CN105859762B - Adjacent carborane derivative, its preparation method and application and prepare the intermediate of this neighbour's carborane derivative - Google Patents
Adjacent carborane derivative, its preparation method and application and prepare the intermediate of this neighbour's carborane derivative Download PDFInfo
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- CN105859762B CN105859762B CN201610286687.9A CN201610286687A CN105859762B CN 105859762 B CN105859762 B CN 105859762B CN 201610286687 A CN201610286687 A CN 201610286687A CN 105859762 B CN105859762 B CN 105859762B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- 230000004044 response Effects 0.000 claims description 34
- 229910000085 borane Inorganic materials 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 18
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 8
- VGISFWWEOGVMED-UHFFFAOYSA-N 1-(chloromethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CCl)=C1 VGISFWWEOGVMED-UHFFFAOYSA-N 0.000 claims description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical group ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 5
- 230000008859 change Effects 0.000 claims description 5
- 239000003495 polar organic solvent Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 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
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 229910052744 lithium 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
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 13
- 201000011510 cancer Diseases 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 210000005170 neoplastic cell Anatomy 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000004821 distillation Methods 0.000 description 29
- 230000006837 decompression Effects 0.000 description 24
- 238000000034 method Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 238000001514 detection method Methods 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- 239000000284 extract Substances 0.000 description 17
- 208000035126 Facies Diseases 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 12
- 239000012153 distilled water Substances 0.000 description 11
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 10
- 229910052796 boron Inorganic materials 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- -1 Epoxide benzyl chloride Chemical class 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229940125898 compound 5 Drugs 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- FUZWQENLBYQWIZ-UHFFFAOYSA-N BrC=1NC=2C(=CC1C)C=CC=CC2 Chemical compound BrC=1NC=2C(=CC1C)C=CC=CC2 FUZWQENLBYQWIZ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical class ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 description 2
- VQUYNUJARXBNPK-UHFFFAOYSA-N 2-chloroethoxybenzene Chemical compound ClCCOC1=CC=CC=C1 VQUYNUJARXBNPK-UHFFFAOYSA-N 0.000 description 2
- ZAPMTSHEXFEPSD-UHFFFAOYSA-N 4-(2-chloroethyl)morpholine Chemical compound ClCCN1CCOCC1 ZAPMTSHEXFEPSD-UHFFFAOYSA-N 0.000 description 2
- 0 CC([C@@]1C(CC2C3=C(C4=C=C4)C3=C=C3C4*2(CC([C@@](C=C2)C(C)=NO*)C=C2OC)C4C2(*C2)CC3)=CC(OC)=CC1)=NO* Chemical compound CC([C@@]1C(CC2C3=C(C4=C=C4)C3=C=C3C4*2(CC([C@@](C=C2)C(C)=NO*)C=C2OC)C4C2(*C2)CC3)=CC(OC)=CC1)=NO* 0.000 description 2
- 108010052832 Cytochromes Proteins 0.000 description 2
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- 230000005764 inhibitory process Effects 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- YFNONBGXNFCTMM-UHFFFAOYSA-N CCCCOc1ccccc1 Chemical compound CCCCOc1ccccc1 YFNONBGXNFCTMM-UHFFFAOYSA-N 0.000 description 1
- DSNYFFJTZPIKFZ-UHFFFAOYSA-N CCCOc1ccccc1 Chemical compound CCCOc1ccccc1 DSNYFFJTZPIKFZ-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N CN1CCCCC1 Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- LBDSXVIYZYSRII-IGMARMGPSA-N alpha-particle Chemical compound [4He+2] LBDSXVIYZYSRII-IGMARMGPSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 231100000045 chemical toxicity Toxicity 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of adjacent carborane derivative, its preparation method and application and prepare the intermediate of this neighbour's carborane derivative.The structure of described adjacent carborane derivative is as shown in formula IV, shown in the structure of described intermediate such as formula (V).Present invention also offers the application of described adjacent carborane derivative.The present invention is with adjacent carborane as starting material, carry out a series of lithiumation, electrophilic, necleophilic reaction finally gives the adjacent carborane derivative with hydrophilic radical, carry out a series of cancer subsequently, test neoplastic cell measures and finds, this compounds specific can be gathered in tumor cell, and has hypotoxicity.
Description
Technical field
The present invention relates to antitumoral compounds, especially a kind of adjacent carborane derivative, its preparation method and application and preparation
The intermediate of described adjacent carborane derivative.
Background technology
Boron neutron capture therapy (BNCT) is exactly first by one boracic (B10) compound injection to human body, pass through blood circulation
Entering intracellular, because selected boron-containing compound and cancer, tumor has affinity characteristic, and it is only enriched in pathological changes cancer or tumor is thin
In born of the same parents.Due to tissue barrier effect, B10Seldom even can not enter in normal cell tissue.When irradiating disease with neutron beam
When becoming position, B10(n、α)Li7Reaction generates alpha-particle and the Li of high linear energy transfer7Core, they can kill≤cancer of 10 μ scopes
Or tumor cell, i.e. can use targeting dual nature (B in cell dimensions10Concentration, the energy of neutron streaming and strong
Degree) regulation, principle is any conventional treatments is unrivaled.
BNCT can be in cell dimensions (micron order), it is achieved strong targeting, the binary (boronation of high linear energy transfer (LET)
Medicine, neutron beam) X-ray therapy, the principle for the treatment of malignant brain tumor is superior to current surgical operation, X-ray therapy, chemotherapeutics
Method, immunotherapy and gene therapy, normal cell is distinguished accurately with cancerous cell physics, to human zero damage, is currently to control by it
Treating unique effective ways of cerebral glioma, BNCT has become international nuclear medicine circle and falls over each other the focus of research since becoming the nineties, I
State is the most blank.Having become customary therapy by the various cancer of this therapy for treating and tumor the most in the world, particularly Japan is in the world
On occupy absolute technical advantage, Nei Ge great medical institutions the most home of Japan, generally carry out BNCT in academy and colleges and universities
Clinical Treatment Test, and with other internal organs tumors such as examination treating the liver cancer, pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, breast carcinoma.Through half a lifetime
The clinical practice recorded, first boron neutron capture therapy is founded 8 annual survival rates in Japan and is reached the unprecedented record of 42%, be classified as
Standard technique.Do not open cranium, treatment position, deep cerebroma D BNCT technology has gone through the extensive experimentation in clinical first and second stage,
Just march toward the phase III, i.e. efficacy experiment.In a word, " neutron capture therapy " (BNCT) is the new neck for the treatment of of cancer research in modern age
Territory, has a extensive future.
In boron neutron capture therapy, when giving with therapeutically effective amount, boron-containing compound must be nontoxic or tool
There is hypotoxicity.Although BPA has the advantage of low chemical toxicity, but the accumulated concentrations in tumor tissues is relatively low, limits it
Application.
Summary of the invention
Goal of the invention: for problems of the prior art, the invention provides the adjacent carborane derivatization that a class is new
Compound, this compounds can being gathered in tumor cell of high concentration, and there is hypotoxicity.
Technical scheme: adjacent carborane derivative of the present invention, it has a general structure as shown in formula IV:
Wherein, R is
●=C,
Zero=BH.
The formula of adjacent carborane is C2B10H12, structure is as follows:
Its size is identical with benzene, is three-dimensional spherical structure, highly stable to heat, strong electron-withdrawing group group, the dissolubility to water
The lowest, the present invention contains 10 boron (B with band10) adjacent carborane be starting material, carry out a series of lithiumation, electrophilic, nucleophilic is anti-
Should finally give the adjacent carborane derivative with hydrophilic radical, carry out a series of cancer subsequently, test neoplastic cell measures
Find, this compounds can being gathered in tumor cell of high concentration, and there is hypotoxicity.
Present invention also offers the preparation method of described adjacent carborane derivative, including:
(1), under the conditions of alkalescence, adjacent carborane reacts with 3-methoxybenzyl chloride, it is thus achieved that the compound shown in formula I:
(2) under the conditions of lewis acid, the compound shown in formula I reacts with acylating reagent, it is thus achieved that the change shown in formula II
Compound:
(3) compound of formula II reacts with oxyammonia, it is thus achieved that the compound shown in formula III:
(4), under the conditions of alkalescence, the hydrogen of the oh group of compound shown in formula III is replaced with halogenated aromatic group, it is thus achieved that institute
Adjacent carborane derivative shown in the formula IV stated；
In formula I～formula IV, ●=C, zero=BH.
In step (1), reaction carry out in organic solvent, described organic solvent include ether, 1,2-dimethoxy second
One or more in alkane, oxolane and toluene；During using multiple mixing as solvent, ether and 1,2-dimethoxy can be selected
The mixing of the mixed solvent of base ethane, 1,2-dimethoxy-ethane and the mixed solvent of oxolane, ether and oxolane is molten
Agent etc.；Preferably, described organic solvent is oxolane.
Step (1), alkali includes n-BuLi, isobutyl group lithium, tert-butyl lithium, Lithamide., lithium hydride, sodium hydride or diisopropyl
Base Lithamide.；Preferably, alkali is n-BuLi.Response time is 2～6 hours, preferably 4～5h.3-methoxybenzyl chloride with
The mol ratio of adjacent carborane is 2～2.5:1, preferably 2～2.2:1.
In step (2), reaction is carried out in organic solvent, and described organic solvent includes dichloromethane, chloroform and tetrachloro
Change one or more in carbon, it is preferred that described organic solvent is dichloromethane.Described lewis acid include aluminum chloride,
One or more in iron chloride, stannic chloride and zinc chloride, it is preferred that described lewis acid is aluminum chloride.Described is acylated
Reagent includes chloroacetic chloride, propionyl chloride etc..Response time is 2～5 hours, preferably 3～4h.Described lewis acid and formula I
The mol ratio of compound is 2～2.8:1, preferably 2.4～2.8:1, more preferably 2.6～2.8:1.The change of described formula I
Compound is 1:2～2.4 with the mol ratio of acylating reagent, preferably 1:2.1～2.2.
In step (3), reaction carry out in polar organic solvent, described polar organic solvent include methanol, ethanol, third
One or more in alcohol and propylene glycol；Preferably, described polar organic solvent is ethanol.Described oxyammonia and formula II chemical combination
The mol ratio of thing is 2～6:1, preferably 5～6:1.Reaction temperature is 50～80 DEG C, and the response time is 2～5 hours, it is preferred that
Reaction temperature is 50～60 DEG C, and the response time is 3～4 hours.
In step (4), reaction is carried out in organic solvent, and described organic solvent includes acetonitrile, oxolane and 1,2-
One or more in dimethoxy-ethane.Alkali includes triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, hydrogen-oxygen
Change one or more in sodium, potassium hydroxide, tert-butyl group sodium, tert-butyl group potassium, sodium phosphate and potassium phosphate, it is preferred that alkali is carbonic acid
Potassium.Reaction temperature is 50～80 DEG C, and the response time is 3～6 hours, it is preferred that reaction temperature is 50～60 DEG C, and the response time is
3～4 hours.
Present invention also offers described adjacent carborane derivative application in preparing antitumor drug.
Present invention also offers a kind of medicine, comprise described adjacent carborane derivative.
Described medicine is antitumor drug.
Present invention also offers the intermediate preparing described adjacent carborane derivative, this intermediate has as shown in (V)
General structure:
Wherein, R1 be H,●=C；Zero=BH.
Compared with prior art, the beneficial effect comprise that
The invention provides the adjacent caborane compounds that a class is new, this compounds low toxicity, high concentration can be gathered in tumor
In cell, therefore it individually or can be prepared antitumor drug with other auxiliary elements pharmaceutically, treat for boron neutron absorption
Ruling by law is treated in cancer.It addition, the good water solubility of neighbour's carborane derivative of the present invention.
Preparation method route of the present invention is reasonable, and simply, easy control of reaction, yield is preferable.
Accompanying drawing explanation
Fig. 1 is the hydrogen spectrogram that in embodiment 1, step 1 prepares compound；
Fig. 2 is the hydrogen spectrogram that in embodiment 1, step 2 prepares compound；
Fig. 3 is the hydrogen spectrogram that in embodiment 1, step 3 prepares compound；
Fig. 4 is the hydrogen spectrogram of compound 1 in embodiment 1；
Fig. 5 is the hydrogen spectrogram of compound 2 in embodiment 2；
Fig. 6 is the hydrogen spectrogram of compound 3 in embodiment 3；
Fig. 7 is the hydrogen spectrogram of compound 4 in embodiment 4；
Fig. 8 is the hydrogen spectrogram of compound 5 in embodiment 5.
Detailed description of the invention
Below in conjunction with specific embodiment, explain the present invention further.
The synthetic reaction formula of neighbour's carborane derivative of the present invention is:
Wherein, being differently formed five kinds of compounds because of substituted radical R, the structural formula of compound 1～compound 5 is distinguished successively
For:
●=C, zero=BH.
The hydrogen general survey test instrument used in detailed description of the invention in the present invention is: Burker 300Hz.
The preparation of embodiment 1 compound 1
Step 1: prepare formula I compound: 3,3-bi-methoxy benzyl neighbour's carborane
Method 1: weigh 1.44g neighbour's carborane, adds in there-necked flask and is dissolved among oxolane 50ml, and temperature is down to-78
DEG C after be slowly added dropwise n-BuLi 9.6ml, time for adding is 30min, during whole dropping temperature be maintained at-75 DEG C～-
78℃；Dripping 3.44g 3-methoxybenzyl chloride again in system, after dropping ,-78 DEG C warm naturally to room temperature (25 DEG C)
During react, the response time is 4h；After question response, decompression distillation organic solvent, add 1mol/L HCl solution 20ml
Stirring 1h, adds dichloromethane 100ml and extracts, and the organic facies obtained adds MgSO4Being dried, filtrated stock, decompression is steamed
Evaporating and obtain 2.2g 3,3-bi-methoxy benzyl neighbour's carborane, yield is 61%, in terms of adjacent carborane.Fig. 1 is detection hydrogen spectrum
Figure, result parameter is as follows:
1H-NMR:7.32-7.29(m,2H),6.91-6.88(m,2H),6.84-6.82(m,2H),6.77(s,2H),
3.83(s,2H),3.61(s,2H),3.2-0.8(br,10H).
Method 2: weigh 1.44g neighbour's carborane, adds in there-necked flask and is dissolved in 1, among 2-dimethoxy-ethane 50ml, temperature
Being slowly added dropwise tert-butyl lithium 9.6ml after being down to-78 DEG C, time for adding is 30min, and whole drip reacting temperature is maintained at-75
DEG C～-78 DEG C, then in system drip 3.44g 3-methoxybenzyl chloride, after dropping ,-78 DEG C warm naturally to room temperature (25
DEG C) during react, the response time is 5h.After question response, decompression distillation organic solvent, add 1N HCl solution 20ml and stir
Mixing 1h, add dichloromethane 100ml and extract, the organic facies obtained adds MgSO4Being dried, filtrated stock decompression distillation obtains
2.1g, 3,3-bi-methoxy benzyl neighbour's carboranes, yield is 59%, in terms of adjacent carborane.Detection parameter is as follows:
1H-NMR:7.32-7.29(m,2H),6.91-6.88(m,2H),6.84-6.82(m,2H),6.77(s,2H),
3.83(s,2H),3.61(s,2H),3.2-0.8(br,10H).
Method 3: weigh 1.44g neighbour's carborane, adds and is dissolved among toluene 30ml in there-necked flask, temperature be down to-78 DEG C it
After rapidly join lithium hydride 0.2g, whole reaction temperature is maintained at-75 DEG C～-78 DEG C, then in system drip 3.16g 3-first
Epoxide benzyl chloride, after dropping ,-78 DEG C warm naturally to room temperature (25 DEG C) continuation reaction 5h.After question response, decompression is steamed
Evaporate organic solvent, add 1N HCl solution 20ml and stir 1h, add dichloromethane 100ml and extract, the organic addition obtained
Enter MgSO4Being dried, filtrated stock decompression distillation obtains 1.9g, 3,3-bi-methoxy benzyl neighbour's carboranes, and yield is 51%, with
Adjacent carborane meter.Detection parameter is as follows:
1H-NMR:7.32-7.29(m,2H),6.91-6.88(m,2H),6.84-6.82(m,2H),6.77(s,2H),
3.83(s,2H),3.61(s,2H),3.2-0.8(br,10H).
Method 4: weigh 1.44g neighbour's carborane, adds in there-necked flask and is dissolved among oxolane 40ml, and temperature is down to-78
Being slowly added dropwise lithium diisopropylamine 9.6ml after DEG C, time for adding is 30min, and during whole dropping, temperature is maintained at-75
DEG C～-78 DEG C；Dripping 3.44g 3-methoxybenzyl chloride again in system, after dropping ,-78 DEG C warm naturally to room temperature (25
DEG C) during react, the response time is 4h；After question response, decompression distillation organic solvent, add 1mol/L HCl solution
20ml stirs 1h, adds dichloromethane 100ml and extracts, and the organic facies obtained adds MgSO4It is dried, filtrated stock, subtracts
Pressure distillation obtains 2.0g 3,3-bi-methoxy benzyl neighbour's carborane, and yield is 56%, in terms of adjacent carborane.Detection parameter is such as
Under:
1H-NMR:7.32-7.29(m,2H),6.91-6.88(m,2H),6.84-6.82(m,2H),6.77(s,2H),
3.83(s,2H),3.61(s,2H),3.2-0.8(br,10H).
Step 2: prepare formula II compound: 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carborane
Method 1: weigh 2.2g 3,3-bi-methoxy benzyl neighbour's carborane, adds in there-necked flask and is dissolved in dichloromethane
Among 30ml, make temperature be down to-5～0 DEG C, be slowly added dropwise mixed solution (chloroacetic chloride 1.1ml and aluminum chloride 2.0g), during dropping
Between be 5min, after dropping-5 DEG C warm naturally to 25 DEG C during react, the response time is 3h；After question response,
Under room temperature condition, adding saturated aqueous sodium carbonate 50ml and stir 1h, add dichloromethane 50ml and extract, obtain is organic
It is added to MgSO4Being dried, filtrated stock, decompression distillation obtains 2.5g 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carbon
Borine, yield is 95%, with 3,3-bi-methoxy benzyl neighbour's carborane meter.Fig. 2 is detection hydrogen spectrogram, and result parameter is as follows:
1H-NMR:7.77-7.74 (d, J=7.8Hz, 2H), 6.89-6.86 (d, J=7.8Hz, 2H), 6.82 (s, 2H),
3.9(s,6H),3.66(s,4H),2.6(s,6H),3.2-0.8(br,10H).
Method 2: weigh 2.2g 3,3-bi-methoxy benzyl neighbour's carborane, add there-necked flask is dissolved in chloroform 30ml it
In, make temperature be down to-5～0 DEG C, be slowly added dropwise into mixed solution (chloroacetic chloride 1.05ml and ferric chloride 2.3g), time for adding
For 5min, after dropping-5 DEG C warm naturally to 25 DEG C during react, the response time is 3h；After question response, room
Under the conditions of temperature, add saturated aqueous sodium carbonate 50ml and stir 1h, add dichloromethane 50ml and extract, the organic facies obtained
Add MgSO4Being dried, filtrated stock, decompression distillation obtains 2.1g 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carbon boron
Alkane, yield is 83%, with 3,3-bi-methoxy benzyl neighbour's carborane meter.Detection parameter is as follows:
1H-NMR:7.77-7.74 (d, J=7.8Hz, 2H), 6.89-6.86 (d, J=7.8Hz, 2H), 6.82 (s, 2H),
3.9(s,6H),3.66(s,4H),2.6(s,6H),3.2-0.8(br,10H).
Method 3: weigh 2.2g 3,3-bi-methoxy benzyl neighbour's carborane, add there-necked flask is dissolved in chloroform 30ml it
In, making temperature be down to-5～0 DEG C, be slowly added dropwise into mixed solution (chloroacetic chloride 1.1ml and zinc chloride 1.9g), time for adding is
5min, after dropping-5 DEG C warm naturally to 25 DEG C during react, the response time is 3h；After question response, room temperature
Under the conditions of, add saturated aqueous sodium carbonate 50ml and stir 1h, add dichloromethane 50ml and extract, the organic addition obtained
Enter MgSO4Being dried, filtrated stock, decompression distillation obtains 1.8g 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carbon boron
Alkane, yield is 74%, with 3,3-bi-methoxy benzyl neighbour's carborane meter.Detection parameter is as follows:
1H-NMR:7.77-7.74 (d, J=7.8Hz, 2H), 6.89-6.86 (d, J=7.8Hz, 2H), 6.82 (s, 2H),
3.9(s,6H),3.66(s,4H),2.6(s,6H),3.2-0.8(br,10H).
Step 3: prepare formula III compound: 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane
Method 1: weigh 2.5g 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carborane, 1.0g oxyammonia (No. CAS
For 7803-49-8), add and two mouthfuls of bottles are dissolved among methanol 25ml, temperature rises to 50 DEG C of reaction 3h, after question response, makes
Temperature of reaction system is down to room temperature, and reduce pressure solvent distillation, adds distilled water 100ml and extracts with dichloromethane 100ml, obtains
Organic facies add MgSO4Being dried, filtrated stock, decompression distillation obtains 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy
Benzyl neighbour's carborane, yield is 93%, with 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carborane meter.Fig. 3 is inspection
Surveying hydrogen spectrogram, result parameter is as follows:
1H-NMR:10.17 (s, 1H), 7.30-7.28 (d, J=7.5Hz, 2H), 7.05 (s, 2H), 6.97-6.95 (d, J
=7.5Hz, 2H), 3.93 (s, 6H), 3.88 (s, 4H), 2.16 (s, 6H), 3.2-0.8 (br, 10H).
The preparation of method 2:2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine
Weigh 2.5g 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carborane, oxyammonia 0.92g, add two mouthfuls of bottles
In be dissolved among ethanol 25ml, temperature rise to 50 DEG C reaction 3h, after question response, make temperature of reaction system be down to room temperature, subtract
Pressure solvent distillation, adds distilled water 100ml and extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4It is dried,
Filtrated stock, decompression distillation obtains 2.5g 2,2-biacetyl hydroxylamine-5, and 5-bi-methoxy benzyl neighbour's carborane, yield is
94%, with 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carborane meter.Detection parameter is as follows:
1H-NMR:10.17 (s, 1H), 7.30-7.28 (d, J=7.5Hz, 2H), 7.05 (s, 2H), 6.97-6.95 (d, J
=7.5Hz, 2H), 3.93 (s, 6H), 3.88 (s, 4H), 2.16 (s, 6H), 3.2-0.8 (br, 10H).
The preparation of method 3:2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine
Weigh 2.5g 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carborane, oxyammonia 1.0g, add two mouthfuls of bottles
In be dissolved among propylene glycol 20ml, temperature rise to 50 DEG C reaction 4h, after question response, make temperature of reaction system be down to room temperature,
Decompression solvent distillation, adds distilled water 100ml and extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4Dry
Dry, filtrated stock, decompression distillation obtains 2.4g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane, yield
It is 91%, with 2,2-diacetyl group-5,5-bi-methoxy benzyl neighbour's carborane meter.Detection parameter is as follows:
1H-NMR:10.17 (s, 1H), 7.30-7.28 (d, J=7.5Hz, 2H), 7.05 (s, 2H), 6.97-6.95 (d, J
=7.5Hz, 2H), 3.93 (s, 6H), 3.88 (s, 4H), 2.16 (s, 6H), 3.2-0.8 (br, 10H).
The preparation of step 4:2,2-biacetyl hydroxylamine-4-morpholine ethyl-5,5-bi-methoxy benzyl neighbour's carborane
Method 1: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine, potassium carbonate 1.8g, add
(2-bromo methyl cycloheptapyridine, No. CAS is: 55401-97-3) 2.2g is dissolved in second cyanogen 25ml in being each added to two mouthfuls of bottles to enter hydrophilic group
Among, temperature rises to 60 DEG C of reaction 3h, after question response, makes temperature of reaction system be down to room temperature, and reduce pressure solvent distillation, adds
Distilled water 100ml extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4Being dried, filtrated stock, decompression is steamed
Evaporate and each obtain 3.2g target compound 1 i.e. 2,2-biacetyl hydroxylamine pyridine-2-methyl-5,5-bi-methoxy benzyl neighbour's carbon
Borine, yield is 93%, with 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane meter.Fig. 4 is detection hydrogen spectrum
Figure, result parameter is as follows:
1H-NMR:8.61-8.59 (d, J=4.7Hz, 2H), 7.76-7.70 (m, 2H), 7.47-7.44 (m, 2H), 7.29-
7.20(m,4H),6.86-6.77(m,4H),5.3(s,2H),3.84(s,6H),3.63(s,4H),2.31(s,6H),3.2-0.8
(br,10H).
Method 2: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane, sodium hydroxide
0.5g, adds hydrophilic group (2-bromo methyl cycloheptapyridine) 2.2g and is each added in two mouthfuls of bottles be dissolved among oxolane 25ml, temperature
Degree rises to 50 DEG C of reaction 3h, after question response, makes temperature of reaction system be down to room temperature, and reduce pressure solvent distillation, adds distilled water
100ml extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4Being dried, filtrated stock, decompression distillation is each
Obtain 2.9g target compound 1 that is 2,2-biacetyl hydroxylamine pyridine-2-methyl-5,5-bi-methoxy benzyl neighbour's carborane,
Yield is 85%, with 2, and 2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane meter.Detection parameter is as follows:
1H-NMR:8.61-8.59 (d, J=4.7Hz, 2H), 7.76-7.70 (m, 2H), 7.47-7.44 (m, 2H), 7.29-
7.20(m,4H),6.86-6.77(m,4H),5.3(s,2H),3.84(s,6H),3.63(s,4H),2.31(s,6H),3.2-0.8
(br,10H).
Method 3: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane, tert-butyl group potassium
1.4g, adds hydrophilic group (2-bromo methyl cycloheptapyridine) 2.2g and is each added in two mouthfuls of bottles be dissolved among oxolane 25ml, temperature
Degree rises to 50 DEG C of reaction 3h, after question response, makes temperature of reaction system be down to room temperature, and reduce pressure solvent distillation, adds distilled water
100ml extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4Being dried, filtrated stock, decompression distillation is each
Obtain 3.0g target compound 1 that is 2,2-biacetyl hydroxylamine pyridine-2-methyl-5,5-bi-methoxy benzyl neighbour's carborane,
Yield is 90%, with 2, and 2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane meter.Detection parameter is as follows:
1H-NMR:8.61-8.59 (d, J=4.7Hz, 2H), 7.76-7.70 (m, 2H), 7.47-7.44 (m, 2H), 7.29-
7.20(m,4H),6.86-6.77(m,4H),5.3(s,2H),3.84(s,6H),3.63(s,4H),2.31(s,6H),3.2-0.8
(br,10H).
Method 4: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane, triethylamine
1.7ml, adds hydrophilic group (2-bromo methyl cycloheptapyridine) 2.2g and is each added in two mouthfuls of bottles be dissolved among second cyanogen 25ml, temperature liter
To 80 DEG C of reaction 3h, after question response, making temperature of reaction system be down to room temperature, reduce pressure solvent distillation, adds distilled water 100ml
Extracting with dichloromethane 100ml, the organic facies obtained adds MgSO4Being dried, filtrated stock, decompression distillation each obtains
2.0g target compound 1 that is 2,2-biacetyl hydroxylamine pyridine-2-methyl-5,5-bi-methoxy benzyl neighbour's carborane, yield
It is 61%, with 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl neighbour's carborane meter.Detection parameter is as follows:
1H-NMR:8.61-8.59 (d, J=4.7Hz, 2H), 7.76-7.70 (m, 2H), 7.47-7.44 (m, 2H), 7.29-
7.20(m,4H),6.86-6.77(m,4H),5.3(s,2H),3.84(s,6H),3.63(s,4H),2.31(s,6H),3.2-0.8
(br,10H).
The preparation of embodiment 2 compound 2
Step 1～step 3 are with embodiment 1.
Step 4: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine, potassium carbonate 1.8g, add
(2-chloroethoxy benzene, No. CAS is: 622-86-6) 2.6g is dissolved in second cyanogen 100ml in being each added to two mouthfuls of bottles to enter hydrophilic group
Among, temperature rises to 60 DEG C of reaction 3h, after question response, makes temperature of reaction system be down to room temperature, and reduce pressure solvent distillation, adds
Distilled water 100ml extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4It is dried, filtrated stock decompression distillation
Each obtain 3.4g target compound 2 that is 2,2-biacetyl hydroxylamine Phenoxyethyl-5,5-bi-methoxy benzyl borine, receive
Rate is 91%, with 2, and 2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine meter.Detection parameter is as follows:
1H-NMR:7.34-7.29(m,6H),7.00-6.95(m,6H),6.83-6.75(m,4H),4.56-4.52(t,J
=5.1Hz, 4H), 4.35-4.28 (t, J=4.8Hz, 4H), 3.85 (s, 6H), 3.64 (s, 4H), 2.22 (s, 6H), 3.2-0.8
(br,10H).
The preparation of embodiment 3 compound 3
Step 1～step 3 are with embodiment 1.
Step 4: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine, potassium carbonate 1.8g, add
(3-bromine propoxyl group benzene, No. CAS is: 588-63-6) 3.4g is dissolved in second cyanogen 100ml in being each added to two mouthfuls of bottles to enter hydrophilic group
Among, temperature rises to 60 DEG C of reaction 3h, after question response, makes temperature of reaction system be down to room temperature, and reduce pressure solvent distillation, adds
Distilled water 100ml extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4Being dried, filtrated stock, decompression is steamed
Evaporate and each obtain 3.2g target compound 3 that is 2,2-biacetyl hydroxylamine phenoxy propyl-5,5-bi-methoxy benzyl borine,
Yield is 89%, with 2, and 2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine meter.Detection parameter is as follows:
1H-NMR:7.33-7.30(m,6H),6.96-6.93(m,6H),6.82-6.74(m,4H),4.40-4.36(t,J
=6.0Hz, 4H), 4.35-4.28 (t, J=6.0Hz, 4H), 3.85 (s, 6H), 3.64 (s, 4H), 2.22-2.17 (m, 10H),
3.2-0.8(br,10H).
The preparation of embodiment 4 compound 4
Step 1～step 3 are with embodiment 1.
Step 4: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine, potassium carbonate 1.8g, add
(1-(2-chloroethyl) piperidines, No. CAS is: 1932-03-2) 2.4g is dissolved in second cyanogen in being each added to two mouthfuls of bottles to enter hydrophilic group
Among 100ml, temperature rises to 60 DEG C of reaction 3h, after question response, makes temperature of reaction system be down to room temperature, and decompression distillation is molten
Agent, adds distilled water 100ml and extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4It is dried, filtrated stock,
Decompression distillation each obtains 3.2g target compound 4 i.e. 2,2-biacetyl hydroxylamine phenoxy propyl-5,5-bi-methoxy benzene first
Base borine, yield is 89%, with 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine meter.Detection parameter is as follows:
1H-NMR:7.31-7.29 (d, J=7.8Hz, 2H), 6.82-6.79 (d, J=7.8Hz, 2H), 6.74 (s, 2H),
4.36-4.32 (t, J=6.0Hz, 4H), 3.85 (s, 6H), 3.63 (s, 4H), 2.76-2.72 (t, J=6.0Hz, 4H), 2.53-
2.51(m,8H),2.19(s,6H),1.88-1.86(m,4H),1.64-1.58(m,8H),1.47-1.45(m,4H),3.2-0.8
(br,10H).
The preparation of embodiment 5 compound 5
Step 1～step 3 are with embodiment 1.
Step 4: weigh 2.5g 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine, potassium carbonate 1.8g, add
(4-(2-chloroethyl) morpholine, No. CAS is: 3240-94-6) 2.4g is dissolved in second cyanogen in being each added to two mouthfuls of bottles to enter hydrophilic group
Among 100ml, temperature rises to 60 DEG C of reaction 3h, after question response, makes temperature of reaction system be down to room temperature, and decompression distillation is molten
Agent, adds distilled water 100ml and extracts with dichloromethane 100ml, and the organic facies obtained adds MgSO4It is dried, filtrated stock,
Decompression distillation each obtains 3.1g target compound 5 i.e. 2,2-biacetyl hydroxylamine-4-morpholine ethyl-5,5-bi-methoxy benzene first
Base borine, yield is 88%, with 2,2-biacetyl hydroxylamine-5,5-bi-methoxy benzyl borine meter.Detection parameter is as follows:
1H-NMR:7.31(s,2H),6.83-6.76(m,4H),3.85(s,6H),3.76-3.73(m,8H),3.64-
3.59(m,8H),2.77-2.72(m,4H),2.55-2.54(m,8H),2.52(s,6H),3.2-0.8(br,10H).
Embodiment 6
Mensuration for compound related performance indicators is this area routine universal method.
1, toxicity
Under different sample concentrations, after being administered 48h, by general mtt assay detection compound to cervical cancer tumer line
HeLa cell growth inhibition situation, finally calculates IC50, by 50% (IC50), to suppress the drug level needed for cell survival
Determine from median lethal dose(LD 50), and result represent meansigma methods ±..
MTT is tetramethyl azo azoles salt, is that one can accept hydrionic weld.Succinum in living cells mitochondrion
Acidohydrogenase (succinate dehydrogenase) and cytochrome C (cytochrome C), can make MTT generate bluish violet
First a ceremonial jade-ladle, used in libation (formazan) crystallization and separate out precipitation, and dead cell is without this function.The first a ceremonial jade-ladle, used in libation of generation is crystallized and is dissolved in dimethyl Asia
After sulfone (DMSO), the light absorption value of solution at 490nM or 570nM can be measured by enzyme-linked immunosorbent assay instrument, monitor the life of first a ceremonial jade-ladle, used in libation
Cheng Liang.And the growing amount of first a ceremonial jade-ladle, used in libation crystallization is directly proportional to viable count, therefore the medicine impact on cell viability can be detected.The method
Because of highly sensitive, economic dispatch feature, it is widely used in screening anti-tumor medicine test.
Concrete experimental technique is: be made into 3 × 10 after HeLa cell dissociation is centrifugal4The cell suspension of individual/m L, in 96 holes
In plate, every hole adds 100 μ L cell suspension, after cellar culture 24h, sucks original fluid, add compound that 200 μ L configure-
1,2,3,4,5,6,7 or BPA sample, the ultimate density of each sample be divided into 300.000 μMs 100.000 μMs, 33.333 μMs,
11.111 μMs, 3.704 μMs, 1.235 μMs, 0.412 μM, 0.137 μM, 0.046 μM of totally 9 concentration, each concentration does 4 multiple holes,
The hole PBS sealing of hole of 96 orifice plate surroundings, and reserve negative control group and blank group, after compound effects 44h, every hole adds
MTT solution 20 μ L, continues to cultivate 4h, and careful suction abandons culture medium in hole, adds DMSO 150 μ L and shakes 10min, in microplate reader
Measure the OD value in each hole at 490n M, be calculated as follows sample suppression ratio under variable concentrations: suppression ratio=(control wells OD
Value-dosing holes OD value)/control wells OD value × 100%.Finally, application related software calculates the IC50 value of sample.
2, boron absorbs
HeLa cell (5 × 103Cell) in various concentration compound-1, train in the presence of 2,3,4,5,6,7 or BPA
Support 24 hours.After washing three times, accumulative boron concentration uses inductively coupled plasma atomic emission spectrum (ICP-AES) to determine.
Value be meansigma methods ±.
Table 1 inhibition concentration (IC50) absorb with boron
Result shows, the toxicity of neighbour's carborane derivative of the present invention and existing BPA compound are substantially suitable, and water solublity can
Reaching 7.14ppm, the relatively BPA of the concentration in tumor cell is greatly improved, and the effect of compound 5 is the most prominent.
Claims (10)
1. an adjacent carborane derivative, it is characterised in that it has a general structure as shown in formula IV:
Wherein, R is
●=C,
Zero=BH.
The preparation method of adjacent carborane derivative the most according to claim 1, it is characterised in that including:
(1), under the conditions of alkalescence, adjacent carborane reacts with 3-methoxybenzyl chloride, it is thus achieved that the compound shown in formula I:
(2) under the conditions of lewis acid, the compound shown in formula I reacts with acylating reagent, it is thus achieved that the compound shown in formula II:
(3) compound shown in formula II and azanol reaction, it is thus achieved that the compound shown in formula III:
(4), under the conditions of alkalescence, the hydrogen of the oh group of compound shown in formula III is replaced with halogenated aromatic group, it is thus achieved that described
Adjacent carborane derivative shown in formula IV；
In formula I～formula IV, ●=C, zero=BH.
Preparation method the most according to claim 2, it is characterised in that in step (1), reaction is carried out in organic solvent,
One or more in ether, 1,2-dimethoxy-ethane, oxolane and toluene of described organic solvent；Alkali is selected from just
Butyl lithium, isobutyl group lithium, tert-butyl lithium, Lithamide., lithium hydride, sodium hydride or lithium diisopropylamine；Response time be 2～
6h；3-methoxybenzyl chloride is 2～2.5:1 with the mol ratio of borine.
Preparation method the most according to claim 2, it is characterised in that in step (2), reaction is carried out in organic solvent,
One or more in dichloromethane, chloroform and carbon tetrachloride of described organic solvent；Described lewis acid is selected from chlorine
Change one or more in aluminum, iron chloride, stannic chloride and zinc chloride；Response time is 2～5 hours；Described lewis acid with
The mol ratio of formula I compound is 2～2.8:1；The compound of described formula I and the mol ratio of acylating reagent be 1:2～
2.4。
Preparation method the most according to claim 2, it is characterised in that described acylating reagent is selected from chloroacetic chloride or propionyl
Chlorine.
Preparation method the most according to claim 2, it is characterised in that in step (3), reaction is entered in polar organic solvent
OK, one or more in methanol, ethanol, propanol and propylene glycol of described polar organic solvent；Described oxyammonia and formula
(II) mol ratio of compound is 2～6:1；Reaction temperature is 50～80 DEG C, and the response time is 2～5h.
Preparation method the most according to claim 2, it is characterised in that in step (4), reaction is carried out in organic solvent,
One or more in acetonitrile, oxolane and 1,2-dimethoxy-ethane of described organic solvent；Alkali selected from triethylamine,
Diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, tert-butyl group sodium, tert-butyl group potassium, sodium phosphate and
One or more in potassium phosphate；Reaction temperature is 50～80 DEG C, and the response time is 3～6 hours.
8. preparing an intermediate for the most adjacent carborane derivative, this intermediate has as shown in formula (V)
General structure:
Wherein, R1 be H,●=C；Zero=BH.
Adjacent carborane derivative application in preparing antitumor drug the most according to claim 1.
10. a medicine, it is characterised in that comprise adjacent carborane derivative as claimed in claim 1.
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Citations (2)
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|---|---|---|---|---|
| US6838574B1 (en) * | 1999-01-22 | 2005-01-04 | Institute Of Medicinal Molecular Design, Inc. | Dicarba-closo-dodecarborane derivatives |
| CN103159792A (en) * | 2011-12-08 | 2013-06-19 | 三星电子株式会社 | Photorefractive composite, spatial light modulator, and hologram display device using the same |
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2016
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6838574B1 (en) * | 1999-01-22 | 2005-01-04 | Institute Of Medicinal Molecular Design, Inc. | Dicarba-closo-dodecarborane derivatives |
| CN103159792A (en) * | 2011-12-08 | 2013-06-19 | 三星电子株式会社 | Photorefractive composite, spatial light modulator, and hologram display device using the same |
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| Title |
|---|
| Palladium-Catalyzed Regioselective Intramolecular Coupling of o-Carborane with Aromatics via Direct Cage B-H Activation;Yangjian Quan;《Journal of the American Chemical Society》;20150308;第137卷(第10期);第3502-3505页 * |
| 碳十硼烷及其衍生物的反应性及应用;赵娟;《化学进展》;20120430;第24卷(第4期);第556-567页 * |
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