CN107011245A - A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate - Google Patents
A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate Download PDFInfo
- Publication number
- CN107011245A CN107011245A CN201710263664.0A CN201710263664A CN107011245A CN 107011245 A CN107011245 A CN 107011245A CN 201710263664 A CN201710263664 A CN 201710263664A CN 107011245 A CN107011245 A CN 107011245A
- Authority
- CN
- China
- Prior art keywords
- dihydro
- naphthalenones
- reaction
- ethyl
- ethyls
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 80
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 239000004327 boric acid Substances 0.000 claims abstract description 10
- -1 methoxyl group Chemical group 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 238000005885 boration reaction Methods 0.000 claims abstract description 9
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 9
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims abstract description 8
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims abstract description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims abstract description 7
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000007069 methylation reaction Methods 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052794 bromium Inorganic materials 0.000 claims abstract 2
- WQWUQDVFRYMMCY-UHFFFAOYSA-N naphthalen-1-yl trifluoromethanesulfonate Chemical compound C1=CC=C2C(OS(=O)(=O)C(F)(F)F)=CC=CC2=C1 WQWUQDVFRYMMCY-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000002585 base Substances 0.000 claims description 43
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- QNQQMXASEGQADC-UHFFFAOYSA-N 6-ethyl-7-hydroxy-3,4-dihydro-1H-naphthalen-2-one Chemical class C(C)C=1C=C2CCC(CC2=CC=1O)=O QNQQMXASEGQADC-UHFFFAOYSA-N 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 5
- 229940113088 dimethylacetamide Drugs 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000003863 metallic catalyst Substances 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 150000002780 morpholines Chemical class 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- VORLTHPZWVELIX-UHFFFAOYSA-N 1-methyl-2h-quinoline Chemical compound C1=CC=C2N(C)CC=CC2=C1 VORLTHPZWVELIX-UHFFFAOYSA-N 0.000 claims 1
- 239000011260 aqueous acid Substances 0.000 claims 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 150000003053 piperidines Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- RZPFVRFSYMUDJO-UHFFFAOYSA-N 2h-naphthalen-1-one Chemical compound C1=CC=C2C(=O)CC=CC2=C1 RZPFVRFSYMUDJO-UHFFFAOYSA-N 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- YYBXNWIRMJXEQJ-UHFFFAOYSA-N 4-piperidin-4-ylmorpholine Chemical class C1CNCCC1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 abstract 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000000376 reactant Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 238000002390 rotary evaporation Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 230000000977 initiatory effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- FOIXQDWOJWQMEF-UHFFFAOYSA-N 1h-indole;phenylhydrazine Chemical compound NNC1=CC=CC=C1.C1=CC=C2NC=CC2=C1 FOIXQDWOJWQMEF-UHFFFAOYSA-N 0.000 description 1
- WZCKOKPKQZIGNU-UHFFFAOYSA-N 1h-naphthalen-2-one Chemical class C1=CC=C2C=CC(=O)CC2=C1 WZCKOKPKQZIGNU-UHFFFAOYSA-N 0.000 description 1
- NGGGZUAEOKRHMA-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoic acid Chemical compound CC(C)(C)OC(=O)CC(O)=O NGGGZUAEOKRHMA-UHFFFAOYSA-N 0.000 description 1
- APYLNYCULQUSLG-UHFFFAOYSA-N 9h-carbazole-3-carbonitrile Chemical compound C1=CC=C2C3=CC(C#N)=CC=C3NC2=C1 APYLNYCULQUSLG-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241000255964 Pieridae Species 0.000 description 1
- AGZVMFHCESVRRI-UHFFFAOYSA-N [Na].CC(C)O Chemical compound [Na].CC(C)O AGZVMFHCESVRRI-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ZTRPYTHOEREHEN-UHFFFAOYSA-N piperazine pyridine Chemical compound N1CCNCC1.N1=CC=CC=C1.N1=CC=CC=C1 ZTRPYTHOEREHEN-UHFFFAOYSA-N 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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Abstract
The invention discloses the preparation method that a kind of Ai Le replaces the naphthalenone of 1,1 dimethyl of Buddhist nun's intermediate 6 ethyl 7 [4 (base of morpholine 4) piperidinyl-1 base] 3,4 dihydro 2.The naphthalenone of 6 bromine, 73,4 dihydro of methoxyl group 2 is successively carried out boration reaction by this method with n-BuLi and organoboron reagent, and the obtained boric acid of 73,4 dihydro of methoxyl group, 2 naphthalenone 6 and bromoethane are carried out into catalyzed coupling reaction；Reaction is hydrolyzed in the obtained naphthalenone of 6 ethyl, 7 methoxyl group, 3,4 dihydro 2 in hydrobromic acid aqueous solution；The obtained naphthalenone of 6 ethyl, 7 hydroxyl, 3,4 dihydro 2 and trifluoromethyl sulfonic acid anhydride are subjected to triflated reaction；By 6 obtained ethyls 1,2,3, the naphthyl triflate of 4 tetrahydrochysene, 2 oxo 7 carries out substitution reaction with 4 (4 piperidyl) morpholines, by obtained [4 (base of morpholine 4) piperidinyl-1 base] 3 of 6 ethyl 7, the naphthalenone of 4 dihydro 2 carries out double methylation reactions with iodomethane, obtains Ai Le for Buddhist nun's intermediate.This method operation simplifies, and cost is relatively low, is a kind of environmental protection process, it is adaptable to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of Ai Le replaces the preparation method of Buddhist nun's intermediate.
Background technology
New anaplastic lymphoma kinase (ALK) inhibitor Ai Le replaces chemical entitled 9- ethyl -6 of Buddhist nun (Alectinib),
6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs,
Its chemical structural formula is：
Ai Le is the original new drug of the branch company ChugaiPharmaceutical inventions of company of Roche Group for Buddhist nun,
The breakthrough medicine recognition of qulifications of U.S. FDA is obtained, accelerates examination ＆ approval as oral anti-lung cancer new drug, for treating ALK bases
Because of late period (metastatic) non-small cell lung cancer (NSCLC) of mutation, or to (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine be resistant to patient treatment.
It is a kind of disclosed in patent US20130143877 and WO2012023597A1 to prepare the synthetic route that Ai Le replaces Buddhist nun：With
7- methoxyl group -3,4- dihydro -2- naphthalenones are initiation material, are methylated and bromination reaction by double, then with the Fischer of phenylhydrazine
Indole synthesis carry out ring-closure reaction, are then passed through oxidation and introduce 11- carbonyls, then the hydroxyl obtained by methoxy hydrolysis is carried out
It is triflated, it is condensed with 4- (4- piperidyls) morpholine, last 9- bromos are replaced by acetenyl, then are obtained through reduction reaction
Ai Le replaces Buddhist nun, and process route is as follows：
Because whole synthetic route step is longer, cumbersome, cost is higher, is unfavorable for amplification production and industrialization is pushed away
Extensively.
Ai Le disclosed in patent US20120083488 replaces the synthetic route of Buddhist nun, with iodo- 4 second of mono-tert-butyl malonate and 3-
Base tert-butyl benzene is initiation material, and by condensation, cyclization, the condensation with 4- (4- piperidyls) morpholine, last cyclization obtains Ai Le
For Buddhist nun, process route is as follows：
Ai Le disclosed in patent CN104402862A is as follows for the synthetic route of Buddhist nun, wherein needing to use indoles parent nucleus
Compound is used as starting raw material：
The above two is combined into the initiation material of route costly, is difficult to obtain, thus needs synthetically prepared；Due to two
The midbody product and final products for being combined into route are impure more with accessory substance, thus purifying needs to use a large amount of solvents,
Cumbersome, yield is relatively low, is unfavorable for industrialization production popularization, it is therefore necessary to explore that technological process is short, simple to operate, cost
Ai Le that is cheap and using suitable industrialized production replaces the synthetic method of Buddhist nun.
For the deficiencies in the prior art and defect, the applicant it is proposed that excessively a patent application, the patent Shen
The synthetic method (application number 201610206224.7) that a kind of Ai Le replaces Buddhist nun please be disclose, the key intermediate being directed to is 1,
1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, its technological process is short, operation
Simply, with low cost and use suitable industrialized production, disclosed synthetic route is：
The content of the invention
It is an object of the invention to provide the preparation method that a kind of Ai Le replaces Buddhist nun's intermediate.The Ai Le replaces the change of Buddhist nun's intermediate
Scientific name is referred to as 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, chemical constitution
Shown in formula such as formula (I)：
To achieve these goals, the technical solution adopted by the present invention is：
The Ai Le comprises the following steps for the preparation method of Buddhist nun's intermediate：
(1) 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones are prepared：By the bromo- 7- methoxyl groups -3,4- dihydros -2- naphthalenes of 6-
Ketone first reacts in the solvent reacted for boration with n-BuLi, then carries out boration reaction with organoboron reagent, obtains
To 7- methoxyl group -3,4- dihydro -2- naphthalenone -6- boric acid, then by 7- methoxyl groups -3,4- dihydro -2- naphthalenone -6- boric acid and bromoethane
Catalyzed coupling reaction is carried out in the system that metallic catalyst, inorganic salts, the solvent for catalyzed coupling reaction and water are constituted, is obtained
To 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones, reaction equation is：
(2) 6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones are prepared：By 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenes
Reaction is hydrolyzed in ketone in hydrobromic acid aqueous solution, obtains 6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones, and reaction equation is：
(3) 6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates are prepared：By 6- ethyl -7- hydroxyls -
3,4- dihydro -2- naphthalenones carry out triflated reaction with trifluoromethyl sulfonic acid anhydride in acid binding agent alkali systems, obtain 6-
Ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates, reaction equation is：
(4) 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones are prepared：By 6- ethyl -1,
2,3,4- tetrahydrochysenes -2- oxos -7- naphthyls triflate is constituted with 4- (4- piperidyls) morpholines in acid binding agent alkali and solvent
Substitution reaction is carried out in system, 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones are obtained, reacted
Formula is：
(5) 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones are prepared：
6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones and iodomethane are constituted in base reagent and solvent
System in carry out double methylation reactions, obtain 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,
4- dihydro -2- naphthalenones, reaction equation is：
Preferably, the solvent for being used for boration reaction described in step (1) is DMF, N, N- dimethyl
Acetamide, tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Institute
The organoboron reagent stated is connection boric acid pinacol ester, trimethylborate, triethyl borate or triisopropyl borate ester；Described metal
Catalyst is four (triphenyl phosphorus) palladiums, [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride or two (triphenylphosphine) dichloros
Change palladium；Described inorganic salts be potassium carbonate, sodium carbonate, potassium phosphate, lithium chloride, sodium bromide, KBr, potassium acetate, KI or
Potassium chloride；The described solvent for catalyzed coupling reaction is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrochysene furan
Mutter, toluene, dichloromethane, 1,2- dichloroethanes, chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Wherein, the bromo- 7- first of 6-
Mol ratio between epoxide -3,4- dihydro -2- naphthalenones, n-BuLi, organoboron reagent, bromoethane, metallic catalyst, inorganic salts
For 1.0: (1.1~1.3): (1.25~1.75): (0.9~1.1): (0.045~0.075): (1.45~2.00), for boric acid
Change reaction solvent, the solvent for catalyzed coupling reaction, water for reaction medium, be not involved in reaction, be not required to limit its with it is anti-
Answer the molar ratio of thing and reagent.
Preferably, the mass percent concentration of step (2) described hydrobromic acid aqueous solution is 48%, wherein, 6- ethyl -7- first
The mol ratio of epoxide -3,4- dihydro -2- naphthalenones and hydrobromic acid aqueous solution is 1.0: (5.0~15.0).
Preferably, the acid binding agent alkali described in step (3) is triethylamine, diethylamine, DIPEA, pyridine, piperazine
Pyridine, 2,6- lutidines or N-methylmorpholine；Wherein, 6- ethyls -7- hydroxyls -3,4- dihydro -2- naphthalenones, trifluoromethane sulfonic acid
Mol ratio between acid anhydride, acid binding agent alkali is 1.0: (1.2~1.5): (1.5~2.5).
Preferably, the acid binding agent alkali described in step (4) is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide or isopropanol
Sodium；Described solvent is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, toluene or 1,4- dioxane；Wherein, 6- second
Mole between base -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyls triflate, 4- (4- piperidyls) morpholine, acid binding agent alkali
Than for 1.0: (1.8~2.7): (2.0~3.0), solvent for reaction medium, be not involved in reaction, be not required to limit itself and reactant
With the molar ratio of reagent.
Preferably, the base reagent described in step (5) is sodium methoxide, caustic alcohol, sodium tert-butoxide or sodium isopropylate；Described is molten
Agent is methanol, ethanol, the tert-butyl alcohol or isopropanol；Wherein, 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydros -
Mol ratio between 2- naphthalenones, iodomethane, base reagent is 1.0: (1.8~3.0): (1.8~3.0), solvent for reaction medium,
Reaction is not involved in, is not required to limit itself and reactant and the molar ratio of reagent.
Preferably, the temperature of the boration reaction described in step (1) is -78 DEG C, and then 20~25 DEG C, the reaction time is 1
~3 hours；The temperature of described catalyzed coupling reaction is 90~120 DEG C, and the reaction time is 12~24 hours；Step (2) is described
Described hydrolysis temperature be 95~105 DEG C, the reaction time be 20~30 hours；Fluoroform sulphur described in step (3)
The temperature of Esterification reaction is -5~25 DEG C, and the reaction time is 0.5~3 hour；The temperature of substitution reaction described in step (4) is
90~110 DEG C, the reaction time is 6~18 hours；The temperature of double methylation reactions described in step (5) is 60~80 DEG C, reaction
Time is 2~6 hours.
The technical scheme that the present invention is provided has following technique effect：First, only making after being completed due to the reaction of each step normal
The post processing and purifying of rule property are without column chromatography, and impurity is less, controllable, can directly carry out next step reaction, therefore
Operation is simplified, while each step can obtain higher yield；Second, the process route initiation material and used of the present invention
Reagent is easy to get, and the technical scheme of synthetic reaction rationally, can largely produce to meet the use demand of bulk drug, it is adaptable to industry
Metaplasia is produced；Third, due to pollutant will not be produced in preparation process, thus environmental protection effect can be embodied.
Embodiment
Technical scheme is further elaborated below in conjunction with specific embodiment, it is clear that protection of the invention
Scope is not limited to embodiment, and the other embodiment of the invention that those skilled in the art are done belongs to what the present invention was protected
Scope.
Embodiment 1
A 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones) are prepared：
The bromo- 7- methoxyl groups -3,4- dihydros -2- naphthalenones (10.0g, 39.2mmol) of 6- are dissolved in N,N-dimethylformamide
(40mL), is cooled to -78 DEG C, and n-BuLi (47.0mmol) THF solution (40mL), -78 DEG C of reactant mixture is slowly added dropwise
Stirring reaction 2 hours, is slowly added to connection boric acid pinacol ester (15.0g, 59.1mmol), -78 DEG C of stirring reactions of reactant mixture 1
Hour, 20 DEG C are risen to naturally and is stirred 10 hours, methanol (16mL) is slowly added to, and reaction solution concentrated by rotary evaporation obtains 7- methoxies to dry
Base -3,4- dihydro -2- naphthalenone -6- boric acid, add bromoethane (4.0g, 36.7mmol), four (triphenyl phosphorus) palladiums (2.2g,
1.9mmol), potassium carbonate (8.0g, 57.9mmol), DMF (40mL) and water (25mL), reactant mixture adds
Hot to 95 DEG C are reacted 14 hours, and TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, and concentrated by rotary evaporation adds acetic acid second to dry
Ester is extracted, and salt washing, magnesium sulfate is dried, and concentrated by rotary evaporation is to doing, and ethyl acetate and n-hexane mixed solvent are recrystallized, and obtain 6-
Ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones, off-white powder (6.4g), yield 80%.
B 6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones (3.0g, 14.7mmol) and the hydrogen of mass percent concentration 48%
The bromic acid aqueous solution (21.8g, 129.3mmol) is added in reaction bulb, and reactant mixture is added to 100 DEG C, return stirring reaction 24
Hour, TLC point plates determine that reaction is finished, and reaction solution is down to 0-5 DEG C, and it is 2 to be slowly added to 50% sodium hydroxide solution regulation pH value,
The crystallization 3h at 0-5 DEG C, filtering, filter cake is recrystallized with ethyl acetate and n-hexane mixed solvent, obtains 6- ethyl -7- hydroxyls
Base -3,4- dihydro -2- naphthalenones, off-white powder (2.7g), yield 97%.
C 6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates) are prepared：
6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones (2.5g, 13.1mmol) be dissolved in triethylamine (2.7g,
26.3mmol), it is slowly added dropwise trifluoromethyl sulfonic acid anhydride (4.8g, 17.0mmol), 20 DEG C of stirring reactions 2 hours, TLC points plate is determined
Reaction is finished, and by post-processing and purifying, obtains 6- ethyls -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates,
Light yellow solid (3.5g), yield 83%.
D 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyls triflates (3.5g, 10.9mmol) are dissolved in N, N-
Dimethylformamide (10mL), adds 4- (4- piperidyls) morpholine (3.7g, 21.7mmol), sodium methoxide (1.5g, 27.8mmol),
100 DEG C of reactant mixture stirring reaction 8 hours, TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, add water (4mL),
It is cooled to -10 DEG C of crystallizations 3 hours, filtering obtains 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenes
Ketone, white solid (3.4g), yield 91%.
E 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones (3.4g, 9.9mmol) are dissolved in first
Alcohol (10mL), is slowly added to sodium methoxide (1.1g, 20.4mmol), is cooled to -10 DEG C or so, be added dropwise iodomethane (2.8g,
19.7mmol), 65 DEG C of reactant mixture stirring reaction 4 hours, TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, add
Watery hydrochloric acid is adjusted to neutrality, and concentrated by rotary evaporation adds ethyl acetate extraction to dry, and magnesium sulfate is dried, concentrated by rotary evaporation to dry, methanol weight
Crystallization, obtains 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, off-white color is solid
Body (3.1g), yield 85%.
Embodiment 2
A 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones) are prepared：
Bromo- 7- methoxyl groups -3, the 4- dihydro -2- naphthalenones (10.0g, 39.2mmol) of 6- are dissolved in tetrahydrofuran (40mL), cooling
To -78 DEG C, n-BuLi (50.5mmol) THF solution (40mL), -78 DEG C of stirring reactions of reactant mixture 1.5 is slowly added dropwise
Hour, trimethylborate (6.8g, 65.4mmol) is slowly added to, -78 DEG C of stirring reactions of reactant mixture 1 hour rise to naturally
20 DEG C are stirred 10 hours, are slowly added to methanol (15mL), and reaction solution concentrated by rotary evaporation obtains 7- methoxyl group -3,4- dihydros -2- to dry
Naphthalenone -6- boric acid, adds bromoethane (4.5g, 41.3mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride
(2.0g, 2.9mmol), sodium carbonate (8.3g, 78.3mmol), DMF (45mL) and water (30mL), reaction are mixed
Compound is heated to 100 DEG C and reacted 24 hours, and TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, concentrated by rotary evaporation to dry, plus
Enter ethyl acetate extraction, salt washing, magnesium sulfate is dried, and concentrated by rotary evaporation is to doing, and ethyl acetate and n-hexane mixed solvent are weighed
Crystallization, obtains 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones, off-white powder (6.8g), yield 85%.
B 6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones (3.0g, 14.7mmol) and the hydrogen of mass percent concentration 48%
The bromic acid aqueous solution (33.7g, 199.9mmol) is added in reaction bulb, and reactant mixture is added to 105 DEG C, return stirring reaction 20
Hour, TLC point plates determine that reaction is finished, and reaction solution is down to 0-5 DEG C, and it is 2 to be slowly added to 50% sodium hydroxide solution regulation pH value,
The crystallization 4h at 0-5 DEG C, filtering, filter cake is recrystallized with ethyl acetate and n-hexane mixed solvent, obtains 6- ethyl -7- hydroxyls
Base -3,4- dihydro -2- naphthalenones, off-white powder (2.6g), yield 93%.
C 6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates) are prepared：
6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones (2.5g, 13.1mmol) are dissolved in N, N- diisopropylethylamine
(4.2g, 32.5mmol), is slowly added dropwise trifluoromethyl sulfonic acid anhydride (5.5g, 19.5mmol), 25 DEG C of stirring reactions 1 hour, TLC points
Plate determines that reaction is finished, and by post-processing and purifying, obtains 6- ethyls -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl fluoroform sulphurs
Acid esters, light yellow solid (3.6g), yield 85%.
D 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyls triflates (3.5g, 10.9mmol) are dissolved in toluene
(12mL), adds 4- (4- piperidyls) morpholine (5.0g, 29.4mmol), caustic alcohol (2.2g, 32.3mmol), reactant mixture
110 DEG C of stirring reactions 6 hours, TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, add water (5mL), are cooled to -10 DEG C
Crystallization 4 hours, filtering, obtains 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, white solid
(3.4g), yield 91%.
E 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones (3.4g, 9.9mmol) are dissolved in second
Alcohol (15mL), is slowly added to caustic alcohol (2.0g, 29.4mmol), is cooled to -10 DEG C or so, be added dropwise iodomethane (4.1g,
28.9mmol), 60 DEG C of reactant mixture stirring reaction 6 hours, TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, add
Watery hydrochloric acid is adjusted to neutrality, and concentrated by rotary evaporation adds ethyl acetate extraction to dry, and magnesium sulfate is dried, concentrated by rotary evaporation to dry, methanol weight
Crystallization, obtains 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, off-white color is solid
Body (3.0g), yield 82%.
Embodiment 3
A 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones) are prepared：
Bromo- 7- methoxyl groups -3, the 4- dihydro -2- naphthalenones (10.0g, 39.2mmol) of 6- are dissolved in toluene (50mL), are cooled to -78
DEG C, n-BuLi (43.3mmol) THF solution (40mL) is slowly added dropwise, -78 DEG C of stirring reactions of reactant mixture 1 hour are delayed
Slow to add triisopropyl borate ester (9.3g, 49.4mmol), -78 DEG C of stirring reactions of reactant mixture 1 hour rise to 20 DEG C and stirred naturally
Mix 12 hours, be slowly added to methanol (15mL), reaction solution concentrated by rotary evaporation to dry, obtain 7- methoxyl group -3,4- dihydro -2- naphthalenones -
6- boric acid, adds bromoethane (4.3g, 39.5mmol), two (triphenylphosphine) palladium chlorides (1.3g, 1.9mmol), lithium chloride
(2.5g, 59.0mmol), DMF (40mL) and water (30mL), it is small that reactant mixture is heated to 95 DEG C of reactions 14
When, TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, and concentrated by rotary evaporation adds ethyl acetate extraction, salt washing, sulphur to dry
Sour magnesium is dried, and concentrated by rotary evaporation is to doing, and ethyl acetate and n-hexane mixed solvent are recrystallized, and obtain 6- ethyl -7- methoxyl group -3,
4- dihydro -2- naphthalenones, off-white powder (6.8g), yield 85%.
B 6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones (3.0g, 14.7mmol) and the hydrogen of mass percent concentration 48%
The bromic acid aqueous solution (13.6g, 80.7mmol) is added in reaction bulb, and reactant mixture is added to 95 DEG C, and return stirring reaction 30 is small
When, TLC point plates determine that reaction is finished, and reaction solution is down to 0-5 DEG C, and it is 2-3 to be slowly added to 50% sodium hydroxide solution regulation pH value,
The crystallization 5h at 0-5 DEG C, filtering, filter cake is recrystallized with ethyl acetate and n-hexane mixed solvent, obtains 6- ethyl -7- hydroxyls
Base -3,4- dihydro -2- naphthalenones, off-white powder (2.5g), yield 89%.
C 6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates) are prepared：
6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones (2.5g, 13.1mmol) are dissolved in pyridine (1.6g, 20.2mmol),
It is slowly added dropwise trifluoromethyl sulfonic acid anhydride (4.5g, 16.0mmol), 0 DEG C of stirring reaction 3 hours, TLC point plates determine that reaction is finished, warp
Later handle and purify, obtain 6- ethyls -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates, light yellow solid
(3.5g), yield 83%.
D 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyls triflates (3.5g, 10.9mmol) are dissolved in 1,4-
Dioxane (15mL), adds 4- (4- piperidyls) morpholine (3.4g, 20.0mmol), sodium tert-butoxide (2.1g, 21.9mmol), instead
90 DEG C of mixture stirring reaction 18 hours is answered, TLC point plates determine that reaction is finished, reaction solution is down to room temperature, add water (5mL), it is cold
But to -10 DEG C of crystallizations 4 hours, filtering obtains 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones,
White solid (3.4g), yield 91%.
E 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones) are prepared：
6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones (3.4g, 9.9mmol) are dissolved in different
Propyl alcohol (15mL), is slowly added to sodium isopropylate (1.5g, 18.3mmol), is cooled to -10 DEG C or so, be added dropwise iodomethane (2.6g,
18.3mmol), 80 DEG C of reactant mixture stirring reaction 2 hours, TLC point plates determine that reaction is finished, and reaction solution is down to room temperature, add
Watery hydrochloric acid is adjusted to neutrality, and concentrated by rotary evaporation adds ethyl acetate extraction to dry, and magnesium sulfate is dried, concentrated by rotary evaporation to dry, methanol weight
Crystallization, obtains 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, off-white color is solid
Body (3.2g), yield 87%.
Claims (7)
1. a kind of Ai Le replace Buddhist nun's intermediate preparation method, the intermediate be 1,1- dimethyl -6- ethyls -7- [4- (morpholine -
4- yls) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, it is characterised in that the preparation method of the intermediate comprises the following steps：
(1) 6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones are prepared：The bromo- 7- methoxyl groups -3,4- dihydros -2- naphthalenones of 6- are existed
In the solvent reacted for boration, first reacted with n-BuLi, then carry out boration reaction with organoboron reagent, obtain 7-
Methoxyl group -3,4- dihydro -2- naphthalenone -6- boric acid, then by 7- methoxyl groups -3,4- dihydro -2- naphthalenone -6- boric acid and bromoethane in gold
Catalyzed coupling reaction is carried out in the system that metal catalyst, inorganic salts, the solvent for catalyzed coupling reaction and water are constituted, 6- is obtained
Ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones；
(2) 6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones are prepared：6- ethyl -7- methoxyl group -3,4- dihydro -2- naphthalenones are existed
Reaction is hydrolyzed in hydrobromic acid aqueous solution, 6- ethyl -7- hydroxyl -3,4- dihydro -2- naphthalenones are obtained；
(3) 6- ethyl -1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates are prepared：By 6- ethyl -7- hydroxyls -3,4-
Dihydro -2- naphthalenones and trifluoromethyl sulfonic acid anhydride carry out triflated reaction in acid binding agent alkali systems, obtain 6- ethyls -
1,2,3,4- tetrahydrochysene -2- oxo -7- naphthyl triflates；
(4) 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones are prepared：By 6- ethyl -1,2,3,
The system that 4- tetrahydrochysenes -2- oxos -7- naphthyls triflate is constituted with 4- (4- piperidyls) morpholines in acid binding agent alkali and solvent
Middle carry out substitution reaction, obtains 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones；
(5) 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones are prepared：By 6-
The body that ethyl -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones are constituted with iodomethane in base reagent and solvent
Double methylation reactions are carried out in system, 1,1- dimethyl -6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- bis- is obtained
Hydrogen -2- naphthalenones.
2. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that step (1) is described
Be used for boration react solvent be N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, toluene, dichloro
Methane, 1,2- dichloroethanes, chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Described organoboron reagent is connection boric acid frequency
That alcohol ester, trimethylborate, triethyl borate or triisopropyl borate ester；Described metallic catalyst be four (triphenyl phosphorus) palladiums,
[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride or two (triphenylphosphine) palladium chlorides；Described inorganic salts are carbonic acid
Potassium, sodium carbonate, potassium phosphate, lithium chloride, sodium bromide, KBr, potassium acetate, KI or potassium chloride；It is described to be used to be catalyzed idol
The solvent of connection reaction is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, toluene, dichloromethane, 1,2- bis-
Chloroethanes, chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Wherein, bromo- 7- methoxyl groups -3,4- dihydro -2- naphthalenones of 6-, just
Mol ratio between butyl lithium, organoboron reagent, bromoethane, metallic catalyst, inorganic salts is 1.0: (1.1~1.3): (1.25
~1.75): (0.9~1.1): (0.045~0.075): (1.45~2.00).
3. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that step (2) is described
The mass percent concentration of hydrobromic acid aqueous solution is 48%；Wherein, 6- ethyls -7- methoxyl groups -3,4- dihydro -2- naphthalenones and hydrogen bromine
The mol ratio of aqueous acid is 1.0: (5.0~15.0).
4. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that step (3) is described
Acid binding agent alkali be triethylamine, diethylamine, N, N- diisopropylethylamine, pyridine, piperidines, 2,6- lutidines or N- methyl
Quinoline；Wherein, the mol ratio between 6- ethyls -7- hydroxyls -3,4- dihydro -2- naphthalenones, trifluoromethyl sulfonic acid anhydride, acid binding agent alkali is
1.0: (1.2~1.5): (1.5~2.5).
5. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that step (4) is described
Acid binding agent alkali be sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide or sodium isopropylate；Described solvent is N, N- dimethyl
Formamide, DMAC N,N' dimethyl acetamide, toluene or 1,4- dioxane；Wherein, 6- ethyls -1,2,3,4- tetrahydrochysene -2- oxos -7-
Mol ratio between naphthyl triflate, 4- (4- piperidyls) morpholine, acid binding agent alkali is 1.0: (1.8~2.7): (2.0~
3.0)。
6. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that step (5) is described
Base reagent be sodium methoxide, caustic alcohol, sodium tert-butoxide or sodium isopropylate；Described solvent is methanol, ethanol, the tert-butyl alcohol or isopropyl
Alcohol；Wherein, between 6- ethyls -7- [4- (morpholine -4- bases) piperidin-1-yl] -3,4- dihydro -2- naphthalenones, iodomethane, base reagent
Mol ratio is 1.0: (1.8~3.0): (1.8~3.0).
7. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun's intermediate, it is characterised in that step (1) is described
Boration reaction temperature be -78 DEG C, then 20~25 DEG C, the reaction time be 1~3 hour；Described catalyzed coupling reaction
Temperature be 90~120 DEG C, the reaction time be 12~24 hours；The temperature of described hydrolysis described in step (2) is 95
~105 DEG C, the reaction time is 20~30 hours；The temperature of triflated reaction described in step (3) is -5~25 DEG C,
Reaction time is 0.5~3 hour；The temperature of substitution reaction described in step (4) is 90~110 DEG C, and the reaction time is 6~18 small
When；The temperature of double methylation reactions described in step (5) is 60~80 DEG C, and the reaction time is 2~6 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103052386A (en) * | 2010-08-20 | 2013-04-17 | 中外制药株式会社 | Composition containing tetracyclic compound |
| CN105777710A (en) * | 2016-04-05 | 2016-07-20 | 湖南欧亚生物有限公司 | Synthesis method of Alectinib |
-
2017
- 2017-04-21 CN CN201710263664.0A patent/CN107011245A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103052386A (en) * | 2010-08-20 | 2013-04-17 | 中外制药株式会社 | Composition containing tetracyclic compound |
| CN105777710A (en) * | 2016-04-05 | 2016-07-20 | 湖南欧亚生物有限公司 | Synthesis method of Alectinib |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
| US11465999B2 (en) | 2017-07-05 | 2022-10-11 | Fresenius Kabi Oncology Ltd. | Process for preparing Alectinib or a pharmaceutically acceptable salt thereof |
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
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