WO2017056031A1 - Process for preparation of lumacaftor - Google Patents
Process for preparation of lumacaftor Download PDFInfo
- Publication number
- WO2017056031A1 WO2017056031A1 PCT/IB2016/055826 IB2016055826W WO2017056031A1 WO 2017056031 A1 WO2017056031 A1 WO 2017056031A1 IB 2016055826 W IB2016055826 W IB 2016055826W WO 2017056031 A1 WO2017056031 A1 WO 2017056031A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lumacaftor
- compound
- formula
- acid
- hydrobromide
- Prior art date
Links
- UFSKUSARDNFIRC-UHFFFAOYSA-N lumacaftor Chemical compound N1=C(C=2C=C(C=CC=2)C(O)=O)C(C)=CC=C1NC(=O)C1(C=2C=C3OC(F)(F)OC3=CC=2)CC1 UFSKUSARDNFIRC-UHFFFAOYSA-N 0.000 title claims abstract description 277
- 229960000998 lumacaftor Drugs 0.000 title claims abstract description 277
- 238000000034 method Methods 0.000 title claims abstract description 153
- 230000008569 process Effects 0.000 title claims abstract description 144
- 238000002360 preparation method Methods 0.000 title claims abstract description 79
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 85
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 144
- 239000000203 mixture Substances 0.000 claims description 122
- 239000002904 solvent Substances 0.000 claims description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 65
- 239000012044 organic layer Substances 0.000 claims description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 34
- 229930195733 hydrocarbon Natural products 0.000 claims description 32
- 150000002430 hydrocarbons Chemical class 0.000 claims description 32
- 150000001298 alcohols Chemical class 0.000 claims description 31
- 150000002148 esters Chemical class 0.000 claims description 30
- 150000002170 ethers Chemical class 0.000 claims description 30
- 150000002576 ketones Chemical class 0.000 claims description 29
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 29
- 239000002585 base Substances 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 25
- 150000008282 halocarbons Chemical class 0.000 claims description 22
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
- -1 boronic acid ester Chemical group 0.000 claims description 16
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 14
- 238000001704 evaporation Methods 0.000 claims description 14
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 14
- 239000012296 anti-solvent Substances 0.000 claims description 13
- 239000012535 impurity Substances 0.000 claims description 13
- 239000007800 oxidant agent Substances 0.000 claims description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 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 12
- 238000001914 filtration Methods 0.000 claims description 11
- 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 claims description 11
- 125000005620 boronic acid group Chemical group 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 238000004108 freeze drying Methods 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 230000003213 activating effect Effects 0.000 claims description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 7
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 claims description 7
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 7
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 claims description 7
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 7
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 6
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 6
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- 239000010409 thin film Substances 0.000 claims description 5
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- BLFRQYKZFKYQLO-UHFFFAOYSA-N 4-aminobutan-1-ol Chemical compound NCCCCO BLFRQYKZFKYQLO-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims description 4
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- MLWPJXZKQOPTKZ-UHFFFAOYSA-N benzenesulfonyl benzenesulfonate Chemical compound C=1C=CC=CC=1S(=O)(=O)OS(=O)(=O)C1=CC=CC=C1 MLWPJXZKQOPTKZ-UHFFFAOYSA-N 0.000 claims description 4
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 229960002510 mandelic acid Drugs 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 claims description 4
- 229940087646 methanolamine Drugs 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 claims description 4
- 229960004889 salicylic acid Drugs 0.000 claims description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims description 3
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 2
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 111
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- 239000000243 solution Substances 0.000 description 101
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 58
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 47
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 45
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 32
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 30
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 30
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 28
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 28
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- 239000010410 layer Substances 0.000 description 20
- 229960004592 isopropanol Drugs 0.000 description 19
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 17
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 17
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 239000008096 xylene Substances 0.000 description 16
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 15
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 15
- 229940044613 1-propanol Drugs 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 229960004756 ethanol Drugs 0.000 description 14
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 14
- 229940011051 isopropyl acetate Drugs 0.000 description 14
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- DDCMBKXJOGOCPM-UHFFFAOYSA-N 6-bromo-5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1Br DDCMBKXJOGOCPM-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 229940113088 dimethylacetamide Drugs 0.000 description 9
- 229920001684 low density polyethylene Polymers 0.000 description 9
- 239000004702 low-density polyethylene Substances 0.000 description 9
- 150000001350 alkyl halides Chemical class 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- RAQYFPHUNLDWFT-UHFFFAOYSA-N 2-bromo-3-methyl-1-oxidopyridin-1-ium Chemical compound CC1=CC=C[N+]([O-])=C1Br RAQYFPHUNLDWFT-UHFFFAOYSA-N 0.000 description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 6
- 239000003610 charcoal Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 5
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 229920001903 high density polyethylene Polymers 0.000 description 5
- 239000004700 high-density polyethylene Substances 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 4
- DBVFWZMQJQMJCB-UHFFFAOYSA-N 3-boronobenzoic acid Chemical compound OB(O)C1=CC=CC(C(O)=O)=C1 DBVFWZMQJQMJCB-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 0 Cc(cc1)c(*)nc1N Chemical compound Cc(cc1)c(*)nc1N 0.000 description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
- 150000001398 aluminium Chemical class 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 235000011118 potassium hydroxide Nutrition 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
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- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
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- KPZRCZMNXPBHEH-UHFFFAOYSA-N 6-chloro-5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1Cl KPZRCZMNXPBHEH-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
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- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
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- 238000005119 centrifugation Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
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- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
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- XXQBEVHPUKOQEO-UHFFFAOYSA-N potassium superoxide Chemical compound [K+].[K+].[O-][O-] XXQBEVHPUKOQEO-UHFFFAOYSA-N 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
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- NYMGGRYETCRBSP-UHFFFAOYSA-N 2-bromo-3-methylpyridin-4-amine Chemical compound CC1=C(N)C=CN=C1Br NYMGGRYETCRBSP-UHFFFAOYSA-N 0.000 description 1
- PZSISEFPCYMBDL-UHFFFAOYSA-N 2-bromo-3-methylpyridine Chemical compound CC1=CC=CN=C1Br PZSISEFPCYMBDL-UHFFFAOYSA-N 0.000 description 1
- RKVUCIFREKHYTL-UHFFFAOYSA-N 2-chloro-3-methylpyridine Chemical compound CC1=CC=CN=C1Cl RKVUCIFREKHYTL-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- JEBYXSWYKXOFLX-UHFFFAOYSA-N 3-hydroxy-2-methylpentanedinitrile Chemical compound N#CC(C)C(O)CC#N JEBYXSWYKXOFLX-UHFFFAOYSA-N 0.000 description 1
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 1
- 101150029409 CFTR gene Proteins 0.000 description 1
- 239000004343 Calcium peroxide Substances 0.000 description 1
- UPZBUMQCVJLHAX-UHFFFAOYSA-N Cc(cc1)c(-c2cc(C#N)ccc2)nc1N Chemical compound Cc(cc1)c(-c2cc(C#N)ccc2)nc1N UPZBUMQCVJLHAX-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- SPAGIJMPHSUYSE-UHFFFAOYSA-N Magnesium peroxide Chemical compound [Mg+2].[O-][O-] SPAGIJMPHSUYSE-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- XDBHWPLGGBLUHH-UHFFFAOYSA-N N#Cc1cccc(B(O)O)c1 Chemical compound N#Cc1cccc(B(O)O)c1 XDBHWPLGGBLUHH-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- FVNYSBKXILOVTD-UHFFFAOYSA-N O=C(C1(CC1)c(cc1O2)ccc1OC2(F)F)Cl Chemical compound O=C(C1(CC1)c(cc1O2)ccc1OC2(F)F)Cl FVNYSBKXILOVTD-UHFFFAOYSA-N 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000012317 TBTU Substances 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- ZJRXSAYFZMGQFP-UHFFFAOYSA-N barium peroxide Chemical compound [Ba+2].[O-][O-] ZJRXSAYFZMGQFP-UHFFFAOYSA-N 0.000 description 1
- 150000005130 benzoxazines Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- LHJQIRIGXXHNLA-UHFFFAOYSA-N calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 description 1
- 235000019402 calcium peroxide Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- DLINORNFHVEIFE-UHFFFAOYSA-N hydrogen peroxide;zinc Chemical compound [Zn].OO DLINORNFHVEIFE-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- PURKAOJPTOLRMP-UHFFFAOYSA-N ivacaftor Chemical compound C1=C(O)C(C(C)(C)C)=CC(C(C)(C)C)=C1NC(=O)C1=CNC2=CC=CC=C2C1=O PURKAOJPTOLRMP-UHFFFAOYSA-N 0.000 description 1
- 229960004508 ivacaftor Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- HPGPEWYJWRWDTP-UHFFFAOYSA-N lithium peroxide Chemical compound [Li+].[Li+].[O-][O-] HPGPEWYJWRWDTP-UHFFFAOYSA-N 0.000 description 1
- 229960004995 magnesium peroxide Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
- 229940105296 zinc peroxide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
Definitions
- the present invention relates to a process for the preparation of amorphous lumacaftor.
- the present invention relates to a process for the preparation of intermediate 6-amino-2-halo-3 -methyl pyridine compounds used in the preparation of lumacaftor.
- the present invention relates to lumacaftor hydrobromide, process for its preparation and conversion thereof to lumacaftor.
- Lumacaftor also known as 3-[6-( ⁇ [l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl ⁇ amino)-3-methylpyridin-2-yl]benzoic acid, is represented by the structure of formula I.
- Lumacaftor in combination with ivacaftor, is indicated for the treatment of cystic fibrosis in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.
- X is selected from the group consisting of CI, Br, I.
- J. Org. Chem., 1962, 27, 2473-2478 discloses preparation of the compound of formula V, wherein X is Br, from rarely available chemical 3-hydroxy-2- methylglutaronitrile with very poor yield. Highly corrosive hydrogen bromide gas was bubbled within the process. Product was isolated via multiple purification steps.
- the object of the present invention is to provide a more convenient and more efficient method, involving less number of steps and avoiding inherently dangerous transformations, than the previously known methods for the synthesis of 6-amino-2-halo- 3-methylpyridine compounds of formula V.
- the object of the present invention is to provide lumacaftor via lumacaftor hydrobromide.
- the present invention provides a process for the preparation of lumacaftor, a compound of formula I
- step (b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide;
- the present invention provides lumacaftor hydrobromide.
- the present invention provides a process for the preparation of lumacaftor hydrobromide, the process comprising: (i) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
- step (ii) adding hydrobromic acid to the solution of step (i);
- the present invention provides an amorphous form of lumacaftor.
- the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
- step (b) obtaining amorphous lumacaftor from the mixture of step (a);
- the present invention provides a stable amorphous form of lumacaftor.
- the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
- step (c) optionally, separating the aqueous and organic layers from the mixture of step (b);
- step (d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).
- the present invention provides use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor.
- the present invention provides a process for the preparation of lumacaftor a compound of formula I,
- the present invention provides a compound of formula
- Figure 1 is the proton NMR spectrum of compound of formula Ila.
- Figure 2 is a characteristic XRPD of amorphous lumacaftor as obtained in example 24.
- Figure 3 is the proton NMR spectrum of lumacaftor hydrobromide.
- Figure 4 is a characteristic XRPD of lumacaftor hydrobromide as obtained in example 20.
- Figure 5 is a TGA thermogram of lumacaftor hydrobromide as obtained in example 20.
- the present invention provides a process for the preparation of lumacaftor, a compound of formula I
- step (b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide;
- room temperature means a temperature of about 25°C to about 30°C.
- X is selected from the group consisting of CI, Br, I; (ii) aminating the compound of form a compound of formula V;
- R represents boronic acid, boronic acid ester
- a suitable oxidising agent includes but is not limited to peroxides such as hydrogen peroxide, sodium peroxide, potassium peroxide, lithium peroxide, barium peroxide, magnesium peroxide, calcium peroxide, zinc peroxide and the like; peracids such as peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid and the like; per carbamide.
- peroxides such as hydrogen peroxide, sodium peroxide, potassium peroxide, lithium peroxide, barium peroxide, magnesium peroxide, calcium peroxide, zinc peroxide and the like
- peracids such as peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid and the like
- per carbamide Preferably, the oxidising agent selected is 3-chloroperbenzoic acid.
- the reaction may be carried out in the presence of a suitable solvent.
- the suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
- the solvent selected is dichloromethane.
- the reaction may be carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, p- toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride.
- the activating reagent selected is trifluoromethansulfonic anhydride, methanesulfonic anhydride.
- the reaction may be carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6- trimethylpyridine.
- a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6- trimethylpyridine.
- the base selected is pyridine, triethylamine.
- the reaction may be carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, ieri-butylamine, ammonia, sodamide.
- an aminating reagent selected is ethanolamine.
- the reaction may be carried out in the presence of a suitable solvent.
- the suitable solvent includes but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof.
- the solvent selected is acetonitrile.
- the compound of formula VII, wherein X is Br, is aminated to give the compound of formula V.
- the compound of formula V is purified by a process comprising: (x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and
- a suitable acid includes but is not limited to /7-toluenesulphonic acid and the like.
- a suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- the compound of formula V is purified by a process comprising:
- the compound of formula V is obtained in a purity of >99%.
- the reaction may be carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.
- a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.
- the base selected is triethylamine, pyridine.
- the reaction may be carried out in the presence of a suitable solvent.
- the suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; N-methyl-2-pyrrolidone; or mixtures thereof.
- the solvent selected is dichloromethane.
- the compound of formula V, wherein X is Br is reacted with the compound of formula IV to ive the compound of formula Ila,
- a suitable metal catalyst includes but is not limited to Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (dppf), Pd(OAc) 2 , NiCl 2 (PPh 3 ) 2 , PdCl 2 (dppb), PdCl 2 (PhCN) 2 , Pd(dba) 2 .
- the metal catalyst selected is PdCl 2 (dppf), PdCl 2 (PPh 3 ) 2 .
- the reaction may be carried out in the presence of a base which includes organic base such as triethylamine, N-methylmorpholine, DBU; inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
- organic base such as triethylamine, N-methylmorpholine, DBU
- inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
- the base is selected from inorganic base and more preferably the base is potassium carbonate.
- the reaction may be carried out in the presence of a suitable solvent.
- the suitable solvent includes but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexan
- the compound of formula II, wherein X is Br is reacted with the compound of formula III, wherein R is boronic acid, to give lumacaftor.
- lumacaftor obtained in step (a) is reacted with hydrobromic acid to form lumacaftor hydrobromide.
- the reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenz
- the reaction may be carried out at a temperature in the range of about 10°C to 100°C.
- the stirring time may range from about 2 hours to about 12 hours, or longer.
- the level of any single impurity in the lumacaftor hydrobromide obtained in step (b) is less than 0.15% w/w of lumacaftor hydrobromide.
- the compound of formula II is less than 0.15% w/w of lumacaftor hydrobromide.
- step (iii) optionally, separating the aqueous and organic layers from the mixture of step (ii); (iv) isolating lumacaftor from the mixture of step (ii) or the organic layer of step (iii).
- the reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenz
- the mixture of lumacaftor hydrobromide in the solvent may be stirred for a period of about 10 hours to about 24 hours, or longer.
- the temperature may range from about 20°C to about 40°C.
- the mixture may be stirred in the presence or absence of a base.
- a suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- step (iii) of the above process the aqueous and organic layers from the mixture of step (ii) are separated to give organic layer which contains lumacaftor.
- step (iv) of the above process lumacaftor is isolated by a process comprising: (p) removing the solvent from the mixture of step (ii) or the organic layer of step (iii); or (q) treating the mixture of step (ii) or the organic layer of step (iii) with an anti-solvent; or
- step (r) partially or completely evaporating the mixture of step (ii) or the organic layer of step (iii) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or
- the anti-solvent is selected such that lumacaftor is precipitated out from the solution.
- the organic solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene,
- Removal of solvent may be accomplished by filtering the obtained solid, substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
- the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
- lumacaftor hydrobromide is converted to lumacaftor by a process comprising:
- step (iii) separating the aqueous and organic layers from the mixture of step (ii);
- step (iv) isolating lumacaftor from the organic layer of step (iii) by completely evaporating the organic layer of step (iii) and adding an organic solvent selected from hydrocarbons to the obtained reaction mass followed by removal of the solvent by filtering the obtained solid.
- the lumacaftor obtained by above process is in polymorphic form I.
- lumacaftor hydrobromide is converted to lumacaftor by a process comprising:
- step (iii) separating the aqueous and organic layers from the mixture of step (ii);
- step (iv) isolating lumacaftor from the organic layer of step (iii) by a process comprising: (r) completely evaporating the organic layer of step (iii) and adding an organic solvent selected from alcohols to the obtained reaction mass followed by removal of the solvent.
- the lumacaftor isolated in step (iv) is in amorphous form.
- the lumacaftor obtained in step (c) has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.
- the present invention provides lumacaftor obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:
- Sample concentration of 500 ppm was prepared in diluent containing Mobile phase A and Mobile phase B (20:80 v/v).
- the retention time of lumacaftor is about 17.5 minutes under these conditions.
- Relative retention time for compound of formula II is about 1.3 with respect to lumacaftor.
- the present invention provides lumacaftor hydrobromide.
- the present invention provides lumacaftor hydrobromide characterized by a proton NMR spectrum having peak positions at 9.13 (s,lH), 7.98-7.92 (m,3H), 7.84-7.82 (m,lH), 7.73-7.70 (m,lH), 7.59-7.52 (m,2H), 7.38-7.30 (m,2H), 2.21 (s,3H), 1.51 (m,2H), 1.17 (m,2H) ppm.
- the present invention provides lumacaftor hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 4.
- XRPD X-ray powder diffraction
- the present invention provides lumacaftor hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 9.08, 10.18, 10.56, 14.34, 17.36, 18.63, 18.8, 25.61 and 25.87 ⁇ 0.2 degrees 2 theta.
- XRPD X-ray powder diffraction
- the present invention provides lumacaftor hydrobromide characterized by TGA thermogram as depicted in Figure 5.
- the present invention provides process for the preparation of lumacaftor hydrobromide, the process comprising:
- step (ii) adding hydrobromic acid to the solution of step (i);
- the solvent used for dissolution includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene
- Suitable temperature for dissolution may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer.
- the solution may be optionally treated with charcoal and filtered to get a particle-free solution.
- step (iii) of the above process lumacaftor hydrobromide is obtained by stirring the mixture of step (ii).
- Stirring may be carried out for a period of about 10 hours to about 24 hours, or longer till lumacaftor hydrobromide is precipitated out from the mixture.
- Lumacaftor hydrobromide is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
- the present invention provides a process for the preparation of lumacaftor, a compound of formula I
- X is selected from the group consisting of CI, Br, I;
- R represents boronic acid, boronic acid ester
- the present invention further provides a process comprising:
- step (i) reacting lumacaftor obtained in step (d) with an acid selected from the group of hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid in a solvent to form salt of lumacaftor; and
- lumacaftor is reacted with hydrobromic acid to form lumacaftor hydrobromide which is converted to lumacaftor.
- the level of any single impurity in the lumacaftor hydrobromide, obtained by a process as described herein, is less than 0.15% w/w of lumacaftor hydrobromide.
- the lumacaftor has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.
- the present invention provides a process for the preparation of salts of lumacaftor, the process comprising:
- step (b) obtaining salt of lumacaftor from the solution of step (a);
- the salt of lumacaftor includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
- the reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenz
- the present invention rovides a compound of formula Ila,
- the present invention provides use of compound of formula Ila in preparation of lumacaftor.
- the present invention provides a process for the preparation of a compound of formula V,
- X is selected from the group consisting of CI, Br, I,
- the reaction conditions are as discussed supra.
- the compound of formula V is purified by a process comprising:
- the compound of formula V is purified by a process comprising:
- the compound of formula V is obtained in a purity of >99%.
- the compound of formula V is further converted to lumacaftor by the process as described herein.
- the present invention provides an amorphous form of lumacaftor.
- the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
- step (b) obtaining amorphous lumacaftor from the mixture of step (a);
- lumacaftor is dissolved in a suitable solvent to form a solution.
- salt of lumacaftor is dissolved in a suitable solvent to form a solution.
- solvate of lumacaftor is dissolved in a suitable solvent to form a solution.
- the salt of lumacaftor includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
- the solvate of lumacaftor includes solvate with water, methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
- the solvent used for dissolution is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene,
- Suitable temperature for dissolution may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer.
- the solution may be optionally treated with charcoal and filtered to get a particle-free solution.
- amorphous lumacaftor is obtained from the solution of step (a).
- the amorphous lumacaftor is obtained by removing the solvent from the solution obtained in (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
- the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
- the amorphous lumacaftor is obtained by adding an anti- solvent to the solution obtained in (a) to form a mixture and optionally, cooling and stirring the obtained mixture.
- the stirring time may range from about 30 minutes to about 10 hours, or longer.
- the temperature may range from about 0°C to about 90°C.
- the anti-solvent is selected such that amorphous lumacaftor is precipitated out from the solution.
- the anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane
- the amorphous lumacaftor is isolated by any method known in the art.
- the method may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
- the present invention provides a stable amorphous form of lumacaftor.
- stable includes the amorphous form of lumacaftor, after storage for a period of at least three months at about 2°C to about 8°C, shows no change in polymorphic form by X-ray powder diffraction.
- the present invention provides stable amorphous lumacaftor, wherein the lumacaftor has no change in the XRPD pattern after storage for three months at about 2°C to about 8°C. [0124] In one embodiment, the present invention provides stable amorphous lumacaftor, wherein the lumacaftor has no change in the XRPD pattern as determined by absence of any crystalline peaks.
- the present invention provides stable amorphous lumacaftor, having no or little tendency to convert to any of the other polymorphic forms or solvates including hydrates.
- the present invention provides amorphous lumacaftor, obtained by processes as described herein, characterized and analyzed by X-ray powder diffraction with the conditions described below:
- the stable amorphous form of lumacaftor is stored under nitrogen atmosphere and packed in a LDPE (low density polyethylene) bag followed by black LDPE bag optionally containing oxygen busters and sealing it, which is kept in triple laminated aluminium pouch optionally containing oxygen busters and sealing it, which is placed in HDPE (high density polyethylene) drum and stored in controlled environment chamber, at a temperature of about below 8°C.
- LDPE low density polyethylene
- HDPE high density polyethylene
- the stable amorphous form of lumacaftor is stored under nitrogen atmosphere and packed in a LDPE bag followed by black LDPE bag and is kept in triple laminated aluminium pouch placed in HDPE drum at about 2°C to about 8°C.
- the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
- step (c) optionally, separating the aqueous and organic layers from the mixture of step (b); (d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).
- the reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenz
- the mixture of lumacaftor hydrobromide in the solvent may be stirred for a period of about 10 hours to about 24 hours, or longer.
- the temperature may range from about 20°C to about 40°C.
- the mixture may be stirred in the presence or absence of a base.
- a suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- step (c) of the above process the aqueous and organic layers from the mixture of step (b) are separated to give organic layer which contains lumacaftor.
- step (d) of the above process amorphous lumacaftor is isolated by a process comprising:
- step (i) removing the solvent from the mixture of step (b) or the organic layer of step (c); or
- step (ii) treating the mixture of step (b) or the organic layer of step (c) with an anti-solvent; or (iii) partially or completely evaporating the mixture of step (b) or the organic layer of step (c) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or
- the anti-solvent is selected such that lumacaftor is precipitated out from the solution.
- the organic solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl
- Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
- the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
- the present invention provides a process for the preparation of amorphous lumacaftor, the process comprising:
- step (c) separating the aqueous and organic layers from the mixture of step (b);
- step (d) isolating lumacaftor from the organic layer of step (c) by completely evaporating the organic layer of step (c) and adding an organic solvent selected from alcohols to the obtained reaction mass followed by removal of the solvent by spray drying or by complete evaporation on rotavapor under reduced pressure.
- the lumacaftor hydrobromide is prepared by a process comprising:
- X is selected from the group consisting of CI, Br, I;
- R represents boronic acid, boronic acid ester
- step (vi) adding hydrobromic acid to the solution of step (v);
- step (vii) obtaining lumacaftor hydrobromide from the mixture of step (vi);
- the present invention provides use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor. [0141] The present invention provides a process for the preparation of lumacaftor, a compound of formula I
- X is selected from the group consisting of CI, Br, I;
- R represents boronic acid, boronic acid ester
- a suitable activating agent includes but is not limited to thionyl chloride, carbonyldiimidazole (CDI), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HC1), 1 -Hhydroxybenzotriazole (HOBt), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-l- oxide hexafluorophosphate (HBTU), 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC),
- the reaction may be optionally carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.
- a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.
- the present invention provides a process for the preparation of lumacaftor re resented schematically in Scheme I.
- the present invention provides a process for the preparation of solvates of lumacaftor, the process comprising:
- step (b) obtaining solvate of lumacaftor from the solution of step (a);
- the solvate of lumacaftor includes solvate with water, n-propanol, isopropanol, n- butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, hexane, n- heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
- the suitable solvent includes water, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
- the additional solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1- butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane
- step (b) of the process for the preparation of solvate of lumacaftor the solvate of lumacaftor is obtained from the solution of step (a), the process comprising:
- step (ii) removing the solvent from the solution obtained in step (a);
- step (iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
- the anti-solvent is selected such that the solvate of lumacaftor is precipitated out from the solution.
- the anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane
- the present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier may be selected from the group consisting of cellulose derivatives such as croscarmellose sodium, microcrystalline cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethyl cellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methylcellulose phthalate (HPMCP), polymethylacrylate, hypromellose; vinylpyrrolidone polymers such as polyvinylpyrrolidone; polyols such as mannitol, sorbitol and the like; sugars such as lactose.
- cellulose derivatives such as croscarmellose sodium, microcrystalline cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethyl cellulose
- the present invention provides a premix comprising salt of lumacaftor and a pharmaceutically acceptable carrier.
- the present invention provides a process for the preparation of a premix comprising lumacaftor and a pharmaceutically acceptable carrier, the process comprising:
- step (b) adding a pharmaceutically acceptable carrier to the solution prepared in step (a);
- step (c) removing the solvent from the mixture obtained in step (b).
- the solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloro
- the present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier, wherein the lumacaftor is in amorphous form.
- the present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier, wherein the premix contains amorphous lumacaftor in stable form.
- the present invention provides pharmaceutical compositions comprising lumacaftor or salt or solvate thereof obtained by the processes herein described, having a D 50 and D 90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
- the particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state lumacaftor or salt or solvate thereof into any of the foregoing desired particle size range.
- EXAMPLE 7 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
- 6-amino-2-bromo-3-methylpyridine (46.7mg) and triethylamine (38.84mg) in dichloromethane (2.5mL)
- l -(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarbonyl chloride in dichloromethane (2.5mL).
- the reaction mixture was stirred at about 85°C to about 90°C for about 4h, then cooled to about 50°C to about 55°C and filtered to remove the catalyst.
- the filtrate was concentrated under reduced pressure at about 50°C to about 55°C.
- ethyl acetate and water were added.
- the mixture was stirred for about 15min and the two layers were separated.
- the organic layer was concentrated under reduced pressure at about 50°C to about 55°C.
- the residue obtained was dissolved in ethyl acetate and treated with 47% aqueous of hydrobromic acid solution.
- the mixture was stirred for about 12h at about room temperature.
- the solid was filtered, washed with ethyl acetate and dried at about 55°C to about 60°C for about 12h. Yield: 14.3g
- the reaction mixture was stirred at about 85°C to about 90°C for about 4h, then cooled to about 65 °C and filtered to remove the catalyst.
- the filtrate was concentrated under reduced pressure at about 55°C.
- ethyl acetate and water were added. The two layers were separated and the organic layer was washed with brine solution and concentrated under reduced pressure at about 50°C and co- distilled with acetone.
- acetone and concentrated hydrochloric acid were added and the mixture was stirred for about 12h at about room temperature. The solid was filtered, washed with acetone and dried at about 60°C for about 4h.
- 300mL solution was used for spray drying (Spray drying: Outer Temperature: 75-85°C, Aspirator Rate: 1200- 2000rpm and Feed Rate: 20rpm) and the remaining 700mL solution was used for complete evaporation on rotavapor under reduced pressure in five lots at about reflux temperature to give amorphous Lumacaftor.
- amorphous lumacaftor of the present invention is stable and does not undergo polymorphic conversion at temperatures -20 ⁇ 5°C and 5 ⁇ 3°C packed in LDPE bag under nitrogen followed by black LDPE bag and kept in triple laminated aluminium pouch placed in HDPE drum.
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Abstract
The present invention relates to a process for the preparation of amorphous lumacaftor. The present invention relates to a process for the preparation of intermediate 6-amino-2- halo-3-methylpyridine compounds used in the preparation of lumacaftor. The present invention relates to lumacaftor hydrobromide, process for its preparation and conversion thereof to lumacaftor.
Description
PROCESS FOR PREPARATION OF LUMACAFTOR
PRIORITY
[0001] This application claims the benefit of Indian Provisional Application 3746/MUM/2015 filed on October 1, 2015, entitled "PROCESS FOR PREPARATION OF LUMACAFTOR", the contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Technical Field
[0002] The present invention relates to a process for the preparation of amorphous lumacaftor. The present invention relates to a process for the preparation of intermediate 6-amino-2-halo-3 -methyl pyridine compounds used in the preparation of lumacaftor. The present invention relates to lumacaftor hydrobromide, process for its preparation and conversion thereof to lumacaftor.
Description of the Related Art
[0003] Lumacaftor, also known as 3-[6-({[l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid, is represented by the structure of formula I.
[0004] Lumacaftor, in combination with ivacaftor, is indicated for the treatment of cystic fibrosis in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.
[0005] The preparation of lumacaftor involves use of 6-amino-2-halo-3-methylpyridine compounds of formula V,
V
wherein, X is selected from the group consisting of CI, Br, I.
[0006] J. Org. Chem., 1962, 27, 2473-2478 discloses preparation of the compound of formula V, wherein X is Br, from rarely available chemical 3-hydroxy-2- methylglutaronitrile with very poor yield. Highly corrosive hydrogen bromide gas was bubbled within the process. Product was isolated via multiple purification steps.
[0007] The preparation of the compound of formula V, wherein X is Br, was also disclosed in Tetrahedron, 2011, 67(47), 9063-9066. Pyridine- 1 -oxides were treated with benzoxazines to give benzoxazinones as 1 : 1 mixture which on purification with HPLC and subsequent treatment with acid afforded 6-amino-2-halo-3-methylpyridine compounds of formula V. Over all yields were about 10% from pyridine- 1 -oxide.
[0008] The object of the present invention is to provide a more convenient and more efficient method, involving less number of steps and avoiding inherently dangerous transformations, than the previously known methods for the synthesis of 6-amino-2-halo- 3-methylpyridine compounds of formula V.
[0009] Further, the object of the present invention is to provide lumacaftor via lumacaftor hydrobromide.
SUMMARY OF THE INVENTION
[0010] The present invention provides a process for the preparation of lumacaftor, a compound of formula I
(a) obtaining lumacaftor;
(b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide; and
(c) converting lumacaftor hydrobromide to lumacaftor.
[0011] In another embodiment, the present invention provides lumacaftor hydrobromide.
[0012] In another embodiment, the present invention provides a process for the preparation of lumacaftor hydrobromide, the process comprising:
(i) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(ii) adding hydrobromic acid to the solution of step (i);
(iii) obtaining lumacaftor hydrobromide from the mixture of step (ii); and
(iv) isolating lumacaftor hydrobromide.
[0013] In another embodiment, the present invention provides an amorphous form of lumacaftor.
[0014] In another embodiment, the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
(a) providing a mixture of lumacaftor, or salt or solvate thereof, in a suitable solvent;
(b) obtaining amorphous lumacaftor from the mixture of step (a); and
(c) isolating the amorphous lumacaftor.
[0015] In another embodiment, the present invention provides a stable amorphous form of lumacaftor.
[0016] In another embodiment, the present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(b) stirring the mixture obtained in step (a);
(c) optionally, separating the aqueous and organic layers from the mixture of step (b);
(d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).
[0017] In another embodiment, the present invention provides use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor.
[0018] In another embodiment, the present invention provides a process for the preparation of lumacaftor a compound of formula I,
(a) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII,
wherein, X is selected from the group consisting of CI, Br, I;
(c) reacting the compound of formula V with a compound of formula IV to give a compound of formula II and
(d) reacting the compound of formula II with a com ound of formula III,
wherein, R represents boronic acid, boronic acid ester,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
[0019] In another embodiment, the present invention provides a compound of formula
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 is the proton NMR spectrum of compound of formula Ila.
[0021] Figure 2 is a characteristic XRPD of amorphous lumacaftor as obtained in example 24.
[0022] Figure 3 is the proton NMR spectrum of lumacaftor hydrobromide.
[0023] Figure 4 is a characteristic XRPD of lumacaftor hydrobromide as obtained in example 20.
[0024] Figure 5 is a TGA thermogram of lumacaftor hydrobromide as obtained in example 20.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention provides a process for the preparation of lumacaftor, a compound of formula I
I
the process comprising:
(a) obtaining lumacaftor;
(b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide; and
(c) converting lumacaftor hydrobromide to lumacaftor.
[0026] In the present application, the term "room temperature" means a temperature of about 25°C to about 30°C.
[0027] In (a) of the above process, lumacaftor is obtained by a process comprising:
VI I I VI I
wherein, X is selected from the group consisting of CI, Br, I;
(ii) aminating the compound of form a compound of formula V;
(iii) reacting the compound of formula V with a compound of formula TV to give a compound of formula II and
I II
wherein, R represents boronic acid, boronic acid ester,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
[0028] In (i) of the process for the preparation of lumacaftor, the compound of formula Vni is reacted with an oxidising agent to give the compound of formula VII.
[0029] A suitable oxidising agent includes but is not limited to peroxides such as hydrogen peroxide, sodium peroxide, potassium peroxide, lithium peroxide, barium peroxide, magnesium peroxide, calcium peroxide, zinc peroxide and the like; peracids such as peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid and the like; per carbamide. Preferably, the oxidising agent selected is 3-chloroperbenzoic acid.
[0030] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof. Preferably, the solvent selected is dichloromethane.
[0031] In one embodiment, the compound of formula VIII, wherein X is Br, is reacted with an oxidising agent to give the compound of formula VII.
[0032] In (ii) of the process for the preparation of lumacaftor, the compound of formula VII is aminated to give the compound of formula V.
[0033] The reaction may be carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, p- toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride. Preferably, the activating reagent selected is trifluoromethansulfonic anhydride, methanesulfonic anhydride.
[0034] The reaction may be carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6- trimethylpyridine. Preferably, the base selected is pyridine, triethylamine.
[0035] The reaction may be carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, ieri-butylamine, ammonia, sodamide. Preferably, the aminating reagent selected is ethanolamine.
[0036] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof. Preferably, the solvent selected is acetonitrile.
[0037] In one embodiment, the compound of formula VII, wherein X is Br, is aminated to give the compound of formula V.
[0038] In one embodiment, the compound of formula V is purified by a process comprising:
(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and
(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.
[0039] A suitable acid includes but is not limited to /7-toluenesulphonic acid and the like.
[0040] A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
[0041] In one embodiment, the compound of formula V is purified by a process comprising:
(x) reacting the compound of formula V with /7-toluenesulphonic acid to form p- toluenesulphonic acid salt of the compound of formula V; and
(y) treating the /7-toluenesulphonic acid salt of the compound of formula V with a base to give the compound of formula V.
[0042] In one embodiment, the compound of formula V is obtained in a purity of >99%.
[0043] In (iii) of the process for the preparation of lumacaftor, the compound of formula V is reacted with the compound of formula IV to give the compound of formula II.
[0044] The reaction may be carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine. Preferably, the base selected is triethylamine, pyridine.
[0045] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; acetonitrile; dimethyl
formamide; dimethyl sulfoxide; dimethyl acetamide; N-methyl-2-pyrrolidone; or mixtures thereof. Preferably, the solvent selected is dichloromethane.
[0046] In one embodiment, the compound of formula V, wherein X is Br, is reacted with the compound of formula IV to ive the compound of formula Ila,
I la
[0047] In (iv) of the process for the preparation of lumacaftor, the compound of formula II is reacted with the compound of formula III in the presence of a metal catalyst to give lumacaftor.
[0048] A suitable metal catalyst includes but is not limited to Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf), Pd(OAc)2, NiCl2(PPh3)2, PdCl2(dppb), PdCl2(PhCN)2, Pd(dba)2. Preferably, the metal catalyst selected is PdCl2(dppf), PdCl2(PPh3)2.
[0049] The reaction may be carried out in the presence of a base which includes organic base such as triethylamine, N-methylmorpholine, DBU; inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Preferably, the base is selected from inorganic base and more preferably the base is potassium carbonate.
[0050] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; acetonitrile; dimethyl formamide; dimethyl sulfoxide; dimethyl acetamide; water or mixtures thereof. Preferably, the solvent selected is toluene, dioxane.
[0051] In one embodiment, the compound of formula II, wherein X is Br, is reacted with the compound of formula III, wherein R is boronic acid, to give lumacaftor.
[0052] In (b) of the above process, lumacaftor obtained in step (a) is reacted with hydrobromic acid to form lumacaftor hydrobromide.
[0053] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.
[0054] The reaction may be carried out at a temperature in the range of about 10°C to 100°C. The stirring time may range from about 2 hours to about 12 hours, or longer.
[0055] In one embodiment, the level of any single impurity in the lumacaftor hydrobromide obtained in step (b) is less than 0.15% w/w of lumacaftor hydrobromide.
I I
[0057] In one embodiment, the compound of formula II is less than 0.15% w/w of lumacaftor hydrobromide.
[0058] In (c) of the above process, lumacaftor hydrobromide is converted to lumacaftor by a process comprising:
(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(ii) stirring the mixture obtained in step (i);
(iii) optionally, separating the aqueous and organic layers from the mixture of step (ii); (iv) isolating lumacaftor from the mixture of step (ii) or the organic layer of step (iii).
[0059] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like;
halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.
[0060] The mixture of lumacaftor hydrobromide in the solvent may be stirred for a period of about 10 hours to about 24 hours, or longer. The temperature may range from about 20°C to about 40°C.
[0061] The mixture may be stirred in the presence or absence of a base. A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
[0062] In step (iii) of the above process, the aqueous and organic layers from the mixture of step (ii) are separated to give organic layer which contains lumacaftor.
[0063] In step (iv) of the above process, lumacaftor is isolated by a process comprising: (p) removing the solvent from the mixture of step (ii) or the organic layer of step (iii); or (q) treating the mixture of step (ii) or the organic layer of step (iii) with an anti-solvent; or
(r) partially or completely evaporating the mixture of step (ii) or the organic layer of step (iii) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or
(s) filtering the mixture of step (ii).
[0064] The anti-solvent is selected such that lumacaftor is precipitated out from the solution.
[0065] The organic solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether,
tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; or mixtures thereof.
[0066] Removal of solvent may be accomplished by filtering the obtained solid, substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
[0067] In one embodiment, lumacaftor hydrobromide is converted to lumacaftor by a process comprising:
(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from ester-water mixture;
(ii) stirring the mixture obtained in step (i);
(iii) separating the aqueous and organic layers from the mixture of step (ii);
(iv) isolating lumacaftor from the organic layer of step (iii) by completely evaporating the organic layer of step (iii) and adding an organic solvent selected from hydrocarbons to the obtained reaction mass followed by removal of the solvent by filtering the obtained solid.
[0068] In one embodiment, the lumacaftor obtained by above process is in polymorphic form I.
[0069] In one embodiment, lumacaftor hydrobromide is converted to lumacaftor by a process comprising:
(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from ester-water mixture;
(ii) stirring the mixture obtained in step (i);
(iii) separating the aqueous and organic layers from the mixture of step (ii);
(iv) isolating lumacaftor from the organic layer of step (iii) by a process comprising:
(r) completely evaporating the organic layer of step (iii) and adding an organic solvent selected from alcohols to the obtained reaction mass followed by removal of the solvent.
[0070] In one embodiment, the lumacaftor isolated in step (iv) is in amorphous form.
[0071] In one embodiment, the lumacaftor obtained in step (c) has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.
[0072] The present invention provides lumacaftor obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:
Column: Zorbax SB, C8, (75 x 4.6mm, 3.5μ)
Mobile Phase A: 0.05% TFA in Water
Mobile Phase B: Acetonitrile containing 0.05% TFA
Sample concentration of 500 ppm was prepared in diluent containing Mobile phase A and Mobile phase B (20:80 v/v).
Gradient elution was performed with a flow rate of 1 mL/min.
The retention time of lumacaftor is about 17.5 minutes under these conditions.
Relative retention time for compound of formula II is about 1.3 with respect to lumacaftor.
[0073] The present invention provides lumacaftor hydrobromide.
[0074] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by a proton NMR spectrum having peak positions at 9.13 (s,lH), 7.98-7.92 (m,3H), 7.84-7.82 (m,lH), 7.73-7.70 (m,lH), 7.59-7.52 (m,2H), 7.38-7.30 (m,2H), 2.21 (s,3H), 1.51 (m,2H), 1.17 (m,2H) ppm.
[0075] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 4.
[0076] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections
at about 9.08, 10.18, 10.56, 14.34, 17.36, 18.63, 18.8, 25.61 and 25.87 ±0.2 degrees 2 theta.
[0077] In one embodiment, the present invention provides lumacaftor hydrobromide characterized by TGA thermogram as depicted in Figure 5.
[0078] The present invention provides process for the preparation of lumacaftor hydrobromide, the process comprising:
(i) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(ii) adding hydrobromic acid to the solution of step (i);
(iii) obtaining lumacaftor hydrobromide from the mixture of step (ii); and
(iv) isolating lumacaftor hydrobromide.
[0079] The solvent used for dissolution includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.
[0080] Suitable temperature for dissolution may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
[0081] In step (iii) of the above process, lumacaftor hydrobromide is obtained by stirring the mixture of step (ii).
[0082] Stirring may be carried out for a period of about 10 hours to about 24 hours, or longer till lumacaftor hydrobromide is precipitated out from the mixture.
[0083] Lumacaftor hydrobromide is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
[0084] The present invention provides a process for the preparation of lumacaftor, a compound of formula I
the process comprising:
VI I I VI I
wherein, X is selected from the group consisting of CI, Br, I;
V
(c) reacting the compound of formula V with a compound of formula IV to give a compound of formula II and
IV I I
(d) reacting the compound of formula II with a com ound of formula III,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
[0085] In (a), (b), (c) and (d) of the process for the preparation of lumacaftor, the reaction conditions are as discussed supra.
[0086] In one embodiment, the present invention further provides a process comprising:
(i) reacting lumacaftor obtained in step (d) with an acid selected from the group of hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid in a solvent to form salt of lumacaftor; and
(ii) converting the salt of lumacaftor to lumacaftor.
[0087] In one embodiment, lumacaftor is reacted with hydrobromic acid to form lumacaftor hydrobromide which is converted to lumacaftor.
[0088] The process of reacting lumacaftor with hydrobromic acid to form lumacaftor hydrobromide is as discussed supra.
[0089] In one embodiment, the level of any single impurity in the lumacaftor hydrobromide, obtained by a process as described herein, is less than 0.15% w/w of lumacaftor hydrobromide.
[0090] The process of converting lumacaftor hydrobromide to lumacaftor is as discussed supra.
[0091] In one embodiment, the lumacaftor has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.
[0092] The present invention provides a process for the preparation of salts of lumacaftor, the process comprising:
(a) dissolving lumacaftor in a suitable solvent to form a solution;
(b) obtaining salt of lumacaftor from the solution of step (a); and
(c) isolating the salt of lumacaftor.
[0093] The salt of lumacaftor includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
[0094] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.
Ma
[0096] The present invention provides use of compound of formula Ila in preparation of lumacaftor.
V
wherein, X is selected from the group consisting of CI, Br, I,
the process comprising:
(a) reacting a compound of formula VIII with an oxidising agent to give a compound of formula VII; and
VI I I VI I
(b) aminating the compound of formula VII to give the compound of formula V.
[0098] In (a) and (b) of the process for the preparation of the compound of formula V, the reaction conditions are as discussed supra.
[0099] In one embodiment, the compound of formula V is purified by a process comprising:
(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and
(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.
[0100] The suitable acids used for the preparation of the acid addition salts of the compound of formula V are as discussed supra.
[0101] The suitable bases used for converting the acid addition salts of the compound of formula V to the compound of formula V are as discussed supra.
[0102] In one embodiment, the compound of formula V is purified by a process comprising:
(x) reacting the compound of formula V with /7-toluenesulphonic acid to form p- toluenesulphonic acid salt of the compound of formula V; and
(y) treating the /7-toluenesulphonic acid salt of the compound of formula V with a base to give the compound of formula V.
[0103] In one embodiment, the compound of formula V is obtained in a purity of >99%.
[0104] In one embodiment, the compound of formula V is further converted to lumacaftor by the process as described herein.
[0105] The present invention provides an amorphous form of lumacaftor.
[0106] The present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
(a) providing a mixture of lumacaftor, or salt or solvate thereof, in a suitable solvent;
(b) obtaining amorphous lumacaftor from the mixture of step (a); and
(c) isolating the amorphous lumacaftor.
[0107] In (a) of the process for the preparation of amorphous lumacaftor, lumacaftor or salt or solvate thereof, is dissolved in a suitable solvent to form a solution.
[0108] In one embodiment, lumacaftor is dissolved in a suitable solvent to form a solution.
[0109] In one embodiment, salt of lumacaftor is dissolved in a suitable solvent to form a solution.
[0110] In one embodiment, solvate of lumacaftor is dissolved in a suitable solvent to form a solution.
[0111] The salt of lumacaftor includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
[0112] The solvate of lumacaftor includes solvate with water, methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
[0113] The solvent used for dissolution but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.
[0114] Suitable temperature for dissolution may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
[0115] In (b) of the process for the preparation of amorphous lumacaftor, amorphous lumacaftor is obtained from the solution of step (a).
[0116] In one embodiment, the amorphous lumacaftor is obtained by removing the solvent from the solution obtained in (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling
the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
[0117] In one embodiment, the amorphous lumacaftor is obtained by adding an anti- solvent to the solution obtained in (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to about 90°C.
[0118] The anti-solvent is selected such that amorphous lumacaftor is precipitated out from the solution.
[0119] The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
[0120] In (c) of the process for the preparation of amorphous lumacaftor, the amorphous lumacaftor is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
[0121] The present invention provides a stable amorphous form of lumacaftor.
[0122] As used herein, the term "stable" includes the amorphous form of lumacaftor, after storage for a period of at least three months at about 2°C to about 8°C, shows no change in polymorphic form by X-ray powder diffraction.
[0123] In one embodiment, the present invention provides stable amorphous lumacaftor, wherein the lumacaftor has no change in the XRPD pattern after storage for three months at about 2°C to about 8°C.
[0124] In one embodiment, the present invention provides stable amorphous lumacaftor, wherein the lumacaftor has no change in the XRPD pattern as determined by absence of any crystalline peaks.
[0125] In one embodiment, the present invention provides stable amorphous lumacaftor, having no or little tendency to convert to any of the other polymorphic forms or solvates including hydrates.
[0126] The present invention provides amorphous lumacaftor, obtained by processes as described herein, characterized and analyzed by X-ray powder diffraction with the conditions described below:
X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X'Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X'Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 2Θ range of 2-50° with a "time-per-step" optimized to 50 sec.
[0127] The stable amorphous form of lumacaftor is stored under nitrogen atmosphere and packed in a LDPE (low density polyethylene) bag followed by black LDPE bag optionally containing oxygen busters and sealing it, which is kept in triple laminated aluminium pouch optionally containing oxygen busters and sealing it, which is placed in HDPE (high density polyethylene) drum and stored in controlled environment chamber, at a temperature of about below 8°C. Preferably, the stable amorphous form of lumacaftor is stored under nitrogen atmosphere and packed in a LDPE bag followed by black LDPE bag and is kept in triple laminated aluminium pouch placed in HDPE drum at about 2°C to about 8°C.
[0128] The present invention provides a process for the preparation of amorphous form of lumacaftor, the process comprising:
(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(b) stirring the mixture obtained in step (a);
(c) optionally, separating the aqueous and organic layers from the mixture of step (b);
(d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).
[0129] The reaction may be carried out in a solvent selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; water; or mixtures thereof.
[0130] The mixture of lumacaftor hydrobromide in the solvent may be stirred for a period of about 10 hours to about 24 hours, or longer. The temperature may range from about 20°C to about 40°C.
[0131] The mixture may be stirred in the presence or absence of a base. A suitable base includes but is not limited to an alkali or an alkaline earth metal hydroxide, an alkali or an alkaline earth metal carbonate and the like, an alkali or an alkaline earth metal bicarbonate for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
[0132] In step (c) of the above process, the aqueous and organic layers from the mixture of step (b) are separated to give organic layer which contains lumacaftor.
[0133] In step (d) of the above process, amorphous lumacaftor is isolated by a process comprising:
(i) removing the solvent from the mixture of step (b) or the organic layer of step (c); or
(ii) treating the mixture of step (b) or the organic layer of step (c) with an anti-solvent; or (iii) partially or completely evaporating the mixture of step (b) or the organic layer of step (c) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or
(iv) filtering the mixture of step (b).
[0134] The anti-solvent is selected such that lumacaftor is precipitated out from the solution.
[0135] The organic solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; or mixtures thereof.
[0136] Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
[0137] In one embodiment, the present invention provides a process for the preparation of amorphous lumacaftor, the process comprising:
(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from ester- water mixture;
(b) stirring the mixture obtained in step (a);
(c) separating the aqueous and organic layers from the mixture of step (b);
(d) isolating lumacaftor from the organic layer of step (c) by completely evaporating the organic layer of step (c) and adding an organic solvent selected from alcohols to the obtained reaction mass followed by removal of the solvent by spray drying or by complete evaporation on rotavapor under reduced pressure.
[0138] In one embodiment, the lumacaftor hydrobromide is prepared by a process comprising:
VIII VI I
wherein, X is selected from the group consisting of CI, Br, I;
V
(iii) reacting the compound of formula V with a compound of formula TV to compound of formula II and
I I I
wherein, R represents boronic acid, boronic acid ester,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
(v) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(vi) adding hydrobromic acid to the solution of step (v);
(vii) obtaining lumacaftor hydrobromide from the mixture of step (vi); and
(viii) isolating lumacaftor hydrobromide.
[0139] In (i), (ii), (iii), (iv), (v), (vi), (vii) and (viii) of the process for the preparation of lumacaftor hydrobromide, the reaction conditions are as discussed supra.
[0140] The present invention provides use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor.
[0141] The present invention provides a process for the preparation of lumacaftor, a compound of formula I
I
the process comprising:
VI I I VI I
wherein, X is selected from the group consisting of CI, Br, I;
(c) reacting the compound of formula V with a compound of formula VI in the presence of an activatin agent to give a compound of formula II; and
I II
wherein, R represents boronic acid, boronic acid ester,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
[0142] In (a), (b) and (d) of the process for the preparation of lumacaftor, the reaction conditions are as discussed supra.
[0143] In (c) of the process for the preparation of lumacaftor, the compound of formula V is reacted with a compound of formula VI in the presence of an activating agent to give a compound of formula II.
[0144] A suitable activating agent includes but is not limited to thionyl chloride, carbonyldiimidazole (CDI), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HC1), 1 -Hhydroxybenzotriazole (HOBt), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazol-l- oxide hexafluorophosphate (HBTU), 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), propylphosphonic anhydride (T3P), dicyclohexylcarbodiimide (DCC), 3-hydroxytriazolo[4,5-b]pyridine (HO AT).
[0145] The reaction may be optionally carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di-isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.
[0146] The present invention provides a process for the preparation of lumacaftor re resented schematically in Scheme I.
Scheme I
[0147] The present invention provides use of compounds of formula ΓΧ and X in preparation of lumacaftor.
[0148] The present invention provides a process for the preparation of solvates of lumacaftor, the process comprising:
(a) dissolving lumacaftor in a suitable solvent, optionally in presence of additional solvent, to form a solution;
(b) obtaining solvate of lumacaftor from the solution of step (a); and
(c) isolating the solvate of lumacaftor.
[0149] The solvate of lumacaftor includes solvate with water, n-propanol, isopropanol, n- butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, hexane, n- heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
[0150] The suitable solvent includes water, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
[0151] The additional solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1- butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
[0152] In (b) of the process for the preparation of solvate of lumacaftor, the solvate of lumacaftor is obtained from the solution of step (a), the process comprising:
(i) cooling and stirring the solution obtained in step (a); or
(ii) removing the solvent from the solution obtained in step (a); or
(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
[0153] The anti-solvent is selected such that the solvate of lumacaftor is precipitated out from the solution.
[0154] The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
[0155] The present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier.
[0156] The pharmaceutically acceptable carrier may be selected from the group consisting of cellulose derivatives such as croscarmellose sodium, microcrystalline cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethyl cellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methylcellulose phthalate (HPMCP), polymethylacrylate, hypromellose; vinylpyrrolidone polymers such as polyvinylpyrrolidone; polyols such as mannitol, sorbitol and the like; sugars such as lactose.
[0157] The present invention provides a premix comprising salt of lumacaftor and a pharmaceutically acceptable carrier.
[0158] In one embodiment, the present invention provides a process for the preparation of a premix comprising lumacaftor and a pharmaceutically acceptable carrier, the process comprising:
(a) dissolving lumacaftor in a solvent;
(b) adding a pharmaceutically acceptable carrier to the solution prepared in step (a); and
(c) removing the solvent from the mixture obtained in step (b).
[0159] The solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons
such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
[0160] In one embodiment, the present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier, wherein the lumacaftor is in amorphous form.
[0161] In one embodiment, the present invention provides a premix comprising lumacaftor and a pharmaceutically acceptable carrier, wherein the premix contains amorphous lumacaftor in stable form.
[0162] In one embodiment, the present invention provides pharmaceutical compositions comprising lumacaftor or salt or solvate thereof obtained by the processes herein described, having a D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state lumacaftor or salt or solvate thereof into any of the foregoing desired particle size range.
[0163] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLES
[0164] EXAMPLE 1 Preparation of 2-bromo-3-methylpyridine-l-oxide
To a stirred solution of 2-bromo-3-methylpyridine (50g) in dichloromethane (500mL) was added 3-chloroperbenzoic acid (100g) at about room temperature. The reaction mixture was stirred for about 12h at about room temperature and was filtered. The filtrate was quenched in to saturated sodium thiosulfate solution. The reaction mixture was stirred for about lh at about room temperature. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The solid was purified by column chromatography (5- 7% methanol in ethyl acetate). Yield: 33g (60%)
1H NMR (300MHz, CDC13): δ 8.30-8.29 (m,lH), 7.14-7.12 (m,2H), 2.47 (s,3H)
JR. 3382, 3051, 1670, 1436, 1410, 1275, 1240, 1067, 958, 786, 695, 599 cm"1
Mass [M+H] +: 188.09
[0165] EXAMPLE 2 Preparation of 6-amino-2-bromo-3-methylpyridine
To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (2g) and pyridine (3.3g) in acetonitrile (20mL) at about 70°C, was added a solution of trifluoromethanesulfonic anhydride (4.2g) in acetonitrile (4mL) over about 20min. The reaction mixture was stirred for about lh at about the same temperature. The reaction mixture was allowed to cool to about 10°C to about 15°C and ethanolamine (6. lg) was added to it. The reaction mixture was stirred for about 3h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The residue was purified by column chromatography (10-15% ethyl acetate in hexane). Yield: 600mg (30%)
1H NMR (300MHz, CDCI3): δ 7.31-7.28 (d,J=7.8Hz,lH), 6.46-6.44 (d,J=7.8Hz,lH), 4.02 (brs,2H), 2.26 (s,3H)
JR. 3364, 3200, 2914, 1634, 1601, 1475, 1373, 1057, 820 cm"1
DSC: 94.73°C
A polar compound was obtained (200mg) which was eluted at 20-25% ethyl acetate in hexane.
1H NMR (300MHz, CDC13): δ 7.80-7.79 (d,J =4.8 Ηζ,ΙΗ), 6.46-6.45 (d,J=4.8Hz,lH), 4.38(brs,2H), 2.20 (s,3H)
JR. 3319, 3194, 2925, 1638, 1590, 1480, 1394, 1273, 1199, 1010, 819 cm"1
DSC: 121.47°C
Mass [M+H]+: 187.11
[0166] EXAMPLE 3 Preparation of 6-amino-2-bromo-3-methylpyridine
To a stirred solution of 2-bromo-3 -methyl pyridine- 1 -oxide (25g) and pyridine (42g) in acetonitrile (250mL) at about 70°C, was added a solution of trifluoromethanesulfonic anhydride (55g) in acetonitrile (50mL). The reaction mixture was stirred for about lh at about the same temperature. The mixture was cooled to about 10°C to about 15°C and ethanolamine (80.52g) was added to it. The reaction mixture was stirred for about 3h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The residue was purified by column chromatography (15-20% ethyl acetate in hexane). Yield: 4g (16%)
1H NMR (300MHz, CDC13): δ 7.26-7.24 (d,J=8.10Hz,lH), 6.42-6.39 (d,J=8.4Hz,lH), 4.28 (brs,2H), 2.22 (s,3H)
13C NMR (400MHz, CDCI3): 156.52, 141.56, 140.50, 122.99, 107.26, 20.58
IR: 3364, 3199, 2913, 1635, 1601, 1373, 1058, 819 cm"1
4-Amino-2-bromo-3 -methyl pyridine (3g) was obtained which was eluted at 25-30% ethyl acetate in hexane.
1H NMR (300MHz, CDCI3): δ 7.82-7.80 (d,J=5.4Hz,lH), 6.48-6.46 (d,J =5.4Hz,lH), 4.35 (brs,2H), 2.21 (s,3H)
13C NMR (400MHz, CDC13): 152.70, 146.94, 145.05, 116.88, 109.25, 15.73
[0167] EXAMPLE 4 Preparation of 6-amino-2-bromo-3-methylpyridine
To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (18g) and pyridine (30mL) in acetonitrile (180mL) at about 71 °C, was added a solution of methanesulfonic anhydride (33.31g) in acetonitrile (40mL). The reaction mixture was stirred for about 90min at about the same temperature and acetonitrile (30mL) was added to it. The reaction mixture was cooled to about 10°C to about 15°C and ethanolamine (58.59g) was added to it. The reaction mixture was stirred for about 13h at about room temperature and water and ethyl
acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 45°C. The residue was purified by column chromatography (25-30 % ethyl acetate in hexane). Yield: lO. lg (56%)
1H NMR (300MHz, CDC13): δ 7.24-7.22 (d,J=8.1 Ηζ,ΙΗ), 6.39-6.36 (d,J=8.4 Ηζ,ΙΗ), 4.27 (brs,2H), 2.21 (s,3H)
JR. 3365, 3200, 2915, 1636, 1601, 1475, 1374, 1058, 820 cm"1
Mass [M+H]+: 187.05
[0168] EXAMPLE 5 Preparation of 6-amino-2-bromo-3-methylpyridine
To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (2g) and triethylamine (3.22g) in acetonitrile (20mL) at about 0°C to about 5°C, was added a solution of trifluoromethanesulfonic anhydride (8.9g) in acetonitrile (4mL) over about lOmin. The reaction mixture was stirred for about 2h at about the same temperature. The temperature of the reaction mixture was raised to about 10°C to about 15°C. Ethanolamine (6.1g) was added to the reaction mixture which was maintained for about 12h at about room temperature. Water and ethyl acetate were added to the reaction mixture. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 40°C. The residue was purified by column chromatography (25-30% ethyl acetate in hexane). Yield: 400mg (20%) 1H NMR (300MHz, CDCI3): δ 7.27-7.24 (d,J=8.4Hz,lH), 6.40-6.37 (d,J =7.8Hz,lH), 4.44 (brs,2H), 2.24 (s,3H)
[0169] EXAMPLE 6 Preparation of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride
To a mixture of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (50mg) in thionyl chloride (lmL) was added dimethyl formamide (0.125mL). The reaction mixture was stirred at about room temperature for about 2h. Excess of thionyl chloride and dimethyl formamide were removed in vacuum after co-distilling with toluene and the resulting product was used directly without further purification.
[0170] EXAMPLE 7 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
To a solution of 6-amino-2-bromo-3-methylpyridine (46.7mg) and triethylamine (38.84mg) in dichloromethane (2.5mL) was added a solution of l -(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropanecarbonyl chloride in dichloromethane (2.5mL). The reaction mixture was stirred at about room temperature for about 15h and water was added to it. The two layers were separated and the organic layer was washed with water, dried and concentrated. The crude product was purified by preparative TLC. Yield: 2mg ESI-MS m/z: 410.97 (M)+
1H NMR (300MHz, DMSO-d6): δ 9.36 (s,lH), 7.90-7.87 (d,lH), 7.74 (d,lH), 7.53 (s,lH), 7.38-7.32 (m,2H), 2.25 (s,3H), 1.49 (m,2H), 1.16 (m,2H)
[0171] EXAMPLE 8 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
To the solution of (2,2-difluoro-l,3-benzodioxol-5-yl)-cyclopropane carboxylic acid (250mg) in dichloromethane (5mL) wad added CDI (335mg) and stirred for about 4h at about room temperature. The solvent was evaporated under reduced pressure. The residue was taken into toluene (5mL) and 6-bromo-5-methylpyridin-2-amine (212.4mg) was added to it. The reaction mixture was maintained at about 110°C to about 115°C for about 18h. The reaction mixture was concentrated under vacuum at about 45°C. The residue was purified by column chromatography. Yield: lOOmg
1H NMR (300MHz, DMSO-d6): δ 9.35 (brs,lH), 7.9-7.87 (d,lH,J=8.4Hz), 7.73-7.71 (d,lH,J=8.1Hz ), 7.52 (s,lH), 7.40-7.37 (d,lH,J=8.4Hz), 7.32-7.29(d,lH,J=8.4Hz), 2.25 (s,3H), 1.48(brs,2H), 1.16(brs,2H)
ESI-MS m/z: 411.17 (M)+
[0172] EXAMPLE 9 Preparation of Lumacaftor
To the solution of N-(2-bromo-3-methylpyridin-2-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (50mg) in toluene (lmL) were added potassium carbonate solution (80.66mg in 0.5mL of water) and bis(diphenylphosphino)ferrocenedichloropalladium(II) (1.98mg) catalyst. The reaction mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (22.12mg) was added to it. The reaction mixture was stirred at about 80°C for about 16h and then filtered to remove the catalyst. The filtrate was concentrated under vacuum and the obtained residue purified by column chromatography or preparative TLC.
[0173] EXAMPLE 10 Preparation of 2-chloro-3-methylpyridine-l-oxide
To a stirred solution of 2-chloro-3 -methyl pyridine (lOg) in dichloromethane (150mL) was added 3-chloroperbenzoic acid (26.9g) at about room temperature. The reaction mixture was stirred for about 12h and was filtered. The filtrate was quenched in to saturated sodium thiosulfate solution. The reaction mixture was stirred for about lh. The two layers were separated and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated under reduced pressure at about 45 °C. The solid was purified by column chromatography (50% methanol in ethyl acetate). Yield: 9.1g (98%). 1H NMR (300 MHz, CDC13): δ 8.19 (m,lH), 7.09-7.07 (m,2H), 2.39 (s,3H)
Mass [M+H]+: 143.57
[0174] EXAMPLE 11 Preparation of 6-amino-2-chloro-3-methylpyridine
To a stirred solution of 2-chloro-3 -methyl pyridine- 1 -oxide (9g) and pyridine (19.9mL) in acetonitrile (90mL) at about 65 °C, was added a solution of trifluoroacetic anhydride (19.53g) in acetonitriie (1 8mL). The reaction mixture was stirred for about l h at about 70°C. The reaction mixture was allowed to cool to about 10°C to about 15°C and ethanolamme (37.82g) was added to it. The reaction mixture was maintained for about 12b at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated brine solution, dried and concentrated under reduced pressure at about 45°C. The residue was purified by column chromatography (20-25% ethyl acetate in hexane). Yield: 4. lg (44%). 1H NMR (300MHz, CDC13): δ 7.29-7.26 (d,J=7.8Hz,lH), 6.37-6.34 (d,J=8.1Hz,lH), 4.22 (brs,2H), 2.22 (s,3H)
Mass [M+H] +: 142.58
[0175] EXAMPLE 12 Preparation of 6-amino-2-bromo-3-methylpyridine
To a stirred solution of 2-bromo-3-methylpyridine-l -oxide (20g) and pyridine (34.2mL) in acetonitrile (160mL) at about 70°C, was added a solution of trifluoroacetic anhydride (33.39g) in acetonitrile (20mL). The reaction mixture was stirred for about lh at about the same temperature. The reaction mixture was allowed to cool to about 10°C to about 15°C and ethanolamine (64.6g) was added to it. The reaction mixture was maintained for about 15h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was washed with water and saturated
brine solution, dried and concentrated under reduced pressure at about 50°C to give a residue. HPLC purity of residue: 80.1%, other isomer 9.89%. The residue was dissolved in ethyl acetate and /7-toluenesulphonic acid (3g) was added to it. The precipitated solid was stirred for about 15h at about room temperature and was filtered and washed with ethyl acetate. HPLC purity of salt: 95.51%, other isomer 3.71%. To a stirred slurry of the obtained solid in water was added a solution of sodium carbonate. The precipitated solid was stirred for about 3h at about room temperature, filtered, washed with water and dried at about 45°C for about 15h. Yield: 9.8g (49%); HPLC purity: 99.56%
[0176] EXAMPLE 13 Preparation of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride
To a mixture of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (20g) in toluene (200mL) and dimethyl formamide (5mL) was added thionyl chloride (14.9mL). The reaction mixture was stirred at about 80°C for about 3h. Excess thionyl chloride and solvents were removed under reduced pressure after co-distilling with dichloromethane and the resulting product was used directly without further purification.
[0177] EXAMPLE 14 Preparation of iV-(2-chloro-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
To a solution of 6-amino-2-chloro-3-methylpyridine (H.8g) and pyridine (19.4g) in dichloromethane (200mL) was added a solution of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride in dichloromethane (40mL). The reaction mixture was stirred at about room temperature for about 3h and water was added to it. The two layers were separated and the organic layer was treated with hydrochloric acid solution and then with sodium bicarbonate solution. The organic layer was washed with water, saturated brine solution, then treated with charcoal, filtered through hyflo bed, concentrated under reduced pressure at about 45 °C and was co-distilled with hexane. A mixture of the obtained residue in hexane was stirred for about 5h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 23. lg (76%)
1H NMR (300MHz, DMSO-d6): δ 9.27 (s,lH), 7.88-7.85 (m,lH), 7.76-7.73 (m,lH), 7.51 (m,lH), 7.39-7.29 (m,2H), 2.24 (s,3H), 1.50 (m,2H), 1.15 (m,2H).
Mass [M+H] +: 366.74
HPLC purity: 99.89%
[0178] EXAMPLE 15 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
To a solution of 6-amino-2-bromo-3-methylpyridine (7.72g) and pyridine (9.7g) in dichloromethane (500mL) was added a solution of l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarbonyl chloride in dichloromethane (20mL). The reaction mixture was stirred at about room temperature for about 3h and water was added to it. The two layers were separated and the organic layer was treated with hydrochloric acid solution and then with sodium bicarbonate solution. The organic layer was washed with water, saturated brine solution, then treated with charcoal, filtered through hyflo bed, concentrated under reduced pressure at about 35°C to about 45 °C and was co-distilled with hexane. A mixture of the obtained residue in hexane was stirred for about 5h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 12.4g (73%).
[0179] EXAMPLE 16 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
To a solution of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (20g) in dichloromethane (120mL) was slowly added Ι,Γ-carbonyldiimidazole (CDI) (14.72g) and the reaction mixture was stirred for about lh at about room temperature. The reaction mixture was concentrated under reduced pressure and was co-distilled with toluene at about 50°C. To the obtained residue in toluene (120mL), was added 6-amino-2-bromo-3- methylpyridine (16g). The reaction mixture was maintained at about reflux temperature for about 40h to about 44h. The reaction mixture was cooled to about room temperature and was stirred for about lh. The solid obtained was filtered and toluene was added to the clear filtrate. The organic layer was washed aqueous sodium hydroxide followed by brine solution and concentrated under reduced pressure at about 50°C. A mixture of the obtained residue in hexane was stirred for about 2h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 22g (65%)
[0180] EXAMPLE 17 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
To a solution of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (25g) in toluene (250mL) and dimethylformamide (6.25mL) was slowly added thionyl chloride (14.3mL) and the reaction mixture was stirred for about 3h at about 110°C. The reaction
mixture was concentrated under reduced pressure and was co-distilled with toluene at about 50°C. To the obtained residue in toluene (50mL) were added 6-amino-2-bromo-3- methylpyridine (21.25g) in toluene (250mL) and di-isopropyl ethylamine (52.29mL) at about room temperature. The reaction mixture was maintained for about 3h at about room temperature and water and ethyl acetate were added to it. The two layers were separated and the organic layer was treated with 10% hydrochloric acid solution. The organic layer was washed with water and brine solution, concentrated under reduced pressure at about 45°C and was co-distilled with hexane. Hexane was added to the obtained residue and the mixture was stirred for about 8h. The solid obtained was filtered and dried at about 50°C for about 2h. Yield: 28. lg (66%)
[0181] EXAMPLE 18 Preparation of iV-(2-bromo-3-methylpyridin-2-yl)-l-(2,2- difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxamide
To a solution of l-(2,2-difluoro-l,3-benzodioxol-5-yl)cyclopropanecarboxylic acid (5g) in toluene (50mL) and dimethylformamide (1.25mL) was slowly added thionyl chloride (3.63mL) and the reaction mixture was stirred for about 3h at about 80°C. The reaction mixture was concentrated under reduced pressure at about 50°C. To the obtained residue in dichloromethane (lOmL) were added 6-amino-2-bromo-3-methylpyridine (3.86g) in dichloromethane (50mL) and pyridine (5mL) at about room temperature. The reaction mixture was maintained for about 3h at about room temperature and water was added to it. The two layers were separated and the organic layer was treated with 10% hydrochloric acid solution and then with sodium bicarbonate solution. The organic layer was washed with water and brine solution, treated with charcoal, filtered, concentrated under reduced pressure at about 50°C and was co-distilled with hexane. Hexane was added to the obtained residue and the mixture was stirred for about 6h. The solid obtained was filtered and dried at about 60°C for about 8h. Yield: 65.3g (76%)
[0182] EXAMPLE 19 Preparation of lumacaftor hydrobromide
To the solution of N-(2-chloro-3-methylpyridin-2-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (12g) in 1,4-dioxane (120mL) were added solution of potassium carbonate (18.57g) in water (120mL) and bis(triphenylphosphine)dichloropalladium (1.99g) catalyst. The reaction mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (6.1 lg)
was added to it. The reaction mixture was stirred at about 85°C to about 90°C for about 4h, then cooled to about 50°C to about 55°C and filtered to remove the catalyst. The filtrate was concentrated under reduced pressure at about 50°C to about 55°C. To the obtained residue, ethyl acetate and water were added. The mixture was stirred for about 15min and the two layers were separated. The organic layer was concentrated under reduced pressure at about 50°C to about 55°C. The residue obtained was dissolved in ethyl acetate and treated with 47% aqueous of hydrobromic acid solution. The mixture was stirred for about 12h at about room temperature. The solid was filtered, washed with ethyl acetate and dried at about 55°C to about 60°C for about 12h. Yield: 14.3g
1H NMR (300MHz, DMSO-d6): δ 9.13 (s,lH), 7.98-7.92(m,3H), 7.84-7.82(m,lH), 7.73- 7.70 (m,lH), 7.59-7.52 (m,2H), 7.38-7.30(m,2H), 2.21 (s,3H), 1.51 (m,2H), 1.17 (m,2H) HPLC: 99.88%
Compound of formula II: 0.04%
HBr Content: 15.3%
[0183] EXAMPLE 20 Preparation of lumacaftor hydrobromide
To the solution of N-(2-bromo-3-methylpyridin-2-yl)-l-(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (12g) in 1,4-dioxane (120mL) was added solution of potassium carbonate (16.5g) in water (120mL). The mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (5.53g) and bis(triphenylphosphine)dichloropalladium (1.8g) were added to it. The mixture was stirred at about 90°C to about 95°C for about 3h, then was cooled to about 50°C to about 55°C and filtered through hyflo bed. The filtrate was concentrated under reduced pressure at about 50°C to about 55°C. To the obtained residue, ethyl acetate and water were added. The mixture was stirred for about 15min and the two layers were separated. The organic layer was treated with charcoal, filtered through hyflo bed and concentrated under reduced pressure at about 45°C to about 50°C. The residue obtained was dissolved in ethyl acetate and treated with 48% aqueous of hydrobromic acid solution. The mixture was stirred for about 16h at about room temperature. The solid was filtered, washed with ethyl acetate and dried at about 60°C to about 65°C for about lOh. Yield: 12.5g
HPLC purity: 100%
Compound of formula II: Not detected
DSC: Endotherm (70.84°C, 215.53°C), Exotherm (219.31°C)
1H NMR (300MHz, DMSO-d6): δ 9.13 (s,lH), 8.003-7.85(m,3H), 7.74 (m,lH), 7.72 (m,lH), 7.61-7.54 (m,2H), 7.34-7.31(m,2H), 2.23 (s,3H), 1.52 (m,2H), 1.19 (m,2H)
[0184] EXAMPLE 21 Preparation of lumacaftor hydrochloride
To the solution of N-(2-bromo-3-methylpyridin-2-yl)-l -(2,2-difluoro-l,3-benzodioxol-5- yl)cyclopropanecarboxamide (lOg) in 1,4-dioxane (70mL) and ethanol (25mL) were added solution of potassium carbonate (12g) in water (70mL) and bis(triphenylphosphine)dichloropalladium (0.852g) catalyst. The reaction mixture was stirred for about lh at about room temperature and 3-carboxyphenylboronic acid (4.14g) was added to it. The reaction mixture was stirred at about 85°C to about 90°C for about 4h, then cooled to about 65 °C and filtered to remove the catalyst. The filtrate was concentrated under reduced pressure at about 55°C. To the obtained residue, ethyl acetate and water were added. The two layers were separated and the organic layer was washed with brine solution and concentrated under reduced pressure at about 50°C and co- distilled with acetone. To the obtained residue, acetone and concentrated hydrochloric acid were added and the mixture was stirred for about 12h at about room temperature. The solid was filtered, washed with acetone and dried at about 60°C for about 4h.
HPLC: 99.53%
Compound of formula II: 0.27%
[0185] EXAMPLE 22 Preparation of crystalline lumacaftor
A slurry of lumacaftor hydrobromide in ethyl acetate (18QmL) and water (1 8QmL) was stirred for about 5h at about room temperature. The two layers were separated and the organic layer was washed with water and concentrated under reduced pressure at about 45°C to about 50°C. Hexane (120mL) was added to the obtained residue and the mixture was stirred for about 2h at about room temperature. The solid obtained was filtered, washed with hexane and dried at about 55°C to about 60°C for about 5h. Yield: 5.2g HPLC purity: 99.8%
Compound of formula II: 0.08%
[0186] EXAMPLE 23 Preparation of amorphous lumacaftor
A slurry of lumacaftor hydrobromide (5g) in ethyl acetate (500mL) and water (500mL) was stirred for about 14h at about room temperature. The two layers were separated and
the organic layer was washed with water and brine solution, dried over sodium sulphate and filtered through hyflo bed. Methanol or isopropyl alcohol (120mL) was added to the filtrate and the mixture was concentrated. Methanol or isopropyl alcohol was added to the residue and the mixture was concentrated up to 500mL solution. 300mL solution was used for spray drying (Spray drying: Outer Temperature: 75-85°C, Aspirator Rate: 1200- 2000rpm and Feed Rate: 20rpm) and the remaining 700mL solution was used for complete evaporation on rotavapor under reduced pressure in five lots at about reflux temperature to give amorphous Lumacaftor.
[0187] EXAMPLE 24 Preparation of amorphous lumacaftor
A solution of lumacaftor (l lg) in methanol (440mL) was completely evaporated on rotavapor under reduced pressure in five lots at about reflux temperature to give amorphous lumacaftor. Yield: 10.5g
Stability data of amorphous lumacaftor prepared by the present invention at periodic intervals under various packaging conditions:
Stability data of amorphous lumacaftor at periodic intervals packed in LDPE bag under nitrogen followed by black LDPE bag and kept in triple laminated aluminium pouch placed in HDPE drum under various storage conditions:
Time -20±5°C 5±3°C 25°C/60%RH
2 Weeks Amorphous pattern Amorphous pattern Amorphous pattern
1 Month Amorphous pattern Amorphous pattern Crystalline pattern
2 Months Amorphous pattern Amorphous pattern Crystalline pattern
3 Months Amorphous pattern Amorphous pattern Crystalline pattern
(RH is relative humidity)
The results indicate that the amorphous lumacaftor of the present invention is stable and does not undergo polymorphic conversion at temperatures -20±5°C and 5±3°C packed in LDPE bag under nitrogen followed by black LDPE bag and kept in triple laminated aluminium pouch placed in HDPE drum.
[0188] EXAMPLE 25 Preparation of amorphous lumacaftor
A solution of lumacaftor (lOg) in ethanol (400mL) was completely evaporated on rotavapor under reduced pressure at about 80°C to about 85°C to give amorphous lumacaftor. Yield: 8g
Claims
1. A process for the reparation of lumacaftor, a compound of formula I,
I
the process comprising:
(a) obtaining lumacaftor;
(b) reacting lumacaftor obtained in step (a) with hydrobromic acid to form lumacaftor hydrobromide; and
(c) converting lumacaftor hydrobromide to lumacaftor.
2. The process of claim 1 , wherein the step (b) is carried out in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof, at a temperature in the range of 10°C to 100°C.
3. The process of claim 1, wherein the step (c) of converting lumacaftor hydrobromide to lumacaftor comprises:
(i) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(ii) stirring the mixture obtained in step (i);
(iii) optionally, separating the aqueous and organic layers from the mixture of step (ii);
(iv) isolating lumacaftor from the mixture of step (ii) or the organic layer of step (iii).
4. The process of claim 3, wherein the step (ii) is carried out in the presence or absence of a base.
5. The process of claim 3, wherein the step (iv) of isolating lumacaftor comprises: (p) removing the solvent from the mixture of step (ii) or the organic layer of step (iii); or (q) treating the mixture of step (ii) or the organic layer of step (iii) with an anti-solvent; or
(r) partially or completely evaporating the mixture of step (ii) or the organic layer of step (iii) and adding an organic solvent selected from esters, halogenated hydrocarbons,
ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or
(s) filtering the mixture of step (ii).
6. The process of claim 1, wherein the level of any single impurity in the lumacaftor hydrobromide obtained in step (b) is less than 0.15% w/w of lumacaftor hydrobromide.
I I
8. The process of claim 7, wherein the compound of formula II is less than 0.15% w/w of lumacaftor hydrobromide.
9. The process of claim 1, wherein the lumacaftor obtained in step (c) has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.
10. The process of claim 1, wherein the lumacaftor obtained in step (a) is prepared by a process comprising:
VIII VII
wherein, X is selected from the group consisting of CI, Br, I;
V
(iii) reacting the compound of formula V with a compound of formula TV to compound of formula II; and
II I
wherein, R represents boronic acid, boronic acid ester,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
11. The process of claim 10, wherein step (ii) is carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, /7-toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride.
12. The process of claim 10, wherein step (ii) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6-trimethylpyridine.
13. The process of claim 10, wherein step (ii) is carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, ieri-butylamine, ammonia, sodamide.
14. The process of claim 10, wherein the compound of formula V is purified by a process comprising:
(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and
(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.
15. The process of claim 14, wherein the acid addition salt is a /7-toluenesulphonic acid salt of the compound of formula V.
16. The process of claim 14, wherein the compound of formula V is obtained in a purity of >99%.
17. Lumacaftor hydrobromide.
18. The lumacaftor hydrobromide of claim 17, characterized by a proton NMR spectrum having peak positions at 9.13 (s,lH), 7.98-7.92 (m,3H), 7.84-7.82 (m,lH), 7.73-
7.70 (m,lH), 7.59-7.52 (m,2H), 7.38-7.30 (m,2H), 2.21 (s,3H), 1.51 (m,2H), 1.17 (m,2H) ppm.
19. The lumacaftor hydrobromide of claim 17, characterized by an X-ray powder diffraction (XRPD) spectrum as depicted in Figure 4.
20. The lumacaftor hydrobromide of claim 17, characterized by a TGA thermogram as depicted in Figure 5.
21. A process for the preparation of lumacaftor hydrobromide, the process comprising:
(i) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(ii) adding hydrobromic acid to the solution of step (i);
(iii) obtaining lumacaftor hydrobromide from the mixture of step (ii); and
(iv) isolating lumacaftor hydrobromide.
22. The process of claim 21, wherein the level of any single impurity in the lumacaftor hydrobromide is less than 0.15% w/w of lumacaftor hydrobromide.
23. An amorphous form of lumacaftor.
24. A process for the preparation of amorphous form of lumacaftor, the process comprising:
(a) providing a mixture of lumacaftor, or salt or solvate thereof, in a suitable solvent; (b) obtaining amorphous lumacaftor from the mixture of step (a); and
(c) isolating the amorphous lumacaftor.
25. The process of claim 24, wherein the step (b) of obtaining lumacaftor in amorphous form comprises:
(i) removing the solvent from the solution obtained in step (a); or
(ii) treating the solution of step (a) with an anti-solvent.
26. The process of claim 25, wherein the solvent is removed from the solution by concentrating the solution, or completely evaporating the solvent, or removing the solvent by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
27. A stable amorphous form of lumacaftor.
28. The stable amorphous form of lumacaftor of claim 27, wherein the lumacaftor has no change in the XRD pattern after storage for three months at 2°C to 8°C.
29. A process for the preparation of amorphous form of lumacaftor, the process comprising:
(a) providing a mixture of lumacaftor hydrobromide in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(b) stirring the mixture obtained in step (a);
(c) optionally, separating the aqueous and organic layers from the mixture of step (b); (d) isolating the amorphous lumacaftor from the mixture of step (b) or the organic layer of step (c).
30. The process of claim 29, wherein the step (b) is carried out in the presence or absence of a base.
31. The process of claim 29, wherein the step (d) of isolating the amorphous lumacaftor comprises:
(i) removing the solvent from the mixture of step (b) or the organic layer of step (c); or
(ii) treating the mixture of step (b) or the organic layer of step (c) with an anti-solvent; or
(iii) partially or completely evaporating the mixture of step (b) or the organic layer of step (c) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or
(iv) filtering the mixture of step (b).
32. The process of claim 31, wherein the solvent is removed from the solution by concentrating the solution, or completely evaporating the solvent, or removing the solvent by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
33. The process of claim 29, wherein the lumacaftor hydrobromide is prepared by a process comprising:
VIII VI I
wherein, X is selected from the group consisting of CI, Br, I;
V
(iii) reacting the compound of formula V with a compound of formula TV to give a compound of formula II and
I I I
wherein, R represents boronic acid, boronic acid ester,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
(v) providing a solution of lumacaftor in a solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, water, or mixtures thereof;
(vi) adding hydrobromic acid to the solution of step (v);
(vii) obtaining lumacaftor hydrobromide from the mixture of step (vi); and
(viii) isolating lumacaftor hydrobromide.
34. The process of claim 33, wherein step (ii) is carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, /7-toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride.
35. The process of claim 33, wherein step (ii) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6-trimethylpyridine.
36. The process of claim 33, wherein step (ii) is carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, /er/-butylamine, ammonia, sodamide.
37. The process of claim 33, wherein the compound of formula V is purified by a process comprising:
(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and
(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.
38. The process of claim 37, wherein the acid addition salt is a /7-toluenesulphonic acid salt of the compound of formula V.
39. The process of claim 37, wherein the compound of formula V is obtained in a purity of >99%.
40. The process of claim 33, wherein the level of any single impurity in the lumacaftor hydrobromide is less than 0.15% w/w of lumacaftor hydrobromide.
41. The process of claim 33, wherein the amorphous lumacaftor has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.
42. The use of lumacaftor hydrobromide in the preparation of amorphous form of lumacaftor.
I
the process comprising:
VIII VII
wherein, X is selected from the group consisting of CI, Br, I;
(c) reacting the compound of formula V with a compound of formula IV to give a compound of formula II and
II I
wherein, R represents boronic acid, boronic acid ester,
in the presence of a metal catalyst to give lumacaftor, the compound of formula I.
44. The process of claim 43, wherein X is Br and R is boronic acid.
45. The process of claim 43, wherein step (b) is carried out in the presence of an activating reagent selected from the group consisting of methanesulfonic anhydride, methanesulfonyl chloride, /7-toluenesulfonic anhydride, /7-toluenesulfonyl chloride, trifluoromethansulfonic anhydride, benzenesulfonic anhydride, benzenesulfonyl chloride, trifluoroacetic anhydride.
46. The process of claim 43, wherein step (b) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, dimethylaminopyridine, 2,4,6-trimethylpyridine.
47. The process of claim 43, wherein step (b) is carried out in the presence of an aminating reagent selected from the group consisting of methanolamine, ethanolamine, propanolamine, butanolamine, pentanolamine, hexanolamine, ieri-butylamine, ammonia, sodamide.
48. The process of claim 43, wherein the compound of formula V is purified by a process comprising:
(x) reacting the compound of formula V with an acid to form an acid addition salt of the compound of formula V; and
(y) treating the acid addition salt of the compound of formula V with a base to give the compound of formula V.
49. The process of claim 48 wherein the acid addition salt is a /7-toluenesulphonic acid salt of the compound of formula V.
50. The process of claim 48, wherein the compound of formula V is obtained in a purity of >99%.
51. The process of claim 43, wherein step (c) is carried out in the presence of a base selected from the group consisting of pyridine, triethylamine, trimethylamine, methylamine, diethylamine, ethylmethylamine, diethylmethylamine, tripropylamine, di- isopropyl ethylamine, dimethylaminopyridine, N-methyl morpholine.
52. The process of claim 43, wherein the metal catalyst is selected from the group consisting of Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf), Pd(OAc)2, NiCl2(PPh3)2, PdCl2(dppb), PdCl2(PhCN)2, Pd(dba)2.
53. The process of claim 43, further comprising:
(i) reacting lumacaftor obtained in step (d) with an acid selected from the group of hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid in a solvent to form salt of lumacaftor; and
(ii) converting the salt of lumacaftor to lumacaftor.
54. The process of claim 53, wherein lumacaftor is reacted with hydrobromic acid to form lumacaftor hydrobromide which is converted to lumacaftor.
55. The process of claim 54, wherein the level of any single impurity in the lumacaftor hydrobromide is less than 0.15% w/w of lumacaftor hydrobromide.
56. The process of claim 54, wherein the lumacaftor has a purity of >99.8% and wherein the level of any single impurity is less than 0.1% w/w of lumacaftor.
I la
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US10479782B2 (en) * | 2015-09-29 | 2019-11-19 | Mylan Laboratories Limited | Forms of lumacaftor and processes for the preparation thereof |
EP3565814A4 (en) * | 2017-01-09 | 2020-08-19 | Laurus Labs Limited | Process and crystalline forms of lumacaftor |
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US8846718B2 (en) * | 2007-12-07 | 2014-09-30 | Vertex Pharmaceuticals Incorporated | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid |
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US8846718B2 (en) * | 2007-12-07 | 2014-09-30 | Vertex Pharmaceuticals Incorporated | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxo1-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid |
Cited By (2)
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US10479782B2 (en) * | 2015-09-29 | 2019-11-19 | Mylan Laboratories Limited | Forms of lumacaftor and processes for the preparation thereof |
EP3565814A4 (en) * | 2017-01-09 | 2020-08-19 | Laurus Labs Limited | Process and crystalline forms of lumacaftor |
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