metal salt in the cocrystal is of from 1 :3 to 3:1 , preferably from 1 :2 to 2:1, more preferably is about 1 :1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat metal salt in the cocrystal is about 2:1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat metal salt in the cocrystal is about 1 : 1.
In a particular embodiment, the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat sodium salt.
In an embodiment, the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat sodium salt referred as form N2, which has an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.3°±0.2°, 7.4°±0.2°, 7.6°±0.2°, 11 .4°±0.2° and 16.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
In an embodiment, the crystal form N2 of daprodustat further comprises peaks at 2theta values of 13.0°±0.2°, 13.5°±0.2°, 14.5°±0.2°, 14.8°±0.2° and 15.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature. In an embodiment, the crystal form N2 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 6.3, 7.4, 7.6, 11.4, 13.0, 13.5, 14.5, 14.8, 15.2, 16.2 ±0.2 degrees 2Theta measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature. In an embodiment, the crystal form N2 of daprodustat is characterized by an XRPD pattern which matches the pattern exhibited in FIG. 1 . In an embodiment, the crystal form N2 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form N2 of daprodustat pattern provided in Table 1.
In certain embodiments, the crystal form N2 of daprodustat is characterized by thermal analysis. A representative DSC plot for crystal form N2 is shown in FIG. 2. In certain embodiments, the crystal form N2 is characterized by a DSC plot comprising an endothermic event with a first onset temperature at about 115°C. In certain embodiments, the crystal form N2 is characterized by a DSC plot further comprising a
second endothermic event with an onset temperature at about 190°C. In certain embodiments, the crystal form N2 is characterized by a DSC plot further comprising a third endothermic event with an onset temperature at about 201 °C. In certain embodiments, the crystal form N2 is characterized by a DSC plot further comprising a fourth endothermic event with an onset temperature at about 228°C.
A representative TGA plot for crystal form N2 of daprodustat is also shown in FIG. 2. In certain embodiments, the crystal form N2 of daprodustat is characterized by a TGA plot comprising a mass loss of about 4.4%, of the total mass of the sample upon heating from about 35°C to about 150°C. In certain embodiments, the crystal form N2 of daprodustat contains water or other solvent in the crystal lattice. In certain embodiments, the crystal form N2 of daprodustat contains water in the crystal lattice. In certain embodiments, the crystal form N2 of daprodustat contains water in an amount from 0.2% to 10%, preferably from 2% to 8%, more preferably from 4% to 6%, by weight with respect to the total weight of the crystal. In certain embodiments, the crystal form N2 of daprodustat is a hydrate. In certain embodiments, the crystal form N2 of daprodustat is a hydrate which contains an amount of water of about 4.4% as measured by TGA analysis.
In certain embodiments, the XRPD pattern of the crystal form N2 of daprodustat is substantially unchanged following the adsorption/desorption analysis. In certain embodiments, the crystal form N2 is stable with respect to humidity. In certain embodiments, the crystal form N2 of daprodustat is slightly hygroscopic according to European Pharmacopoeia 6.0 (5.11).
In certain embodiments, the crystal form N2 of daprodustat is characterized by proton nuclear magnetic resonance (1H-NMR) as shown in FIG. 3. In certain embodiments, the crystal form N2 of daprodustat is characterized by having a proton NMR spectrum with signals 5 (ppm) at 10.13, 4.66, 3.96, 2.31, 1.77, 1.57, and 1.20. In certain embodiments, the crystal form N2 of daprodustat is characterized by having a proton NMR spectrum with signals at: 1 .20 ppm (m, 6H), 1 .57 ppm (m, 6H), 1 .77 ppm (m, 4H), 2.31 ppm (m, 4H), 3.96 ppm (d, 2H, J=6 Hz), 4.66 ppm (m, 2H), and 10.13 ppm (t, 1 H, J=6 Hz).
In certain embodiments, the crystal form N2 of daprodustat is characterized by an infrared absorption spectrum (FTIR) which has a spectrum shown in FIG. 4, and has peaks at the following wavenumbers (cm 1): 691 , 761 , 789, 840, 895, 924, 966, 1000, 1024, 1057, 1132, 1178, 1237, 1266, 1306, 1338, 1379, 1420, 1444, 1479, 1522, 1586, 1670, 1716, 2849, 2914, 2930, 2973, 3233, 3522, and 3649. Although the wavenumbers (cm 1) may contain an error of ±0.5% according to the measuring apparatus, measurement conditions, etc., such a level of error is within an acceptable range in the present invention.
In certain embodiments, the molar ratio of daprodustat free acid to daprodustat sodium salt in the crystal form N2 is of from 1 :3 to 3:1 , preferably from 1 :2 to 2:1, more preferably is about 1 :1. In certain embodiments,
the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N2 is about 2: 1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N2 is about 1 :1.
In certain embodiments, the crystal form N2 of daprodustat is characterized by its stability profile. In certain embodiments, the crystal form N2 of daprodustat material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon grinding or milling and compression.
In certain embodiments, the crystal form N2 of daprodustat keeps its form unchanged in a dry environment at room temperature, at 45°C and at 60°C for at least one month. In certain embodiments, the crystal form N2 of daprodustat keeps its form unchanged under accelerated conditions at 40°C and 75% RH (Relative Humidity) for at least one month or for at least two months.
In certain embodiments, the crystal form N2 of daprodustat keeps its form unchanged upon slurry in water at room temperature for at least one hour. In other words, the crystal form N2 of daprodustat does not undergo dissociation (i.e., phase separation into their individual constituents) in the presence of water.
In a particular embodiment, the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat sodium salt referred as form N4 which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2theta values of 6.4°±0.2°, 7.4°±0.2°, 7.6°±0.2°, 13.4° ±0.2° and 16.7°±0.2, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
In an embodiment, the crystal form N4 of daprodustat further comprises peaks at 2theta values of 15.0°±0.2°, 26.9°±0.2°, 27.5°±0.2°, 27.7°±0.2° and 28.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
In an embodiment, the crystal form N4 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 6.4, 7.4, 7.6, 13.4, 15.0, 16.7, 26.9, 27.5, 27.7 and 28.2 ±0.2 degrees 2Theta.
In certain embodiments, the crystal form N4 is characterized by an XRPD pattern which matches the pattern exhibited in FIG.5. In an embodiment, the crystal form N4 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form N4 of daprodustat pattern provided in Table 2.
Table 2
In certain embodiments, a representative DSC/TGA plots for crystal form N4 is shown in FIG. 6. In certain embodiments, the crystal form N4 of daprodustat is characterized by a DSC plot comprising an endothermic event with a first onset temperature at about 107°C. In certain embodiments, form N4 is characterized by a DSC plot further comprising a second endothermic event with an onset temperature at about 190°C. In certain embodiments, form N4 is characterized by a DSC plot further comprising a third endothermic event with an onset temperature at about 200°C. In certain embodiments, form N4 is characterized by a DSC plot further comprising a fourth endothermic event with an onset temperature at about 228°C.ln certain embodiments, the crystal form N4 of daprodustat is characterized by a TGA plot comprising a mass loss of about 4.0%, of the total mass of the sample upon heating from about 35°C to about 150°C. In certain embodiments, the crystal form N4 of daprodustat contains water or other solvents in the crystal lattice. In certain embodiments, the crystal form N4 of daprodustat contains water in the crystal lattice. In certain embodiments, the crystal form N4 of daprodustat contains water in an amount of from 0.2% to 10%, preferably from 0.2% to 5%, more preferably from 2% to 5%, even more preferably from 3.9% to 4.5% by weight with respect to the total weight of the crystal. In certain embodiments, the crystal form N4 of daprodustat is a hydrate. In certain embodiments, the crystal form N4 of daprodustat is a hydrate which contains an amount of water of about 4.0% as measured by TGA analysis.
In certain embodiments, the XRPD pattern of the crystal form N4 of daprodustat is substantially unchanged following the adsorption/desorption analysis. In certain embodiments, the crystal form N4 is stable with respect to humidity. In certain embodiments, the crystal form N4 of daprodustat is slightly hygroscopic
according to European Pharmacopoeia 6.0 (5.11). In certain embodiments, the water content in the crystal form N4 of daprodustat is lower than the water content in the crystal form N2 of daprodustat.
In certain embodiments, the molar ratio of daprodustat free acid to daprodustat sodium salt in the crystal form N4 is of from 1 :3 to 3:1, preferably from 1 :2 to 2:1 , more preferably is about 1 :1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N4 is about 2: 1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat sodium salt in the crystal form N4 is about 1 :1.
In certain embodiments, the crystal form N4 of daprodustat is characterized by its stability profile. In certain embodiments, the crystal form N4 of daprodustat material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon grinding or milling and compression.
In a particular embodiment, the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat potassium salt.
In an embodiment, the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat potassium salt referred as form K2, which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2theta values of 5.5°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 16.8°±0.2° and 18.0°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
In an embodiment, the crystal form K2 of daprodustat further comprises peaks at 2theta values of 7.8°±0.2°, 11.8°±0.2°, 12.7°±0.2°, 13.7°±0.2° and 27.6°±0.2°, measured with Ko radiation of copper having an X- ray wavelength of 1 .5406 A at room temperature.
In an embodiment, the crystal form K2 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 5.5, 6.3, 7.0, 7.8, 11.8, 12.7, 13.7, 16.8, 18.0, and 27.6 ±0.2 degrees 2Theta.
In an embodiment, the crystal form K2 of daprodustat is characterized by an XRPD pattern which matches the pattern exhibited in FIG. 7. In an embodiment, the crystal form K2 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form K2 of daprodustat pattern provided in Table 3.
Table 3
In certain embodiments, the crystal form K2 of daprodustat is characterized by thermal analysis. A representative DSC plot for the crystal form K2 is shown in FIG. 8. In certain embodiments, the crystal form K2 is characterized by a DSC plot comprising a first endothermic event with an onset temperature at about 33°C. In certain embodiments, the crystal form K2 is characterized by a DSC plot further comprising a second endothermic event with an onset temperature at about 248°C.
A representative TGA plot for the crystal form K2 of daprodustat is also shown in FIG. 8. In certain embodiments, the crystal form K2 of daprodustat is characterized by a TGA plot comprising a mass loss of about 5.4%, of the total mass of the sample upon heating from about 30°C to about 130°C. In certain embodiments, the crystal form K2 of daprodustat contains water or other solvent in the crystal lattice. In certain embodiments, the crystal form K2 of daprodustat contains water in the crystal lattice. In certain embodiments, the crystal form K2 of daprodustat contains water in an amount from 0.2% to 10%, preferably from 2% to 8%, more preferably from 4% to 6% by weight with respect to the total weight of the crystal. In certain embodiments, the crystal form K2 of daprodustat is a hydrate. In certain embodiments, the crystal form K2 of daprodustat is a hydrate which contains an amount of water of about 5.4% as measured by TGA analysis.
In certain embodiments, the XRPD pattern of the crystal form K2 of daprodustat is substantially unchanged following the adsorption/desorption analysis. In certain embodiments, the crystal form K2 is stable with respect to humidity.
In certain embodiments, the crystal form K2 of daprodustat is characterized by proton nuclear magnetic resonance (1H-NMR) as shown in FIG. 9. In certain embodiments, the crystal form K2 of daprodustat is characterized by having a proton NMR spectrum with signals 5 (ppm) at 10.08, 4.65, 3.93, 2.30, 1.77, 1.57, and 1.20. In certain embodiments, the crystal form K2 of daprodustat is characterized by having a proton NMR spectrum with signals at: 1.20 ppm (m, 6H), 1.57 ppm (m, 6H), 1.77 ppm (m, 4H), 2.30 ppm (m, 4H), 3.93 ppm (d, 2H, J=6 Hz), 4.65 ppm (m, 2H), and 10.08 ppm (t, 1 H, J=6 Hz).
In certain embodiments, the crystal form K2 of daprodustat is characterized by an infrared absorption spectrum (FTIR) which has a spectrum shown in FIG. 10, and has peaks at the following wavenumbers (cm 1): 693, 740, 762, 790, 882, 894, 918, 996, 1054, 1134, 1187, 1235, 1258, 1302, 1340, 1378, 1446, 1472, 1506, 1522, 1589, 1669, 2655, 2852, 2935, 2977, 3180, 3477, and 3546. Although the wavenumbers (cm 1) may contain an error of ±0.5% according to the measuring apparatus, measurement conditions, etc., such a level of error is within an acceptable range in the present invention.
In certain embodiments, the molar ratio of daprodustat free acid to daprodustat potassium salt in the crystal form K2 is of from 1 :3 to 3: 1 , preferably from 1 :2 to 2: 1 , more preferably is 1 : 1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K2 is about 2: 1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K2 is about 1 :1.
In certain embodiments, the crystal form K2 of daprodustat is characterized by its stability profile. In certain embodiments, the crystal form K2 of daprodustat material is stable, e.g., its XRPD pattern remains substantially unchanged, upon exposure to elevated temperature, upon exposure to elevated humidity, upon exposure to one or more solvents, and/or upon grinding or milling and compression.
In certain embodiments, the crystal form K2 of daprodustat keeps its form unchanged in a dry environment at room temperature, at 45°C and at 60°C for at least one month. In certain embodiments, the crystal form K2 of daprodustat keeps its form unchanged under accelerated conditions at 40°C and 75% RH (Relative Humidity) for at least one month or for at least two months.
In certain embodiments, the crystal form K2 of daprodustat keeps its form unchanged in a dry environment under vacuum at 45°C and at 60°C least 12 hours (i.e., overnight).
In certain embodiments, the crystal form K2 of daprodustat keeps its form unchanged upon slurry in water at room temperature for at least one hour. In other words, the crystal form K2 of daprodustat does not undergo dissociation (i.e., phase separation into their individual constituents) in the presence of water.
In certain embodiments, a sample of the crystal form N2 of daprodustat comprises particles having needles (acicular) morphology. In certain embodiments, a sample of the crystal form N2 of daprodustat comprises acicular crystals as shown in FIG. 11. In certain embodiments, the particles of the crystal form N2 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns. In certain embodiments, the particles of the crystal form N2 of daprodustat have a size between 100 to 5 microns, between 80 to 5 microns, between 60 to 5 microns, between 40 to 5 microns or between 30 to 5 microns. In certain embodiments, the particles of the crystal form N2 of daprodustat comprises acicular crystals having a size as shown in FIG. 13.
In certain embodiments, a sample of the crystal form N4 of daprodustat comprises particles having needles (acicular) morphology. In certain embodiments, the particles of the crystal form N4 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns. In certain embodiments, the particles of the crystal form N4 of daprodustat have a size between 100 to 5 microns, between 80 to 5 microns, between 60 to 5 microns, between 40 to 5 microns, or between 30 to 5 microns.
In certain embodiments, a sample of the crystal form K2 of daprodustat comprises particles having needles (acicular) morphology. In certain embodiments, a sample of the crystal form K2 of daprodustat comprises acicular crystals as shown in FIG. 12. In certain embodiments, the particles of the crystal form K2 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns. In certain embodiments, the particles of the crystal form N2 of daprodustat have a size between 120 to 10 microns, between 90 to 10 microns, between 60 to 10 microns, or between 30 to 10 microns. In certain embodiments, the particles of the crystal form K2 of daprodustat comprises acicular crystals having a size as shown in FIG. 14.
In an embodiment, the invention relates to a crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and daprodustat potassium salt referred as form K1 , which has an X-ray powder diffraction (XRPD) pattern comprising peaks at 2theta values of 5.4°±0.2°, 7.9°±0.2°, 14.6°±0.2°,
15.6°±0.2° and 17.5°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
In an embodiment, the crystal form K1 of daprodustat further comprises peaks at 2theta values of 10.2°±0.2°, 11.3°±0.2°, 12.1 °±0.2°, 15.8°±0.2° and 16.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
In an embodiment, the crystal form K1 of daprodustat is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine or ten of the following approximate positions: 5.4, 7.9, 10.2, 11.3, 12.1 , 14.6, 15.6, 15.8, 16.2, and 17.5 ±0.2 degrees 2Theta.
In an embodiment, the crystal form K1 of daprodustat is characterized by an XRPD pattern which matches the pattern exhibited in FIG. 15. In an embodiment, the crystal form K1 of daprodustat is characterized by an XRPD pattern having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24 or 25 peaks matching peaks in the representative crystal form K1 of daprodustat pattern provided in Table 4.
In certain embodiments, the crystal form K1 of daprodustat is characterized by thermal analysis. A representative DSC plot for the crystal form K1 is shown in FIG. 16. In certain embodiments, the crystal form K1 is characterized by a DSC plot comprising a first endothermic event with an onset temperature at about 56°C. In certain embodiments, the crystal form K1 is characterized by a DSC plot further comprising an
exothermic event with an onset temperature at about 202°C. In certain embodiments, the crystal form K1 is characterized by a DSC plot further comprising two overlapped endothermic events with onset temperatures at about 251 °C and about 254°C, respectively.
A representative TGA plot for the crystal form K1 of daprodustat is also shown in FIG. 16. In certain embodiments, the crystal form K1 of daprodustat is characterized by a TGA plot comprising a mass loss of about 13.2%, of the total mass of the sample upon heating from about 40°C to about 130°C. In certain embodiments, the crystal form K1 of daprodustat contains water or other solvent in the crystal lattice. In certain embodiments, the crystal form K1 of daprodustat contains water in the crystal lattice. In certain embodiments, the crystal form K1 of daprodustat is a hydrate. In certain embodiments, the crystal form K1 of daprodustat is a hydrate which contains an amount of water between 10% and 14% as measured by TGA analysis.
In certain embodiments, the molar ratio of daprodustat free acid to daprodustat potassium salt in the crystal form KI is of from 1 :3 to 3:1 , preferably from 1 :2 to 2:1, more preferably is about 1 :1. In certain embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K1 is about 2:1. In preferred embodiments, the molar ratio of daprodustat free acid and daprodustat potassium salt in the crystal form K1 is about 1 :1.
In certain embodiments, a sample of the crystal form K1 of daprodustat comprises particles having needles (acicular) morphology. In certain embodiments, the particles of the crystal form K1 of daprodustat have a size of less than about 300 microns, less than about 250 microns, less than about 200 microns, less than about 150 microns, less than about 100 microns, less than about 50 microns, less than about 25 microns or less than about 10 microns. In certain embodiments, the particles of the crystal form K1 of daprodustat have a size between 120 to 10 microns, between 90 to 10 microns, between 60 to 10 microns, or between 30 to 10 microns.
The invention further encompasses the crystal form N2, the crystal form N4, the crystal form K2 and the crystal form K1 of daprodustat in pure form or when admixed with other materials, for example, other polymorphs, solvates or remaining reaction solvents or side products. Particularly, the invention also refers to mixtures comprising crystal form of N2 with crystal form N4 thereof. Particularly, the invention also refers to mixtures of crystal form of K2 with crystal form K1 thereof.
According to the second aspect, the invention provides a process for the preparation of crystal forms of daprodustat as defined above, comprising the following steps: a) providing daprodustat free acid in a solvent or a mixture of solvents,
b) optionally, heating the mixture of step (a) at a suitable temperature, preferably from 70°C to 100°C, more preferably from 75°C to 95°C, c) adding a source of a pharmaceutically acceptable metal inorganic base, preferably an alkali metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, more preferably in the form of an alkali metal hydroxide, in an amount of about 0.5 molar equivalents with respect to daprodustat free acid of step (a), d) optionally, cooling the solution resulting from step (c) to room temperature, and e) isolating the crystal form of daprodustat.
Daprodustat free acid used in (a) may be in solvate, hydrate, anhydrous, crystalline form, or non-crystalline form thereof. Preferably, daprodustat free acid is in crystalline form, even more preferably daprodustat free acid used in step (a) is in anhydrous form. Daprodustat solvate used in step (a) may be a diethyl ether solvate as prepared in Ex. 18 Method 1 of W02007/150011 A2.
In certain embodiments, daprodustat solvate is methyl tert-butyl ether solvate, dioxane solvate, tetrahydrofuran solvate, methanol solvate, ethanol solvate, isopropanol solvate, tert-butanol solvate, dimethylformamide (DMF) solvate or dimethylsulfoxide (DMSO) solvate, all prepared in Table 5 of example 1.
Suitable solvent used in step (a) may be selected from the group of (C6-Ci4)aromatic hydrocarbon solvents such as toluene, o-xylene, m-xylene, and p-xylene; halogenated (Ci-Ci2)hydrocarbon solvents such as 1 ,2- dichloroethane, dichloromethane, chloroform; (Ci-Ci2)ether solvents such as diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 ,4-dioxane; (Ci-Ci2)alcohol solvents such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1 -propanol, 1-butanol, 2-butanol, 1- pentanol, 3-methyl-1 -butanol, tert-butanol, 1 -octanol, benzylalcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol; nitrobenzene; N,N-dimethylformamide; N,N,- dimethylacetamide; N-methyl-2-pyrrolidone; or acetonitrile. In some embodiments, the solvent may be formed by the combination of two or more solvents. In certain embodiments, the solvent used in step (a) is selected from the group consisting of (Ci-Cejalcohol, acetonitrile, dichloromethane (DCM), toluene, tetrahydrofuran, and a combination thereof.
In certain embodiments, the solvent used in step (a) is a mixture of water and another solvent selected from the group consisting of (Ci-C6)alcohol, acetonitrile, dichloromethane (DCM), toluene, and tetrahydrofuran. In certain embodiments, the solvent of step (a) is mixture of a (Ci-Ce)alcohol or acetonitrile with water. In preferred embodiments, the solvent used in step (a) is a mixture of acetonitrile and water. In preferred
embodiments, the solvent used in step (a) is a mixture of acetonitrile and water in a ratio from 5: 1 (v/v) to 15:1 (v/v), preferably from 8: 1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v).
In certain embodiments, the pharmaceutically acceptable metal inorganic base, particularly a metal hydroxide, is an alkali metal inorganic base, selected from a sodium and a potassium inorganic base. In certain embodiments, the source of the pharmaceutically acceptable metal hydroxide of step (b) is in the form of an alkali metal hydroxide. In certain embodiments, the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide. In certain embodiments, the pharmaceutically acceptable metal inorganic base is sodium to provide the cocrystal of daprodustat and daprodustat sodium salt. In certain embodiments, the pharmaceutically acceptable metal inorganic base is potassium to provide the cocrystal of daprodustat and daprodustat potassium salt.
In certain embodiments, step (b) is carried out to provide a solution. In certain embodiments, step (d) is carried out to induce the crystallization of the crystal form. In certain embodiments, seeding with the desired crystal form of daprodustat is used to control the crystallization before step (d) is carried out. In a preferred embodiment, steps (b) and (d) are carried out. In a more preferred embodiment, steps (b) and (d) are carried out, and seeding with the desired crystal form of daprodustat is used before step (d) is carried out.
In one embodiment, in the process for the preparation of the crystal form of daprodustat according to the second aspect, daprodustat free acid of step (a) is prepared by the process as defined in the sixth aspect, or alternatively by the process as defined in any of the eighth aspect, or alternatively by the process as defined in the tenth aspect.
Alternatively, according to the third aspect, the preparation of crystal forms of daprodustat which are cocrystals comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt such as a sodium or a potassium salt, comprises the steps of:
I. providing an ester intermediate of formula (VI),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (Cs-C^heteroaryl, preferably R is ethyl, in a solvent or a mixture of solvents, ii. optionally, heating the mixture of step (i) at a suitable temperature, preferably from room temperature to 100°C, more preferably from 30°C to 75°C, iii. adding a source of a pharmaceutically acceptable metal inorganic base, preferably an alkali metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide-salt, , more preferably in the form of an alkali metal hydroxide, in an amount from 1.0 to 1.2, or alternatively from 1.0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat alkali metal of formula (la),
wherein M is an alkali metal such as sodium or potassium, iv. adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
In an embodiment in the above process, step (iii) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (I); and step (iv) comprises adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii).
Advantageously, the process for the preparation of crystal forms of daprodustat as defined herein starting from ester intermediate of formula (VI), wherein R is as defined above, is reproducible and does not generate an excess of inorganic impurities difficult to remove from final product.
Ester intermediate used in step (i) as starting material may be prepared as described in W02007/150011 A2, particularly compound VI wherein R is ethyl, i.e. N-[(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 , 2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine as prepared in Example 18.
Suitable solvent used in step (i) may be selected from the group of water, (Ci-Ci2)alcohol solvents such as methanol, ethanol, isopropanol, 1-propanol, 2-methyl- 1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3- methyl-1 -butanol, tert-butanol, 1 -octanol, benzylalcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol; (Ci-Ci2)ether solvents such as diethyl ether, tert-butyldimethyl ether, tetrahydrofuran and dioxane; nitrobenzene; N,N-dimethylformamide; N,N, -dimethylacetamide; N-methyl-2- pyrrolidone; and acetonitrile. In certain embodiments, the solvent may be formed by the combination of two or more solvents. In certain embodiments, the solvent used in step (i) is a (Ci-Ci2)alcohol or acetonitrile. In certain embodiments, the solvent of step (i) is methanol, ethanol, isopropanol, 1-propanol or acetonitrile.
In certain embodiments, the solvent of step (i) is a mixture of a (Ci-Ci2)alcohol or acetonitrile with water. In certain embodiments, the (Ci-Ci2)alcohol is selected from methanol, ethanol, isopropanol and 1-propanol. In certain embodiments, the solvent used in step (i) is a mixture of ethanol or acetonitrile with water. In certain embodiments, the solvent used in step (i) is a mixture of ethanol or acetonitrile with water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9: 1 (v/v).
In certain embodiments, the pharmaceutically acceptable metal salt of step (iii) is an alkali metal salt selected from a sodium and a potassium salt. In certain embodiments, the source of the pharmaceutically acceptable metal inorganic base, particularly a metal hydroxide, of step (iii) is in the form of an alkali metal hydroxide. In certain embodiments, the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide. In an embodiment, metal hydroxide of step (iii) is added as an aqueous solution. In certain embodiments, the pharmaceutically acceptable metal salt of step (iii) is sodium to provide the cocrystal of daprodustat free acid and daprodustat sodium salt. In certain embodiments, the pharmaceutically acceptable metal salt of step (iii) is potassium to provide the cocrystal of daprodustat free acid and daprodustat potassium salt.
In certain embodiments, the step (iii) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (I) by evaporation or distillation, and (iii.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
In certain embodiments, in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (iii.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M is an alkali metal such as sodium or potassium.
Suitable acid used in step (iv) is an inorganic or an organic acid. Suitable acids are those which have a pKa (relative to water) below 5, preferably below 3, more preferably below 1. Preferably, the acid has a pKa (relative to water) from -10 to 5, preferably from -10 to 3, more preferably from -10 to 1 . Examples of suitable acids include but are not limited to hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, dichloroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid. Preferably, the acid used in step (iv) is a hydracid such as hydrochloric, hydrobromic or hydroiodic acid, which may be present either as gas or as an aqueous solution or generated in situ, for example from an alkylsilyl halogenide in the presence of a protic solvent. More preferably, the acid used in step (iv) is hydrochloric acid in aqueous solution.
In certain embodiments, step (ii) is carried out to provide a solution. In certain embodiments, step (v) is carried out to induce the crystallization of the crystal form. In certain embodiments, seeding with the desired crystal form of daprodustat is used to control the crystallization before step (v) is carried out. In certain embodiments, seeding with the desired crystal form of daprodustat is carried out before or during step (iv). In certain embodiments, seeding with the desired crystal form of daprodustat is carried out as many times as necessary to control the desired crystal form of daprodustat. In a preferred embodiment, steps (ii) and (v) are carried out. In a more preferred embodiment, steps (ii) and (v) are carried out, and seeding with the desired crystal form of daprodustat is used before step (v) is carried out. In a preferred embodiment, steps (ii) and (v) are carried out, and seeding with the desired crystal form of daprodustat is used before step (v), or before or during step (iv) are carried out. In certain embodiments, hot filtration of the resulting mixture of step (iii) may be carried out to remove any insoluble material.
In certain embodiments, the present invention refers to the potassium salt of daprodustat of formula (la) wherein M is potassium. In certain embodiments, the potassium salt of daprodustat of formula (la) wherein M is potassium is in solvate, hydrate, crystalline form, or non-crystalline form thereof.
In one embodiment, in the process for the preparation of the crystal form of daprodustat according to the third aspect, wherein the ester intermediate of formula (VI) is prepared by the process as defined in the ninth aspect.
In certain embodiments, the preparation of crystal form N2 of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat sodium salt, comprises the steps of: i. providing an ester intermediate of formula (VI),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (Cs-C^heteroaryl, preferably R is ethyl, in a solvent or a mixture of solvents, ii. optionally, heating the mixture of step (i) at a suitable temperature, preferably from room temperature to 100°C, more preferably from 30°C to 75°C, iii. adding a source of an alkali metal which is sodium, preferably in the form of an alkali metal hydroxide which is sodium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat sodium salt, iv. adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
In an embodiment in the above process, step (iii) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (i); and step (iv) comprises adding an acid, preferably a hydracid
such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii).
In certain embodiments, steps (ii) and (v) as defined above are carried out. In certain embodiments, seeding with crystal form N2 of daprodustat is used to control the crystallization before step (v) is carried out.
In certain embodiments, the step (iii) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (i) by evaporation or distillation, and (iii.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
In certain embodiments, in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (iii.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M is sodium.
In certain embodiments, the preparation of crystal form K2 of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat potassium salt, comprises the steps of: i. providing an ester intermediate of formula (VI),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (Cs-C^heteroaryl, preferably R is ethyl, in a solvent or a mixture of solvents, ii. optionally, heating the mixture of step (i) at a suitable temperature, preferably from room temperature to 100°C, more preferably from 30°C to 75°C, iii. adding a source of an alkali metal which is potassium, preferably in the form of an alkali metal hydroxide which is potassium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat potassium salt,
iv. adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1.7 molar equivalents to the mixture of step (ill), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
In an embodiment in the above process, step (ill) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (I); and step (iv) comprises adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (ill).
In certain embodiments, steps (II) and (v) as defined above are carried out. In certain embodiments, seeding with crystal form K2 of daprodustat is used to control the crystallization before step (v) is carried out.
In certain embodiments, the step (ill) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (I) by evaporation or distillation, and (ill.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
In certain embodiments, in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (ill.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M potassium.
It also forms part of the invention, a process for the preparation of crystal form K1 of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat potassium salt, the process comprising the steps of:
I. providing an ester intermediate of formula (VI),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (Cs-C^heteroaryl, preferably R is ethyl, in a solvent or a mixture of solvents ii. optionally, heating the mixture of step (i) at a suitable temperature, preferably from room temperature to 100°C, more preferably from 30°C to 75°C, iii. adding a source of an alkali metal which is potassium, preferably in the form of an alkali metal hydroxide which is potassium hydroxide, in an amount from 1 .0 to 1 .2, or alternatively from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat potassium salt, iv. adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 0.7, or alternatively from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
In an embodiment in the above process, step (iii) comprises adding a source of a pharmaceutically acceptable metal inorganic base, particularly a pharmaceutically acceptable metal hydroxide, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of formula (VI), wherein R is as defined above, of step (I); and step (iv) comprises adding an acid, preferably a hydracid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, more preferably hydrochloric acid, in an amount from 0.5 to 1 .7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii).
In certain embodiments, steps (ii) and (v) as defined above are carried out. In certain embodiments, seeding with crystal form K1 of daprodustat is used to control the crystallization before step (v) is carried out.
In certain embodiments, the step (iii) further comprises the substeps of: (iii.1) removing completely or partially the solvent or mixture of solvents of step (I) by evaporation or distillation, and (iii.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
In certain embodiments, in substep (iii.1) the solvent is a (Ci-Ci2)alcohol and is removed partially or completely by evaporation or distillation, and in substep (iii.2) the solvent is a mixture of acetonitrile and water in a ratio from 5:1 (v/v) to 15:1 (v/v), preferably from 8:1 (v/v) to 12:1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v) to provide a solution or a suspension of the corresponding daprodustat alkali metal of formula (la), wherein M potassium.
It also forms part of the invention, a process for the preparation of a crystal form N4 of daprodustat which comprises drying the crystal form N2 of daprodustat under vacuum and isolating the crystal form N4 of daprodustat. In certain embodiments, the process for the preparation of a crystal form N4 comprises drying the crystal form N2 of daprodustat under vacuum (about 12 mbar) at a temperature from room temperature to 75°C, preferably from 45°C to 60°C, for at least 6 hours, preferably for at least 12 hours, and isolating the crystal form N4 of daprodustat. In certain embodiments, the process for the preparation of a crystal form N4 comprises drying the crystal form N2 of daprodustat under vacuum (about 12 mbar) at a temperature from 45°C to 60°C for at least 6 hours, preferably for at least 12 hours, and isolating the crystal form N4 of daprodustat.
The above processes may further provide the crystal form N2, the crystal form N4, the crystal form K2 and the crystal form K1 of daprodustat in pure form or when admixed with other materials, for example, other polymorphs, solvates or remaining reaction solvents or side products. Particularly, the above processes may provide mixtures comprising crystal form of N2 with crystal form N4 thereof. Particularly, the above processes may provide mixtures of crystal form of K2 with crystal form K1 thereof.
According to the fourth aspect of the invention, the pharmaceutical compositions comprising crystal forms of daprodustat selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 , and a combination thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients may further contain disintegrants, glidants, lubricants, binders, colorants, and combinations thereof. In an embodiment, the pharmaceutical compositions comprising crystal forms of daprodustat selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 may be tablets, dispersible tablets or granules suitable for oral use.
According to the fifth aspect, the crystal forms of daprodustat selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, a crystal form K1 , and a combination thereof may be particularly
indicated for the treatment of symptomatic anaemia associated with chronic kidney disease (CKD), in adults on chronic maintenance dialysis or in adults not in dialysis.
As mentioned above a sixth aspect of the present invention relates to a process for preparing daprodustat of formula (I), or a salt thereof which comprises hydrolysing a compound of formula (VI) in the presence of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and a solvent, and optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
In an embodiment, the amount of the quaternary ammonium hydroxide, preferably tetramethylammonium hydroxide (TMAH), is in a molar ratio from 1 : 1 to 4: 1 of base to compound of formula (VI), preferably from 2:1 to 3: 1 of base to compound of formula (VI).
In an embodiment, suitable solvents of the sixth aspect are selected from the group consisting of a (Ci- Cajalcohols, preferably methanol, ethanol or isopropanol; water; and mixtures thereof.
In an embodiment, the solvent is a mixture of a (Ci-C3)alcohols, preferably methanol, ethanol or isopropanol, and water in a volume ratio from 10: 1 to 1 :2, preferably from 5:1 to 1 :2, even more preferably from 10: 1 to 5:1.
In an embodiment of the sixth aspect after the hydrolysis reaction has been finished an acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic acid (TFA), preferably trifluoroacetic acid (TFA), is added.
In an embodiment, the amount of acid, preferably trifluoroacetic acid (TFA), is in a molar ratio from 1 : 1 to 4:1 of acid to compound of formula (VI), preferably from 2:1 to 3: 1 of base to compound of formula (VI).
In an embodiment, daprodustat is further purified by slurrying or crystallizing it in an organic solvent selected from alcohols, preferably (Ci-C3)alcohols, more preferably methanol, ethanol or isopropanol, more preferably in ethanol, or an acid solvent such as acetic acid. In an embodiment, daprodustat is purified by crystallization in acetic acid.
In an embodiment of the sixth aspect, the compound (VI) is obtained by reacting a compound of formula (V) with an isocyanatoacetate of formula (IV), in the presence of a base and a solvent, wherein the compound of formula (V) is preferably obtained according to the process of the seventh aspect.
In an embodiment of the sixth aspect, the compound (VI) is obtained from a compound of formula (II), preferably according to the process of the fourth aspect.
In an embodiment of the sixth aspect, the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the second aspect of the invention.
The seventh aspect of the invention provides a process for preparing key intermediate 1 ,3-dicyclohexyl barbituric acid of formula (V), which comprises the steps of:
(i) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(ii) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(iii) optionally, heating the mixture of step (ii) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V).
In an embodiment of the seventh aspect, the compound (V) is further converted into daprodustat by reacting it with an isocyanatoacetate of formula (IV), in the presence of a base and a solvent to provide the compound of formula (VI); and hydrolyzing compound of formula (VI) in the presence of a base and a solvent, preferably according to the process of the sixth aspect, or alternatively using NaOH or KOH instead of a quaternary ammonium hydroxide, followed by neutralization with an acid such as hydrochloric acid.
In an embodiment of the seventh aspect of the invention, the amount of malonic acid in step (i) to dicyclohexylurea (DCU) is in a molar ratio from 2:1 to 1 :1 , preferably from 1.5:1 to 1.1 :1.
In an embodiment, the amount of AC2O used in step (i) to dicyclohexylurea (DCU) is in a molar ratio from 4:1 to 2: 1 , preferably from 3: 1 to 2:1.
In an embodiment, the mixture of step (i) is heated at a temperature from 70°C to 95°C, preferably from 85°C to 90°C.
In an embodiment, the amount of antisolvent, preferably water, of step (ii) is from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V).
In an embodiment, the mixture of compound of formula (V) and the antisolvent, preferably water, of step (ii) is heated at a temperature from 20°C to 85°C, preferably from 20°C to 30°C as the yield increases.
In an embodiment, compound of formula (V) is further purified by crystallization or slurrying it in an organic solvent selected from (Ci-C3)alcohols, preferably methanol, ethanol or isopropanol, more preferably in isopropanol.
In an embodiment of the eighth aspect, the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the second aspect of the invention.
A ninth aspect of the present invention provides a process for preparing a compound of formula (VI), wherein R is (Ci-Cio)alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (Cs-C^heteroaryl, preferably R is ethyl, which comprises the steps of: a) converting a formamide of formula (II), into a compound an isocyanoacetate of formula (III), wherein R is as defined above, preferably R is ethyl; b) converting the isocyanoacetate of formula (III) of step (a) into an isocyanatoacetate of formula (IV), wherein R is as defined above, preferably R is ethyl; c) reacting the isocyanatoacetate of formula (IV) obtained in step (b) with a 1 ,3-dicyclohexyl barbituric acid of formula (V), in the presence of a base and a solvent to provide the compound of formula (VI); wherein steps (b) and (c) are carried out in a consecutive manner.
In an embodiment, the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of trimethyl orthoformate or triethyl orthoformate. In an embodiment, the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of methyl formate or ethyl formate and a base, preferably an organic base such as TEA. In an embodiment, the formamide of formula (II) is alternatively prepared from glycine ethyl ester in the presence of methyl formate. In an embodiment, the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of ethyl formate and a base, preferably an organic base such as TEA.
In an embodiment, the reaction mixture may be heated at a temperature from 20°C to 85°C, preferably from 35°C to 85°C, more preferably from 45°C to 85°C, for the time sufficient to complete the reaction (e.g., from 4 to 48 h).
In an embodiment, the organic salt (e.g., triethylamine hydrochlrohide) formed in the preparation of formamide of formula (II) when using methyl formate or ethyl formate and a base, preferably an organic
base such as TEA, may be removed by adding an organic solvent, preferably from (C6-Ci4)aromatic hydrocarbon solvent such as toluene. In an embodiment, the formamide of formula (II) is purified by fractioned distillation. In an embodiment, the formamide of formula (II) is used in the next step without further purification.
In an embodiment of the ninth aspect, step (a) is carried out in the presence of a dehydrating agent and a base. Examples of dehydrating agent include but are not limited to phosgene, phosphorus oxychloride (POCh), p-toluensulfonic chloride, triphenylphosphine (PPh3)/iodine (I2), Burgess reagent, Appel reagent, or trifluoromethyl sulfonic acid anhydride. Preferably, the dehydrating agent is POCI3. Suitable base may be an organic base selected from ammonia derivatives, such as diethylamine, triethylamine (TEA), N,N- dicyclohexylmethylamine, N,N-dicyclohexylamine, and N, N-diisopropylethylamine (DIPEA), and heterocyclic bases such as pyridine, and diazabicycloundecene (DBU), and mixtures thereof. Preferably, the base is TEA and DIPEA.
In an embodiment, the isocyanoacetate of formula (III) is used in the next step (b) without further purification.
In an embodiment, step (b) is carried out in the presence of dimethylsulfoxide (DMSO) and trifluoroacetic anhydride (TFAA). Alternatively, step (b) is carried out using mercuric oxide, lead tetraacetate, ozone, halogen- or acid-catalyzed oxidations by dimethyl sulfoxide (DMSO) and pyridine N-oxide.
In an embodiment, the temperature used in step (b) is from -20°C to -40°C, preferably about -30°C.
In an embodiment, for the preparation of compound (IV) a solution of DMSO in a solvent is added to a solution of compound (III) and trifluoroacetic anhydride in a solvent.
In an embodiment, in step (c) the amount of the isocyanatoacetate of formula (IV), preferably wherein R is ethyl, to compound of formula (V) is in a molar ratio from 1 :1 to 2:1 , preferably from 1 :1 to 1.5: 1 , more preferably from 1 :1 to 1.2:1.
In an embodiment, step (c) is carried out in the presence of a base and a solvent to provide the compound of formula (VI). A suitable base may be an organic base including ammonia derivatives, such as diethylamine, triethylamine (TEA), N,N-dicyclohexyl-methylamine, N,N-dicyclohexylamine, and N,N- diisopropylethylamine (DIPEA), and heterocyclic bases such as pyridine, diazabicycloundecene (DBU) and mixtures thereof. Preferably, the base used in step (c) is an organic base selected from TEA or DIPEA. In an embodiment, the amount of base may be from 1 .0 to 3.0, preferably from 1 .1 to 2.5, more preferably from 1 .1 to 1 .5 molar equivalents with respect to compound of formula (V).
A suitable solvent for steps (a), (b) and (c) may be an aprotic organic solvent. In an embodiment, the aprotic solvent may be selected from halogenated hydrocarbon solvents (e.g., 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), aromatic hydrocarbon solvents (e.g., toluene, o-xylene, m-xylene, and p-xylene), and ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.). Preferably, the solvent is dichloromethane, toluene or tetrahydrofuran.
In an embodiment, the 1 ,3-dicyclohexyl barbituric acid of formula (V) is added to the isocyanatoacetate of formula (IV). In an embodiment, compound of formula (V) is added in solid form or dissolved in solution or suspended in an aprotic solvent with or without the presence of a base. In an embodiment, a solution of isocyanatoacetate of formula (IV) in solution of an aprotic solvent is added to a solution or a suspension of compound of formula (V) in an aprotic solvent. In a preferred embodiment, a solution of compound of formula (V) in an aprotic is added to a solution of isocyanatoacetate of formula (IV) in an aprotic solvent. The aprotic solvent is as defined above for step (c). Preferably, the aprotic solvent is dichloromethane, toluene or tetrahydrofuran.
In an embodiment, for the preparation of compound (VI), compound (V) is added in solution of an aprotic solvent, preferably DCM, with or without base. Additionally, the reaction medium of compound (IV) is added into another vessel containing compound (V), with or without base and with or without an aprotic solvent.
In an embodiment of the ninth aspect, the compound (VI) is further converted into daprodustat by hydrolysis in the presence of a base and a solvent, preferably according to the process of the sixth aspect, or alternatively using NaOH or KOH, instead of a quaternary ammonium hydroxide, followed by neutralization with an acid such as hydrochloric acid.
In an embodiment of the ninth aspect, the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the third aspect of the invention.
In an embodiment, the invention relates to a process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof,
which comprises:
1) converting a formamide of formula (II),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5- Ci2)heteroaryl, preferably R is ethyl; into a compound an isocyanoacetate of formula (III),
wherein R is as defined above, preferably R is ethyl;
2) converting the isocyanoacetate of formula (III) of step (1) into an isocyanatoacetate of formula (IV), wherein R is as defined above, preferably R is ethyl;
3) preparing 1 ,3-dicyclohexyl barbituric acid of formula (V),
by a process which comprises the steps of:
(i) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(ii) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V);
4) reacting the isocyanatoacetate of formula (IV) obtained in step (2) with the 1 ,3-dicyclohexyl barbituric acid of formula (V) obtained in step (3), in the presence of a base and a solvent to provide the compound of formula (VI)
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, heterocycloalkyl, aryl and heteroaryl, particularly, selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl; wherein steps (2) and (4) are carried out in a consecutive manner;
5) converting a compound of formula (VI) into daprodustat of formula (I) by hydrolysis in the presence of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and a solvent, and optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
In an embodiment, after the hydrolysis reaction of step (5) has been finished an acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic acid (TFA), preferably trifluoroacetic acid (TFA) is added.
In an embodiment, daprodustat is further purified by slurrying in an organic solvent selected from alcohols, preferably (Ci-C3)alcohols, more preferably methanol, ethanol or isopropanol, more preferably in ethanol. In
another embodiment, daprodustat is further purified by crystallizing it in an acid solvent, preferably acetic acid.
In an embodiment of the tenth aspect, the process further comprises the preparation of a crystal form of daprodustat as defined above by the process as defined in the second aspect of the invention.
In the following, the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. Unless indicated otherwise, all indications of percentage are by weight and temperatures are in degrees Celsius.
EXAMPLES
GENERAL METHODS
X-Ray Powder Diffraction (XRPD)
Sample preparation: Approximately 20 mg of non-manipulated sample were prepared in standard sample holders using two foils of polyacetate.
Data acquisition: Powder diffraction pattern was acquired on a Bruker D8 Advance Series 2Theta/Theta powder diffraction system using CuKo 1 -radiation in transmission geometry. The system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and a radial seller. Programs used: Data collection with DIFFRAC plus XRD Commander V.2.5.1 , and evaluation with HighScore Plus V.4.9.
Measurement conditions: The samples were measured at room temperature in a range from 4° to 40° in 20 in a 0.5 hours measurement using an angular step of 0.049° and a time per step of 2787 s.
The skilled person can appreciate that powder X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. It is generally known that intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed and the relative intensity values can e.g., vary by ±30%. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about ± 0.2 degrees 2Theta, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the present invention are not limited to the crystalline forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying figures.
Differential Scanning Calorimetry (DSC)
Sample preparation: Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 pL aluminium crucibles with a pinhole lid.
Data acquisition: DSC analyses were recorded in a Mettler Toledo DSC822e calorimeter. Programs used: Data collection and evaluation with software STARe.
Measurement conditions: The samples were heated under dry nitrogen (flow rate: 50 mL/min) at 10 °C/min from 30 to 300 °C.
Thermal Gravimetric Analysis (TGA)
Sample preparation: Approximately 1-4 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 40 L aluminium crucibles with a pinhole lid.
Data acquisition: Thermogravimetric analyses were recorded in a Mettler Toledo TGA/DSC 3+ with a balance XP1 type. Programs used: Data collection and evaluation with software STARe.
Measurement conditions: The samples were heated under dry nitrogen (flow rate: 10 mL/min) at 10 °C/min from 30 to 300 °C.
Proton nuclear magnetic resonance (1H-NMR)
Sample preparation: Approximately 2-5 mg of sample were dissolved in 0.7 mL of deuterated solvent (dimethylsulfoxide-d6).
Data acquisition: Proton nuclear magnetic resonance analyses were recorded in a Bruker 300 NMR spectrometer, equipped with a z gradient 5 mm BBC (Broadband Observe) probe with ATM and an automatic autosampler.
Measurement conditions: The samples were analyzed at room temperature.
Fourier Transformed Infrared spectroscopy analysis (FTIR)
The FTIR spectra were recorded using an Agilent Technologies Cary 630 FTIR spectrometer, equipped with an Agilent Diamond single reflection ATR system, a mid-infrared source as the excitation source and a DTGS detector. The spectra were acquired in 32 scans at a resolution of 4 cm 1 in the range of 4000- 650 cm’1.
Dynamic Vapor Sorption Analysis (DVS)
Sample preparation: Approximately 5-10 mg of sample were weighed (using a MX5 Mettler Toledo microbalance) into 150 pL platinum crucibles without lid.
Data acquisition: The experiments were performed in a Mettler Toledo TGA I DSC 1 LF instrument equipped with a LF SDTA FRS2 sensor and coupled with a Modular Humidity Generator MHG 32. Data collection and evaluation was done with STARe software.
Measurement conditions: The samples were analysed following a humidity cycle from 5%RH up to 90%RH and down to 5%RH in 10% steps of 60 minutes at 25°C (RH: Relative Humidity).
Optical Microscopy
Sample preparation: Crystals of the sample were immersed in perfluorinated oil.
Equipment description: Zeiss Stemi SV 11 stereomicroscope has a variable amplification in the range between 15x and 154x and is equipped with cross coupled polarization filters (Carl Zeiss Pol 45517 and 455174) and a I/2 filter (Carl Zeiss Lambda 455172). For sample illumination, a transmission cold light source Zeiss KL2500 LCD is used. The size of the crystals can be measured using a standard microscale (5+100/100 mm, Carl Zeiss 474026).
Environmental Scanning Electron Microscopy (ESEM)
Sample preparation: The samples were mounted on an aluminium stub using a double adhesive carbon conductive tab.
Equipment: Environmental Scanning Electron Microscopy from FEI company, model Quanta 600 with attached EDX (Energy Dispersive X-ray Spectroscopy) from Oxford Instruments. For the samples morphology images secondary electrons were collected. The working conditions are: Working Distance (WD) = 9.9-10.3 mm; Accelerating Voltage (HV) = 20 kV; Magnification (Mag) = variable (1000x to 4000x).
Atomic absorption spectrometry (AAS)
Equipment: ICP-OES, Optima 8000 Perkin Elmer
Measurement conditions: wavelength for sodium: 589,592 nm; wavelength for potassium: 766,490 nm Sample preparation: 25 mg of a sample, 3 mL of concentrated HNO3 and 1 mL of H2O2 were digested in a digester ultraWAVE Milestone. The temperature was heated at 100°C in 5 min, at 170°C in 10 min, and finally at 240°C in 10 min. The sample was kept at this final temperature for 15 min. Then, the sample was diluted in 25 mL of an aqueous solution of 2% of HNO3 followed by a second dilution of 1 mL in 20 mL of an aqueous solution of 2% of HNO3.
Example 1 : Synthesis of daprodustat solvates
Various daprodustat solvates (Form A, Form B, Form C, Form D, Form E, Form F, Form G and Form H) were prepared as shown in Table 5. All solids obtained herein were crystalline solvates of daprodustat as characterized by XRPD and DSC/TGA analysis.
V: Volume
General methods:
Evaporation: A sample of daprodustat obtained by reproducing the Method 2 of W02007/150011 A2 (50 mg) was dissolved in the minimum quantity of solvent and evaporated at ambient conditions until a solid was obtained.
Cooling crystallization: A sample of daprodustat obtained by reproducing the Method 2 of WC2007/150011 A2 (50 mg) was dissolved in the minimum quantity of solvent at 75°C in a solvent and the obtained solution was slowly cooled down to room temperature or 4°C to induce crystallization.
Slurry: A sample of daprodustat obtained by reproducing the Method 2 of WC2007/150011 A2 (50 mg) was suspended in a solvent at 75°C, and the obtained suspension was stirred at this temperature for 2 hours and cooled down to room temperature.
Example 2: Synthesis of cocrystal of daprodustat sodium salt and daprodustat free acid
A sample of daprodustat obtained by reproducing the Method 2 of W02007/150011 A2 (1 g, 2.54 mmol) was suspended in a mixture of acetonitrile and water (9:1 respectively, 55 mL) at 95°C. To the resulting solution, an aqueous solution of sodium hydroxide (1 M, 0.5 equiv., 1.28 mL) was added dropwise, and the obtained suspension was left to cool down to room temperature. The resulting solid was filtered off, dried under vacuum (2 mbar, 40°C, 3 hours).
XRPD (FIG. 1): Crystalline.
DSC (FIG. 2): Endothermic peaks with onset temperatures at 115°C (-63 J/g), 190°C (-11 J/g), 202°C (-2 J/g) and 228°C (-39 J/g).
TGA (FIG. 2): Weight loss of 4.4% between 33 and 150°C (probable loss of water; 2 theoretical equivalents: 4.3%). Decomposition starting at about 230°C.
1H-NMR (300 MHz, DMSO, FIG. 3): 5 (ppm): 10.13 (t, 1 H, J=6 Hz), 4.66 (m, 2H), 3.96 (d, 2H, J=6 Hz), 2.31 (m, 4H), 1.77 (m, 4H), 1.57 (m, 6H), 1.20 (m, 6H). No residual solvents detected.
FTIR: v (cm 1, FIG. 4): 691 , 761 , 789, 840, 895, 924, 966, 1000, 1024, 1057, 1132, 1178, 1237, 1266, 1306, 1338, 1379, 1420, 1444, 1479, 1522, 1586, 1670, 1716, 2849, 2914, 2930, 2973, 3233, 3522, 3649.
DVS: Weight increase of about 0.4% between 10% and 80% Relative Humidity (slightly hygroscopic). No changes observed in the XRPD before and after the analysis.
AAS: 2.9 % Na (which corresponds to a 1 : 1 molar ratio of daprodustat free acid and daprodustat sodium salt)
Example 3: Synthesis of cocrystal of daprodustat potassium salt and daprodustat free acid
A sample of daprodustat obtained by reproducing the Method 2 of W02007/150011 A2 (1 g, 2.54 mmol) was suspended in a mixture of acetonitrile and water (9:1 respectively, 55 mL) at 95°C. To the resulting solution, an aqueous solution of potassium hydroxide (1 M, 0.5 equiv., 1.28 mL) was added dropwise, and the obtained suspension was left to cool down to room temperature. The resulting solid was filtered off, dried under vacuum (2 mbar, 40°C, 3 hours).
XRPD (FIG. 7): Crystalline.
DSC (FIG. 8): Endothermic peaks with onset temperatures at 33°C (-87 J/g) and 248°C (-46 J/g).
TGA (FIG. 8): Weight loss of 5.4% between 27 and 125°C (probable loss of water; 2.5 theoretical equivalents: 5.2%). Decomposition starting at about 250°C.
1H-NMR (300 MHz, DMSO, FIG. 9): 5 (ppm): 10.08 (t, 1 H, J=6 Hz), 4.65 (m, 2H), 3.93 (d, 2H, J=6 Hz), 2.30 (m, 4H), 1.77 (m, 4H), 1.57 (m, 6H), 1.20 (m, 6H). No residual solvents detected.
FTIR: v (cm 1, FIG. 10): 693, 740, 762, 790, 882, 894, 918, 996, 1054, 1134, 1187, 1235, 1258, 1302, 1340, 1378, 1446, 1472, 1506, 1522, 1589, 1669, 2655, 2852, 2935, 2977, 3180, 3477, 3546.
DVS: Weight increase of about 3.9% between 10% and 80% Relative Humidity (hygroscopic). No changes observed in the XRPD before and after the analysis.
AAS: 4.6 % K (which corresponds to a 1 :1 molar ratio of daprodustat free acid and daprodustat potassium salt)
Example 4: Temperature stability study
Samples of crystals N2 and K2 were stored in closed vials at different temperatures (T), for instance at 45°C and at 60°C. After some time, solids were separated and analysed by XRPD analysis. Results are gathered in Table 6.
Table 6
Example 5: Solubility study
Solubility test method according to the Chinese Pharmacopoeia was used and different pHs of different organs in human body were considered: FeSSIF (Fed state simulated intestinal fluids, pH=5.0), FaSSIF (Fasted state simulated intestinal fluids, pH=6.5) and pure water. Prior art form CS1, crystal form N2 and crystal form K2 of daprodustat were suspended in the different mediums at 25°C to obtain saturated solutions. The solutions were sampled at fixed time points (1 h, 4 hours and 24 hours). Concentrations values in mg/mL were measured by HPLC. The results are listed in Table 7.
High Performance Liquid Chromatography (HPLC):
Equipment: Agilent Technologies 1200 series
Column: Zorbax C18 (50mm x2.1) 1.8pm
Eluent: ACN/H2O 6:4
Flow rate: 0.5 ml/min
Wavelength: 266nm
Injection volume: 5 pL
As from the results obtained in Table 7, the crystal form N2 of daprodustat showed improved solubility at pH=6.5 and pure water compared to prior art form CS1. Also, the crystal form K2 of daprodustat showed improved solubility at pH=5.0, pH=6.5 and pure water compared to prior art form CS1 .
Example 6: Drying stability study
Samples of crystals N2 and K2 were dried overnight in vacuum (12 mbar) at different temperatures (T) in a vacuum drying oven. The resulting solids were analyzed by XRPD. Results are gathered in Table 8.
Table 8
As shown in table 8, the crystal form K2 of daprodustat kept its form unchanged by XRPD analysis. The crystal form N2 of daprodustat transformed to the crystal form N4 characterized by XRPD, DSC/TGA and DVS analysis as shown below.
XRPD (FIG. 5 and Table 2): Crystalline (very similar to crystal form N2).
DSC (FIG. 6): Endothermic peaks with onset temperatures at 107°C (-62 J/g), 190°C (-6 J/g), 200°C (-2 J/g) and 229°C (-38 J/g).
TGA (FIG. 6): Weight loss of 4.0% between 39°C and 141°C (probable loss of water; 2 theoretical equivalents: 4.3%). Decomposition starting at about 220°C.
DVS: Weight increase of about 0.5% between 10% and 80% Relative Humidity (slightly hygroscopic). No changes observed in the XRPD before and after the analysis.
Example 7: Slurry experiments
Samples of crystals N2 and K2 were suspended in water (100 mg in 1 mL) and stirred for 1 hour at room temperature. After that, the resulting solids were separated and analysed by XRPD. Crystal form N2 kept its form unchanged as confirmed by XRPD analysis. Crystal form K2 kept its form unchanged as confirmed by XRPD analysis.
Samples of crystals N2 and K2 were suspended in water (100 mg in 1 mL) and stirred for 30 min and for 60 min at three different temperatures of 40°C, of 60°C and of 80°C. Crystal form N2 kept its form unchanged in all experiments as confirmed by XRPD analysis. Crystal form K2 kept its form unchanged in all experiments as confirmed by XRPD analysis.
Example 8: Synthesis of crystal form N2 of daprodustat from intermediate compound (VI) wherein R is ethyl
Ethyl (1 ,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycinate (5.0 g, 11.9 mmol, 1.0 eq.) was suspended in ethanol (20 mL). An 1 M aqueous solution of NaOH (23.8 mL, 23.8 mmol, 2.0 equiv.) was added and stirred at 20-25 °C for 2 h. The solvent was distilled off at reduced pressure at 40 °C. Acetonitrile (25 mL) was added, the medium was heated at 40 °C until a solution was obtained and then the solvent was distilled off at reduced pressure at 40 °C. This operation was repeated once. Acetonitrile (248 mL) and water (10 mL) were added. To the obtained solution an 1 M aqueous solution of HCI (11.9 mL, 11.9 mmol, 1.0 equiv.) was added at 20-25 °C. The white solution was seeded with crystal form N2 of daprodustat (as prepared in example 2). Then, an 1 M aqueous solution of HCI (6.0 mL, 6.0 mmol, 0.5 equiv.) was added at
20-25 °C. The white solution was seeded with crystal form N2 of daprodustat (as prepared in example 2) and stirred at 20-25 °C for 20 h. The white solid was filtered at reduced pressure. The obtained white solid was suspended in water (100 mL) at 20-25 °C for 1 hour. The white suspension was filtered and washed with water (2x25 mL) at reduced pressure. The obtained white solid was suspended once again in water (100 mL) at 20-25 °C for 1 hour. The white solid was filtered, washed with water (2x25 mL) at reduced pressure and dried at reduced pressure at 40 °C for 4 h (3.3g, 7.8 mmol, Yield: 66%) XRPD: Crystal form N2 of daprodustat.
Example 9: Synthesis of crystal form K1 of daprodustat from intermediate compound (VI) wherein R is ethyl
Ethyl (1 ,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycinate (5.0 g, 11.9 mmol, 1.0 equiv.) was suspended in ethanol (20 mL). An 1 M aqueous solution of KOH (23.8 mL, 23.8 mmol, 2.0 equiv.) was added and stirred at 20-25 °C for 2 h. The solvent was distilled off at reduced pressure at 40 °C. Acetonitrile (25 mL) was added, the medium was heated at 40 °C until a solution was obtained and then the solvent is distilled off at reduced pressure at 40 °C. This operation was repeated once. Acetonitrile (248 mL) and water (10 mL) were added. To the obtained solution an 1 M aqueous solution of HCI (11.9 mL, 11.9 mmol, 1.0 equiv.) was added at 20-25 °C. The white solution was seeded with crystal form K2 of daprodustat. Then, an 1 M aqueous solution of HCI (6.0 mL, 6.0 mmol, 0.5 equiv.) was added at 20-25 °C. The white solution was seeded with crystal form K2 of daprodustat (as prepared in example 3) and stirred at 20-25 °C for 20 h. The white solid was filtered at reduced pressure. The obtained white solid was suspended in water (100 mL) at 20-25 °C for 1 h. The white suspension was filtered and washed with water (2x25 mL) at reduced pressure. The obtained white solid was suspended once again in water (100 mL) at 20-25 °C for 1 h. The white solid was filtered, washed with water (2x25 mL) at reduced pressure and dried at reduced pressure at 40 °C for 4 h (3.1 g, 7.0 mmol, Yield: 60%).
XRPD (FIG. 15 and Table 4): Crystalline crystal form K1 of daprodustat.
DSC (FIG. 16): Endothermic peaks with onset temperatures at 56°C (-142 J/g) and 251 °C (-76 J/g). TGA (FIG. 16): Weight loss of 13.2% between 40°C and 130°C. Decomposition starting at about 250°C. KF: 11.57%
Crystal form K1 of daprodustat obtained above was dried under vacuum at room temperature to provide crystal form K2 of daprodustat.
Example 10: Synthesis of 1,3-dicyclohexylpyrimidine-2,4,6(1 H,3H,5H)-trione (Compound V)
1 ,3-dicyclohexylurea (DCU) (175.0 g, 780.0 mmol, 1.0 equiv.) and malonic acid (97.4 g, 936.0 mmol, 1.2 equiv.) were stirred with acetic acid (700 mL) at 20-25 °C. To the resulting white suspension, acetic anhydride (199.1 g, 184.0 mL, 1.950 mol, 2.5 eq.) was added at 20-25 °C. The resulting mixture was heated at 80-85 °C and stirred at this temperature for 5 h. Then, the system was cooled down to 20 25 °C and water
(700 mL) was added. The resulting suspension was stirred at 20-25 °C for 16 h. The white solid was separated by filtration at reduced pressure at 20-25 °C and washed with a 1 :1 mixture of acetic acid and water (2 x 85 mL), water (175 mL) and isopropanol (175 mL). The resulting solid was slurried from isopropanol (1300 mL) at 80 °C and stirred 10 min at this temperature. Then, the mixture was cooled to 20- 25 °C and stirred at this temperature for 16 h and then stirred for 1 h at 0-5 °C. The white solid was separated by filtration at reduced pressure at 0-5 °C, washed with ice-cooled isopropanol (2x100 mL) and dried at 40- 45 °C.
Yield: 70% (158.6 g, 542.5 mmol)
Purity by HPLC: 99.54%
Example 11 : Synthesis of ethyl formylglycinate (Compound II)
Ethyl glycinate hydrochloride (100.0 g, 716.4 mmol, 1.0 equiv.) was mixed with trimethyl orthoformate (300 mL, 291.0 g, 3.8 equiv.) at 20-25 °C. The resulting white suspension was heated at reflux temperature and stirred at this temperature for 4 h. Then, the solvent was distilled at reduced pressure at 40-75 °C. The brownish residue obtained was purified by fractioned distillation at reduced pressure to give a clear oil. Yield: 86% (80.8 g, 616.2 mmol) Purity by HPLC: 98.23%
Example 12: Synthesis of ethyl formylglycinate (Compound II)
Ethyl glycinate hydrochloride (25.0 g, 179 mmol, 1.0 equiv.) was mixed with ethyl formate (75.0 mL, 69.1 g, 932 mmol, 5.2 equiv.) and triethylamine (26.2 mL, 19,0 g, 188 mmol, 1 ,05 equiv.) at 20-25 °C. The resulting white suspension was heated at reflux temperature and stirred at this temperature for 24 h. The reaction medium was cooled down to 20-25 °C and the white solid was filtered off and washed with ethyl formate. The solvent of the filtrate was distilled at reduced pressure at 40 °C. The residue obtained was mixed with toluene (100 mL) and the resulting mixture was stirred for 1 h at 20-25 °C. The white solid was filtered off and washed with toluene. Then, the solvent of the filtrate was distilled at reduced pressure at 40 °C. The brownish oil obtained was purified by distillation at reduced pressure to give a clear oil.
Yield: 81 % (19.0 g, 145 mmol).
Purity by HPLC: 99,69%
Example 13: Synthesis of ethyl (1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carbonyl)glycinate (Compound VI)
A solution of ethyl formyl glycinate (compound II, 48-0 g, 366.0 mmol, 1.0 equiv.) and triethylamine (92.6 g, 128 mL, 915.1 mmol, 2.5 equiv.) in dichloromethane (288 mL) was cooled to 0-5 °C. A solution of phosphorus oxychloride (61.7 g, 37.5 mL, 403 mmol, 1.1 equiv.) in dichloromethane (96 mL) was slowly added keeping the temperature of the system under 5 °C. The resulting mixture was stirred at 0-5 °C for 1
h. At that point a 10% aqueous solution of potassium carbonate (384 mL) was added at a temperature under 25 °C. Then the mixture was stirred at 20-25 °C for 1 h. The phases were separated and the aqueous phase was extracted with dichloromethane (96 mL). The organic phases were joined and washed with a saturated aqueous solution of sodium bicarbonate (96 mL) and water (96 mL). The solvent of the organic phase was distilled at reduced pressure to yield a reddish oil, corresponding to ethyl 2-isocyanoacetate (compound III). This oil was used in the next step without further purification.
A solution of the reddish oil (compound III) and DMSO (35.7 g, 32.5 mL, 457.5 mmol, 1.25 equiv.) in dichloromethane (240 mL) was cooled between -30 °C and -35 °C and a solution of trifluoroacetic anhydride (7.7 g, 5.2 mL, 36.6 mmol, 0.10 equiv.) in dichloromethane (48 mL) was slowly added. The system was stirred at -35 °C for 30 min. Ethyl 2-isocyanatoacetate (compound IV) was formed in the reaction medium.
At this point, 1 ,3-dicyclohexylpyrimidine-2,4,6(1 H,3H,5H)-trione (compound V) (95.8 g, 327.7 mmol, 0.94 equiv.) and diisopropylethylamine (90.1 g, 121 mL, 697.1 mmol, 2.0 equiv.) were added. The resulting solution was stirred at 20-25 °C for 16 h. Then, a 3N aqueous solution of hydrochloric acid (300 mL) was added and the mixture was stirred at 20-25 °C for 15 min. The phases were separated, and the aqueous phase was extracted with dichloromethane (200 mL). The organic phases were joined and washed with a saturated aqueous solution of sodium bicarbonate (200 mL) and with water (200 mL). The solvent of the organic phase was distilled at reduced pressure and swapped with isopropanol (1056 mL) to yield a yellowish suspension, which was heated at reflux temperature to yield a solution that was cooled to 20-25 °C. The obtained suspension was stirred at this temperature for 1 h. The white solid was separated by filtration at reduced pressure at 20-25 °C and washed with isopropanol (2 x 100 mL). The white solid was recrystallized from IPA (1000 mL), filtered off and dried at 40-45 °C.
Yield: 70% (96.7 g, 229.4 mmol)
Purity by HPLC: 99.66%
Example 14: Synthesis of ethyl (1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1, 2,3,4- tetrahydropyrimidine-5-carbonyl)glycinate (Compound VI)
A solution of ethyl formylglycinate (compound II, 35.0 g, 267 mmol, 1.0 equiv.) and triethylamine (59.4 g, 81.8 mL, 587 mmol, 2.2 equiv.) in dichloromethane (210 mL) was cooled to 0-5 °C. A solution of phosphorus oxychloride (45.0 g, 27.4 mL, 294 mmol, 1.1 equiv.) in dichloromethane (70 mL) was slowly added keeping the temperature of the reaction medium under 5 °C. The resulting mixture was stirred at 0-5 °C for 2 h. At that point, a 10% aqueous solution of potassium carbonate (350 mL) was added at a temperature under 25 °C. Then the mixture was stirred at 20-25 °C for 1 h. The phases were separated and the aqueous phase was extracted twice with dichloromethane (2x70 mL). The organic phases were joined and washed with
water (70 mL) and brine (70 mL). The solvent of the organic phase was distilled at reduced pressure to yield a reddish oil, corresponding to ethyl 2-isocyanoacetate 30 (compound III). This oil was used in the next step without further purification.
A mixture of DMSO (24.0 g, 21.8 mL, 308 mmol, 1.2 equiv.) in dichloromethane (55 mL) was cooled to a temperature between -30 °C and -35 °C. Trifluoroacetic anhydride (5.38 g, 3.62 mL, 25.6 mmol, 0.10 equiv.) was slowly added at this temperature. Then, a solution of the reddish oil previously obtained (compound III) in dichloromethane (50 mL) was slowly added keeping the temperature between -30 °C and -35 °C. The solution was stirred at this temperature for 30 min. Ethyl 2-isocyanatoacetate (compound IV) was formed in the reaction medium.
At this point, a solution of 1 ,3-dicyclohexylpyrimidine-2,4,6(1 H,3H,5H)-trione (compound V) (59.9 g, 205 mmol, 0.8 equiv.) and diisopropylethylamine (36.4 g, 49.1 mL, 282 mmol, 1.1 equiv.) in dichloromethane (120 mL) was added, keeping the temperature below 0 °C. The resulting solution was stirred at 20-25 °C for 4 h. Then, a solution of HCI 37% (50 mL) in water (450 mL) was added and the mixture was stirred at 20- 25 °C for 15 min. The phases were separated, and the aqueous phase was extracted with dichloromethane (70 mL). The organic phases were joined and washed with water (70 mL) and a saturated aqueous solution of sodium bicarbonate (70 mL). The solvent of the organic phase was distilled at reduced pressure and swapped with isopropanol (700 mL) to yield a yellowish suspension, which was heated at reflux temperature to yield a solution that was cooled to 20-25 °C. The obtained suspension was stirred at this temperature for 16 h. The white solid was separated by filtration at 20-25 °C and washed with isopropanol (3x35 mL). The white solid was recrystallized from IPA (6600 mL), filtered and dried at 40-45 °C.
Yield: 74% (63.5 g, 151 mmol)
Purity by HPLC: 99.50%
Example 15: Synthesis of (1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- carbonyl)glycine (Compound I)
To a suspension of ethyl (1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1 ,2,3,4-tetrahydro-pyrimidine-5- carbonyl)glycinate (compound VI as obtained above) (5.0 g, 11.9 mmol, 1.0 equiv.) in ethanol (60 mL) cooled to 0-5 °C was added 25% of an aqueous solution of tetramethylammonium hydroxide (9.0 mL, 26 mmol, 2.2 equiv.) at 0-5 °C. The resulting mixture was heated at 20-25 °C for 1 h. Afterwards, trifluoroacetic acid (3.0 g, 2.0 mL, 26 mmol, 2.2 equiv.) was added and the resulting white suspension was stirred at 20-25 °C for 1 h. The solid was filtered, washed with ethanol (2 x 5 mL) and dried at 40-45 °C.
Yield 90 % (4.2 g, 10.7 mmol)
Purity by HPLC: 99.93%
Claims
1 . A crystal form of daprodustat which is a cocrystal comprising daprodustat free acid and a daprodustat pharmaceutically acceptable metal salt, wherein the metal salt is an alkali metal salt.
2. The crystal form of daprodustat according to claim 1, wherein the molar ratio of daprodustat free acid and daprodustat metal salt is from 1 :3 to 3: 1 , preferably from 1 :2 to 2: 1 , more preferably is about 1 :1.
3. The crystal form of daprodustat according to any of the claims 1 to 2, wherein the alkali metal salt is a sodium salt.
4. The crystal form of daprodustat according claim 3, which is a cocrystal referred as form N2 and has an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.3°±0.2°, 7.4°±0.2°, 7.6°±0.2°, 11 .4°±0.2° and 16.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1 .5406 A at room temperature.
5. The crystal form of daprodustat according to claim 4, wherein the X-ray powder diffraction pattern of the crystal N2 further comprises peaks at 2theta values of 13.0°±0.2°, 13.5°±0.2°, 14.5°±0.2°, 14.8°±0.2° and 15.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
6. The crystal form of daprodustat according to any one of the claims 4 to 5, wherein the crystal N2 contains water in an amount from 0.2% to 10% by weight, preferably from 2% to 8% by weight, more preferably from 4.0% to 6.0% by weight, with respect to the total weight of the crystal.
7. The crystal form of daprodustat according claim 3, which is a cocrystal referred as form N4 and has an X-ray powder diffraction pattern comprising peaks at 2theta values of 6.4°±0.2°, 7.4°±0.2°, 7.6°±0.2°, 13.4°±0.2° and 16.7°±0.2, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
8. The crystal form of daprodustat according to claim 7, wherein the X-ray powder diffraction pattern of the crystal N4 further comprises peaks at 2theta values of 15.0°±0.2°, 26.9°±0.2°, 27.5°±0.2°, 27.7°±0.2° and 28.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
9. The crystal form of daprodustat according to any one of the claims 7 to 8, wherein the crystal N4 contains
water in an amount from 0.2% to 5% by weight, preferably from 2% to 5% by weight, more preferably from 3.9% to 4.5% by weight, with respect to the total weight of the crystal.
10. The crystal form of daprodustat according to any one of the claims 1 to 2, wherein the alkali metal salt is a potassium salt.
11 . The crystal form of daprodustat according claim 10, which is a cocrystal referred as form K2 and has an X-ray powder diffraction pattern comprising peaks at 2theta values of 5.5°±0.2°, 6.3°±0.2°, 7.0°±0.2°, 16.8°±0.2° and 18.0°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
12. The crystal form of daprodustat according to claim 11, wherein the X-ray powder diffraction pattern of the crystal K2 further comprises peaks at 2theta values of 7.8°±0.2°, 11.8°±0.2°, 12.7°±0.2°, 13.7°±0.2° and 27.6°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
13. The crystal form of daprodustat according to any one of the claims 11 to 12, wherein the crystal K2 contains water in an amount from 0.2% to 10% by weight, preferably from 2% to 8% by weight, more preferably from 4.0% to 6.0% by weight with respect to the total weight of the crystal.
14. The crystal form of daprodustat according to claim 10, which is a cocrystal referred as form K1 and has an X-ray powder diffraction pattern comprising peaks at 2theta values of 5.4°±0.2°, 7.9°±0.2°, 14.6°±0.2°, 15.6°±0.2° and 17.5°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
15. The crystal form of daprodustat according to claim 14, wherein the X-ray powder diffraction pattern of the crystal K1 further comprises peaks at 2theta values of 10.2°±0.2°, 11.3° ±0.2°, 12.1 °±0.2°, 15.8°±0.2° and 16.2°±0.2°, measured with Ko radiation of copper having an X-ray wavelength of 1.5406 A at room temperature.
16. The crystal form of daprodustat according to any one of the claims 14 to 15, wherein the crystal K1 contains water in an amount from 10% to 14% by weight with respect to the total weight of the crystal.
17. A process for the preparation of the crystal form of daprodustat as defined in claims 1 to 16, which comprises the steps of:
a) providing daprodustat free acid in a solvent or a mixture of solvents, b) optionally, heating the mixture of step (a) at a suitable temperature, preferably from 70°C to 100°C, more preferably from 75°C to 95°C, c) adding a source of a pharmaceutically acceptable metal inorganic base, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount of about 0.5 molar equivalents with respect to daprodustat free acid of step (a), d) optionally, cooling the solution resulting from step (c) to room temperature, and e) isolating the crystal form of daprodustat.
18. The process according to claim 17, wherein the source of the pharmaceutically acceptable metal inorganic base is a source of an alkali metal inorganic base, preferably the alkali metal inorganic base is an alkali metal hydroxide selected from the group of sodium hydroxide and potassium hydroxide.
19. The process according to any one of claims 17 to 18, wherein the solvent used in step (a) is selected from the group consisting of acetonitrile, dichloromethane (DCM), toluene, tetrahydrofuran, and a combination thereof.
20. The process according to any one of claims 17 to 18, wherein the solvent used in step (a) is a mixture of water and another solvent selected from the group consisting of acetonitrile, dichloromethane (DCM), toluene, and tetrahydrofuran, preferably the solvent used in step (a) is a mixture of water and acetonitrile.
21 . The process according to any one of claims 14 to 20, wherein steps b) and d) are carried out.
22. A process for the preparation of the crystal form of daprodustat as defined in claims 1 to 16, which comprises the steps of:
I. providing an ester intermediate of formula (VI),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)ary I and (Cs-C^heteroaryl, preferably R is ethyl,
in a solvent or a mixture of solvents
II. optionally, heating the mixture of step (I) at a suitable temperature, preferably from room temperature to 100°C, more preferably from 30°C to 75°C, iii. adding a source of a pharmaceutically acceptable metal inorganic base, preferably an alkali metal inorganic base, more preferably in the form of an alkali metal hydroxide, in an amount from 1 .0 to 2.2, preferably from 2.0 to 2.2 molar equivalents with respect to the ester intermediate of step (i) to form the corresponding daprodustat alkali metal salt of formula (la),
wherein M is an alkali metal, iv. adding hydrochloric acid in an amount from 0.5 to 1.7, preferably from 1 .5 to 1 .7 molar equivalents to the mixture of step (iii), v. optionally, cooling the mixture resulting from step iv) to room temperature, and vi. isolating the crystal form of daprodustat.
23. The process according to claim 22, wherein the source of a pharmaceutically acceptable metal inorganic base is an alkali metal inorganic base, preferably the alkali metal inorganic base is an alkali metal hydroxide selected from the group of sodium hydroxide and potassium hydroxide.
24. The process according to any one of claims 22 to 23, wherein the solvent used in step (I) is a mixture of water and another solvent selected from the group consisting of (Ci-Ci2)alcohol and acetonitrile.
25. The process according to claim 24, wherein the (Ci-Ci2)alcohol is selected from methanol, ethanol, isopropanol and 1-propanol.
26. The process according to any one of claims 22 to 25, wherein steps (II) and (v) are carried out.
27. The process according to any one of claims 22 to 26, wherein step (iii) further comprises the substeps of: iii.1) removing completely or partially the solvent or mixture of solvents of step (I) by evaporation or distillation, and
iii.2) adding a different solvent or mixture of solvents to provide a solution or a suspension.
28. The process according to claim 27, wherein the solvent or mixture of solvents in (ill.1 ) is a (Ci-Ci2)alcohol and the solvent or mixture of solvents in (iii.2) is a mixture of acetonitrile and water in a ratio from 5: 1 (v/v) to 15: 1 (v/v), preferably from 8: 1 (v/v) to 12: 1 (v/v), more preferably acetonitrile and water in a ratio of 9:1 (v/v).
29. The process according to any one of claims 22 to 28, wherein the process further comprises seeding with the desired crystal form of daprodustat before step (v) is carried out or before or during step (iv) is carried out.
30. A pharmaceutical composition comprising the crystal form of daprodustat as defined in any one of claims 1 to 16, wherein daprodustat is in a crystal form selected from the group consisting of crystal form N2, crystal form N4, a crystal form K2, and crystal form K1, and a combination thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
31 . The crystal form of daprodustat as defined in any one of claims 1 to 16 for use in the treatment of renal anemia.
32. A process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof,
which comprises converting a compound of formula (VI)
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Cs-Cejcycloalkyl, (Cs-C^heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl, into daprodustat of formula (I) by hydrolysis in the presence of a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH), and a solvent, and optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
33. The process according to claim 32, wherein the solvent is selected from the group consisting of a (Ci- Cajalcohols, preferably methanol, ethanol or isopropanol; water; and mixtures thereof.
34. The process according to claim 33, wherein the solvent is a mixture of a (Ci-C3)alcohols and water in a volume ratio from 10:1 to 1 :2, preferably from 5:1 to 1 :2, more preferably from 10:1 to 5: 1.
35. The process according to any one of claims 32 to 34, wherein after the hydrolysis reaction has been finished and acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic acid (TFA), preferably trifluoroacetic acid (TFA) is added.
36. The process according to any one of claims 32 to 35, wherein the compound of formula (VI) is prepared by reacting an isocyanatoacetate of formula (IV),
wherein R is (Ci-Cio)alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl, with 1,3-dicyclohexyl barbituric acid of formula (V),
in the presence of a base and a solvent.
39. The process according to any one of claims 32 to 35, wherein the compound of formula (VI) is prepared by a process which comprises the steps of: a) converting a formamide of formula (II),
into a compound an isocyanoacetate of formula (III),
wherein R is as defined in claim 36, preferably R is ethyl; b) converting the isocyanoacetate of formula (III) of step (a) into an isocyanatoacetate of formula (IV),
wherein R is as defined in claim 36, preferably R is ethyl; c) reacting the isocyanatoacetate of formula (IV) obtained in step (b) with a 1 ,3-dicyclohexyl barbituric acid of formula (V),
in the presence of a base and a solvent to provide the compound of formula (VI); wherein steps (b) and (c) are carried out in a consecutive manner.
40. The process according to any one of claims 36 to 39, wherein the solvent used in the reaction of the isocyanatoacetate of formula (IV) with a 1 ,3-dicyclohexyl barbituric acid of formula (V) is an aprotic solvent, preferably dichloromethane (DCM), toluene or tetrahydrofuran.
41 . The process according to any one of claims 36 to 40, wherein the base used in the reaction of the isocyanatoacetate of formula (IV) with 1 ,3-dicyclohexyl barbituric acid of formula (V) is an organic base, preferably triethylamine (TEA) or diisopropylamine (DIPEA).
42. The process according to any one of claims 36 to 41, wherein the 1 ,3-dicyclohexyl barbituric acid of formula (V) is prepared by a process which comprises the steps of:
(I) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(II) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V).
43. The process according to claim 42, wherein step (I) is carried out at a temperature from 70°C to 95°C, preferably from 85°C to 90°C.
44. The process according to any one of claims 42 to 43, wherein step (ill) is carried out.
45. The process according to any one of claims 36 to 44, wherein the 1 ,3-dicyclohexyl barbituric acid of formula (V) is added to the isocyanatoacetate of formula (IV).
46. The process according to claim any one of claims 37 to 45, wherein the conversion of the isocyanoacetate of formula (III) into the isocyanatoacetate of formula (IV) is carried out in the presence of dimethylsulfoxide (DMSO) and trifluoroacetic anhydride (TFAA).
47. The process according to any one of claims 37 to 46, wherein the conversion of the isocyanoacetate of formula (III) into the isocyanatoacetate of formula (IV) is carried out at a temperature from -20°C to -40°C, preferably about -30°C.
48. The process according to any one of claims 38 to 47, wherein the conversion of the formamide of formula (II) into the isocyanoacetate of formula (III) is carried out in the presence of a dehydrating agent, preferably POCI3, and a base, preferably an organic base selected from triethylamine (TEA) or diisopropylamine (DIPEA).
49. The process according to any one of claims 38 to 48, wherein the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of trimethyl orthoformate or triethylorthoformate.
50. A process for preparing a 1 ,3-dicyclohexyl barbituric acid of formula (V),
which comprises the steps of:
(I) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(II) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V).
51. A process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof,
which comprises: a1) preparing a 1 ,3-dicyclohexyl barbituric acid of formula (V)
by a process which comprises the steps of:
(I) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(ii) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V); a2) reacting the 1 ,3-dicyclohexyl barbituric acid of formula (V) obtained in step (a1) with an isocyanatoacetate of formula (IV),
wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, (Cs-C^Jheterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl, in the presence of a base and a solvent to provide the compound of formula (VI);
wherein R is as defined above, preferably R is ethyl; a3) converting the compound of formula (VI) into daprodustat of formula (I) by hydrolysis in the presence of a base and a solvent; and a4) optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
52. The process according to any one of claims 50 to 51 , wherein step (i) is carried out at a temperature from 70°C to 95°C, preferably from 85°C to 90°C.
53. The process according to any one of claims 50 to 52, wherein step (ill) is carried out.
54. The process according to any one of claims 51 to 53, wherein the solvent used in step (a2) is an aprotic solvent, preferably dichloromethane (DCM), toluene or tetrahydrofuran.
55. The process according to any one of claims 51 to 54, wherein the base used in step (a2) is an organic base selected from triethylamine (TEA) or diisopropylamine (DIPEA).
56. The process according to any one of claims 51 to 55, wherein the 1 ,3-dicyclohexyl barbituric acid of formula (V) is added to the isocyanatoacetate of formula (IV).
57. The process according to any one of claims 51 to 56, wherein the base used in step (a3) is an inorganic base selected from NaOH and KOH, preferably followed by neutralization with an acid such as hydrochloric acid.
58. The process according to any one of claims 51 to 56, wherein the base used in step (a3) is a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH).
59. The process according to claim 58, wherein in step (a3) after the hydrolysis reaction has been finished an acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic (TFA), preferably
trifluoroacetic acid (TFA), is added.
60. The process according to any one of claims 51 to 59, wherein the solvent used in step (a3) is selected from the group consisting of a (Ci-C3)alcohols, preferably methanol, ethanol or isopropanol; water; and mixtures thereof.
61 . The process according to claim 60, wherein the solvent used in step (a3) is a mixture of a (Ci-C3)alcohols and water in a volume ratio from 10: 1 to 1 :2, preferably from 5: 1 to 1 :2, more preferably from 10: 1 to 5:1.
64. The process according to claim 63, wherein the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of trimethyl orthoformate or ethylorthoformate.
65. The process according to any one of claims 51 to 61, wherein the isocyanatoacetate of formula (IV) is prepared by a process which comprises the steps of: a) converting a formamide of formula (II),
into a compound an isocyanoacetate of formula (III),
wherein R is as defined in claim 51, preferably R is ethyl; and b) converting the isocyanoacetate of formula (III) of step (a) into an isocyanatoacetate of formula (IV),
wherein R is as defined in claim 51, preferably R is ethyl; and wherein steps (b) and (a) are carried out in a consecutive manner.
66. The process according to claim any one of claims 62 to 65, wherein the conversion of the isocyanoacetate of formula (III) into the isocyanatoacetate of formula (IV) is carried out in the presence of dimethylsulfoxide (DMSO) and trifluoroacetic anhydride (TFAA).
67. The process according to any one of claims 62 to 66, wherein the conversion of the isocyanoacetate of formula (III) into the isocyanatoacetate of formula (IV) is carried out at a temperature from -20 °C to -40 °C, preferably about -30 °C.
68. The process according to any one of claims 63 to 67, wherein the conversion of the formamide of formula (II) into the isocyanoacetate of formula (III) is carried out in the presence of a dehydrating agent, preferably POCI3, and a base, preferably an organic base selected from triethylamine (TEA) or diisopropylamine (DIPEA).
(VI), wherein R is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, heterocycloalkyl, (C3-Ci2)heterocycloalkyl, (Ce- Ci4)aryl and (Cs-C^heteroaryl, preferably R is ethyl, which comprises the steps of: a) converting a formamide of formula (II),
into a compound an isocyanoacetate of formula (III),
wherein R is as defined above, preferably R is ethyl; b) converting the isocyanoacetate of formula (III) of step (a) into an isocyanatoacetate of formula (IV),
wherein R is as defined above, preferably R is ethyl; c) reacting the isocyanatoacetate of formula (IV) obtained in step (b) with a 1 ,3-dicyclohexyl barbituric acid of formula (V),
in the presence of a base and a solvent to provide the compound of formula (VI); wherein steps (b) and (c) are carried out in a consecutive manner.
70. A process for preparing daprodustat of formula (I), or a pharmaceutically or veterinary acceptable salt thereof,
which comprises: b1) converting a formamide of formula (II),
into a compound an isocyanoacetate of formula (III),
wherein R is is (Ci-C )alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cs-Cecycloalkyl, (Cs-Cejcycloalkyl, (C3- Ci2)heterocycloalkyl, (Ce-Ci4)aryl and (C5-Ci2)heteroaryl, preferably R is ethyl; b2) converting the isocyanoacetate of formula (III) of step (b1) into an isocyanatoacetate of formula (IV),
wherein R is as defined above, preferably R is ethyl; b3) reacting the isocyanatoacetate of formula (IV) obtained in step (b2) with a 1 ,3-dicyclohexyl barbituric acid of formula (V),
in the presence of a base and a solvent to provide the compound of formula (VI)
wherein R is as defined above, preferably R is ethyl; wherein steps (b2) and (b3) are carried out in a
consecutive manner, b4) converting the compound of formula (VI) into daprodustat of formula (I) by hydrolysis in the presence of a base and a solvent; and b5) optionally converting daprodustat of formula (I) into a pharmaceutically or veterinary acceptable salt thereof.
71. The process according to any one of claims 69 to 70, wherein the solvent used in the reaction of the isocyanatoacetate of formula (IV) with a 1 ,3-dicyclohexyl barbituric acid of formula (V) is an aprotic solvent, preferably dichloromethane (DCM), toluene or tetrahydrofuran.
72. The process according to any one of claims 69 to 71, wherein the base used in the reaction of the isocyanatoacetate of formula (IV) with 1 ,3-dicyclohexyl barbituric acid of formula (V) is an organic base selected from triethylamine (TEA) or diisopropylamine (DIPEA).
73. The process according to any one of claims 69 to 72, wherein the 1 ,3-dicyclohexyl barbituric acid of formula (V) is prepared by a process which comprises the steps of:
(I) reacting dicyclohexylurea (DCU) with malonic acid in the presence of AC2O in acetic acid to provide compound of formula (V),
(II) adding an antisolvent, preferably water, in an amount from 1 to 10 volumes per g of compound (V), preferably from 3 to 6 volumes per g of compound of formula (V),
(ill) optionally, heating the mixture of step (II) at a temperature from 20°C to 85°C, preferably from 20°C to 30°C, and
(iv) isolating the compound of formula (V).
74. The process according to claim 73, wherein step (I) is carried out at a temperature from 70°C to 95°C, preferably from 85°C to 90°C.
75. The process according to any one of claims 73 to 74, wherein step (II) is carried out.
76. The process according to any one of claims 69 to 75, wherein the 1 ,3-dicyclohexyl barbituric acid of formula (V) is added to the isocyanatoacetate of formula (IV).
77. The process according to claim any one of claims 69 to 76, wherein the conversion of the isocyanoacetate of formula (III) into the isocyanatoacetate of formula (IV) is carried out in the presence of dimethylsulfoxide (DMSO) and trifluoroacetic anhydride (TFAA).
78. The process according to any one of claims 69 to 77, wherein the conversion of the isocyanoacetate of formula (III) into the isocyanatoacetate of formula (IV) is carried out at a temperature from -20°C to -40°C, preferably about -30°C.
79. The process according to any one of claims 69 to 78, wherein the conversion of the formamide of formula (II) into the isocyanoacetate of formula (III) is carried out in the presence of a dehydrating agent, preferably POCI3, and a base, preferably an organic base selected from triethylamine (TEA) or diisopropylamine (DIPEA).
80. The process according to any one of claims 69 to 79, wherein the formamide of formula (II) is prepared from glycine ethyl ester hydrochloride in the presence of trimethyl orthoformate or ethylorthoformate.
81 . The process according to any one of claims 70 to 80, wherein the base used in step (b4) is an inorganic base selected from NaOH and KOH, preferably followed by neutralization with an acid such as hydrochloric acid.
82. The process according to any one of claims 70 to 80, wherein the base used in step (b4) is a quaternary ammonium hydroxide of formula N[(Ci-C4)alkyl]4OH, preferably tetramethylammonium hydroxide (TMAH).
83. The process according to claim 82, wherein in step (b4) after the hydrolysis reaction has been finished an acid selected from formic, acetic, monochloroacetic, trichloroacetic and trifluoroacetic acid (TFA), preferably trifluoroacetic acid (TFA), is added.
84. The process according to any one of claims 70 to 83, wherein the solvent used in step (b4) is selected from the group consisting of a (Ci-C3)alcohols, preferably methanol, ethanol or isopropanol; water; and mixtures thereof.
85. The process according to claim 84, wherein the solvent is a mixture of a (Ci-C3)alcohols and water in a volume ratio from 10:1 to 1 :2, preferably from 5:1 to 1.2, more preferably from 10:1 to 5: 1.
86. The process according to any one of claims 32 to 49, further comprising the preparation of a crystal form of daprodustat as defined in the claims 1 to 16 by the process as defined in any of the claims 17 to 21.
87. The process according to any one of claims 51 to 68, further comprising the preparation of a crystal form of daprodustat as defined in the claims 1 to 16 by the process as defined in any of the claims 17 to 21.
88. The process according to any one of claims 70 to 85, further comprising the preparation of a crystal form of daprodustat as defined in the claims 1 to 16 by the process as defined in any of the claims 17 to 21.
89. The process according to claim 69, further comprising the preparation of a crystal form of daprodustat as defined in the claims 1 to 16 by the process as defined in any of the claims 22 to 29.
90. The process for the preparation of the crystal form of daprodustat according to claims 17 to 21 , wherein daprodustat free acid is prepared by the process as defined in any of the claims 32 to 49, or alternatively by the process as defined in any of the claims 51 to 68, or alternatively by the process as defined in any of the claims 70 to 85.
91 . The process for the preparation of the crystal form of daprodustat according to claims 22 to 29, wherein the ester intermediate of formula (VI) is prepared by the process as defined in claim 69.
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