CN102234295B - Platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand and preparation method thereof - Google Patents
Platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand and preparation method thereof Download PDFInfo
- Publication number
- CN102234295B CN102234295B CN201010162020.0A CN201010162020A CN102234295B CN 102234295 B CN102234295 B CN 102234295B CN 201010162020 A CN201010162020 A CN 201010162020A CN 102234295 B CN102234295 B CN 102234295B
- Authority
- CN
- China
- Prior art keywords
- formula
- alkyl
- platinum
- trans
- title complex
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 81
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 title claims abstract description 27
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical class N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 title abstract description 5
- 239000003446 ligand Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- -1 carboxylic acid anion Chemical class 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 239000003999 initiator Substances 0.000 claims abstract description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 44
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 27
- 229910052697 platinum Inorganic materials 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 241000723346 Cinnamomum camphora Species 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000003863 ammonium salts Chemical class 0.000 claims description 4
- 229960000846 camphor Drugs 0.000 claims description 4
- 229930008380 camphor Natural products 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052709 silver Inorganic materials 0.000 claims description 4
- 239000004332 silver Substances 0.000 claims description 4
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 claims description 3
- ZLPNWTJXLKERCL-UHFFFAOYSA-N 3-hydroxycyclobutane-1,1-dicarboxylic acid Chemical compound OC1CC(C(O)=O)(C(O)=O)C1 ZLPNWTJXLKERCL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- NULQQEJVHKUOAK-UHFFFAOYSA-N propan-2-yl ethaneperoxoate Chemical group CC(C)OOC(C)=O NULQQEJVHKUOAK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract description 4
- 206010006187 Breast cancer Diseases 0.000 abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 3
- 206010009944 Colon cancer Diseases 0.000 abstract description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 abstract description 3
- 201000005202 lung cancer Diseases 0.000 abstract description 3
- 208000020816 lung neoplasm Diseases 0.000 abstract description 3
- 229910052700 potassium Inorganic materials 0.000 abstract description 3
- 239000011591 potassium Substances 0.000 abstract description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 abstract 1
- 201000010989 colorectal carcinoma Diseases 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 201000007270 liver cancer Diseases 0.000 abstract 1
- 208000014018 liver neoplasm Diseases 0.000 abstract 1
- 102100028735 Dachshund homolog 1 Human genes 0.000 description 53
- 101000915055 Homo sapiens Dachshund homolog 1 Proteins 0.000 description 53
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 description 53
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- 239000000843 powder Substances 0.000 description 35
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- 239000011734 sodium Substances 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000376 reactant Substances 0.000 description 7
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 6
- 101150065749 Churc1 gene Proteins 0.000 description 6
- 102100038239 Protein Churchill Human genes 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- YMHQVDAATAEZLO-UHFFFAOYSA-N cyclohexane-1,1-diamine Chemical compound NC1(N)CCCCC1 YMHQVDAATAEZLO-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000003252 repetitive effect Effects 0.000 description 3
- 238000005201 scrubbing Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910000474 mercury oxide Inorganic materials 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical class [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 1
- VPMIAOSOTOODMY-KJAPKAAFSA-N (4r)-6-[(e)-2-[6-tert-butyl-4-(4-fluorophenyl)-2-propan-2-ylpyridin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1/C=C/C=1C(C(C)C)=NC(C(C)(C)C)=CC=1C1=CC=C(F)C=C1 VPMIAOSOTOODMY-KJAPKAAFSA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
- QRDAPCMJAOQZSU-KQQUZDAGSA-N (e)-3-[4-[(e)-3-(3-fluorophenyl)-3-oxoprop-1-enyl]-1-methylpyrrol-2-yl]-n-hydroxyprop-2-enamide Chemical compound C1=C(\C=C\C(=O)NO)N(C)C=C1\C=C\C(=O)C1=CC=CC(F)=C1 QRDAPCMJAOQZSU-KQQUZDAGSA-N 0.000 description 1
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- AKBHYCHPWZPGAH-UHFFFAOYSA-N 2-[3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one Chemical compound CC1=C(Cl)C=C(COC2CN(C2)C(=O)C2CC3(C2)COC(=O)N3)C=C1 AKBHYCHPWZPGAH-UHFFFAOYSA-N 0.000 description 1
- QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- REDUQXCPUSNJOL-UHFFFAOYSA-N C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O Chemical compound C(C1=CC=CC=C1)NC(CN(C(C1=CC=C(C=C1)C(C)C)=O)CC1=CC=C(C=C1)C(NO)=O)=O REDUQXCPUSNJOL-UHFFFAOYSA-N 0.000 description 1
- 0 CC*C1CCCCC1 Chemical compound CC*C1CCCCC1 0.000 description 1
- LTGYRKOQQQWWAF-UHFFFAOYSA-N CCCCCCCNC Chemical compound CCCCCCCNC LTGYRKOQQQWWAF-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 1
- 229940126650 Compound 3f Drugs 0.000 description 1
- KGPGFQWBCSZGEL-ZDUSSCGKSA-N GSK690693 Chemical compound C=12N(CC)C(C=3C(=NON=3)N)=NC2=C(C#CC(C)(C)O)N=CC=1OC[C@H]1CCCNC1 KGPGFQWBCSZGEL-ZDUSSCGKSA-N 0.000 description 1
- 190000032366 Miboplatin Chemical compound 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- KSKBQJRQWJDWJG-GHMZBOCLSA-N N[C@H](CCCC1)[C@@H]1NC1CCCC1 Chemical compound N[C@H](CCCC1)[C@@H]1NC1CCCC1 KSKBQJRQWJDWJG-GHMZBOCLSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- CDVMXMZPDJHSCC-UHFFFAOYSA-N chembl1684662 Chemical compound C=1C=C2C=C(C=3C4=NC=CC=C4NN=3)NC2=CC=1CC(=O)C1=CC=CC=C1 CDVMXMZPDJHSCC-UHFFFAOYSA-N 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 229940126115 compound 4f Drugs 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229950002777 miboplatin Drugs 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand and a preparation method thereof. A structural formula of the Platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand is represented as a formula (1a) and a formula (1b), wherein Y is organic carboxylic acid anion, Z is organic dicarboxylic acid dianion, and R is C3-8 alkyl. The preparation method comprises the following steps: a compound represented by formula (3) is obtained wherein trans 1,2- diaminocyclohexane protected by single Boc is an initiator, and the compound reacts with potassium tetrahaloplatinate to obtain a compound represented by a formula (2); the compound represented by the formula (2) is subjected to a reaction to generate the compound represented by the formula (1a) or the formula (1b). The platinum (II) complex represented by the formula (1a) and the formula (1b) has obvious inhibition effect to human body liver cancer cell HepG-2, human body breast cancer cell MCF-7, human body lung cancer cell A549 and human body colorectal carcinoma cell HCT-116.
Description
Technical field
The present invention relates to the N-alkyl replace trans 1, the platinum that the 2-cyclohexanediamine is part (II) title complex and preparation method thereof.
Technical background
Nearest more than ten years, based on to the understanding in depth of platinum complex resistance mechanism, the research of relevant platinum medicine no longer is confined to the classical structure activity relationship of cis-platinum, and people start to explore new approach and research and develop novel platinum medicine.Designed so far the multiple non-classical platinum medicine that is different from original structure activity relationship, one of them has sterically hindered platinum complex exactly.Such representational compound is exactly to have entered the ZD0473 of clinical trial at present, and cis-dichloro ammonia (2-picoline) closes platinum (II).Trans 1, the 2-cyclohexanediamine, its chiral isomer [1R particularly, 2R-(-)-1, the 2-cyclohexanediamine, as the carrier aglucon, be often used in the antitumor platinum complexes of preparation, typical medicine oxaliplatin (Oxaplatin) and the Miboplatin (Miroplatin) of compound as gone on the market.The researchist wishes to be modified on the basic structure of 2-cyclohexanediamine trans 1, thereby using, this prepares the platinum complex of novel texture as part, further filters out efficient, low toxicity, water-soluble or fat-soluble good, drug candidate that selectivity is high.
Summary of the invention
Main purpose of the present invention be to provide the N-alkyl replace trans 1, the platinum complex that the 2-cyclohexanediamine is part.
The present invention also aims to provide above-mentioned N-alkyl to replace trans 1, the preparation method of the platinum complex that the 2-cyclohexanediamine is part.
It is trans 1 that a kind of N-alkyl replaces, the platinum that the 2-cyclohexanediamine is part (II) title complex, and structure is suc as formula shown in (1a) and formula (1b);
Formula (1a) formula (1b)
Y in formula (1a) is the organic carboxyl acid negatively charged ion, and the Z in formula (1b) is the organic dicarboxylic acid dianion; In formula (1a) and formula (1b), R is C
3-C
8alkyl, asterisk * represents chiral carbon atom, shown in formula (1a) and formula (1b), compound is to have 1R, 2R-configuration and/or 1S, the chiral isomer of 2S-configuration.Above-mentioned C
3-C
8alkyl can be chain-like alkyl or cyclic alkyl.
As preferred version, the Y in formula (1a) is C
1-C
16alkoxy acetic acid root or C
2-C
18the alkyl carboxylic acid root; Z in formula (1b) is the organic dicarboxylic acid dianion, comprise oxalate, malonate, 1,1-cyclobutanedicarboxylic acid, 3-hydroxyl-1,1-cyclobutanedicarboxylic acid, 3-alkoxyl group-1,1-cyclobutanedicarboxylic acid, 3-azepine-1, the 3-azepine-1 that 1-cyclobutanedicarboxylic acid, N-replace, 1-cyclobutanedicarboxylic acid or camphor two acid groups; The 3-azepine-1 that N-replaces, in the 1-cyclobutanedicarboxylic acid, substituting group is benzyl, C
1-C
4benzyl, C that alkyl replaces
1-C
4the benzyl that the benzyl that alkoxyl group replaces or halogen atom replace, wherein the substituting group on benzyl can be in arbitrary position of aromatic ring.
As preferred version, it is trans 1 that a kind of N-alkyl replaces, and the structure of the platinum that the 2-cyclohexanediamine is part (II) title complex is suc as formula shown in (1b), and wherein R is butyl, cyclopentyl, and Z is oxalate, malonate, 1, the 1-cyclobutanedicarboxylic acid; Preferred structure is: R is sec-butyl, cyclopentyl, and Z is oxalate, malonate, 1, the 1-cyclobutanedicarboxylic acid.
As another kind of preferred version, it is trans 1 that the N-alkyl replaces, and the structure of the platinum that the 2-cyclohexanediamine is part (II) title complex is suc as formula shown in (1a) or formula (1b), and wherein R is propyl group, and Y is C
2-C
4the alkoxy acetic acid root, Z is the 3-azepine-1 that N-replaces, the 1-cyclobutanedicarboxylic acid, the 3-azepine-1 that N-replaces, in the 1-cyclobutanedicarboxylic acid, the benzyl that the benzyl that substituting group is benzyl, methyl substituted benzyl, methoxy substitution or halogen atom replace; Preferred structure is: R is sec.-propyl, Y is isopropoxy acetate moiety or tert.-butoxy acetate moiety, Z is the 3-azepine-1 that N-replaces, the 1-cyclobutanedicarboxylic acid, the 3-azepine-1 that N-replaces, in the 1-cyclobutanedicarboxylic acid, the benzyl that the benzyl that substituting group is methyl substituted benzyl, methoxy substitution or halogen atom replace.
Trans 1 of a kind of N-alkyl replacement, the platinum that the 2-cyclohexanediamine is part (II) title complex, as trans 1 of preparation aforementioned formula (1a) and the described N-alkyl replacement of formula (1b), the intermediate of the platinum that the 2-cyclohexanediamine is part (II) title complex, structure is suc as formula shown in (2):
Formula (2)
Wherein, Hal represents Cl
-, Br
-or I
-, asterisk * represents chiral carbon atom, the described compound of formula (2) is to have 1R, 2R-configuration and/or 1S, the chiral isomer of 2S-configuration.
Trans 1 of described N-alkyl replacement, the preparation method of the platinum that the 2-cyclohexanediamine is part (II) title complex comprises the following steps: with trans 1 of single Boc protection, the 2-cyclohexanediamine is initiator (D.W.Lee, H.-J.Ha, W.K.Lee, SyntheticCommunications, 2007,37,737-742) obtain the compound of formula (3) representative by following synthetic route I, then close the sour nak response of platinum (II) with compound shown in formula (3) and four halogen, obtain the described compound of formula (2);
Formula (3)
Described single Boc protection trans 1, the 2-cyclohexanediamine is meaned by formula (4)
Formula (4)
Wherein Boc represents tertbutyloxycarbonyl;
Route I is as follows:
In route I, R is as the described C of claim 1-6 any one
3-C
8alkyl, described alkanoic is C
3-C
8chain-like alkyl aldehyde, described aliphatic ketone is C
3-C
8chain or cyclic alkyl ketone, when R is chain-like alkyl, use chain-like alkyl aldehyde or chain-like alkyl ketone; When using chain-like alkyl aldehyde, R1 is C
2-C
7alkyl, R2 is hydrogen atom; When using chain-like alkyl ketone, R1 and R2 are respectively C
1-C
6chain-like alkyl, both carbonatoms sums should be less than 7 or equal 7; When R is cyclic alkyl, use cyclic alkyl ketone, wherein X is C
2-C
7alkylidene group.The preparation method of the described compound of above-mentioned formula (3) is open in first to file (CN200910027237.8).Boc protection trans 1, when the 2-cyclohexanediamine react with aldehydes or ketones, the formation Schiff's base that first dewaters, one can be after separation and purification, for next step reaction.But be not suitable for while for reactant, being rudimentary alkanoic or aliphatic ketone, because the boiling point of these reactants is lower, do not have suitable organic solvent to dewater, do not make again aldehydes or ketones steam with steam; In addition corresponding Schiff's base one be liquid, also be difficult for purifying.Therefore trans 1 for the Boc protection, 2-cyclohexanediamine and alkanoic or alkenolic the reaction, in route I, the Schiff's base of the first step gained can separate usually, directly enters next step reaction.
Trans 1 of the N-alkyl replacement prepared according to route I method, the 2-cyclohexanediamine mainly obtains with the form of its hydrochloride, hydrochloride and quantitative alkali are acted in water as sodium hydroxide or potassium hydroxide, can obtain corresponding N-mono-substituted trans 1, the 2-cyclohexanediamine.
Close the sour nak response of platinum (II) with compound shown in formula (3) and four halogen, the concrete grammar that obtains the described compound of formula (2) can be: four halogen are closed to the sour potassium of platinum (II) (6.00mmol) and the N-alkyl replaces trans 1,2-cyclohexanediamine (6.00mmol) is mixed in 50mL water, the room temperature lucifuge stirs spends the night, there are a large amount of yellow mercury oxides to generate, filter difference water, dehydrated alcohol, ether repetitive scrubbing, the dry yellow powder that obtains.
The described compound of formula (2) can be according to compound described in known reactions production (1a) or formula (1b), as following any method, method 1: under the lucifuge condition, in the aqueous solution, remove the halogen ion in formula (2) by silver ions, then react platinum (II) title complex shown in production (1a) with the alkali metal salts or ammonium salt of the defined Y of formula (1a), or react platinum (II) title complex shown in production (1b) with the alkali metal salts or ammonium salt of the defined Z of formula (1b); Method 2: under the lucifuge condition, in the aqueous solution, the silver salt of the defined Y of through type (1a) reacts platinum (II) title complex shown in production (1a) with platinum (II) title complex shown in formula (2), or the silver salt of the defined Z of through type (1b) reacts platinum (II) title complex shown in production (1b) with platinum (II) title complex shown in formula (2).
Concrete steps are as follows:
Method 1:
By the dihalo-shown in formula (2), [the N-alkyl replaces trans 1, the 2-cyclohexanediamine] close platinum (II) and (2.90mmol) be suspended in 100mL water, add Silver Nitrate (5.80mmol), after 60 ℃ of lower lucifuges are reacted 24-36 hour, the diatomite aided filter.The 30mL aqueous solution that adds carboxylic acid sodium (5.80mmol) or Sodium Dicarboxylic Acid (2.90mmol) in filtrate, then in 80 ℃ of lower lucifuge reaction 24-48 hour, that solution is concentrated, separate out a large amount of solids.Filter, water, ethanol, ether repetitive scrubbing, vacuum-drying, obtain target product.
Method 2:
By the dihalo-shown in formula (2), [the N-alkyl replaces trans 1, the 2-cyclohexanediamine] close platinum (II) and (2.90mmol) be suspended in 100mL water with silver carboxylate (2.90mmol) or carboxylic acid two silver medals (1.45mmol) of new system, in 70 ℃ of lucifuge reaction 24-48 hour, then use the diatomite aided filter, filtrate is concentrated, separate out a large amount of solids, filter, vacuum-drying, obtain target product.
The compound prepared by the inventive method infrared spectra, nucleus magnetic hydrogen spectrum and mass spectrum has been determined the molecular structure of compound.
Shown in formula of the present invention (1a) and formula (1b), platinum (II) title complex has obvious restraining effect to human hepatoma cell HepG-2, human breast cancer cell MCF-7, Human Lung Cancer cell A549 and human colon cancer cell HCT-116, related compound and contrast to the restraining effect of different carcinoma cell in Table 1.
Specific embodiment
The present invention obtains further instruction by following embodiment, but these explanations are not restriction the present invention.Except particularly pointing out, it is trans 1 that the alkyl of N-described in embodiment replaces, and the configuration of two chiral carbon atoms of 2-cyclohexanediamine part is respectively 1R and 2R; In the nucleus magnetic hydrogen spectrum data, it is trans 1 that DACH represents, the skeleton of 2-cyclohexanediamine.
Embodiment 1. compound 1a (C
16h
32n
2o
6pt) preparation
By method 1 preparation, buff powder, productive rate: 51%.IR(KBr，cm
-1)：3113(br)，2935，2871，1616，1450，1385，1198，1116，988，942，713，595；
1H-NMR(d
6-DMSO/TMS，ppm)：δ0.90(t，3H，CH
2CH
3)，δ2.06-1.02(m，12H，CH
2?of?DACH?and?CH
3CH
2CH
2)，δ2.14(m，2H，NHCH
2)，δ2.50-2.34(m，2H，NHCH)，δ3.23(s，6H，OCH
3)，δ3.81(s，4H，COCH
2O)，δ5.11(m，1H，CH
2NH)，δ6.10-5.99(dd，2H，CHNH
2)；ESI-MS：m/z[M+Na]
+＝566(100％)。
Embodiment 2. compound 2a (C
22h
44n
2o
6pt) preparation
By method 1 preparation, buff powder, 55%.IR(KBr，cm
-1)：3461(br)，3124，2971，2935，2870，1624，1456，1385，1310，1192，1108，892，837，712；
1H-NMR(d
6-DMSO/TMS，ppm)：δ0.90(t，3H，CH
2CH
3)，δ1.11(S，18H，2C(CH
3)
3)，δ1.95-0.98(m，12H，CH
2?of?DACH?and?CH
3CH
2CH
2)，δ2.15(m，2H，NHCH
2)，δ2.62-2.42(m，2H，NHCH)，δ3.85(s，4H，COCH
2O)，δ5.95(m，1H，CH
2NH)，δ6.69-6.17(dd，2H，CHNH
2)；ESI-MS?m/z：[M+Na]
+＝650(100％)。
Embodiment 3. compound 3a (C
23h
35n
3o
5pt) preparation
By method 2 preparations, buff powder, productive rate: 65%.IR(KBr，cm
-1)：3417(br)，3078，2936，2865，1627，1495，1458，1380，1250，1048，1025，758；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.90(t，3H，CH
2CH
3)，δ0.98-1.96(m，12H，CH
2?of?DACH?and?CH
3CH
2CH
2)，δ2.27(m，2H，NHCH
2)，δ2.44-2.62(m，2H，NHCH)，δ3.43(m，2H，CH
2Ph)，δ3.59(s，3H，PhOCH
3)，δ3.85-4.08(m，4H，N(CH
2)
2)，δ5.74(m，1H，CH
2NH)，δ6.21-6.26(dd，2H，CHNH
2)，δ6.88-7.21(m，4H，Ar-H)；ESI-MS：m/z[M+H]
+＝629(100％)。
Embodiment 4. compound 4a (C
22h
32clN
3o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 55%.IR(KBr，cm
-1)：3403(br)，3189，2936，2861，1591，1471，1443，1358，1210，1183，1049，910，871，753，698，591；
1H-NMR(d
6-DMSO/TMS，ppm)：δ0.92(t，3H，CH
2CH
3)，δ1.97-0.95(m，12H，CH
2?of?DACH?and?CH
3CH
2CH
2)，δ2.32(m，2H，NHCH
2)，δ2.75-2.50(m，2H，NHCH)，δ3.63(s，2H，CH
2Ph)，δ3.94-3.78(m，4H，N(CH
2)
2)，δ5.20(m，1H，CH
2NH)，δ6.29-5.93(dd，2H，CHNH
2)，δ7.44-7.26(m，4H，Ar-H)；ESI-MS?m/z：[M+H]
+＝634(100％)。
Embodiment 5. compound 5a (C
22h
32clN
3o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 54%.IR(KBr，cm
-1)：3403(br)，3092，2937，2862，1596，1473，1455，1379，1210，1181，1130，1078，866，785，733，682，525；
1H-NMR(d
6-DMSO/TMS，ppm)：δ0.90(t，3H，CH
2CH
3)，δ2.06-1.02(m，12H，CH
2?of?DACH?and?CH
3CH
2CH
2)，δ2.27(m，2H，NHCH
2)，δ2.75-2.50(m，2H，NHCH)，δ3.60(s，2H，CH
2Ph)，δ3.86-3.77(m，4H，N(CH
2)
2)，δ5.19(m，1H，CH
2NH)，δ6.28-5.91(dd，2H，CHNH
2)，δ7.52-7.26(m，4H，Ar-H)；ESI-MS?m/z：[M+H]
+＝634(100％)。
Embodiment 6. compound 6a (C
22h
32clN
3o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 59%.IR(KBr，cm
-1)：3403(br)，3094，2936，2864，1615，1491，1451，1382，1282，1210，1177，1091，1015，910，855，811，773，728，699，591；
1H-NMR(d
6-DMSO/TMS，ppm)：δ0.90(t，3H，CH
2CH
3)，δ2.08-1.03(m，12H，CH
2?of?DACHand?CH
3CH
3CH
2)，δ2.27(m，2H，NHCH
2)，δ2.84-2.50(m，2H，NHCH)，δ3.45(S，2H，CH
2Ph)，δ4.20-3.71(m，4H，N(CH
2)
2)，δ5.75(m，1H，CH
2NH)，δ6.64-6.32(dd，2H，CHNH
2)，δ7.51-7.25(m，4H，Ar-H)；ESI-MS?m/z：[M+H]
+＝634(100％)。
Embodiment 7. compound 1b (C
19h
38n
2o
6pt) preparation
By method 1 preparation, buff powder, productive rate: 56%.IR(KBr，cm
-1)：3448(br)，3134，2972，2936，2867，1648，1384，1177，1126，1021，934，828，715，607；
1H-NMR(d
6-DMSO/TMS，ppm)：δ1.41-1.06(m，18H，CH(CH
3)
2and?2CH(CH
3)
2)，δ2.25-1.06(m，9H，CH
2?of?DACH?and?CH(CH
3)
2)，δ2.94-2.49(m，2H，NHCH)，δ3.65(m，2H，2OCH(CH
3)
2)，δ3.97(m，4H，(CO
2)
2CH
2O)，δ5.42(m，1H，CH
2NH)，δ5.65(br，2H，CH
2NH
2)；ESI-MS?m/z：[M+Na]
+＝608(100％)。
Embodiment 8. compound 2b (C
21h
42n
2o
6pt) preparation
By method 1 preparation, buff powder, productive rate: 59%.IR(KBr，cm
-1)：3438(br)，3150，2973，2937，2869，1616，1385，1252，1192，1099，916，892，828，713，613，529；
1H-NMR(d
6-DMSO/TMS，ppm)：δ1.40-1.07(m，24H，CH(CH
3)
2and?2C(CH
3)
3)，δ2.24-0.93(m，9H，CH
2?of?DACH?and?CH(CH
3)
2)，δ2.93-2.49(m，2H，NHCH)，δ3.89-3.58(m，4H，(CO
2)
2CH
2O)，δ5.38(m，1H，CH
2NH)，δ5.59(br，2H，CH
2NH
2)；ESI-MS?m/z：[M+Na]
+＝636(100％)。
Embodiment 9. compound 3b (C
22h
33n
3o
5pt) preparation
By method 2 preparations, white powder, productive rate: 54%.IR(KBr，cm
-1)：3417(br)，3122，2937，2863，1622，1494，1457，1376，1250，1176，1024；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.04-2.10(m，15H，CH
2?ofDACH?and?CH(CH
3)
2)，δ1.83-2.50(m，4H，NHCH?and?NHCH
2)，δ3.45(m，2H，CH
2Ph)，δ3.78(s，3H，PhOCH
3)，δ3.43-3.92(m，4H，N(CH
2)
2)，δ5.45(m，1H，CH
2NH)，δ5.87-6.20(m，2H，CHNH
2)，δ6.86-7.45(m，4H，Ar-H)；ESI-MS：m/z[M+H]
+＝615(100％)。
Embodiment 10. compound 4b (C
22h
33n
3o
5pt) preparation
By method 2 preparations, white powder, productive rate: 51%.IR(KBr，cm
-1)：3416(br)，3122，2938，2864，1602，1491，1455，1390，1266，1178，1045；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.03-2.12(m，15H，CH
2?ofDACH?and?CH(CH
3)
2)，δ1.92-2.51(m，4H，NHCH?and?NHCH
2)，δ3.45(m，2H，CH
2Ph)，δ3.79(s，3H，PhOCH
3)，δ3.45-4.14(m，4H，N(CH
2)
2)，δ5.50(m，1H，CH
2NH)，δ5.89-6.18(m，2H，CHNH
2)，δ6.76-7.41(m，4H，Ar-H)；ESI-MS：m/z[M+Na]
+＝637(50％)。
Embodiment 11. compound 5b (C
22h
33n
3o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 60%.IR(KBr，cm
-1)：3417(br)，2939，2863，1616，1455，1389，1176，1079，957；
1HNMR(d
6-DMSO/TMS，ppm)：δ1.03-2.10(m，15H，CH
2?of?DACH?andCH(CH
3)
2)，δ1.82-2.30(m，4H，NHCH?and?NHCH
2)，δ2.27(s，3H，PhCH
3)，δ3.43(m，2H，CH
2Ph)，δ3.61-4.08(m，4H，N(CH
2)
2)，δ5.30(m，1H，CH
2NH)，δ5.89-6.35(m，2H，CHNH
2)，δ7.10-7.32(m，4H，Ar-H)；ESI-MS：m/z[M+H]
+＝599(100％)。
Embodiment 12. compound 6b (C
22h
33n
3o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 59%.IR(KBr，cm
-1)：3417(br)，3121，2938，2864，1609，1449，1390，1180，1071，916；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.03-1.93(m，15H，CH
2?ofDACH?and?CH(CH
3)
2)，δ1.93-2.52(m，4H，NHCH?and?NHCH
2)，δ2.27(s，3H，PhCH
3)，δ3.42(m，2H，CH
2Ph)，δ3.42-4.14(m，4H，N(CH
2)
2)，δ5.30(m，1H，CH
2NH)，δ5.89-6.19(m，2H，CHNH
2)，δ7.00-7.34(m，4H，Ar-H)；ESI-MS：m/z[M+Na]
+＝621(100％)。
Embodiment 13. compound 1c (C
12h
22n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 58%.IR(KBr，cm
-1)：3446(br)，3199，3103，2938，2864，1703，1672，1452，1385，1249，1173，1068，1032；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.84-1.17(m，6H，CH
3CHCH
2CH
3)，δ1.18-2.25(m，10H，CH
2ofDACH?and?CHCH
2CH
3)，δ2.70-3.45(m，3H，NHCH?and?NH
2CH)，δ5.31(d，1H，CHNH)，δ5.85-6.13(m，2H，CHNH
2)；ESI-MS：m/z[M+Na]
+＝476(100％)。
Embodiment 14. compound 2c (C
13h
24n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 63%.IR(KBr，cm
-1)：3434(br)，3167，3103，2938，2865，1647，1451，1385，1255，1212，1070，1017；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.85-1.08(m，6H，CH
3CHCH
2CH
3)，δ1.23-2.14(m，10H，CH
2?of?DACH?and?CHCH
2CH
3)，δ2.29-3.48(m，3H，NHCH?and?NH
2CH)，δ3.22(m，2H，CH
2(CO)
2)，δ5.21-5.94(m，3H，CH
2NH?and?CHNH
2)；ESI-MS：m/z[M+Na]
+＝490(100％)。
Embodiment 15. compound 3c (C
16h
28n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 59%.IR(KBr，cm
-1)：3444(br)，3173，3108，2940，2864，1646，1455，1364，1117，1069，1030；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.83-1.21(m，6H，CH
3CHCH
2CH
3)，δ1.23-2.68(m，16H，CH
2?of?DACH?and?CHCH
2CH
3?and?cyclobutyl)，δ2.63-2.68(m，2H，NHCH)，δ3.43(m，1H，NH
2CH)，δ4.31-5.86(m，3H，CH
2NH?and?CHNH
2)；ESI-MS：m/z[M+Na]
+＝530(100％)。
Embodiment 16. compound 1d (C
13h
24n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 65%.IR(KBr，cm
-1)：3434(br)，3122，2941，2863，1647，1453，1363，1251，1119，1071，1023，906，777；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.89-1.09(m，6H，CH
2CH(CH
3)
2)，δ1.12-2.15(m，9H，CH(CH
3)
2and?CH
2of?DACH)，δ2.12-2.44(m，4H，NHCH
2?and?NHCH?and?NH
2CH)，δ3.12-3.23(m，2H，CH
2(CO)
2)，δ5.31-6.12(m，3H，CH
2NHand?CHNH
2)；ESI-MS：m/z[M+Na]
+＝490(100％)。
Embodiment 17. compound 2d (C
18h
36n
2o
6pt) preparation
By method 1 preparation, buff powder, productive rate: 52%.IR(KBr，cm
-1)：3425(br)，3159，3097，2942，2867，1644，1452，1385，1169，1092，959，932，741，592；
1H-NMR(D
2O/TMS，ppm)：δ1.10-0.87(m，12H，CH(CH
3)
2?and?2CH
2CH
3)，δ2.27-1.10(m，9H，CH
2?of?DACH?and(CH
3)
2CH)，δ2.49(m，2H，NHCH
2)，δ3.90-3.42(m，12H，NHCH?and?NHCH
2?and?CO
2CH
2OCH
2CH
3)；ESI-MS?m/z：[M+H]
+＝570(100％)。
Annotate: N-replaces trans 1, and 2-cyclohexanediamine part is racemic modification.
Embodiment 18. compound 3d (C
22h
44n
2o
6pt) preparation
By method 1 preparation, buff powder, productive rate 58%.IR(KBr，cm
-1)：3425(br)，3159，3097，2942，2867，1644，1452，1385，1169，1092，959，932，741，592；
1H-NMR(D
2O/TMS，ppm)：δ0.88(t，6H，2CH
2CH
3)，δ1.28(dd，6H，CH(CH
3)
2)，δ2.27-1.06(m，17H，CH
2of?DACH?and(CH
3)
2CH?and2CH
3CH
2CH
2)，δ2.49(m，2H，NHCH
2)，δ3.39(m，6H，2OCH
2and?NHCH
2)；ESI-MS?m/z：[M+H]
+＝626(100％)。
Annotate: N-replaces trans 1, and 2-cyclohexanediamine part is racemic modification.
Embodiment 19. compound 1e (C
24h
37n
3o
5pt) preparation
By method 2 preparations, buff powder, productive rate: 69%.IR(KBr，cm
-1)：3422(br)，3263，3129，2940，2864，1611，1515，1462，1390，1345，1251，1180，1033，823；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.03-1.08(m，9H，C(CH
3)
3)，δ1.27-1.55(m，8H，CH
2?of?DACH)，δ1.95(m，4H，NHCH
2?andNHCH?and?NH
2CH)，δ3.41-3.45(m，4H，CH
2NCH
2)，δ3.52(s，3H，PhOCH
3)，δ3.71-3.77(m，2H，NCH
2Ar)，δ6.83-7.17(m，4H，ArH)；ESI-MS：[M+H]
+＝643(100％)。
Annotate: N-replaces trans 1, and the configuration of two chiral carbon atoms of 2-cyclohexanediamine part is respectively 1S and 2S.
Embodiment 20. compound 2e (C
24h
37n
3o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 60%.IR(KBr，cm
-1)：3420(br)，3121，2940，2863，1615，1518，1455，1387，1339，1209，1168，1036，815；
1HNMR(d
6-DMSO/TMS，ppm)：δ1.02-1.11(m，9H，C(CH
3)
3)，δ1.21-1.56(m，8H，CH
2?of?DACH)，δ1.98-2.27(m，4H，NHCH
2?and?NHCH?andNH
2CH)，δ2.32(s，3H，PhCH
3)，δ3.42-3.47(m，4H，CH
2NCH
2)，δ3.55(m，2H，NCH
2Ar)，δ7.09-7.25(m，4H，ArH)；ESI-MS：m/z[M+H]
+＝627(100％)。
Annotate: N-replaces trans 1, and the configuration of two chiral carbon atoms of 2-cyclohexanediamine part is respectively 1S and 2S.
Embodiment 21. compound 1f (C
13h
22n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 61%.IR(KBr，cm
-1)：3445(br)，3120，3117，2943，2866，1704，1672，1450，1384，1312，1242，1071，1027；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.04-1.23(m，4H，CH
2?of?DACH)，δ1.39-1.52(m，4H，CH
2?of?cyclopentyl)，δ1.61-1.63(m，1H，CH
2?ofDACH)，δ1.67-1.72(m，1H，CH
2?of?cyclopentyl)，δ1.82-2.22(m，6H，CH
2?of?DACH?andcyclopentyl)，δ2.17-2.22(m，1H，CHNH?of?DACH)，δ2.31-2.39(m，1H，CHNH?of?DACH)，δ3.11-3.15(p，1H，CHNH?of?cyclopentyl)；ESI-MS：m/z[M+Na]
+＝488(50％)。
Embodiment 22. compound 2f (C
14h
24n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 59%.IR(KBr，cm
-1)：3436(br)，3110，3098，2942，2866，1637，1449，1384，1307，1177，1072，1028；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.03-1.20(m，4H，CH
2?of?DACH)，δ1.36-1.51(m，4H，CH
2?of?cyclopentyl)，δ1.62-2.24(m，8H，CH
2?of?DACH?andcyclopentyl)，δ2.15-2.24(m，1H，CHNH?of?DACH)，δ2.37-2.44(m，1H，CHNH?of?DACH)，δ3.09-3.18(m，2H，COCH
2CO)，δ3.25-3.30(p，1H，CNHH?of?cyclopentyl)；ESI-MS：m/z[M+Na]
+＝502(65％)。
Embodiment 23. compound 3f (C
17h
28n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 50%.IR(KBr，cm
-1)：3455(br)，3142，2944，2866，1647，1455，1365，1252，1117，1071，1026；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.00-1.21(m，4H，CH
2?ofDACH)，δ1.37-1.52(m，4H，CH
2?of?cyclopentyl)，δ1.62-1.73(m，2H，CH
2?of?DACH)，δ1.62-1.73(m，2H，CH
2?of?cyclobutyl)，δ1.77-2.29(m，6H，CH
2?of?DACH?and?cyclopentyl)，δ2.15-2.29(m，1H，CHNH?of?DACH)，δ2.35--2.43(m，1H，CHNH?of?DACH)，δ2.60-2.81(m，4H，CH
2?of?cyclobutyl)，δ3.12-3.15(p，1H，CNHH?ofcyclopentyl)；ESI-MS：m/z[M+K]
+＝558(85％)，[M+Na]
+＝542(80％)。
Embodiment 24. compound 4f (C
24h
35n
3o
5pt) preparation
By method 2 preparations, buff powder, productive rate: 54%.IR(KBr，cm
-1)：3416(br)，3082，2941，2865，1603，1494，1450，1376，1290，1248，1176，1026；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.03-1.48(m，12H，CH
2?of?DACH?and?cyclopentyl)，δ1.63-2.17(m，4H，CH
2?of?DACH?and?cyclopentyl)，δ2.33-2.30(m，3H，CH?of?DACH?and?cyclopentyl)，δ3.36-3.67(m，4H，CH
2NCH
2)，δ3.50(s，3H，PhOCH
3)，δ3.79-3.90(m，2H，NCH
2Ar)，δ7.18-7.27(m，4H，ArH)；ESI-MS：m/z[M+H]
+＝641(100％)。
Embodiment 25. compound 1g (C
18h
30n
2o
5pt) preparation
By method 2 preparations, white powder, productive rate: 54%.IR(KBr，cm
-1)：3427(br)，3204，2935，2858，1641，14530，1374，1240，1150，1072，1045，898；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.03-2.09(m，18H，CH
2?of?DACH?and?cyclohexyl)，δ2.23-2.62(m，4H，CH
2?of?cyclobutyl)，δ2.90-3.45(m，3H，2CHNH，CHNH
2)，δ3.84(m，1H，CHOH)，δ4.91(s，1H，CHOH)，δ5.10(m，1H，CH
2NH)，δ5.92(m，2H，CHNH
2)；ESI-MS：m/z[M+Na]
+＝558(85％)。
Embodiment 26. compound 2g (C
24h
35n
3o
4pt) preparation
By method 2 preparations, white powder, productive rate: 61%.IR(KBr，cm
-1)：3418(br)，3090，2934，2858，1622，1453，1375，1178，1067，1028；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.08-1.48(m，14H，CH
2?of?DACHand?cyclopentyl)，δ1.72-2.11(m，4H，CH
2?of?DACH?and?cyclopentyl)，δ2.11(m，3H，CH?ofDACH?and?cyclopentyl)，δ3.43-3.60(m，4H，CH
2NCH
2)，δ3.74-3.91(m，2H，NCH
2Ar)，δ7.22-7.45(m，5H，ArH)；ESI-MS：m/z[M+H]
+＝625(100％)。
Embodiment 27. compound 3g (C
25h
37n
3o
4pt) preparation
By method 2 preparations, white powder, productive rate: 60%.IR(KBr，cm
-1)：3403(br)，3104，2935，2858，1609，1450，1383，1176，1069；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.06-1.50(m，12H，CH
2?of?DACH?andcyclopentyl)，δ1.72-1.91(m，6H，CH
2?of?DACH?and?cyclopentyl)，δ2.16(m，3H，CH?of?DACHand?cyclopentyl)，δ2.29(s，3H，PhCH
3)，δ3.36-3.58(m，4H，CH
2NCH
2)，δ3.76(m，2H，NCH
2Ar)，δ7.10-7.31(m，4H，ArH)；ESI-MS：m/z[M]+H
+＝639(100％)。
Embodiment 28. compound 4g (C
25h
37n
3o
4pt) preparation
By method 2 preparations, white powder, productive rate: 51%.IR(KBr，cm
-1)：3421(br)，3051，2933，2858，1609，1449，1363，1177，1068，1036；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.09-1.50(m，12H，CH
2?of?DACHand?cyclopentyl)，δ1.72-2.16(m，6H，CH
2?of?DACH?and?cyclopentyl)，δ2.25(m，3H，CH?ofDACH?and?cyclopentyl)，δ2.32(s，3H，PhCH
3)，δ3.42-3.55(m，4H，CH
2NCH
2)，δ3.75-3.79(m，2H，NCH
2Ar)，δ7.07-7.25(m，4H，ArH)；ESI-MS：m/z[M+H]
+＝639(100％)。
Embodiment 29. compound 1h (C
19h
34n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 50%.IR(KBr，cm
-1)：3420(br)，2939，1596(br)，1457，1384，1350，1173，1126，801；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.74-0.86(m，3H，CCH
3?ofcamphorato)，δ0.97-1.37(m，20H，CH
2?of?DACH?and?CHCH
2CH
2C，CH
3of?camphorato?andCH(CH
3)
2)，δ1.51(m，4H，CH
2of?DACH)，δ2.01(m，3H，NHCH?and?CH?of?camphorato)，δ3.45(m，1H，CH(CH
3)
2)，δ5.80-6.80(m，3H，CHNH?and?CHNH
2)；ESI-MS：m/z[M+H]
+＝550(80％)，[M+Na]
+＝572(20％)。
Annotate: the camphor acid group is transformed and is obtained by natural camphor acid.
Embodiment 30. compound 2h (C
20h
36n
2o
4pt) preparation
By method 2 preparations, buff powder, productive rate: 50%.IR(KBr，cm
-1)：3429(br)，2957，1603(br)，1457，1382，1348，1169，1125，909，801；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.75(m，3H，CCH
3?ofcamphorato)，δ0.89-1.39(m，21H，CH
2?of?DACH?and?CHCH
2CH
2C，CH
3?of?camphorato?andNHCH
2CH
2CH
2CH
3?of?n-Bu)，δ1.49(m，4H，CH
2?of?DACH)，δ1.95(m，3H，NHCH?and?CH?ofcamphorato)，δ3.40(m，2H，NHCH
2?of?n-Bu)，δ4.80-6.80(m，3H，CHNH?and?CHNH
2)；ESI-MS：m/z[M+H]
+＝564(50％)，[M+Na+CH
3OH]
+＝619(20％)。
Annotate: the camphor acid group is transformed and is obtained by natural camphor acid.
Embodiment 31. compound 1x (C
10h
22cl
2n
2pt) preparation
Preparation by the following method: tetrachloro is closed to the sour potassium of platinum (II) (6.00mmol) and N-normal-butyl-1R, the trans cyclohexanediamine of 2R-(6.00mmol) is mixed in 50mL water, the room temperature lucifuge stirs spends the night, there are a large amount of yellow mercury oxides to generate, filter, difference water, dehydrated alcohol, ether repetitive scrubbing, dry yellow powder, the productive rate: 89% of obtaining.IR(KBr，cm
-1)：3490(br)，3187，3117，2935，2863，1582，1451，1380，1239，1192，1157，1068，1038，1014，908；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.90(t，3H，CH
2CH
3)，δ1.02-1.97(m，12H，CH
2?of?DACH?and?CH
3CH
2CH
2)，δ2.12(m，2H，NHCH
2)，δ2.48-2.50(m，2H，NHCH)，δ5.37(m，1H，CH
2NH)，δ6.10-6.45(dd，2H，CHNH
2)；ESI-MS：m/z[M+Na]
+＝459(100％)。
Embodiment 32. compound 2x (C
9h
20cl
2n
2pt) preparation
The preparation method is with embodiment 31, yellow powder, productive rate: 90%.IR(KBr，cm
-1)：3475(br)，3258，3194，2924，2867，1594，1451，1423，1390，1267，1190，1157，1124，1068，1006，920，797；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.07-1.35(m，6H，CH(CH
3)
2)，δ1.04-2.17(m，9H，CH
2?of?DACH?andCH(CH
3)
2)，δ3.01-3.45(m，2H，NHCH)，δ5.38(m，1H，CH
2NH)，δ6.05-6.14(dd，2H，CHNH
2)；ESI-MS：m/z[M+Na]
+＝445(100％)。
Embodiment 33. compound 3x (C
10h
22cl
2n
2pt) preparation
The preparation method is with embodiment 31, yellow powder, productive rate: 88%.IR(KBr，cm
-1)：3495(br)，3249，3186，3117，2936，2864，1581，1450，1392，1368，1186，1156，1132，1070，1032，997；
1H?NMR(d
6-DMSO/TMS，ppm)：δ0.90-1.07(m，6H，CH
2CH(CH
3)
2)，δ1.10-2.15(m，9H，CH(CH
3)
2?and?CH
2?of?DACH)，δ2.12-2.44(m，4H，NHCH
2?and?NHCH?and?NH
2CH)，δ5.31-6.10(m，3H，CH
2NH?and?CHNH
2)；ESI-MS：m/z[M+Na]
+＝459(100％)。
Embodiment 34. compound 4x (C
11h
22cl
2n
2pt) preparation
The preparation method is with embodiment 31, yellow powder, productive rate: 88%.IR(KBr，cm
-1)：3257，3178，3142，2938，2864，1591，1566，1447，1127，1066；
1H?NMR(d
6-DMSO/TMS，ppm)：δ1.00-1.21(m，4H，CH
2?ofDACH)，δ1.37-1.50(m，4H，CH
2?of?cyclopentyl)，δ1.59-1.60(m，1H，CH
2?of?DACH)，δ1.65-1.70(m，1H，CH
2?of?cyclopentyl)，δ1.79-2.18(m，6H，CH
2?of?DACH?and?cyclopentyl)，δ2.20-2.25(m，1H，CHNH?of?DACH)，δ2.30-2.37(m，1H，CHNH?of?DACH)，δ3.09-3.12(m，1H，CHNH?of?cyclopentyl)；ESI-MS：m/z[M+Na]
+＝471(100％)。
The single Boc of embodiment 35. protection trans 1, the preparation of 2-cyclohexanediamine
Measure 500mL methyl alcohol, put into the 2L flask, add 500mmol 1R, the trans cyclohexanediamine of 2R-or 1S, the trans cyclohexanediamine of 2S-, stirring at room is dissolved, and stirs the lower 2.5mol/L hydrogenchloride/methanol solution 200mL that slowly drips, and controls temperature and is no more than 5 ℃.Return to room temperature after finishing, add 200mL water, under room temperature, stir 30min.With 250mL dissolve with methanol 550mmol (Boc)
2o, drop to above-mentioned solution under room temperature, about 30min adds, then stirring at room 1h.Stopped reaction, 250mL methyl alcohol is removed in decompression, adds 300mL water, by extracted with diethyl ether 3 times (250mL/ time).Water is regulated pH value 10 left and right with the 5M aqueous sodium hydroxide solution, with dichloromethane extraction 4 times (250mL/ time), merges organic phase, and with 2 times (100mL/ time) of saturated nacl aqueous solution washing, organic phase is spent the night with anhydrous sodium sulfate drying, filters.Filtrate decompression is concentrated into about 200mL left and right, adds 400mL sherwood oil (60-90 ℃) recrystallization, obtains white needles solid 83.0g (77.0%).IR(KBr，cm
-1)：3350，3291，3183(br)，2978，2931，2857，1695，1592，1554，1445，1183，1041，849，761；
1H-NMR(CDCl
3/TMS)：δ1.45(S，9H，C(CH
3)
3)，δ2.01-1.02(m，8H，CH
2?of?DACH)，δ3.14-2.28(m，2H，NH
2CH)，δ4.49(br，1H，CONH)；ESI-MS?m/z：[M+H]
+＝215(100％)。
Synthetic (the route I) of embodiment 36. ligand 1s-R.2HCl
Take SM-R 17.12g (80mmol), insert in the 500mL there-necked flask, use the 350mL dissolve with methanol, add 17.28g (240mmol) butyraldehyde-n, stir about 20min under room temperature after adding sodium borohydride 9.00g (240mmol), then stirs 3h in batches.Removal of solvent under reduced pressure, add 300mL acetic acid ethyl dissolution residue, 150mL saturated aqueous common salt washed twice for organic phase, and the 150mL water washing is once.Use the anhydrous sodium sulfate drying organic phase, filter removal of solvent under reduced pressure.Dissolve with the 200mL anhydrous diethyl ether, add 150mL 4M hydrogenchloride/ethyl acetate, after stir about 10min, have gas to emerge, the adularescent solid is separated out gradually, the about 6h of stirring at room.Filter, anhydrous diethyl ether washing 3 times for filter cake, vacuum-drying, obtain white solid 15.6g (80.1%).IR(KBr，cm
-1)：3416(br)，2942，2870，1607，1458，1027；
1H-NMR(D
2O/TMS)：δ0.94(t，3H，CH
2CH
3)，δ1.41-1.39(m，4H，CH
3CH
2CH
2)，δ2.32-1.52(m，8H，CH
2?of?DACH)，δ3.26-3.04(m，2H，NHCH
2)，δ3.50-3.40(m，2H，NHCH)；ESI-MS?m/z：[M-2HCl+H]
+＝171(100％)。
Synthetic (the route I) of embodiment 37. part 2-R.2HCl
Take SM-R as initiator, and isobutyric aldehyde is reactant, by embodiment 36 methods, obtains white solid 15.0g (77.0%).IR(KBr，cm
-1)：3430(br)，2945，2871，1027，1001；
1H-NMR(D
2O/TMS)：δ1.02(d，6H，CH
3CHCH
3)，δ2.34-1.38(m，8H，CH
2?of?DACH)，δ2.09(m，1H，CH(CH
3)
2)，δ3.11-2.94(d，2H，NH?CH
2)，δ3.52-3.41(m，2H，CHNH)；ESI-MS?m/z：[M-2HCl+H]
+＝171(100％)。
Synthetic (the route I) of embodiment 38. part 3-R.2HCl
Take SM-R as initiator, and butanone is reactant, by embodiment 36 methods, obtains white solid 14.5g (74.5%).IR(KBr，cm
-1)：3428(br)，2942，2986，1096，1024；
1H-NMR(D
2O/TMS)：δ1.01-0.95(m，3H，CH
3CH
2)，δ2.32-1.37(m，8H，CH
2?of?DACH)，δ1.37-1.30(m，3H，CHCH
3)，δ1.38-1.30(m，2H，CH
3CH
2)，δ3.39-3.38(m，1H，NHCHCH
3)，δ3.48-3.40(m，2H，CHNH)；ESI-MS?m/z：[M-2HCl+H]
+＝171(100％)。
Synthetic (the route I) of embodiment 39. part 4-R.2HCl
Take SM-R as initiator, and acetone is reactant, by embodiment 36 methods, obtains white solid 13.0g (70.9%).IR(KBr，cm
-1)：3431(br)，2975，2946，1098，1032；
1H-NMR(D
2O/TMS)：δ1.38-1.25(m，6H，CH(CH
3)
2)，δ2.26-1.38(m，8H，CH
2?of?DACH)，δ3.67-3.58(m，1H，NHCHCH
3)，δ3.41-3.35(m，2H，NHCH)；ESI-MS?m/z：[M-2HCl+H]
+＝157(100％)。
Synthetic (the route I) of embodiment 40. part 5-R.2HCl
Take SM-R as initiator, and pimelinketone is reactant, by embodiment 36 methods, obtains white solid 18.0g (84.0%).IR(KBr，cm
-1)：3429(br)，2939，2860，1030；
1H-NMR(D
2O/TMS)：δ2.27-1.13(m，18H，CH
2?of?DACH?andCHX)，δ3.45-3.32(m，3H，NHCH)；ESI-MS?m/z：[M-2HCl+H]
+＝197(100％)。
Annotate: CHX represents cyclohexyl.
Synthetic (the route I) of embodiment 41. part 6-R.2HCl
Take SM-R as initiator, and cyclopentanone is reactant, by embodiment 36 methods, obtains white solid 16.1g (79.1%).IR(KBr，cm
-1)：3430(br)，2940，2869，2814，1030；
1H-NMR(D
2O/TMS)：δ2.36-1.37(m，16H，CH
2?of?DACHand?CPX)，δ3.47-3.40(m，3H，NHCH)；ESI-MS?m/z：[M-2HCl+H]
+＝183(100％)。
Annotate: CPX represents cyclopentyl.
The anti tumor activity in vitro of embodiment 42. typical compounds is measured
Some typical platinum (II) title complexs shown in formula (1a) and formula (1b) have been done to anti tumor activity in vitro mensuration, cancer cells used has human hepatoma cell HepG-2, human breast cancer cell MCF-7, Human Lung Cancer cell A549 and human colon cancer cell HCT-116, and positive control used is existing medicine cis-platinum, oxaliplatin or carboplatin.Concrete experimental technique is as follows:
Use mtt assay to detect cell survival rate, be about to be grown in the cell of logarithmic phase, the trysinization through 0.01%, counting, be seeded in 100mL in 96 orifice plates with the cell density of 2.0 * 103/well, is placed in 5%CO
237 ℃ of overnight incubation in incubator.Each compound is established six concentration gradients, and each concentration is established three multiple holes, and each concentration joins respectively in corresponding aperture, 5%CO
2cultivate 72 hours in 37 ℃ of incubators, add the 5mg/mL MTT of 20mL.37 ℃ hatch 3 hours after, inhale and to abandon supernatant, add the DMSO of 100mL to dissolve, use SpectraMAX 340 to survey 550nm (L1) absorbance value, reference wavelength 690nm (L2), to the mapping of inhibitor different concns, obtain IC through formula fitting by (L1-L2) value
50value.
The IC of table 1. platinum (II) title complex
50value
Claims (8)
1. it is trans 1 that a N-alkyl replaces, and the platinum that the 2-cyclohexanediamine is part (II) title complex, is characterized in that, its structure is suc as formula shown in (1a) or formula (1b):
Y in formula (1a) is for being C
1-C
16alkoxy acetic acid root or C
2-C
18the alkyl carboxylic acid root, Z in formula (1b) is oxalate, malonate, 1,1-cyclobutanedicarboxylic acid, 3-hydroxyl-1,1-cyclobutanedicarboxylic acid, 3-azepine-1, the 3-azepine-1 that 1-cyclobutanedicarboxylic acid, N-replace, 1-cyclobutanedicarboxylic acid or camphor two acid groups, the 3-azepine-1 that N-replaces, in the 1-cyclobutanedicarboxylic acid, substituting group is benzyl, C
1-C
4benzyl, C that alkyl replaces
1-C
4the benzyl that the benzyl that alkoxyl group replaces or halogen atom replace, in formula (1a) and formula (1b), R is C
3-C
8alkyl, cyclopentyl, asterisk * represents chiral carbon atom, formula (1a) and the described compound of formula (1b) they are to have 1R, the chiral isomer of 2R-configuration.
2. it is trans 1 that N-alkyl as claimed in claim 1 replaces, and the platinum that the 2-cyclohexanediamine is part (II) title complex, is characterized in that, its structure is suc as formula shown in (1b), and wherein R is that butyl, Z are oxalate, malonate, 1, the 1-cyclobutanedicarboxylic acid.
3. it is trans 1 that N-alkyl as claimed in claim 2 replaces, and the platinum that the 2-cyclohexanediamine is part (II) title complex is characterized in that R is sec-butyl, cyclopentyl, and Z is oxalate, malonate, 1, the 1-cyclobutanedicarboxylic acid.
4. it is trans 1 that N-alkyl as claimed in claim 1 replaces, and the platinum that the 2-cyclohexanediamine is part (II) title complex, is characterized in that, its structure is suc as formula shown in (1a) or formula (1b), and wherein R is propyl group, and Y is C
2-C
4the alkoxy acetic acid root, Z is the 3-azepine-1 that N-replaces, the 1-cyclobutanedicarboxylic acid, the 3-azepine-1 that N-replaces, in the 1-cyclobutanedicarboxylic acid, the benzyl that the benzyl that substituting group is benzyl, methyl substituted benzyl, methoxy substitution or halogen atom replace.
N-alkyl as claimed in claim 4 replace trans 1, the platinum that the 2-cyclohexanediamine is part (II) title complex, it is characterized in that, R is sec.-propyl, and Y is isopropoxy acetate moiety or tert.-butoxy acetate moiety, and Z is the 3-azepine-1 that N-replaces, the 1-cyclobutanedicarboxylic acid, the 3-azepine-1 that N-replaces, in the 1-cyclobutanedicarboxylic acid, the benzyl that substituting group is methyl substituted benzyl or methoxy substitution.
6. it is trans 1 that a N-alkyl replaces, and the platinum that the 2-cyclohexanediamine is part (II) title complex, is characterized in that, its structure is suc as formula shown in (2);
Wherein, Hal represents Cl
-, Br
-or I
-, R is as the described C of claim 1-5 any one
3-C
8alkyl, asterisk * represents chiral carbon atom, the described compound of formula (2) is to have 1R, the chiral isomer of 2R-configuration.
N-alkyl as claimed in claim 6 replace trans 1, the preparation method of the platinum that the 2-cyclohexanediamine is part (II) title complex, it is characterized in that, comprise the following steps: with trans 1 of single Boc protection, the 2-cyclohexanediamine is that initiator obtains the compound of formula (3) representative by following synthetic route I, then close the sour nak response of platinum (II) with compound shown in formula (3) and four halogen, obtain the described compound of formula (2);
Described single Boc protection trans 1, the 2-cyclohexanediamine is meaned by formula (4):
Wherein Boc represents tertbutyloxycarbonyl;
Route I is as follows:
In route I, R is as the described C of claim 1-5 any one
3-C
8alkyl, described alkanoic is C
3-C
8chain-like alkyl aldehyde, described aliphatic ketone is C
3-C
8chain or cyclic alkyl ketone, when R is chain-like alkyl, use chain-like alkyl aldehyde or chain-like alkyl ketone, when using chain-like alkyl aldehyde, R1 is C
2-C
7alkyl, R2 is hydrogen atom; When using chain-like alkyl ketone, R1 and R2 are respectively C
1-C
6chain-like alkyl, both carbonatoms sums should be less than 7 or equal 7; When R is cyclic alkyl, use cyclic alkyl ketone, wherein X is C
2-C
7alkylidene group.
N-alkyl as claimed in claim 1 replace trans 1, the preparation method of the platinum that the 2-cyclohexanediamine is part (II) title complex, it is characterized in that, the method for being reacted compound described in production (1a) or formula (1b) by the described compound of formula (2) is:
Under the lucifuge condition, in the aqueous solution, remove the halogen ion in formula (2) by silver ions, then react platinum (II) title complex shown in production (1a) with the alkali metal salts or ammonium salt of the defined Y of formula (1a), or react platinum (II) title complex shown in production (1b) with the alkali metal salts or ammonium salt of the defined Z of formula (1b);
Perhaps,
Under the lucifuge condition, in the aqueous solution, the silver salt of the defined Y of through type (1a) reacts platinum (II) title complex shown in production (1a) with platinum (II) title complex shown in formula (2), or the silver salt of the defined Z of through type (1b) reacts platinum (II) title complex shown in production (1b) with platinum (II) title complex shown in formula (2).
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010162020.0A CN102234295B (en) | 2010-05-05 | 2010-05-05 | Platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand and preparation method thereof |
| PCT/CN2011/073630 WO2011137739A1 (en) | 2010-05-05 | 2011-05-04 | Platinum (ii) complexes having n-alkyl substituted trans-1,2-diaminocyclohexanes as ligands and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010162020.0A CN102234295B (en) | 2010-05-05 | 2010-05-05 | Platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102234295A CN102234295A (en) | 2011-11-09 |
| CN102234295B true CN102234295B (en) | 2014-01-08 |
Family
ID=44885466
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010162020.0A Expired - Fee Related CN102234295B (en) | 2010-05-05 | 2010-05-05 | Platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102234295B (en) |
| WO (1) | WO2011137739A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9561237B1 (en) | 2016-01-28 | 2017-02-07 | King Fahd University Of Petroleum And Minerals | Bis-(triethylphosphine)platinum(II) complexes with thiones as anti cancer agents |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924528B (en) * | 2012-10-29 | 2015-04-15 | 东南大学 | Anti-tumor bivalent platinum complex and preparation method for complex and ligand of complex |
| CN103145762B (en) * | 2013-02-27 | 2016-03-02 | 东南大学 | Divalence platinum complex containing aryl steric group, preparation method and application thereof |
| CN104788498B (en) * | 2015-03-23 | 2017-09-26 | 东南大学 | A kind of platinum (II) complex using chiral bicyclic diamines as carrier ligand and its preparation method and application |
| CN113999142B (en) * | 2021-11-29 | 2023-01-24 | 蚌埠中实化学技术有限公司 | Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0925285A (en) * | 1995-07-13 | 1997-01-28 | Ss Pharmaceut Co Ltd | Platinum complex and pharmaceutical containing the complex |
| CN101130556A (en) * | 2007-08-31 | 2008-02-27 | 高健 | Anticancer diaminocyclohexane metallic complex |
| CN101381380B (en) * | 2008-10-17 | 2011-05-11 | 东南大学 | Platinum (II) complexes and antineoplastic activity thereof |
-
2010
- 2010-05-05 CN CN201010162020.0A patent/CN102234295B/en not_active Expired - Fee Related
-
2011
- 2011-05-04 WO PCT/CN2011/073630 patent/WO2011137739A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9561237B1 (en) | 2016-01-28 | 2017-02-07 | King Fahd University Of Petroleum And Minerals | Bis-(triethylphosphine)platinum(II) complexes with thiones as anti cancer agents |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011137739A1 (en) | 2011-11-10 |
| CN102234295A (en) | 2011-11-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lv et al. | Lipophilicity-dependent ruthenium N-heterocyclic carbene complexes as potential anticancer agents | |
| Sama et al. | Aminoalcohols and benzoates-friends or foes? Tuning nuclearity of Cu (II) complexes, studies of their structures, magnetism, and catecholase-like activities as well as performing DFT and TDDFT studies | |
| Dokorou et al. | The triphenyltin (VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents | |
| CN102234295B (en) | Platinum (II) complex adopting N-alkyl substituted trans 1,2-diaminocyclohexane as ligand and preparation method thereof | |
| Abdolmaleki et al. | Synthesis, characterization, spectral studies and cytotoxic effects of mixed-ligand mono and binuclear copper (II) complexes and their amide ligands | |
| Buchler et al. | Tunable TACN/pyrazolate hybrid ligands as dinucleating scaffolds for metallobiosite modeling—dinickel (II) complexes relevant to the urease active site | |
| JP6159818B2 (en) | Anti-tumor divalent platinum complex and method for producing complex and complex ligand | |
| Habib et al. | Unsymmetrically substituted benzimidazolium based Silver (I)-N-heterocyclic carbene complexes: Synthesis, characterization and in vitro anticancer study against human breast cancer and colon cancer | |
| Krumm et al. | Palladium-1-methylcytosine chemistry: N3 and N3, N4 metal binding to 1-methylcytosine and an unexpected trans. fwdarw. cis isomerization of two diamminepalladium (II) entities | |
| Godó et al. | Synthesis and X-ray diffraction structures of novel half-sandwich Os (II)-and Ru (II)-hydroxamate complexes | |
| Eremina et al. | Synthesis, crystal structures, spectroscopic, and cytotoxicity study of Cu (II), Co (II), Ni (II) and Pd (II) complexes with 2-anilinomethylidene-5, 5-dimethylcyclohexane-1, 3-dione | |
| Iqbal et al. | Substitution of the chlorido ligand for PPh3 in anticancer organoruthenium complexes of sulfonamide-functionalized pyridine-2-carbothioamides leads to high cytotoxic activity | |
| Kong et al. | New tetraazamacrocyclic ligand with neutral pendent groups 1, 4, 7, 10-tetrakis (2-cyanoethyl)-1, 4, 7, 10-tetraazacyclododecane (L) and its cobalt (II), nickel (II) and copper (II) complexes: synthesis, structural characterization and antitumor activity | |
| Kim et al. | Reactivity of alkynyl Pd (II) azido complexes toward organic isocyanides, isothiocyanates, and nitriles | |
| Al Isawi et al. | Are nanojars unique to copper? Solution and solid state characterization of high-symmetry octanuclear nickel (II)-pyrazolate complexes | |
| Kovalchukova et al. | Synthesis, characterization, spectroscopic and crystallographic investigation of metal complexes of N-benzyl-N-nitrosohydroxylamine | |
| CN111138372A (en) | Preparation and application of acetylpyrazine thiosemicarbazone metal chelating agent and metal complex thereof | |
| Berners-Price et al. | Gold (I) and silver (I) complexes of 2, 3-bis (diphenylphosphino) maleic acid: Structural studies and antitumour activity | |
| CN103145762B (en) | Divalence platinum complex containing aryl steric group, preparation method and application thereof | |
| Baul et al. | An organomercury enzyme activator as a versatile template for new organomercury (II) compounds encompassing homobimetallic (RHg/Hg) and heterobimetallic (RHg/Cd) compositions: Syntheses, photoluminescence and structures | |
| Khunoad et al. | Self-assembled Cu (II) cluster from aerobic oxidation of Cu (I) Br with tris (triazolyl) methanol | |
| Mitchenko et al. | Formation and thermodynamic stability of novel methyl–vinyl derivatives of PtIV as possible intermediates for Csp3–Csp2 cross-coupling | |
| Chang et al. | Reactivity of the hydrido platinum (II) azide trans-PtH (N3)(PEt3) 2 toward organic isocyanides and isothiocyanates: Synthesis and structures of cis-PtH (PEt3) 2 (CN4-2, 6-Me2C6H3) and trans-Pt {S [CN4 (Ph)] 2}(PEt3) 2 | |
| Mautner et al. | Coordinative diversity of lanthanum (III), praseodymium (III), yttrium (III) and zinc (II) complexes based cyclen-tetraphenolate | |
| Liu et al. | Synthesis and cancer cell cytotoxicity of gold (III) tetraarylporphyrins with a C5-carboxylate substituent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140108 Termination date: 20160505 |