CN105837525B - 2,4-二胺-1,3,5-三嗪类化合物及其制备方法与应用 - Google Patents
2,4-二胺-1,3,5-三嗪类化合物及其制备方法与应用 Download PDFInfo
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- CN105837525B CN105837525B CN201610176235.5A CN201610176235A CN105837525B CN 105837525 B CN105837525 B CN 105837525B CN 201610176235 A CN201610176235 A CN 201610176235A CN 105837525 B CN105837525 B CN 105837525B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 20
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052802 copper Inorganic materials 0.000 claims abstract description 10
- 239000010949 copper Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 3
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- -1 chlorphenyl Chemical group 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 8
- 239000003480 eluent Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 3
- 229940112669 cuprous oxide Drugs 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- 238000013459 approach Methods 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims 1
- 238000004176 ammonification Methods 0.000 claims 1
- 125000004802 cyanophenyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 abstract description 2
- 229940124350 antibacterial drug Drugs 0.000 abstract 1
- 239000002547 new drug Substances 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 18
- PHRJJOSPUYLRST-UHFFFAOYSA-N 2-n,2-n-dimethyl-6-phenyl-1,3,5-triazine-2,4-diamine Chemical class CN(C)C1=NC(N)=NC(C=2C=CC=CC=2)=N1 PHRJJOSPUYLRST-UHFFFAOYSA-N 0.000 description 11
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 9
- 150000003918 triazines Chemical class 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- JXMZUNPWVXQADG-UHFFFAOYSA-N 1-iodo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1I JXMZUNPWVXQADG-UHFFFAOYSA-N 0.000 description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical class NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- HHOXWPCTCQMHNN-UHFFFAOYSA-N C1(=CC=CC=C1)I.[F] Chemical compound C1(=CC=CC=C1)I.[F] HHOXWPCTCQMHNN-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 1
- IGZGUYVVBABKOY-UHFFFAOYSA-N 1-iodo-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1I IGZGUYVVBABKOY-UHFFFAOYSA-N 0.000 description 1
- DVQWNQBEUKXONL-UHFFFAOYSA-N 1-iodo-2-methoxybenzene Chemical compound COC1=CC=CC=C1I DVQWNQBEUKXONL-UHFFFAOYSA-N 0.000 description 1
- UDHAWRUAECEBHC-UHFFFAOYSA-N 1-iodo-4-methylbenzene Chemical compound CC1=CC=C(I)C=C1 UDHAWRUAECEBHC-UHFFFAOYSA-N 0.000 description 1
- CASHWAGXBJSQDV-UHFFFAOYSA-N 2-(1,3,5-triazin-2-yl)-1,3,5-triazine Chemical compound C1=NC=NC(C=2N=CN=CN=2)=N1 CASHWAGXBJSQDV-UHFFFAOYSA-N 0.000 description 1
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 1
- RVEQXLQKLMGPHL-UHFFFAOYSA-N 4-iodo-1-nitro-2-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC=C(I)C=C1C(F)(F)F RVEQXLQKLMGPHL-UHFFFAOYSA-N 0.000 description 1
- HKJCELUUIFFSIN-UHFFFAOYSA-N 5-bromo-1,2,3-trifluorobenzene Chemical class FC1=CC(Br)=CC(F)=C1F HKJCELUUIFFSIN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FRLYPQRGKDBGRU-UHFFFAOYSA-N C#N.IC=1C=CC=CC1 Chemical compound C#N.IC=1C=CC=CC1 FRLYPQRGKDBGRU-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000001099 anti-trypanosomal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical class ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- ISGJFJAUYRUFNM-UHFFFAOYSA-N n,4-diphenyl-1,3,5-triazin-2-amine Chemical class N=1C=NC(C=2C=CC=CC=2)=NC=1NC1=CC=CC=C1 ISGJFJAUYRUFNM-UHFFFAOYSA-N 0.000 description 1
- HHKPKUHIZXTEKR-UHFFFAOYSA-N n,n,4-trimethyl-1,3,5-triazin-2-amine Chemical class CN(C)C1=NC=NC(C)=N1 HHKPKUHIZXTEKR-UHFFFAOYSA-N 0.000 description 1
- FMRBCDBWXGFHHC-UHFFFAOYSA-N n,n-dimethyl-1,3,5-triazin-2-amine Chemical class CN(C)C1=NC=NC=N1 FMRBCDBWXGFHHC-UHFFFAOYSA-N 0.000 description 1
- SIULLDWIXYYVCU-UHFFFAOYSA-N n-(4-iodophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(I)C=C1 SIULLDWIXYYVCU-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
- C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
- C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明提供了一种式(III)所示的2,4‑二胺‑1,3,5‑三嗪类化合物,其制备方法为:在反应容器中,加入式(I)所示化合物、式(II)所示化合物、金属铜催化剂、配体、碱性物质和溶剂,在80~140℃下搅拌反应6~14h,之后反应液经后处理,得到式(III)所示产物;本发明工艺反应条件温和,操作方便,成本低,有着广泛的工业应用前景;本发明所提供的2,4‑二胺‑1,3,5‑三嗪类化合物显示出一定的抗菌活性,可应用于抗菌药物及抗菌剂的制备,为新药筛选及开发奠定了基础,具有较好的实用价值;
Description
(一)技术领域
本发明涉及一种2,4-二胺-1,3,5-三嗪类化合物及其制备方法与应用。
(二)背景技术
2,4-二取代胺基-1,3,5-三嗪类化合物具有多种药理活性,如抗菌活性,抗锥虫活性,抗逆转录病毒活性,细胞毒活性及抑制血管新生活性等。目前,该类化合物的合成方法主要有以下几种:(1)由芳基异硫氰酸酯、胍和脒在氯化汞催化下制得;(2)由溴苯、取代苯胺、二乙胺和三聚氯氰,在氰基硼氢化钠催化下,经多步反应制得;(3)由2,4-二氯-1,3,5-三嗪与胺通过取代反应制得。上述方法存在诸如使用高毒试剂、昂贵催化剂或配体、反应条件不易控制、步骤繁琐及收率不佳等缺点,在使用过程中受到一定限制。因此,制备新颖的2,4-二胺-均三嗪类化合物具有重要的理论意义和实际应用价值。
(三)发明内容
本发明的目的是提供一种2,4-二胺-1,3,5-三嗪类化合物及其制备方法与应用。
为实现上述目的,本发明采用如下技术方案:
一种式(III)所示的2,4-二胺-1,3,5-三嗪类化合物:
式(III)中:
R1,R2各自独立为氢、C1~C10烷基或C6~C10芳基,或者R1、R2和两者之间的N组合形成含N或含N、O的C4~C8杂环;优选R1,R2各自独立为甲基或苯基,或者R1、R2和两者之间的N组合形成哌啶环或吗啉环;
R3为氢、C1~C10烷基、C4~C8杂芳基、C6~C12芳烷基、C6~C10芳基或被一个或多个取代基取代的C6~C10芳基(所述的取代基为C1~C10烷基、C1~C10烷氧基或卤素);优选R3为氢、甲基、苯基、噻吩基、对甲氧基苯基、间氯苯基、苄基或苯乙基;
R4为C6~C10芳基或被一个或多个取代基取代的C6~C10芳基(所述的取代基为C1~C10烷基、C1~C10烷氧基、卤素、三氟甲基、苯基、氰基、硝基或乙酰氨基);优选R4为对甲基苯基、对甲氧基苯基、邻甲氧基苯基、对乙氧基苯基、对三氟甲基苯基、对苯基苯基、对氰基苯基、对硝基苯基、对氟苯基、对氯苯基、间氯苯基、对溴苯基、对乙酰氨基苯基、对硝基间三氟甲基苯基或3,4,5-三氟苯基。
本发明还提供了一种式(III)所示2,4-二胺-1,3,5-三嗪类化合物的制备方法,所述的制备方法为:
在反应容器中,加入式(I)所示化合物、式(II)所示化合物、金属铜催化剂、配体、碱性物质和溶剂,在80~140℃下搅拌反应6~14h,之后反应液经后处理,得到式(III)所示产物;所述式(I)所示化合物与式(II)所示化合物、金属铜催化剂、配体、碱性物质的投料物质的量之比为1:0.5~3.0:0.1~0.5:0.3~1.2:2.0~4.0;
式(I)中,R1、R2、R3各自如上述所定义;
式(II)中,R4如上述所定义;X为卤素,优选为碘或溴。
所述制备方法中,所述的溶剂可以为醚类、芳烃类、亚砜类或氰类,具体可选自1,4-二氧六环、甲苯、二甲苯、二甲基亚砜或乙腈,优选1,4-二氧六环或乙腈;推荐所述溶剂的体积用量以式(I)所示化合物的质量计为10~50mL/g。
所述的金属铜催化剂可以为铜的卤化物、铜盐或铜的氧化物,具体可选自碘化亚铜、溴化亚铜、醋酸铜、硫酸铜或氧化亚铜。
所述的配体可以为芳香氮杂环或有机胺类,具体可选自2,2’-联吡啶、乙二胺、N,N’-二甲基乙二胺或L-脯氨酸。
所述的碱性物质可以为有机碱或无机碱,具体可选自三乙胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯、碳酸钾、氢氧化钾、叔丁醇钾、碳酸铯或磷酸钾。
通常所述的后处理方法为:反应结束后,加氨水(至反应液中的固体物质完全溶解),再加饱和NaCl水溶液,用乙酸乙酯萃取,合并有机层,浓缩,柱层析分离,洗脱剂为石油醚/乙酸乙酯体积比5:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到目标化合物(III)。
本发明所使用的原料式(I)所示化合物由式(IV)所示的酯类化合物和式(V)所示的双胍类化合物在甲醇钠作用下,于室温反应制得;式(IV)所示的酯类化合物与式(V)所示的双胍类化合物、甲醇钠的投料物质的量之比为1:0.4:1;具体合成方法参见文献(Bioorganic&Medicinal Chemistry Letters,19(2009),5644-5647),反应式如下:
式(IV)或式(V)中,R1、R2、R3各自如上述所定义。
本发明所述的2,4-二胺-1,3,5-三嗪类化合物对大肠杆菌有一定的抑制作用,在抗菌药物及抗菌剂的制备中具有应用前景。
本发明的有益效果在于:
本发明开发了结构新颖的2,4-二胺-1,3,5-三嗪类化合物及其制备方法,该工艺反应条件温和,操作方便,成本低,有着广泛的工业应用前景;本发明所提供的2,4-二胺-1,3,5-三嗪类化合物显示出一定的抗菌活性,为新药筛选及开发奠定了基础,具有较好的实用价值。
(四)具体实施方式
下面通过具体实施例对本发明作进一步的说明,但本发明的保护范围并不仅限于此。
实施例1 2-氨基-1,3,5-三嗪类化合物(I)的制备
以2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪为例,其制备方法为:
将苯甲酸甲酯(反应物IV,0.1362g,1mmol)、二甲双胍盐酸盐(反应物V,0.0662g,0.4mmol)、甲醇钠(0.0540g,1mmol)在甲醇(10mL)中混合,在室温(25℃)条件下反应,TLC跟踪监测,反应12h,之后反应液蒸除溶剂,加水10mL,过滤,滤饼用甲醇重结晶得到白色晶体,干燥后制得2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪0.0563g,产率65.4%。
实施例2~9 2-氨基-1,3,5-三嗪类化合物(I)的制备
以下实施例2~9按照实施例1所述方法进行制备,其中不同的反应底物及其投料量、不同的反应产物及其产率列于表1。
表1实施例2~9中的反应底物及其投料量,反应产物及其产率
实施例10:化合物(III-1)的制备
在反应容器中加入2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪(0.1076g,0.50mmol),对甲氧基碘苯(0.1170g,0.50mmol),碘化亚铜(0.0285g,0.15mmol),碳酸钾(0.1380g,1.00mmol),N,N'-二甲基乙二胺(DMEDA,0.0396g,0.45mmol)和溶剂乙腈(3mL),回流反应10小时。反应结束后冷却,加氨水4mL,搅拌5分钟,再加饱和NaCl水溶液(20mL),用乙酸乙酯萃取(20mL×3),合并有机层,浓缩,柱层析(洗脱剂为石油醚:乙酸乙酯=5:1,v:v),收集Rf值0.4~0.45的洗脱液(TLC监测,展开剂同洗脱剂),减压蒸馏除去溶剂,干燥得目标化合物(III-1)0.1222g,收率76.0%。1H NMR(500MHz,CDCl3):δ8.44-8.42(m,2H),7.58(d,J=9.0Hz,2H),7.53-7.46(m,3H),7.17(br,1H),6.91(d,J=9.0Hz,2H),3.83(s,3H),3.34(s,3H),3.23(s,3H).
实施例11:
将DMEDA用量改为(0.0132g,0.15mmol),其他操作同实施例10,得量0.0906g,收率56.4%。
实施例12:
将DMEDA用量改为(0.0528g,0.60mmol),其他操作同实施例10,得量0.1177g,收率为73.2%。
实施例13:
将碳酸钾改为叔丁醇钾(0.1124g,1.00mmol),其他操作同实施10,得量0.0563g,收率为35.0%。
实施例14:
将碳酸钾改为三乙胺(0.1011g,1.00mmol),其他操作同实施例10,得量0.0339g,收率为21.1%。
实施例15:
将碳酸钾改为1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU,0.1529g,1.00mmol),其他操作同实施例10,得量0.0682g,收率为42.4%。
实施例16:
将碳酸钾改为磷酸钾(0.2122g,1.00mmol),其他操作同实施例10,得量0.8833g,收率为72.6%。
实施例17:
将碳酸钾改为氢氧化钾(0.0561g,1.00mmol),其他操作同实施例10,得量0.0205g,收率为12.7%。
实施例18:
将碳酸钾改为碳酸铯(0.3258g,1.00mmol),其他操作同实施例10,得量0.0587g,收率为36.5%。
实施例19:
将DMEDA改为L-脯氨酸(0.0517g,0.45mmol),其他操作同实施例10,收率低于5.0%。
实施例20:
将DMEDA改为2,2’-联吡啶(0.0707g,0.45mmol),其他操作同实施例10,收率低于5.0%。
实施例21:
将DMEDA改为乙二胺(0.0266g,0.45mmol),其他操作同实施例10,得量0.0415g,收率25.8%。
实施例22:
将碘化亚铜改为溴化亚铜(0.0214g,0.15mmol),其他操作同实施例10,得量0.0731g,收率45.5%。
实施例23:
将碘化亚铜改为氧化亚铜(0.0218g,0.15mmol),其他操作同实施例10,得量0.0825g,收率51.3%。
实施例24:
将碘化亚铜改为醋酸铜(0.0297g,0.15mmol),其他操作同实施例10,得量0.0841g,收率52.3%。
实施例25:
将碘化亚铜改为硫酸铜(0.0379g,0.15mmol),其他操作同实施例10,得量0.0836g,收率52.0%。
实施例26:
将DMEDA用量改为0.0132g(0.15mmol),反应时间改为14小时,其他操作同实施例10,得量0.0933g,收率58.1%。
实施例27:
将DMEDA用量改为0.0132g(0.15mmol),反应时间改为6小时,其他操作同实施例10,得量0.0725g,收率45.1%。
实施例28:
将溶剂改为二甲基亚砜(3mL),DMEDA用量改为0.0132g(0.15mmol),反应时间改为14小时,反应温度为140℃,其他操作同实施例10,得量0.0594g,收率36.9%。
实施例29:
将溶剂改为二甲苯(3mL),DMEDA用量改为0.0132g(0.15mmol),反应时间改为14小时,反应温度为140℃,其他操作同实施例10,得量0.0302g,收率18.8%。
实施例30:
将溶剂改为甲苯(3mL),DMEDA用量改为0.0132g(0.15mmol),反应时间改为14小时,其他操作同实施例10,得量0.0932g,收率58.0%。
实施例31:
将溶剂改为1,4-二氧六环(3mL),DMEDA用量改为0.0132g(0.15mmol),反应时间改为14小时,反应温度为120℃,其他操作同实施例10,得量0.0961g,收率59.8%。
实施例32:
将溶剂改为1,4-二氧六环(3mL),DMEDA用量改为0.0132g(0.15mmol),碳酸钾用量改为0.2740g(2.00mmol),反应时间改为14小时,其他操作同实施例10,得量0.0961g,收率44.8%。
实施例33:
将溶剂改为1,4-二氧六环(3mL),碘化亚铜用量改为0.0095g(0.05mmol),DMEDA的量改为0.0044g(0.05mmol),反应时间改为14小时,反应温度为120℃,其他操作同实施例10,得痕迹量产物。
实施例34:
将溶剂改为1,4-二氧六环(3mL),碘化亚铜用量改为0.0475g(0.25mmol),DMEDA的量改为0.0229g(0.25mmol),反应时间改为14小时,反应温度为120℃,其他操作同实施例10,得量0.0976g,收率60.7%。
实施例35:化合物(III-2)的制备
操作同实施例10,只是将对碘苯甲醚换成4-甲基碘苯(0.1090g,0.50mmol),制得目标化合物(III-2),0.1076g,收率为70.5%。1H NMR(500MHz,CDCl3):δ8.45-8.43(m,2H),7.58(d,J=8.4Hz,2H),7.54-7.46(m,3H),7.17(d,J=8.4Hz,2H),7.14(br,1H),3.35(s,3H),3.25(s,3H),2.36(s,3H).
实施例36:化合物(III-3)的制备
操作同实施例10,只是将对碘苯甲醚换成对碘苯乙醚(0.1246g,0.50mmol),制得目标化合物(III-3),0.1182g,收率为70.5%。1H NMR(500MHz,CDCl3):δ8.43-8.42(m,2H),7.57(d,J=8.9Hz,2H),7.51-7.45(m,3H),7.04(br,1H),6.91(d,J=8.9Hz,2H),4.05(q,J=7.0Hz,2H),3.34(s,3H),3.23(s,3H),1.43(t,J=7.0Hz,3H).
实施例37:化合物(III-4)的制备
操作同实施例10,只是将对碘苯甲醚换成对三氟甲基碘苯(0.1360g,0.50mmol),制得目标化合物(III-4),0.1120g,收率为62.4%。1H NMR(500MHz,CDCl3):δ8.44-8.43(m,2H),7.80(d,J=8.6Hz,2H),7.59(d,J=8.6Hz,2H),7.55-7.52(m,1H),7.52-7.47(m,3H),3.37(s,3H),3.27(s,3H).
实施例38:化合物(III-5)的制备
操作同实施例10,只是将对碘苯甲醚换成对氯碘苯(0.1197g,0.50mmol),制得目标化合物(III-5),0.1156g,收率为71.1%。1H NMR(500MHz,CDCl3):δ8.43-8.42(m,2H),7.62(d,J=8.8Hz,2H),7.54-7.47(m,3H),7.30-7.27(m,3H),3.35(s,3H),3.24(s,3H).
实施例39:化合物(III-6)的制备
操作同实施例10,只是将对碘苯甲醚换成对氟碘苯(0.1664g,0.75mmol),制得目标化合物(III-6),0.0956g,收率为61.9%。
1H NMR(500MHz,CDCl3):δ8.43-8.41(m,2H),7.63-7.62(m,1H),7.58-7.56(m,1H),7.55-7.41(m,5H),7.29(br,1H),3.35(s,3H),3.23(s,3H).
实施例40:化合物(III-7)的制备
操作同实施例10,只是将对碘苯甲醚换成4-碘联苯(0.1405g,0.50mmol),制得目标化合物(III-7),0.1438g,收率为78.3%。1H NMR(500MHz,CDCl3):δ8.48-8.47(m,2H),7.79-7.78(m,2H),7.64-7.61(m,4H),7.54-7.44(m,5H),7.36-7.33(m,1H),7.32(br,1H),3.37(s,3H),3.29(s,3H).
实施例41:化合物(III-8)的制备
操作同实施例10,只是将对碘苯甲醚换成4-碘苯甲腈(0.1149g,0.50mmol),制得目标化合物(III-8),0.1346g,收率为85.1%。1H NMR(500MHz,CDCl3):δ8.42-8.41(m,2H),7.82(br,1H),7.74(d,J=8.7Hz,2H),7.56(d,J=8.7Hz,2H),7.53-7.46(m,3H),3.36(s,3H),3.23(s,3H).
实施例42:化合物(III-9)的制备
操作同实施例10,只是将对碘苯甲醚换成对硝基碘苯(0.1248g,0.50mmol),制得目标化合物(III-9),0.1509g,收率为89.8%。1H NMR(500MHz,DMSO-d6):δ10.31(s,1H),8.39-8.37(m,2H),8.20(d,J=9.2Hz,2H),8.08(d,J=9.2Hz,2H),7.58-7.51(m,3H),3.26(s,3H),3.19(s,3H)
实施例43:化合物(III-10)的制备
操作同实施例10,只是将对碘苯甲醚换成间氯碘苯(0.1193g,0.50mmol),制得目标化合物(III-10),0.1028g,收率为63.2%。1H NMR(500MHz,CDCl3):δ8.44-8.43(m,2H),8.01(t,J=2.0Hz,1H),7.54-7.47(m,3H),7.37-7.36(m,1H),7.29(br,1H),7.24(t,J=8.0Hz,1H),7.03(dd,J=8.0Hz,1.2Hz,1H),3.36(s,3H),3.26(s,3H).
实施例44:化合物(III-11)的制备
操作同实施例10,只是将对碘苯甲醚换成邻甲氧基碘苯(0.1167g,0.50mmol),制得目标化合物(III-11),0.0989g,收率为61.5%。1H NMR(500MHz,CDCl3):δ8.65(d,J=7.2Hz,1H),8.52-8.40(m,2H),7.72(br,1H),7.54-7.42(m,3H),7.09-6.97(m,2H),6.93-6.91(m,1H),3.94(s,3H),3.35(s,3H),3.28(s,3H).
实施例45:化合物(III-12)的制备
操作同实施例10,只是将对碘苯甲醚换成3-三氟甲基-4-硝基碘苯(0.1582g,0.50mmol),制得目标化合物(III-12),0.0769g,收率为38.0%。1H NMR(500MHz,DMSO-d6):δ10.45(s,1H),8.78(s,1H),8.33-8.31(m,2H),8.13(d,J=8.6Hz,1H),8.05(d,J=8.6Hz,1H),7.57-7.47(m,3H),3.20(s,3H),3.10(s,3H).
实施例46:化合物(III-13)的制备
操作同实施例10,只是将对碘苯甲醚换成N-(4-碘苯基)乙酰胺(0.1309g,0.50mmol),制得目标化合物(III-13),0.1464g,收率为84.1%。1H NMR(500MHz,DMSO-d6):δ9.87(s,1H),9.57(br,1H),8.38-8.36(m,2H),7.74-7.72(m,2H),7.57-7.50(m,5H),3.26(s,3H),3.18(s,3H),2.04(s,3H).
实施例47:化合物(III-14)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-苯基-6-(哌啶-1-基)-1,3,5-三嗪(0.1277g,0.50mmol),对碘苯甲醚换成对硝基碘苯(0.1246g,0.50mmol),制得目标化合物(III-14),0.1390g,收率为73.9%。1H NMR(500MHz,DMSO-d6):δ10.34(s,1H),8.39-8.37(m,2H),8.25(d,J=9.2Hz,2H),8.07(d,J=9.2Hz,2H),7.61-7.52(m,3H),3.97-3.93(m,2H),3.86-3.83(m,2H),1.68-1.60(m,6H).
实施例48:化合物(III-15)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-吗啉基-6-苯基-1,3,5-三嗪(0.1288g,0.50mmol),对碘苯甲醚换成对硝基碘苯(0.1249g,0.50mmol),制得目标化合物(III-15),0.1804g,收率为95.4%。1H NMR(500MHz,DMSO-d6):δ10.41(s,1H),8.40-8.38(m,2H),8.23(d,J=9.2Hz,2H),8.05(d,J=9.2Hz,2H),7.61-7.57(m,1H),7.58-7.52(m,2H),3.96-3.82(m,4H),3.76-3.68(m,4H).
实施例49:化合物(III-16)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-苯基-6-苯胺基-1,3,5-三嗪(0.1316g,0.50mmol),制得目标化合物(III-16),0.1196g,收率为64.8%。1H NMR(500MHz,CDCl3):δ8.44-8.43(m,2H),7.65(d,J=6.4Hz,2H),7.58-7.49(m,5H),7.46(br,2H),7.35(t,J=7.3Hz,2H),7.11(t,J=7.4Hz,1H),6.92(d,J=8.4Hz,2H),3.84(s,3H).
实施例50:化合物(III-17)的制备
操作同实施例10,只是将对碘苯甲醚换成3,4,5-三氟溴苯(0.1057g,0.50mmol),制得目标化合物(III-17),0.1218g,收率为70.6%。1H NMR(500MHz,CDCl3):δ8.41-8.39(m,2H),7.55-7.47(m,3H),7.39-7.36(m,3H),3.37(s,3H),3.25(s,3H).
实施例51:化合物(III-18)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-二甲胺基-6-(3-氯苯基)-1,3,5-三嗪(0.1249g,0.50mmol),制得目标化合物(III-18),0.1193g,收率为67.1%。1H NMR(500MHz,CDCl3):δ8.40(s,1H),8.30(d,J=7.5Hz,1H),7.57(d,J=8.6Hz,2H),7.47(d,J=7.7Hz,1H),7.40-7.37(m,1H),7.06(br,1H),6.92(d,J=8.6Hz,2H),3.83(s,3H),3.33(s,3H),3.22(s,3H).
实施例52:化合物(III-19)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-二甲胺基-1,3,5-三嗪(0.0698g,0.50mmol),制得目标化合物(III-19),0.0688g,收率为56.1%。1H NMR(500MHz,CDCl3):δ8.40(br,1H),8.25(s,1H),7.51-7.49(m,2H),6.99-6.70(m,2H),3.80(s,3H),3.19(s,3H),3.16(s,3H)。
实施例53:化合物(III-20)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-甲基-6-二甲胺基-1,3,5-三嗪(0.0769g,0.50mmol),制得目标化合物(III-20),0.0787g,收率为60.7%。1H NMR(500MHz,CDCl3):δ7.50(d,J=9.0Hz,2H),7.25(br,1H),6.87(d,J=9.0Hz,2H),3.81(s,3H),3.20(s,3H),3.16(s,3H),2.32(s,3H).
实施例54:化合物(III-21)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-二甲胺基-6-苯乙基-1,3,5-三嗪(0.1213g,0.50mmol),制得目标化合物(III-21),0.1132g,收率为65.7%。1H NMR(500MHz,CDCl3):δ7.75(d,J=9.0Hz,2H),7.59(d,J=9.0Hz,2H),7.35(br,1H),7.32-7.09(m,5H),3.25(s,3H),3.20(s,3H),3.13-3.10(m,2H),2.94-2.90(m,2H).
实施例55:化合物(III-22)的制备
操作同实施例10,只是将2-氨基-4-二甲胺基-6-苯基-1,3,5-三嗪换成2-氨基-4-吗啉基-6-(噻吩-2-基)-1,3,5-三嗪(0.1316g,0.50mmol),将对碘苯甲醚换成对氟碘苯(0.1110g,0.50mmol),制得目标化合物(III-22),0.1457g,收率为81.5%。1H NMR(500MHz,CDCl3):δ8.00(dd,J=3.7,1.2Hz,1H),7.52(br,1H),7.50-7.49(m,2H),7.14(dd,J=5.0,1.2Hz,1H),7.00(br,1H),6.92-6.89(m,2H),4.05-3.85(m,4H),3.83(s,3H),3.81-3.74(m,4H).
实施例56:
操作同实施例10,只是将对碘苯甲醚换成对溴苯甲醚(0.0930g,0.50mmol),制得目标化合物(III-1),0.1223g,收率为76.1%。
实施例57:
操作同实施例10,只是将对碘苯甲醚换成对溴甲苯(0.0850g,0.5mmol),制得目标化合物(III-2),0.1033g,收率为67.7%。
实施例58:对大肠杆菌(E.coli,Ec)的体外抑菌活性测试
采用扩散法(打孔法)研究了目标化合物在浓度为10mg/mL时对大肠杆菌(E.coli,Ec)的体外抑菌作用。
方法:用灭过菌的打孔器在涂布菌液的平皿上十字对称打6个孔,用无菌微量注射器分别加入100μL质量浓度为10mg/mL的样品二甲基亚砜溶液,并以氨苄青霉素为对照品。将培养皿置于恒温(28℃)培养箱中培养24h,取出观察有无抑菌作用,结果见表2。
表2化合物浓度为10mg/mL体外抗菌活性
测试编号 | 化合物 | Ec |
1 | (III-14) | + |
2 | (III-18) | + |
3 | (III-22) | ++ |
对照品 | 氨苄青霉素 | +++ |
Claims (2)
1.一种式(III)所示2,4-二胺-1,3,5-三嗪类化合物的制备方法,所述的制备方法为:
在反应容器中,加入式(I)所示化合物、式(II)所示化合物、金属铜催化剂、配体、碱性物质和溶剂,在80~140℃下搅拌反应6~14h,之后反应液经后处理,得到式(III)所示产物;
所述式(I)所示化合物与式(II)所示化合物、金属铜催化剂、配体、碱性物质的投料物质的量之比为1:0.5~3.0:0.1~0.5:0.3~1.2:2.0~4.0;
所述的配体为N,N’-二甲基乙二胺;
所述的溶剂为1,4-二氧六环、甲苯或乙腈,所述溶剂的体积用量以式(I)所示化合物的质量计为10~50mL/g;
所述的金属铜催化剂为碘化亚铜、醋酸铜、硫酸铜或氧化亚铜;
所述的碱性物质为碳酸钾或磷酸钾;
式(I)、(II)或(III)中:
R1,R2各自独立为甲基或苯基,或者R1、R2和两者之间的N组合形成哌啶环或吗啉环;
R3为氢、甲基、苯基、噻吩基、对甲氧基苯基、间氯苯基、苄基或苯乙基;
R4为对甲基苯基、对甲氧基苯基、邻甲氧基苯基、对乙氧基苯基、对三氟甲基苯基、对苯基苯基、对氰基苯基、对硝基苯基、对氟苯基、对氯苯基、间氯苯基、对溴苯基、对乙酰氨基苯基或3,4,5-三氟苯基;
X为卤素。
2.如权利要求1所述的制备方法,其特征在于,所述的后处理方法为:反应结束后,加氨水,再加饱和NaCl水溶液,用乙酸乙酯萃取,合并有机层,浓缩,柱层析分离,洗脱剂为石油醚/乙酸乙酯体积比5:1的混合液,收集含目标化合物的洗脱液,减压蒸除溶剂并干燥,得到目标化合物(III)。
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