CN106866624B - It is a kind of to block than the chemical synthesis process for Buddhist nun - Google Patents
It is a kind of to block than the chemical synthesis process for Buddhist nun Download PDFInfo
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- CN106866624B CN106866624B CN201710105737.3A CN201710105737A CN106866624B CN 106866624 B CN106866624 B CN 106866624B CN 201710105737 A CN201710105737 A CN 201710105737A CN 106866624 B CN106866624 B CN 106866624B
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- buddhist nun
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- ethyl acetate
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- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 239000012044 organic layer Substances 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229940125782 compound 2 Drugs 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 239000011701 zinc Substances 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 239000010410 layer Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- DBMRSXHNJMWYGQ-UHFFFAOYSA-N n-fluoro-4-iodoaniline Chemical class FNC1=CC=C(I)C=C1 DBMRSXHNJMWYGQ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- ZLWLTDZLUVBSRJ-UHFFFAOYSA-K chembl2360149 Chemical compound [Na+].[Na+].[Na+].O=C1C(N=NC=2C=CC(=CC=2)S([O-])(=O)=O)=C(C(=O)[O-])NN1C1=CC=C(S([O-])(=O)=O)C=C1 ZLWLTDZLUVBSRJ-UHFFFAOYSA-K 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 17
- 230000000977 initiatory effect Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 238000011938 amidation process Methods 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- YJPHJYYUYIEGIG-UHFFFAOYSA-N FCC1=C(C#N)C=CC(=C1CF)CF Chemical compound FCC1=C(C#N)C=CC(=C1CF)CF YJPHJYYUYIEGIG-UHFFFAOYSA-N 0.000 abstract 1
- 238000007259 addition reaction Methods 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 238000005457 optimization Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 8
- 201000001441 melanoma Diseases 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229910052723 transition metal Inorganic materials 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- -1 transition metal salt Chemical class 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 229940124647 MEK inhibitor Drugs 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- WJFTZTWFUUOBLV-UHFFFAOYSA-N 2-(azetidin-3-yl)piperidine Chemical class C1NCC1C1NCCCC1 WJFTZTWFUUOBLV-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 102000018471 Proto-Oncogene Proteins B-raf Human genes 0.000 description 2
- 108010091528 Proto-Oncogene Proteins B-raf Proteins 0.000 description 2
- 229910052772 Samarium Inorganic materials 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- BSMCAPRUBJMWDF-KRWDZBQOSA-N cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 description 2
- 229960002271 cobimetinib Drugs 0.000 description 2
- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- DRNJIKRLQJRKMM-UHFFFAOYSA-N 4-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=C(C#N)C=C1 DRNJIKRLQJRKMM-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 229910052779 Neodymium Inorganic materials 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- RHFUXPCCELGMFC-UHFFFAOYSA-N n-(6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl)-n-phenylmethoxyacetamide Chemical compound OC1C(C)(C)OC2=CC=C(C#N)C=C2C1N(C(=O)C)OCC1=CC=CC=C1 RHFUXPCCELGMFC-UHFFFAOYSA-N 0.000 description 1
- QEFYFXOXNSNQGX-UHFFFAOYSA-N neodymium atom Chemical compound [Nd] QEFYFXOXNSNQGX-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 239000003579 shift reagent Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000005059 solid analysis Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention belongs to the field of chemical synthesis, and in particular to a kind of to block than the preparation method for Buddhist nun.This method, for initiation material, is obtained card ratio by steps such as substitution reaction, deprotection reaction, amidation process, catalytic addition reactions and replaces Buddhist nun with 2,3,4 trifluoromethyl benzonitrile acid benzyl esters.This method raw material is cheap and easy to get, and process route section, work course of reaction is easily operated, high income, and environment-friendly, is adapted to industrial mass production.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of antineoplastic card is than the chemical synthesis process for Buddhist nun.
Background technology
Melanoma, also known as malignant mela noma, a kind of malignant tumour of melanocyte is derived from, is common in skin
Skin, also see the positions such as mucous membrane, ocular choroid.Human body is for a long time the master that melanoma is formed under ultraviolet irradiation
Want reason.Although melanoma only accounts for the 5% of all cutaneum carcinoma patients, recent decades rapid development.Melanoma is that skin swells
, easily there is DISTANT METASTASES IN, and the death rate is high in grade malignancy highest knurl kind in knurl.
Malignant mela noma treatment method mainly has:Operative treatment, chemotherapy, immunization therapy and targeted therapy.Maligna
The grade malignancy of plain knurl is high, easily transfer, should surgery excision, therefore surgical resection lesion is to treat the disease as early as possible once making a definite diagnosis
Main method, more after it is poor, easily recurrence, therefore clinical Common Chemotherapy method treat, although chemotherapeutics once once conduct
The standard scheme of malignant mela noma brain metastes treatment, but existing chemotherapeutics is not apparent from extending patient survival, treatment effect
Fruit is limited.Immunization therapy mainly has (CTLA4) Antybody therapy of anti-cell poison T lymphocytes GAP-associated protein GAP 4 and anti-program at present
Property dead -1 (PD-1) Antybody therapy.But price is very expensive, can not popularize.Targeted therapy includes c-Kit kinase inhibitions
Agent, B-RAF inhibitor and MEK inhibitor.By c- in US National synthesis cancer network (NCCN) treatment guidelines in 2013
Direction of medication usage of the Kit kinase inhibitors Imatinib (imatinib) as the Kit metastasis melanin tumors being mutated.Prestige sieve
Fei Ni (Vemurafenib) and card are than replacing Buddhist nun (Cobimetinib) respectively as B-RAF inhibitor and MEK inhibitor, more targets
Point blocks cell pathway, reduces bad hair and answers incidence, and moderate, has obtained very high degree of recognition, has clinically been worth
It must promote.
Card is than replacing the anti-cancer agent that Buddhist nun is Exelixis companies of the U.S. and Genentech companies cooperative research and development, trade name
For Cotellic, after developed by Roche Holding Ag of Switzerland for treatment of solid tumors.The medicine belongs to oral small molecule MEK inhibitor,
MEk is a kind of protein kinase, is a part for RAS-RAF-MEK-ERK signal paths, the path can promote cell division and
Survival, is often active in human cancer (including melanoma).Blocking ratio being capable of selective exclusion MEK albumen for Buddhist nun
Activity, so as to block signal path downstream to conduct.In vitro with the research of Xenograft Tumor Models, card ratio replaces Buddhist nun
Concentration is high in tumour and the residence time is grown, and has significant antitumor activity.
Block than chemical entitled [bis- fluoro- 2- of 3,4- [(the fluoro- 4- iodophenyls of 2-) amino] the phenyl] [3- hydroxyls -3- for Buddhist nun
(2S) -2- piperidyl -1- azelidinyls] ketone, molecular formula C21H21F3IN3O2, molecular weight 531.31, structural formula is such as
Under：
On card than the chemical synthesis process existing multiple patents and document report for Buddhist nun.Patent
WO2007044515A1, WO2008076415A1, WO2008124085A3 and document Novel Carboxamide-Based
Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518
(GDC-0973)（KD Rice, N Aay, NK Anand, et al. Acs Medicinal Chemistry Letters,
2012, 3(5):416-421）A kind of following card is reported than the synthetic route for Buddhist nun.It is more due to being needed in building-up process
Secondary chiral resolution, synthesis step is cumbersome, and yield is low, so as to limit the industrial prospect of the synthetic method.
Patent WO2014059422 discloses a kind of preparation method blocked than replacing Buddhist nun and the like, and this method is with chiral ammonia
Base alcohol is chiral shift reagent, makes its chiral acquisition more convenient and economical.Its synthetic route is as follows.But it reacts bar
Excessively harsh (the ultralow temperature -78 of partoC, absolute anaerobic), expensive raw material price, it is difficult to obtain, strong basic reagent stability is poor
Limit the industrialized production of this route.
For patent CN201510906811.2 patent disclosures card than the synthetic method for Buddhist nun, this method synthetic route is as follows,
Using (2S) -2- piperidines as initiation material, synthesize to obtain target product by multistep, be related to cyaniding during this circuit combination
Thing, and synthetic route is grown, comprehensive yield is low, and building-up process has the shortcomings that high risk, high pollution and synthesis cost are high.
Patent CN201510121274.0 discloses a kind of derivative of 3- (piperidin-2-yl)-aza-cyclobutane -3-alcohol
Synthetic method, and card ratio replaces Buddhist nun with the compound synthesis, this method passes through using 3- carbonyls-N- substitutions-ring butylamine as initiation material
Cross multistep and synthesize to obtain the derivative of 3- (piperidin-2-yl)-aza-cyclobutane -3-alcohol, the compound by further amidatioon,
Deprotection has obtained target product card ratio and has replaced Buddhist nun.This circuit is related to n-BuLi and ultralow temperature (- 50oC~-78oC) and
Chiral resolution is needed, limits the industrialization amplification application of this route.
Patent CN201610361955.9 disclose it is a kind of block than the synthetic method for Buddhist nun, this method is by (R)-N-Boc-2-
Carboxylic acid piperidin successively carry out salt-forming reaction, bromination reaction, grignard reaction, desamination reaction, amidation process, substitution reaction and
Deprotection reaction, obtain card ratio and replace Buddhist nun.This circuit is related to grignard reaction twice, and operation is cumbersome, and cost is higher.
In summary, reported currently for card than the existing more research of synthetic method for Buddhist nun, but many defects be present,
Such as raw material is rare, synthesis step is long, the relatively low fractionation difficulty of yield is big, environmental pollution is serious.These unfavorable factors limit
Card is than the industrialized production for Buddhist nun, it is therefore necessary to develops that initiation material is cheap and easily-available, and synthesis technique is succinctly easy to operate, synthesized
Journey is economic and environment-friendly, the preparation technology that final product has good quality.
The content of the invention
For above-mentioned technical problem existing for existing synthesis technique, it is an object of the invention to provide a kind of new card to compare for Buddhist nun
Preparation method.This method raw material is cheap and easily-available, and reaction condition is gentle, and reaction scheme is short, and synthetic yield is high, environmental pollution is low
Advantage, suitable industrialized production.
To achieve the above object, technical scheme is as follows：
It is a kind of to block than the chemical synthesis process for Buddhist nun, comprise the following steps：
1）：In the presence of an organic base, compound 1 reacts to obtain compound 2 with the fluoro- 4- Iodoanilines of 2-；
2）：In the presence of Pd/C, the hydrogenation of compound 2 is deprotected to obtain compound 3；
3）：In the presence of condensation reagent, compound 3 obtains compound 4 through amidation process；
4）：In the presence of transition metal and/or transition metal salt, compound 4 is reacted in a solvent with 2- halopiperidines
Card ratio replaces Buddhist nun.
As the further optimization of technical solution of the present invention, above-mentioned steps 1）In organic base used be triethylamine, N, N- bis-
Any of wopropyl ethyl amine, piperidines, pyridine.
As the further optimization of technical solution of the present invention, above-mentioned steps 1）In organic base used be that organic base used is N,
N- diisopropylethylamine.
As the further optimization of technical solution of the present invention, above-mentioned steps 2）In Pd/C used be 10%Pd/C.
As the further optimization of technical solution of the present invention, above-mentioned steps 3）In condensation reagent used be EDCI/DMAP,
Any of PyBOP/DIEA, HOBt/DIC.
As the further optimization of technical solution of the present invention, above-mentioned steps 3）In condensation reagent used be EDCI/DMAP.
As the further optimization of technical solution of the present invention, above-mentioned steps 4）In 2- halopiperidines used be (R) -2- chlorine piperazines
Any of pyridine, (R) -2- bromines piperidines, (R) -2- iodine piperidines.
As the further optimization of technical solution of the present invention, above-mentioned steps 4）Middle solvent for use is the mixing of water organic solvent
Solvent；
Step 4）Described in transition metal be zinc, tin, indium, samarium, any of neodymium；Step 4）Described in transition metal salt
For any of stannous chloride, inidum chloride, indium trichloride, samarium diodide.
As the further optimization of technical solution of the present invention, above-mentioned steps 4）Middle solvent for use H2O and THF mixing is molten
Agent；Step 4）Described in transition metal be zinc；The transition metal salt is indium trichloride.
As the further optimization of technical solution of the present invention, foregoing card for the chemical synthesis process of Buddhist nun than including following step
Suddenly：
1）：Compound 1 is dissolved in DMF, stirs dissolved clarification, after adding the fluoro- 4- Iodoanilines of 2-, 0oN is added dropwise in stirring under C,
N- diisopropylethylamine, 60 are placed in after chargingo6h is reacted under C, HCl solution stirring is then added into reaction solution, then
Ethyl acetate is added into reaction solution, is extracted, collected organic layer, water layer is extracted with ethyl acetate, merges organic layer, anhydrous slufuric acid
Magnesium is dried, and filtering, is evaporated under reduced pressure and is removed ethyl acetate, obtain yellow oily liquid, compound 2 is purified to obtain through column chromatography；
2）：10% Pd/C and compound 2 are dissolved in absolute ethyl alcohol, H under room temperature condition2Compressive reaction is stayed overnight, diatomite
Pd/C is filtered to remove, collects filtrate, removal of solvent under reduced pressure obtains compound 3；
3）：Compound 3,3- aza-oxo-cyclobutanes hydrochloride and EDCI are dissolved in DCM, then add DMAP, at room temperature
Stirring, gone out after reacting 9h with water quenching, water layer is extracted with DCM, merges organic layer, saturated common salt washing, anhydrous sodium sulfate drying, mistake
Filter, yellow solid is obtained after filtrate concentration, and yellow solid is dissolved in into dichloromethane, instilled in normal heptane, 2h is stirred, there is solid analysis
Go out, solid is collected by filtration, dry, obtain compound 4；
4）：By the NH of compound 4, metallic zinc and saturation4The Cl aqueous solution mixes, and stirs at room temperature, by (R) -2- bromine piperidines
It is added dropwise to after being dissolved in THF in the above-mentioned reaction solution containing compound 4, charging, which finishes, stirs 6 h~10h under room temperature condition, filter,
Filtrate is collected, ethyl acetate extraction, collected organic layer, washing, saturated common salt washing, anhydrous sodium sulfate drying, is filtered, decompression is steamed
Evaporate to obtain yellow oily liquid, column chromatography, which purifies, must block than for Buddhist nun.
EDCI English names described in technical solution of the present invention：1-Ethyl-3-(3-dimethyllaminopropyl)
Carbodiimide hydrochloride, Chinese name：1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, CAS
No. ：25952-53-8；DMAP English names：4-dimethylaminopyridine, Chinese name：DMAP, CAS
No. ：1122-58-3；PyBOP English names：Benzotriazol-1-yl-oxytripyrrolidinophosphonium six
Fluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus CAS:128625-52-5；DIEA English names：N-
Ethyldiisopropylamine, Chinese name：DIPEA, CAS No.：7087-68-5；HOBt English names：
1-Hydroxybenzotriazole, Chinese name：I-hydroxybenzotriazole, CAS No.：2592-95-2；DIC English names：
N, N-diisopropylcarbodiimide, Chinese name：N, N- DIC, CAS No.：693-13-0；
DMF English names：N, N-dimethylformamide, Chinese name：DMF, CAS No.：68-12-2；DCM
English name：Dichloromethane, Chinese name：Dichloromethane, CAS No. 75-09-2；THF English names：
Tetrahydrofuran, Chinese name：Tetrahydrofuran, CAS No.：109-99-9.Mentioned reagent is conventional chemical reagent,
Commercial sources enrich.
By contrasting courseware with the synthetic route of existing literature report, card of the invention than for Buddhist nun's synthetic route with cheap
2 to be easy to get, 3,4- trifluoromethyl benzonitrile acid benzyl esters are initiation material, react obtained card ratio through 4 steps and replace Buddhist nun, and do not need extra chirality
Splitting step, the succinct yield of synthesis step is high, and synthesis condition gently reacts easily controllable, and it is conventional just that existing process is not used
The toxicity explosive high pollution high-risk reagent such as butyl lithium, process route is safe, and belongs to environmentally friendly synthetic route,
Beneficial to Industry Promotion.
Embodiment
Below in conjunction with the detailed explanation present invention of specific embodiment, the embodiment is only used for explaining the technical side of the present invention
Case, it is impossible to be interpreted as limiting protection scope of the present invention.
The synthesis of the compound 2 of embodiment 1
Compound 1 (26.6g, 0.1mol, 1.0eq) is dissolved in DMF (200ml), stirs dissolved clarification, adds the fluoro- 4- Iodoanilines of 2-
(26.07g, 0.11mol, 1.1eq), is placed on 0oUnder conditions of C, DIPEA is added dropwise under stirring
(69.3ml, 0.5mol, 5.0eq), after charging, reaction solution is placed in 60o6h is reacted under the conditions of C, is added into reaction solution
0.5mol/L HCl solution 1000ml, 10min is stirred, ethyl acetate 500ml, extraction are then added into reaction solution, collection has
Machine layer, water layer are extracted (500ml × 3) with ethyl acetate, merge organic layer, and anhydrous magnesium sulfate dries 2h, filtering, and vacuum distillation removes
Ethyl acetate is removed, obtains yellow oily liquid, the yellow oily liquid purifies through column chromatography（200-300 mesh silica gel is stationary phase,
Dichloromethane：Methanol=4:1 is elutriant）Obtain compound 2（Pale yellowish oil liquid）47.16g, yield 97.6%.Compound 2
Magnetic resonance collection of illustrative plates and mass spectrometric data it is as follows：
1H NMR(500Hz,CDCl3):δ 7.631-7.624(m, 1H), 7.472-7.461(m,2H), 7.382-
7.369(m, 3H), 7.149-7.137(m,1H), 7.024-7.008(d, J=8.0Hz, 1H), 6.733-6.712(m,
1H), 6.427-6.411(m, 1H), 5.11(s, 2H)。
13C NMR(500Hz,CDCl3):δ 167.512, 159.133, 153.275, 144.352, 141.643,
136.585, 135.174, 129.303, 128.606, 127.047, 126.325, 126.6, 123.973,
122.366, 111.784, 105.985, 91.249, 48.568。
MS(EI): 484.06(MH+)。
The synthesis of the compound 3 of embodiment 2
Load under argon gas in glass autoclave 10% Pd/C (11.7g, 4.4mmol, 0.05eq, 60.2%ww water, 10%
Ww palladium carbons) and compound 2 (42.7g, 0.088mol, 1.0eq) be dissolved in 200ml absolute ethyl alcohols, H at room temperature2Pressurization (20 ~
60psi) overnight, diatomite is filtered to remove 10% Pd/C for reaction, collects filtrate, removal of solvent under reduced pressure obtains compound 3（Yellow oil
Shape thing）34.20g yield 98.8%.The magnetic resonance collection of illustrative plates and mass spectrometric data of compound 3 are as follows：
1H NMR(500Hz,CDCl3):δ7.704-7.695(m,1H),7.198-7.185(m,1H), 7.064-7.054
(m,1H), 6.815-6.802(m, 1H), 6.556-6.545(m, 1H)。
13C NMR(500Hz,CDCl3):δ 169.743, 160.221, 154.859, 147.094, 138.428,
136.272, 130.569, 127.149, 125.144, 123.296, 112.885, 107.493, 94.195。
MS(EI): 393.98(MH+)。
The synthesis of the compound 4 of embodiment 3
Weigh Compound 3 (33.07g, 0.08mmol, 1.0eq), 3- aza-oxo-cyclobutanes hydrochloride (10.36g,
0.088mmol, 1.1eq), EDCI (18.41g, 0.096mol, 1.2eq) is dissolved in DCM (300ml), then adds DMAP
(0.49g, 4mmol, 0.05eq), stirring reaction 9h at room temperature, add 200ml water quenchings and go out reaction, water layer DCM extract (200ml ×
2), collected organic layer, anhydrous sodium sulfate drying after saturated common salt washing.Filtering, yellow solid is obtained after filtrate concentration, the solid
20ml dichloromethane is dissolved in, is instilled in 300ml normal heptanes, after being added dropwise, 2h is stirred, there is solid precipitation, it is solid that this is collected by filtration
Body, dry, obtain compound 4（White solid matter）32.85g yield 91.9%.The magnetic resonance collection of illustrative plates and mass spectrometric data of compound 4
It is as follows：
1H NMR(500Hz,CDCl3):δ 7.628-7.614(m, 1H), 7.245-7.231(m,1H), 7.151-
7.139(m, 1H), 6.864-6.850(m, 1H), 6.649-6.637(m, 1H), 4.932-4.919(m, 4H)。
13C NMR(500Hz,CDCl3):δ 191.894, 170.235, 160.862, 155.473, 148.659,
139.032, 135.581, 131.011, 127.196, 125.894, 123.967, 120.051, 108.162,
94.993, 59.159。
MS(EI): 447.01(MH+)。
The card of embodiment 4 is than the synthesis for Buddhist nun
The addition compound 4 (26.8g, 0.06mol, 1.0eq) in reaction bulb, metallic zinc (9.75g, 0.15mmol,
2.5eq), the NH of saturation4The Cl aqueous solution (100ml) stirs at room temperature.Separately weigh (R) -2- bromines piperidines (24.8g, 0.15mol,
THF (100ml) 2.5eq) is dissolved in, drop wise under nitrogen is added in above-mentioned reaction solution.Charging finishes stirs 7.2h under room temperature condition,
Filtering, filtrate is collected, ethyl acetate extraction (200ml × 3), collected organic layer, is washed (200ml × 1), saturated common salt washing
(200ml × 1) anhydrous sodium sulfate drying afterwards.Filtering, yellow oily liquid is obtained after filtrate concentration, the yellow oily liquid is through post
Chromatographic purifying（200-300 mesh silica gel, ethyl acetate：Petroleum ether=1:2 are used as elutriant）, obtain card ratio and replace Buddhist nun（White solid thing
Matter）29.38g yield 93.1%.Block as follows than the magnetic resonance collection of illustrative plates for Buddhist nun and mass spectrometric data：
1H NMR(500Hz,CDCl3):δ 7.674-7.663(m, 1H), 7.271-7.259(m, 1H), 7.137-
7.122(m,1H), 6.649-6.633(m, 1H), 6.478-6.465(m, 1H), 4.432-4.415(m, 2H),
4.077-4.059 (m, 2H), 2.894-2.872(dd, J1=11.0Hz, J2=4.0Hz, 1H), 2.801-2.788(m,
1H), 2.722-2.709(m, 1H), 1.602-1.467(m, 3H), 1.377-1.245(m, 2H), 1.154-1.140
(m, 1H)。
13C NMR(500Hz,CDCl3):δ 174.375, 162.133, 156.493, 149.479, 138.226,
131.845, 128.596, 126.693, 124.747, 121.882, 120.004, 107.395, 97.652,
74.389, 60.135, 57.328, 40.512, 30.119, 21.561, 19.852。
MS(EI): 532.14(MH+)。
The card of embodiment 5 is than the synthesis for Buddhist nun
The addition compound 4 (10.7g, 0.024mol, 1.0eq) in reaction bulb, metallic zinc (3.12g, 0.048mmol,
2.0eq), indium trichloride is InCl3(10.60g, 0.048mmol, 2.0eq), then adds THF into reaction bulb:H2O=1:1
(volume ratio, 90ml), is stirred at room temperature.Separately weigh (R) -2- bromines piperidines (9.84g, 0.06mol, 2.5eq) and be dissolved in THF
(10ml), it is added dropwise under nitrogen protection in above-mentioned reaction solution.After charging, 9.3h is stirred at room temperature, is filtered, and collects filter
Liquid, ethyl acetate extraction (100ml × 3), collected organic layer, wash (100ml × 1), after saturated common salt washing (100ml × 1)
Anhydrous sodium sulfate drying.Filtering, yellow oily liquid is obtained after filtrate concentration, the yellow oily liquid purifies through column chromatography
（200-300 mesh silica gel, ethyl acetate：Petroleum ether=1:2 are used as elutriant）, obtain card ratio and replace Buddhist nun（White solid matter）
11.85g yield 88.5%.Block as follows than the magnetic resonance collection of illustrative plates for Buddhist nun and mass spectrometric data：
1H NMR(500Hz,CDCl3):δ 7.674-7.663(m, 1H), 7.271-7.259(m, 1H), 7.137-
7.122(m,1H), 6.649-6.633(m, 1H), 6.478-6.465(m, 1H), 4.432-4.415(m, 2H),
4.077-4.059 (m, 2H), 2.894-2.872(dd, J1=11.0Hz, J2=4.0Hz, 1H), 2.801-2.788(m,
1H), 2.722-2.709(m, 1H), 1.602-1.467(m, 3H), 1.377-1.245(m, 2H), 1.154-1.140
(m, 1H)。
13C NMR(500Hz,CDCl3):δ 174.375, 162.133, 156.493, 149.479, 138.226,
131.845, 128.596, 126.693, 124.747, 121.882, 120.004, 107.395, 97.652,
74.389, 60.135, 57.328, 40.512, 30.119, 21.561, 19.852。
MS(EI): 532.14(MH+)。
The card of embodiment 6 is than the synthesis for Buddhist nun
The addition compound 4 (13.2g, 0.0295mol, 1.0eq) in reaction bulb, metallic zinc (4.81g, 0.074mmol,
2.5eq), the NH of saturation4The Cl aqueous solution (50ml), stir under room temperature condition.Separately weigh (R) -2- iodine piperidines (15.61g,
0.074mol, 2.5eq) THF (50ml) is dissolved in, it is added dropwise under nitrogen protection in above-mentioned reaction solution.Room temperature after charging
Lower stirring 8.6h, filtering, filtrate is collected, ethyl acetate extraction (100ml × 3), collected organic layer, is washed (100ml × 1), is satisfied
(100ml × 1) anhydrous sodium sulfate drying afterwards is washed with salt.Filtering, yellow oily liquid is obtained after filtrate concentration, the yellow oil
Shape liquid purifies through column chromatography（200-300 mesh silica gel, ethyl acetate：Petroleum ether=1:2 are used as elutriant）, obtain card ratio and replace Buddhist nun
（White solid matter）14.01g yield 89.1%.Block as follows than the magnetic resonance collection of illustrative plates for Buddhist nun and mass spectrometric data：
1H NMR(500Hz,CDCl3):δ 7.674-7.663(m, 1H), 7.271-7.259(m, 1H), 7.137-
7.122(m,1H), 6.649-6.633(m, 1H), 6.478-6.465(m, 1H), 4.432-4.415(m, 2H),
4.077-4.059 (m, 2H), 2.894-2.872(dd, J1=11.0Hz, J2=4.0Hz, 1H), 2.801-2.788(m,
1H), 2.722-2.709(m, 1H), 1.602-1.467(m, 3H), 1.377-1.245(m, 2H), 1.154-1.140
(m, 1H)。
13C NMR(500Hz,CDCl3):δ 174.375, 162.133, 156.493, 149.479, 138.226,
131.845, 128.596, 126.693, 124.747, 121.882, 120.004, 107.395, 97.652,
74.389, 60.135, 57.328, 40.512, 30.119, 21.561, 19.852。
MS(EI): 532.14(MH+)。
The card of embodiment 7 is than the synthesis for Buddhist nun
The addition compound 4 (9.5g, 0.021mol, 1.0eq) in reaction bulb, metallic zinc (3.46g, 0.053mmol,
2.5eq), the NH of saturation4The Cl aqueous solution (40ml), is stirred at room temperature.Separately weigh (R) -2- bromines piperidines (8.73g, 0.053mol,
2.5eq) it is dissolved in toluene i.e. PhCH3(40ml), it is added dropwise under nitrogen protection in above-mentioned reaction solution.After charging, room temperature
Lower stirring 6.7h, filtering, filtrate is collected, ethyl acetate extraction (80ml × 3), collected organic layer, is washed (80ml × 1), saturation
Salt washes (80ml × 1) anhydrous sodium sulfate drying afterwards.Filtering, yellow oily liquid is obtained after filtrate concentration, the yellow oily
Liquid purifies through column chromatography（200-300 mesh silica gel, ethyl acetate：Petroleum ether=1:2 are used as elutriant）, obtain card ratio and replace Buddhist nun（In vain
Color solid matter）10.21g yield 90.2%.Block as follows than the magnetic resonance collection of illustrative plates for Buddhist nun and mass spectrometric data：
1H NMR(500Hz,CDCl3):δ 7.674-7.663(m, 1H), 7.271-7.259(m, 1H), 7.137-
7.122(m,1H), 6.649-6.633(m, 1H), 6.478-6.465(m, 1H), 4.432-4.415(m, 2H),
4.077-4.059 (m, 2H), 2.894-2.872(dd, J1=11.0Hz, J2=4.0Hz, 1H), 2.801-2.788(m,
1H), 2.722-2.709(m, 1H), 1.602-1.467(m, 3H), 1.377-1.245(m, 2H), 1.154-1.140
(m, 1H)。
13C NMR(500Hz,CDCl3):δ 174.375, 162.133, 156.493, 149.479, 138.226,
131.845, 128.596, 126.693, 124.747, 121.882, 120.004, 107.395, 97.652,
74.389, 60.135, 57.328, 40.512, 30.119, 21.561, 19.852。
MS(EI): 532.14(MH+)。
Gently each step and gross production rate are equal for technical scheme synthesis step neat conditions it can be seen from embodiment
It is higher, and the chemical reaction of high pollution catalyst and high explosion danger is not used, suitable for large-scale industrial production.
Claims (1)
1. a kind of block than the chemical synthesis process for Buddhist nun, it is characterised in that comprises the following steps：
1)：Compound 1 is dissolved in DMF, stirs dissolved clarification, is stirred after adding the fluoro- 4- Iodoanilines of 2-, at 0 DEG C and N, N- bis- is added dropwise
Wopropyl ethyl amine, it is placed in after charging at 60 DEG C and reacts 6h, HCl solution stirring is then added into reaction solution, then to anti-
Answer and ethyl acetate is added in liquid, extract, collected organic layer, water layer is extracted with ethyl acetate, merges organic layer, and anhydrous magnesium sulfate is done
It is dry, filtering, it is evaporated under reduced pressure and removes ethyl acetate, obtain yellow oily liquid, compound 2 is purified to obtain through column chromatography；
2)：10%Pd/C and compound 2 are dissolved in absolute ethyl alcohol, H under room temperature condition2Compressive reaction is stayed overnight, and diatomite, which is crossed, to be filtered out
Pd/C is removed, collects filtrate, removal of solvent under reduced pressure obtains compound 3；
3)：Compound 3,3- aza-oxo-cyclobutanes hydrochloride and EDCI are dissolved in DCM, DMAP is then added, stirs at room temperature,
Gone out after reaction 9h with water quenching, water layer is extracted with DCM, is merged organic layer, saturated common salt washing, anhydrous sodium sulfate drying, is filtered, filter
Yellow solid is obtained after liquid concentration, yellow solid is dissolved in dichloromethane, instilled in normal heptane, 2h is stirred, there is solid precipitation, is filtered
Solid is collected, dries, obtains compound 4；
4)：By the NH of compound 4, metallic zinc and saturation4The Cl aqueous solution mixes, and stirs at room temperature, (R) -2- bromine piperidines is dissolved in
It is added dropwise to after THF in the above-mentioned reaction solution containing compound 4, charging finishes stirring 6h~10h under room temperature condition, filters, and collects
Filtrate, ethyl acetate extraction, collected organic layer, washing, saturated common salt washing, anhydrous sodium sulfate drying, filtering, it is evaporated under reduced pressure to
To yellow oily liquid, column chromatography, which purifies, must block than for Buddhist nun.
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| WO2008124085A2 (en) * | 2007-04-03 | 2008-10-16 | Exelixis, Inc. | Methods of using combinations of mek and jak-2 inhibitors |
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| EP2920144A4 (en) * | 2012-11-15 | 2016-06-29 | Univ Holy Ghost Duquesne | Carboxylic acid ester prodrug inhibitors of mek |
| CA2923835C (en) * | 2013-09-11 | 2022-11-29 | The Administrators Of The Tulane Educational Fund | Novel anthranilic amides and the use thereof |
| CN104725352B (en) * | 2015-03-19 | 2017-11-10 | 上海皓元生物医药科技有限公司 | A kind of preparation method and use of the derivative of the alcohol of 3 (base of piperidines 2) azetidine 3 |
| CN105330643B (en) * | 2015-12-09 | 2017-12-05 | 苏州明锐医药科技有限公司 | Card is than the preparation method for Buddhist nun |
| CN106045969B (en) * | 2016-05-27 | 2019-04-12 | 湖南欧亚药业有限公司 | A kind of synthetic method of the card than replacing Buddhist nun |
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