CN114746410A - 用于生产式(i)的方法和中间体 - Google Patents
用于生产式(i)的方法和中间体 Download PDFInfo
- Publication number
- CN114746410A CN114746410A CN202080082518.8A CN202080082518A CN114746410A CN 114746410 A CN114746410 A CN 114746410A CN 202080082518 A CN202080082518 A CN 202080082518A CN 114746410 A CN114746410 A CN 114746410A
- Authority
- CN
- China
- Prior art keywords
- methyl
- formula
- compound
- pyrimidin
- difluorophenyl
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000000543 intermediate Substances 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- -1 3, 4-difluorophenyl Chemical group 0.000 claims description 22
- GSBLXHMFDLPKBM-CQSZACIVSA-N C(C1=CC=C(F)C(F)=C1)N1[C@@H](COC)CN2C=C(C3=NC(=NC=C3C)S(=O)(=O)C)N=C2C1=O Chemical compound C(C1=CC=C(F)C(F)=C1)N1[C@@H](COC)CN2C=C(C3=NC(=NC=C3C)S(=O)(=O)C)N=C2C1=O GSBLXHMFDLPKBM-CQSZACIVSA-N 0.000 claims description 8
- XMOOQHLTOHYUCX-UHFFFAOYSA-N CC=1C(=NC(=NC=1)SC)C=1N=C(NC=1)C(=O)O Chemical compound CC=1C(=NC(=NC=1)SC)C=1N=C(NC=1)C(=O)O XMOOQHLTOHYUCX-UHFFFAOYSA-N 0.000 claims description 8
- JESRNIJXVIFVOV-UHFFFAOYSA-N 2-methylpyrazol-3-amine Chemical compound CN1N=CC=C1N JESRNIJXVIFVOV-UHFFFAOYSA-N 0.000 claims description 7
- ANTBWAMYVUDOHR-UHFFFAOYSA-N FC=1C=C(C=CC=1F)CNC(=O)C=1NC=C(N=1)C1=NC(=NC=C1C)SC Chemical compound FC=1C=C(C=CC=1F)CNC(=O)C=1NC=C(N=1)C1=NC(=NC=C1C)SC ANTBWAMYVUDOHR-UHFFFAOYSA-N 0.000 claims description 6
- VPXPTMPXXDPJIU-CYBMUJFWSA-N [C@H]1(CO)CN2C=C(C3=NC(=NC=C3C)SC)N=C2C(=O)N1CC1=CC(=C(F)C=C1)F Chemical compound [C@H]1(CO)CN2C=C(C3=NC(=NC=C3C)SC)N=C2C(=O)N1CC1=CC(=C(F)C=C1)F VPXPTMPXXDPJIU-CYBMUJFWSA-N 0.000 claims description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 6
- XXIGZIRKMOMTPB-CQSZACIVSA-N C1=C(C(F)=CC=C1CN1[C@@H](COC)CN2C=C(C3=NC(=NC=C3C)SC)N=C2C1=O)F Chemical compound C1=C(C(F)=CC=C1CN1[C@@H](COC)CN2C=C(C3=NC(=NC=C3C)SC)N=C2C1=O)F XXIGZIRKMOMTPB-CQSZACIVSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 4
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 claims description 3
- SULGSLUIIZBEEN-UHFFFAOYSA-N 3,4-difluoro-n-methylaniline Chemical compound CNC1=CC=C(F)C(F)=C1 SULGSLUIIZBEEN-UHFFFAOYSA-N 0.000 claims description 3
- 239000012022 methylating agents Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 55
- 239000000243 solution Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000001361 adipic acid Substances 0.000 description 7
- 235000011037 adipic acid Nutrition 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- HVIGNZUDBVLTLU-MRXNPFEDSA-N (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one Chemical compound FC=1C=C(CN2C(C=3N(C[C@@H]2COC)C=C(N=3)C2=NC(=NC=C2C)NC2=CC=NN2C)=O)C=CC=1F HVIGNZUDBVLTLU-MRXNPFEDSA-N 0.000 description 3
- MDDULEPFNKVNRJ-PKLMIRHRSA-N (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one hexanedioic acid Chemical compound OC(=O)CCCCC(O)=O.COC[C@H]1Cn2cc(nc2C(=O)N1Cc1ccc(F)c(F)c1)-c1nc(Nc2ccnn2C)ncc1C MDDULEPFNKVNRJ-PKLMIRHRSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WFJJURSVRKLJTJ-UHFFFAOYSA-N CC(C(=O)OCN1C(=NC(=C1)C)C(=O)OCC)(C)C Chemical compound CC(C(=O)OCN1C(=NC(=C1)C)C(=O)OCC)(C)C WFJJURSVRKLJTJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- 238000005897 peptide coupling reaction Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- ANBMMPHCGLGFII-MIXQCLKLSA-N (1z,5z)-cycloocta-1,5-diene;iridium;methanolate Chemical compound [Ir].[Ir].[O-]C.[O-]C.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 ANBMMPHCGLGFII-MIXQCLKLSA-N 0.000 description 1
- NMIZONYLXCOHEF-UHFFFAOYSA-N 1h-imidazole-2-carboxamide Chemical compound NC(=O)C1=NC=CN1 NMIZONYLXCOHEF-UHFFFAOYSA-N 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- NPAXPTHCUCUHPT-UHFFFAOYSA-N 3,4,7,8-tetramethyl-1,10-phenanthroline Chemical compound CC1=CN=C2C3=NC=C(C)C(C)=C3C=CC2=C1C NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 description 1
- QZXWPYARYIQHIS-UHFFFAOYSA-N 4-chloro-5-methyl-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=C(C)C(Cl)=N1 QZXWPYARYIQHIS-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- GQDMLGLGLBGLRP-UHFFFAOYSA-N CCOC(=O)C1=NC(=CN1COC(=O)C(C)(C)C)C2=NC(=NC=C2C)SC Chemical compound CCOC(=O)C1=NC(=CN1COC(=O)C(C)(C)C)C2=NC(=NC=C2C)SC GQDMLGLGLBGLRP-UHFFFAOYSA-N 0.000 description 1
- RHEMJCOTYVWSPU-UHFFFAOYSA-N CCOC(=O)C1=NC=CN1COC(=O)C(C)(C)C Chemical compound CCOC(=O)C1=NC=CN1COC(=O)C(C)(C)C RHEMJCOTYVWSPU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- UHYNYIGCGVDBTC-UHFFFAOYSA-N ethyl 1h-imidazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=CN1 UHYNYIGCGVDBTC-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- ZUVAACFIEPYYOP-UHFFFAOYSA-N methoxycyclopropane Chemical group COC1CC1 ZUVAACFIEPYYOP-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ORWHXHCSDYWSCI-ZETCQYMHSA-N tert-butyl (4S)-4-(methoxymethyl)-2,2-dioxooxathiazolidine-3-carboxylate Chemical compound COC[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C ORWHXHCSDYWSCI-ZETCQYMHSA-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
- 230000001225 therapeutic effect Effects 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
一种用于制备式(I)化合物的方法和中间体。
Description
发明领域
本说明书涉及一种用于生产式(I)化合物或其药学上可接受的盐或共晶体的方法和中间体:
背景技术
国际专利申请案WO2017/080979A1描述作为ERK的抑制剂且可用于治疗癌症的式(I)化合物(其中的实例18)。WO2017/080979A1进一步描述式(I)化合物的己二酸共晶体(其中的实例34)。式(I)化合物也以其化学名称已知:(R)-7-(3,4-二氟苄基)-6-(甲氧基甲基)-2-(5-甲基-2-((l-甲基-lH-吡唑-5-基)氨基)嘧啶-4-基)-6,7-二氢咪唑并[1,2-a]吡嗪-8(5H)-酮。
WO2017/080979A1进一步描述一种用于生产式(I)化合物的方法,所述方法概述于以下反应图1中。反应图1中使用以下缩写:SEM=2-(三甲基硅基)乙氧基甲基;NBS=N-溴代琥珀酰亚胺;pin=频哪醇根基(pinacolato);Ac=乙酰基,TFA=三氟乙酸;18-冠醚-6=1,4,7,10,13,16-六氧杂环十八烷;和Boc=叔丁基氧基羰基。
虽然描述于现有技术中的合成途径提供一种用于在实验室规模上生产式(I)化合物的可靠方法,但是所述途径具有许多缺点。这些缺点包括:
(i)合成途径相对较长,在最长线顺序中有10种分离的中间体;
(ii)所述途径取决于式(A)化合物,另外其已知的化学名称为(4S)-4-(甲氧基甲基)-2,2-二氧代-氧杂四氢噻唑-3-甲酸叔丁酯,所述化合物成本高且在室温下化学稳定性有限;和
(iii)通过此方法形成的式(I)化合物需要通过色谱纯化,所述纯化在大规模上为昂贵的。
反应图1
因此,虽然显示于反应图1中的合成途径足以在实验室规模上制备式(I)化合物,但仍需要适于大规模生产式(I)化合物的方法。
发明内容
我们现已发现一种改良的合成方法,所述合成方法基本上克服以上所述缺点。所述改良的方法概述于以下反应图2中。
反应图2
在反应图2中,使用以下其它缩写:Piv=特戊酰基;RuPhos Pd G3=(2-二环己基膦基-2′,6′-二异丙氧基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]甲磺酸钯(II);CDMT=2-氯-4,6,-二甲氧基-1,3,5-三嗪;DIPEA=N,N-二异丙基乙胺;mCPBA=间氯过氧苯甲酸;和LHMDS=双(三甲基硅基)酰胺锂。方括号指示在合成顺序期间不必分离化合物。
显示反应图2的改良的方法适于制造数千克级的式(I)化合物。确切地说:
(i)不必分离式(V)化合物或式(III)化合物,因此仅6种中间体需要分离;
(ii)改良的方法无需式(A)化合物,降低商品成本;和
(iii)式(I)化合物以足够的纯度形成,其可通过用己二酸结晶以形成式(I)化合物的己二酸共晶体进行分离,从而无需色谱。
在第一方面中,本说明书提供一种用于生产式(I)化合物的方法:
所述方法包括式(II)化合物(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基磺酰基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
与2-甲基吡唑-3-胺(VIII)反应
在下一个方面中,本说明书提供一种式(II)化合物,(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基磺酰基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
在下一个方面中,本说明书提供一种式(III)化合物,(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
在下一个方面中,本说明书提供一种式(IV)化合物,(6R)-7-[(3,4-二氟苯基)甲基]-6-(羟基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
在下一个方面中,本说明书提供一种式(V)化合物,N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1-[[(2R)-环氧乙烷-2-基]甲基]咪唑-2-甲酰胺:
在下一个方面中,本说明书提供一种式(VI)化合物,N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酰胺:
在下一个方面中,本说明书提供一种式(VII)化合物,4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酸:
如以上所述,提供一种用于生产式(I)化合物的方法:
所述方法包括步骤(i):使式(II)化合物(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基磺酰基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
与2-甲基吡唑-3-胺(VIII)反应:
在一个实施例中,所述反应是在碱(如双(三甲基硅基)酰胺锂、双(三甲基硅基)酰胺钠、双(三甲基硅基)酰胺钾、叔丁醇钾或氢化钠)的存在下实施。在另一个实施例中,所述碱为双(三甲基硅基)酰胺锂。
在实施例中,所述方法包括另外的步骤(ii):使式(III)化合物(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
和氧化剂反应来制备式(II)化合物。在实施例中,氧化剂为过氧化氢、发氧方(oxone)或mCPBA。在其它实施例中,氧化剂为mCPBA。
在实施例中,所述方法包括另外的步骤(iii):使式(IV)化合物,(6R)-7-[(3,4-二氟苯基)甲基]-6-(羟基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
与甲基化剂(如碘甲烷、硫酸二甲酯或三氟甲磺酸甲酯)反应来制备式(III)化合物。在其它实施例中,甲基化剂为碘甲烷。在其它实施例中,所述反应是在碱(如氢化钠、双(三甲基硅基)酰胺锂、双(三甲基硅基)酰胺钠、双(三甲基硅基)酰胺钾或叔丁醇钾)的存在下实施。在其它实施例中,所述碱为氢化钠。
在实施例中,所述方法包括另外步骤(iv):使式(V)化合物,N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1-[[(2R)-环氧乙烷-2-基]甲基]咪唑-2-甲酰胺:
与溴化锂反应来制备式(IV)化合物。
在实施例中,所述方法包括另外步骤(v):使式(VI)化合物,N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酰胺:
与(S)-(+)-表氯醇(IX)反应来制备式(V)化合物:
在实施例中,所述反应是在4-二甲基氨基吡啶的存在下实施。在其它实施例中,所述反应是在碱(如DIPEA、三乙胺或三丁胺)的存在下实施。在其它实施例中,所述碱为DIPEA。
在实施例中,所述方法包括另外的步骤(vi):使式(VII)化合物,4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酸:
与(3,4-二氟苯基)甲胺(X)反应来制备式(VI)化合物:
在其它实施例中,所述反应是在肽偶联剂(如2-氯-4,6-二甲氧基-1,3,5-三嗪与4-甲基吗啉的组合、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺与羟基苯并三唑的组合、六氟磷酸苯并三唑-1-基-氧基三吡咯啶并磷鎓、丙烷膦酸酸酐、四氟硼酸O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓、1,1'-羰基二咪唑、酰卤形成试剂或酸酐形成试剂)的存在下实施。在其它实施例中,肽偶联剂为2-氯-4,6-二甲氧基-1,3,5-三嗪与4-甲基吗啉的组合。
在一个实施例中,提供一种式(II)化合物,(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基磺酰基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
在另一个实施例中,式(II)化合物的对映异构体超量(%ee)为≥95%、≥98%或≥99%。在进一步的实施例中,式(II)化合物的对映异构体超量(%ee)为≥99%。
在一个实施例中,提供一种式(III)化合物,(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
在另一个实施例中,式(III)化合物的对映异构体超量(%ee)为≥95%、≥98%或≥99%。在另一个实施例中,式(III)化合物的对映异构体超量(%ee)为≥99%。
在一个实施例中,提供一种式(IV)化合物,(6R)-7-[(3,4-二氟苯基)甲基]-6-(羟基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮:
在另一个实施例中,式(IV)化合物的对映异构体超量(%ee)为≥95%、≥98%或≥99%。在另一个实施例中,式(IV)化合物的对映异构体超量(%ee)为≥99%。
在一个实施例中,提供一种式(V)化合物,N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1-[[(2R)-环氧乙烷-2-基]甲基]咪唑-2-甲酰胺:
在另一个实施例中,式(V)化合物的对映异构体超量(%ee)为≥95%、≥98%或≥99%。在另一个实施例中,式(V)化合物的对映异构体超量(%ee)为≥99%。
在一个实施例中,提供一种式(VI)化合物,N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酰胺:
在一个实施例中,提供一种式(VII)化合物,4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酸:
描述于本说明书中的化合物可形成酸加成盐或碱加成盐。
具体实施方式
一般来说,可使用各种无机酸或有机酸来制备酸加成盐。此类盐可通常通过例如使用本领域中已知的各种方法将化合物与酸(例如,化学计量量的酸)混合而形成。此种混合可在水、有机溶剂(例如醚、乙酸乙酯、乙醇、异丙醇或乙腈)或水性/有机混合物中发生。酸加成盐可例如使用选自由盐酸组成的群组的无机酸来形成。
对于可形成碱加成盐的化合物,可通过用含在水性介质中的碱金属或碱土金属氢氧化物或醇盐(例如乙醇盐或甲醇盐)或适宜碱性有机胺(例如胆碱或葡甲胺)处理化合物来制备例如碱金属(如钠、钾或锂)或碱土金属(如钙)盐。
制备盐的一般原理和技术可见于Berge等人,J.Pharm.Sci.,66,1-19(1977)。
描述于本说明书中的化合物可以溶剂化形式和非溶剂化形式存在。例如,溶剂化形式可为水合形式,如半水合物、一水合物、二水合物、三水合物或其另外的数量。本说明书涵盖所有此类溶剂化和非溶剂化形式。
描述于本说明书中的化合物和盐的原子可以其同位素存在。本说明书涵盖其中某一原子经一个或多个其同位素置换的所有此类化合物(例如其中一个或多个碳原子为11C或13C碳同位素或其中一个或多个氢原子为2H或3H同位素的化合物)。
通过本文所述的方法制备的式(I)化合物可用于提供调配物,如片剂,以用作治疗癌症的药物。适宜调配物和经如此制备的药剂的治疗性用途描述于WO2017/080979A1中,所述案的内容是以引用的方式并入本文中。
通过以下实例来说明各种实施例。本发明不应解释为限于所述实例。在制备实例期间,一般来说:
i.除非另有说明,否则操作在环境温度下(即在约17到30℃的范围内)且在惰性气体(如氮气)的气氛下进行;
ii.产率(若存在)不一定为可达成的最大值;
iii.通过核磁共振(NMR)光谱法确认化合物,其中在δ尺度上测量NMR化学位移值。使用Bruker advance 700(700MHz)、Bruker Avance 500(500MHz)、Bruker 400(400MHz)或Bruker 300(300MHz)仪器来确定质子磁共振光谱;除非另有指定,否则测量在约20到30℃下进行;使用以下缩写:s=单峰;d=双峰;t=三重峰;q=四重峰;p=五重峰(pentet/quintet);m=多重峰;dd=双二重峰;ddd=双双二重峰;dt=双三重峰;td=三二重峰;qd=四二重峰;bs=宽峰信号;
iv.还通过液相色谱后的高分辨率质谱(LC-MS)来表征化合物。LC-MS使用连接到以正电喷雾模式操作的Waters Synapt G2-Si ESI质谱仪和Acquity BEH RP18柱(2.1x100mm,1.7mm)的Waters H-Class Bio UPLC进行,其流速为0.6mL/min,使用以下溶剂体系:历时12分钟从90/5/5A/B/C到5/90/5A/B/C,接着保持在5/90/5A/B/C持续1.2分钟,其中A=水,B=乙腈和C=250mM乙酸铵水溶液;
v.IUPAC名称使用BIOVIATM Draw(16.1版)生成。
vi.使用以下缩写:CDMT=2-氯-4,6-二甲氧基-1,3,5-三嗪;CPME=环丙基甲基醚;DIPEA=N,N-二异丙基乙胺;DMF=二甲基甲酰胺;LHMDS=双(三甲基硅基)酰胺锂;mCPBA=间氯过氧苯甲酸;Piv=特戊酰基;和RuPhos Pd G3=(2-二环己基膦基-2′,6′-二异丙氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]甲磺酸钯(II)。
vii.(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-[5-甲基-2-[(2-甲基吡唑-3-基)氨基]嘧啶-4-基]-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮己二酸共晶体晶种对应于WO2017/080979A1的实例34(其中的第180页)且可根据其中所公开的方法来制备。
1-(2,2-二甲基丙酰基氧基甲基)咪唑-2-甲酸乙酯
在40℃下,历时2小时将特戊酸氯甲酯(632.5mmol,95.25g,91.15mL)逐滴添加到1H-咪唑-2-甲酸乙酯(80.58g,575.0mmol)、碳酸钾(690.0mmol,95.36g)和乙腈(730mL)的搅拌混合物。然后在40℃下搅拌所得混合物20小时。然后将此混合物冷却到20℃且过滤,用乙腈(160mL)洗涤。在真空下浓缩所得滤液。通过三个用庚烷处理残余物且然后在真空下浓缩所得混合物的循环来移除残余乙腈。然后过滤所得悬浮液,用庚烷(160mL)洗涤,以产生呈灰白色固体的标题化合物(134g,92%);1H NMR(500MHz,DMSO-d6)δppm 1.1(s,9H)1.3(t,J=7.1Hz,3H)4.3(q,J=7.1Hz,2H)6.2(s,2H)7.1(d,J=1.1Hz,1H)7.6(d,J=1.1Hz,1H);m/z=254.28。
1-(2,2-二甲基丙酰基氧基甲基)-4-(5-甲基-2-甲基硫基-嘧啶-4-基)咪唑-2-甲酸乙酯
将(1,5-环辛二烯)(甲氧基)铱(I)二聚体(2.06mmol,1.37g)添加到1-(2,2-二甲基丙酰基氧基甲基)咪唑-2-甲酸乙酯(138mmol,35.0g)、双(频哪醇根基)二硼(145mmol,36.7g)和3,4,7,8-四甲基-1,10-菲咯啉(4.13mmol,0.976g)在CPME(140mL)中的搅拌混合物且在53℃下搅拌所得混合物1小时。然后过滤所得混合物,用CPME(35mL)洗涤,以产生粗制中间体1-(2,2-二甲基丙酰基氧基甲基)-4-甲基-咪唑-2-甲酸乙酯。
将RuPhos Pd G3(3.44mmol,2.88g)添加到4-氯-5-甲基-2-(甲基硫基)嘧啶(138mmol,24.0g)、碳酸钾(275mmol,38.0g)、CPME(280mL)和水(140mL)的混合物且在55℃下搅拌所得混合物。将粗制中间体1-(2,2-二甲基丙酰基氧基甲基)-4-甲基-咪唑-2-甲酸乙酯添加到所得混合物,然后在55℃下搅拌所述混合物1小时。然后在40℃下将所述混合物滤过CELITETM(35.0g),用CPME(35mL)洗涤。移除所得滤液的水层,且用水(140mL)洗涤有机层。然后在真空下浓缩有机层且冷却到5℃,以得到固体,过滤所述固体,用CPME(35mL)洗涤,以得到呈浅粉色固体的标题化合物(54.0g,138mmol);1H NMR(500MHz,氯仿-d)δppm1.0(s,9H)1.5(t,J=7.1Hz,3H)2.3(d,J=0.5Hz,3H)2.6(s,3H)4.5(q,J=7.1Hz,2H)6.7(s,2H)7.5(s,1H)8.5-8.5(m,1H);m/z=392.47。
N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酰胺
在15℃下,历时15分钟将氢氧化钠水溶液(2.0M,441.2mmol,220.6mL)逐滴添加到1-(2,2-二甲基丙酰基氧基甲基)-4-(5-甲基-2-甲基硫基-嘧啶-4-基)咪唑-2-甲酸乙酯(55.07g,140.3mmol)在THF(330mL)和水(550mL)中的搅拌混合物。在15℃下搅拌所述混合物12小时,然后在15℃下,历时15分钟逐滴添加磷酸(646mmol,85质量%,74.5g,44.06mL)在水(275mL)中的溶液。在再10分钟后,过滤所述混合物,用水(275mL)洗涤,以得到中间体4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酸;1H NMR(400MHz,DMSO-d6)δppm 2.5(s,3H)2.6(s,3H)8.0(s,1H)8.5(s,1H);m/z=250.28。
将中间体溶解于DMF(720mL)中且冷却到0℃,然后用CDMT(210.5mmol,36.95g)处理。在0℃下搅拌反应混合物10分钟,然后历时15分钟用经预冷却到15℃的(3,4-二氟苯基)甲胺(168.4mmol,24.10g,19.9mL)和4-甲基吗啉(168.4mmol,24.10g,19.9mL)在DMF(83mL)中的溶液逐滴处理,其中使所述反应混合物保持在0℃。在0℃下搅拌所述反应混合物2小时,然后在5℃下历时10分钟用水(250mL)处理。然后过滤所得混合物,用DMF(55mL)和水(55mL)的混合物洗涤。在真空下干燥所得滤饼且然后在20℃下加入甲醇(275mL)。搅拌所得浆液且在20℃下用碳酸钾(199.2mmol,27.54g)在水(253mL)中的溶液处理。在20℃下搅拌所述混合物12小时,然后过滤且依序用水(275mL)和甲醇(275mL)洗涤。在真空下干燥所过滤的固体以得到呈固体的标题化合物(42.9g,114mmol);1H NMR(500MHz,DMSO-d6)δppm2.5-2.5(m,3H)2.6(br s,3H)4.5(d,J=6.4Hz,2H)7.1-7.2(m,1H)7.3-7.5(m,2H)7.7-8.2(m,1H)8.4(s,1H)9.0(br s,1H)13.6(br s,1H);19F NMR(470MHz,DMSO-d6)δppm-141.7--141.4(m,1F)-139.1--138.9(m,1F);13C NMR(126MHz,DMSO-d6)δppm 13.5(s,1C)16.8(s,1C)41.3(s,1C)116.3(d,J=17.3Hz,1C)117.2(d,J=16.8Hz,1C)121.9(s,1C)123.1(s,1C)124.0(dd,J=6.6,3.4Hz,1C)137.3(dd,J=4.3Hz,1C)140.3(s,1C)141.2(s,1C)148.4(dd,J=244.1,12.5Hz,1C)149.2(dd,J=245.2,12.7Hz,1C)156.8(s,1C)158.3(s,1C)159.7(s,1C)167.7(s,1C);m/z=375.4。
(6R)-7-[(3,4-二氟苯基)甲基]-6-(羟基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮
在20℃下,搅拌N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1H-咪唑-2-甲酰胺(115.8mmol,43.47g)、4-二甲基氨基吡啶(3.474mmol,0.4244g)、DIPEA(115.8mmol,14.97g,20.2mL)和(S)-(+)-表氯醇(926.4mmol,85.71g,72.51mL)在THF(535mL)中的混合物,然后历时1小时加热到50℃。然后在50℃下加热所得混合物24小时以得到N-[(3,4-二氟苯基)甲基]-4-(5-甲基-2-甲基硫基-嘧啶-4-基)-1-[[(2R)-环氧乙烷-2-基]甲基]咪唑-2-甲酰胺的浆液。然后将此浆液冷却到30℃且在30℃下历时10分钟用溴化锂(162.1mmol,14.08g)逐份地处理。然后在40℃下搅拌所述混合物16小时,然后冷却到20℃。然后过滤所述混合物,用THF(87mL)洗涤。然后在20℃下在甲醇(430mL)中搅拌所过滤的固体1小时,然后过滤所述混合物,用甲醇(87mL)洗涤。在真空下干燥滤饼,以得到呈固体的标题化合物(49.97g,115.8mmol);1H NMR(500MHz,DMSO-d6)δppm 2.5(s,3H)2.5-2.6(m,3H)3.2-3.3(m,1H)3.4-3.5(m,1H)3.8-3.8(m,1H)4.4(d,J=15.5Hz,1H)4.4(dd,J=13.6,4.9Hz,1H)4.5-4.5(m,1H)5.1(d,J=15.5Hz,1H)5.2(t,J=5.4Hz,1H)7.2-7.3(m,1H)7.4(dt,J=10.8,8.5Hz,1H)7.5(ddd,J=11.6,7.9,2.0Hz,1H)8.2(s,1H)8.5(d,J=0.6Hz,1H);m/z=431.46。
(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基磺酰基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮
在20℃下,搅拌(6R)-7-[(3,4-二氟苯基)甲基]-6-(羟基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮(61.2g,142mmol)在THF(551mL)中的混合物15分钟,然后冷却到0℃。然后在0℃下历时20分钟用氢化钠(60质量%含在矿物油中,170mmol,6.81g)逐份地处理所述混合物。在0℃下搅拌所述混合物1小时且然后在0℃下历时10分钟用碘甲烷(213mmol,30.2g,13.3mL)逐滴处理。用THF(61mL)作为管线清洗剂(line wash)处理所述混合物,然后在0℃下搅拌30分钟,然后历时1小时升温到35℃且然后在35℃下搅拌1小时。然后将所述混合物冷却到20℃且用氯化钠(314mmol,18.4g)在水(122mL)中的溶液处理。在20℃下搅拌所述混合物10分钟,然后移除水层。搅拌有机层且用氯化钠(314mmol,18.4g)在水(122mL)中的溶液处理。在20℃下搅拌所述混合物10分钟,然后移除水层。在真空下浓缩有机层,然后用二氯甲烷(612mL)和水(122mL)处理。在20℃下搅拌所得混合物10分钟,然后移除水层,以得到(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基硫基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮的溶液[1HNMR(400MHz,氯仿-d)δppm 2.6(s,3H)2.7(s,3H)3.3(s,3H)3.4(m,1H)3.7(m,1H)3.8(m,1H)4.2(m,2H)4.4(d,1H)5.4(d,1H)7.1-7.2(m,3H)7.9(s,1H)8.4(s,1H);m/z=445.49]。将此冷却到5℃且在5℃下历时20分钟用mCPBA(312mmol,77质量%,69.9g)逐份地处理。在5℃下搅拌所述混合物1小时,然后历时30分钟升温到20℃,然后在20℃下搅拌10小时。然后用亚硫酸钠(486mmol,61.2g)在水(282mL)中的溶液处理所述混合物且在20℃下再搅拌10分钟。然后移除水层,且用碳酸钾(221mmol,30.6g)在水(282mL)中的溶液处理有机层。搅拌所述混合物10分钟,然后移除水层,且用碳酸钾(221mmol,30.6g)在水(282mL)中的溶液处理有机层。搅拌所述混合物10分钟,然后移除水层,且用硫酸镁(153mmol,18.4g)逐份地处理有机层。搅拌所述混合物10分钟,然后滤过CELITETM(18.4g),用二氯甲烷(245mL)洗涤。在真空下浓缩滤液,然后在20℃下历时20分钟添加到二异丙醚(918mL)。使用二氯甲烷(12.2mL)来洗涤残余滤液到混合物中。然后在20℃下搅拌所述混合物3小时,然后过滤,用二异丙醚(122mL)洗涤。在真空下干燥滤饼,以得到呈固体的标题化合物(67.7g,142mmol);1H NMR(500MHz,DMSO-d6)δppm 2.7(s,3H)3.2(s,3H)3.3-3.4(m,1H)3.4(dd,J=10.1,4.8Hz,1H)3.4-3.4(m,3H)4.0-4.1(m,1H)4.4(d,J=15.6Hz,1H)4.5(d,J=3.0Hz,2H)5.1(d,J=15.6Hz,1H)7.2-7.3(m,1H)7.4(dt,J=10.7,8.5Hz,1H)7.4-7.5(m,1H)8.4(s,1H)8.9(s,1H);13C NMR(126MHz,DMSO-d6)δppm 17.5(s,1C)39.0(s,1C)44.3(s,1C)47.5(s,1C)54.3(s,1C)58.6(s,1C)70.8(s,1C)116.7(d,J=17.3Hz,1C)117.4(d,J=17.3Hz,1C)124.5(dd,J=6.4,3.6Hz,1C)126.3(s,1C)129.6(s,1C)135.5(s,1C)138.4(s,1C)139.9(s,1C)148.6(dd,J=244.8,12.3Hz,1C)149.4(dd,J=245.5,12.9Hz,1C)155.6(s,1C)157.4(s,1C)160.8(s,1C)163.1(s,1C);19F NMR(470MHz,DMSO-d6)δppm -140.9(d,J=22.1Hz,1F)-138.6(d,J=22.1Hz,1F);m/z=477.48。
(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-[5-甲基-2-[(2-甲基吡唑-3-基)氨基]嘧啶-4-基]-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮和其己二酸共晶体
在20℃下,搅拌(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-(5-甲基-2-甲基磺酰基-嘧啶-4-基)-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮(35.0g,73.3mmol)和2-甲基吡唑-3-胺(21.4g,220mmol)在THF(875mL)中的混合物。然后通过在大气压力下蒸馏,浓缩所述混合物。将另外THF(175mL)添加到所述混合物,且再次通过在大气压下蒸馏,浓缩所述混合物。卡尔费歇尔(Karl-Fisher)分析证实,所述混合物的水含量低于400ppm。然后将所述混合物冷却到-10℃且在-10℃下历时30分钟用LHMDS(1M含在THF中)和THF(220mL)的预形成混合物处理。将THF(17.5mL)作为管线清洗剂添加到所述混合物。在-10℃下搅拌所述混合物45分钟,然后历时15分钟用磷酸(366mmol,85质量%,42.3g)在水(131mL)中的溶液处理。在15℃下再搅拌所述混合物10分钟,且然后移除水层。在15℃下用氯化钠(427mmol,25.0g)和磷酸(366mmol,85质量%,42.3g)在水(150mL)中的溶液处理有机层。在15℃下搅拌所述混合物10分钟且移除水层。用氯化钠(427mmol,25.0g)在水(150mL)中的溶液处理有机层且在15℃下搅拌10分钟。移除水层,且在15℃下历时15分钟用碳酸氢钠(12.0g)在水(169mL)中的溶液处理有机层。在15℃下再搅拌所述混合物10分钟且移除水层。通过大气压蒸馏,浓缩有机层。用乙醇(599mL)处理残余物和通过大气压蒸馏浓缩所得混合物,以得到粗产物(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-[5-甲基-2-[(2-甲基吡唑-3-基)氨基]嘧啶-4-基]-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮。
用乙醇(7mL)处理粗产物且将所得混合物加热到70℃以得到粗产物溶液。用乙醇(70mL)处理己二酸(0.510当量,37.4mmol,100质量%,5.46g)且加热到30℃直到获得溶液。然后历时15分钟将所述己二酸溶液的30%添加到粗产物溶液,且将粗产物溶液保持在70℃。然后将所述粗产物溶液冷却到55℃且加入(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-[5-甲基-2-[(2-甲基吡唑-3-基)氨基]嘧啶-4-基]-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮己二酸共晶体晶种(3.09mmol,1.75g)。将所得混合物保持在55℃1小时。使用乙醇(7mL)作为管线冲洗液,历时3小时将剩余己二酸溶液逐滴添加到粗产物溶液,且将粗产物溶液保持在55℃。历时3小时将所得混合物冷却到5℃,且然后再保持在5℃3小时。过滤所得混合物,用乙醇(70mL)洗涤。然后在20℃下将固体与正庚烷(175mL)一起搅拌1小时且再次过滤,用正庚烷(70mL)洗涤。然后在真空下干燥固体,以得到呈固体的(6R)-7-[(3,4-二氟苯基)甲基]-6-(甲氧基甲基)-2-[5-甲基-2-[(2-甲基吡唑-3-基)氨基]嘧啶-4-基]-5,6-二氢咪唑并[1,2-a]吡嗪-8-酮己二酸共晶体(41.6g,73.3mmol)。1H NMR(500MHz,甲醇-d4)d ppm1.5-1.7(m,4H)2.2-2.4(m,4H)2.5(s,6H)3.2(s,6H)3.4(dd,J=9.4,7.2Hz,2H)3.5(dd,J=10.0,4.6Hz,2H)3.7(s,6H)3.9-4.1(m,2H)4.4(dd,J=13.2,5.1Hz,2H)4.5(d,J=15.2Hz,2H)4.5(dd,J=13.6,1.1Hz,2H)5.2(d,J=15.2Hz,2H)6.3(d,J=2.0Hz,2H)7.2-7.2(m,2H)7.2-7.3(m,2H)7.4(ddd,J=11.3,7.7,1.6Hz,2H)7.4(d,J=2.0Hz,2H)7.8(s,2H)8.2(s,2H);19F NMR(470MHz,甲醇-d4)d ppm-142.0(d,J=20.4Hz,2F)-139.9(d,J=20.4Hz,2F);13C NMR(126MHz,甲醇-d4)d ppm 17.0(s,1C)25.5(s,2C)34.6(s,2C)35.6(s,2C)45.7(s,1C)56.4(s,2C)59.5(s,2C)72.3(s,2C)100.1(s,2C)118.2(d,J=18.2Hz,2C)118.4-118.8(m,2C)120.2(s,2C)125.2(s,2C)125.7(dd,J=6.6,3.9Hz,4C)136.2(s,1C)139.1(s,2C)139.2(s,2C)140.6(s,2C)143.6(s,2C)151.2(dd,J=247.5,12.7Hz,2C)151.6(dd,J=247.0,12.7Hz,2C)158.3(s,2C)159.0(s,2C)160.0(s,2C)161.7(s,2C)177.3(s,2C);m/z=567.57(游离碱=494.5)。
Claims (12)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962943851P | 2019-12-05 | 2019-12-05 | |
US62/943,851 | 2019-12-05 | ||
PCT/EP2020/084580 WO2021110893A1 (en) | 2019-12-05 | 2020-12-04 | Process and intermediates for the production of formula (i) |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114746410A true CN114746410A (zh) | 2022-07-12 |
Family
ID=73748050
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080082518.8A Pending CN114746410A (zh) | 2019-12-05 | 2020-12-04 | 用于生产式(i)的方法和中间体 |
Country Status (13)
Country | Link |
---|---|
US (1) | US20230046093A1 (zh) |
EP (1) | EP4069687B1 (zh) |
JP (1) | JP2023505771A (zh) |
KR (1) | KR20220112764A (zh) |
CN (1) | CN114746410A (zh) |
AR (1) | AR120685A1 (zh) |
AU (1) | AU2020397222B2 (zh) |
CA (1) | CA3157504A1 (zh) |
CO (1) | CO2022008102A2 (zh) |
IL (1) | IL293382A (zh) |
MX (1) | MX2022006856A (zh) |
TW (1) | TW202134242A (zh) |
WO (1) | WO2021110893A1 (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160304496A1 (en) * | 2015-04-17 | 2016-10-20 | Abbvie Inc. | Indazolones as modulators of tnf signaling |
CN106659721A (zh) * | 2014-04-09 | 2017-05-10 | 基因泰克公司 | 用于制备药物的方法 |
WO2017080979A1 (en) * | 2015-11-09 | 2017-05-18 | Astrazeneca Ab | Dihydroimidazopyrazinone derivatives useful in the treatment of cancer |
TW201726675A (zh) * | 2015-12-23 | 2017-08-01 | 默沙東藥廠 | M4毒蕈鹼乙醯膽鹼受體之異位調節劑6,7-二氫-5h-吡咯并[3,4-b]吡啶-5-酮 |
-
2020
- 2020-12-04 WO PCT/EP2020/084580 patent/WO2021110893A1/en unknown
- 2020-12-04 MX MX2022006856A patent/MX2022006856A/es unknown
- 2020-12-04 KR KR1020227018235A patent/KR20220112764A/ko unknown
- 2020-12-04 CN CN202080082518.8A patent/CN114746410A/zh active Pending
- 2020-12-04 TW TW109142775A patent/TW202134242A/zh unknown
- 2020-12-04 AU AU2020397222A patent/AU2020397222B2/en active Active
- 2020-12-04 JP JP2022533631A patent/JP2023505771A/ja not_active Withdrawn
- 2020-12-04 IL IL293382A patent/IL293382A/en unknown
- 2020-12-04 CA CA3157504A patent/CA3157504A1/en active Pending
- 2020-12-04 US US17/782,661 patent/US20230046093A1/en active Pending
- 2020-12-04 EP EP20820820.7A patent/EP4069687B1/en active Active
- 2020-12-04 AR ARP200103398A patent/AR120685A1/es unknown
-
2022
- 2022-06-07 CO CONC2022/0008102A patent/CO2022008102A2/es unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106659721A (zh) * | 2014-04-09 | 2017-05-10 | 基因泰克公司 | 用于制备药物的方法 |
US20160304496A1 (en) * | 2015-04-17 | 2016-10-20 | Abbvie Inc. | Indazolones as modulators of tnf signaling |
WO2017080979A1 (en) * | 2015-11-09 | 2017-05-18 | Astrazeneca Ab | Dihydroimidazopyrazinone derivatives useful in the treatment of cancer |
TW201726675A (zh) * | 2015-12-23 | 2017-08-01 | 默沙東藥廠 | M4毒蕈鹼乙醯膽鹼受體之異位調節劑6,7-二氫-5h-吡咯并[3,4-b]吡啶-5-酮 |
Non-Patent Citations (1)
Title |
---|
RICHARD A. WARD,等: "Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)", 《J. MED. CHEM.》, 11 November 2019 (2019-11-11), pages 11004 * |
Also Published As
Publication number | Publication date |
---|---|
WO2021110893A1 (en) | 2021-06-10 |
AU2020397222B2 (en) | 2023-07-06 |
JP2023505771A (ja) | 2023-02-13 |
IL293382A (en) | 2022-07-01 |
KR20220112764A (ko) | 2022-08-11 |
EP4069687A1 (en) | 2022-10-12 |
CO2022008102A2 (es) | 2022-07-08 |
TW202134242A (zh) | 2021-09-16 |
CA3157504A1 (en) | 2021-06-10 |
AR120685A1 (es) | 2022-03-09 |
MX2022006856A (es) | 2022-07-11 |
US20230046093A1 (en) | 2023-02-16 |
AU2020397222A1 (en) | 2022-04-28 |
EP4069687B1 (en) | 2024-01-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2021261879B2 (en) | Synthesis of N-(heteroaryl)-pyrrolo[2,3-d]pyrimidin-2-amines | |
EP3710439B1 (en) | Kras g12c inhibitors | |
EP3458445B1 (en) | Kras g12c inhibitors | |
CA3011761C (en) | New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them | |
ES2718218T3 (es) | Derivados de 4,5,6,7-tetrahidropirazolo[1,5-a]pirazina sustituidos como inhibidores de caseína cinasa 1 D/E | |
EP2318413A1 (en) | Pyrrolobenzodiazepines | |
KR20170102887A (ko) | 브루톤 티로신 키나제 저해제의 합성 | |
CA3104116A1 (en) | Process for preparing btk inhibitors | |
CN113039178A (zh) | 吡啶并[2,3-d]嘧啶-7(8H)-酮的合成 | |
IL300555A (en) | Process and intermediates for preparing a JAK inhibitor | |
CN114746410A (zh) | 用于生产式(i)的方法和中间体 | |
KR102104957B1 (ko) | 코판리십의 제조방법 | |
CN107108604B (zh) | 制备三环内酰胺化合物的方法 | |
AU2021300294A1 (en) | Methods and intermediates for preparing JAK inhibitors | |
TW202208370A (zh) | 嘧啶基-3,8-二氮雜雙環[3.2.1]辛烷基甲酮衍生物及其鹽之製備 | |
EA044335B1 (ru) | Способ и промежуточные соединения для получения соединения, имеющего формулу (i) | |
RU2774253C2 (ru) | Синтез n-(гетероарил)-пирроло[3,2-d]пиримидин-2-аминов | |
EA042733B1 (ru) | СИНТЕЗ N-(ГЕТЕРОАРИЛ)ПИРРОЛО[3,2-d]ПИРИМИДИН-2-АМИНОВ | |
AU2022428318A1 (en) | Method for producing n-alkyl amino acid and peptide including n-alkyl amino acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40076657 Country of ref document: HK |