CN105330643B - 卡比替尼的制备方法 - Google Patents
卡比替尼的制备方法 Download PDFInfo
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- CN105330643B CN105330643B CN201510906811.2A CN201510906811A CN105330643B CN 105330643 B CN105330643 B CN 105330643B CN 201510906811 A CN201510906811 A CN 201510906811A CN 105330643 B CN105330643 B CN 105330643B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- 150000002168 ethanoic acid esters Chemical class 0.000 claims abstract description 8
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 230000032050 esterification Effects 0.000 claims abstract description 7
- 238000005886 esterification reaction Methods 0.000 claims abstract description 7
- 150000003053 piperidines Chemical class 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000007259 addition reaction Methods 0.000 claims abstract description 5
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001264 acyl cyanides Chemical class 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000002585 base Substances 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 19
- -1 triazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester Chemical class 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 7
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 6
- 239000005711 Benzoic acid Substances 0.000 claims description 5
- 235000010233 benzoic acid Nutrition 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 4
- 238000007333 cyanation reaction Methods 0.000 claims description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 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
- 230000004224 protection Effects 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 150000002118 epoxides Chemical class 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 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 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 claims description 2
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims 3
- FMWBMTMZVBVYNZ-UHFFFAOYSA-N C[PH2](C)C Chemical compound C[PH2](C)C FMWBMTMZVBVYNZ-UHFFFAOYSA-N 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- WWILHZQYNPQALT-UHFFFAOYSA-N 2-methyl-2-morpholin-4-ylpropanal Chemical compound O=CC(C)(C)N1CCOCC1 WWILHZQYNPQALT-UHFFFAOYSA-N 0.000 claims 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 1
- SMYDMMALUBNVRU-UHFFFAOYSA-N CN(C)[P] Chemical compound CN(C)[P] SMYDMMALUBNVRU-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- 235000019445 benzyl alcohol Nutrition 0.000 claims 1
- 229960004217 benzyl alcohol Drugs 0.000 claims 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims 1
- 229940073608 benzyl chloride Drugs 0.000 claims 1
- 229910052796 boron Inorganic materials 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims 1
- 229910000071 diazene Inorganic materials 0.000 claims 1
- DWYMPOCYEZONEA-UHFFFAOYSA-L fluoridophosphate Chemical compound [O-]P([O-])(F)=O DWYMPOCYEZONEA-UHFFFAOYSA-L 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 claims 1
- 229960002271 cobimetinib Drugs 0.000 abstract description 8
- 238000005516 engineering process Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- BSMCAPRUBJMWDF-KRWDZBQOSA-N cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 abstract description 4
- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 abstract description 4
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 abstract description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明揭示了一种卡比替尼(Cobimetinib，XL518，GDC‑0973)(I)的制备方法，其制备步骤包括：以(2S)‑2‑哌啶甲酸为原料，经酰腈化、水解、酯化和Boc保护制得中间体[2‑氧代‑2‑((2S)‑1‑叔丁氧羰基哌啶‑2‑基)]乙酸酯，该中间体经加成反应、还原反应和环合反应制得中间体(2S)‑1‑叔丁氧羰基‑2‑(3‑羟基氮杂环丁烷‑3‑基)哌啶，继而与侧链发生缩合反应制得卡比替尼(I)。该制备方法原料易得，工艺简洁，经济环保，适合工业化生产。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种用于治疗黑色素瘤的药物卡比替尼的制备方法。
背景技术
卡比替尼(Cobimetinib，XL518，GDC-0973)是由罗氏公司(Roche)开发的一种口服小分子MEK抑制剂。Cobimetinib旨在选择性阻断MEK蛋白的活性，从而阻断其下游的信号通路传导。该药2015年8月首次获得瑞士药品管理局的批准，并于2015年11月获得美国FDA的上市批准，用于联合维罗菲尼(Zelboraf)治疗不可切除或转移性黑色素瘤的治疗。由于该药还没有标准的中文名称，故本申请人在此将其音译为“卡比替尼”。
卡比替尼(Cobimetinib，I)的化学名为：[3,4-二氟-2-[(2-氟-4-碘苯基)氨基]苯基][3-羟基-3-(2S)-2-哌啶基-1-氮杂环丁基]甲酮，其结构式为：
卡比替尼(I)的合成已有文献报道。从其结构分析可知，该化合物的合成难度主要体现在如何快捷、经济和高纯度地获得分子结构中的手性基团。对于该化合物的制备目前主要有两条路线。
PCT专利WO2007044515、WO 2008076415、WO2008124085以及《ACS MedicinalChemistry Letters》2012年第3卷第5期第416–421页等文献均报道了一种卡比替尼(I)的合成方法。虽然上述文献在侧链链接方式上有些变化，如：先形成一个三氟苯基酰化物，再通过其中的一个氟原子与另一个含有氟和碘的苯胺进行取代从而完成整个侧链的链接(分步法)；或者先制成含有两个取代苯环的侧链的苯甲酸或酰氯，再经过酰胺化反应制得卡比替尼(一步法)。但其核心手性中间体(II)的制备均是先制备消旋体，再经过拆分剂(R)-α-甲氧基-α-三氟甲基苯基-乙酰氯的手性拆分，来制得所需的S-构型目标中间体(II)。从反应过程和收率来看，由于需要至少3次以上的反复拆分，其步骤相当繁琐，且需要消耗大量的拆分剂和其他辅助材料，且拆分收率最高也仅为50％，从而限制了该工艺的工业化。
PCT专利WO2014059422介绍了另一种卡比替尼(I)及其类似物的制备方法，该方法放弃了效率较低的拆分法，而是利用手性氨基醇作为手性诱导试剂，使其手性的获得更加方便和经济。但是，由于含有腈基的手性诱导试剂(原料)难以获得、强碱二异丙基氨基锂不稳定以及需要超低温(-78℃)和绝对无水无氧等反应条件，同样限制了该合成路线的工业化前景。
针对现有工艺中存在的缺陷，开发工艺简洁、经济环保且质量上乘的制备技术，尤其是寻求能够适应工业化生产的工艺技术，对该药品的经济和社会效益提高有着重要的现实意义。
发明内容
本发明的目的在于提供一种原料易得、工艺简洁、经济环保且适合工业化生产的卡比替尼的制备方法。
为实现上述发明目的，本发明采用了如下主要技术方案：一种卡比替尼(I)的制备方法，
其制备步骤包括：(2S)-2-哌啶甲酸(III)与二氯亚砜、腈基化试剂和相转移催化剂发生酰腈化反应，所得产物经腈基水解、与醇发生酯化反应及采用二碳酸二叔丁酯对哌啶氨基进行保护，制得[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸酯(IV)；所述[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸酯(IV)与硝基甲烷在催化剂作用下发生加成反应制得[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸酯(V)；所述[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸酯(V)依次发生酯基和硝基的还原反应制得[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇(VI)；所述[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇(VI)在偶氮试剂和有机膦试剂作用下发生环合反应制得(2S)-1-叔丁氧羰基-2-(3-羟基氮杂环丁烷-3-基)哌啶(II)；所述(2S)-1-叔丁氧羰基-2-(3-羟基氮杂环丁烷-3-基)哌啶(II)与3,4-二氟-2-[(2-氯-4-碘苯基)氨基]苯甲酸在缩合剂和碱促进剂作用下发生缩合反应制得卡比替尼(I)。
其中酯化反应所用的醇为甲醇、乙醇、正丙醇、异丙醇、丙烯醇或苄醇，即所得相对应的酯为甲酯、乙酯、正丙酯、异丙酯、烯丙酯或苄基酯。
此外，本发明还提出如下附属技术方案：
所述酰腈化反应中的腈基化试剂为氰化钠、氰化锌、氰化亚铜或三甲基硅基氰，优选氰化亚铜。
所述酰腈化反应所采用的相转移催化剂为苄基三乙基氯化铵、四丁基溴化铵、四丁基氯化铵、四丁基硫酸氢铵、三辛基甲基氯化铵、十二烷基三甲基氯化铵或十四烷基三甲基氯化铵，优选四丁基溴化铵或四丁基氯化铵。
所述酰腈化反应温度为50-150℃，优选90-100℃；反应溶剂为苯/水、甲苯/水、二甲苯/水或1,2-二氯乙烷/水，其体积比为1-5/1，优选甲苯/水，体积比为2/1。
所述腈基水解反应的催化剂为氯化钠和硫酸，反应温度为45-50℃。
所述酯化反应所用的醇为甲醇、乙醇、正丙醇、异丙醇、丙烯醇或苄醇，优选甲醇或乙醇。
所述酯化反应的温度为50-90℃，优选为70-80℃。
所述哌啶氨基保护反应的催化剂为N,N-二乙基-1,2-二胺。
所述加成反应的催化剂为甲醇钠、乙醇钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、叔丁醇钠或叔丁醇钾，优选甲醇钠、乙醇钠或氢氧化钾。
所述加成反应的温度为0-100℃，优选50-60℃。
所述酯基还原反应的还原剂为硼氢化钠、硼氢化钾、硼烷或四氢铝锂，优选硼氢化钠或四氢铝锂。
所述硝基还原反应的还原剂为铁、锌、二氯化锡、四氢铝锂或氢气，优选四氢铝锂或氢气。
所述硝基还原反应的还原剂为氢气时，需要加入的催化剂为钯碳或雷尼镍。
所述环合反应的偶氮试剂为偶氮二羧酸二乙酯、偶氮二羧酸二异丙酯、偶氮二羧酸二叔丁酯或偶氮二羧酸二对氯苄基酯，优选偶氮二羧酸二乙酯。
所述环合反应的有机膦试剂为三苯基膦、三正丁基膦、三甲基膦、(氰亚甲基)三正丁基正膦或(氰亚甲基)三甲基正膦，优选三苯基膦。
所述环合反应的原料[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇(VI)、偶氮试剂及有机膦试剂的投料摩尔比为1:1-2:1-2，优选1:1.1-1.5:1.1-1.5。
所述环合反应的温度为室温，溶剂为二氯甲烷、二氧六环、乙腈或四氢呋喃，优选四氢呋喃。
所述缩合反应的缩合剂为N,N,-二环己基碳二亚胺、羰基二咪唑、N,N′-二异丙基碳二亚胺、1-羟基-苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、O-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。
所述缩合反应的碱促进剂为三乙胺、吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1,5-二氮杂二环[4.3.0]-壬-5-烯、1,8-二氮杂双环[5.4.0]-十一-7-烯或1,4-二氮杂二环[2.2.2]辛烷，优选二异丙基乙胺。
所述缩合反应的溶剂为甲苯、二甲苯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、氯仿、二甲亚砜、N,N-二甲基甲酰胺或乙腈，优选N,N-二甲基甲酰胺或乙腈。
所述缩合反应的温度为0-120℃，优选40-55℃。
相比于现有技术，本发明所涉及的卡比替尼(I)的制备方法，通过易得的手性源试剂和其他通用试剂，采用公知单元反应，实现了目标化合物的制备。该制备方法具有原料易得、工艺简洁和经济环保等特点，故而利于该原料药的工业化生产，促进其经济技术的发展。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。其中起始原料(2S)-2-哌啶甲酸(III)及其Boc保护的方法可参见“Journal of the AmericanChemical Society,132(35),12216-12217；2010”或“Tetrahedron:Asymmetry,14(12),1685-1689；2003”等文献。侧链3,4-二氟-2-[(2-氯-4-碘苯基)氨基]苯甲酸可参见文献“ACS Medicinal Chemistry Letters,3(5),416-421；2012”的相关制备方法。
实施例一：
于反应瓶中加入(2S)-2-哌啶甲酸(III)(6.45g,50mmol)和二氯亚砜15mL，回流反应3小时，减压蒸馏过量的二氯亚砜，得棕色油状物。室温下，于通风橱内向该油状物中加入甲苯50mL、水25mL和相转移催化剂四丁基溴化铵0.1g，搅拌下加入氰化亚铜(8.05g,90mmol)，升温至90-100oC，搅拌反应2-3小时。降温，静置分层，水相用甲苯萃取2次，减压回收溶剂，所得油状物中加入氯化钠(0.32g,5.5mmol)、水(1.0g,55mmol)和硫酸(5.4g,55mmol)，保持温度45-50℃，反应2-4小时，加入酯化试剂甲醇20mL，升温至70-75℃，反应3小时，TLC检测反应结束。减压浓缩，剩余物用二氯甲烷溶解，依次用水、10％碳酸氢钠溶液和饱和食盐水洗涤，无水硫酸钠干燥，浓缩，所得粘稠油状物再用甲醇25mL溶解，室温滴加二碳酸二叔丁酯(8.72g,40mmol)的50mL甲醇溶液，反应2小时后，加入N,N-二乙基-1,2-二胺(0.88g,10mmol)，继续搅拌反应1小时，反应完成。减压浓缩，残余物用乙酸乙酯溶解，依次用水、5％盐酸和饱和食盐水洗涤，分层，有机相用无水硫酸钠干燥，浓缩，所得粗品用正己烷和乙酸乙酯(1:1，V/V)重结晶，真空干燥得类白色固体[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸甲酯(IV)7.45g，收率55.0％；质谱(EI)：m/z 272(M+H)。
实施例二：
同实施例一，采用乙醇作为酯化试剂，得类白色固体[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸乙酯(IV)7.35g，收率51.4％；质谱(EI)：m/z 286(M+H)。实施例三：
于反应瓶中加入[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸甲酯(IV)(2.71g,10mmol)、甲醇钠(0.65g,12mmol)和硝基甲烷15mL，升温至50-60oC，搅拌反应5-7小时，TLC检测反应结束。减压回收过量的硝基甲烷，残余物中加入二氯甲烷，用水和饱和食盐水洗涤，无水硫酸钠干燥。浓缩得淡黄色固体[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸甲酯(V)2.96g，收率89.4％；质谱(EI)：m/z 333(M+H)。
实施例四：
于反应瓶中加入[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸乙酯(IV)(2.85g,10mmol)、氢氧化钾(0.67g,12mmol)、硝基甲烷(1.22g,20mmol)和乙醇25mL，升温至50-60oC，搅拌反应5-7小时，TLC检测反应结束。减压回收溶剂，残余物中加入二氯甲烷，用水和饱和食盐水洗涤，无水硫酸钠干燥。浓缩得黄色固体[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸乙酯(V)2.92g，收率84.4％；质谱(EI)：m/z 347(M+H)。
实施例五：
于反应瓶中加入[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸甲酯(V)(1.66g,5mmol)和甲醇50mL，分批加入硼氢化钠(0.38g,10mmol)，并保持温度为20-30oC，搅拌反应6小时。滤去少量不溶物，滤液转入至氢化反应器。加入5％的钯碳0.15g，保持温度35-40oC及2Kg氢气压力，反应5-6小时。过滤，回收催化剂，浓缩，析出固体。粗品用乙酸乙酯/正己烷(1/2)重结晶，得到[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇(VI)1.07g，收率78.1％；质谱(EI)：m/z 275(M+H)。
实施例六：
于干燥反应瓶中加入[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸乙酯(V)(1.73g,5mmol)和四氢呋喃25mL，分批加入四氢铝锂(0.62g,16mmol)，加毕后，室温搅拌反应5-6小时。用20％的氢氧化钠淬灭反应，并用乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗涤一次，浓缩。粗品用乙酸乙酯/正己烷(1/2)重结晶，得到[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇(VI)1.12g，收率81.7％；质谱(EI)：m/z 275(M+H)。
实施例七：
于反应瓶中加入[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇(VI)(1.37g，5mmol)、三苯基膦(1.58g,6mmol)和四氢呋喃25mL，冰浴下滴加偶氮二甲酸二乙酯(1.04g,6mmol)的四氢呋喃25mL溶液，滴毕，升至室温，搅拌反应3-4小时，TLC检测反应完成。减压蒸馏，残余物用乙酸乙酯和正己烷溶解，滤去不溶物，滤液用水洗涤，无水硫酸钠干燥。浓缩，粗品用正己烷/甲醇重结晶得类白色固体(2S)-1-叔丁氧羰基-2-(3-羟基氮杂环丁烷-3-基)哌啶(II)1.08g，收率84.4％；1H NMR(400MHz,CD3OD)4.31(m,1H),3.85(brs,1H),3.71(d,J＝8.8Hz,1H),3.54(d,J＝9.2Hz,1H),3.42(d,J＝9.6Hz,1H),3.39(d,J＝9.2Hz,1H),3.37(brs,1H),1.90-1.97(m,2H),1.55-1.78(m,6H),1.47(s,9H)；MS(EI)：m/z257(M+H)。实施例八：
于反应瓶中加入3,4-二氟-2-[(2-氟-4-碘苯基)氨基]苯甲酸(1.96g，5mmol)和N,N-二甲基甲酰胺25mL，室温滴加六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(2.6g,5mmol)的N,N-二甲基甲酰胺25mL溶液，30分钟内滴完。加入(2S)-1-叔丁氧羰基-2-(3-羟基氮杂环丁烷-3-基)哌啶(II)(1.92g,7.5mmol)和二异丙基乙胺(1.29g,10mmol)。升温至45-50℃，搅拌反应3-4小时，TLC检测反应完成。向反应液中加入乙酸乙酯和10％的氢氧化钠溶液，搅拌15分钟后分出有机层。有机层用水洗涤3次，用饱和食盐水洗涤1次，无水硫酸钠干燥。浓缩，所得固体中加入4N的二氧六环氯化氢溶液25mL，升温至55-60℃，搅拌反应2-4小时，降至室温，减压浓缩，粗品经乙酸乙酯/正己烷(1/1)重结晶，得类白色固体卡比替尼(I)1.86g，收率70.1％；M.p.170-172℃；1H NMR(400MHz,CDCl3)8.39(m,1H),7.40(dd,1H),7.37(dd,1H),7.12(m,1H),6.81(m,1H),6.62(m,1H),4.09(m,3H),3.96(m,1H),3.09(dd,1H),2.69(dd,1H),2.63(m,2H),1.76(m,1H),1.64-1.22(m,7H)；MS(EI)：m/z 532(M+H)。
需要指出的是，上述实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (9)
1.一种卡比替尼的制备方法，
其制备步骤包括：(2S)-2-哌啶甲酸与二氯亚砜、腈基化试剂氰化钠、氰化锌、氰化亚铜或三甲基硅基氰和相转移催化剂苄基三乙基氯化铵、四丁基溴化铵、四丁基氯化铵、四丁基硫酸氢铵、三辛基甲基氯化铵、十二烷基三甲基氯化铵或十四烷基三甲基氯化铵发生酰腈化反应，所得产物经腈基水解、与醇发生酯化反应及采用二碳酸二叔丁酯对哌啶氨基进行保护，制得[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸酯；所述[2-氧代-2-((2S)-1-叔丁氧羰基哌啶-2-基)]乙酸酯与硝基甲烷在催化剂甲醇钠、乙醇钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、叔丁醇钠或叔丁醇钾作用下发生加成反应制得[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸酯；所述[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-硝基]丙酸酯依次发生酯基和硝基的还原反应制得[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇；所述[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇在偶氮试剂偶氮二羧酸二乙酯、偶氮二羧酸二异丙酯、偶氮二羧酸二叔丁酯或偶氮二羧酸二对氯苄基酯和有机膦试剂三苯基膦、三正丁基膦、三甲基膦、(氰亚甲基)三正丁基正膦或(氰亚甲基)三甲基正膦的作用下发生环合反应制得(2S)-1-叔丁氧羰基-2-(3-羟基氮杂环丁烷-3-基)哌啶；所述(2S)-1-叔丁氧羰基-2-(3-羟基氮杂环丁烷-3-基)哌啶与3,4-二氟-2-[(2-氯-4-碘苯基)氨基]苯甲酸在缩合剂和碱促进剂作用下发生缩合反应制得卡比替尼(I)；其中发生酯化反应的醇为甲醇、乙醇、正丙醇、异丙醇、丙烯醇或苄醇。
2.如权利要求1所述卡比替尼的制备方法，所述酰腈化反应的温度为50-150℃；反应溶剂为苯/水、甲苯/水、二甲苯/水或1,2-二氯乙烷/水，其体积比为1-5/1。
3.如权利要求1所述卡比替尼的制备方法，所述腈基水解反应的催化剂为氯化钠和硫酸，反应温度为45-50℃。
4.如权利要求1所述卡比替尼的制备方法，所述加成反应的温度为0-100℃。
5.如权利要求1所述卡比替尼的制备方法，所述酯基还原反应的还原剂为硼氢化钠、硼氢化钾、硼烷或四氢铝锂；所述硝基还原反应的还原剂为铁、锌、二氯化锡、四氢铝锂或氢气。
6.如权利要求1所述卡比替尼的制备方法，所述环合反应的原料[2-羟基-2-((2S)-1-叔丁氧羰基哌啶-2-基)-3-氨基]丙醇、偶氮试剂及有机膦试剂的投料摩尔比为1:1-2:1-2。
7.如权利要求1所述卡比替尼的制备方法，所述缩合反应的缩合剂为N,N,-二环己基碳二亚胺、羰基二咪唑、N,N′-二异丙基碳二亚胺、1-羟基-苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、O-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。
8.如权利要求1所述卡比替尼的制备方法，所述缩合反应的碱促进剂为三乙胺、吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1,5-二氮杂二环[4.3.0]-壬-5-烯、1,8-二氮杂双环[5.4.0]-十一-7-烯或1,4-二氮杂二环[2.2.2]辛烷。
9.如权利要求1所述卡比替尼的制备方法，所述缩合反应的溶剂为甲苯、二甲苯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、氯仿、二甲亚砜、N,N-二甲基甲酰胺或乙腈，所述缩合反应的温度为0-120℃。
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| CN104725352A (zh) * | 2015-03-19 | 2015-06-24 | 上海皓元生物医药科技有限公司 | 一种3-(哌啶-2-基)-氮杂环丁烷-3-醇的衍生物的合成方法及其用途 |
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| WO2008124085A2 (en) * | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
| US9532987B2 (en) * | 2013-09-05 | 2017-01-03 | Genentech, Inc. | Use of a combination of a MEK inhibitor and an ERK inhibitor for treatment of hyperproliferative diseases |
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| WO2007044515A1 (en) * | 2005-10-07 | 2007-04-19 | Exelixis, Inc. | Azetidines as mek inhibitors for the treatment of proliferative diseases |
| WO2008076415A1 (en) * | 2006-12-14 | 2008-06-26 | Exelixis, Inc. | Methods of using mek inhibitors |
| WO2014059422A1 (en) * | 2012-10-12 | 2014-04-17 | Exelixis, Inc. | Novel process for making compounds for use in the treatment of cancer |
| CN104725352A (zh) * | 2015-03-19 | 2015-06-24 | 上海皓元生物医药科技有限公司 | 一种3-(哌啶-2-基)-氮杂环丁烷-3-醇的衍生物的合成方法及其用途 |
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| US10407403B2 (en) | 2019-09-10 |
| WO2017096996A1 (zh) | 2017-06-15 |
| US20180273506A1 (en) | 2018-09-27 |
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