CN105646467B - A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method - Google Patents
A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method Download PDFInfo
- Publication number
- CN105646467B CN105646467B CN201610104439.8A CN201610104439A CN105646467B CN 105646467 B CN105646467 B CN 105646467B CN 201610104439 A CN201610104439 A CN 201610104439A CN 105646467 B CN105646467 B CN 105646467B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- anhydrous
- synthetic method
- several kinds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 68
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 13
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 claims abstract description 3
- VYNPRPGSCKKCQV-UHFFFAOYSA-N 4-chlorothiophene Chemical compound ClC1=[C]SC=C1 VYNPRPGSCKKCQV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229930192474 thiophene Natural products 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- -1 ethylamino- Chemical class 0.000 claims description 11
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Natural products O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 2
- GVSGVBVZXJOLDD-UHFFFAOYSA-N (n'-ethylcarbamimidoyl)azanium;chloride Chemical class [Cl-].CCN=C(N)[NH3+] GVSGVBVZXJOLDD-UHFFFAOYSA-N 0.000 claims description 2
- KCMZYCFSSYXEQR-UHFFFAOYSA-N CCCC[K] Chemical group CCCC[K] KCMZYCFSSYXEQR-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 239000001569 carbon dioxide Substances 0.000 claims description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 150000001879 copper Chemical class 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003863 metallic catalyst Substances 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims 3
- 229960000789 guanidine hydrochloride Drugs 0.000 claims 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 claims 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- 238000003786 synthesis reaction Methods 0.000 abstract 2
- 150000001412 amines Chemical class 0.000 abstract 1
- CXGFWBPQQXZELI-UHFFFAOYSA-N n-ethylpyridin-2-amine Chemical compound CCNC1=CC=CC=N1 CXGFWBPQQXZELI-UHFFFAOYSA-N 0.000 abstract 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102100032306 Aurora kinase B Human genes 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 101000798306 Homo sapiens Aurora kinase B Proteins 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000005441 aurora Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 102000003989 Aurora kinases Human genes 0.000 description 3
- 108090000433 Aurora kinases Proteins 0.000 description 3
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 3
- 239000003719 aurora kinase inhibitor Substances 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GBJVVSCPOBPEIT-UHFFFAOYSA-N AZT-1152 Chemical compound N=1C=NC2=CC(OCCCN(CC)CCOP(O)(O)=O)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 GBJVVSCPOBPEIT-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C)(C)OC(N/C1=C/C=C(/C(*CC=C2)C2S2)\C2=C/C=C1)=O Chemical compound CC(C)(C)OC(N/C1=C/C=C(/C(*CC=C2)C2S2)\C2=C/C=C1)=O 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 description 2
- 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- FBZVZUSVGKOWHG-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethylethanamine Chemical compound COC(C)(OC)N(C)C FBZVZUSVGKOWHG-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- NLOGSHMIAWCODV-UHFFFAOYSA-N 2-piperazin-4-ium-1-ylethanesulfonate Chemical compound OS(=O)(=O)CCN1CCNCC1 NLOGSHMIAWCODV-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical class ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000008266 oncogenic mechanism Effects 0.000 description 1
- 108700025694 p53 Genes Proteins 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 235000008521 threonine Nutrition 0.000 description 1
- 150000003588 threonines Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of anticancer compound Aomeis to replace Buddhist nun and its synthesis technology, the Aomei entitled for Buddhist nun's chemistry:(4 (4 chlorothiophene, 2 base) N (6 (2 (ethylamino-) pyridine, 4 base) hexichol [b, d] 2 base of thiophene) 1 amine of phthalazinyl), for its structural formula as shown in following formula I, synthesis technology is as follows:
Description
Technical field
The present invention relates to a kind of anticancer compound Aomeis to replace Buddhist nun and its synthetic method, belongs to medicament research and development and synthetic technology neck
Domain.
Background technology
Aurora families are a kind of protein serine/threonines, mammal have Aurora-A, Aurora-B,
Aurora-C three types.Aurora A inhibitor is the frontier of tumor cells targeted therapy.3 members of Aurora families
Function be to participate in adjusting centerbody, micro-pipe function, ensure that being precisely separated for chromosome detach with effective endochylema, they are usual
It all peaks in the G/M phases, adjusts G2/M in the cell cycle and convert, be the key factor being in progress the adjusting M phases.Wherein
Aurora-A and Aurora-B and tumour are closely related.First, Aurora-A is located in 20q13, and Aurora-B is located in
17p13, all in transposition, missing or the active chromosome segment of amplification, it is meant that they have natural unstability;Secondly,
The two chromosomal regions in breast cancer and colorectal cancer tumor tissues and breast cancer, oophoroma, colon cancer, prostate cancer,
Generally existing expands in neuroblastoma and Cervical cancer cell strain;Again, when the high expression of transfection in Ratl, NIH3T3 cell
Aurora-A can make the cell transformation at tumour cell, this Zhai transfectional cell, which is injected into visual tumors in nude mouse, to be formed.
Aurora A leads oncogenic mechanism, and to be unable to Accurate classification related for chromosome and chromatin with during mitosis, such as
Aurora A passes through p53 genes, BRCAl genes, PTEN/PDK/AKT signal paths, Aurora gene polymorphics in breast cancer
Property, the factor interactions such as estrogen participate in breast cancer tumour and are formed.
In the prior art, it by inhibiting aurora kinases to reach the existing research of compound of antitumous effect, but also deposits
It is such as poor to the inhibition of kinases, selective low in some defects.
Invention content
Goal of the invention:The present invention provides a kind of anticancer compound Aomeis to replace Buddhist nun and its synthetic method.
Technical solution:To achieve the above object, a kind of anticancer compound Aomei of present invention offer replaces Buddhist nun, chemistry entitled:(4-
(4- chlorothiophene -2- bases)-N- (6- (2- (ethylamino-) pyrimidine-4-yl) hexichol [b, d] thiophene -2- bases)-phthalazinyl -1- amine), knot
Structure formula is as shown in following formula I:
The present invention also provides the synthetic methods that the anticancer compound Aomei replaces Buddhist nun, by formula (1) compound as starting
Formula (I) compound, i.e., the described anticancer compound is finally made through following series reaction in raw material:
Preferably, compound (2) is made with carbon dioxide addition after dehydrogenation in the compound (1), reaction equation is as follows
It is shown:
Its reaction condition is:Reaction dissolvent be selected from anhydrous tetrahydro furan, anhydrous ether, anhydrous methylene chloride, dry toluene,
Anhydrous acetonitrile, the one or several kinds in anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofurans, wherein preferred solvent are anhydrous
Tetrahydrofuran;Reaction temperature is -78~25 DEG C, and wherein preferable temperature is -20~-30 DEG C;Alkali used in reaction is selected from just
Butyl lithium, tert-butyl lithium, s-butyl lithium, sodium hydride, the one or several kinds in hydrofining and lithium diisopropylamine, wherein excellent
It is tert-butyl lithium and s-butyl lithium to select alkali.
As another preferred embodiment, compound (3), reaction is made in the compound (2) after chlorination and addition substitution reaction
Formula is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous DMA, and anhydrous DMSO, dry toluene, anhydrous methylene chloride is anhydrous
Methyl tertiary butyl ether(MTBE), the one or several kinds in anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans, wherein preferred solvent are
Anhydrous tetrahydro furan;Reaction temperature is 0~80 DEG C, and wherein preferable temperature is 0-25 DEG C;Metallic catalyst used in reaction
Selected from stannous chloride, dichloride copper, the one or several kinds in dibrominated copper and cuprous bromide, wherein preferred catalyst is dichloro
Change copper;Compound (2) and the molar ratio of catalyst are 100:1~10.
As another preferred embodiment, compound (4), the following institute of reaction equation is made through a step substitution reaction in the compound (3)
Show:
Its reaction condition is:Reaction dissolvent is selected from dichloromethane, methyl tertiary butyl ether(MTBE), toluene, chloroform, tetrahydrofuran and 2-
One or several kinds in methyltetrahydrofuran, wherein preferred solvent are tetrahydrofuran and dichloromethane;Reaction temperature be 25~
120 DEG C, wherein preferable temperature is 80~90 DEG C;Alkali used in reaction is selected from triethylamine (NEt3), diisopropylethylamine
(DIPEA), n,N-Dimethylaniline, DABCO and 1, one kind in 11 carbon -7- alkene (DBU) of 8- diazabicylos [5.4.0] or
Person is several, wherein it is preferred that alkali is triethylamine;Compound (3) and the molar ratio of N,N-dimethylformamide dimethylacetal are 1:1
~1:2, wherein preferred molar ratio is 1:1.05.
As another preferred embodiment, compound is made through ring closure reaction with N- ethyl hydrochloric acid guanidine hydrochlorides in the compound (4)
(5), reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous DMSO, anhydrous DMF, anhydrous DMA, anhydrous acetonitrile, anhydrous tetrahydrochysene furan
It mutters, absolute methanol, absolute ethyl alcohol, the one or several kinds in anhydrous isopropyl alcohol and anhydrous 2- methyltetrahydrofurans, wherein it is preferred that
Solvent is absolute methanol;Reaction temperature is 25~100 DEG C, and wherein preferable temperature is 45~55 DEG C;Alkali choosing used in reaction
From sodium methoxide, sodium ethoxide, sodium tert-butoxide, the one or several kinds in potassium tert-butoxide and sodium hydrogen, wherein it is preferred that alkali is sodium methoxide;Change
The molar ratio for closing object (4) and N- ethyl guanidine hydrochlorides is 1:1~1:2, wherein preferred molar ratio is 1:1.05.
As another preferred embodiment, compound (6) is made through deprotection reaction in the compound (5), reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, normal propyl alcohol, n-butanol and 2-
One or several kinds in butanol, wherein preferred solvent are tetrahydrofuran;Reaction temperature is 0~40 DEG C, and wherein preferable temperature is
20~30 DEG C.
As another preferred embodiment, the compound (6) and compound (7), which are substituted reaction, is made described anticancer compound Austria
U.S. replaces Buddhist nun, reaction equation as follows:
Its reaction condition is:Reaction dissolvent is selected from absolute methanol, and absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous DMF is anhydrous
One or several kinds in DMSO and anhydrous acetonitrile, wherein preferred solvent are anhydrous DMSO;Reaction temperature is 25~120 DEG C,
Middle preferable temperature is 90~100 DEG C;The molar ratio of compound (6) and compound (7) is 1:1~1:2, wherein preferred molar ratio is
1:1.05;Alkali used in reaction is selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, lithium carbonate, LiHMDS,
NaHMDS, KHMDS, cesium carbonate, tertiary butyl sodium alkoxide, tertiary butyl potassium alcoholate, triethylamine, diisopropylethylamine, n,N-Dimethylaniline
With the one or several kinds in 1,8- diazabicylos [5.4.0], 11 carbon -7- alkene (DBU), wherein it is preferred that alkali be cesium carbonate.
The compounds of this invention Aomei is a kind of Novel ATP competitiveness small molecule aurora kinase inhibitors for Buddhist nun.In HeLa
In cell, Aomei inhibits aurora-A and-B autophosphorylations for Buddhist nun, and inhibits group on a kind of proximal end substrate Ser of aurora-B
The phosphorylation of albumen H3.Main cell responsing reaction of the tumour cell to Aomei for Buddhist nun's treatment makes cell division stop, without prolonging
Long mitosis deadtime, this eventually results in cell death.Aomei replaces Buddhist nun (about 2-4nM) under low nanomolar concentration, suppression
Make 23 tumor cell lines proliferation, including resistance to antimitotic drug cell line and other resistance to aurora kinase inhibitors (AZD1152,
MK-0457 etc.) cell line.In addition, Aomei is drug resistant to AZD1152 containing aurora-B mutant (W221L) for Buddhist nun
HCT116 variant cell lines are active.
Aomei is a kind of effective, highly selective pan-Aurora kinases inhibitor for Buddhist nun, acts on Aurora
A/B/C, IC50Respectively 4nM/2nM/1nM (similar similar marketed products are 8-10nM), acts on Aurora A and is compared to be used for
P 38 alpha, Tyk2, JNK2,20 times of Met and Tie2 high selectivities or more.
Advantageous effect:The compounds of this invention is a kind of effective, high selectivity pan-Aurora kinase inhibitors, is made
Reach anticancer effect for Aurora A to effectively inhibit the growth of tumour cell;In addition, the compounds of this invention synthesizes
Method is simple and practicable, at low cost, high income, good product quality, is suitble to big industrialized production.
Specific implementation mode
For ease of understanding, the present invention will be described in detail by specific embodiment below.It needs to particularly point out
, specific example is merely to explanation, it is clear that those skilled in the art can be according to illustrating, the present invention's herein
Various amendments are made to the present invention in range.
Embodiment 1
The preparation of compound (2)
Under nitrogen protection, 1.5kg (5mol) compound (1) is added into 50L reaction kettles under the conditions of -20 DEG C in 15L
In anhydrous tetrahydro furan, 352g (5.5mol) s-butyl lithium is slowly added dropwise.It is dry that 264g (6mol) is slowly added to after stirring half an hour
Ice, after the completion of TLC monitoring reactions, it is 6.8 that reaction solution is neutralized to pH with 5% dilute hydrochloric acid, and filtering, filter cake is washed with 5L tetrahydrofurans
It washs, merging filtrate and cleaning solution, is concentrated to give compound (3) crude product, crude product obtains compound (3) highly finished product through re-crystallizing in ethyl acetate
1.65kg (4.8mol), yield 96%.HPLC detects purity:99.2%.
1H NMR(400MHz,DMSO-d6) δ 12.62 (b, 1H), 9.88 (s, 1H), 8.79 (dd, J=14.9,3.0Hz,
1H), 8.20 (dd, J=14.9,3.0Hz, 1H), 8.07 (d, J=3.0Hz, 1H), 7.72 (dt, J=14.7,7.4Hz, 2H),
7.48 (dd, J=14.9,3.0Hz, 1H), 1.49 (s, 9H)
ESI+[M+H]+=344.
The preparation of compound (3)
Under nitrogen protection, 1.5kg (4.4mol) compound (2) and three is added into 50L reaction kettles at ambient temperature
Phenylphosphine 1.4kg (5.3mol) is slowly added to N- chlorosuccinimides (NCS) 708g (5.3mol) in the anhydrous tetrahydrochysene furans of 15L
In muttering, control temperature is less than 30 DEG C.After the completion of TLC monitoring reactions, filtering, filtrate is cooled to 0 DEG C or so, and dichloride copper is added
7.5g (0.044mol) is slowly added to methyl grignard reagent (methyl-magnesium-bromide) 536g (4.5L) (4.5mol, 1M THF solution),
It controls temperature and is not higher than 5 DEG C, after the completion of TLC monitoring reactions, it is 6.8 that reaction solution is neutralized to pH with 5% dilute hydrochloric acid, filtering, filter cake
It is washed with 5L tetrahydrofurans, merging filtrate and cleaning solution, is concentrated to give compound (3) crude product, crude product is through ethyl acetate/normal heptane
(1/3) compound (3) highly finished product 1.36kg (3.97mol), yield 90.2% are recrystallized to obtain.HPLC detects purity:95.9%.
1H NMR(400MHz,DMSO-d6) δ 9.88 (s, 1H), 8.64 (dd, J=14.8,3.1Hz, 1H), 8.07 (d, J=
3.0Hz, 1H), 7.73 (dd, J=15.0,2.3Hz, 2H), 7.62 (t, J=14.9Hz, 1H), 7.48 (dd, J=14.9,
3.0Hz,1H),2.83(s,3H),1.49(s,9H).
ESI+[M+H]+=342.
The preparation of compound (4)
1.3kg (3.8mol) compound (3) and triethylamine 395g is added into 50L reaction kettles at ambient temperature
(3.9mol) is in 15L tetrahydrofurans.It is slowly added to n,N-dimethylacetamide dimethylacetal 531g (3.99mol), is heated up
It is concentrated to give compound (4) crude product, which is directly used in the next step after the completion of TLC monitoring reactions to reflux.
ESI+[M+H]+=397.
The preparation of compound (6)
Under nitrogen protection, above-mentioned gained compound (4) crude product is added into 50L reaction kettles at ambient temperature
(3.8mol) and 1.44kg (3.99mol) N- ethyl hydrochloric acid guanidine hydrochlorides are in 20L absolute methanols.It is slowly added to sodium methoxide 430g
(8mol) is warming up to 50 DEG C, (generates compound (5) completely) after the completion of TLC monitoring reactions, be slowly added to methanol hydrochloride solution
After the completion of 2kg (20%), TLC monitoring reaction, the mashing of 10L tetrahydrofurans, filtering, filter cake 2L are poured into concentration in concentrate
Tetrahydrofuran wash, filter cake through 40 DEG C be dried in vacuo compound (6) highly finished product (hydrochloride) 1.2kg (3.4mol), yield are
89% (three step total recoverys).HPLC detects purity:99.3%.
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.26(s,1H),7.92(s,1H),7.70(s,1H),
7.48 (s, 1H), 7.20 (d, J=20.0Hz, 2H), 7.01 (s, 1H), 6.63 (s, 1H), 4.26 (s, 2H), 3.47 (s, 2H),
1.19(s,3H).
ESI+[M+H]+=321.
Aomei replaces the preparation of Buddhist nun
1.2kg (3.4mol) compound (6) hydrochloride and 1.0kg is added into 20L reaction kettles at ambient temperature
(3.6mol) compound (7) is in the anhydrous DMSO of 6L.It is slowly added to cesium carbonate 2.4kg (7.2mol) under stirring, is warming up to 95 DEG C,
After the completion of TLC monitoring reactions, it is down to room temperature, 6L pure water is added, is filtered after stirring and crystallizing 2h, filter cake is washed with water, and 50 DEG C true
It is empty dry that Aomei replaces Buddhist nun 1.75kg (3.1mol), yield 91%.HPLC detects purity:99.8%.
1H NMR(400MHz,DMSO-d6) δ 8.82 (s, 1H), 8.55 (dd, J=15.0,3.1Hz, 1H), 8.34 (dd, J
=11.2,6.9Hz, 1H), 8.26 (d, J=15.0Hz, 1H), 8.17 (dd, J=11.0,6.9Hz, 1H), 7.92 (dd, J=
15.0,3.1Hz, 1H), 7.81 (dd, J=11.1,6.9Hz, 2H), 7.70 (t, J=14.9Hz, 1H), 7.63-7.54 (m,
3H), 7.18 (d, J=15.0Hz, 1H), 7.12 (d, J=3.1Hz, 1H), 7.06-6.96 (m, 2H), 3.47 (q, J=
12.5Hz, 2H), 1.19 (t, J=12.6Hz, 3H)
ESI+[M+H]+=566.
Embodiment 2:Inhibiting effect of the compounds of this invention to aurora kinases
Aurora A HTRF experiments
In the presence of the polypeptide PLK of the biotinylation of ATP phosphorylations, start the Aurora-A-TPX2- of Aurora-A
HTRF is tested.Experiment is added detection reagent extraction and goes out after about carrying out 120 minutes, 120 minutes.These detection reagents are swashed by diluting
It enzyme and chelates heavy metal ion with EDTA and stops reacting.It is stood overnight after adding detection reagent so that detection reagent reaches flat
Weighing apparatus.
Aurora-A-HTRF experiments have used 1uL Aomeis for 100% DMSO solution of Buddhist nun, the ATP and biology of 20uL
The acylated PLK of element, the Aurora-A-TPX2-KGDGST kinases of 20uL.Buffer conditions are:HEPES (the 4- ethoxys of 60mM
Piperazine ethanesulfonic acid) pH 7.5, the sodium-chloride water solution of 25mM, the MgCl aqueous solutions of 10mM, the DTT (dithiothreitol (DTT)) of 2mM,
0.05% BSA (bovine serum albumin(BSA)).
The experiment detection reagent extraction of 160uL is gone out, and detection reagent composition is:The Tris (trishydroxymethylaminomethane) of 50mM
The sodium-chloride water solution of pH 7.5,100mM, the EDTA solution of 3mM, 0.05% BSA solution and 0.1% soil temperature 20.
Breadboard Rubystar efficient time resolved fluorometric detector reading numerical values.Eu-anti-PLK swashs at 320nm
Hair, then radiates energy, above-mentioned energy excitation SA-APC, SA-APC radianies at 655nm at 615nm.Ratio
SA-APK (655nm)/Eu-anti-PLK (615nm) is the numerical value of substrate phosphorylation.
Measurement result shows that the compounds of this invention acts on Aurora-A, Aurora-B and Aurora-C, IC50Respectively
For 4nM, 2nM and 1nM.
Embodiment 3:High selectivity of the compounds of this invention to aurora kinases
It selects containing Aurora A, p 38 alpha, Tyk2, JNK2, Met or Tie2 to be cultivated, this hair is then added
Bright gained compound is detected.
Measurement result shows, the compounds of this invention acts on Aurora A and is compared to be used for p 38 alpha, Tyk2, JNK2, Met and
Tie2 is selectively 28 times, 35 times, 24 times, 38 times and 35 times high respectively.
Claims (8)
1. a kind of anticancer compound Aomei replaces Buddhist nun, chemistry entitled:(((2- (ethylamino-) is phonetic by 6- by 4- (4- chlorothiophene -2- bases)-N-
Pyridine -4- bases) hexichol [b, d] thiophene -2- bases)-phthalazinyl -1- amine), structural formula is as shown in following formula I:
2. anticancer compound Aomei described in claim 1 replaces the synthetic method of Buddhist nun, which is characterized in that by formula (1) compound conduct
Formula (I) compound, i.e., the described anticancer compound is finally made through following series reaction in starting material:
3. synthetic method according to claim 2, which is characterized in that the compound (1) after dehydrogenation with carbon dioxide
Compound (2) is made in addition, and reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous tetrahydro furan, and anhydrous ether, anhydrous methylene chloride, dry toluene is anhydrous
Acetonitrile, the one or several kinds in anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofurans;Reaction temperature is -78~25 DEG C;Instead
Alkali used in answering is selected from n-BuLi, tert-butyl lithium, s-butyl lithium, sodium hydride, in hydrofining and lithium diisopropylamine
One or several kinds.
4. synthetic method according to claim 2, which is characterized in that the compound (2) replaces anti-through chlorination and addition
Compound (3) should be made afterwards, reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from anhydrous DMA, anhydrous DMSO, dry toluene, anhydrous methylene chloride, anhydrous methyl
Tertbutyl ether, the one or several kinds in anhydrous tetrahydro furan and anhydrous 2- methyltetrahydrofurans;Reaction temperature is 0~80 DEG C;
Metallic catalyst used in reaction is selected from stannous chloride, dichloride copper, one kind in dibrominated copper and cuprous bromide or
It is several;Compound (2) and the molar ratio of catalyst are 100:1~10.
5. synthetic method according to claim 2, which is characterized in that the compound (3) is made through a step substitution reaction
Compound (4), reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from dichloromethane, methyl tertiary butyl ether(MTBE), toluene, chloroform, tetrahydrofuran and 2- methyl
One or several kinds in tetrahydrofuran;Reaction temperature is 25~120 DEG C;Alkali used in reaction is selected from triethylamine
(NEt3), diisopropylethylamine (DIPEA), n,N-Dimethylaniline, DABCO and 1,11 carbon of 8- diazabicylos [5.4.0]-
One or several kinds in 7- alkene (DBU);Compound (3) and the molar ratio of N,N-dimethylformamide dimethylacetal are 1:1
~1:2.
6. synthetic method according to claim 2, which is characterized in that the compound (4) is with N- ethyls guanidine hydrochloride through closing
Compound (5) is made in ring reaction, and reaction equation is as follows:
Its reaction condition is:Reaction dissolvent be selected from anhydrous DMSO, anhydrous DMF, anhydrous DMA, anhydrous acetonitrile, anhydrous tetrahydro furan,
Absolute methanol, absolute ethyl alcohol, the one or several kinds in anhydrous isopropyl alcohol and anhydrous 2- methyltetrahydrofurans;Reaction temperature is 25
~100 DEG C;Alkali used in reaction is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and one kind in sodium hydrogen or
It is several;Compound (4) and the molar ratio of N- ethyl guanidine hydrochlorides are 1:1~1:2.
7. synthetic method according to claim 2, which is characterized in that the compound (5) is through deprotection reaction obtainedization
Object (6) is closed, reaction equation is as follows:
Its reaction condition is:Reaction dissolvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, normal propyl alcohol, n-butanol and 2- butanol
In one or several kinds;Reaction temperature is 0~40 DEG C.
8. synthetic method according to claim 2, which is characterized in that the compound (6) and compound (7) are substituted instead
The anticancer compound Aomei, which should be made, replaces Buddhist nun, reaction equation as follows:
Its reaction condition is:Reaction dissolvent be selected from absolute methanol, absolute ethyl alcohol, anhydrous isopropyl alcohol, anhydrous DMF, anhydrous DMSO and
One or several kinds in anhydrous acetonitrile;Reaction temperature is 25~120 DEG C;The molar ratio of compound (6) and compound (7) is 1:
1~1:2;Alkali used in reaction is selected from potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, lithium carbonate, LiHMDS,
NaHMDS, KHMDS, cesium carbonate, tertiary butyl sodium alkoxide, tertiary butyl potassium alcoholate, triethylamine, diisopropylethylamine, n,N-Dimethylaniline
With the one or several kinds in 11 carbon -7- alkene (DBU) of 1,8- diazabicylos [5.4.0].
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610104439.8A CN105646467B (en) | 2016-02-25 | 2016-02-25 | A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610104439.8A CN105646467B (en) | 2016-02-25 | 2016-02-25 | A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105646467A CN105646467A (en) | 2016-06-08 |
CN105646467B true CN105646467B (en) | 2018-07-20 |
Family
ID=56488628
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610104439.8A Expired - Fee Related CN105646467B (en) | 2016-02-25 | 2016-02-25 | A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105646467B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110183464B (en) * | 2019-05-31 | 2021-08-31 | 淮阴工学院 | Anti-cancer compound estinib and synthesis method and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003024935A2 (en) * | 2001-09-19 | 2003-03-27 | Pharmacia Corporation | Substituted pyrazolyl compounds for the treatment of inflammation |
WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7473691B2 (en) * | 2000-09-15 | 2009-01-06 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
-
2016
- 2016-02-25 CN CN201610104439.8A patent/CN105646467B/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003024935A2 (en) * | 2001-09-19 | 2003-03-27 | Pharmacia Corporation | Substituted pyrazolyl compounds for the treatment of inflammation |
WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
CN103702990A (en) * | 2011-07-27 | 2014-04-02 | 阿斯利康(瑞典)有限公司 | 2-(2,4,5-substituted -anilino) pyrimidine derivatives as egfr modulators useful for treating cancer |
Also Published As
Publication number | Publication date |
---|---|
CN105646467A (en) | 2016-06-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2947084B1 (en) | Five-and-six-membered heterocyclic compound, and preparation method, pharmaceutical composition and use thereof | |
CN101166732B (en) | Cyanopyridine derivative and use thereof as medicine | |
EP2287155A1 (en) | Acylthiourea compound or salt thereof, and use of the compound or the salt | |
KR20050042055A (en) | Quinazoline derivaives as antitumor agents | |
EP3150599B1 (en) | Novel tetrahydropyridopyrimidine compound or salt thereof | |
EP3381916B1 (en) | Condensed pyrimidine compound or salt thereof | |
CN105315285A (en) | 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medical uses thereof | |
EP3066099B1 (en) | Pyrido[2,3-d]pyrimidin-4-one compounds as tankyrase inhibitors | |
IL267303A (en) | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one | |
CN105646467B (en) | A kind of anticancer compound Aomei replaces Buddhist nun and its synthetic method | |
CN111606889A (en) | Process for the preparation of 4- (1-cyclopropyl-1H-indol-3-yl) -N-phenylpyrimidin-2-amine derivatives | |
CN102249997A (en) | Group of 4-substituted phenylaminoquinoline compounds having antitumor activity | |
JP7190755B2 (en) | Oxazinoquinazoline and oxazinoquinoline compounds, and methods of preparation and uses thereof | |
CN101171245A (en) | Indolylamino quinazoline derivatives as antitumor agents | |
CN101171244A (en) | Indazolylamino quinazoline derivatives as antitumor agents | |
CN115477639B (en) | Polysubstituted pyrimidine compound with FGFR1 as target point, and preparation method and application thereof | |
JP2009508917A (en) | Quinazoline derivatives as anticancer agents | |
CN110183464A (en) | A kind of anticancer compound Ai Si is for Buddhist nun and its synthetic method and application | |
CN111484484A (en) | 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof | |
KR102335637B1 (en) | Novel compounds of inhibiting cdk7, and their pharmaceutically acceptable salts | |
CN107793417A (en) | Pyrrolo- [2,3 d] pyrimidines and its salt, and preparation method and pharmaceutical usage | |
CN114014847A (en) | Benzothiophene pyrimidine derivative, preparation method thereof and application thereof in preparation of antitumor drugs | |
KR20020051675A (en) | 4-phenylaminothiano [3,2-d] pyrimidine derivative and preparing method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20180629 Address after: 211100 204, room 5, 18 Zhi Lan Road, Jiangning District, Nanjing, Jiangsu. Applicant after: NANJING DIYUAN MEDICINE SCIENCE & TECHNOLOGY CO., LTD. Address before: 210037 Gulou District and Yantai Road Taihe Park 01-1507, Nanjing, Jiangsu Applicant before: Huang Yange |
|
TA01 | Transfer of patent application right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180720 Termination date: 20190225 |
|
CF01 | Termination of patent right due to non-payment of annual fee |