CN106008526A - Preparation method of ibrutinib - Google Patents
Preparation method of ibrutinib Download PDFInfo
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- CN106008526A CN106008526A CN201610435692.1A CN201610435692A CN106008526A CN 106008526 A CN106008526 A CN 106008526A CN 201610435692 A CN201610435692 A CN 201610435692A CN 106008526 A CN106008526 A CN 106008526A
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- pyrimidine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title abstract description 8
- 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 title abstract description 8
- 229960001507 ibrutinib Drugs 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000006751 Mitsunobu reaction Methods 0.000 claims abstract description 5
- 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 21
- 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
- 239000008346 aqueous phase Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000012190 activator Substances 0.000 claims description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 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
- 238000001953 recrystallisation Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-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
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 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
- 239000012141 concentrate Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011261 inert gas Substances 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
- 238000000926 separation method 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
- 230000035484 reaction time Effects 0.000 claims 2
- 150000007984 tetrahydrofuranes Chemical group 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 acrylic ester Chemical class 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000001816 cooling Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 231100000086 high toxicity Toxicity 0.000 abstract description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract 1
- 230000003213 activating effect Effects 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 12
- 230000004044 response 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
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000003786 synthesis reaction 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
- 230000000694 effects Effects 0.000 description 5
- 238000005516 engineering process Methods 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
- 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
- 230000008859 change Effects 0.000 description 4
- 239000000463 material Substances 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
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000376 reactant 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
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 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
- 229910052756 noble gas Inorganic materials 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
- 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
- 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
- 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
- ZBARNRZZPLEMDK-UHFFFAOYSA-N C(=O)=C1NCCCC1O.[O] Chemical compound C(=O)=C1NCCCC1O.[O] ZBARNRZZPLEMDK-UHFFFAOYSA-N 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
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 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
- 210000004027 cell Anatomy 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
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical class C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 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
- 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
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification 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
- 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
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-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
- 230000001105 regulatory effect Effects 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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 invention relates to the technical field of medicine, in particular to a preparation method of ibrutinib. The preparation method of ibrutinib comprises the following steps that 4-amino-3-(4-phenoxy phenyl)-1H-pyrazol[3,4-d]pyrimidine and S-1-tert-butyloxycarbonyl-3-hydroxyl piperidine are prepared into a compound shown in the formula IV (please see the formula in the description) through a Mitsunobu reaction, and a Boc protecting group of the compound shown in the formula IV is removed to prepare a compound shown in the formula V (please see the formula in the description); the compound shown in the formula V and acrylic ester are prepared into a compound shown in the formula I (please see the formula in the description) in the presence of a catalyst and an activating agent. According to the preparation method, the reaction process is mild in condition, few reaction steps are needed, high temperature and copious cooling are not needed, no high-toxicity reagent is adopted, and the whole synthesizing process is stable and controllable; ibrutinib prepared through the method is high in yield and quality and has the advantages of being good in stability, high in purity, convenient to store and the like.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to a kind of preparation method replacing Buddhist nun according to Shandong.
Background technology
According to Shandong for Buddhist nun (English name Ibrutinib, trade name Imbruvica, molecular formula C25H24N6O2, molecular weight 440.50)
Having the structure shown in Formulas I, chemical name is 1-[(3R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-
D] pyrimidine-1-base)-piperidino)-2-propylene-1-ketone.Buddhist nun (Ibrutinib) is replaced to be a kind of by the U.S. according to Shandong
Pharmacyclics and Johson & Johnson develop jointly a kind of oral bruton's tyrosine kinase (BTK) inhibitor of listing
Pioneering new drug, this medicine by with target protein Btk activity site cysteine residue (Cys-481) optionally covalent bond, no
Reversibly suppress BTK, thus effectively stop tumor to move to be adapted to the lymphoid tissue of tumor growth environment from B cell.
Since on November 13rd, 2013 obtain FDA approval listing since, according to Shandong for Buddhist nun be used for lymphoma mantle cell (MCL),
5 indications such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) gradually obtain in the U.S. and criticize
Accurate.
Document ChemMedChem.2007,2 (1): 56-61 report the preparation method replacing Buddhist nun according to Shandong,
The method with 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine (II) for raw material, with S-1-
Tertbutyloxycarbonyl-3-hydroxy piperidine (III) reacts through Mitsunobu, sloughs Boc protection group and acrylated three-step reaction, system
Get Yi Lu replaces Buddhist nun (I).This route steps is many, and deprotection needs single reactions steps, uses the reaction of acryloyl chloride, although live
Property high, but it is acrylated to easily cause many sites N-, generates by-product, causes purification difficult.
China Patent Publication No. CN103121999 reports a kind of preparation method replacing Buddhist nun (I) according to Shandong.
The method 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 through cesium carbonate catalytic reaction, then trifluoroacetylation, de-Boc protection group and third
Alkene acyl chloride reaction and the reaction of de-trifluoroacetyl group, prepare according to Shandong for Buddhist nun (I).This route first step inorganic base catalytic reaction, optics
Purity can not be guaranteed, it addition, add trifluoroacetylation to prepare intermediate (VI) and de-trifluoroacetylation prepares intermediate
(VII) step, reactions steps is many, and cost increases, and is unfavorable for industrialized production.
China Patent Publication No. CN104557945A reports the another kind of preparation method replacing Buddhist nun (I) according to Shandong.
This method, does not separates by Suzuki coupling and Kumada coupling reaction as raw material 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 protection group and obtain intermediate (V), then mixed with what acyl chlorides and sulfonic acid chloride generated with acrylic acid
Anhydride acylation, this method employs expensive palladium catalyst (Pd (dppf)2Cl2And Pd2(dba)3), operation inconvenience, it is unfavorable for work
Industryization is amplified.
Summary of the invention
The shortcoming of prior art in view of the above, it is an object of the invention to provide a kind of preparation side replacing Buddhist nun according to Shandong
Method, is used for solving the problems of the prior art.
For achieving the above object and other relevant purposes, the present invention provide a kind of according to Shandong for Buddhist nun (Ibrutinib, Formulas I chemical combination
Thing) preparation method, comprise the 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) reacts through Mitsunobu, prepares formula IV compound, and formula IV compound takes off
Going Boc protection group to prepare Formula V compound, reaction equation is as follows:
In some embodiments of the present invention, described Mitsunobu reaction can be at azodicarboxy acid diesters and three alkane
Under conditions of (fragrant) base phosphine (such as, trialkyl phosphine and/or triaryl phosphine) exists, alcohol is carried out with the nucleopilic reagent with reactive hydrogen
Dehydration condensation.
Concrete, described step 1) in, the mole of S-1-tertbutyloxycarbonyl-3-hydroxy piperidine generally 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) mol ratio of-1H-pyrazolo [3,4-d] pyrimidine and S-1-tertbutyloxycarbonyl-3-hydroxy piperidine can be 1:1～3, and also
Can be 1:1.2～2.
Concrete, described step 1) in, the reaction temperature of Mitsunobu reaction can be 15～60 DEG C, it is also possible to is 25
～55 DEG C, it is also possible to it is 25～40 DEG C.
Those skilled in the art can adjust the response time according to real reaction situation, such as, can adjust according to reaction process
In the response time, reaction process can be monitored by methods such as such as TLC, HPLC, more such as, the response time can be 2～
20 hours, it is also possible to be 4～16 hours.
Concrete, described step 1) in, reaction is carried out under inert gas atmosphere, described noble gas be often referred to be difficult to
There is the gaseous material of chemical reaction in the main component (such as Formula II, formula III compound etc.) in reaction system, the most applicable
The example of noble gas include but not limited to: one or more in nitrogen, helium, neon, argon, Krypton, xenon etc.
Combination.
Concrete, described step 1) in, azodicarboxy acid diesters can be selected from DEAD (diethyl azodiformate), DIAD
The combination of one or more in (diisopropyl azodiformate), DBAD (tert-butyl azodicarboxylate) etc..
Concrete, described step 1) in, the mole of azodicarboxy acid diesters generally can be with equivalent or be in excess in 4-ammonia
The mole of base-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine, 4-amino-3-(4-Phenoxyphenyl)-1H-
Pyrazolo [3,4-d] pyrimidine can be 1:1.2～5 with the mol ratio of azodicarboxy acid diesters, it is also possible to for 1:1.5～4.
Concrete, described step 1) in, trialkyl phosphine one in TBP (tributylphosphine), TMP (trimethyl-phosphine) etc.
Or multiple combination.
Concrete, described step 1) in, triaryl phosphine one in TPP (triphenylphosphine), diphenyl methyl phosphine etc.
Or multiple combination.
Concrete, described step 1) in, the mole of trialkyl phosphine and/or triaryl phosphine generally can be with equivalent or excess
In the mole of 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine, 4-amino-3-(4-phenoxy group benzene
Base) mol ratio of-1H-pyrazolo [3,4-d] pyrimidine and trialkyl phosphine and/or triaryl phosphine can be 1:1.2～5, it is also possible to
For 1:1.5-4.
When only using trialkyl phosphine, above-mentioned ratio refers specifically to, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo
[3,4-d] pyrimidine and the mol ratio of trialkyl phosphine；When only using triaryl phosphine, above-mentioned ratio refers specifically to, 4-amino-3-
(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and the mol ratio of triaryl phosphine；When using trialkyl phosphine and triaryl
During phosphine, above-mentioned ratio refers specifically to, the mole of 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine with
The ratio of the mole sum of trialkyl phosphine and triaryl phosphine.
Concrete, described step 1) in, reaction is carried out in the presence of a solvent, and described solvent is selected from non-proton molten
Agent.
More specifically, described step 1) in, solvent is in benzene, dioxane, oxolane, ether, dichloromethane etc.
The combination of one or more.
Described step 1) in, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and S-1-tertiary fourth oxygen
Carbonyl-3-hydroxy piperidine is after Mitsunobu reacts, and the product prepared can not be purified (employing one pot synthesis),
Directly carry out formula IV compound to slough Boc protection group and prepare the operation of Formula V compound.
Concrete, described step 1) in, formula IV compound is sloughed Boc protection group and is prepared the concrete side of Formula V compound
Method is: formula IV compound is sloughed Boc protection group in acid condition and prepared Formula V compound.
More specifically, described step 1) in, acid condition is specifically as follows pH=0～3, it is also possible to for pH=0～2, basis
It, for regulating the pH value of reaction system, can be specifically such as hydrochloric acid etc. that skilled person can be selected for suitably acid, regulates pH
Time reaction system can be cooled down, such as can regulate the pH value of reaction system under the conditions of 0-10 DEG C.
More specifically, described step 1) in, formula IV compound is sloughed Boc protection group and is prepared the process of Formula V compound
In, reaction temperature can be 20 DEG C～55 DEG C.
Those skilled in the art can adjust the response time according to real reaction situation, such as, can adjust according to reaction process
In the response time, reaction process can be monitored by methods such as such as TLC, HPLC, more such as formula IV compound is sloughed Boc and protected
Protecting base and prepare the response time during Formula V compound can be 1～16 hour.
In the present invention one preferred implementation, described step 1) in, formula IV compound is sloughed Boc protection group and is prepared
During Formula V compound, reaction temperature can be 30～50 DEG C, it is also possible to is 35～45 DEG C, and the response time is 0.5～1.5
Hour, it is also possible to it is 0.8～1.2 hour.
Concrete, described step 1) in, the post-processing approach of reaction is: add water in reaction products therefrom, organic solvent
After washing, the pH of regulation aqueous phase to alkalescence, collects the white solid separated out and is Formula V compound.
It is furthermore preferred that the pH of described regulation aqueous phase refers specifically to regulate to pH ＞ 10 pH value of aqueous phase to alkalescence.
2) Formula V compound and acrylate (Formula X II compound) are under conditions of catalyst and activator exist, and preparation obtains
Obtaining compound of formula I, reaction equation is as follows:
Concrete, described step 2) in, the mole of Formula V compound generally can be with equivalent or be in excess in acrylate
Mole, acrylate can be 1:1～1.5 with the mol ratio of Formula V compound, it is also possible to for 1:1～1.2.
Concrete, in described Formula X II compound, R is selected from there being side chain or unbranched, saturated or unsaturated, optional
The most mono-substituted C in ground1-10Aliphatic group, it is also possible to for C1-6Aliphatic group, it is also possible to for C1-4Aliphatic group, also may be used
Think C1-3Aliphatic group.
In some detailed description of the invention of the present invention, described R is selected from methyl and/or ethyl.
Concrete, described step 2) in, reaction temperature is 50～90 DEG C, it is also possible to be 60～80 DEG C.
Those skilled in the art can adjust the response time according to real reaction situation, such as, can adjust according to reaction process
In the response time, reaction process can be monitored by methods such as such as TLC, HPLC, more such as, the response time can be 2～
20 hours, it is also possible to be 6～16 hours.
Concrete, described step 2) in, catalyst is selected from Zr (Ot-Bu)4(tetrabutyl zirconate), Ti (Oi-Pr) 4 (metatitanic acid
Four isopropyl esters), the combination of one or more in Hf (Ot-Bu) 4 (hafnium acid four butyl esters).
Those skilled in the art generally can determine the usage amount of catalyst, institute according to the kind of catalyst and reaction system
The usage amount stating catalyst is usually catalytic amount, and usual and Formula V compound mol ratio can be 0.01～0.20:1, it is also possible to
For 0.04-0.10:1.
Concrete, described step 2) in, activator may generally function as promoting the effect of catalyst activity, art technology
Personnel can select suitable activator according to the kind of catalyst, and such as, described activator can be selected from HOAt (1-hydroxyl-7-
Azo BTA), HOBt (I-hydroxybenzotriazole), HYP (2 hydroxy pyrimidine), DMAP (DMAP), PFP
The combination of one or more in (Pentafluorophenol).
Those skilled in the art generally can determine the usage amount of activator, institute according to the kind of activator and reaction system
Stating usual and Formula V compound the mol ratio of activator can be 0.01～0.2:1, it is also possible to be 0.04～0.15:1.
Concrete, described step 2) in, reaction is carried out in the presence of a solvent, and described solvent is selected from non-proton molten
Agent.
More specifically, described step 2) in, solvent is selected from oxolane, dioxane, toluene, methyl tertiary butyl ether(MTBE), second
The combination of one or more in nitrile etc..
Concrete, described step 2) in, the method for post-reaction treatment is: will react cancellation, solid-liquid separation, and liquid phase concentrates weight
Compound of formula I is i.e. obtained after crystallization.
Those skilled in the art can be selected for suitable method and reaction carried out cancellation, it is, for example possible to use appropriate methanol
And/or dichloromethane, water carry out cancellation to reaction.
Those skilled in the art can be selected for suitable method and carry out recrystallization, such as, in some specific embodiment parties of the present invention
In formula, isopropanol is used to carry out recrystallization as solvent.
A kind of preparation method replacing Buddhist nun according to Shandong provided by the present invention, whole course of reaction mild condition, reactions steps is few,
Without high temperature, deep cooling, and do not use high toxicity reagent, whole building-up process to stablize controlled, utilize formula IV compound cleverly not
Separate " one pot synthesis ", shorten purification procedures, save the energy and and environmental friendliness, utilize acrylate replace acryloyl
The process for acylating of chlorine, has the features such as good, the process safety of yield, and the product that its synthesis obtains is without potential safety issue.Logical
Cross that this preparation method prepares according to Shandong for Buddhist nun's yield and superior in quality, there is good stability, purity is high, it is excellent to be easy to storage etc.
Point.
Accompanying drawing explanation
Fig. 1 be shown as that the embodiment of the present invention 4 synthesis obtains according to Shandong for Buddhist nun1H-NMR spectrum.
Fig. 2 is shown as the mass spectrum replacing Buddhist nun according to Shandong that the embodiment of the present invention 4 synthesis obtains.
Detailed description of the invention
Below by way of specific instantiation, embodiments of the present invention being described, those skilled in the art can be by this specification
Disclosed content understands other advantages and effect of the present invention easily.The present invention can also be by the most different concrete realities
The mode of executing is carried out or applies, the every details in this specification can also based on different viewpoints and application, without departing from
Various modification or change is carried out under the spirit of the present invention.
It should be clear that conventional equipment in the concrete process equipment indicated or device all use this area in the following example or
Device.
In addition, it is to be understood that the one or more method steps mentioned in the present invention do not repel before and after described combination step
Additive method step can also be there is or additive method step can also be inserted between these steps specifically mentioned, unless separately
It is described；Should also be understood that the combination annexation between the one or more equipment/devices mentioned in the present invention is not repelled
Can also exist before and after described unit equipment/device other equipment/devices or these two equipment/devices specifically mentioned it
Between can also insert other equipment/devices, except as otherwise noted.And, except as otherwise noted, the numbering of various method steps is only
Differentiate the convenient tool of various method steps, rather than for limiting the ordering of various method steps or limiting the enforceable model of the present invention
Enclose, being altered or modified of its relativeness, in the case of without essence change technology contents, enforceable when being also considered as the present invention
Category.
Embodiment 1
(R) synthesis of-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo (3,4-d) pyrimidine-4-amine (5)
1L there-necked flask adds 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine 20g
(66mmol)；S-1-tertbutyloxycarbonyl-3-hydroxy piperidine 13.3g (66mmol)；Triphenylphosphine 34.6g (132mmol), adds dry
Dry oxolane 300mL, is cooled to 5-10 DEG C.Under nitrogen protection, in bottle, it is slowly added dropwise diisopropyl azodiformate
26.7g (132mmol), drips off, and 30 DEG C are reacted 10 hours.Reactant liquor is cooled to 0-10 DEG C again, drips 36% hydrochloric acid 13.4g
(132mmol), drip off be warming up to 40 DEG C react 1 hour.Add water, stirring, extract 3 times with dichloromethane, collect aqueous phase, use hydrogen
Sodium hydroxide solution regulation aqueous phase one-tenth alkalescence (pH ＞ 10), separates out solid, filters, and collects solid, 50 DEG C of baking material of air blast 8 hours, obtains
Off-white color solid (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)
1L there-necked flask adds 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine 20g
(66mmol)；S-1-tertbutyloxycarbonyl-3-hydroxy piperidine 26.6g (132mmol)；Triphenylphosphine 51.9g (198mmol), adds
The oxolane 400mL being dried, is cooled to 5-10 DEG C.Under nitrogen protection, in bottle, it is slowly added dropwise diisopropyl azodiformate
40g (198mmol), drips off, and 30 DEG C are reacted 12 hours.Reactant liquor is cooled to 0-10 DEG C again, drips 36% hydrochloric acid 20g
(198mmol), drip off be warming up to 40 DEG C react 1 hour.Add water, stirring, extract 3 times with dichloromethane, collect aqueous phase, use hydrogen
Sodium hydroxide solution regulation aqueous phase one-tenth alkalescence (pH ＞ 10), separates out solid, filters, and collects solid, 50 DEG C of baking material of air blast 12 hours, obtains
Off-white color solid (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)
1L there-necked flask adds 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine 20g
(66mmol)；S-1-tertbutyloxycarbonyl-3-hydroxy piperidine 26.6g (132mmol)；Triphenylphosphine 51.9g (198mmol), adds
The oxolane 400mL being dried, is cooled to 5-10 DEG C.Under nitrogen protection, in bottle, it is slowly added dropwise diisopropyl azodiformate
40g (198mmol), drips off, and 30 DEG C are reacted 12 hours.Reactant liquor is cooled to 0-10 DEG C again, drips trifluoroacetic acid 22.5g
(198mmol), drip off be warming up to 40 DEG C react 1 hour.TLC monitoring reaction terminates.Add water, stirring, extract 3 with dichloromethane
Secondary, collect aqueous phase, become alkalescence (pH ＞ 10) with sodium hydroxide solution regulation aqueous phase, separate out solid, filter, collect solid, air blast
50 DEG C of baking material 12 hours, obtain off-white color solid (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
Acrylic acid methyl ester. 0.86g (10mmol) and (R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo
(3,4-d) pyrimidine-4-amine (V) (embodiment 1 prepares) 4.25g (11mmol) is dissolved in the oxolane of 15ml, adds Zr (Ot-
Bu)40.19g (0.5mmol) and HOAt 0.07g (0.5mmol), stirring, it is warming up to 60 DEG C, insulation continues stirring 12 hours.
System is naturally cooling to room temperature, adds methanol and dichloromethane cancellation reaction.Filter by silicagel pad, wash with dichloromethane, collect
Filtrate, is spin-dried for, recrystallisation from isopropanol, 50 DEG C of forced air dryings 8 hours, obtains 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 prepares) 4.25g (11mmol) is dissolved in the dioxane of 20ml, adds Zr (Ot-Bu)4
0.19g (0.5mmol) and HOAt 0.14g (1mmol), stirring, it is warming up to 80 DEG C, insulation continues stirring 16 hours.System is natural
It is cooled to room temperature, adds methanol and dichloromethane cancellation reaction.Filter by silicagel pad, wash with dichloromethane, collect filtrate, rotation
Dry, recrystallisation from isopropanol, 50 DEG C of forced air dryings 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
Acrylic acid methyl ester. 0.95g (11mmol) and (R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo
(3,4-d) pyrimidine-4-amine (V) (embodiment 3 prepares) 4.25g (11mmol) is dissolved in the toluene of 20ml, adds Zr (Ot-Bu)4
0.19g (0.5mmol) and HOBt 0.14g (1mmol), stirring, it is warming up to 60 DEG C, insulation continues stirring 12 hours.System is natural
It is cooled to room temperature, adds methanol and dichloromethane cancellation reaction.Filter by silicagel pad, wash with dichloromethane, collect filtrate, rotation
Dry, it is spin-dried for, recrystallisation from isopropanol, 50 DEG C of forced air dryings 12 hours, obtains 4.0g according to Shandong for Buddhist nun, yield 82%, purity 99.4%.
In sum, the present invention effectively overcomes various shortcoming of the prior art and has high industrial utilization.
The principle of above-described embodiment only illustrative present invention and effect thereof, not for limiting the present invention.Any ripe
Above-described embodiment all can be modified under the spirit and the scope of the present invention or change by the personage knowing this technology.Cause
This, have usually intellectual such as complete with institute under technological thought without departing from disclosed spirit in art
All equivalences become are modified or change, and must be contained by the claim of the present invention.
Claims (7)
1., according to Shandong for the preparation method of Buddhist nun, comprise the steps:
1) 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and S-1-tertbutyloxycarbonyl-3-hydroxy piperidine
Reacting through Mitsunobu, prepare formula IV compound, formula IV compound is sloughed Boc protection group and is prepared Formula V compound,
Reaction equation is as follows:
2) Formula V compound and acrylate are under conditions of catalyst and activator exist, and prepare compound of formula I, reaction
Equation is as follows:
2. preparation method as claimed in claim 1, it is characterised in that described step 1) in, 4-amino-3-(4-phenoxy group benzene
Base) mol ratio of-1H-pyrazolo [3,4-d] pyrimidine and S-1-tertbutyloxycarbonyl-3-hydroxy piperidine is 1:1～3；
And/or, described step 1) in, the reaction temperature of Mitsunobu reaction is 15 DEG C-60 DEG C；
And/or, described step 1) in, reaction is carried out under inert gas atmosphere；
And/or, described step 1) in, the combination of one or more in DEAD, DIAD, DBAD of the azodicarboxy acid diesters；
And/or, described step 1) in, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and azodicarboxy
The mol ratio of acid diesters is 1:1.2～5；
And/or, described step 1) in, the trialkyl phosphine combination of one or more in TBP, TMP；
And/or, described step 1) in, the triaryl phosphine combination of one or more in TPP, diphenyl methyl phosphine；
And/or, described step 1) in, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and trialkyl phosphine
And/or the mol ratio of triaryl phosphine can be 1:1.2～5；
And/or, described step 1) in, reaction is carried out in the presence of a solvent, and described solvent is selected from aprotic solvent；
And/or, described step 1) in, formula IV compound is sloughed Boc protection group and is prepared Formula V compound method particularly includes:
Formula IV compound is sloughed Boc protection group in acid condition and is prepared Formula V compound；
And/or, described step 1) in, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and the tertiary fourth of S-1-
Oxygen carbonyl-3-hydroxy piperidine is after Mitsunobu reacts, and the product prepared is not purified, and directly carries out formula IV chemical combination
Thing is sloughed Boc protection group and is prepared the operation of Formula V compound；
And/or, described step 1) in, the post-processing approach of reaction is: add water in reaction products therefrom, organic solvent washing
After, the pH of regulation aqueous phase to alkalescence, collects the white solid separated out and is Formula V compound.
3. preparation method as claimed in claim 2, it is characterised in that described step 1) in, 4-amino-3-(4-phenoxy group benzene
Base) mol ratio of-1H-pyrazolo [3,4-d] pyrimidine and S-1-tertbutyloxycarbonyl-3-hydroxy piperidine is 1:1.2～2；
And/or, described step 1) in, the reaction temperature of Mitsunobu reaction is 25 DEG C～55 DEG C；
And/or, described step 1) in, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and azodicarboxy
The mol ratio of acid diesters is 1:1.5～4；
And/or, described step 1) in, 4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine and trialkyl phosphine
And/or the mol ratio of triaryl phosphine is 1:1.5～4；
And/or, described step 1) in, solvent one or many in benzene, oxolane, ether, dioxane, dichloromethane
The combination planted；
And/or, described step 1) in, acid condition is specially pH=0～3；
And/or, described step 1) in, formula IV compound is sloughed during Boc protection group prepares Formula V compound, reaction
Temperature is 30 DEG C-50 DEG C；
And/or, described step 1) in, formula IV compound is sloughed during Boc protection group prepares Formula V compound, reaction
Time is 0.5～1.5 hour；
And/or, described step 1) in, the pH of described regulation aqueous phase to alkalescence refers specifically to regulate to pH ＞ 10 pH value of aqueous phase.
4. preparation method as claimed in claim 3, it is characterised in that described step 1) in, acid condition be specially pH=0～
2；
And/or, described step 1) in, formula IV compound is sloughed during Boc protection group prepares Formula V compound, reaction
Temperature is 35～45 DEG C；
And/or, described step 1) in, formula IV compound is sloughed during Boc protection group prepares Formula V compound, reaction
Time is 0.8～1.2 hour.
5. preparation method as claimed in claim 1, it is characterised in that described step 2) in, acrylate and Formula V compound
Mol ratio can be 1:1～1.5；
And/or, in described Formula X II compound, R is selected from there being side chain or unbranched, saturated or unsaturated, the most at least
Mono-substituted C1-10Aliphatic group；
And/or, described step 2) in, reaction temperature is 50～90 DEG C；
And/or, described step 2) in, catalyst is selected from Zr (Ot-Bu)4、Ti(Oi-Pr)4、Hf(Ot-Bu)4In one or many
The combination planted；
And/or, described step 2) in, the activator combination of one or more in HOAt, HOBt, HYP, DMAP, PFP；
And/or, described step 2) in, reaction is carried out in the presence of a solvent, and described solvent is selected from aprotic solvent；
And/or, described step 2) in, the method for post-reaction treatment is: will react cancellation, solid-liquid separation, and liquid phase concentrates recrystallization
After i.e. obtain compound of formula I.
6. preparation method as claimed in claim 5, it is characterised in that described step 2) in, acrylate and Formula V compound
Mol ratio can be 1:1～1.2；
And/or, in described Formula X II compound, R is selected from there being side chain or unbranched, saturated or unsaturated, the most at least
Mono-substituted C1-6Aliphatic group；
And/or, described step 2) in, reaction temperature is 60～80 DEG C；
And/or, described step 2) in, solvent is selected from oxolane, dioxane, toluene, methyl tertiary butyl ether(MTBE), acetonitrile
Kind or multiple combination.
7. preparation method as claimed in claim 6, it is characterised in that described step 2) in, in described Formula X II compound, R selects
From methyl and/or ethyl.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831788A (en) * | 2017-01-22 | 2017-06-13 | 鲁南制药集团股份有限公司 | Yi Bu replaces Buddhist nun's process for purification |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831788A (en) * | 2017-01-22 | 2017-06-13 | 鲁南制药集团股份有限公司 | Yi Bu replaces Buddhist nun's process for purification |
| CN106831788B (en) * | 2017-01-22 | 2020-10-30 | 鲁南制药集团股份有限公司 | Ibutotinib refining method |
| CN111004239A (en) * | 2018-10-08 | 2020-04-14 | 上海柏狮生物科技有限公司 | Preparation method of ibrutinib precursor |
| CN111116593A (en) * | 2019-11-27 | 2020-05-08 | 河北合佳医药科技集团股份有限公司 | Continuous and low-cost preparation method of imatinib |
| CN113583001A (en) * | 2021-07-13 | 2021-11-02 | 江苏君若药业有限公司 | Preparation of ibrutinib |
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| CN106008526B (en) | 2018-12-04 |
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