CN106008526B - A kind of preparation method for replacing Buddhist nun according to Shandong - Google Patents
A kind of preparation method for replacing Buddhist nun according to Shandong Download PDFInfo
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- CN106008526B CN106008526B CN201610435692.1A CN201610435692A CN106008526B CN 106008526 B CN106008526 B CN 106008526B CN 201610435692 A CN201610435692 A CN 201610435692A CN 106008526 B CN106008526 B CN 106008526B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 26
- 125000006239 protecting group Chemical group 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000012190 activator Substances 0.000 claims abstract description 10
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims abstract description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 23
- YYVUOZULIDAKRN-UHFFFAOYSA-N 3-(4-phenoxyphenyl)-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C=12C(N)=NC=NC2=NNC=1C(C=C1)=CC=C1OC1=CC=CC=C1 YYVUOZULIDAKRN-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- 239000012071 phase Substances 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 150000005690 diesters Chemical class 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 238000013459 approach Methods 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 238000007867 post-reaction treatment Methods 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- 239000000010 aprotic solvent Substances 0.000 claims 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 claims 1
- -1 4- Phenoxyphenyl Chemical group 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 238000001816 cooling Methods 0.000 abstract description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 2
- 231100000086 high toxicity Toxicity 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000003053 piperidines Chemical class 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 4
- 229960001507 ibrutinib Drugs 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 238000005583 trifluoroacetylation reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- RBCUYJOFTYACGB-UHFFFAOYSA-N 1-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(N2C3=NC=NC=C3C=N2)C=CC=1OC1=CC=CC=C1 RBCUYJOFTYACGB-UHFFFAOYSA-N 0.000 description 1
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical compound C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 1
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005577 Kumada cross-coupling reaction Methods 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- BSDOQSMQCZQLDV-UHFFFAOYSA-N butan-1-olate;zirconium(4+) Chemical compound [Zr+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] BSDOQSMQCZQLDV-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052735 hafnium Inorganic materials 0.000 description 1
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to pharmaceutical technology fields, more particularly to a kind of preparation method for replacing Buddhist nun according to Shandong.The present invention provides a kind of preparation method that Buddhist nun is replaced according to Shandong; include the following steps: 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3; 4-d] pyrimidine reacts with S-1- tertbutyloxycarbonyl -3- hydroxy piperidine through Mitsunobu; formula IV compound is prepared, formula IV compound sloughs Boc protecting group and prepares Formula V compound；Under the conditions of Formula V compound and acrylate are existing for the catalyst and activator, compound of formula I is prepared.Preparation method reaction process mild condition provided by the present invention, reaction step is few, is not necessarily to high temperature, deep cooling, and high toxicity reagent is not used, entire synthesis process is stably and controllable, prepare according to Shandong for Buddhist nun's yield and superior in quality, have many advantages, such as stability it is good, it is with high purity, convenient for storing.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly to a kind of preparation method for replacing Buddhist nun according to Shandong.
Background technique
Buddhist nun (English name Ibrutinib, trade name Imbruvica, molecular formula C are replaced according to Shandong25H24N6O2, molecular weight 440.50)
With structure shown in Formulas I, chemical name is 1- [(3R) -3- (4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-
D] pyrimidine -1- base) -1- piperidyl) -2- propylene -1- ketone.Replacing Buddhist nun (Ibrutinib) according to Shandong is one kind by the U.S.
Pharmacyclics and Johson & Johnson develop jointly a kind of oral bruton's tyrosine kinase (BTK) inhibitor of listing
Pioneering new drug, the medicine by with target protein Btk activity site cysteine residue (Cys-481) selectively covalent bond, no
Reversibly inhibit BTK, to effectively tumour be prevented to move to the lymphoid tissue for being adapted to tumour growth environment from B cell.
Since acquisition FDA on November 13rd, 2013 approval listing since, according to Shandong for Buddhist nun have so far for lymphoma mantle cell (MCL),
5 indications such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are gradually criticized in the U.S.
It is quasi-.
Document ChemMedChem.2007,2 (1): 56-61 reports the preparation method that Buddhist nun is replaced according to Shandong,
This method with 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine (II) be raw material, with S-1-
Tertbutyloxycarbonyl -3- hydroxy piperidine (III) reacts through Mitsunobu, sloughs Boc protecting group and acrylated three-step reaction, makes
Get Yi Lu replaces Buddhist nun (I).The route steps are more, and deprotection needs individual reaction step, using the reaction of acryloyl chloride, although living
Property it is high, but easily cause multidigit point N- acrylated, generate by-product, lead to purification difficult.
China Patent Publication No. CN103121999 reports a kind of preparation method that Buddhist nun (I) is replaced according to Shandong.
This method is also with 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine (II) for raw material, with 3
(S)-hydroxy piperidine -1- t-butyl formate (III) is catalyzed through cesium carbonate to react, then trifluoroacetylation, de- Boc protecting group and third
Alkene acyl chloride reaction and the reaction of de- trifluoroacetyl group, are made and replace Buddhist nun (I) according to Shandong.The inorganic base catalyzed reactions of the route first step, optics
Purity cannot be guaranteed, in addition, increasing, intermediate (VI) is made in trifluoroacetylation and intermediate is made in de- trifluoroacetylation
(VII) the step of, reaction step is more, and increased costs are unfavorable for industrialized production.
China Patent Publication No. CN104557945A reports another preparation method that Buddhist nun (I) is replaced according to Shandong.
The method for raw material, by Suzuki coupling and Kumada coupling reaction, is not separated with 4- halogenated diphenyl ether (IX)
Obtain intermediate (R) -3- [4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine -1- base] piperidines -1- carboxylic
Tert-butyl acrylate (IV), then slough Boc protecting group and obtain intermediate (V), it is then generated with acrylic acid and acyl chlorides and sulfonic acid chloride mixed
Anhydride acylation, the palladium catalyst (Pd (dppf) which has used price more expensive2Cl2And Pd2(dba)3), it is inconvenient, it is unfavorable for work
Industryization amplification.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide a kind of preparation sides that Buddhist nun is replaced according to Shandong
Method, for solving the problems of the prior art.
In order to achieve the above objects and other related objects, the present invention provides one kind according to Shandong for Buddhist nun (Ibrutinib, Formulas I chemical combination
Object) preparation method, include the following steps:
1) 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine (Formula II compound) and the tertiary fourth of S-1-
Oxygen carbonyl -3- hydroxy piperidine (formula III compound) is reacted through Mitsunobu, prepares formula IV compound, and formula IV compound is de-
Boc protecting group is gone to prepare Formula V compound, reaction equation is as follows:
In some embodiments of the present invention, the Mitsunobu reaction be can be in azodicarboxy acid diesters and three alkane
Under the conditions of (virtue) base phosphine (for example, trialkyl phosphine and/or triaryl phosphine) is existing, alcohol is carried out with the nucleopilic reagent with reactive hydrogen
Dehydration condensation.
Specifically, in the step 1), the mole of S-1- tertbutyloxycarbonyl -3- hydroxy piperidine usually can with equivalent or
It is in excess in the mole of 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine, 4- amino -3- (4- phenoxy group
Phenyl) molar ratio of -1H- pyrazolo [3,4-d] pyrimidine and S-1- tertbutyloxycarbonyl -3- hydroxy piperidine can be 1:1~3, also
It can be 1:1.2~2.
Specifically, the reaction temperature of Mitsunobu reaction can be 15~60 DEG C in the step 1), it can also be 25
~55 DEG C, can also be 25~40 DEG C.
Those skilled in the art can adjust the reaction time according to real reaction situation, such as can be adjusted according to reaction process
Reaction time, reaction process can be monitored for example, by the methods of TLC, HPLC, for another example the reaction time can for 2~
20 hours, can also be 4~16 hours.
Specifically, in the step 1), reaction carries out under inert gas atmosphere, the inert gas be often referred to be not easy with
The gaseous material that main component (such as Formula II, formula III compound etc.) in reaction system chemically reacts, it is specific applicable
The example of inert gas include but is not limited to: one of nitrogen, helium, neon, argon gas, Krypton, xenon etc. are a variety of
Combination.
Specifically, azodicarboxy acid diesters can be selected from DEAD (diethyl azodiformate), DIAD in the step 1)
One of (diisopropyl azodiformate), DBAD (tert-butyl azodicarboxylate) etc. or a variety of combinations.
Specifically, the mole of azodicarboxy acid diesters usually with equivalent or can be in excess in 4- ammonia in the step 1)
The mole of base -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine, 4- amino -3- (4- Phenoxyphenyl) -1H-
The molar ratio of pyrazolo [3,4-d] pyrimidine and azodicarboxy acid diesters can be 1:1.2~5, can also be 1:1.5~4.
Specifically, trialkyl phosphine is selected from one of TBP (tributylphosphine), TMP (trimethyl-phosphine) etc. in the step 1)
Or a variety of combination.
Specifically, triaryl phosphine is selected from one of TPP (triphenylphosphine), diphenyl methyl phosphine etc. in the step 1)
Or a variety of combination.
Specifically, the mole of trialkyl phosphine and/or triaryl phosphine usually can be with equivalent or excess in the step 1)
In the mole of 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine, 4- amino -3- (4- phenoxy group benzene
Base) molar ratio of -1H- pyrazolo [3,4-d] pyrimidine and trialkyl phosphine and/or triaryl phosphine can be 1:1.2~5, it can be with
For 1:1.5-4.
When trialkyl phosphine is used only, above-mentioned ratio is referred specifically to, 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo
The molar ratio of [3,4-d] pyrimidine and trialkyl phosphine；When triaryl phosphine is used only, above-mentioned ratio is referred specifically to, 4- amino -3-
The molar ratio of (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and triaryl phosphine；When use trialkyl phosphine and triaryl
When phosphine, above-mentioned ratio is referred specifically to, the mole of 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine with
The ratio of the sum of the mole of trialkyl phosphine and triaryl phosphine.
Specifically, reaction carries out in the presence of a solvent in the step 1), the solvent is selected from non-proton molten
Agent.
More specifically, in the step 1), solvent is in benzene, dioxane, tetrahydrofuran, ether, methylene chloride etc.
One or more combinations.
In the step 1), 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and the tertiary fourth oxygen of S-1-
Carbonyl -3- hydroxy piperidine after Mitsunobu reacts, the product for preparing can without purifying (using one pot synthesis),
It directly carries out formula IV compound and sloughs the operation that Boc protecting group prepares Formula V compound.
Specifically, formula IV compound sloughs the specific side that Boc protecting group prepares Formula V compound in the step 1)
Method are as follows: formula IV compound sloughs Boc protecting group in acid condition and prepares Formula V compound.
More specifically, in the step 1), acid condition is specifically as follows pH=0~3, can also be pH=0~2, this
Suitable acid can be selected for adjusting the pH value of reaction system in field technical staff, specifically can be such as hydrochloric acid, adjusts pH
When reaction system can be cooled down, such as the pH value of reaction system can be adjusted under the conditions of 0-10 DEG C.
More specifically, in the step 1), formula IV compound sloughs the process that Boc protecting group prepares Formula V compound
In, reaction temperature can be 20 DEG C~55 DEG C.
Those skilled in the art can adjust the reaction time according to real reaction situation, such as can be adjusted according to reaction process
Reaction time, reaction process can be monitored for example, by the methods of TLC, HPLC, then such as formula IV compound sloughs Boc guarantor
The reaction time can be 1~16 hour during shield base prepares Formula V compound.
In a preferred embodiment of the invention, in the step 1), formula IV compound is sloughed Boc protecting group and is prepared
During Formula V compound, reaction temperature can be 30~50 DEG C, can also be 35~45 DEG C, the reaction time is 0.5~1.5
Hour, it can also be 0.8~1.2 hour.
Specifically, in the step 1), the post-processing approach of reaction are as follows: add water, organic solvent in reaction products therefrom
After washing, the pH of water phase is adjusted to alkalinity, the white solid for collecting precipitation is Formula V compound.
It is furthermore preferred that the pH for adjusting water phase refers specifically to the pH value of water phase being adjusted to pH > 10 to alkaline.
2) under the conditions of Formula V compound and acrylate (Formula XII compound) are existing for the catalyst and activator, preparation is obtained
Compound of formula I is obtained, reaction equation is as follows:
Specifically, the mole of Formula V compound usually with equivalent or can be in excess in acrylate in the step 2)
The molar ratio of mole, acrylate and Formula V compound can be 1:1~1.5, can also be 1:1~1.2.
Specifically, R, which is selected from, branch or unbranched, saturated or unsaturated, optional in the Formula XII compound
At least mono-substituted C in ground1-10Aliphatic group can also be C1-6Aliphatic group can also be C1-4Aliphatic group may be used also
Think C1-3Aliphatic group.
In some specific embodiments of the present invention, the R is selected from methyl and/or ethyl.
Specifically, reaction temperature is 50~90 DEG C in the step 2), it can also be 60~80 DEG C.
Those skilled in the art can adjust the reaction time according to real reaction situation, such as can be adjusted according to reaction process
Reaction time, reaction process can be monitored for example, by the methods of TLC, HPLC, for another example the reaction time can for 2~
20 hours, can also be 6~16 hours.
Specifically, catalyst is selected from Zr (Ot-Bu) in the step 2)4(tetrabutyl zirconate), 4 (metatitanic acid of Ti (Oi-Pr)
Tetra-isopropyl), one of Hf (Ot-Bu) 4 (hafnium acid four butyl esters) or a variety of combinations.
Those skilled in the art can usually determine the usage amount of catalyst, institute according to the type and reaction system of catalyst
The usage amount for stating catalyst is usually catalytic amount, can be usually 0.01~0.20:1 with the molar ratio of Formula V compound, can be with
For 0.04-0.10:1.
Specifically, activator may generally function as the effect for promoting catalyst activity, art technology in the step 2)
Personnel can select suitable activator according to the type of catalyst, for example, the activator can be selected from HOAt (1- hydroxyl -7-
Azo benzotriazole), HOBt (I-hydroxybenzotriazole), HYP (2 hydroxy pyrimidine), DMAP (4-dimethylaminopyridine), PFP
One of (Pentafluorophenol) or a variety of combination.
Those skilled in the art can usually determine the usage amount of activator, institute according to the type and reaction system of activator
Stating activator can be usually 0.01~0.2:1 with the molar ratio of Formula V compound, can also be 0.04~0.15:1.
Specifically, reaction carries out in the presence of a solvent in the step 2), the solvent is selected from non-proton molten
Agent.
More specifically, in the step 2), solvent is selected from tetrahydrofuran, dioxane, toluene, methyl tertiary butyl ether(MTBE), second
One of nitrile etc. or a variety of combinations.
Specifically, in the step 2), the method for post-reaction treatment are as follows: reaction is quenched, is separated by solid-liquid separation, liquid phase concentration weight
Up to compound of formula I after crystallization.
Those skilled in the art can be selected suitable method and reaction be quenched, and it is, for example, possible to use suitable methanol
And/or reaction is quenched in methylene chloride, water.
Those skilled in the art can be selected suitable method and recrystallize, for example, in some specific embodiment parties of the present invention
In formula, isopropanol is used to be recrystallized as solvent.
A kind of preparation method for replacing Buddhist nun according to Shandong provided by the present invention, entire reaction process mild condition, reaction step is few,
Without high temperature, deep cooling, and high toxicity reagent is not used, entire synthesis process is stably and controllable, cleverly not using formula IV compound
Separation " one pot synthesis ", shorten purification procedures, it is energy saving and with it is environmental-friendly, using acrylate replace acryloyl
The process for acylating of chlorine has the characteristics that yield is good, process safety, synthesizes the product obtained without potential safety issue.It is logical
Cross that the preparation method prepares according to Shandong for Buddhist nun's yield and superior in quality, have stability good, with high purity, excellent convenient for storage etc.
Point.
Detailed description of the invention
Fig. 1 be shown as the embodiment of the present invention 4 synthesize obtain according to Shandong for Buddhist nun1H-NMR spectrum.
Fig. 2 is shown as the embodiment of the present invention 4 and synthesizes the obtained mass spectrogram for replacing Buddhist nun according to Shandong.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.
It should be clear that in the following example not specifically dated process equipment or device be all made of conventional equipment in the art or
Device.
In addition, it should also be understood that, one or more method and step mentioned in the present invention does not repel before and after the combination step
It can also be inserted into other methods step there may also be other methods step or between these explicitly mentioned steps, unless separately
It is described；It should also be understood that the combination connection relationship between one or more equipment/device mentioned in the present invention is not repelled
The two equipment/devices specifically mentioned before and after the unit equipment/device there may also be other equipment/device or at these it
Between can also be inserted into other equipment/device, unless otherwise indicated.Moreover, unless otherwise indicated, the number of various method steps is only
Identify the convenient tool of various method steps, rather than for the arrangement order of limitation various method steps or limits the enforceable model of the present invention
It encloses, relativeness is altered or modified, and without material changes in technical content, when being also considered as, the present invention is enforceable
Scope.
Embodiment 1
(R) synthesis of -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo (3,4-d) pyrimidine -4- amine (5)
4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine 20g is added in 1L there-necked flask
(66mmol)；S-1- tertbutyloxycarbonyl -3- hydroxy piperidine 13.3g (66mmol)；Triphenylphosphine 34.6g (132mmol) is added dry
Dry tetrahydrofuran 300mL, is cooled to 5-10 DEG C.Under nitrogen protection, diisopropyl azodiformate is slowly added dropwise into bottle
26.7g (132mmol), drips off, and 30 DEG C are reacted 10 hours.Reaction solution is cooled to 0-10 DEG C again, and 36% hydrochloric acid 13.4g is added dropwise
(132mmol) is dripped off and is warming up to 40 DEG C of reactions 1 hour.Water is added, stirring is extracted with dichloromethane 3 times, collects water phase, uses hydrogen
Sodium hydroxide solution adjusts water phase at alkaline (pH > 10), solid is precipitated, solid is collected in filtering, and 50 DEG C of air blast baking material 8 hours obtains
Off-white powder (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo (3,4-d) pyrimidine -4- amine (V)
20.2g, molar yield 79.2%.(HPLC purity 99.2%；Optical purity >=99.8%).1H-NMR(DMSO-d6, 400MHz) and δ
8.25 (s, 1H), 7.67 (d, J=7.9Hz, 2H), 7.43 (t, J=7.2Hz, 2H), 7.15 (dt, J=12.0,7.8Hz, 5H),
4.70 (t, J=10.3Hz, 1H), 3.19 (s, 1H), 3.09 (d, J=9.0Hz, 1H), 2.95 (dd, J=24.7,12.8Hz,
2H), 2.47 (d, J=11.5Hz, 1H), 2.22-2.07 (m, 1H), 2.01 (d, J=17.3Hz, 1H), 1.75 (d, J=
12.3Hz, 1H), 1.56 (d, J=12.2Hz, 1H)；MS (ESI, m/z): 387.2 [M+H]+.
Embodiment 2
(R) synthesis of -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo (3,4-d) pyrimidine -4- amine (5)
4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine 20g is added in 1L there-necked flask
(66mmol)；S-1- tertbutyloxycarbonyl -3- hydroxy piperidine 26.6g (132mmol)；Triphenylphosphine 51.9g (198mmol) is added
Dry tetrahydrofuran 400mL, is cooled to 5-10 DEG C.Under nitrogen protection, diisopropyl azodiformate is slowly added dropwise into bottle
40g (198mmol), drips off, and 30 DEG C are reacted 12 hours.Reaction solution is cooled to 0-10 DEG C again, and 36% hydrochloric acid 20g is added dropwise
(198mmol) is dripped off and is warming up to 40 DEG C of reactions 1 hour.Water is added, stirring is extracted with dichloromethane 3 times, collects water phase, uses hydrogen
Sodium hydroxide solution adjusts water phase at alkaline (pH > 10), solid is precipitated, solid is collected in filtering, and 50 DEG C of air blast baking material 12 hours obtains
Off-white powder (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo (3,4-d) pyrimidine -4- amine (V)
22.4g, molar yield 87.9%.(HPLC purity 99.6%；Optical purity >=99.8%).
Embodiment 3
(R) synthesis of -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo (3,4-d) pyrimidine -4- amine (5)
4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine 20g is added in 1L there-necked flask
(66mmol)；S-1- tertbutyloxycarbonyl -3- hydroxy piperidine 26.6g (132mmol)；Triphenylphosphine 51.9g (198mmol) is added
Dry tetrahydrofuran 400mL, is cooled to 5-10 DEG C.Under nitrogen protection, diisopropyl azodiformate is slowly added dropwise into bottle
40g (198mmol), drips off, and 30 DEG C are reacted 12 hours.Reaction solution is cooled to 0-10 DEG C again, and trifluoroacetic acid 22.5g is added dropwise
(198mmol) is dripped off and is warming up to 40 DEG C of reactions 1 hour.TLC monitoring reaction terminates.Water is added, stirring is extracted with dichloromethane 3
It is secondary, water phase is collected, water phase is adjusted at alkaline (pH > 10) with sodium hydroxide solution, solid is precipitated, solid, air blast are collected in filtering
50 DEG C baking material 12 hours, obtain off-white powder (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo (3,4-
D) pyrimidine -4- amine 21.8g (V), molar yield 85.5%.(HPLC purity 99.5%；Optical purity >=99.8%).
Embodiment 4
The synthesis of Buddhist nun (I) is replaced according to Shandong
Methyl acrylate 0.86g (10mmol) and (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo
(3,4-d) pyrimidine -4- amine (V) (embodiment 1 is made) 4.25g (11mmol) is dissolved in the tetrahydrofuran of 15ml, and Zr (Ot- is added
Bu)40.19g (0.5mmol) and HOAt 0.07g (0.5mmol), stirring are warming up to 60 DEG C, and heat preservation continues stirring 12 hours.
System is naturally cooling to room temperature, and methanol and methylene chloride quenching reaction is added.It is filtered with silicagel pad, is washed with methylene chloride, collected
Filtrate is spin-dried for, recrystallisation from isopropanol, 50 DEG C forced air drying 8 hours, obtain 3.6g according to Shandong for Buddhist nun, yield 74%, purity 99.5%,1H-NMR(DMSO-d6, 400MHz) δ 9.48 (brs, 1H), 8.66 (s, 1H), 8.14 (brs, 1H), 7.69 (d, J=8.0Hz,
2H), 7.46 (t, J=7.6Hz, 2H), 7.22-7.12 (m, 5H), 6.90-6.66 (m, 1H), 6.15-6.05 (dd, J=
25.2Hz, 17.2Hz, 1H), 5.73-5.59 (dd, J=43.6Hz, 10.8Hz, 1H), 4.82-4.74 (m, 1H), 4.59 (d, J
=11.2Hz, 0.5H), 4.25 (m, 1H), 4.08 (d, J=12.8Hz, 0.5H), 3.77-3.68 (m, 0.5H), 3.28-3.19
(m, 1H), 3.09 (t, J=10.4Hz, 0.5H), 2.27-2.17 (m, 2H), 1.95 (d, J=13.6Hz, 1H), 1.63-1.60
(m, 1H)；LCMS (ESI, m/z): 441.3 [M+H]+。
Embodiment 5
The synthesis of Buddhist nun (I) is replaced according to Shandong
Ethyl acrylate 1g (10mmol) and (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo (3,
4-d) pyrimidine -4- amine (V) (embodiment 2 is made) 4.25g (11mmol) is dissolved in the dioxane of 20ml, is added Zr (Ot-Bu)4
0.19g (0.5mmol) and HOAt 0.14g (1mmol), stirring are warming up to 80 DEG C, and heat preservation continues stirring 16 hours.System is natural
It is cooled to room temperature, methanol and methylene chloride quenching reaction is added.It is filtered with silicagel pad, is washed with methylene chloride, collect filtrate, rotation
It is dry, recrystallisation from isopropanol, 50 DEG C forced air drying 10 hours, obtain 3.4g according to Shandong for Buddhist nun, yield 70%, purity 99.5%.
Embodiment 6
The synthesis of Buddhist nun (I) is replaced according to Shandong
Methyl acrylate 0.95g (11mmol) and (R) -3- (4- Phenoxyphenyl) -1- (piperidines -3- base) -1H- pyrazolo
(3,4-d) pyrimidine -4- amine (V) (embodiment 3 is made) 4.25g (11mmol) is dissolved in the toluene of 20ml, is added Zr (Ot-Bu)4
0.19g (0.5mmol) and HOBt 0.14g (1mmol), stirring are warming up to 60 DEG C, and heat preservation continues stirring 12 hours.System is natural
It is cooled to room temperature, methanol and methylene chloride quenching reaction is added.It is filtered with silicagel pad, is washed with methylene chloride, collect filtrate, rotation
It is dry, be spin-dried for, recrystallisation from isopropanol, 50 DEG C forced air drying 12 hours, obtain 4.0g according to Shandong for Buddhist nun, yield 82%, purity 99.4%.
In conclusion the present invention effectively overcomes various shortcoming in the prior art and has high industrial utilization value.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (6)
1. a kind of preparation method for replacing Buddhist nun according to Shandong, includes the following steps:
1) 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and S-1- tertbutyloxycarbonyl -3- hydroxy piperidine
It being reacted through Mitsunobu, prepares formula IV compound, formula IV compound sloughs Boc protecting group and prepares Formula V compound,
Reaction equation is as follows:
In the step 1), 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and S-1- tertiary butyloxycarbonyl
Base -3- hydroxy piperidine is after Mitsunobu reacts, and for the product prepared without purifying, directly progress formula IV compound is de-
Boc protecting group is gone to prepare the operation of Formula V compound；
In the step 1), the post-processing approach of reaction are as follows: in reaction products therefrom plus water, after organic solvent washing, adjust
For the pH of water phase to alkalinity, the white solid for collecting precipitation is Formula V compound；
2) under the conditions of Formula V compound and acrylate are existing for the catalyst and activator, compound of formula I is prepared, is reacted
Equation is as follows:
In the Formula XII compound, R is selected from the C for having branch or unbranched saturation1-6Aliphatic group；
In the step 2), the molar ratio of acrylate and Formula V compound is 1:1~1.5；
In the step 2), reaction temperature is 50~90 DEG C；
In the step 2), catalyst is selected from Zr (Ot-Bu)4、Ti(Oi-Pr)4、Hf(Ot-Bu)4One of or a variety of groups
It closes；
In the step 2), activator is selected from one of HOAt, HOBt, HYP, DMAP, PFP or a variety of combinations；
In the step 2), reaction carries out in the presence of a solvent, and the solvent is selected from aprotic solvent；
In the step 2), the method for post-reaction treatment are as follows: reaction is quenched, is separated by solid-liquid separation, after liquid phase concentration recrystallization to obtain the final product
Compound of formula I.
2. preparation method as described in claim 1, which is characterized in that in the step 1), 4- amino -3- (4- phenoxy group benzene
Base) molar ratio of -1H- pyrazolo [3,4-d] pyrimidine and S-1- tertbutyloxycarbonyl -3- hydroxy piperidine is 1:1~3；
And/or in the step 1), the reaction temperature of Mitsunobu reaction is 15 DEG C -60 DEG C；
And/or in the step 1), reaction carries out under inert gas atmosphere；
And/or in the step 1), azodicarboxy acid diesters are selected from one of DEAD, DIAD, DBAD or a variety of combinations；
And/or in the step 1), 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and azodicarboxy
The molar ratio of acid diesters is 1:1.2~5；
And/or in the step 1), trialkyl phosphine is selected from one of TBP, TMP or a variety of combinations；
And/or in the step 1), triaryl phosphine is selected from one of TPP, diphenyl methyl phosphine or a variety of combinations；
And/or in the step 1), 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and trialkyl phosphine
And/or the molar ratio of triaryl phosphine is 1:1.2~5；
And/or in the step 1), reaction carries out in the presence of a solvent, and the solvent is selected from aprotic solvent；
And/or in the step 1), formula IV compound sloughs Boc protecting group and prepares Formula V compound method particularly includes:
Formula IV compound sloughs Boc protecting group in acid condition and prepares Formula V compound.
3. preparation method as claimed in claim 2, which is characterized in that in the step 1), 4- amino -3- (4- phenoxy group benzene
Base) molar ratio of -1H- pyrazolo [3,4-d] pyrimidine and S-1- tertbutyloxycarbonyl -3- hydroxy piperidine is 1:1.2~2；
And/or in the step 1), the reaction temperature of Mitsunobu reaction is 25 DEG C~55 DEG C；
And/or in the step 1), 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and azodicarboxy
The molar ratio of acid diesters is 1:1.5~4；
And/or in the step 1), 4- amino -3- (4- Phenoxyphenyl) -1H- pyrazolo [3,4-d] pyrimidine and trialkyl phosphine
And/or the molar ratio of triaryl phosphine is 1:1.5~4；
And/or in the step 1), solvent is selected from one of benzene, tetrahydrofuran, ether, dioxane, methylene chloride or more
The combination of kind；
And/or in the step 1), acid condition is specially pH=0~3；
And/or in the step 1), formula IV compound sloughs reaction during Boc protecting group prepares Formula V compound
Temperature is 30 DEG C -50 DEG C；
And/or in the step 1), formula IV compound sloughs reaction during Boc protecting group prepares Formula V compound
Time is 0.5~1.5 hour；
And/or in the step 1), the pH for adjusting water phase to alkalinity refers specifically to the pH value of water phase being adjusted to pH > 10.
4. preparation method as claimed in claim 3, which is characterized in that in the step 1), acid condition be specially pH=0~
2；
And/or in the step 1), formula IV compound sloughs reaction during Boc protecting group prepares Formula V compound
Temperature is 35~45 DEG C；
And/or in the step 1), formula IV compound sloughs reaction during Boc protecting group prepares Formula V compound
Time is 0.8~1.2 hour.
5. preparation method as described in claim 1, which is characterized in that in the step 2), acrylate and Formula V compound
Molar ratio is 1:1~1.2；
And/or in the step 2), reaction temperature is 60~80 DEG C；
And/or in the step 2), solvent in tetrahydrofuran, dioxane, toluene, methyl tertiary butyl ether(MTBE), acetonitrile one
Kind or a variety of combinations.
6. preparation method as claimed in claim 5, which is characterized in that in the step 2), in the Formula XII compound, R choosing
From methyl and/or ethyl.
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| CN111116593B (en) * | 2019-11-27 | 2020-11-24 | 河北合佳医药科技集团股份有限公司 | Continuous preparation method of imatinib |
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