US20170022183A1 - Process for the manufacturing of medicaments - Google Patents
Process for the manufacturing of medicaments Download PDFInfo
- Publication number
- US20170022183A1 US20170022183A1 US15/285,781 US201615285781A US2017022183A1 US 20170022183 A1 US20170022183 A1 US 20170022183A1 US 201615285781 A US201615285781 A US 201615285781A US 2017022183 A1 US2017022183 A1 US 2017022183A1
- Authority
- US
- United States
- Prior art keywords
- chloro
- methyl
- fluorophenyl
- pyridin
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 89
- 230000008569 process Effects 0.000 title claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- -1 aryl sulfonic acid Chemical group 0.000 claims abstract description 42
- 150000003839 salts Chemical group 0.000 claims abstract description 33
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 117
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 98
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 80
- 239000002904 solvent Substances 0.000 claims description 48
- 239000002585 base Substances 0.000 claims description 34
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 32
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 31
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 29
- TWSFAQBOAWKKIH-GMUIIQOCSA-N benzenesulfonic acid 1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one Chemical compound C1(=CC=CC=C1)S(=O)(=O)O.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F TWSFAQBOAWKKIH-GMUIIQOCSA-N 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 21
- QGKBOJYLVWQNIO-GMUIIQOCSA-N C1(=CC=C(C=C1)S(=O)(=O)O)C.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F Chemical compound C1(=CC=C(C=C1)S(=O)(=O)O)C.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F QGKBOJYLVWQNIO-GMUIIQOCSA-N 0.000 claims description 20
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 20
- JESRNIJXVIFVOV-UHFFFAOYSA-N 2-methylpyrazol-3-amine Chemical compound CN1N=CC=C1N JESRNIJXVIFVOV-UHFFFAOYSA-N 0.000 claims description 18
- RAEXTEKKMYSCEX-UHFFFAOYSA-N CS(=O)(=O)C1=NC=CC(=N1)C1=CC(NC=C1)=O Chemical compound CS(=O)(=O)C1=NC=CC(=N1)C1=CC(NC=C1)=O RAEXTEKKMYSCEX-UHFFFAOYSA-N 0.000 claims description 18
- MZTDOZRNTSWXLO-GMUIIQOCSA-N C=1(C(=CC=C2C=CC=CC12)S(=O)(=O)O)S(=O)(=O)O.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F Chemical compound C=1(C(=CC=C2C=CC=CC12)S(=O)(=O)O)S(=O)(=O)O.ClC1=C(C=C(C=C1)[C@@H](CO)N1C(C=C(C=C1)C1=NC(=NC=C1)NC1=CC=NN1C)=O)F MZTDOZRNTSWXLO-GMUIIQOCSA-N 0.000 claims description 17
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 17
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- FRSBDALHVZFPHT-UHFFFAOYSA-N 2-chloro-1-(4-chloro-3-fluorophenyl)ethanone Chemical compound FC1=CC(C(=O)CCl)=CC=C1Cl FRSBDALHVZFPHT-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 14
- ZNGGAPYUQROFJC-QMMMGPOBSA-N (1r)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol Chemical compound OC[C@H](O)C1=CC=C(Cl)C(F)=C1 ZNGGAPYUQROFJC-QMMMGPOBSA-N 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- ATHKVJCNHIGEBV-UHFFFAOYSA-N 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone Chemical compound OCC(=O)C1=CC=C(Cl)C(F)=C1 ATHKVJCNHIGEBV-UHFFFAOYSA-N 0.000 claims description 12
- FYJKEHKQUPSJDH-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;potassium Chemical group [K].C[Si](C)(C)N[Si](C)(C)C FYJKEHKQUPSJDH-UHFFFAOYSA-N 0.000 claims description 12
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 11
- 239000003880 polar aprotic solvent Substances 0.000 claims description 11
- 108010050375 Glucose 1-Dehydrogenase Proteins 0.000 claims description 10
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 claims description 10
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical group COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 239000000010 aprotic solvent Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 238000004064 recycling Methods 0.000 claims description 8
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical group CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 8
- 102000004190 Enzymes Human genes 0.000 claims description 7
- 108090000790 Enzymes Proteins 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 claims description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 claims description 5
- AGYWDGVTLKNTBS-UHFFFAOYSA-N 4-bromo-1-chloro-2-fluorobenzene Chemical compound FC1=CC(Br)=CC=C1Cl AGYWDGVTLKNTBS-UHFFFAOYSA-N 0.000 claims description 5
- DFOHHQRGDOQMKG-UHFFFAOYSA-N 4-chloro-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(Cl)=N1 DFOHHQRGDOQMKG-UHFFFAOYSA-N 0.000 claims description 5
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims description 5
- 150000002901 organomagnesium compounds Chemical class 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 5
- 235000019254 sodium formate Nutrition 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 5
- SCOJKGRNQDKFRP-UHFFFAOYSA-N 2-chloro-n-methoxy-n-methylacetamide Chemical compound CON(C)C(=O)CCl SCOJKGRNQDKFRP-UHFFFAOYSA-N 0.000 claims description 4
- ADPRIAVYIGHFSO-UHFFFAOYSA-N 2-fluoro-4-iodopyridine Chemical compound FC1=CC(I)=CC=N1 ADPRIAVYIGHFSO-UHFFFAOYSA-N 0.000 claims description 4
- HQHQCDLTSLUGBE-UHFFFAOYSA-N 4-(2-fluoropyridin-4-yl)-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(C=2C=C(F)N=CC=2)=N1 HQHQCDLTSLUGBE-UHFFFAOYSA-N 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 239000006184 cosolvent Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 150000003333 secondary alcohols Chemical class 0.000 claims description 4
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 claims description 3
- 108010020056 Hydrogenase Proteins 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 108010036197 NAD phosphite oxidoreductase Proteins 0.000 claims description 3
- 239000004280 Sodium formate Substances 0.000 claims description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 claims description 3
- 239000011260 aqueous acid Substances 0.000 claims description 3
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- 102000007698 Alcohol dehydrogenase Human genes 0.000 claims description 2
- 108010021809 Alcohol dehydrogenase Proteins 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 101710088194 Dehydrogenase Proteins 0.000 claims description 2
- 102000002794 Glucosephosphate Dehydrogenase Human genes 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims description 2
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 4
- 239000000243 solution Substances 0.000 description 140
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 92
- 238000006243 chemical reaction Methods 0.000 description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- 239000000203 mixture Substances 0.000 description 64
- 235000002639 sodium chloride Nutrition 0.000 description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 44
- RZUOCXOYPYGSKL-GOSISDBHSA-N 1-[(1s)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one Chemical compound CN1N=CC=C1NC1=NC=CC(C2=CC(=O)N([C@H](CO)C=3C=C(F)C(Cl)=CC=3)C=C2)=N1 RZUOCXOYPYGSKL-GOSISDBHSA-N 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 38
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- 239000002002 slurry Substances 0.000 description 25
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 21
- 239000003153 chemical reaction reagent Substances 0.000 description 20
- 238000000113 differential scanning calorimetry Methods 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 18
- 239000000523 sample Substances 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 239000012458 free base Substances 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 229960004592 isopropanol Drugs 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 10
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 10
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000013019 agitation Methods 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 8
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 235000008504 concentrate Nutrition 0.000 description 8
- 229960004132 diethyl ether Drugs 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 238000005191 phase separation Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- MBVRZOISNGJZGC-OAQYLSRUSA-N 1-[(1s)-2-[tert-butyl(dimethyl)silyl]oxy-1-(4-chloro-3-fluorophenyl)ethyl]-4-(2-methylsulfanylpyrimidin-4-yl)pyridin-2-one Chemical compound CSC1=NC=CC(C2=CC(=O)N([C@H](CO[Si](C)(C)C(C)(C)C)C=3C=C(F)C(Cl)=CC=3)C=C2)=N1 MBVRZOISNGJZGC-OAQYLSRUSA-N 0.000 description 7
- IZXJYMSZBOMDMU-HSZRJFAPSA-N 1-[(1s)-2-[tert-butyl(dimethyl)silyl]oxy-1-(4-chloro-3-fluorophenyl)ethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one Chemical compound CN1N=CC=C1NC1=NC=CC(C2=CC(=O)N([C@H](CO[Si](C)(C)C(C)(C)C)C=3C=C(F)C(Cl)=CC=3)C=C2)=N1 IZXJYMSZBOMDMU-HSZRJFAPSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 229940093499 ethyl acetate Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical group C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
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- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
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- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
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- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/165—Heterorings having nitrogen atoms as the only ring heteroatoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the processes involved in tumor growth progression and metastasis are mediated by signaling pathways that are activated in cancer cells.
- the ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface receptor tyrosine kinase (“RTK's”), such as ErbB family, PDGF, FGF, and VEGF receptor tyrosine kinases.
- RTK's ligand-bound cell surface receptor tyrosine kinase
- Activation of an RTK induces a cascade of phosphorylation events that begins with activation of Ras.
- Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase.
- Raf Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERK1/2.
- ERK1/2 phosphorylates several downstream targets involved in a multitude of cellular events, including cytoskeletal changes and transcriptional activation.
- the ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors.
- Ras genes which are upstream of ERK1/2, are mutated in several cancers, including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors.
- BRAF a serine-threonine kinase of the Raf family
- ERK1/2 signaling pathway is an attractive pathway for anti-cancer therapies in a broad spectrum of human tumors.
- the ERK pathway has also been cited as a promising therapeutic target for the treatment of pain and inflammation (Ma, Weiya and Remi, Quirion. “The ERK/MAPK Pathway, as a Target For The Treatment Of Neuropathic Pain” Expert Opin. Ther. Targets. 2005 9(4):699-713, and Sommer, Stephan and Frank Birklein “Resolvins and Inflammatory Pain” F 1000 Medicine Reports 2011 3:19).
- small-molecular inhibitors of ERK activity i.e., ERK1 and/or ERK2 activity
- ERK1 and/or ERK2 activity would be useful for treating a broad spectrum of cancers, such as, for example, melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer, as well as a and rheumatism.
- the present invention provides a process and intermediates for making (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, pharmaceutically acceptable salts thereof, and crystalline forms of the salts.
- the present invention also provides pharmaceutical compositions comprising the salts or crystalline forms of the salts, and methods of using the salts and crystalline forms of the salts.
- the present invention provides processes for the manufacture of I which is a useful intermediate that can be used in the manufacture VIII.
- Compound VIII is an ERK inhibitor and a useful medicament for treating hyperproliferative disorders.
- the process provides an efficient route to VIII and to the useful intermediates VI and VII. Alkylation of VII with VI affords I, which ultimately is condensed with 1-methyl-1H-pyrazol-5-amine (XIV). (SCHEME A)
- the present invention further provides an asymmetric enzymatic reduction which permits the stereospecific reduction of 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone to afford (R)-1-(4-chloro-3-fluorophenyl)ethan-1,2-diol (IV).
- the present invention also provides an improved process to prepare 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (VII).
- the present invention provides a crystalline besylate salt (VIIIb) with desirable physical properties that permit ready formulation and good bioavailability.
- the present invention provides processes for the preparation of a compound of formula VIII, the processes comprising the steps of:
- the present invention provides processes according to embodiment 1 wherein the ketoreductase in step (c) affords an enantiomeric excess at least about 98%.
- the present invention provides processes of embodiment 2 wherein the ketoreductase in step (c) is KRED-NADH-112.
- step (c) further comprises NADH or NADPH as a cofactor.
- the present invention provides processes of embodiment 4 wherein the cofactor is regenerated with a cosubstrate selected from a secondary alcohol or from an additional enzyme selected from alcohol dehydrogenase, glucose dehydrogenase, formatted dehydrogenase, glucose-6-phosphate dehydrogenase, phosphite dehydrogenase or hydrogenase.
- a cosubstrate selected from a secondary alcohol or from an additional enzyme selected from alcohol dehydrogenase, glucose dehydrogenase, formatted dehydrogenase, glucose-6-phosphate dehydrogenase, phosphite dehydrogenase or hydrogenase.
- the present invention provides processes of any of embodiment 2 to 5 wherein the ketoreductase step is performed in an aqueous medium in the presence of organic cosolvent at a temperature between 1 and 50° C.
- the present invention provides processes of embodiment 6 wherein the ketoreductase step produces a homogeneous suspension.
- the present invention provides processes of embodiment 1 wherein the silyl chloride is tert-butyldimethylsilyl chloride, the sulfonyl chloride is methanesulfonyl chloride, the bases in step (d) are DMAP and TEA and the non-polar aprotic solvent is DCM and in step (e) the organic solvent is dioxane.
- the present invention provides processes of embodiment 1 wherein (R a ) 3 Si is tert-butyldimethylsilyl, R b is methyl, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme.
- the present invention provides processes of embodiment 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent glucose dehydrogenase, in step (d) (R a ) 3 Si is tert-butyldimethylsilyl, R b is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme.
- the present invention provides processes of embodiment 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent is glucose dehydrogenase, in step (d) (R a ) 3 Si is tert-butyldimethylsilyl, R b is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, and in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF.
- the present invention provides processes of embodiment 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and cofactor recycling agent is glucose dehydrogenase, in step (d) (R a ) 3 Si is tert-butyldimethylsilyl, R b is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF, and in step (h) the desilylating agent is methanolic HCl.
- the present invention provides processes according to embodiment 1 wherein the compound VIII from step h is contacted with a sulfonic acid in an organic solvent and water to afford a salt of VIIIa where R c is an aryl sulfonic acid
- the present invention provides processes according to embodiment 13 wherein R c SO 3 H is benzenesulfonic acid and the solvent is methyl ethyl ketone and water to afford the besylate salt VIIIb.
- the present invention provides processes for the preparation of 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII) comprising the steps of:
- the present invention provides processes according to embodiment 15 wherein the palladium catalyst is (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride, the metallating agent is i-PrMgCl and LiCl, and the aprotic solvent is THF.
- the palladium catalyst is (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride
- the metallating agent is i-PrMgCl and LiCl
- the aprotic solvent is THF.
- the present invention provides the compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
- the present invention provides pharmaceutical compositions comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate and a pharmaceutically acceptable excipient.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern comprising peaks at 6.16 ⁇ 0.2, 7.46 ⁇ 0.2, 16.36 ⁇ 0.2, 25.76 ⁇ 0.2 and 25.98 ⁇ 0.2 2 ⁇
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 13 C NMR pattern substantially as shown in FIG. 19 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 19 F NMR pattern substantially as shown in FIG. 20 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 13 C NMR pattern substantially as shown in FIG. 19 and a 19 F NMR pattern substantially as shown in FIG. 20 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 19 F NMR pattern comprising peaks at ⁇ 111.1 ⁇ 0.4 ppm and ⁇ 115.4 ⁇ 0.4 ppm relative to CFCl 3 (at 293 K).
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 13 C NMR pattern comprising peaks at 157.7 ⁇ 0.2 ppm, 129.6 ⁇ 0.2 ppm, 125.8 ⁇ 0.2 ppm, and 117.0 ⁇ 0.2 ppm relative to tetramethylsilane (at 293 K).
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having a DSC pattern substantially as shown in FIG. 2 .
- the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate in accordance with any one of embodiments 19 to 27 and a pharmaceutically acceptable excipient.
- the present invention provides the compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid.
- the present invention provides pharmaceutical compositions comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid and a pharmaceutically acceptable excipient.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A having an X-ray powder diffraction pattern comprising peaks at. 5.76 ⁇ 0.2, 13.44 ⁇ 0.2, 15.64 ⁇ 0.2, 19.40 ⁇ 0.2 2 ⁇ .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A having an X-ray powder diffraction pattern substantially as shown in FIG. 12 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A having a DSC pattern substantially as shown in FIG. 13 .
- the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A in accordance with any one of claims 31 to 35 and a pharmaceutically acceptable excipient.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B. having an X-ray powder diffraction pattern comprising peaks at 7.02 ⁇ 0.2, 16.30 ⁇ 0.2, 17.30 ⁇ 0.2, 21.86 ⁇ 0.2 2 ⁇ .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B having an X-ray powder diffraction pattern substantially as shown in FIG. 15 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B having a DSC pattern substantially as shown in FIG. 16 .
- the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B in accordance with any one of embodiments 37 to 40 and a pharmaceutically acceptable excipient.
- the present invention provides the compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid.
- the present invention provides pharmaceutical compositions comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid and a pharmaceutically acceptable excipient.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I having an X-ray powder diffraction pattern comprising peaks at 12.50 ⁇ 0.2, 13.86 ⁇ 0.2 2 ⁇ .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I having an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I having a DSC pattern substantially as shown in FIG. 7 .
- the present invention provide pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form Tin accordance with any one of embodiments 44 to 48 and a pharmaceutically acceptable excipient.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II.
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxy ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2 (1H)-one naphthalenedisulfonic acid Form II having an X-ray powder diffraction pattern comprising peaks at 12.80 ⁇ 0.2, 22.42 ⁇ 0.2, 24.92 ⁇ 0.2 2 ⁇ .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II having an X-ray powder diffraction pattern substantially as shown in FIG. 8 .
- the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II having a DSC pattern substantially as shown in FIG. 9 .
- the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II in accordance with any one of claims 50 to 53 and a pharmaceutically acceptable excipient.
- the present invention provides amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
- the present invention provides amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern substantially as shown in FIG. 21 .
- the present invention provides amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having a DSC pattern substantially as shown in FIG. 22 .
- the present invention provides pharmaceutical compositions comprising amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate in accordance with any one of embodiments 55 to 57 and a pharmaceutically acceptable excipient.
- FIG. 1 shows the XRPD pattern of VIII crystalline besylate form A.
- FIG. 2 shows the DSC and TGA analysis of VIII crystalline besylate form A.
- FIG. 3 shows the single crystal structure analysis of VIII crystalline besylate form A.
- FIG. 4 shows the XRPD pattern of VIII free base.
- FIG. 5 shows the DSC analysis of VIII free base.
- FIG. 6 shows the XRPD pattern of VIII naphthalenedisulfonic acid form I.
- FIG. 7 shows the DSC analysis of VIII naphthalenedisulfonic acid form I.
- FIG. 8 shows the XRPD pattern of VIII naphthalenedisulfonic acid form II with a small amount of form I.
- FIG. 9 shows the DSC analysis of VIII naphthalenedisulfonic acid form II.
- FIG. 10 shows the DVS pattern of VIII naphthalenedisulfonic acid form I.
- FIG. 11 shows the XRPD pattern of VIII toluenesulfonic acid IPA solvate.
- FIG. 12 shows the XRPD pattern of VIII toluenesulfonic acid form A.
- FIG. 13 shows the DSC analysis of VIII toluenesulfonic acid form A.
- FIG. 14 shows the DVS pattern of VIII toluenesulfonic acid form A.
- FIG. 15 shows the XRPD pattern of a mixture of VIII toluenesulfonic acid amorphous and form B.
- FIG. 16 shows the DSC analysis of a mixture of VIII toluenesulfonic acid amorphous and form B.
- FIG. 17 shows the XRPD pattern of VIII toluenesulfonic acid amorphous.
- FIG. 18 shows the DVS analysis of VIII besylate salt, form A.
- FIG. 19 shows the 13 C solid state NMR pattern of VIII crystalline besylate form A.
- FIG. 20 shows the 19 F solid state NMR pattern of VIII crystalline besylate form A.
- FIG. 21 shows the XRPD pattern of VIII besylate amorphous.
- FIG. 22 shows the DSC analysis of VIII besylate amorphous.
- the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”.
- the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
- the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components.
- chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
- stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
- Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated under high resolution analytical procedures such as electrophoresis and chromatography.
- enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
- d and 1 or (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or 1 meaning that the compound is levorotatory.
- a compound prefixed with (+) or d is dextrorotatory.
- these stereoisomers are identical except that they are mirror images of one another.
- a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
- a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
- the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
- the present process as described herein also can be used to prepare isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses.
- Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I or 125 I.
- Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
- Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability.
- isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
- proton tautomers also known as prototropic tautomers
- Valence tautomers include interconversions by reorganization of some of the bonding electrons.
- aprotic (or nonpolar) solvent means organic solvents such as diethyl ether, ligroin, pentane, hexane, cyclohexane, heptane, chloroform, benzene, toluene, dioxane, tetrahydrofuran, dichloromethane or ethyl acetate.
- polar aprotic solvent refers to organic solvents such as formamide, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or hexamthylphosphoramide.
- polar protic solvent refers to organic solvents such as lower alkanols, formic acid or acetic acid.
- ethereal solvent refers to solvents such as tetrahydofuran, dimethoxyethane, dioxane, or dialkyl ethers such as diethyl ether and methyl tertbutyl ether.
- derivative of a compound as used herein means a compound obtainable from the original compound by a simple chemical process.
- protecting group refers to a chemical group that (a) preserves a reactive group from participating in an undesirable chemical reaction; and (b) can be easily removed after protection of the reactive group is no longer required.
- the benzyl group is a protecting group for a primary hydroxyl function.
- hydroxyl protecting group or “alcohol protecting group” means a protecting group that preserves a hydroxy group that otherwise would be modified by certain chemical reactions.
- a hydroxyl protecting group can be an ether, an ester, or silane that can be removed easily after completion of all other reaction steps, such as a lower acyl group (e.g., the acetyl or propionyl group or a dimethyl-t-butylsilyl group), or an aralkyl group (e.g., the benzyl group, optionally substituted at the phenyl ring).
- sil chloride as used herein refers to (R a ) 3 SiCl wherein R a is independently in each occurrence C 1-6 alkyl or phenyl.
- deprotecting reagent refers to reagents contacted with a protected chemical moiety to remove the protecting groups. Reagents and protocols for deprotection are well known and can be found in Greene and Wuts or in Harrison and Harrison (infra). One skilled in the chemical arts will appreciate that on occasion protocols must be optimized for a particular molecule and such optimization is well with the ability of one skilled in these arts.
- aryl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
- the term “treating,” “contacting” or “reacting” when referring to a chemical reaction means to add or mix two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents that were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
- leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.
- halo such as chloro, bromo, and iodo
- alkanesulfonyloxy arenesulfonyloxy
- alkylcarbonyloxy e.g., acetoxy
- arylcarbonyloxy mesyloxy, tosyl
- sulfonyl chloride refers to a compound R b S(O) 2 Cl wherein R b is selected from C 1-4 alkyl or phenyl, optionally substituted with 1 to 3 groups independently selected from C 1-3 alkyl, halogen, nitro, cyano, C 1-3 alkoxy.
- a Wittig reagent can be used to form an alkene from an aldehyde.
- the Wittig reagent is usually prepared from a phosphonium salt, which is in turn made by the reaction of triphenylphosphine with an alkyl halide.
- the phosphonium salt is suspended in a solvent such as diethyl ether or THF and treated with a strong base such as phenyllithium or n-butyllithium.
- the Sharpless dihydroxylation or bishydroxylation is used in the enantioselective preparation of 1,2-diols from prochiral olefins.
- This procedure is performed with an osmium catalyst and a stoichiometric oxidant [e.g. K 3 Fe(CN) 6 or N-methylmorpholine oxide (NMO)]; it is carried out in a buffered solution to ensure a stable pH, since the reaction proceeds more rapidly under slightly basic conditions.
- Enantioselectivity is achieved through the addition of enantiomerically-enriched chiral ligands [(DHQD) 2 PHAL, (DHQ) 2 PHAL or their derivatives].
- the present procedures can use the Karl Fischer method for determining trace amounts of water in a sample. This method can be abbreviated “KF.”
- reaction products from one another and/or from starting materials.
- the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by techniques common in the art.
- separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
- Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
- SMB simulated moving bed
- reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
- reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
- the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
- the present invention provides a process for the preparation of(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (VIII) which has the structure
- arylsulfonic acid refers to a benzene sulfonic acid or a naphthalene mono- or disulfonic acid in which the aryl ring is optionally substituted with methyl or halogen.
- the present invention further provides a process for the manufacture of intermediate I by first treating 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (VII) with strong base and alkylating the resulting compound with (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (VI).
- N-Alkylation of amides can be carried out under a variety of basic conditions well known to someone skilled in the art.
- the reaction is typically carried out in aprotic solvents such as THF, DMF, DMSO, NMP or mixtures thereof at temperatures between ⁇ 78° C. and 100° C.
- bases are Grignard reagents, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide.
- Treating VII with potassium hexamethyldisilazide in diglyme at RT allow formation of the lithium salt of VII after which the mesylate VI was introduced and the reaction heated at 90° for 4 h.
- Oxidation of a thioether to a sulfoxide or sulfone is typically facile and numerous reagents are known that are capable of carrying out this transformation. Sulfur oxidations are commonly carried out with aqueous solution of hydrogen peroxide, NaIO 4 , tert-butylhypochlorite, acyl nitrites, sodium perborate potassium hydrogen persulfate or peracids such as peracetic acid and meta-chloroperbenzoic acid. Typically with about one equivalent of oxidant the sulfoxide can be isolated. Exposure to two or more equivalents results in oxidation to the sulfone. Oxidation of XI with MCPBA in MTBE at ambient temperature affords I.
- the mesylate VI was prepared in five steps starting from 1-bromo-4-chloro-3-fluorobenzene, which was converted to the Grignard reagent and contacted with 2-chloro-N-methoxy-N-methylacetamide to afford the ketone II. Condensation of organolithium and organomagnesium compounds with N,O-dimethylhydroxyamides affords the corresponding ketones. (S. Nahm and D. M. Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815) The Grignard reagent was formed by treating 1-bromo-4-chloro-3-fluorobenzene with isopropyl magnesium chloride in the presence of LiCl.
- Enzyme-catalyzed reduction of ketones frequently proceeds with high stereoselectivity, usually in the presence of NADH or NADPH as cofactor which is regenerated in situ.
- Preferred microbial oxidoreductase enzymes found in yeasts, bacteria or from mammalian cells and theoxidoreductase can be applied in the form of the isolated enzyme(s) or whole cells, optionally in immobilized form by one of the numerous conventional methods described in literature.
- the oxidized cofactor is as a rule continuously regenerated with a secondary alcohol as cosubstrate.
- Typical cosubstrates can be selected from 2-propanol, 2-butanol, pentan-1,4-diol, 2-pentanol, 4-methyl-2-pentanol, 2-heptanol, hexan-1,5-diol, 2-heptanol or 2-octanol, preferably 2-propanol.
- the cofactor is regenerated by means of the cosubstrate at the same enzyme also catalyzing the target reaction.
- the acetone formed when 2-propanol is used as cosubstrate is in a further preferred embodiment continuously removed from the reaction mixture.
- the cofactor can be regenerated by incorporating an additional enzyme oxidizing its natural substrate and providing the reduced cofactor.
- an additional enzyme oxidizing its natural substrate and providing the reduced cofactor.
- secondary alcohol dehydrogenase/alcohol glucose dehydrogenase/glucose, formate dehydrogenase/formic acid, glucose-6-phosphate dehydrogenase/glucose-6-phosphate, phosphite dehydrogenase/phosphite or hydrogenase/molecular hydrogen and the like.
- electrochemical regeneration methods are known as well as chemical cofactor regeneration methods comprising a metal catalyst and a reducing agent are suitable.
- the preferred catalyst/cofactor/cosubstrate systems may vary with different ketones.
- the enzymatic reduction is performed in an aqueous medium in the presence of an organic cosolvent which can be selected, for example, from glycerol, 2-propanol, diethylether, tert-butylmethylether, diisopropylether, dibutylether, ethylacetate, butylacetate, heptane, hexane or cyclohexene or mixtures thereof.
- the presence of an organic cosolvent is particularly advantageous as a homogenous suspension can be formed which allows simple separation of the desired alcohol of formula IV.
- the reaction temperature for enzymatic reductions is usually kept in a range between 1° C. and 50° C., preferably between 20° C. and 40° C.
- the reaction concentration i.e., the concentration of ketone and corresponding alcohol
- the reaction concentration is typically maintained at 1% to 25%, preferable between 10 and 20%.
- the asymmetric reduction of III was catalysed by KRED-NADH-112 (Codexis Inc., Redwood City, Calif., USA) in the presence of the oxidized cofactor NAD, the recycling enzyme GDH-105 (Codexis Inc., Redwood City, Calif., USA) and the final reductant glucose affording (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol in 99.5% enantiomeric excess in a quantitative chemical conversion.
- the final steps include the selective protection of the primary alcohol with tert-butyldimethylsilyl chloride, 4-dimethylaminopyridine (DMAP) and triethylamine (TEA) in DCM and subsequent formation of the methansulfonate ester with methansulfonyl chloride DMAP and TEA in DCM, which may be carried out sequentially in a single reaction vessel to afford (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (VI).
- DMAP 4-dimethylaminopyridine
- TEA triethylamine
- the Grignard reagent was prepared by transmetallation with i-PrMgCl in the presence of LiCl (Krasovskiy, supra) and treating the resulting heteroaryl Grignard with XIII in the presence of PEPPSI (i-Pr) ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, CASRN 905459-27-0).
- a 2,4-disubstituted pyrimidine derivative such as 2,4-dichloro-pyrimidine or 4-chloro-2-methylthiopyrimidine
- a 2,4-disubstituted pyrimidine derivative is coupled with 2-fluoropyridin-4-ylboronic acid (Pd(dppf)Cl 2 , K 3 PO4, dioxane) to afford 2-chloro-4-(2-fluoropyridin-4-yl)pyrimidine, which is condensed with 1-methyl-1H-pyrazol-5-amine (LiHMDS, THF) and hydrolyzed to afford 4-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one which can be alkylated as described previously using two equivalents of base.
- 2-fluoropyridin-4-ylboronic acid Pd(dppf)Cl 2 , K 3 PO4, dioxane
- Ts saturated
- TBME tert-butymethyl ether
- TBS tert-butyldimethylsilyl or t-BuMe 2 Si
- Ts triethylamine
- Ts triflate or CF 3 SO 2 —
- Ts trifluoroacetic acid
- THF O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate
- TLC thin layer chromatography
- THF tetrahydrofuran
- TEDA tetramethylethylenediamine
- TMS 2-(trimethylsilyl)ethoxymethyl
- SEM p-toluenesulfonic acid monohydrate
- TsOH or pTsOH 4-Me-C 6 H 4 SO 2 — or tosyl
- N-urethane-N-carboxyanhydride N-urethane-N-carboxyanhydride
- the original synthetic process involves an eight step linear synthesis (10 steps overall) from three commercially available materials, 4-chloro-3-fluorobenzaldehyde 1, 4-chloro-2-(methylthio)pyrimidine XIII and (2-fluoropyridin-4-yl)boronic acid 6-2 (Scheme 1).
- Wittig reaction of 1 produced olefin intermediate 2 in 55% yield.
- Asymmetric Sharpless dihydroxylation of styrene followed by a selective mono-protection of diol IV with TBSCl afforded intermediate V in 55% yield over two steps.
- One of the intermediates VI was obtained through a mesylation of secondary alcohol.
- pyridone intermediate VII was synthesized through a Suzuki cross coupling between XIII and 6-2, followed by a hydrolysis with aqueous HCl solution. A purification of VII by a Soxhlet extraction with EtOAc over 3 days was required to ensure a good purity of 6 and a reasonable conversion in the subsequent reaction. Sn2 displacement of VI and VII was able to afford intermediate XI in 50% yield over 2 steps from intermediate V. An oxidation with m-CPBA afforded sulfone intermediate I that underwent a SnAr displacement with commercially available aminopyrazole, 2-methylpyrazole-3-amine, to generate intermediate IX in 60% yield. Finally an acid promoted TBS deprotection afforded free base VIII in 85% yield.
- Step 1 4-bromo-1-chloro-2-fluorobenzene (64 kg) and dry toluene (170 kg) were charged to the 2000 L steel reaction vessel under nitrogen.
- the reactor was evacuated and backfilled with N 2 for three times, and cooled to between ⁇ 10 and 5° C. under nitrogen atmosphere.
- To the solution was added dropwise i-PrMgCl.LiCl (280 kg, 1.3M in THF) at between ⁇ 10 and 10° C.
- the reaction was stirred for a further 15 to 30 min at between ⁇ 10 and 10° C. and then warmed to about 20 to 25° C. over 1 h.
- the reaction mixture was stirred for another 6 h stir to complete the exchange.
- Step 2 The solution of II (51.7 kg) in toluene was concentrated and solvent exchanged to EtOH to afford a suspension of II in EtOH (326 kg).
- the solid was filtered and the filter cake washed with water (400 kg) to remove the residual HCOONa and HCOOH.
- the 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone obtained was suspended in EtOAc (41 kg) and n-heptane (64 kg), then warmed to between 45 and 50° C., stirred for 2 h, then cooled to between ⁇ 2 and 5° C. for over 2 h and stirred at this temperature for 2 h.
- the solids were filtered and dried in vacuo at between 40 and 50° C. for 12 h to afford the product as white solid (40.0 kg, 99.3% purity, 84.5% yield).
- Step 3 A 500 L reactor under nitrogen was charged with purified water (150 kg), 4-morpholineethanesulfonic acid (0.90 kg), anhydrous MgCl 2 (0.030 kg), n-heptane (37 kg), 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone (30 kg), D-(+)-glucose monohydrate (34.8 kg) and PEG 6000 (30.0 kg).
- the pH of the solution was adjusted to between 6.5 and 7.0 with 1N aq. NaOH at between 28 and 32° C.
- the cofactor recycling enzyme glucose dehydrogenase GDH-105 (0.300 kg)(Codexis Inc., Redwood City, Calif., USA), the cofactor nicotinamide adenine dinucleotide NAD (0.300 kg)(Roche) and the oxidoreductase KRED-NADH-112 (0.300 kg) (Codexis Inc., Redwood City, Calif., USA) were added.
- the resulting suspension was stirred at between 29 and 31° C. for 10 to 12 h while adjusting the pH to maintain the reaction mixture pH between 6.5 and 7.0 by addition of 1N aq. NaOH (160 kg).
- Step 4 A 1000 L reactor under nitrogen was charged with (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (29.5 kg) and dry DCM (390 kg). The solution was cooled to between ⁇ 5 and 0° C. tert-Butylchlorodimethylsilane (25.1 kg) was added in portions while maintaining the temperature between ⁇ 5 and 2° C. A solution of DMAP (0.95 kg) and TEA (41.0 kg) in dry DCM (122 kg) was added dropwise to above solution at between ⁇ 5 and 2° C. The reaction solution was stirred for 1 h, then warmed to between 20 and 25° C. and stirred for 16 h.
- Step 1 A 1000 L reactor was charged with 2-fluoro-4-iodopyridine (82.2 kg) and dry THF (205 kg). The reactor was evacuated and backfilled with N 2 three times then cooled to between ⁇ 30 and ⁇ 20° C. To the solution was added dropwise i-PrMgCl.LiCl (319 kg, 1.3M in THF). The reaction was warmed to between ⁇ 20 and ⁇ 10° C. and stirred for 1.5 h to complete the transmetallation.
- a 2000 L reactor was charged with 4-chloro-2-methylthiopyrimidine (45.6 kg), dry THF (205 kg) and [1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium(II) dichloride (PEPPSITM-IPr, 1.850 kg).
- the 2000 L reactor was evacuated and backfilled with N 2 three times and heated to between 55 and 57° C.
- To the reactor was added over 0.5 to 1 h, the solution of (2-fluoropyridin-4-yl)magnesium chloride while maintaining the temperature between 50 and 62° C.
- the resulting reaction mixture was stirred at between 50 and 62° C.
- Step 2 The solution of 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (38.2 kg) in THF was concentrated and co-evaporated with THF to remove residual water. The suspension was filtered through a pad of diatomaceous earth to remove inorganic salts. To the resulting solution in THF (510 kg) was added tert-BuOK (39.7 kg) in portions while maintaining the temperature between 15 and 25° C. The mixture was warmed to between 20 and 25° C. and stirred for 5 h. NaHCO 3 (14.9 kg) added charged and then a citric acid solution (5 kg) in THF (15 kg) was added to adjust the pH to between 8 and 9. Water (230 kg) was added.
- Step 1 The THF was co-evaporated from the THF solution of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (25.5 kg) to remove residual water. Dry bis-(2-methoxyethyl)ether (75 kg) was added. A solution of KHMDS (131 kg, 1M in THF) was added dropwise while maintaining the temperature between 25 and 40° C. The mixture was heated to between 75 and 80° C. and stirred for 30 to 40 min. The resulting mixture was cooled to between 20 and 30° C. under nitrogen atmosphere.
- KHMDS 131 kg, 1M in THF
- Step 2 To a solution of (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (44.6 kg) in EtOAc (401 kg, 10 vol) cooled to between 5 and 10° C. was added in portions MCPBA (58 kg). The reaction mixture was added to a solution of NaHCO 3 (48.7 kg) in water (304 kg) at a temperature between 10 and ⁇ 20° C. A solution of Na 2 S 2 O 3 (15 kg) in water (150 kg) was added dropwise to consume residual MCBPA.
- EtOAc 401 kg, 10 vol
- MCPBA 58 kg
- the reaction mixture was added to a solution of NaHCO 3 (48.7 kg) in water (304 kg) at a temperature between 10 and ⁇ 20° C.
- Step 1 A clean 100 L cylindrical reaction vessel was charged with THF (13 kg) then (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (I, 5 kg) and 1-methyl-1H-pyrazol-5-amine (1.1 kg) were added sequentially with medium agitation followed by THF (18 kg). The mixture was cooled to ⁇ 35° C.
- the reaction was diluted with EtOAc (18 kg) and the phases separated, the organic layer was washed with H 3 PO 4 solution (1.1 kg of 85% H 3 PO 4 and 12 kg of water) followed by a second H 3 PO 4 wash (0.55 kg of 85% H 3 PO 4 and 12 kg of water). If 1-methyl-1H-pyrazol-5-remained, the organic layer was washed again with H 3 PO 4 solution (0.55 kg of 85% H 3 PO 4 and 12 kg of water). Finally the organic layer was washed sequentially with water (20 kg) and a NaCl and NaHCO 3 solution (2 kg of NaCl, 0.35 kg of NaHCO 3 and 10 kg of water).
- Step 2 To the methanolic (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (IX) solution in MeOH was added HCl (10.7 kg, 1.25 M in MeOH) at RT. It was slightly exothermic. After the addition was completed, the reaction was heated to 45° C. If the reaction was incomplete after 14 to 16 h, additional HCl (1 kg, 1.25 M in MeOH) was added and agitation at 45° C. was continued for 2 h.
- the reaction was equipped with a distillation setup with acid scrubber. The reaction was concentrated to between 20 and 30 L under a vacuum below 50° C. To the resulting solution was added MeOH (35 kg) and the reaction was concentrated to 20 to 30 L again under a vacuum below 50° C. The solvent was then switched to EtOAc using 40 kg of EtOAc. The solvent ratio was monitored by Headspace GC and the solvent swap continued until it was less than 1/5. The solution was concentrated to between 20 and 30 L under a vacuum below 50° C. After the solution was cooled below 30° C., aqueous NaHCO 3 (1.2 kg of NaHCO 3 and 20 kg of water) was added slowly with a medium agitation and followed by EtOAc (40 kg).
- Step 3 The solution of VIII in MEK was transferred to a second 100 L cylindrical reaction vessel through a 1 ⁇ m line filter.
- benezenesulfonic acid solution 1.3 kg of benzenesulfonic acid, 1.4 kg of water and 4.4 kg of MEK.
- the filtered VIII solution was heated to 75° C. and to the resulting solution was added 0.7 kg of the benzenesulfonic acid solution through a 1 ⁇ m line filter.
- the clear solution was seeded with crystalline benzenesulfonic acid salt of VIII (0.425 kg) as a slurry in MEK (0.025 kg of VIIIb crystalline seed and 0.4 kg of MEK) which produced a thin slurry.
- the remaining benzenesulfonic acid solution was then added through a 1 ⁇ m line filter in 2 h.
- the slurry was heated at 75° C. for additional 1 h and then cooled to 18° C. in a minimum of 3 h.
- the resulting thick slurry was agitated at 20° C. for 14 to 16 h.
- the solid was filtered using an Aurora dryer.
- the mother liquor was assayed by HPLC (about 0.3% loss).
- the solid was then washed with 1 ⁇ m line filtered 15.8 kg of MEK and water solution (0.8 kg of water and 15 kg of MEK) and followed by 1 ⁇ m line filtered 30 kg of MEK. Washes were assayed by HPLC ( ⁇ 1% loss).
- the wet cake was dried under a vacuum and a nitrogen sweep at a jacket temperature of 45° C. for a minimum 12 h to afford the benzenesulfonic acid salt of VIII, which is labeled VIIIb
- the reaction was quenched at the same temperature with 19.4 kg of H 3 PO 4 solution (4.4 kg of 85% H 3 PO 4 and 15 kg of water) slowly and the internal temperature was remained below 30° C.
- the reaction was diluted with 18 kg of EtOAc.
- the organic layer was washed with 13.1 kg of H 3 PO 4 solution (1.1 kg of 85% H 3 PO 4 and 12 kg of water) and then with 12.6 kg of H 3 PO 4 solution (0.55 kg of 85% H 3 PO 4 and 12 kg of water).
- the organic layer was assayed for the 1-methyl-1H-pyrazol-5-amine level by HPLC.
- the organic layer needed an additional wash with 12.6 kg of H 3 PO 4 solution (0.55 kg of 85% H 3 PO 4 and 12 kg of water). Otherwise, the organic layer was washed with 20 kg of water. The organic layer was assayed again for the 1-methyl-1H-pyrazol-5-amine level. If the HPLC result indicated >2 ⁇ g/mL of 1-methyl-1H-pyrazol-5-amine, the organic layer needed an additional wash with 20 kg of water. Otherwise, the organic layer was washed with 12.4 kg of NaCl and NaHCO 3 solution (2 kg of NaCl, 0.35 kg of NaHCO 3 and 10 kg of water).
- the solvent was then switched to EtOAc using 40 kg of EtOAc.
- the solvent ratio was monitored by Headspace GC. If the ratio of MeOH/EtOAc was greater than 1/5, the solvent swap should be continued. Otherwise, the solution was concentrated to 20 to 30 L under a vacuum below 50° C. After the solution was cooled below 30° C., 21.2 kg of NaHCO 3 solution (1.2 kg of NaHCO 3 and 20 kg of water) was charged slowly with a medium agitation and followed by 40 kg of EtOAc. After the phase separation, the organic layer was washed with 2 ⁇ 10 kg of water. The organic layer was concentrated to 20 to 30 L under a vacuum below 50° C. The solvent was then switched to MEK using 35 kg of MEK. The residue MeOH was monitored by Headspace GC. If the level of MeOH was >0.3%, the solvent swap should be continued. Otherwise, the solution was concentrated to 20 to 30 L under a vacuum below 50° C. for the next step.
- the VIII solution in MEK from the last step was transferred to a second 100 L cylindrical reaction vessel through a 3 ⁇ m line filter.
- a separated container was prepared 7.1 kg of benzenesulfonic acid solution (1.3 kg of benzenesulfonic acid, 1.4 kg of water and 4.4 kg of MEK).
- the filtered G02584994 solution was heated to 75° C. and to the resulting solution was charged 0.7 kg of benzenesulfonic acid solution (10%) through a 3 ⁇ m line filter.
- To the clear solution was charged 0.425 kg of VIIIb crystalline seed slurry in MEK (0.025 kg of VIIIb crystalline seed and 0.4 kg of MEK). This resulted in a thin slurry.
- the reaction was quenched at the same temperature with 16.7 kg of H 3 PO 4 solution (3.7 kg of 85% H 3 PO 4 and 13 kg of water) slowly and the internal temperature was remained below 30° C.
- the reaction was diluted with 17 kg of EtOAc.
- the organic layer was washed with 13.1 kg of H 3 PO 4 solution (1.1 kg of 85% H 3 PO 4 and 12 kg of water) and then with 10.5 kg of H 3 PO 4 solution (0.46 kg of 85% H 3 PO 4 and 10 kg of water).
- the organic layer was assayed for the 1-methyl-1H-pyrazol-5-amine level by HPLC.
- the HPLC result indicated 2 ⁇ g/mL of 1-methyl-1H-pyrazol-5-amine.
- the organic layer was washed with 15.8 kg of NaCl solution (0.3 kg of NaCl and 15.5 kg of water). The organic layer was assayed again for the G02586778 level.
- the HPLC result indicated 0.5 ⁇ g/mL of 1-methyl-1H-pyrazol-5-amine.
- the organic layer was washed with 10.3 kg of NaCl and NaHCO 3 solution (1.7 kg of NaCl, 0.6 kg of NaHCO 3 and 8 kg of water).
- residue water in organic solution was removed through an azeotropic distillation with EtOAc to ⁇ 0.5% (by KF) and then the solution was concentrated to 20 to 30 L under a vacuum below 50° C. The solvent was then swapped to MeOH using 30 kg of MeOH and then concentrated to 20 to 30 L for the next step.
- the solution was concentrated to 20 L under a vacuum below 50° C.
- 18 kg of NaHCO 3 solution (1 kg of NaHCO 3 and 17 kg of water) was charged slowly with a medium agitation and followed by 34 kg of EtOAc.
- the organic layer was washed with 2 ⁇ 8 kg of water.
- the organic layer was concentrated to 20 L under a vacuum below 50° C.
- the solvent was then switched to MEK using 35 kg of MEK.
- the residue MeOH was monitored by Headspace GC. If the level of MeOH was >0.3%, the solvent swap should be continued. Otherwise, the solution was concentrated to 20 L under a vacuum below 50° C. for the next step.
- the VIII solution in MEK from the last step was transferred to a second 100 L cylindrical reaction vessel through a 1 ⁇ m polish filter.
- a separated container was prepared 6.0 kg of benzenesulfonic acid solution (1.1 kg of benzenesulfonic acid, 1.2 kg of water and 3.7 kg of MEK).
- the filtered solution was heated to 75° C. and to the resulting solution was charged 0.6 kg of benzenesulfonic acid solution (10%) through a 1 ⁇ m line filter.
- To the clear solution was charged 0.36 kg of VIIIb crystalline seed slurry in MEK (0.021 kg of VIIIb crystalline seed and 0.34 kg of MEK). This resulted in a thin slurry.
- the resulting slurry was agitated at 18° C. for 14-16 h.
- Solid was filtered using a filter dryer.
- Solid was then washed with 1 ⁇ m line filtered 8.6 kg of EtOH and water solution (0.4 kg of water and 8.2 kg of EtOH).
- the solution was introduced in two equal portions.
- the solid was then washed by 1 ⁇ m line filtered 6.7 kg of MEK.
- the wet cake was dried under a vacuum and the nitrogen sweep at a jacket temperature of 35-40° C. for a minimum 12 h.
- Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 24479 reflections in the range 3° ⁇ 63°.
- the refined mosaicity from DENZO/SCALEPACK was 0.59°, indicating moderate crystal quality [Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307].
- the space group was determined by the program XPREP [Bruker, XPREP in SHELXTL v. 6.12., Bruker AXS Inc., Madison, Wis., USA, 2002]. There were no systematic absences, and the space group was determined to be P1 (no. 1).
- the data were collected to a maximum 2 ⁇ value of 126.9°, at a temperature of 293 ⁇ 1 K.
- the standard deviation of an observation of unit weight (goodness of fit) was 1.385.
- the highest peak in the final difference Fourier had a height of 0.85 e/ ⁇ 3 . This is rather high and indicative of the poor quality of the structure refinement.
- the minimum negative peak had a height of ⁇ 0.28 e/ ⁇ 3 .
- the Flack factor for the determination of the absolute structure [Flack, H. D. Acta Cryst. 1983, A39, 876] refined to ⁇ 0.01(4).
- One of the hydroxyl groups of one of the molecules in the asymmetric unit was refined using disorder. This leads to the splitting of the O22 and H22 atoms into the O22A, H22A and O22B, H22B pairs of atomic coordinates.
- FIG. 3 A representation of a single molecule of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt crystalline Form A, determined from the single crystal analysis, is shown in FIG. 3 . Disorder in the hydroxymethyl group can be observed in the upper right of FIG. 3 .
- the initial freezing of the compound was done under a vacuum at ⁇ 70° C. for 1.5 hours at 500 mTorr pressure. This ensures that the entire solution is completely frozen before primary drying is started.
- Primary drying is done to remove the bulk solvent via sublimation. From ⁇ 70° C., the temperature is raised to ⁇ 35° C. and the pressure is lowered to 100 mTorr for 1 hour. After drying at ⁇ 35° C. for 1 hour, the temperature is raised to 5° C. and dried for an additional 28 hours at the same pressure. Primary drying ends with the last step at 15° C. which is held for 16 hours. The lyophilization pressure is lowered to 50 mTorr and the temperature is raised to 35° C. for 16 hours.
- Powder X-ray diffraction patterns of samples were obtained using the Rigaku MiniFlexII powder X-ray diffractometer using reflection geometry.
- the copper radiation source was operated at the voltage of 30 kV and the current 15 mA.
- Each sample was placed in the cavity of an aluminum sample holder fitted with a zero background quartz insert and flattened with a glass slide to present a good surface texture and inserted into the sample holder. All samples were measured in the 2 ⁇ angle range between 2° and 40° with a scan rate of 2°/min and a step size of 0.02°.
- a TA Instruments differential scanning calorimeter (Model Q100 or Model Q2000) with a mechanical cooler and a standard cell (configured the same as the sample pan) was used to measure the thermal properties of the powder samples.
- Each sample was loaded into a closed aluminium pan with a non-crimped lid containing zero to one pin hole and placed into the differential scanning calorimetery (DSC) cell.
- the cell has a nitrogen purge flowing at approximately 50 cm 3 /min.
- the cell and sample were equilibrated at 20° C.
- the cell was then heated to 209° C. or 250-350° C. at 10.00° C./min while monitoring the heat flow difference between the empty reference pan and the sample pan.
- Modulated DSC was used to analyze (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one amorphous free base.
- a TA Instruments differential scanning calorimeter (Model Q2000) with a mechanical cooler and a standard cell (configured the same as the sample pan) was used to measure the thermal properties of the powder samples. Each sample was loaded into a closed aluminium pan with a non-crimped lid containing zero to one pin hole and placed into the differential scanning calorimetery (DSC) cell.
- DSC differential scanning calorimetery
- the cell has a nitrogen purge flowing at approximately 50 cm 3 /min.
- the cell and sample were equilibrated at 25° C., the temperature was modulated at ⁇ 1° C. every 60 seconds, and held isothermally for 5 minutes. Data storage was turned on and the sample ramped at 3° C. to 100° C. The sample was then ramped to 25° C. at 3° C./minute. The sample was then heated at 3° C./minute to 200° C. The reversing signal is shown.
- the free base of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one is an amorphous solid (XRPD, FIG. 4 ).
- the glass transition temperature (TG) varies from about 74-96° C. depending on purity and solvent content as measured by differential scanning calorimetry (DSC, FIG. 5 ).
- the crystalline material obtained was determined to be ⁇ 1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.
- a salt screen was conducted to determine if a suitable salt form could be discovered.
- the pK a of the free base was determined to be less than 2, which limited the range of possible salt coformers.
- salts derived from (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one free base would have a pH max less than 2 and would be expected to disproportionate in water.
- a crystalline salt could be prepared or that any salt would have acceptable exposure in vivo (an aqueous environment).
- the peaks may be shifted up or down depending on the conditions under which the XRPD analysis was conducted. In general, the peaks may shift by +/ ⁇ 0.2. In another aspect, the peaks may be shifted by +/ ⁇ 0.1.
- Whether a pharmaceutical product contains a particular crystalline form of a substance, typically in a tablet or capsule, may be determined, for example, using X-ray diffraction, Raman spectroscopy and/or solid state NMR techniques.
- the solid state 13 C and 19 F NMR spectra of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt crystalline Form A is set forth in FIGS. 19 and 20 , respectively.
- the procedure for obtaining the NMR spectra is set forth below.
- the pulse sequence for 13 C acquisition employed ramped cross polarization (CP), 1-3 5- ⁇ total sideband suppression (TOSS), 4 and high power 1 H decoupling with a SPINAL64 5 scheme and field strength of 90 kHz.
- Magic-angle spinning (MAS) was performed at 8000 ⁇ 3 Hz.
- the 1 H 90° pulse width was 2.79 ⁇ s and the TOSS sequence employed 13 C 180° pulses of 6.50 ⁇ s.
- the CP contact time was 3 ms
- the recycle delay was 18 s
- a total of 3888 scans were averaged to generate the spectrum.
- Chemicals shifts were externally referenced by setting the methyl peak of 3-methylglutaric acid to 18.84 ppm relative to tetramethylsilane. 6
- the pulse sequence for 19 F acquisition employed ramped CP 1-3 and high power 1 H decoupling with a SPINAL64 5 scheme and field strength of 71 kHz.
- Magic-angle spinning (MAS) was performed at 14000 ⁇ 5 Hz.
- the 1 H 90° pulse width was 3.54 ⁇ s
- the CP contact time was 3 ms
- the recycle delay was 18 s
- a total of 16 scans were averaged to generate the spectrum.
- Chemicals shifts were externally referenced by setting the fluorine peak of polytetrafluoroethylene (PTFE) to ⁇ 122.38 ppm relative to CFCl 3 (determined experimentally by spiking CFCl 3 into a PTFE sample).
- PTFE polytetrafluoroethylene
- Form A is characterized by strong peaks at chemical shifts of 157.7 ⁇ 0.2 ppm, 129.6 ⁇ 0.2 ppm, 125.8 ⁇ 0.2 ppm, and 117.0 ⁇ 0.2 ppm relative to tetramethylsilane (at 293 K).
- the 19 F spectrum is characterized by two isotropic peaks at chemical shifts of ⁇ 111.1 ⁇ 0.4 ppm and -115.4 ⁇ 0.4 ppm relative to CFCl 3 (at 293 K).
- the crystalline besylate salt of VIII is a highly crystalline material with a melting point that is acceptable for pharmaceutical dosage form development.
- the besylate salt form is preferred over the tosylate and 1,5-naphthalenesulfonic acid salt forms based on it's simple solid state landscape (only one crystalline form identified).
- the lower hygroscopicity of the besylate salt compared to the tosylate and 1,5-naphthalenedisulfonic acid salt forms is highly desired.
- the free base of VIII has a low pKa, less than 1.8, and therefore, any salts identified were expected to be unstable in the presence of water due to disproportionation to free base and acid. Therefore, the non-hygroscopicity of the besylate salt was unexpected and led to enhanced stability compared to the tosylate and naphthalenesulfonic acid salt forms.
- the present invention provides pharmaceutical compositions comprising a compound of the present invention or a salt or crystalline form of the salt and a pharmaceutically acceptable excipient, such as a carrier, adjuvant, or vehicle.
- a pharmaceutically acceptable excipient such as a carrier, adjuvant, or vehicle.
- the composition is formulated for administration to a patient in need thereof.
- patient refers to an animal, such as a mammal, such as a human. In one embodiment, patient or individual refers to a human.
- pharmaceutically acceptable means that the compound or composition referred to is compatible chemically and/or toxicologically with the other ingredients (such as excipients) comprising a formulation and/or the patient being treated, particularly humans.
- compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block
- compositions comprising a compound of the present invention may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the composition comprising a compound of the present invention is formulated as a solid dosage form for oral administration.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the solid oral dosage form comprising a compound of formula (I) or a salt thereof further comprises one or more of (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and (ii) filler or extender such as starches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such as glycerol, (v) disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates or sodium carbonate, (vi) solution retarding agents
- the solid oral dosage form is formulated as capsules, tablets or pills.
- the solid oral dosage form further comprises buffering agents.
- such compositions for solid oral dosage forms may be formulated as fillers in soft and hard-filled gelatin capsules comprising one or more excipients such as lactose or milk sugar, polyethylene glycols and the like.
- tablets, dragees, capsules, pills and granules of the compositions comprising a compound of formula I or salt thereof optionally comprise coatings or shells such as enteric coatings. They may optionally comprise opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- coatings or shells such as enteric coatings.
- opacifying agents can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- embedding compositions include polymeric substances and waxes, which may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- a composition comprises micro-encapsulated compound of the present invention, and optionally, further comprises one or more excipients.
- compositions comprise liquid dosage formulations comprising a compound of formula I or salt thereof for oral administration and optionally further comprise one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage form optionally, further comprise one or more of an inert diluent such as water or other solvent, a solubilizing agent, and an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters of sorbitan, and mixtures thereof.
- liquid oral compositions optionally further comprise one or more adjuvant, such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.
- sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the rate of compound release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides).
- Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- the composition for rectal or vaginal administration are formulated as suppositories which can be prepared by mixing a compound of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of the present invention.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of the present invention.
- Example dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the compound of the present invention is admixed under sterile conditions with a pharmaceutically acceptable carrier, and optionally preservatives or buffers. Additional formulation examples include an ophthalmic formulation, ear drops, eye drops or transdermal patches.
- Transdermal dosage forms can be made by dissolving or dispensing the compound of the present invention in medium, for example ethanol or dimethylsulfoxide.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- Nasal aerosol or inhalation formulations of a compound of the present invention may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- compositions may be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions are administered without food. In certain embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
- Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
- the amount of a provided compound of the present invention in the composition will also depend upon the particular compound in the composition.
- the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
- oral unit dosage forms such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.
- An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or salt thereof, and further comprises about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium stearate.
- the process of formulating the tablet comprises mixing the powdered ingredients together and further mixing with a solution of the PVP.
- the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
- An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of a compound of formula I or salt thereof, in a suitable buffer solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a salt such sodium chloride, if desired.
- a suitable buffer solution e.g. a phosphate buffer
- a tonicifier e.g. a salt such sodium chloride
- the solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.
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Abstract
Description
- This application is a continuation of and claims priority to PCT international application no. PCT/CN2015/076083, filed Apr. 8, 2015, and claims priority under 35 U.S.C. §119 to PCT international application no. PCT/CN2014/075011, filed Apr. 9, 2014, which applications are hereby incorporated by reference in their entirety.
- The processes involved in tumor growth progression and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface receptor tyrosine kinase (“RTK's”), such as ErbB family, PDGF, FGF, and VEGF receptor tyrosine kinases. Activation of an RTK induces a cascade of phosphorylation events that begins with activation of Ras. Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERK1/2. When activated, ERK1/2 phosphorylates several downstream targets involved in a multitude of cellular events, including cytoskeletal changes and transcriptional activation. The ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors. Ras genes, which are upstream of ERK1/2, are mutated in several cancers, including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors. In addition, mutations of BRAF, a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers. These observations indicate that the ERK1/2 signaling pathway is an attractive pathway for anti-cancer therapies in a broad spectrum of human tumors (M. Hohno and J. Pouyssegur, Prog. in Cell Cycle Res. 2003 5:219).
- The ERK pathway has also been cited as a promising therapeutic target for the treatment of pain and inflammation (Ma, Weiya and Remi, Quirion. “The ERK/MAPK Pathway, as a Target For The Treatment Of Neuropathic Pain” Expert Opin. Ther. Targets. 2005 9(4):699-713, and Sommer, Claudia and Frank Birklein “Resolvins and Inflammatory Pain” F1000 Medicine Reports 2011 3:19).
- Therefore, small-molecular inhibitors of ERK activity (i.e., ERK1 and/or ERK2 activity) would be useful for treating a broad spectrum of cancers, such as, for example, melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer, as well as a and rheumatism. The present invention provides a process and intermediates for making (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, pharmaceutically acceptable salts thereof, and crystalline forms of the salts. The present invention also provides pharmaceutical compositions comprising the salts or crystalline forms of the salts, and methods of using the salts and crystalline forms of the salts. A synthesis of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one is set forth in WO 2013/130976.
- The present invention provides processes for the manufacture of I which is a useful intermediate that can be used in the manufacture VIII. (WO2013/130976) Compound VIII is an ERK inhibitor and a useful medicament for treating hyperproliferative disorders. The process provides an efficient route to VIII and to the useful intermediates VI and VII. Alkylation of VII with VI affords I, which ultimately is condensed with 1-methyl-1H-pyrazol-5-amine (XIV). (SCHEME A)
- The present invention further provides an asymmetric enzymatic reduction which permits the stereospecific reduction of 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone to afford (R)-1-(4-chloro-3-fluorophenyl)ethan-1,2-diol (IV).
- The present invention also provides an improved process to prepare 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (VII).
- The present invention provides a crystalline besylate salt (VIIIb) with desirable physical properties that permit ready formulation and good bioavailability.
- In
embodiment 1, the present invention provides processes for the preparation of a compound of formula VIII, the processes comprising the steps of: -
- (a) contacting 4-bromo-1-chloro-2-fluorobenzene with a metallating agent in an aprotic organic solvent to afford an organomagnesium compound, which is reacted with 2-chloro-N-methoxy-N-methylacetamide to afford 2-chloro-1-(4-chloro-3-fluorophenyl)ethanone (II);
-
- (b) contacting II with sodium formate and formic acid in aqueous ethanol to afford 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone (III)
-
- (c) contacting III with a ketoreductase to afford (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (IV);
-
- (d) contacting IV with a silyl chloride (Ra)3SiCl and at least one base in a non-polar aprotic solvent to afford (V), and subsequently adding sulfonylchloride RbS(O)2Cl to afford VI, wherein Ra is independently in each occurrence C1-6 alkyl or phenyl and Rb is selected from C1-4 alkyl or phenyl, optionally substituted with 1 to 3 groups independently selected from C1-3 alkyl, halogen, nitro, cyano, or C1-3 alkoxy;
-
- (e) contacting 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII) with a strong base in an organic solvent and subsequently adding VI to afford XI;
-
- (f) treating XI with an oxidizing agent to afford I;
-
- (g) treating 1-methyl-1H-pyrazol-5-amine with a strong base in an aprotic solvent at reduced temperature and adding the compound of formula I to afford IX; and,
-
- (h) contacting IX with a de-silylating agent to afford VIII.
- In
embodiment 2, the present invention provides processes according toembodiment 1 wherein the ketoreductase in step (c) affords an enantiomeric excess at least about 98%. - In
embodiment 3, the present invention provides processes ofembodiment 2 wherein the ketoreductase in step (c) is KRED-NADH-112. - In embodiment 4, the present invention provides processes of
embodiment 2 wherein step (c) further comprises NADH or NADPH as a cofactor. - In
embodiment 5, the present invention provides processes of embodiment 4 wherein the cofactor is regenerated with a cosubstrate selected from a secondary alcohol or from an additional enzyme selected from alcohol dehydrogenase, glucose dehydrogenase, formatted dehydrogenase, glucose-6-phosphate dehydrogenase, phosphite dehydrogenase or hydrogenase. - In
embodiment 6, the present invention provides processes of any ofembodiment 2 to 5 wherein the ketoreductase step is performed in an aqueous medium in the presence of organic cosolvent at a temperature between 1 and 50° C. - In embodiment 7, the present invention provides processes of
embodiment 6 wherein the ketoreductase step produces a homogeneous suspension. - In
embodiment 8, the present invention provides processes ofembodiment 1 wherein the silyl chloride is tert-butyldimethylsilyl chloride, the sulfonyl chloride is methanesulfonyl chloride, the bases in step (d) are DMAP and TEA and the non-polar aprotic solvent is DCM and in step (e) the organic solvent is dioxane. - In embodiment 9, the present invention provides processes of
embodiment 1 wherein (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme. - In
embodiment 10, the present invention provides processes ofembodiment 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent glucose dehydrogenase, in step (d) (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme. - In embodiment 11, the present invention provides processes of
embodiment 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent is glucose dehydrogenase, in step (d) (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, and in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF. - In embodiment 12, the present invention provides processes of
embodiment 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and cofactor recycling agent is glucose dehydrogenase, in step (d) (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF, and in step (h) the desilylating agent is methanolic HCl. - In
embodiment 13, the present invention provides processes according toembodiment 1 wherein the compound VIII from step h is contacted with a sulfonic acid in an organic solvent and water to afford a salt of VIIIa where Rc is an aryl sulfonic acid - In embodiment 14, the present invention provides processes according to
embodiment 13 wherein RcSO3H is benzenesulfonic acid and the solvent is methyl ethyl ketone and water to afford the besylate salt VIIIb. - In embodiment 15, the present invention provides processes for the preparation of 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII) comprising the steps of:
-
- (a) contacting 2-fluoro-4-iodopyridine with a metallating agent in an aprotic organic solvent to afford an organomagnesium compound, which is reacted with 4-chloro-2(methylthio)pyrimidine in the presence of a palladium catalyst to afford 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (X);
- (b) treating X with potassium tert-butoxide in THF and subsequently with an aqueous acid to afford 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII).
- In embodiment 16, the present invention provides processes according to
embodiment 15 wherein the palladium catalyst is (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride, the metallating agent is i-PrMgCl and LiCl, and the aprotic solvent is THF. - In embodiment 17, the present invention provides the compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
- In embodiment 18, the present invention provides pharmaceutical compositions comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate and a pharmaceutically acceptable excipient.
- In embodiment 19, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
- In
embodiment 20, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern comprising peaks at 6.16±0.2, 7.46±0.2, 16.36±0.2, 25.76±0.2 and 25.98±0.2 2θ - In embodiment 21, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern substantially as shown in
FIG. 1 . - In
embodiment 22, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 13C NMR pattern substantially as shown inFIG. 19 . - In embodiment 23, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 19F NMR pattern substantially as shown in
FIG. 20 . - In embodiment 24, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 13C NMR pattern substantially as shown in
FIG. 19 and a 19F NMR pattern substantially as shown inFIG. 20 . - In
embodiment 25, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 19F NMR pattern comprising peaks at −111.1±0.4 ppm and −115.4±0.4 ppm relative to CFCl3 (at 293 K). - In embodiment 26, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an 13C NMR pattern comprising peaks at 157.7±0.2 ppm, 129.6±0.2 ppm, 125.8±0.2 ppm, and 117.0±0.2 ppm relative to tetramethylsilane (at 293 K).
- In embodiment 27, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having a DSC pattern substantially as shown in
FIG. 2 . - In embodiment 28, the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate in accordance with any one of embodiments 19 to 27 and a pharmaceutically acceptable excipient.
- In embodiment 29, the present invention provides the compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid.
- In
embodiment 30, the present invention provides pharmaceutical compositions comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid and a pharmaceutically acceptable excipient. - In
embodiment 31, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid. - In embodiment 32, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A.
- In embodiment 33, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A having an X-ray powder diffraction pattern comprising peaks at. 5.76±0.2, 13.44±0.2, 15.64±0.2, 19.40±0.2 2θ.
- In embodiment 34, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A having an X-ray powder diffraction pattern substantially as shown in
FIG. 12 . - In
embodiment 35, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A having a DSC pattern substantially as shown inFIG. 13 . - In embodiment 36, the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A in accordance with any one of
claims 31 to 35 and a pharmaceutically acceptable excipient. - In embodiment 37, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B.
- In embodiment 38, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B. having an X-ray powder diffraction pattern comprising peaks at 7.02±0.2, 16.30±0.2, 17.30±0.2, 21.86±0.2 2θ.
- In embodiment 39, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B having an X-ray powder diffraction pattern substantially as shown in
FIG. 15 . - In
embodiment 40, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B having a DSC pattern substantially as shown inFIG. 16 . - In embodiment 41, the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B in accordance with any one of embodiments 37 to 40 and a pharmaceutically acceptable excipient.
- In embodiment 42, the present invention provides the compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid.
- In embodiment 43, the present invention provides pharmaceutical compositions comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid and a pharmaceutically acceptable excipient.
- In embodiment 44, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid.
- In embodiment 45, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I.
- In embodiment 46, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I having an X-ray powder diffraction pattern comprising peaks at 12.50±0.2, 13.86±0.2 2θ.
- In embodiment 47, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I having an X-ray powder diffraction pattern substantially as shown in
FIG. 6 . - In embodiment 48, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I having a DSC pattern substantially as shown in
FIG. 7 . - In embodiment 49, the present invention provide pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form Tin accordance with any one of embodiments 44 to 48 and a pharmaceutically acceptable excipient.
- In
embodiment 50, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II. - In embodiment 51, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxy ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2 (1H)-one naphthalenedisulfonic acid Form II having an X-ray powder diffraction pattern comprising peaks at 12.80±0.2, 22.42±0.2, 24.92±0.2 2θ.
- In embodiment 52, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II having an X-ray powder diffraction pattern substantially as shown in
FIG. 8 . - In
embodiment 53, the present invention provides crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II having a DSC pattern substantially as shown inFIG. 9 . - In embodiment 54, the present invention provides pharmaceutical compositions comprising crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II in accordance with any one of
claims 50 to 53 and a pharmaceutically acceptable excipient. - In embodiment 55, the present invention provides amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
- In embodiment 56, the present invention provides amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern substantially as shown in
FIG. 21 . - In embodiment 57, the present invention provides amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having a DSC pattern substantially as shown in
FIG. 22 . - In embodiment 58, the present invention provides pharmaceutical compositions comprising amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate in accordance with any one of embodiments 55 to 57 and a pharmaceutically acceptable excipient.
-
FIG. 1 shows the XRPD pattern of VIII crystalline besylate form A. -
FIG. 2 shows the DSC and TGA analysis of VIII crystalline besylate form A. -
FIG. 3 shows the single crystal structure analysis of VIII crystalline besylate form A. -
FIG. 4 shows the XRPD pattern of VIII free base. -
FIG. 5 shows the DSC analysis of VIII free base. -
FIG. 6 shows the XRPD pattern of VIII naphthalenedisulfonic acid form I. -
FIG. 7 shows the DSC analysis of VIII naphthalenedisulfonic acid form I. -
FIG. 8 shows the XRPD pattern of VIII naphthalenedisulfonic acid form II with a small amount of form I. -
FIG. 9 shows the DSC analysis of VIII naphthalenedisulfonic acid form II. -
FIG. 10 shows the DVS pattern of VIII naphthalenedisulfonic acid form I. -
FIG. 11 shows the XRPD pattern of VIII toluenesulfonic acid IPA solvate. -
FIG. 12 shows the XRPD pattern of VIII toluenesulfonic acid form A. -
FIG. 13 shows the DSC analysis of VIII toluenesulfonic acid form A. -
FIG. 14 shows the DVS pattern of VIII toluenesulfonic acid form A. -
FIG. 15 shows the XRPD pattern of a mixture of VIII toluenesulfonic acid amorphous and form B. -
FIG. 16 shows the DSC analysis of a mixture of VIII toluenesulfonic acid amorphous and form B. -
FIG. 17 shows the XRPD pattern of VIII toluenesulfonic acid amorphous. -
FIG. 18 shows the DVS analysis of VIII besylate salt, form A. -
FIG. 19 shows the 13C solid state NMR pattern of VIII crystalline besylate form A. -
FIG. 20 shows the 19F solid state NMR pattern of VIII crystalline besylate form A. -
FIG. 21 shows the XRPD pattern of VIII besylate amorphous. -
FIG. 22 shows the DSC analysis of VIII besylate amorphous. - Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. The invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.
- As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term “comprising” means that the compound or composition includes at least the recited features or components, but may also include additional features or components. Additionally, the words “include,” “including,” and “includes” when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.
- The term “about” when used in conjunction with hours, denotes ±5 hours. The term “about” when used in conjunction with temperatures denotes ±5 Celsius degrees. The term “about” when used in conjunction with percentages or other values, denotes ±10%.
- The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
- The term “isomer” refers to compounds with the same formula, but a different arrangement of atoms in the molecule and different properties.
- The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
- “Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated under high resolution analytical procedures such as electrophoresis and chromatography.
- The term “enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
- Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds described herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
- The present process as described herein also can be used to prepare isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I or 125I. Certain isotopically-labeled compounds of the present invention (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 15O, 13N, 11C and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
- The term “aprotic (or nonpolar) solvent means organic solvents such as diethyl ether, ligroin, pentane, hexane, cyclohexane, heptane, chloroform, benzene, toluene, dioxane, tetrahydrofuran, dichloromethane or ethyl acetate.
- The term “polar aprotic solvent” refers to organic solvents such as formamide, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or hexamthylphosphoramide.
- The term “polar protic solvent” refers to organic solvents such as lower alkanols, formic acid or acetic acid.
- The term “ethereal solvent” refers to solvents such as tetrahydofuran, dimethoxyethane, dioxane, or dialkyl ethers such as diethyl ether and methyl tertbutyl ether.
- The term “derivative” of a compound as used herein means a compound obtainable from the original compound by a simple chemical process.
- The term “protecting group” as used herein refers to a chemical group that (a) preserves a reactive group from participating in an undesirable chemical reaction; and (b) can be easily removed after protection of the reactive group is no longer required. For example, the benzyl group is a protecting group for a primary hydroxyl function.
- The term “hydroxyl protecting group” or “alcohol protecting group” means a protecting group that preserves a hydroxy group that otherwise would be modified by certain chemical reactions. A hydroxyl protecting group can be an ether, an ester, or silane that can be removed easily after completion of all other reaction steps, such as a lower acyl group (e.g., the acetyl or propionyl group or a dimethyl-t-butylsilyl group), or an aralkyl group (e.g., the benzyl group, optionally substituted at the phenyl ring). The term “silyl chloride” as used herein refers to (Ra)3SiCl wherein Ra is independently in each occurrence C1-6 alkyl or phenyl.
- The term “deprotecting reagent” as used herein refers to reagents contacted with a protected chemical moiety to remove the protecting groups. Reagents and protocols for deprotection are well known and can be found in Greene and Wuts or in Harrison and Harrison (infra). One skilled in the chemical arts will appreciate that on occasion protocols must be optimized for a particular molecule and such optimization is well with the ability of one skilled in these arts.
- The term “optional” or “optionally” as used herein means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “aryl group optionally mono- or di-substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
- As used herein, the term “treating,” “contacting” or “reacting” when referring to a chemical reaction means to add or mix two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents that were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
- The term “leaving group” has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like. The term “sulfonyl chloride” refers to a compound RbS(O)2Cl wherein Rb is selected from C1-4 alkyl or phenyl, optionally substituted with 1 to 3 groups independently selected from C1-3 alkyl, halogen, nitro, cyano, C1-3 alkoxy.
- A Wittig reagent can be used to form an alkene from an aldehyde. The Wittig reagent is usually prepared from a phosphonium salt, which is in turn made by the reaction of triphenylphosphine with an alkyl halide. To form the Wittig reagent (ylide), the phosphonium salt is suspended in a solvent such as diethyl ether or THF and treated with a strong base such as phenyllithium or n-butyllithium.
- The Sharpless dihydroxylation or bishydroxylation is used in the enantioselective preparation of 1,2-diols from prochiral olefins. This procedure is performed with an osmium catalyst and a stoichiometric oxidant [e.g. K3Fe(CN)6 or N-methylmorpholine oxide (NMO)]; it is carried out in a buffered solution to ensure a stable pH, since the reaction proceeds more rapidly under slightly basic conditions. Enantioselectivity is achieved through the addition of enantiomerically-enriched chiral ligands [(DHQD)2PHAL, (DHQ)2PHAL or their derivatives]. These reagents are also available as stable, prepackaged mixtures (AD-mix α and AD-mix β, AD=asymmetric dihydroxylation) for either enantiopreference.
- The present procedures can use the Karl Fischer method for determining trace amounts of water in a sample. This method can be abbreviated “KF.”
- In the methods of preparing compounds described herein, it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
- Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
- Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.
- The present invention provides a process for the preparation of(S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (VIII) which has the structure
- and is a potent inhibitor of ERK kinase and useful as a medicament for the treatment of cancer or other hyperproliferative disorders. Condensation of I and 1-methyl-1H-pyrazol-5-amine (XIV) in the presence of strong base affords the IX, which is readily converted to VIII by contacting the silyl ether with aqueous acid. The amorphous free base obtained can be converted to a crystalline arylsulfonic acid salt. The term “arylsulfonic acid” as used herein refers to a benzene sulfonic acid or a naphthalene mono- or disulfonic acid in which the aryl ring is optionally substituted with methyl or halogen.
- The present invention further provides a process for the manufacture of intermediate I by first treating 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (VII) with strong base and alkylating the resulting compound with (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (VI).
- N-Alkylation of amides can be carried out under a variety of basic conditions well known to someone skilled in the art. The reaction is typically carried out in aprotic solvents such as THF, DMF, DMSO, NMP or mixtures thereof at temperatures between −78° C. and 100° C. Typically used bases are Grignard reagents, sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide. Treating VII with potassium hexamethyldisilazide in diglyme at RT allow formation of the lithium salt of VII after which the mesylate VI was introduced and the reaction heated at 90° for 4 h.
- Oxidation of a thioether to a sulfoxide or sulfone is typically facile and numerous reagents are known that are capable of carrying out this transformation. Sulfur oxidations are commonly carried out with aqueous solution of hydrogen peroxide, NaIO4, tert-butylhypochlorite, acyl nitrites, sodium perborate potassium hydrogen persulfate or peracids such as peracetic acid and meta-chloroperbenzoic acid. Typically with about one equivalent of oxidant the sulfoxide can be isolated. Exposure to two or more equivalents results in oxidation to the sulfone. Oxidation of XI with MCPBA in MTBE at ambient temperature affords I.
- The mesylate VI was prepared in five steps starting from 1-bromo-4-chloro-3-fluorobenzene, which was converted to the Grignard reagent and contacted with 2-chloro-N-methoxy-N-methylacetamide to afford the ketone II. Condensation of organolithium and organomagnesium compounds with N,O-dimethylhydroxyamides affords the corresponding ketones. (S. Nahm and D. M. Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815) The Grignard reagent was formed by treating 1-bromo-4-chloro-3-fluorobenzene with isopropyl magnesium chloride in the presence of LiCl. The addition of salts is thought to increase reactivity of the Grignard reagents by promoting the breakup of polymeric aggregates known to exist in classical solutions of Grignard reagents. (A. Krasovskiy and P. Knochel, Angew. Chem. Int. Ed. 200443:3333). After the Grignard reaction was quenched with 1N HCl, the organic phase washed with water and concentrated. Sodium formate, formic acid ethanol and water were added and the mixture heated at 80-90° C. to afford the α-hydroxy ketone III.
- Enzyme-catalyzed reduction of ketones frequently proceeds with high stereoselectivity, usually in the presence of NADH or NADPH as cofactor which is regenerated in situ. (J. C. Moore et al., Acc. Chem. Res, 2007 40(12):1412-19) Preferred microbial oxidoreductase enzymes found in yeasts, bacteria or from mammalian cells and theoxidoreductase can be applied in the form of the isolated enzyme(s) or whole cells, optionally in immobilized form by one of the numerous conventional methods described in literature.
- The oxidized cofactor is as a rule continuously regenerated with a secondary alcohol as cosubstrate. Typical cosubstrates can be selected from 2-propanol, 2-butanol, pentan-1,4-diol, 2-pentanol, 4-methyl-2-pentanol, 2-heptanol, hexan-1,5-diol, 2-heptanol or 2-octanol, preferably 2-propanol. Preferably, the cofactor is regenerated by means of the cosubstrate at the same enzyme also catalyzing the target reaction. The acetone formed when 2-propanol is used as cosubstrate is in a further preferred embodiment continuously removed from the reaction mixture.
- The cofactor can be regenerated by incorporating an additional enzyme oxidizing its natural substrate and providing the reduced cofactor. For example, secondary alcohol dehydrogenase/alcohol, glucose dehydrogenase/glucose, formate dehydrogenase/formic acid, glucose-6-phosphate dehydrogenase/glucose-6-phosphate, phosphite dehydrogenase/phosphite or hydrogenase/molecular hydrogen and the like. In addition electrochemical regeneration methods are known as well as chemical cofactor regeneration methods comprising a metal catalyst and a reducing agent are suitable. The preferred catalyst/cofactor/cosubstrate systems may vary with different ketones.
- The enzymatic reduction is performed in an aqueous medium in the presence of an organic cosolvent which can be selected, for example, from glycerol, 2-propanol, diethylether, tert-butylmethylether, diisopropylether, dibutylether, ethylacetate, butylacetate, heptane, hexane or cyclohexene or mixtures thereof. The presence of an organic cosolvent is particularly advantageous as a homogenous suspension can be formed which allows simple separation of the desired alcohol of formula IV. The reaction temperature for enzymatic reductions is usually kept in a range between 1° C. and 50° C., preferably between 20° C. and 40° C.
- The reaction concentration (i.e., the concentration of ketone and corresponding alcohol) is typically maintained at 1% to 25%, preferable between 10 and 20%.
- In a particular embodiment of the present process the asymmetric reduction of III was catalysed by KRED-NADH-112 (Codexis Inc., Redwood City, Calif., USA) in the presence of the oxidized cofactor NAD, the recycling enzyme GDH-105 (Codexis Inc., Redwood City, Calif., USA) and the final reductant glucose affording (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol in 99.5% enantiomeric excess in a quantitative chemical conversion.
- The final steps include the selective protection of the primary alcohol with tert-butyldimethylsilyl chloride, 4-dimethylaminopyridine (DMAP) and triethylamine (TEA) in DCM and subsequent formation of the methansulfonate ester with methansulfonyl chloride DMAP and TEA in DCM, which may be carried out sequentially in a single reaction vessel to afford (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (VI).
- One skilled in the art will appreciate that the process can be advantageously applied other substituted bromobenzene derivatives.
- 4-(2-(Methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (VII) was prepared by palladium-catalyzed coupling of 4-chloro-2-thiomethylpyrimidine (XIII) and 2-fluoro-4-iodopyridine (XII). The Grignard reagent was prepared by transmetallation with i-PrMgCl in the presence of LiCl (Krasovskiy, supra) and treating the resulting heteroaryl Grignard with XIII in the presence of PEPPSI (i-Pr) ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, CASRN 905459-27-0). Reaction of X with potassium tert-butoxide afforded 4-(2-(tert-butoxy)pyridin-4-yl)-2-(methylthio)pyrimidine, which was treated with H2SO4 to remove the tert-butyl group and afford VII.
- The sequence of steps can be modified without departing from the invention as disclosed herein. In a variation, a 2,4-disubstituted pyrimidine derivative, such as 2,4-dichloro-pyrimidine or 4-chloro-2-methylthiopyrimidine, is coupled with 2-fluoropyridin-4-ylboronic acid (Pd(dppf)Cl2, K3PO4, dioxane) to afford 2-chloro-4-(2-fluoropyridin-4-yl)pyrimidine, which is condensed with 1-methyl-1H-pyrazol-5-amine (LiHMDS, THF) and hydrolyzed to afford 4-(2-(1-methyl-1H-pyrazol-5-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one which can be alkylated as described previously using two equivalents of base.
- Commonly used abbreviations which may appear include: acetyl (Ac), aqueous (aq.), atmospheres (Atm), tert-butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), benzotriazol-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate (BOP), butyl (Bu), benzoyl (Bz), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), dibenzylideneacetone (DBA), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N′-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD), di-iso-butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1′-bis-(diphenylphosphino)ethane (dppe), 1,1′-bis-(diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), diethyl ether (Et2O), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium hexafluorophosphate acetic acid (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosp (HBTU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), iso-propanol (IPA), lithium hexamethyldisilazide (LiHMDS), lithium diisopropylamide (LDA), methanol (MeOH), melting point (mp), MeSO2— (mesyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl tert-butyl ether (MTBE), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), petroleum ether (pet ether, i.e. hydrocarbons), )phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), pounds per square inch (psi), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP), pyridine (pyr), room temperature (rt or RT), satd. (saturated), tert-butymethyl ether (TBME), tert-butyldimethylsilyl or t-BuMe2Si (TBDMS or TBS), triethylamine (TEA or Et3N), triflate or CF3SO2— (Ts), trifluoroacetic acid (TFA), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF), tetramethylethylenediamine (TMEDA), trimethylsilyl or Me3Si (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2— or tosyl (Ts), N-urethane-N-carboxyanhydride (UNCA), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), extracellular signal-regulated kinase (ERK), tetrahydrofuran (THF), hour(s) (h), metachloroperoxybenzoic acid (MCPBA or mCPBA), nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), 4-dimethylaminopyridine (DMAP), phenyl (Ph), methyl (Me), ethyl (Et), tert-butyl (t-Bu), tert-butyldimethylsilyl chloride (TBSCl), mesyl (Ms), ethyl acetate (EtOAc), gas chromatography (GC), methylethyl ketone (MEK), high pressure liquid chromatography (HPLC), X-ray powder diffraction (XRPD), nuclear magnetic resonance (NMR), glass transition temperature (TG), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), polytetrafluoroethylene (PTFE). Conventional nomenclature including the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert- or -t) and neo-have their customary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.).
- In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical procedures described herein may be adapted to suit available equipment and circumstances. Additionally, reagents such as the selection of leaving groups, activating groups, protecting groups and reagents, such as strong bases and palladium catalysts may be altered without deviating from the disclosed invention.
- The original synthetic process involves an eight step linear synthesis (10 steps overall) from three commercially available materials, 4-chloro-3-
fluorobenzaldehyde 1, 4-chloro-2-(methylthio)pyrimidine XIII and (2-fluoropyridin-4-yl)boronic acid 6-2 (Scheme 1). Wittig reaction of 1 produced olefin intermediate 2 in 55% yield. Asymmetric Sharpless dihydroxylation of styrene followed by a selective mono-protection of diol IV with TBSCl afforded intermediate V in 55% yield over two steps. One of the intermediates VI was obtained through a mesylation of secondary alcohol. On the other hand, pyridone intermediate VII was synthesized through a Suzuki cross coupling between XIII and 6-2, followed by a hydrolysis with aqueous HCl solution. A purification of VII by a Soxhlet extraction with EtOAc over 3 days was required to ensure a good purity of 6 and a reasonable conversion in the subsequent reaction. Sn2 displacement of VI and VII was able to afford intermediate XI in 50% yield over 2 steps from intermediate V. An oxidation with m-CPBA afforded sulfone intermediate I that underwent a SnAr displacement with commercially available aminopyrazole, 2-methylpyrazole-3-amine, to generate intermediate IX in 60% yield. Finally an acid promoted TBS deprotection afforded free base VIII in 85% yield. The chemistry of this route suffered from low yields in several individual steps. A lot of tedious purifications such as distillation, flash chromatography and Soxhlet extraction were needed due to fairly complicate reaction profiles. Use of less desireable solvents and reagents such as dichloromethane, sodium hydride and osmium oxide also detered the chemistry from being scaled up. - An improved route to synthesize I was identified. Hydroxyl ketone intermediate III was obtained in 72% yield over two steps. Grignard exchange of commercially available arene 3-1 and subsequent nucleophilic addition to Weinreb amide generated intermediate II that was then hydrolyzed to give III. An enzymatic asymmetric ketone reduction afforded the same diol intermediate IV with high yield and high enantioselectivity. The same processes of selective TBS protection and mesylation were used to produce intermediate VI. The synthesis of pyridone VII was improved. Kumada coupling catalyzed by PEPPSI-IPr was used to generate intermediate X in a higher yield and better purity profile. A two-step sequence of hydrolysis was applied to avoid formation of corrosive HF during the original process. A displacement of fluoride with t-BuOK in THF followed removal of tert-butyl group under acidic condition afforded pyridone intermediate VII in 80% yield. Sn2 displacement was improved by using different base and solvent compared to the original route. Intermediate XI was oxidized under the same conditions to give I.
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- Step 1: 4-bromo-1-chloro-2-fluorobenzene (64 kg) and dry toluene (170 kg) were charged to the 2000 L steel reaction vessel under nitrogen. The reactor was evacuated and backfilled with N2 for three times, and cooled to between −10 and 5° C. under nitrogen atmosphere. To the solution was added dropwise i-PrMgCl.LiCl (280 kg, 1.3M in THF) at between −10 and 10° C. The reaction was stirred for a further 15 to 30 min at between −10 and 10° C. and then warmed to about 20 to 25° C. over 1 h. The reaction mixture was stirred for another 6 h stir to complete the exchange. The resulting solution was cooled to between −50 and −40° C. A solution of 2-chloro-N-methoxy-N-methylacetamide (44.5 kg) in dry toluene (289 kg) was added dropwise to the above solution at while maintaining the temperature between −50 and −30° C. The reaction mixture was warmed to between 20 and 25° C. over 1 h and then stirred for 3 h to complete the reaction. The reaction was quenched by addition of 1N aq. HCl (8081 g) at a temperature between −5 and 15° C. The aqueous layer was separated and organic layer was filtered through a pad of diatomaceous earth. The organic layer was washed with 10% aq. NaCl solution (320 kg) twice, then concentrated to about 300 L to obtain 1-(4-chloro-3-fluorophenyl)-2-chloroethanone (51.8 kg, 81.9% yield) as product in toluene.
- Step 2: The solution of II (51.7 kg) in toluene was concentrated and solvent exchanged to EtOH to afford a suspension of II in EtOH (326 kg). A solution of HCOONa.2H2O (54.8 kg) and HCOOH (44.5 kg) in water (414 kg) was added at a temperature between 15 and 35° C. under a nitrogen atmosphere. The resulting mixture was heated to reflux and stirred for 4 to 5 h. The solution was cooled to between 20 and 30° C. after over 95% conversion occurred. Water (450 kg) was added dropwise at between 10 and 30° C. for over 2 h. The resulting suspension was cooled to between −10 and −3° C. and the cooled solution stirred for 1 to 2 h. The solid was filtered and the filter cake washed with water (400 kg) to remove the residual HCOONa and HCOOH. The 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone obtained was suspended in EtOAc (41 kg) and n-heptane (64 kg), then warmed to between 45 and 50° C., stirred for 2 h, then cooled to between −2 and 5° C. for over 2 h and stirred at this temperature for 2 h. The solids were filtered and dried in vacuo at between 40 and 50° C. for 12 h to afford the product as white solid (40.0 kg, 99.3% purity, 84.5% yield).
- Step 3: A 500 L reactor under nitrogen was charged with purified water (150 kg), 4-morpholineethanesulfonic acid (0.90 kg), anhydrous MgCl2 (0.030 kg), n-heptane (37 kg), 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone (30 kg), D-(+)-glucose monohydrate (34.8 kg) and PEG 6000 (30.0 kg). The pH of the solution was adjusted to between 6.5 and 7.0 with 1N aq. NaOH at between 28 and 32° C. The cofactor recycling enzyme, glucose dehydrogenase GDH-105 (0.300 kg)(Codexis Inc., Redwood City, Calif., USA), the cofactor nicotinamide adenine dinucleotide NAD (0.300 kg)(Roche) and the oxidoreductase KRED-NADH-112 (0.300 kg) (Codexis Inc., Redwood City, Calif., USA) were added. The resulting suspension was stirred at between 29 and 31° C. for 10 to 12 h while adjusting the pH to maintain the reaction mixture pH between 6.5 and 7.0 by addition of 1N aq. NaOH (160 kg). The pH of the reaction mixture was adjusted to between 1 and 2 by addition of 49% H2SO4 (20 kg) to quench the reaction. EtOAc (271 kg) was added and the mixture was stirred at between 20 and 30° C. for 10-15 min then filtered through a pad of diatomaceous earth. The filter cake was washed with EtOAc (122 kg). The combined organic layers were separated and aqueous layer was extracted with EtOAc (150 kg). Water (237 kg) was added to the combined organic layers. The pH of the mixture was adjusted to between 7.0 and 8.0 by addition of solid NaHCO3. The organic layer was separated, concentrated and then diluted with DCM to afford (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (30.9 kg, yield 100%) as product in DCM.
- Step 4: A 1000 L reactor under nitrogen was charged with (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (29.5 kg) and dry DCM (390 kg). The solution was cooled to between −5 and 0° C. tert-Butylchlorodimethylsilane (25.1 kg) was added in portions while maintaining the temperature between −5 and 2° C. A solution of DMAP (0.95 kg) and TEA (41.0 kg) in dry DCM (122 kg) was added dropwise to above solution at between −5 and 2° C. The reaction solution was stirred for 1 h, then warmed to between 20 and 25° C. and stirred for 16 h. The solution of (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethanol was recooled to between −10 and −5° C. A solution of methanesulfonyl chloride (19.55 kg) in dry DCM (122 kg) was added dropwise to the above solution of while maintaining the temperature between −10 and 0° C. The reaction solution was stirred at between −10 and 0° C. for 20 to 30 min, and then warmed to between 0 and 5° C. for over 1 h, and stirred. The reaction solution was washed with water (210 kg), followed by 5% aq. citric acid (210 kg), 2% aq. NaHCO3 (210 kg) and finally water (2×210 kg). The resulting DCM solution was dried (Na2SO4), filtered and concentrated in vacuo below 15° C. (jacket temperature below 35° C.) to afford (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (49.5 kg, 83.5% yield, KarlFischer=0.01%) as product in DCM.
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- Step 1: A 1000 L reactor was charged with 2-fluoro-4-iodopyridine (82.2 kg) and dry THF (205 kg). The reactor was evacuated and backfilled with N2 three times then cooled to between −30 and −20° C. To the solution was added dropwise i-PrMgCl.LiCl (319 kg, 1.3M in THF). The reaction was warmed to between −20 and −10° C. and stirred for 1.5 h to complete the transmetallation.
- A 2000 L reactor was charged with 4-chloro-2-methylthiopyrimidine (45.6 kg), dry THF (205 kg) and [1,3-bis(2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium(II) dichloride (PEPPSI™-IPr, 1.850 kg). The 2000 L reactor was evacuated and backfilled with N2 three times and heated to between 55 and 57° C. To the reactor was added over 0.5 to 1 h, the solution of (2-fluoropyridin-4-yl)magnesium chloride while maintaining the temperature between 50 and 62° C. The resulting reaction mixture was stirred at between 50 and 62° C. for a further 2 h. The reaction mixture was cooled to between 5 and 25° C. while the reaction was quenched with water (273 kg). The pH of the mixture was adjusted to 8 to 9 by adding solid citric acid monohydrate (7.3 kg). The organic layer was separated, washed with 12.5% aqNaCl (228 kg) and concentrated in vacuo below 50° C. to afford 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (38.3 kg, 61% yield) as product in THF.
- Step 2: The solution of 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (38.2 kg) in THF was concentrated and co-evaporated with THF to remove residual water. The suspension was filtered through a pad of diatomaceous earth to remove inorganic salts. To the resulting solution in THF (510 kg) was added tert-BuOK (39.7 kg) in portions while maintaining the temperature between 15 and 25° C. The mixture was warmed to between 20 and 25° C. and stirred for 5 h. NaHCO3 (14.9 kg) added charged and then a citric acid solution (5 kg) in THF (15 kg) was added to adjust the pH to between 8 and 9. Water (230 kg) was added. The mixture was filtered and the filter cake was washed with THF (100 kg). The combined THF solutions were washed with 12.5% aqueous NaCl (320 kg) and concentrated to about 380 L to afford a solution of 4-(2-(tert-butoxy)pyridin-4-yl)-2-(methylthio)pyrimidine in THF.
- To the THF solution cooled to between 15 and 30° C. was added 1N H2SO4 aq. solution (311 kg). The mixture was stirred at this temperature for 4 h. MTBE (280 kg) was charged and the pH of reaction solution was adjusted to 14 with 30% aqueous NaOH (120 kg). The aqueous layer was separated and the organic phase filtered to remove inorganic salts. The obtained aqueous layer was washed with MTBE (2×280 kg). 2-MeTHF (1630 kg) and i-PrOH (180 kg) were added to the aqueous solution. The pH was then adjusted to 8 slowly with conc. HCl (19 kg). An organic layer separated and aqueous layer was extracted with 2-MeTHF (305 kg). The combined 2-MeTHF extracts were washed with water (300 kg) and concentrated to about 100 L. MTBE (230 kg) was added and stirred at 20-30° C. for 0.5 h. The solid was filtered and slurried in a mixture solvent of 2-MeTHF (68 kg) and MTBE (230 kg). The suspension was stirred at 35-50° C. for 3 h, and then cooled to 0 to 10° C. and stirred at a further 2 h. The solid was filtered and dried in vacuo at between 50 and 62° C. for 20 h to afford product 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one as brown solid (33.55 kg, 89.6% assay, 79.4% yield).
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- Step 1: The THF was co-evaporated from the THF solution of 4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (25.5 kg) to remove residual water. Dry bis-(2-methoxyethyl)ether (75 kg) was added. A solution of KHMDS (131 kg, 1M in THF) was added dropwise while maintaining the temperature between 25 and 40° C. The mixture was heated to between 75 and 80° C. and stirred for 30 to 40 min. The resulting mixture was cooled to between 20 and 30° C. under nitrogen atmosphere. A solution of (R)-2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (47.6 kg) in THF (50 kg) was added over 30 to 60 min while maintaining the temperature between 20 and 40° C. The reaction solution was warmed to between 80 and 85° C. and stirred for 7 h. The solution was cooled to between 5 and 15° C. and water (155 kg) was added. The pH of the solution was adjusted to 7.5 with 30% aqueous citric acid (30 kg). EtOAc (460 kg) was added and the mixture was stirred for 20 min. The organic layer was separated and washed with 12.5% aqueous NaCl (510 kg). The combined aqueous layers were extracted with EtOAc (115 kg). The ethyl acetate layers were concentrated to about 360 L to afford (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (44.6 kg, 75.7% yield) as product in EtOAc.
- Step 2: To a solution of (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (44.6 kg) in EtOAc (401 kg, 10 vol) cooled to between 5 and 10° C. was added in portions MCPBA (58 kg). The reaction mixture was added to a solution of NaHCO3 (48.7 kg) in water (304 kg) at a temperature between 10 and −20° C. A solution of Na2S2O3 (15 kg) in water (150 kg) was added dropwise to consume residual MCBPA. The organic layer was separated and aqueous layer was extracted with EtOAc (130 kg). The combined organic layers were washed with water (301 kg), concentrated and solvent exchanged to DCM to afford (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (45.0 kg, 94.9% yield) as product in DCM. The DCM solution was concentrated to about 100 L, filtered through a pad of SiO2 (60 kg) and eluted with an EtOAc/DCM gradient (0, 25 and 50% EtOAc). The fractions were combined and concentrated to get the product which was re-slurried with (acetone: n-heptane=1:3 v/v) four times to afford the final product (31.94 kg, 71% yield).
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- Step 1: A clean 100 L cylindrical reaction vessel was charged with THF (13 kg) then (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (I, 5 kg) and 1-methyl-1H-pyrazol-5-amine (1.1 kg) were added sequentially with medium agitation followed by THF (18 kg). The mixture was cooled to −35° C. and to the resulting thin slurry was added slowly a THF solution of LiHMDS (17.4 kg, 1.0 M) at a rate that maintained the internal temperature below −25° C. After the addition was completed, the reaction was held between −35 and −25° C. for 20 min and monitored by HPLC. If the HPLC result indicated ≦98.5% conversion, additional LiHMDS (0.34 kg, 1.0 M, 0.05 mol %) was added slowly at −35° C. The reaction was quenched slowly at the same temperature with H3PO4 solution (4.4 kg of 85% H3PO4 and 15 kg of water) and the internal temperature was kept below 30° C. The reaction was diluted with EtOAc (18 kg) and the phases separated, the organic layer was washed with H3PO4 solution (1.1 kg of 85% H3PO4 and 12 kg of water) followed by a second H3PO4wash (0.55 kg of 85% H3PO4 and 12 kg of water). If 1-methyl-1H-pyrazol-5-remained, the organic layer was washed again with H3PO4 solution (0.55 kg of 85% H3PO4 and 12 kg of water). Finally the organic layer was washed sequentially with water (20 kg) and a NaCl and NaHCO3 solution (2 kg of NaCl, 0.35 kg of NaHCO3 and 10 kg of water). After the phase separation, residue water in organic solution was removed through an azeotropic distillation with EtOAc to <0.5% (by KF) and then solution was concentrated to 20-30 L under a vacuum below 50° C. The solvent was then swapped to MeOH using 35 kg of MeOH and then concentrated to between 20 and 30 L for the next step.
- Step 2: To the methanolic (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (IX) solution in MeOH was added HCl (10.7 kg, 1.25 M in MeOH) at RT. It was slightly exothermic. After the addition was completed, the reaction was heated to 45° C. If the reaction was incomplete after 14 to 16 h, additional HCl (1 kg, 1.25 M in MeOH) was added and agitation at 45° C. was continued for 2 h. The reaction was equipped with a distillation setup with acid scrubber. The reaction was concentrated to between 20 and 30 L under a vacuum below 50° C. To the resulting solution was added MeOH (35 kg) and the reaction was concentrated to 20 to 30 L again under a vacuum below 50° C. The solvent was then switched to EtOAc using 40 kg of EtOAc. The solvent ratio was monitored by Headspace GC and the solvent swap continued until it was less than 1/5. The solution was concentrated to between 20 and 30 L under a vacuum below 50° C. After the solution was cooled below 30° C., aqueous NaHCO3 (1.2 kg of NaHCO3 and 20 kg of water) was added slowly with a medium agitation and followed by EtOAc (40 kg). The organic layer was washed with water (2×10 kg) then concentrated to 20-30 L under a vacuum below 50° C. The solvent was then switched to MEK using 35 kg of MEK. The residue MeOH was monitored by Headspace GC and the solvent swap continued until the MeOH was <0.3%. The solution containing (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (VIII) was concentrated to 20 to 30 L under a vacuum below 50° C. for the next step.
- Step 3: The solution of VIII in MEK was transferred to a second 100 L cylindrical reaction vessel through a 1 μm line filter. In a separate container was prepared benezenesulfonic acid solution (1.3 kg of benzenesulfonic acid, 1.4 kg of water and 4.4 kg of MEK). The filtered VIII solution was heated to 75° C. and to the resulting solution was added 0.7 kg of the benzenesulfonic acid solution through a 1 μm line filter. The clear solution was seeded with crystalline benzenesulfonic acid salt of VIII (0.425 kg) as a slurry in MEK (0.025 kg of VIIIb crystalline seed and 0.4 kg of MEK) which produced a thin slurry. The remaining benzenesulfonic acid solution was then added through a 1 μm line filter in 2 h. After addition, the slurry was heated at 75° C. for additional 1 h and then cooled to 18° C. in a minimum of 3 h. The resulting thick slurry was agitated at 20° C. for 14 to 16 h. The solid was filtered using an Aurora dryer. The mother liquor was assayed by HPLC (about 0.3% loss). The solid was then washed with 1 μm line filtered 15.8 kg of MEK and water solution (0.8 kg of water and 15 kg of MEK) and followed by 1 μm line filtered 30 kg of MEK. Washes were assayed by HPLC (<1% loss). The wet cake was dried under a vacuum and a nitrogen sweep at a jacket temperature of 45° C. for a minimum 12 h to afford the benzenesulfonic acid salt of VIII, which is labeled VIIIb
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- To a clean 100 L cylindrical reaction vessel was charged 13 kg of THF first. With a medium agitation, 5.0 kg of I and 1.1 kg of 1-methyl-1H-pyrazol-5-amine was charged sequentially and followed by the rest of THF (18 kg). At −35° C. to the resulting thin slurry was added 17.4 kg of LiHMDS (1.0 mol/L) in THF slowly and the internal temperature was remained below −25° C. After addition, the reaction was held between −35 and −25° C. for 20 min. The reaction was monitored by HPLC. If the HPLC result indicated <98.5% conversion, additional 0.34 kg (0.05 mol %) of LiHMDS (1.0 mol/L) in THF was charged slowly at −35° C. Otherwise, the reaction was quenched at the same temperature with 19.4 kg of H3PO4 solution (4.4 kg of 85% H3PO4 and 15 kg of water) slowly and the internal temperature was remained below 30° C. The reaction was diluted with 18 kg of EtOAc. After the phase separation, the organic layer was washed with 13.1 kg of H3PO4 solution (1.1 kg of 85% H3PO4 and 12 kg of water) and then with 12.6 kg of H3PO4 solution (0.55 kg of 85% H3PO4 and 12 kg of water). The organic layer was assayed for the 1-methyl-1H-pyrazol-5-amine level by HPLC. If the HPLC result indicated ≧20 μg/mL of 1-methyl-1H-pyrazol-5-amine, the organic layer needed an additional wash with 12.6 kg of H3PO4 solution (0.55 kg of 85% H3PO4 and 12 kg of water). Otherwise, the organic layer was washed with 20 kg of water. The organic layer was assayed again for the 1-methyl-1H-pyrazol-5-amine level. If the HPLC result indicated >2 μg/mL of 1-methyl-1H-pyrazol-5-amine, the organic layer needed an additional wash with 20 kg of water. Otherwise, the organic layer was washed with 12.4 kg of NaCl and NaHCO3 solution (2 kg of NaCl, 0.35 kg of NaHCO3 and 10 kg of water). After the phase separation, residue water in organic solution was removed through an azeotropic distillation with EtOAc to <0.5% (by KF) and then the solution was concentrated to 20 to 30 L under a vacuum below 50° C. The solvent was then swapped to MeOH using 35 kg of MeOH and then concentrated to 20 to 30 L for the next step.
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- To the IX solution in MeOH from the last step was charged 10.7 kg of HCl (1.25 M in MeOH) at the ambient temperature. It was observed slightly exothermic. After addition, the reaction was heated to 45° C. After 14-16 h, the reaction was monitored by HPLC. If the HPLC result indicated the conversion was <98%, an additional 1 kg of HCl (1.25 M in MeOH) was charged and the reaction was agitated at 45° C. for additional 2 h. Otherwise, the reaction was equipped with a distillation setup with acid scrubber. The reaction was concentrated to 20 to 30 L under a vacuum below 50° C. To the resulting solution was charged 35 kg of MeOH and the reaction was concentrated to 20 to 30 L again under a vacuum below 50° C. The solvent was then switched to EtOAc using 40 kg of EtOAc. The solvent ratio was monitored by Headspace GC. If the ratio of MeOH/EtOAc was greater than 1/5, the solvent swap should be continued. Otherwise, the solution was concentrated to 20 to 30 L under a vacuum below 50° C. After the solution was cooled below 30° C., 21.2 kg of NaHCO3 solution (1.2 kg of NaHCO3 and 20 kg of water) was charged slowly with a medium agitation and followed by 40 kg of EtOAc. After the phase separation, the organic layer was washed with 2×10 kg of water. The organic layer was concentrated to 20 to 30 L under a vacuum below 50° C. The solvent was then switched to MEK using 35 kg of MEK. The residue MeOH was monitored by Headspace GC. If the level of MeOH was >0.3%, the solvent swap should be continued. Otherwise, the solution was concentrated to 20 to 30 L under a vacuum below 50° C. for the next step.
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- The VIII solution in MEK from the last step was transferred to a second 100 L cylindrical reaction vessel through a 3 μm line filter. In a separated container was prepared 7.1 kg of benzenesulfonic acid solution (1.3 kg of benzenesulfonic acid, 1.4 kg of water and 4.4 kg of MEK). The filtered G02584994 solution was heated to 75° C. and to the resulting solution was charged 0.7 kg of benzenesulfonic acid solution (10%) through a 3 μm line filter. To the clear solution was charged 0.425 kg of VIIIb crystalline seed slurry in MEK (0.025 kg of VIIIb crystalline seed and 0.4 kg of MEK). This resulted in a thin slurry. The rest of benzenesulfonic acid solution was then charged through a 3 μm line filter in 2 h. After addition, the slurry was heated at 75° C. for additional 1 h and then cooled to 20° C. in a minimum of 3 h. The resulting thick slurry was agitated at 20° C. for 14-16 h. Solid was filtered using a filter dryer. Mother liquor was assayed by HPLC (about 3% loss). Solid was then washed with 3 μm line filtered 15.8 kg of MEK and water solution (0.8 kg of water and 15 kg of MEK) and followed by 3 μm line filtered 30 kg of MEK. Washes were assayed by HPLC (<1% loss). The wet cake was dried under a vacuum and the nitrogen sweep at a jacket temperature of 45° C. for a minimum 12 h.
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- To a clean 100 L cylindrical reaction vessel was charged 16 kg of EtOH first. With a medium agitation, 3.5 kg of VIIIb was charged and then followed by the rest of EtOH (8.5 kg). The thick slurry was heated to 78° C. and water (˜1.1 kg) was charge until a clear solution was obtained. The hot solution was filtered through a 3 μm line filter to a second clean 100 L cylindrical reaction vessel. The temperature dropped to 55-60° C. and the solution remained clear. To the resulting solution was charged with 0.298 kg of VIIIb crystalline seed slurry in EtOH (0.018 kg of VIIIb crystalline seed and 0.28 kg of EtOH). The thick slurry was concentrated to 20 to 30 L at 60° C. under a vacuum and then cooled 20° C. in 3 h. The resulting slurry was agitated at 20° C. for 14 to 16 h. Solid was filtered using a filter dryer. The mother liquor was assayed by HPLC (about 10% loss). Solid was then washed with 3 μm line filtered 11.1 kg of EtOH and water solution (0.56 kg of water and 11 kg of EtOH) and followed by 3 μm line filtered 21 kg of MEK. Washes were assayed by HPLC (3% loss). The wet cake was dried under a vacuum and the nitrogen sweep at a jacket temperature of 45° C. for a minimum 12 h.
- An additional synthetic process is set forth below.
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- To a clean 100 L cylindrical reaction vessel was charged 18 kg of THF first. With a medium agitation, 4.2 kg of I and 0.91 kg of 1-methyl-1H-pyrazol-5-amine was charged sequentially and followed by the rest of THF (21 kg). At −40° C. to the resulting thin slurry was added 14.9 kg of LiHMDS (1.0 mol/L) in THF slowly and the internal temperature was remained below −30° C. After addition, the reaction was held between −35 and −40° C. for 20 min. The reaction was monitored by HPLC. The HPLC result indicated 99.1% conversion. The reaction was quenched at the same temperature with 16.7 kg of H3PO4 solution (3.7 kg of 85% H3PO4 and 13 kg of water) slowly and the internal temperature was remained below 30° C. The reaction was diluted with 17 kg of EtOAc. After the phase separation, the organic layer was washed with 13.1 kg of H3PO4 solution (1.1 kg of 85% H3PO4 and 12 kg of water) and then with 10.5 kg of H3PO4 solution (0.46 kg of 85% H3PO4 and 10 kg of water). The organic layer was assayed for the 1-methyl-1H-pyrazol-5-amine level by HPLC. The HPLC result indicated 2 μg/mL of 1-methyl-1H-pyrazol-5-amine. The organic layer was washed with 15.8 kg of NaCl solution (0.3 kg of NaCl and 15.5 kg of water). The organic layer was assayed again for the G02586778 level. The HPLC result indicated 0.5 μg/mL of 1-methyl-1H-pyrazol-5-amine. The organic layer was washed with 10.3 kg of NaCl and NaHCO3 solution (1.7 kg of NaCl, 0.6 kg of NaHCO3 and 8 kg of water). After the phase separation, residue water in organic solution was removed through an azeotropic distillation with EtOAc to <0.5% (by KF) and then the solution was concentrated to 20 to 30 L under a vacuum below 50° C. The solvent was then swapped to MeOH using 30 kg of MeOH and then concentrated to 20 to 30 L for the next step.
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- To the IX solution in MeOH from the last step was charged 9.0 kg of HCl (1.25 M in MeOH) at the ambient temperature. It was observed slightly exothermic. After addition, the reaction was heated to 45° C. After 16 h, the reaction was monitored by HPLC. The HPLC result indicated the conversion was 99.4%. The reaction was equipped with a distillation setup. The reaction was concentrated to 20 L under a vacuum below 50° C. To the resulting solution was charged 35 kg of MeOH and the reaction was concentrated to 20 L again under a vacuum below 50° C. The solvent was then switched to EtOAc using 40 kg of EtOAc. The solvent ratio was monitored by Headspace GC. If the ratio of MeOH/EtOAc was greater than 1/5, the solvent swap should be continued. Otherwise, the solution was concentrated to 20 L under a vacuum below 50° C. After the solution was cooled below 30° C., 18 kg of NaHCO3 solution (1 kg of NaHCO3 and 17 kg of water) was charged slowly with a medium agitation and followed by 34 kg of EtOAc. After the phase separation, the organic layer was washed with 2×8 kg of water. The organic layer was concentrated to 20 L under a vacuum below 50° C. The solvent was then switched to MEK using 35 kg of MEK. The residue MeOH was monitored by Headspace GC. If the level of MeOH was >0.3%, the solvent swap should be continued. Otherwise, the solution was concentrated to 20 L under a vacuum below 50° C. for the next step.
-
- The VIII solution in MEK from the last step was transferred to a second 100 L cylindrical reaction vessel through a 1 μm polish filter. In a separated container was prepared 6.0 kg of benzenesulfonic acid solution (1.1 kg of benzenesulfonic acid, 1.2 kg of water and 3.7 kg of MEK). The filtered solution was heated to 75° C. and to the resulting solution was charged 0.6 kg of benzenesulfonic acid solution (10%) through a 1 μm line filter. To the clear solution was charged 0.36 kg of VIIIb crystalline seed slurry in MEK (0.021 kg of VIIIb crystalline seed and 0.34 kg of MEK). This resulted in a thin slurry. The rest of benzenesulfonic acid solution was then charged through a 1 μm line filter in 2 h. After addition, the slurry was heated at 75° C. for additional 1 h and then cooled to 18° C. in a minimum of 3 h. The resulting thick slurry was agitated at 18° C. for 14-16 h. Solid was filtered using an Aurora dryer. Solid was then washed with 1 μm line filtered 8.15 kg of MEK and water solution (0.35 kg of water and 7.8 kg of MEK) and followed by 1 μm line filtered 12 kg of MEK.
-
- To a clean 100 L cylindrical reaction vessel was charged 21 kg of EtOH first. With a medium agitation, 3.5 kg of VIIIb was charged and then followed by the rest of EtOH (9 kg). The thick slurry was heated to 78° C. and water (1.2 kg) was charge until a clear solution was obtained. The hot solution was filtered through a 1 μm line filter to a second clean 100 L cylindrical reaction vessel. The temperature dropped to 69° C. and the solution remained clear. To the resulting solution was charged with 0.37 kg of VIIIb crystalline seed slurry in EtOH (0.018 kg of VIIIb crystalline seed and 0.35 kg of EtOH). The thin slurry was concentrated to 20 L at 60-70° C. under a vacuum and then cooled 18° C. in 3 h. The resulting slurry was agitated at 18° C. for 14-16 h. Solid was filtered using a filter dryer. Solid was then washed with 1 μm line filtered 8.6 kg of EtOH and water solution (0.4 kg of water and 8.2 kg of EtOH). The solution was introduced in two equal portions. The solid was then washed by 1 μm line filtered 6.7 kg of MEK. The wet cake was dried under a vacuum and the nitrogen sweep at a jacket temperature of 35-40° C. for a minimum 12 h.
-
-
-
- 1.
Charge compound 1 and MeBrPPh3 to a four-necked jacketed flask with a paddle stirrer under N2 - 2. Charge THF (5.0V., KF<0.02%) to the flask (Note: V is the volume of solution to mass of limited reagent or L/Kg)
- 3. Stir the suspension at 0° C.
- 4. Add the NaH (60% suspended in mineral oil) portionwise to the flask at 0° C.
- 5. Stir at 0° C. for 30 min
- 6. Heat to 30° C. and stir for 6 hrs
- 7. Cool to 0° C.
- 8. Charge PE (petroleum ether) (5.0V.) to the flask
- 9. Add the crystal seed of TPPO (triphenylphospine oxide)(1 to about 5% wt of total TPPO) to the flask
- 10. Stir at −10° C. for 2 hrs
- 11. Filter, and wash the cake with PE (5.0V.)
- 12. Concentrate the filtrate to dryness
- 13. Purification of the product by distillation under reduced pressure affords 2 as colorless oil
-
-
- 1. Add (DHQD)2PHAL, Na2CO3, K2Fe(CN)6, K2OsO2(OH)4 into a flask under N2 (Ad-mix beta, Aldrich, St. Louis, Mo.).
- 2. Cool to 0° C.
- 3. Add tBuOH (5V) and H2O (5V)
- 4. Add 2
- 5. Stir the mixture at 0° C. for 6 h
- 6. Cool to 0° C.
- 7. Add Na2SO3 to quench the reaction
- 8. Stir at 0° C. for 2 h
- 9. Filter and wash the cake with EA (ethyl acetate)
- 10. Separate the organic layer
- 11. Filter and concentrate to dryness
-
-
- 1. Add IV (1 eq.) and DCM (5V) to a flask under N2
- 2. Cool to 0° C.
- 3. Add DMAP (0.1 eq.), then TEA (1.5 eq.)
- 4. Add TBSCl (1.05 eq.) dropwise at 0° C.
- 5. Stir the mixture at 0° C. for 1 h
- 6. Add water to quench the reaction
- 7. Separate the layers
- 8. Dry the organic layer over Na2SO4
- 9. Filter
- 10. Concentrate the filtrate to dryness
- 11. Use for next step directly
-
-
- 1. Add V (1.0 eq.) and DCM (5V) into a flask under N2.
- 2. Cool to 0° C.
- 3. Add TEA (1.51 eq.)
- 4. Add MsCl (1.05 eq.) dropwise at 0° C.
- 5. Stir the mixture at rt for 1 h
- 6. Add DCM to dilute the mixture for better stirring
- 7. Add water to quench the reaction
- 8. Separate the layers
- 9. Wash the organic layer with NaHCO3
- 10. Dry over Na2SO4
- 11. Filter and concentrate the filtrate to dryness
- 12. Used for next step directly
-
-
- 1. Add VII (leg.) and DGME (20V) into flask under N2
- 2. Cool to 0° C.
- 3. Add KHMDS (1M in THF, 1 eq.)
- 4. Add VI (1.2-1.5 eq.) in DGME solution
- 5. Stir at 0° C. for 5 min
- 6. Heat to reflux (
jacket 120° C.) and stir for over 4 h - 7. Cool down
- 8. Quench with water and extraction with MTBE
- 9. Wash with 20% NaCl
- 10. Dry over Na2SO4
- 11. Concentrate to dryness and use to next step directly
-
-
- 1. Charge XI (leg.), DCM (8V) into flask under N2
- 2. Add mCPBA by portions
- 3. Stir at room temperature for 2 h
- 4. Add 7% NaHCO3 aq. to wash
- 5. Quench with Na2S2O4 aq.
- 6. Wash with 20% NaCl aq.
- 7. Dry over Na2SO4
- 8. Filter and concentrate to dryness
- 9. Slurry the result in MTBE (3V) to afford I
-
-
- 1. Add I (leq.), 1-methyl-1H-pyrazol-5-amine (4 eq.), Cs2CO3, DMF (4V) into a flask under N2
- 2. Stir at room temperature for 3 h
- 3. Work-up to afford product.
-
-
-
- 1. IX was dissolved in MeOH
- 2. HCl (1.25 M in MeOH) was charged at the ambient temperature.
- 3. After addition, the reaction was heated to 45° C. for 16 h.
- 4. The reaction was cooled to rt and quenched with aqueous NaHCO3 and diluted with EtOAc
- 5. After the phase separation, the organic layer was washed with water. The organic layer was concentrated to afford the crude VIII
-
-
- 1. Charge compound 6-2, XIII, Pd-catalyst and sodium bicarbonate to a four-necked jacketed flask
- with paddle stirrer under N2
- 2. Charge water and 1,4-dioxane (5.0V., KF<0.02%) to the flask
- 3. Stir the suspension at 85° C. for 16 hrs
- 4. Filter through the silica-gel (2.0×) and diatomaceous earth (0.5×)
- 5. Remove the 1,4-dioxane by distillation under a vacuum
- 6. Partition between water (2.0V) and EtOAc (5.0V)
- 7. Separate the organic phase and concentrate
- 8. Purify by re-crystallization from PE and EtOAc
-
-
-
- Add X into a flask
- Add 2M HCl (10-15V)
- Heat to 100° C. and stir for 3 h
- Cool down
- Neutralize pH to 7 to 8 with 30% NaOH aq.
- Extract with THF
- Wash with 20% NaCl aq.
- Dry over Na2SO4
- Filter and concentrate to dryness
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (21.1 mg, 0.048 mmol) was dissolved in MEK (0.5 mL). Benzenesulfonic acid (Fluka, 98%, 7.8 mg, 0.049 mmol) was dissolved in MEK (0.5 mL) and the resulting solution added drop wise to the free base solution with stirring. Precipitation occurred and the precipitate slowly dissolved as more benzenesulfonic acid solution was added. A small amount of sticky solid remained on the bottom of the vial. The vial contents were sonicated for 10 minutes during which further precipitation occurred. The solid was isolated after centrifugation and vacuum dried at 40° C. using house vacuum.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt (23.1 mg) was dissolved in hot isopropanol (5 mL) in a heating block set to 90° C. The heat was turned off on the heating block and the solution was allowed to cool to ambient and then placed in a freezer at about −20° C. The solid was collected while still cold and analyzed by XRPD to give (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt Form A.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt crystalline Form A: Crystals of suitable quality for structure determination were grown in methanol via stirring at approximately 50° C., isolating into Paratone-N oil after approximately 1 day and storing under ambient conditions.
- Structural solution: A colorless plate of C27H23ClFN6O5S [C21H18ClFN6O2, C6H5O3S] having approximate dimensions of 0.16×0.16×0.06 mm, was mounted on a fiber in random orientation. Preliminary examination and data collection were performed with Cu Kα radiation (λ=1.54178 Å) on a Rigaku Rapid II diffractometer equipped with confocal optics. Refinements were performed using SHELX2013 [Sheldrick, G. M. Acta Cryst., 2008, A64, 112].
- Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 24479 reflections in the
range 3°<θ<63°. The refined mosaicity from DENZO/SCALEPACK was 0.59°, indicating moderate crystal quality [Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307]. The space group was determined by the program XPREP [Bruker, XPREP in SHELXTL v. 6.12., Bruker AXS Inc., Madison, Wis., USA, 2002]. There were no systematic absences, and the space group was determined to be P1 (no. 1). - The data were collected to a maximum 2θ value of 126.9°, at a temperature of 293±1 K.
- Frames were integrated with HKL3000 [Flack, H. D.; Bernardinelli, G., Acta Cryst. 1999, A55, 908]. A total of 24479 reflections were collected, of which 6536 were unique. Lorentz and polarization corrections were applied to the data. The linear absorption coefficient is 2.450 mm−1 for Cu Kα radiation. An empirical absorption correction using SCALEPACK [Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307] was applied. Transmission coefficients ranged from 0.564 to 0.863. A secondary extinction correction was applied [Glusker, Jenny Pickworth; Trueblood, Kenneth N. Crystal Structure Analysis: A Primer, 2nd ed.; Oxford University press: New York, 1985; p. 87]. The final coefficient, refined in least-squares, was 0.00170 (in absolute units). Intensities of equivalent reflections were averaged. The agreement factor for the averaging was 9.8% based on intensity.
- The structure was solved by direct methods using SHELXT [Burla, M. C., Caliandro, R., Camalli, M,. Carrozzini, B., Cascarano, G. L., De Caro, L., Giacovazzo, C., Polidori, G., and Spagna, R., J. Appl. Cryst. 2005, 38, 381]. The remaining atoms were located in succeeding difference Fourier syntheses.
- They hydrogen atoms residing on nitrogen atoms were refined independently. All other hydrogen atoms were included in the refinement but restrained to ride on the atom to which they are bonded. The structure was refined in full-matrix least-squares by minimizing the function:
-
Σ(|F o|2 −|F c|2)2 - The weight w is defined as 1/[σ2(Fo 2)+(0.2000 P)2+(0.0000 P)], where P=(Fo 2+2Fc 2)/3.
- Scattering factors were taken from the “International Tables for Crystallography” [International Tables for Crystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.1.4]. Of the 6536 reflections used in the refinements, only the reflections with Fo 2>2σ(Fo 2) were used in calculating the fit residual, R. A total of 5796 reflections were used in the calculation. The final cycle of refinement included 771 variable parameters and converged (largest parameter shift was <0.01 times its estimated standard deviation) with unweighted and weighted agreement factors of:
-
R=Σ|F o −F c |/ΣF o=0.096 -
R w=√{square root over ((Σw(F o 2 −F c 2)2/Σw(F o 2)2))}=0.283 - The standard deviation of an observation of unit weight (goodness of fit) was 1.385. The highest peak in the final difference Fourier had a height of 0.85 e/Å3. This is rather high and indicative of the poor quality of the structure refinement. The minimum negative peak had a height of −0.28 e/Å3. The Flack factor for the determination of the absolute structure [Flack, H. D. Acta Cryst. 1983, A39, 876] refined to −0.01(4).
- One of the hydroxyl groups of one of the molecules in the asymmetric unit was refined using disorder. This leads to the splitting of the O22 and H22 atoms into the O22A, H22A and O22B, H22B pairs of atomic coordinates.
- A representation of a single molecule of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt crystalline Form A, determined from the single crystal analysis, is shown in
FIG. 3 . Disorder in the hydroxymethyl group can be observed in the upper right ofFIG. 3 . -
-
Formula C27H24ClFN6O5S formula weight 598.04 space group P1 (No. 1) a, Å 7.7973(9) b, Å 12.2869(13) c, Å 14.7832(14) α, deg 103.489(7) β, deg 91.519(8) γ, deg 97.231(10) V, Å3 1364.0(2) Z′ 2 temperature, K 293 mosaicity, deg 0.59 Rint 0.098 R(Fo) 0.096 Rw(Fo2) 0.283 goodness of fit 1.385 absolute structure determination Flack parameter (−0.01(4)) Hooft parameter (−0.045(17)) - (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt crystallizes in chiral triclinic space group P-1 with two symmetrically independent cation anion pairs. Although the geometrical parameters indicate that all of the intermolecular interactions can be treated as relatively strong, both cations are highly disordered. Two conformations of the chlorofluorophenyl groups were found with an occupancy ratio of about 60:40. In addition, the hydroxymethyl group was also disordered with an occupancy ratio of about 50:50. The absolute stereochemistry is assigned the S-configuration.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((l-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate salt (39.6 mg) in tert-butanol (about 20 mL) was heated to 60° C. in a heating block. The tert-butanol has been melted at about 30° C. prior to addition to the besylate salt. Water (200 g) was added and heated until a clear solution resulted. The solutions were cooled and filtered through a 0.2 μm filter and placed in a lyophillizer. This compound was lyophilized using a SP Scientific VirTis AdVantage 2.0 Benchtop Freeze Dryer. A 70-hour recipe was used to remove solvent from the compound.
- The initial freezing of the compound was done under a vacuum at −70° C. for 1.5 hours at 500 mTorr pressure. This ensures that the entire solution is completely frozen before primary drying is started. Primary drying is done to remove the bulk solvent via sublimation. From −70° C., the temperature is raised to −35° C. and the pressure is lowered to 100 mTorr for 1 hour. After drying at −35° C. for 1 hour, the temperature is raised to 5° C. and dried for an additional 28 hours at the same pressure. Primary drying ends with the last step at 15° C. which is held for 16 hours. The lyophilization pressure is lowered to 50 mTorr and the temperature is raised to 35° C. for 16 hours. Secondary drying continues with the temperature lowering to 30° C. and pressure lowering to 10 mTorr for 6 hours. The final step of the lyophilization cycle has the temperature lowered to 25° C. and the pressure raised back to 2500 mTorr for 1 hour.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (21.8 mg, 0.0494 mmol) was dissolved in MEK (0.5 mL). 1,5-naphthalenedisulfonic acid tetrahydrate (25.1 mg, 0.0871 mmol) was dissolved in methanol (1.0 mL) and about 0.36 mL of the solution was added drop wise to the free base solution with stirring. Precipitation occurred. The suspension was allowed to slowly evaporate until only a trace of solvent remained. The solid was vacuum dried at 40° C. using house vacuum.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (103.3 mg, 0.234 mmol) was dissolved in MEK (2.5 mL). 1,5-naphthalenedisulfonic acid tetrahydrate (110.4 mg, 0.383 mmol) was dissolved in methanol (2.0 mL) and about 0.77 mL of the solution was added drop wise to the free base solution with stirring. Precipitation occurred including one big chunk. The chunk was broken up with a spatula followed by addition of methanol (0.77 mL). The suspension was allowed to stir for 3 day. The solid was isolated by filtration and dried at 60° C. using house vacuum to give 57 mg of a yellow solid.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (105.1 mg, 0.239 mmol) was mostly dissolved in isopropanol (1 mL) using sonication. p-Toluenesulfonic acid monohydrate (97.5% pure, 52.9 mg, 0.271 mmol) was dissolved in isopropanol (1 mL). The toluenesulfonic acid solution was added drop wise to the free base solution with stirring to give a yellow solid. Additional isopropanol was added (1 mL). The the solid was isolated by filtration and the reactor and solids were rinsed with 1 mL isopropanol. The solid was analyzed by XRPD in a holder open to the atmosphere while still wet with solids to give a disordered (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, tosylate IPA solvate. TG analysis was conducted on the XRPD sample.
- The remaining solid was dried at 60° C. under a vacuum for 4 days to give (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, tosylate crystalline Form A.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (104.3 mg, 0.237 mmol) was dissolved in diethyl ether (60 mL). p-Toluenesulfonic acid monohydrate (52.0 mg, 0.273 mmol) was dissolved in diethyl ether (5 mL). The toluenesulfonic acid solution was added drop wise to the free base solution with stirring and the suspension stirred overnight. The ether was decanted and the solid allowed to air dry to get 103 mg of a yellow solid.
- (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxy ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one tosylate, amorphous form, (10.8 mg) was placed into a vial with a stir bar. Methyl ethyl ketone (MEK, 0.3 mL) was added and the slurry stirred for 4 days. Solvent was evaporated under a vacuum at 60° C. to give a yellow solid.
- Powder X-ray diffraction patterns of samples were obtained using the Rigaku MiniFlexII powder X-ray diffractometer using reflection geometry. The copper radiation source was operated at the voltage of 30 kV and the current 15 mA. Each sample was placed in the cavity of an aluminum sample holder fitted with a zero background quartz insert and flattened with a glass slide to present a good surface texture and inserted into the sample holder. All samples were measured in the 2θ angle range between 2° and 40° with a scan rate of 2°/min and a step size of 0.02°.
- A TA Instruments differential scanning calorimeter (Model Q100 or Model Q2000) with a mechanical cooler and a standard cell (configured the same as the sample pan) was used to measure the thermal properties of the powder samples. Each sample was loaded into a closed aluminium pan with a non-crimped lid containing zero to one pin hole and placed into the differential scanning calorimetery (DSC) cell. The cell has a nitrogen purge flowing at approximately 50 cm3/min. The cell and sample were equilibrated at 20° C. The cell was then heated to 209° C. or 250-350° C. at 10.00° C./min while monitoring the heat flow difference between the empty reference pan and the sample pan.
- Modulated DSC was used to analyze (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one amorphous free base. A TA Instruments differential scanning calorimeter (Model Q2000) with a mechanical cooler and a standard cell (configured the same as the sample pan) was used to measure the thermal properties of the powder samples. Each sample was loaded into a closed aluminium pan with a non-crimped lid containing zero to one pin hole and placed into the differential scanning calorimetery (DSC) cell. The cell has a nitrogen purge flowing at approximately 50 cm3/min. The cell and sample were equilibrated at 25° C., the temperature was modulated at ±1° C. every 60 seconds, and held isothermally for 5 minutes. Data storage was turned on and the sample ramped at 3° C. to 100° C. The sample was then ramped to 25° C. at 3° C./minute. The sample was then heated at 3° C./minute to 200° C. The reversing signal is shown.
- Automated vapor sorption data were collected on a TA Instruments Q5000SA vapor sorption analyzer. NaCl and PVP were used as calibration standards. Samples were not dried prior to analysis. Adsorption and desorption data were collected at 25° C. over a range from 5 to 95% RH at 10% RH increments under a nitrogen purge. Samples were held at the corresponding RH for 1 hour prior to moving to the next RH range. Data were not corrected for the initial moisture content of the samples.
- The free base of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one is an amorphous solid (XRPD,
FIG. 4 ). The glass transition temperature (TG) varies from about 74-96° C. depending on purity and solvent content as measured by differential scanning calorimetry (DSC,FIG. 5 ). - Approximately 200 crystallization experiments were conducted without success in an attempt to find a crystalline form of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one free base. Small amounts of crystals were observed in multiple experiments, but these were identified as impurities generated from the synthetic sequence or from raw materials and not as (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one free base. One exception was noted from experiments conducted using nitromethane as a solvent and heptane as antisolvent in a vapor diffusion experiment. A mixture of amorphous and crystalline material was isolated. The crystalline material obtained was determined to be ±1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one.
- A salt screen was conducted to determine if a suitable salt form could be discovered. The pKa of the free base was determined to be less than 2, which limited the range of possible salt coformers. In addition, salts derived from (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one free base would have a pHmax less than 2 and would be expected to disproportionate in water. Thus, it was not clear that a crystalline salt could be prepared or that any salt would have acceptable exposure in vivo (an aqueous environment). Initial attempts to prepare crystalline salts using hydrogen chloride, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, and ethanedisulfonic acid failed to give any crystalline salt. Eventually crystalline salts were obtained from 1,5-naphthalenedisulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid.
- Below are tables showing the primary XRPD peak information for the salts described herein. It is well known to those skilled in the art that the peaks may be shifted up or down depending on the conditions under which the XRPD analysis was conducted. In general, the peaks may shift by +/−0.2. In another aspect, the peaks may be shifted by +/−0.1.
-
-
Reflection position °2θ d spacing (Angstroms) Relative area 6.16 14.342 99.3 7.46 11.840 19.4 16.36 5.414 100 25.76 3.456 80.6 25.98 3.423 90.2 -
-
Reflection position °2θ d spacing (Angstroms) Relative area 4.98 17.728 100 13.28 6.662 20.7 16.28 5.440 60.4 19.72 4.499 73.8 -
-
Reflection position °2θ d spacing (Angstroms) Relative area 5.76 15.327 58.4 13.44 6.584 36.0 15.64 5.662 51.9 19.40 4.572 100 -
-
Reflection position °2θ d spacing (Angstroms) Relative area 7.02 12.584 40.1 16.302 5.433 42.7 17.30 5.122 57.8 21.86 4.063 100 -
-
Reflection position °2θ d spacing (Angstroms) Relative area 12.50 7.076 18.3 13.86 6.385 18.6 -
-
Reflection position °2θ d spacing (Angstroms) Relative area 12.80 6.910 60 22.42 3.962 76.2 24.92 3.570 100 - Whether a pharmaceutical product contains a particular crystalline form of a substance, typically in a tablet or capsule, may be determined, for example, using X-ray diffraction, Raman spectroscopy and/or solid state NMR techniques. For Example, the solid state 13C and 19F NMR spectra of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt crystalline Form A is set forth in
FIGS. 19 and 20 , respectively. The procedure for obtaining the NMR spectra is set forth below. - (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((l-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzenesulfonate salt crystalline Form A was analyzed using 13C and 19F solid-state NMR spectroscopy. Spectra were acquired using a Bruker Avance III NMR spectrometer operating at 500.13 MHz for 1H, 125.77 MHz for 13C, and 470.55 MHz for 19F. 13C experiments utilized a Bruker HX double resonance probe tuned for 1H and 13C, with a 4 mm magic-angle spinning (MAS) module. 19F experiments employed a Bruker HFC triple resonance probe tuned to 1H, 19F, and 13C, also equipped with a 4 mm MAS module. Samples were packed into 4 mm ZrO2 rotors and sealed with Kel-F drive tips. All data were collected at 293 K. Data were collected, processed, and analyzed using Bruker TopSpin™ 3.2 software.
- The pulse sequence for 13C acquisition employed ramped cross polarization (CP),1-3 5-π total sideband suppression (TOSS),4 and high power 1H decoupling with a SPINAL645 scheme and field strength of 90 kHz. Magic-angle spinning (MAS) was performed at 8000±3 Hz. The 1H 90° pulse width was 2.79 μs and the TOSS sequence employed 13
C 180° pulses of 6.50 μs. The CP contact time was 3 ms, the recycle delay was 18 s, and a total of 3888 scans were averaged to generate the spectrum. Chemicals shifts were externally referenced by setting the methyl peak of 3-methylglutaric acid to 18.84 ppm relative to tetramethylsilane.6 - The pulse sequence for 19F acquisition employed ramped CP1-3 and high power 1H decoupling with a SPINAL645 scheme and field strength of 71 kHz. Magic-angle spinning (MAS) was performed at 14000±5 Hz. The 1H 90° pulse width was 3.54 μs, the CP contact time was 3 ms, the recycle delay was 18 s, and a total of 16 scans were averaged to generate the spectrum. Chemicals shifts were externally referenced by setting the fluorine peak of polytetrafluoroethylene (PTFE) to −122.38 ppm relative to CFCl3 (determined experimentally by spiking CFCl3 into a PTFE sample).
-
- 1. Pines, A.; Gibby, M. G.; Waugh, J. S., Proton-enhanced nuclear induction spectroscopy. Method for high-resolution NMR of dilute spins in solids. J. Chem. Phys. 1972, 56(4), 1776-7.
- 2. Stejskal, E. O.; Schaefer, J.; Waugh, J. S., Magic-angle spinning and polarization transfer in proton-enhanced NMR. J. Magn. Reson. (1969-1992) 1977, 28 (1), 105-12.
- 3. Metz, G.; Wu, X.; Smith, S. O., Ramped-amplitude cross polarization in magic-angle-spinning NMR. J. Magn. Reson. Ser. A 1994, 110 (2), 219-27.
- 4. Song, Z.; Antzutkin, O. N.; Feng, X.; Levitt, M. H., Sideband suppression in magic-angle-spinning NMR by a sequence of 5 pi pulses. Solid State Nucl. Magn. Reson. 1993, 2 (3), 143-6.
- 5. Fung, B. M.; Khitrin, A. K.; Ermolaev, K., An improved broadband decoupling sequence for liquid crystals and solids. J. Magn. Reson. 2000, 142 (1), 97-101.
- 6. Barich, D. H.; Gorman, E. M.; Zell, M. T.; Munson, E. J., 3-Methylglutaric acid as a 13C solid-state NMR standard. Solid State Nucl. Magn. Reson. 2006, 30 (3-4), 125-129.
- The 13C solid-state NMR spectrum of (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hy droxy ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one, benzene sulfonate salt crystalline
- Form A is characterized by strong peaks at chemical shifts of 157.7±0.2 ppm, 129.6±0.2 ppm, 125.8±0.2 ppm, and 117.0±0.2 ppm relative to tetramethylsilane (at 293 K). The 19F spectrum is characterized by two isotropic peaks at chemical shifts of −111.1±0.4 ppm and -115.4±0.4 ppm relative to CFCl3 (at 293 K).
- The crystalline besylate salt of VIII is a highly crystalline material with a melting point that is acceptable for pharmaceutical dosage form development. The besylate salt form is preferred over the tosylate and 1,5-naphthalenesulfonic acid salt forms based on it's simple solid state landscape (only one crystalline form identified). In addition, the lower hygroscopicity of the besylate salt compared to the tosylate and 1,5-naphthalenedisulfonic acid salt forms is highly desired. The free base of VIII has a low pKa, less than 1.8, and therefore, any salts identified were expected to be unstable in the presence of water due to disproportionation to free base and acid. Therefore, the non-hygroscopicity of the besylate salt was unexpected and led to enhanced stability compared to the tosylate and naphthalenesulfonic acid salt forms.
- In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention or a salt or crystalline form of the salt and a pharmaceutically acceptable excipient, such as a carrier, adjuvant, or vehicle. In certain embodiments, the composition is formulated for administration to a patient in need thereof.
- The term “patient” or “individual” as used herein, refers to an animal, such as a mammal, such as a human. In one embodiment, patient or individual refers to a human.
- The term “pharmaceutically acceptable” means that the compound or composition referred to is compatible chemically and/or toxicologically with the other ingredients (such as excipients) comprising a formulation and/or the patient being treated, particularly humans.
- The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
- Compositions comprising a compound of the present invention may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, vaginally, intraperitoneal, intrapulmonary, intradermal, epidural or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- In one embodiment, the composition comprising a compound of the present invention is formulated as a solid dosage form for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, the solid oral dosage form comprising a compound of formula (I) or a salt thereof further comprises one or more of (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and (ii) filler or extender such as starches, lactose, sucrose, glucose, mannitol, or silicic acid, (iii) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose or acacia, (iv) humectants such as glycerol, (v) disintegrating agent such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates or sodium carbonate, (vi) solution retarding agents such as paraffin, (vii) absorption accelerators such as quaternary ammonium salts, (viii) a wetting agent such as cetyl alcohol or glycerol monostearate, (ix) absorbent such as kaolin or bentonite clay, and (x) lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycols or sodium lauryl sulfate. In certain embodiments, the solid oral dosage form is formulated as capsules, tablets or pills. In certain embodiments, the solid oral dosage form further comprises buffering agents. In certain embodiments, such compositions for solid oral dosage forms may be formulated as fillers in soft and hard-filled gelatin capsules comprising one or more excipients such as lactose or milk sugar, polyethylene glycols and the like.
- In certain embodiments, tablets, dragees, capsules, pills and granules of the compositions comprising a compound of formula I or salt thereof optionally comprise coatings or shells such as enteric coatings. They may optionally comprise opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions include polymeric substances and waxes, which may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- In another embodiment, a composition comprises micro-encapsulated compound of the present invention, and optionally, further comprises one or more excipients.
- In another embodiment, compositions comprise liquid dosage formulations comprising a compound of formula I or salt thereof for oral administration and optionally further comprise one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In certain embodiments, the liquid dosage form optionally, further comprise one or more of an inert diluent such as water or other solvent, a solubilizing agent, and an emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols or fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments, liquid oral compositions optionally further comprise one or more adjuvant, such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent and a perfuming agent.
- Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- In certain embodiments, the composition for rectal or vaginal administration are formulated as suppositories which can be prepared by mixing a compound of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, for example those which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound of the present invention.
- Example dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The compound of the present invention is admixed under sterile conditions with a pharmaceutically acceptable carrier, and optionally preservatives or buffers. Additional formulation examples include an ophthalmic formulation, ear drops, eye drops or transdermal patches. Transdermal dosage forms can be made by dissolving or dispensing the compound of the present invention in medium, for example ethanol or dimethylsulfoxide. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- Nasal aerosol or inhalation formulations of a compound of the present invention may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- In certain embodiments, pharmaceutical compositions may be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions are administered without food. In certain embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
- Specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided compound of the present invention in the composition will also depend upon the particular compound in the composition.
- In one embodiment, the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.
- An example tablet oral dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or salt thereof, and further comprises about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30 and about 1-10 mg magnesium stearate. The process of formulating the tablet comprises mixing the powdered ingredients together and further mixing with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of a compound of formula I or salt thereof, in a suitable buffer solution, e.g. a phosphate buffer, and adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants. The features disclosed in the foregoing description, or the following claims, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the invention in diverse forms thereof
- The foregoing invention has been described in some detail by way of illustration and examples, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.
- The patents, published applications, and scientific literature referred to herein establish the knowledge of those skilled in the art and are hereby incorporated by reference in their entirety to the same extent as if each was specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the specific teachings of this specifications shall be resolved in favor of the latter. Likewise, any conflict between an art-understood definition of a word or phrase and a definition of the word or phrase as specifically taught in this specification shall be resolved in favor of the latter.
Claims (23)
1. A process for the preparation of a compound of formula VIII, the process comprising the steps of:
(a) contacting 4-bromo-1-chloro-2-fluorobenzene with a metallating agent in an aprotic organic solvent to afford an organomagnesium compound, which is reacted with 2-chloro-N-methoxy-N-methylacetamide to afford 2-chloro-1-(4-chloro-3-fluorophenyl)ethanone (II);
(b) contacting II with sodium formate and formic acid in aqueous ethanol to afford 1-(4-chloro-3-fluorophenyl)-2-hydroxyethanone (III)
(c) contacting III with a ketoreductase to afford (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (IV);
(d) contacting IV with a silyl chloride (Ra)3SiCl and at least one base in a non-polar aprotic solvent to afford (V), and subsequently adding sulfonylchloride RbS(O)2Cl to afford VI, wherein Ra is independently in each occurrence C1-6 alkyl or phenyl and Rb is selected from C1-4 alkyl or phenyl, optionally substituted with 1 to 3 groups independently selected from C1-3 alkyl, halogen, nitro, cyano, or C1-3 alkoxy;
(e) contacting 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII) with a strong base in an organic solvent and subsequently adding VI to afford XI;
(g) treating 1-methyl-1H-pyrazol-5-amine with a strong base in an aprotic solvent at reduced temperature and adding the compound of formula I to afford IX; and,
2. The process according to claim 1 wherein the ketoreductase in step (c) affords an enantiomeric excess at least about 98%.
3. The process of claim 2 wherein the ketoreductase in step (c) is KRED-NADH-112.
4. The process of claim 2 wherein step (c) further comprises NADH or NADPH as a cofactor.
5. The process of claim 4 wherein the cofactor is regenerated with a cosubstrate selected from a secondary alcohol or from an additional enzyme selected from alcohol dehydrogenase, glucose dehydrogenase, formatted dehydrogenase, glucose-6-phosphate dehydrogenase, phosphite dehydrogenase or hydrogenase.
6. The process of claim 2 wherein the ketoreductase step is performed in an aqueous medium in the presence of organic cosolvent at a temperature between 1 and 50° C.
7. The process of claim 6 wherein the ketoreductase step produces a homogeneous suspension.
8. The process of claim 1 wherein the silyl chloride is tert-butyldimethylsilyl chloride, the sulfonyl chloride is methanesulfonyl chloride, the bases in step (d) are DMAP and TEA and the non-polar aprotic solvent is DCM and in step (e) the organic solvent is dioxane.
9. The process of claim 1 wherein (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme.
10. The process of claim 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent glucose dehydrogenase, in step (d) (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, and in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme.
11. The process of claim 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and the cofactor recycling agent is glucose dehydrogenase, in step (d) (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, and in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF.
12. The process of claim 1 wherein in step (a) the metallating agent is i-PrMgCl and LiCl and the solvent is THF, in step (c) the ketoreductase is KRED-NADH-112 and step (c) further comprises the cofactor NAD and cofactor recycling agent is glucose dehydrogenase, in step (d) (Ra)3Si is tert-butyldimethylsilyl, Rb is methyl, the bases are DMAP and TEA and the non-polar aprotic solvent is DCM, in step (e) the strong base is potassium hexamethyldisilazane and the organic solvent is diglyme, in step (g) the strong base is potassium hexamethyldisilazane and the aprotic solvent is THF, and in step (h) the desilylating agent is methanolic HCl.
14. A process according to claim 13 wherein RcSO3H is benzenesulfonic acid and the solvent is methyl ethyl ketone and water to afford the besylate salt VIIIb.
15. A process for the preparation of 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII) comprising the steps of:
(a) contacting 2-fluoro-4-iodopyridine with a metallating agent in an aprotic organic solvent to afford an organomagnesium compound, which is reacted with 4-chloro-2(methylthio)pyrimidine in the presence of a palladium catalyst to afford 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (X);
(b) treating X with potassium tert-butoxide in THF and subsequently with an aqueous acid to afford 4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (VII).
16. The process according to claim 15 wherein the palladium catalyst is (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride, the metallating agent is i-PrMgCl and LiCl, and the aprotic solvent is THF.
17. The compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
18. A pharmaceutical composition comprising (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate and a pharmaceutically acceptable excipient.
19. Crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
20. Crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate having an X-ray powder diffraction pattern comprising peaks at 6.16±0.2, 7.46±0.2, 16.36±0.2, 25.76±0.2 and 25.98±0.2 20; or an X-ray powder diffraction pattern substantially as shown in FIG. 1 ; or an 13C NMR pattern substantially as shown in FIG. 19 ; or an 19F NMR pattern substantially as shown in FIG. 20 ; or an 19F NMR pattern comprising peaks at −111.1±0.4 ppm and −115.4±0.4 ppm relative to CFCl3 (at 293 K); or an 13C NMR pattern comprising peaks at 157.7±0.2 ppm, 129.6±0.2 ppm, 125.8±0.2 ppm, and 117.0±0.2 ppm relative to tetramethylsilane (at 293 K); or a DSC pattern substantially as shown in FIG. 2 .
21. The compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form A; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one p-toluenesulfonic acid Form B.
22. The compound (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form I; or crystalline (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one naphthalenedisulfonic acid Form II.
23. Amorphous (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one benzenesulfonate.
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Cited By (1)
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---|---|---|---|---|
US10519126B2 (en) * | 2012-03-01 | 2019-12-31 | Array Biopharma Inc. | Serine/threonine kinase inhibitors |
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US9532987B2 (en) | 2013-09-05 | 2017-01-03 | Genentech, Inc. | Use of a combination of a MEK inhibitor and an ERK inhibitor for treatment of hyperproliferative diseases |
WO2015085007A1 (en) | 2013-12-06 | 2015-06-11 | Genentech, Inc. | Serine/threonine kinase inhibitors |
KR20200038553A (en) * | 2014-04-09 | 2020-04-13 | 제넨테크, 인크. | Process for the manufacturing of medicaments |
DK3374359T3 (en) | 2015-11-09 | 2020-03-30 | Astrazeneca Ab | DIHYDROIMIDAZOPYRAZINO DERIVATIVES USED FOR CANCER TREATMENT |
JP2019518426A (en) | 2016-04-15 | 2019-07-04 | ジェネンテック, インコーポレイテッド | Cancer diagnosis and treatment method |
CA3073073A1 (en) | 2017-09-08 | 2019-03-14 | F. Hoffmann-La Roche Ag | Diagnostic and therapeutic methods for cancer |
US20210008047A1 (en) | 2018-02-13 | 2021-01-14 | Vib Vzw | Targeting minimal residual disease in cancer with rxr antagonists |
EP3546447A1 (en) * | 2018-03-29 | 2019-10-02 | Heidelberg Pharma GmbH | Synthesis of (2s,3r,4r)-4,5-dihydroxyisoleucine and derivatives |
IL293382A (en) * | 2019-12-05 | 2022-07-01 | Astrazeneca Ab | Process and intermediates for the production of formula (i) |
CN115710158A (en) * | 2021-08-23 | 2023-02-24 | 凯特立斯(深圳)科技有限公司 | Method for preparing ticagrelor intermediate through asymmetric catalysis |
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US8697715B2 (en) * | 2012-03-01 | 2014-04-15 | Array Biopharma, Inc. | Serine/threonine kinase inhibitors |
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MY130778A (en) * | 2001-02-09 | 2007-07-31 | Vertex Pharma | Heterocyclic inhibitiors of erk2 and uses thereof |
US6869966B2 (en) * | 2002-09-30 | 2005-03-22 | Banyu Pharmaceutical Co., Ltd. | N-substituted-2-oxodihydropyridine derivatives |
PL2001849T3 (en) * | 2006-03-29 | 2015-04-30 | Hoffmann La Roche | Pyridine and pyrimidine derivatives as mglur2 antagonists |
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US9867667B2 (en) * | 2014-02-27 | 2018-01-16 | Canon Usa Inc. | Placement apparatus |
KR20200038553A (en) * | 2014-04-09 | 2020-04-13 | 제넨테크, 인크. | Process for the manufacturing of medicaments |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8697715B2 (en) * | 2012-03-01 | 2014-04-15 | Array Biopharma, Inc. | Serine/threonine kinase inhibitors |
Non-Patent Citations (1)
Title |
---|
Swarbrick et al., eds., Encyclopeadia of Pharmaceutical Technology 13 (Marcel Dekker, NY 1996), pages 453-499. * |
Cited By (1)
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US10519126B2 (en) * | 2012-03-01 | 2019-12-31 | Array Biopharma Inc. | Serine/threonine kinase inhibitors |
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