CN112028874B - Synthesis method of eritinib - Google Patents
Synthesis method of eritinib Download PDFInfo
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- CN112028874B CN112028874B CN202010946680.1A CN202010946680A CN112028874B CN 112028874 B CN112028874 B CN 112028874B CN 202010946680 A CN202010946680 A CN 202010946680A CN 112028874 B CN112028874 B CN 112028874B
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- eritinib
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- 238000001308 synthesis method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 25
- 230000008569 process Effects 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims description 22
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- -1 alkylaluminum halides Chemical class 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000010949 copper Substances 0.000 claims description 8
- YYBXNWIRMJXEQJ-UHFFFAOYSA-N 4-piperidin-4-ylmorpholine Chemical compound C1CNCCC1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000543 intermediate Substances 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- SZSZDBFJCQKTRG-UHFFFAOYSA-N 1h-indole-6-carbonitrile Chemical compound N#CC1=CC=C2C=CNC2=C1 SZSZDBFJCQKTRG-UHFFFAOYSA-N 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical class N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052802 copper Inorganic materials 0.000 claims description 5
- SWRGUMCEJHQWEE-UHFFFAOYSA-N ethanedihydrazide Chemical class NNC(=O)C(=O)NN SWRGUMCEJHQWEE-UHFFFAOYSA-N 0.000 claims description 5
- 239000002808 molecular sieve Substances 0.000 claims description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
- 229910021556 Chromium(III) chloride Inorganic materials 0.000 claims description 4
- 229910021581 Cobalt(III) chloride Inorganic materials 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- YKYOUMDCQGMQQO-UHFFFAOYSA-L cadmium dichloride Chemical compound Cl[Cd]Cl YKYOUMDCQGMQQO-UHFFFAOYSA-L 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- PHFQLYPOURZARY-UHFFFAOYSA-N chromium trinitrate Chemical compound [Cr+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O PHFQLYPOURZARY-UHFFFAOYSA-N 0.000 claims description 4
- 239000011636 chromium(III) chloride Substances 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical class [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 229910019213 POCl3 Inorganic materials 0.000 claims description 3
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 239000011651 chromium Substances 0.000 claims description 3
- 229910052804 chromium Inorganic materials 0.000 claims description 3
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 claims description 3
- 239000010941 cobalt Chemical class 0.000 claims description 3
- 229910017052 cobalt Chemical class 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical class [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- 229910015845 BBr3 Inorganic materials 0.000 claims description 2
- 229910021560 Chromium(III) bromide Inorganic materials 0.000 claims description 2
- 229910021564 Chromium(III) fluoride Inorganic materials 0.000 claims description 2
- 229910021583 Cobalt(III) fluoride Inorganic materials 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- 229910021592 Copper(II) chloride Inorganic materials 0.000 claims description 2
- 229910005267 GaCl3 Inorganic materials 0.000 claims description 2
- 229910003074 TiCl4 Inorganic materials 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 claims description 2
- 229910001627 beryllium chloride Inorganic materials 0.000 claims description 2
- LWBPNIJBHRISSS-UHFFFAOYSA-L beryllium dichloride Chemical compound Cl[Be]Cl LWBPNIJBHRISSS-UHFFFAOYSA-L 0.000 claims description 2
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 2
- UZDWIWGMKWZEPE-UHFFFAOYSA-K chromium(iii) bromide Chemical compound [Cr+3].[Br-].[Br-].[Br-] UZDWIWGMKWZEPE-UHFFFAOYSA-K 0.000 claims description 2
- QSQUFRGBXGXOHF-UHFFFAOYSA-N cobalt(III) nitrate Inorganic materials [Co].O[N+]([O-])=O.O[N+]([O-])=O.O[N+]([O-])=O QSQUFRGBXGXOHF-UHFFFAOYSA-N 0.000 claims description 2
- WZJQNLGQTOCWDS-UHFFFAOYSA-K cobalt(iii) fluoride Chemical compound F[Co](F)F WZJQNLGQTOCWDS-UHFFFAOYSA-K 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 claims description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012024 dehydrating agents Substances 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- UPWPDUACHOATKO-UHFFFAOYSA-K gallium trichloride Chemical compound Cl[Ga](Cl)Cl UPWPDUACHOATKO-UHFFFAOYSA-K 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- FTBATIJJKIIOTP-UHFFFAOYSA-K trifluorochromium Chemical compound F[Cr](F)F FTBATIJJKIIOTP-UHFFFAOYSA-K 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 2
- 239000010457 zeolite Substances 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 3
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 claims 1
- 229910021536 Zeolite Inorganic materials 0.000 claims 1
- 239000003377 acid catalyst Substances 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 239000011968 lewis acid catalyst Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- HIKRJHFHGKZKRI-UHFFFAOYSA-N 2,4,6-trimethylbenzaldehyde Chemical compound CC1=CC(C)=C(C=O)C(C)=C1 HIKRJHFHGKZKRI-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
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- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
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- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
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- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- 235000011054 acetic acid Nutrition 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- JBAKCAZIROEXGK-LNKPDPKZSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O JBAKCAZIROEXGK-LNKPDPKZSA-N 0.000 description 1
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- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
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- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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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
- C07D401/02—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a process for the preparation of eritinib or a pharmaceutically acceptable salt thereof. The invention also relates to intermediate compounds useful in this process and to the preparation of such intermediate compounds.
Description
Technical Field
The present invention relates to a process for the preparation of eritinib or a pharmaceutically acceptable salt thereof. The invention also relates to intermediate compounds useful in this process and to the preparation of such intermediate compounds.
Background
The chemical name of the Alitinib (Alectonib) is 9-ethyl-6, 11-dihydro-6, 6-dimethyl-8- [4- (4-morpholinyl) -1-piperidyl ] -11-oxo-5H-benzo [ b ] carbazole-3-carbonitrile, and the structural formula can be represented by the following formula I
Eritinib eride is a second generation oral drug that selectively inhibits Anaplastic Lymphoma Kinase (ALK) activity. It is particularly useful for treating non-small cell lung cancer (NSCLC) expressing ALK-EML4 (acanthocortin microtubule-associated protein-like 4) fusion protein, thereby causing NSCLC cell proliferation. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT, thereby reducing the viability of tumor cells.
The synthesis of eritinib and its hydrochloride salts is described in WO2010143664, WO2012023597, Bioorganic & Medicinal Chemistry Letters,2012,20, 1271-. In general, there are three synthetic routes, as shown in the following scheme:
Route 1：
Route 2：
Route 3：
the three synthetic routes described above all have several disadvantages: the high cost, expensive reagents and/or catalysts and inconvenient operating conditions inherent to long reaction sequences.
Therefore, there is still much room for improvement in this process, and there is a need to develop an efficient, simple, and industrially feasible synthetic route to overcome the disadvantages of the prior art.
In order to overcome the problems associated with the prior art, the present invention describes a new and improved process which provides eritinib, or a pharmaceutically acceptable salt thereof, in higher yields using cheaper and less toxic reagents.
Definition of
The following definitions apply to definitions relating to the present application, unless otherwise indicated.
The term "room temperature" means a temperature of between 15 ℃ and 35 ℃, preferably a temperature of between 20 ℃ and 30 ℃, more preferably a temperature of 25 ℃.
The term "pharmaceutically acceptable salts" includes salts with inorganic acids, such as hydrochloric acid, hydroiodic acid, phosphoric acid, phosphonic acid, sulfuric acid, hydrobromic acid, or organic acids; organic acids, for example formic acid, acetic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, salicylic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, benzoic acid or sulfonic acids, such as p-toluenesulfonic acid or methanesulfonic acid.
The term "alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 12 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "aryl" refers to a monocyclic or polycyclic ring system in which one or more of the fused rings is aromatic. Typical examples of aryl groups include, but are not limited to, anthracenyl, fluorenyl, indenyl, naphthyl, and phenyl.
Abbreviations
TEA: trimethylamine;
DBU: 1, 8-diazabicycloundec-7-ene;
DIPEA: diisopropylethylamine
And (3) Acac: acetylacetone
DCE: 1, 2-dichloroethane
Disclosure of Invention
In one aspect, the invention provides a method of preparing eritinib of formula I or a pharmaceutically acceptable salt thereof,
the method is characterized by comprising the following steps:
(a) reacting a compound of formula II with 4- (4-piperidinyl) morpholine in the presence of a base, a copper catalyst and a ligand to form a compound of formula III,
wherein X is selected from Cl, Br, I, OSO2Ar and OSO2CF3；R1Is any alkyl, preferably CH, CH2CH3Or C (CH)3)3；
(b) By CH3CH2Reacting Y with a compound of formula III in the presence of a catalyst to form a compound of formula IV,
wherein Y is selected from Cl, Br and I;
(C) hydrolysis of the compound of formula IV to the corresponding carboxylic acid, followed by SOCl2、PCl5Or POCl3It is converted into a compound of formula V.
(d) Reacting 6-cyanoindole with a compound of formula V in the presence of a catalyst to form a compound of formula VI,
(e) in the presence of a dehydrating reagent and a catalyst of the formulaVI compound reacts with acetone to generate eritinib, wherein the dehydrating reagent is selected from MgCl2、AlCl3，CaCl2、
Molecular sieves and silica gel; the catalyst is selected from salts and/or complexes of chromium and cobalt.
The above procedure is preferably carried out by isolating all the intermediate compounds, i.e. the intermediates of formulae III, IV, V and VI. It is also preferred to carry out this process without isolation of intermediates of formulae III, IV, V and VI. More preferably, the above process is carried out as a one-pot reaction, i.e. the synthesis of eritinib or a pharmaceutically acceptable salt thereof, preferably the hydrochloride salt, is accomplished directly without isolation of any intermediate product of formulae iii, iv, v and vi.
The invention relates to a new and alternative synthesis method for synthesizing the eritinib shown in the formula I. The synthetic methods described herein provide for the preparation of eritinib by reducing production time and cost, and increasing cost effectiveness.
This process provides an economical process for the low cost production of eritinib. In order to achieve a strategy based on cheap, readily available chemical raw materials, step economy and overall high efficiency, the present invention relies on new reactions to be established in each synthetic step.
In a first aspect, the following scheme outlines the synthetic method described above:
in the presence of a base, a copper catalyst and a ligandThe compound of formula II is coupled with 4- (4-piperidinyl) morpholine to form a compound of formula III. Wherein X is selected from Cl, Br, I, OSO2Ar and OSO2CF3； R1Is any alkyl, preferably CH, CH2CH3Or C (CH)3)3。
The first step is a copper-catalyzed C-N coupling, the base can be any organic or inorganic base, such as TEA, DB, DIPEA, KOH, K2CO3、NaOH、Na2CO3、Cs2CO3、CsOH， K3PO4，k2HPO4、Na3PO4And Na2HPO4. Examples of copper catalysts include CuI, CuCl, CuBr, Cu2O、Cu(acac)2、CuCl2、CuBr2、CuI2、Cu(OAc)2、Cu(OTf)2、 Cu(ClO4)2And CuSO4. The ligand is selected from the group consisting of compounds of formula VII,
wherein R is2Selected from any alkyl group, substituted/unsubstituted aryl group. R2Preferably selected from methyl, ethyl, propyl, isopropyl, t-butyl and substituted/unsubstituted anthracenyl, fluorenyl, indanyl, indenyl, naphthyl and phenyl. Some examples of formula VII are as follows (L1-L10):
the present invention utilizes for the first time the compound of formula VII in the coupling reaction of C-N bonds. The compound of formula VII is convenient to prepare, shows excellent selectivity and reaction efficiency in the coupling reaction of C-N bond, and is suitable for a wide range of substrates with different substituents.
The compound of formula VII can be prepared by reacting aldehyde, oxalyl hydrazine and ammonium acetate, and the reaction scheme is as follows:
the second step in the synthesis of eritinib is represented by formula III and CH3CH2Y is alkylated by Friedel-Crafts in the presence of a catalyst to form the compound of formula IV. Wherein Y is selected from Cl, Br and I, and the catalyst for Friedel-Crafts is selected from Lewis acids, such as AlCl3、BeCl2、CdCl2、 BF3、BBr3、GaCl3、AlBr3、FeCl3、TiCl4、SnCl4、SbCl5Lanthanide trihalides and alkylaluminum halides (AlRX)2)。
Next, the ester group of the compound of formula IV is hydrolyzed to a carboxylic acid, which is then reacted with SOCl2、 PCl5Or POCl3The reaction is converted to the compound of formula V.
Treatment of a compound of formula V with a 6-cyanoindole in the presence of a catalyst produces a compound of formula VI, which is typically a Friedel-Crafts acylation reaction. The catalyst for Friedel-Crafts acylation is selected from Lewis acids such as AlCl3、AlBr3Lanthanide trifluorides, zeolites, protic acids (e.g. H)2SO4、H3PO4)、FeCl3，ZnCl2And polyphosphoric acid.
The final step of the synthesis is the cyclization of a compound of formula VI with acetone in the presence of a dehydrating agent selected from MgCl and a catalyst to form eritinib2、AlCl3、CaCl2、
Molecular sieves and silica gel; the catalyst is selected from salts and/or complexes of chromium and cobalt, such as CrCl3， CrF3，CrBr3，Cr(NO3)3，CoCl3，CoF3，CoBr3、Co(NO3)3。
As shown in the scheme below, an example synthesis of eritinib starts from the coupling of methyl 4-bromobenzoate (II-1) and 4- (4-piperidinyl) morpholine. The resulting compound of formula iii is alkylated with ethyl bromide to form the compound of formula iv, which is converted to the compound of formula v by hydrolysis and chlorination. Friedel-Crafts acylation of compounds of formula V with 6-cyanoindoles provides compounds of formula VI. Finally, the compound of formula vi cyclizes with acetone in the presence of a dehydrating reagent and a catalyst to form eritinib.
Detailed Description
The following examples provide detailed experimental methods and parameters suitable for preparing eritinib, or a pharmaceutically acceptable salt thereof, according to the present invention, which experiments are intended to be illustrative and not limiting.
Unless otherwise indicated, all materials, solvents and reagents, including anhydrous solvents such as DMF and DCM, were best grade obtained from commercial suppliers without further purification. All reactions involving air or moisture sensitive compounds were carried out under nitrogen or argon atmosphere unless otherwise stated.
1H (400MHz) and13c NMR (100MHz) data Using CDCl3Or DMSO-D6Obtained as solvent on Bruker AVANCE II 400 MHz. Chemical shifts (. delta.) are in ppm and coupling constants (J) are in Hz.1H NMR spectra were recorded with tetramethylsilane (δ ═ 0.00ppm) as internal reference;13CDCl for C NMR spectrum3(delta 77.00 pp pm) or DMSO-D6(δ 39.5ppm) was recorded as an internal reference.
Synthesis of L1:
to a solution of cyclohexanal (11.2g,100mmol), oxalyl hydrazine (6.5g, 55mmol) and ammonia acetate (8.5g, 110mmol) in methanol (200mL) was added iodine (2.5g, 10 mmol). The reaction mixture was refluxed for 20h and then filtered. The resulting solid was washed three times with methanol (50mL) and diethyl ether (50mL) and then dried under vacuum to give the desired L1 as a yellow solid. Yield: 12g and 80 percent.1H NMR(400MHz,CDCl3)δ11.12(brs,2H),2.69-2.75(m,2H), 1.61-1.86(m,8H),1.33-1.63(m,12H)。13C NMR(100MHz,CDCl3) δ 163.5,159.3,39.5,33.0,26.1, 26.4. Calculation of C by ESI-TOF-HRMS16H24N6Na (M + Na)323.1960 molecular weight, found 323.1924.
Synthesis of L6: .
To a solution of benzaldehyde (10.6g, 100mmol), oxalyl hydrazine (6.5g, 55mmol) and ammonium acetate (8.5g, 110mmol) in methanol (200mL) was added iodine (2.5g, 10 mmol). The reaction mixture was refluxed for 18h and filtered. The resulting solid was washed three times with methanol (50mL) and diethyl ether (50mL) and then dried under vacuum to give the desired L6 as a yellow solid. Yield: 11 g, 77%.1H NMR(400MHz,CDCl3)δ11.12(brs,2H)，85-89(m，4h)， 7.43-7.51(m，6h)。13C NMR(100MHz,CDCl3) δ 163.5,157.6,132.5,131.1,129.2,127.5. Calculation of C by ESI-TOF-HRMS16H12N6Na (M + Na)311.1021 molecular weight, found 311.1003.
Synthesis of L7: .
To a solution of 2,4, 6-trimethylbenzaldehyde (14.8g, 100mmol), oxalyl hydrazine (6.5g, 55mmol) and ammonia acetate (8.5g, 110mmol) in methanol (200mL) was added iodine (2.5g, 10 mmol). The reaction mixture was refluxed for 24h and filtered. The resulting solid was washed three times with methanol (50mL) and diethyl ether (50mL) and then dried under vacuum to give the desired L7 as a yellow solid. Yield: 12g, 65 percent.1H NMR(400MHz,CDCl3)δ11.12(brs,2H),7.01 (s,4H),2.57(s,12H),2.48(s,6H)。13C NMR(100MHz,CDCl3) δ 163.5,157.6,138.2,136.1,128.2,122.5,21.9, 19.3. Calculation of C by ESI-TOF-HRMS22H24N6Na (M + Na)395.1960 molecular weight, found 395.1932.
Synthesis of Compounds of formula III-1 with L1
To methyl 4-bromobenzoate (21.5g, 100mmol), 4- (piperidin-4-yl) morpholine (18.7g, 110mmol) and K3PO4To a solution of (23.3g,110mmol) in DMF (100mL) was added CuI (1.9g, 10mmol) and L1(3g, 10 mmol). The reaction mixture was stirred at 100 ℃ for 10h, then extracted with ethyl acetate (300mL) and water (100 mL). The organic mixture was over MgSO4Drying, vacuum filtering, concentrating to obtain crude product, and purifying by flash column chromatography (n-hexane/ethyl acetate 5/1 eluate). The target compound of formula III-1 was obtained as a colorless oil. Yield: 22 g, 73 percent.1H NMR(400MHz,CDCl3)δ7.84(d,J＝7.5Hz,2H),6.93(d, J＝7.5Hz,2H),3.89(s,3H),3.57(t,J＝7.1Hz,4H),3.03-3.16 (m,4H),2.59-2.64(m,1H),2.48(t,J＝7.1Hz,4H),1.65-1.73 (m,2H),1.40-1.47(m,2H).13C NMR(100MHz,CDCl3) Delta 165.9, 153.9,130.8,123.1,111.7,70.4,67.0,52.1,52.0,51.5,28.1 ESI-TOF-HRMS calculation of C17H24N2NaO3(M + Na)327.1685 molecular weight, found 327.1648.
Synthesis of a Compound of formula III-1 with L6:
to methyl 4-bromobenzoate (21.5g, 100mmol), 4- (piperidin-4-yl) morpholine (18.7g, 110mmol) and K3CO3(15.2g,110mmol) in DMSO (100mL) Cu (OTF) was added2(3.6g, 10mmol) and L6(2.9g, 10 mmol). The reaction mixture was stirred at 100 ℃ for 12h, then extracted with ethyl acetate (300mL) and water (100 mL). Organic mixture in MgSO4Drying, vacuum filtering, concentrating to obtain crude product, and purifying by flash column chromatography (n-hexane/ethyl acetate 5/1 eluate). The target compound of formula III-1 was obtained as a colorless oil. Yield: 23 g, 77%.
Synthesis of a Compound of formula III-1 with L7: .
To methyl 4-bromobenzoate (21.5g, 100mmol), 4- (piperidin-4-yl) morpholine (18.7g, 110mmol) and Cs2CO3(35.8g,110mmol) of CH3Adding Cu (acac) into CN (100mL)2(2.6g, 10mmol) and L7(3.7g, 10 mmol). The reaction mixture was stirred at 100 ℃ for 12h, then extracted with ethyl acetate (300mL) and water (100 mL). The organic mixture was over MgSO4Drying, vacuum filtering, concentrating to obtain crude product, and purifying by flash column chromatography (n-hexane/ethyl acetate 5/1 eluate). The target compound of formula III-1 was obtained as a colorless oil. Yield: 24 g, 80 percent.
Synthesis of compounds of formula iv:
stirring a mixture of formula III-1 (15g, 50mmol) and bromoethane (5.9g, 55mmol) and adding AlCl3(13g, 100 mmol). The reaction mixture was stirred at 120 ℃ for 5h and then cooled to room temperature. DCM (200mL) was then added and the resulting mixture stirred for a further 1h before ice (200g) was added. The mixture was partitioned between DCM and water. The organic mixture was over MgSO4Drying, vacuum filtering, concentrating to obtain crude product, and purifying by flash column chromatography (n-hexane/ethyl acetate 6/1 eluate). The target compound of formula iv was obtained as a colorless oil. Yield: 12g and 72 percent.1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.50(d,J＝7.5Hz,1H), 6.84(d,J＝7.5Hz,1H),3.89(s,3H),3.57(t,J＝7.1Hz,4H), 3.03-3.16(m,4H),2.56-2.64(m,3H),2.48(t,J＝7.1Hz,4H), 1.65-1.73(m,2H),1.40-1.47(m,2H),1.12(t,J＝8.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 165.9,150.3,129.8,128.0,123.5, 119.5,108.7,70.4,67.0,52.4,52.0,51.5,28.1,23.7, 14.5. Calculation of C by ESI-TOF-HRMS19H28N2NaO3(M + Na)355.1998 molecular weight, found 355.1974.
Synthesis of compounds of formula v.
Stirring CH of formula IV (6.6g, 20mmol)3CN (50mL) and water (50mL), LiOH (0.5g, 22mmol) was added. The reaction mixture was refluxed for 8h and cooled to room temperature. The resulting mixture was concentrated on a rotary evaporator to a volume of 60 mL. THF (80mL) was then added slowly to the crude reaction to give a white precipitate, which was filtered, washed with methanol (3X 30mL), and dried in vacuo. The resulting white solid was then dissolved in DCM (100mL), cooled to 0 deg.C, and SOCl was slowly added to the reaction mixture2(2.6g, 22 mmol). The reaction mixture was allowed to stand at room temperature for more than 1h and then stirred at room temperature for 4 h. All volatiles were then removed under vacuum to give the crude product of formula v, which was used directly in the next step without purification.
Synthesis of a compound of formula vi:
the crude product of formula V from the previous step was dissolved in DCE (100mL), 6-cyanoindole (2.8g, 20mmol) was added followed by AlCl3(5.2g, 40 mmol). The reaction mixture was refluxed for 10h and cooled to room temperature and ice (100g) was added. The mixture was partitioned between DCM and water. The organic mixture was over MgSO4Drying, vacuum filtering, concentrating to obtain crude product, and purifying by flash column chromatography (n-hexane/ethyl acetate 4/1 eluate). The target compound of the formula VI is obtained as a yellow solid. Yield: 5.2g, 59% (based on compound IV).1H NMR(400MHz,CDCl3)δ 11.69(s,1H),8.71(s,1H),8.11(d,J＝7.5Hz,1H),7.78(s, 1H),7.58(s,1H),7.53(d,J＝7.5Hz,1H),7.36(d,J＝7.5Hz, 1H),6.92(d,J＝7.5Hz,1H),3.57(t,J＝7.1Hz,4H),3.03-3.16 (m,4H),2.56-2.64(m,3H),2.48(t,J＝7.1Hz,4H),1.65-1.73 (m,2H),1.40-1.47(m,2H),1.12(t,J＝8.0Hz,3H)。13C NMR (100MHz,CDCl3) δ 196.3,149.3,136.2,130.6129.5,127.8, 125.9,125.2,124.5,123.7,123.4,119.5,118.6,114.3,108.5, 99.5,70.4,67.0,52.4,52.0,51.5,28.1,23.7, 14.5. Calculation of C by ESI-TOF-HRMS27H30N4NaO2(M + Na)465.2266 molecular weight, found 465.2234.
Using AlCl3And CoCl3Synthesizing the eritinib:
stirring a mixture of formula VI (4.4g, 10mmol) and acetone (20mL), adding AlCl3(2.6g, 20mmol) and CoCl3(0.33g, 2 mmol). The stirred mixture was sealed and kept at 100 ℃ for 4h, then cooled to room temperature. DCM (100mL) was then added and the resulting mixture stirred for an additional 0.5h before ice (50g) was added. The mixture was partitioned between DCM and water. The organic mixture was over MgSO4Dried and concentrated by vacuum filtration to give the crude product which is recrystallized from hot MeOH (50 mL). The pure product was a non-white solid. Yield: 3.2 g, 67%.
1H NMR(400MHz,DMSO)δ12.46(s,1H),8.21(d,J＝8.2Hz, 1H),8.05(d,J＝2.5Hz,1H),7.78(d,J＝2.0Hz,1H),7.53 (dd,J＝8.1,1.8Hz,1H),7.32(s,1H),3.92(s,4H),3.42(b, 4H),3.19(b,1H),2.98(m,J＝10.9Hz,4H),2.72(q,J＝7.6 Hz,2H),1.82(s,4H),1.69(d,J＝45.9Hz,6H),1.24(t,J＝ 7.6Hz,3H)。13C NMR (100MHz, DMSO) δ 179.73,150.81,150.01, 146.65,142.65,136.73,132..31,131.85,127.16,124.91, 122.10,120.50,116.91,11.89,105.11,100.10,76.81,72.41, 66.81, 66.41,36.65,30.47,28.22,27.92, 15.92; calculation of C by ESI-TOF-HRMS30H35N4O2(M + H)483.2755 molecular weight, found 483.2728.
With MgCl2And CrCl3Synthesizing the eritinib:
stirring a mixture of formula VI (4.4g, 10mmol) and acetone (20mL), adding MgCl2(1.9g, 20mmol) and CrCl3(0.32g, 2 mmol). The stirred mixture was sealed and kept at 100 ℃ for 4h, then cooled to room temperature. DCM (100mL) was then added and the resulting mixture stirred for an additional 0.5h before ice (50g) was added. The mixture was partitioned between DCM and water. The organic mixture was over MgSO4Dried and concentrated by vacuum filtration to give the crude product which is recrystallized from hot MeOH (50 mL). The pure product was a non-white solid. Yield: 3.0 g, 63%.
By using
Molecular sieves and Co (NO)3)3Synthesizing the eritinib:
a mixture of formula VI (4.4g, 10mmol) and acetone (20mL) was stirred and added
Molecular sieves (5g) and Co (NO)3)3(0.48g, 2 mmol). The stirred mixture was sealed and kept at 100 ℃ for 4h, then cooled to room temperature. DCM (100mL) was then added and the resulting mixture stirred for an additional 0.5h before ice (50g) was added. The mixture was partitioned between DCM and water. The organic mixture was over MgSO4Dried and concentrated by vacuum filtration to give the crude product which is recrystallized from hot MeOH (50 mL). The pure product was a non-white solid. Yield: 3.3g, 69%.
Claims (11)
1. A method for preparing eritinib of formula I or a pharmaceutically acceptable salt thereof,
the method is characterized by comprising the following steps:
(a) reacting a compound of formula II with 4- (4-piperidinyl) morpholine in the presence of a base, a copper catalyst and a ligand to form a compound of formula III,
wherein X is selected from Cl, Br, I, OSO2Ar and OSO2CF3Wherein Ar is selected from the group consisting of anthracenyl, fluorenyl, indenyl, naphthyl, and phenyl; r1Is a C1-12 alkyl group,
the ligand is selected from the group consisting of compounds of formula VII,
wherein R is2Selected from C1-12 alkyl, anthracenyl, fluorenyl, indenyl, naphthyl, and phenyl;
(b) by CH3CH2Reacting Y with a compound of formula III in the presence of a Lewis acid catalyst to form a compound of formula IV,
wherein Y is selected from Cl, Br and I;
(c) hydrolysis of the compound of formula IV to the corresponding carboxylic acid, followed by SOCl2、PCl5Or POCl3It is converted into a compound of the formula V,
(d) reacting 6-cyanoindole with a compound of formula V in the presence of a Lewis acid or protonic acid catalyst to form a compound of formula VI,
(e) reacting a compound of formula VI with acetone in the presence of a dehydrating agent selected from MgCl and a catalyst to form eritinib2、AlCl3、CaCl24 Å molecular sieves and silica gel; the catalyst is selected from salts of chromium and cobalt.
2. The method of claim 1, wherein R is1Is selected from CH3、CH2CH3Or C (CH)3)3。
3. The method of claim 1, wherein R is2The C1-12 alkyl group of (B) is selected from methyl, ethyl, propyl, isopropyl or tert-butyl.
4. The process of claim 1 wherein the intermediates of formulae iii, iv, v and vi are isolated at each step and subjected to the next step.
5. A process according to claim 3, wherein the ligand compound of formula vii is selected from one or more of the following compounds:
6. the method of claim 1, wherein the base of step (a) is selected from the group consisting of: TEA, DBU, DIPEA, KOH, K2CO3、NaOH、Na2CO3、Cs2CO3、CsOH、K3PO4、K2HPO4、Na3PO4And Na2HPO4。
7. The method of claim 1, wherein the copper catalyst of step (a) is selected from the group consisting of CuI, CuCl, CuBr, Cu2O、Cu(acac)2、CuCl2、CuBr2、CuI2、Cu(OAc)2、Cu(OTf)2、Cu(ClO4)2And CuSO4。
8. The process of claim 1, wherein the catalyst of step (b) is selected from the group consisting of AlCl3、BeCl2、CdCl2、BF3、BBr3、GaCl3、AlBr3、FeCl3、TiCl4、SnCl4、SbCl5Lanthanide trihalides and alkylaluminum halides.
9. The process of claim 1, wherein the catalyst of step (d) is selected from AlCl3、AlBr3Lanthanide-series trifluoride, zeolite, FeCl3，ZnCl2And polyphosphoric acid.
10. The process of claim 1, wherein the catalyst of step (e) is selected from CrCl3，CrF3，CrBr3，Cr(NO3)3，CoCl3，CoF3，CoBr3、Co(NO3)3。
11. A process as claimed in any one of claims 1 to 5, wherein the ligand compound of formula VII is prepared by reacting a substituted aldehyde, oxalyl hydrazine and ammonia acetate:
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