CN104016904A - 多取代脒化合物、制备方法及其用途 - Google Patents
多取代脒化合物、制备方法及其用途 Download PDFInfo
- Publication number
- CN104016904A CN104016904A CN201410244556.5A CN201410244556A CN104016904A CN 104016904 A CN104016904 A CN 104016904A CN 201410244556 A CN201410244556 A CN 201410244556A CN 104016904 A CN104016904 A CN 104016904A
- Authority
- CN
- China
- Prior art keywords
- various replacements
- various
- benzyl
- alkyl
- methyl
- 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.)
- Granted
Links
- -1 amidine compound Chemical class 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001409 amidines Chemical class 0.000 claims abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000002585 base Substances 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 18
- 239000000741 silica gel Substances 0.000 claims description 18
- 229910002027 silica gel Inorganic materials 0.000 claims description 18
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- HSVFKFNNMLUVEY-UHFFFAOYSA-N sulfuryl diazide Chemical compound [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-] HSVFKFNNMLUVEY-UHFFFAOYSA-N 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 15
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 12
- 150000003335 secondary amines Chemical class 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 9
- VVJKKWFAADXIJK-UHFFFAOYSA-N allylamine Natural products NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 7
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 7
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000003921 oil Substances 0.000 claims description 7
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 7
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001345 alkine derivatives Chemical class 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000012360 testing method Methods 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000012847 fine chemical Substances 0.000 abstract 1
- 239000011734 sodium Substances 0.000 description 16
- 229960001866 silicon dioxide Drugs 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 3
- 208000036566 Erythroleukaemia Diseases 0.000 description 3
- 208000021841 acute erythroid leukemia Diseases 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- BJYLNGGDLHKELP-UHFFFAOYSA-N copper;formic acid Chemical compound [Cu].OC=O BJYLNGGDLHKELP-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940013688 formic acid Drugs 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- DOEISOKZZWYJFQ-ZIADKAODSA-N CC(CC(CCCN1Cc2ccccc2)/C1=N/S(c1ccc(C)cc1)(=O)=O)c1ccccc1 Chemical compound CC(CC(CCCN1Cc2ccccc2)/C1=N/S(c1ccc(C)cc1)(=O)=O)c1ccccc1 DOEISOKZZWYJFQ-ZIADKAODSA-N 0.000 description 1
- SIFIGORDKKIKHH-MSUUIHNZSA-N CS(/N=C1\N(Cc2ccccc2)CCCC1CC=C)(=O)=O Chemical compound CS(/N=C1\N(Cc2ccccc2)CCCC1CC=C)(=O)=O SIFIGORDKKIKHH-MSUUIHNZSA-N 0.000 description 1
- VVZUABOQBCMFNI-MRCUWXFGSA-N Cc(cc1)ccc1S(/N=C(/C=C)\N(CC=C)Cc(cc1)ccc1[N+]([O-])=O)(=O)=O Chemical compound Cc(cc1)ccc1S(/N=C(/C=C)\N(CC=C)Cc(cc1)ccc1[N+]([O-])=O)(=O)=O VVZUABOQBCMFNI-MRCUWXFGSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000003360 nephrocyte Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了多取代脒化合物、制备方法及其用途，涉及药物化学技术领域。还对这两类脒的生物活性做了简单测试。本发明为设计脒类药物分子提供了思路，扩宽了脒类化合物的化学空间和就够多样性，为制备官能化的脒衍生物提供了技术路线，在化学制药和精细化工领域有广阔的应用。
Description
技术领域
本发明涉及药物化学技术领域，涉及两类新型脒类化合物，含所述化合物的制备及其用途。
背景技术
脒是一类重要的有机化合物，脒官能团具有特别的化学与生物活性，存在于许多天然产物和药物分子中，也被应用于功能材料中。脒因其独特的结构，具有独特的性质和潜在用途。但目前用于药物化学领域的脒大多数是简单的芳香族脒，结构简单单一。比如，
(1)二芳香醚1和2具有抗真菌活性(Molecules2013,18,11250-11263；DOI:10.3390/molecules180911250)。
(2)芳基二脒阳离子3和4是有效的DNA结合剂(Chem.Sci.,2014,5,1901，DOI:10.1039/c3sc53317d)。
(3)脒5和6具有很好的抗病毒活性(J.Med.Chem.2014,57,759-769，DOI:10.1021/jm401492x)。
这些脒都是较简单的脒，氮上的取代基不超过两个，缺少结构多样性。考虑到以上缺 点，本发明将要阐述两种新的结构复杂脒结构及其初步生物活性。
发明内容
本发明的目的是阐述一种新型多取代脒，具体来说就是发明了一系列新型多取代磺酰环脒和一系列多取代开链磺酰脒，并且验证了其潜在的生物活性。本发明主要目的是提供该类化合物的化学结构和医学用途。
本发明的目标化合物结构可由结构通式7和8表示。7代表多取代环状磺酰脒，8代表多取代链状磺酰脒。
分子结构通式7和8中的R为各种取代的芳基(如对甲氧基笨基、对乙酰氨基苯基、邻甲氧基苯基等)、各种取代的烷基(如苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基、取代烯丙基等)，具体为苄基、对甲氧基苄基、对氯苄基、对三氟甲基苄基、对硝基苄基、对甲氧基苯基、烯丙基、肉桂烯丙基、羧酸脂基烯丙基、乙酸脂基等；R1为各种取代的芳基(各种取代苯基、各种取代萘基等)、各种取代的烷基(如苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基等)、各种取代的烷氧基(如甲氧基、乙氧基、异丙基样机、苄氧基)、各种取代的芳基氧基(苯氧基、对氯苯氧基、对溴苯氧基等)等，具体为苯基、羧酸脂基、环丙基、环戊基等；R2为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基、卤素等，具体为甲基、环丙基、甲酸脂基、苄基、苯基、甲基、乙基等；R3为各种取代的芳基、各种取代的烷基，各种取代的烷氧基、各种取代的芳基氧基、各种取代一级胺基、各种取代二级胺基等，具体为对甲基苯基、对甲氧基苯基、对硝基苯基、邻硝基苯基、2,4-二硝基苯基、甲基、三甲基硅基乙基等；n为0,1,2,3等。
多取代环脒7按照下述反应式(1)进行制备：
多取代环脒7制备方法，按照下述步骤进行：在氮气保护下，按一定比例将烯丙基胺炔9、磺酰叠氮、碱和铜盐混合在一种有机溶剂中搅拌，根据底物和试剂特性，温度控制在一定温度之间，一定时间后，停止反应，加入水，用有机溶剂乙酸乙酯或二氯甲烷萃取三遍，有机相合并后用饱和食盐水洗，再用无水硫酸钠干燥，减压蒸除溶剂，残留物用乙酸乙酯和石油醚为洗脱剂，硅胶柱色谱分离纯化，得到相应环脒7。或者反应完成后减压蒸除有机溶剂，残渣直接硅胶色谱柱分离。
其中所述烯丙基胺炔的结构式为其中R为各种取代的芳基、各种取代的烷基、各种取代的烯基等，具体为苄基、对甲氧基苄基、对氯苄基、对三氟甲基苄基、对硝基苄基、对甲氧基苯基、烯丙基、肉桂烯丙基、羧酸脂基烯丙基、乙酸脂基等；R1为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基、卤素等，具体为苯基、羧酸脂基、环丙基、环戊基等；R2为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基、卤素等，具体为甲基、环丙基、甲酸脂基、苄基、苯基、甲基、乙基等；n为0,1,2，3等；磺酰叠氮结构式为R3SO2N3，其中R3为各种取代的烷基和芳香基，具体为对甲基苯基、对甲氧基苯基、对硝基苯基、邻硝基苯基、2,4-二硝基苯基、甲基、三甲基硅基乙基等。
其中所述溶剂为四氢呋喃、甲苯、二氯甲烷、三氯甲烷、1,2-二氯甲烷、乙酸乙酯、醚等非极性溶剂和二甲亚砜，N,N-二甲基甲酰胺,。
其中所述的烯丙基胺炔、磺酰叠氮、碱、溶剂和铜盐的摩尔比为1.0：1.1：1.0:10：0.01到1.0：1.1：10:100:0.1之间。
其中所述的磺酰叠氮为各种烷基和芳基磺酰叠氮、烷氧基或胺基磺酰叠氮等。
其中所述的碱为三乙胺、二异丙基乙基胺、三甲胺、三乙烯基二胺、吡啶、2,6-二甲基 吡啶、2,6-二叔丁基吡啶、4-N,N-二甲基胺基吡啶、N-甲基四氢吡咯等有机碱和碳酸钠、碳酸钾、碳酸铯等无机碱。
其中所述的铜盐为碘化亚铜、溴化亚铜、氯化亚铜、三氟乙酸亚铜、三氟甲磺酸亚铜乙酸亚铜等。
其中所述反应温度在-30-60摄氏度之间。
其中所述反应时间为10分钟到5小时之间。
多取代环脒8按照下述反应式(2)进行制备：
多取代环脒8制备方法，按照下述步骤进行：在氮气保护下，按一定比例将炔10、三级胺11磺酰叠氮、碱和铜盐混合在一种有机溶剂中搅拌，根据底物和试剂特性，温度控制在一定温度之间，一定时间后，停止反应，加入水，用有机溶剂乙酸乙酯或二氯甲烷萃取三遍，有机相合并后用饱和食盐水洗，再用无水硫酸钠干燥，减压蒸除溶剂，残留物用乙酸乙酯和石油醚为洗脱剂，硅胶柱色谱分离纯化，得到相应环脒8。或者反应完成后减压蒸除有机溶剂，残渣直接硅胶色谱柱分离。
其中所述炔的结构式为其中R为各种取代的芳基、各种取代的烷基、各种取代的烯基等，具体为苄基、对甲氧基苄基、对氯苄基、对三氟甲基苄基、对硝基苄基、对甲氧基苯基、烯丙基、肉桂烯丙基、羧酸脂基烯丙基、乙酸脂基等；；三级胺的结构式为 其中R1、R2、R5为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基，具体为苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基；磺酰叠氮结构式为R3SO2N3，其中R3为各种取代的烷基和芳香基，具体为对甲基苯基、对甲氧基苯基、对硝基苯基、邻硝基苯基、2,4-二硝基苯基、甲基、三甲基硅基乙基等。
其中所述溶剂为四氢呋喃、甲苯、二氯甲烷、三氯甲烷、1,2-二氯甲烷、乙酸乙酯、醚等非极性溶剂和二甲亚砜，N,N-二甲基甲酰胺,。
其中所述的烯丙基胺炔、磺酰叠氮、碱、溶剂和铜盐的摩尔比为1.0：1.1：1.0:10：0.01到1.0：1.1：10:100:0.10之间。
其中所述的磺酰叠氮为各种烷基和芳基磺酰叠氮、烷氧基和胺基磺酰叠氮等。
其中所述的铜盐为碘化亚铜、溴化亚铜、氯化亚铜、三氟乙酸亚铜、三氟甲磺酸亚铜乙酸亚铜等。
其中所述反应温度在-30-60摄氏度之间。
其中所述反应时间为10分钟到5小时之间。
用MTT法测定了目标化合物对四种人癌细胞增殖的抑制作用。选取SH-SY5Y(神经母细胞瘤细胞)、DU145(***癌细胞)、K562(红白血病细胞)、MCF-7(乳腺癌细胞)4种肿瘤细胞为测试细胞株，并用一个正常细胞Vero(非洲猴肾细胞)作为对照，采用MTT法对所合成的化合物进行体外抗肿瘤活性评价，并以空白为对照。取对数生长期的肿瘤细胞，离心后用RPMI1640或DMEM培养液稀释成5x104个/mL,接种于96孔板中。37oC培养过夜后加入不同浓度的样品，再孵育72小时，加入10uL/孔的MTT溶液(5mg/mL),与37oC孵化4小时后每孔加入100uL DMSO。10分钟后，震荡，将孔板置于自动微孔板分光光度计上，在570nm和630nm处测定吸收度值，并用Bliss法计算半数有效抑制浓度值(IC50)。每组样品进行3次平行测试。
本发明的优点
1、发明了两类结构新颖的多取代脒。
2、这些脒化合物有多官能团，易于进一步衍生。
3、初步活性测试表明该类化合物具有潜在的生物活性，是可能的先导化合物。
具体实施方式
下面通过实例对本发明给予做进一步说明：
下述非限制性实施例1-3#或对比实施例1-2#用来解释说明本发明，而不是对本发明进行限制，在本发明的精神和权利要求的保护范围内，对本发明作出的任何修改和改变，都属于本发明的保护范围。
本发明所使用的原料、试剂及催化剂是通过参考相关文献制备，溶剂经过纯化和精制。
实施例1
在氮气保护下，将1.0毫摩尔烯丙基胺炔9a(R＝CH2CHCHCO2Et，R1＝H，R2＝H，n＝1)、1.1毫摩尔对甲基苯磺酰叠氮、1.0摩尔二异 丙基乙基胺混合在5毫升甲苯中，在-30度下加入0.01摩尔2-噻唑甲酸铜，搅拌混合均匀，5小时后，加入2毫升饱和氯化铵溶液，继续搅拌5小时，先后用5毫升水、5毫升饱和食盐水洗，分出有机相并用无水硫酸钠干燥，过滤后出去有机溶剂，加入1克200目硅胶和6毫升二氯甲烷混合均匀，小心蒸出溶剂，剩余硅胶上硅胶柱，用乙酸乙酯/石油醚洗脱，收集组分，得到43％环脒7a。
7a:黄色油状物,43％；1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.3Hz,2H),7.18(d,J＝8.0Hz,2H),6.01-5.92(m,1H),5.60(ddt,J＝16.5,10.3,6.1Hz,1H),5.24(dd,J＝17.1,0.9Hz,1H),5.17(dd,J＝10.3,1.6Hz,1H),5.07(ddd,J＝15.2,10.4,1.2Hz,2H),4.34-4.25(m,2H),4.21-4.11(m,2H),4.02-3.91(m,2H),3.30-3.18(m,2H),2.34(s,3H),1.93-1.81(m,2H),1.76-1.68(m,1H),1.64-1.56(m,1H),1.24(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ171.8,165.3,141.9,141.5,131.6,131.1,128.9,125.9,120.6,118.5,61.0,53.7,51.9,48.0,39.6,22.4,21.3,20.4,14.2；HRMS(ESI)m/z理论值forC21H29N2O4S+[M+H]+405.1843,实测值405.1859.
实施例2
在氮气保护下，将1.0毫摩尔炔9b1.1毫摩尔对甲基苯磺酰叠氮、10.0摩尔二异丙基乙基胺混合在50毫升甲苯中，在60摄氏度下加入0.10摩尔2-噻唑甲酸铜，搅拌混合均匀，10分钟后，加入2毫升饱和氯化铵溶液，继续搅拌5小时，先后用5毫升水、5毫升饱和食盐水洗，分出有机相并用无水硫酸钠干燥，过滤后出去有机溶剂，加入1克200目硅胶和6毫升二氯甲烷混合均匀，小心蒸出溶剂，剩余硅胶上硅胶柱，用乙酸乙酯/石油醚洗脱，收集组分，得到96％环脒7b。
7b:94％；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.2Hz,2H),7.20(d,J＝8.0Hz,2H),7.07(d,J＝8.6Hz,2H),6.77(d,J＝8.7Hz,2H),5.89-5.78(m,1H),5.12-5.08(m,2H),4.66(d,J＝14.2Hz,1H),4.48(d,J＝14.2Hz,1H),3.87-3.84(m,1H),3.77(s,3H),3.33-3.25(m,2H),3.02-2.98(m,1H),2.42(s,3H),2.30-2.21(m,1H),1.87-1.82(m,2H),1.70-1.64(m,2H)；13C NMR(100MHz,CDCl3)δ168.4,159.1,141.9,141.5,135.4,129.4,129.0,127.9,126.0,117.6,114.0,55.2,52.8,47.9,36.7,36.3,21.6,21.3,17.2；HRMS(ESI)m/z理论值C23H29N2O2S+[M+H]+413.1893,实测值413.1892.
以下实施例都使用前述反应式(1)方法、条件及操作进行
实施例3
7c:88％；1H NMR(500MHz,CDCl3)δ7.76(d,J＝8.3Hz,2H),7.26-7.25(m,3H),7.18(d,J＝8.1Hz,2H),7.14-7.12(m,2H),5.85(dddd,J＝16.8,10.1,9.1,5.2Hz,1H),5.13-5.09(m,2H),4.75(d,J＝14.5Hz,1H),4.53(d,J＝14.4Hz,1H),3.90-3.87(m,1H),3.37-3.25(m,2H),3.04-3.01(m,1H),2.37(s,3H),2.31-2.24(m,1H),1.89-1.86(m,2H),1.75-1.70(m,2H)；13C NMR(125MHz,CDCl3)δ168.8,141.8,141.6,135.9,135.5,129.0,128.7,128.0,127.7,126.0,117.70,53.5,48.2,36.8,36.4,21.7,21.4,17.3；HRMS(ESI)m/z理论值C22H26N2O2SNa+[M+Na]+405.1607,实测值405.1601.
实施例4
7d:93％；1H NMR(400MHz,CDCl3)δ7.72(d,J＝7.0Hz,2H),7.19(d,J＝7.8Hz,4H),7.05(d,J＝7.4Hz,2H),5.88-5.78(m,1H),5.13-5.09(m,2H),4.64(d,J＝14.5Hz,1H),4.50(d,J＝14.5Hz,1H),3.87-3.85(m,1H),3.34-3.29(m,2H),3.00-2.97(m,1H),2.38(s,3H),2.30-2.22(m,1H),1.88-1.85(m,2H),1.71-1.68(m,2H)；13C NMR(100MHz,CDCl3)δ168.6,141.7,141.6,135.3,134.5,133.4,129.3,129.0,128.8,125.9,117.7,53.0,48.5,36.7,36.3,21.6,21.4,17.3；HRMS(ESI)m/z理论值C22H25N2O2SClNa+[M+Na]+439.1217,实测值439.1238.
实施例5
7e:95％；1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.1Hz,2H),7.48(d,J＝8.0Hz,2H),7.21(d,J＝8.1Hz,2H),7.16(d,J＝8.0Hz,2H),5.84(ddd,J＝15.8,9.2,5.2Hz,1H),5.15-5.10(m,2H),4.73(d,J＝14.8Hz,1H),4.59(d,J＝14.8Hz,1H),3.90-3.87(m,1H),3.38-3.34(m,2H),3.01-2.98(m,1H),2.37(s,3H),2.33-2.24(m,2H),1.98-1.88(m,2H),1.75-1.72(m,2H)；13C NMR(100MHz,CDCl3)δ168.9,141.8,141.5,140.1,135.3,129.8(q,J＝32.3Hz),129.0,128.0,126.0,125.6(q,J＝3.7Hz),124.1(q,J＝290.3Hz),117.8,53.4,49.0,36.8,36.3,21.7,21.4,17.3；HRMS(ESI)m/z理论值C23H25F3N2O2SNa+[M+Na]+473.1481,实测值473.1469.
实施例6
7f:93％；1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.7Hz,2H),7.65(d,J＝8.2Hz,2H),7.23(d,J＝8.7Hz,2H),7.16(d,J＝8.1Hz,2H),5.83(dtd,J＝15.8,9.1,5.2Hz,1H),5.16-5.11(m,2H),4.72(d,J＝15.1Hz,1H),4.62(d,J＝15.1Hz,1H),3.90-3.87(m,1H),3.44-3.39(m,2H),3.00-2.96(m,1H),2.37(s,3H),2.34-2.26(m,1H),2.02-1.89(m,2H),1.77-1.70(m,2H)；13C NMR(100MHz,CDCl3)δ168.8,147.2,143.6,142.0,141.3,135.2,129.0,128.3,125.9,123.8,117.9,53.4,49.5,36.8,36.3,21.7,21.4,17.4；HRMS(ESI)m/z理论值C22H25N3O4SNa+[M+Na]+450.1458,实测值450.1482.
实施例7
7g:90％；1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.1Hz,2H),7.21(d,J＝8.0Hz,2H),5.82(tdd,J＝15.1,9.5,5.2Hz,1H),5.14-5.09(m,2H),4.13(d,J＝16.7Hz,1H),4.01-3.90(m,2H),3.88(d,J＝16.7Hz,1H),3.81-3.79(m,1H),3.52-3.41(m,2H),2.96-2.92(m,1H),2.37(s,3H),2.35-2.26(m,1H),2.03-1.98(m,1H),1.89-1.85(m,1H),1.77-1.73(m,2H),1.12(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ169.2,167.8,141.6,141.5,135.3,128.8,125.8,117.5,61.1,52.3,50.5,36.6,35.9,21.6,21.3,17.2,13.8；HRMS(ESI)m/z理论值C19H27N2O4S+[M+H]+379.1686,实测值379.1696.
实施例8
7h:93％；1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.2Hz,2H),7.22-7.12(m,5H),6.98(d,J＝7.1Hz,2H),5.91(dd,J＝17.5,10.7Hz,1H),5.00(ddd,J＝11.0,8.6,1.0Hz,2H),4.92(d,J＝14.4Hz,1H),4.41(d,J＝14.4Hz,1H),4.18(dd,J＝7.5,3.2Hz,1H),3.41-3.34(m,1H),3.15-3.09(m,1H),2.37(s,3H),1.90-1.77(m,3H),1.48-1.44(m,1H),1.31(s,3H),1.27(s,3H)；13C NMR(100MHz,CDCl3)δ167.7,145.9,142.5,141.2,135.7,129.0,128.5,128.1,127.6,126.0,112.6,53.9,47.3,44.1,41.9,26.8,26.6,21.8,21.4,21.2；HRMS(ESI)m/z理论值C24H31N2O2S+[M+H]+411.2101,实测值411.2121.
实施例9
7i:93％；1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.2Hz,2H),7.55(d,J＝7.3Hz,2H),7.28(t,J＝7.6Hz,2H),7.20-7.14(m,4H),7.08-7.03(m,4H),5.27(s,1H),5.09(s,1H),4.57(d,J＝14.5Hz,1H),4.43(d,J＝14.5Hz,1H),3.85-3.77(m,2H),3.27-3.23(m,1H),3.18-3.11(m,1H),2.52(dd,J＝13.3,11.2Hz,1H),2.25(s,3H),1.84-1.77(m,1H),1.61-1.57(m,1H),1.51-1.48(m,1H),1.39-1.32(m,1H)；13C NMR(100MHz,CDCl3)δ168.8,145.6,141.8,141.5,139.5,135.9,128.9,128.7,128.4,127.9,127.8,127.6,126.0,115.7,53.4,48.2,37.2,35.1,21.4,16.9；HRMS(ESI)m/z理论值C28H31N2O2S+[M+H]+459.2101,实测值459.2092.
实施例10
7j:92％；1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.3Hz,2H),7.25(d,J＝8.3Hz,2H),7.21-7.04(m,10H),6.36(d,J＝15.9Hz,1H),6.20-6.13(m,1H),4.70(d,J＝14.4Hz,1H),4.40(d,J＝14.4Hz,1H),3.90-3.87(m,1H),3,28-3,14(m,2H),3.09-3.05(m,1H),2.43-2.35(m,1H),2.27(s,3H),1.82-1.77(m,2H),1.67-1.58(m,2H)；13C NMR(100MHz,CDCl3)δ168.5,141.8,141.5,137.2,135.8,132.8,129.0,128.7,128.5,127.9,127.7,127.2,127.1,126.1,126.0,53.5,48.2,36.9,36.2,22.0,21.4,17.4；HRMS(ESI)m/z理论值C28H31N2O2S+[M+H]+459.2101,实测值459.2122.
实施例11
7k:92％；1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.2Hz,2H),7.19-7.13(m,3H),7.11(d,J＝8.1Hz,2H),7.06-7.04(m,2H),5.92(dt,J＝17.2,9.9Hz,1H),5.22(d,J＝17.1Hz,1H),5.10(dd,J＝10.3,1.3Hz,1H),4.54(dd,J＝18.9,13.7Hz,2H),4.37(dt,J＝7.3,5.1Hz,1H),4.29(dd,J＝9.5,5.0Hz,1H),4.18-4.10(m,2H),3.22-3.16(m,2H),2.29(s,3H),1.89-1.67(m,3H),1.57-1.51(m,1H),1.21(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ171.9,165.8,141.8,141.6,135.5,131.5,129.0,128.6,128.2,127.8,126.0,121.0,61.2,54.2,52.1,48.2,39.7,22.5,21.4,20.59,14.2；HRMS(ESI)m/z理论值C25H31N2O4S+[M+H]+455.1999,实测值455.2026.
实施例12
7l:95％；1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.2Hz,2H),7.51(d,J＝7.5Hz,2H),7.33(t,J＝7.6Hz,2H),7.26-7.13(m,8H),6.23(dt,J＝16.9,10.0Hz,1H),5.32(dd,J＝16.9,1.4Hz,1H),5.19(dd,J＝10.2,1.8Hz,1H),4.82(dd,J＝9.8,4.5Hz,1H),4.66(q,J＝14.4Hz,2H),4.37-4.33(m,1H),3.33-3.23(m,2H),2.37(s,3H),1.84-1.80(m,1H),1.70-1.65(m,1H),1.58-1.52(m,1H)；13C NMR(100MHz,CDCl3)δ167.2,142.2,141.4,141.3,135.6,134.3,129.0,128.5,128.4,128.3,128.0,127.7,126.5,126.0,54.2,51.6,48.6,43.2,21.9,21.4,21.3；HRMS(ESI)m/z理论值C28H31N2O2S+[M+H]+459.2101,实测值459.2118.
实施例13
7m:42％；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.2Hz,2H),7.17(d,J＝8.1Hz,2H),6.68(dt,J＝15.7,5.6Hz,1H),5.84-5.73(m,1H),5.68(d,J＝15.8Hz,1H),5.10-5.06(m,2H),4.18-4.04(m,4H),3.79-3.75(m,1H),3.35-3.25(m,2H),2.94-2.90(m,1H),2.34(s,3H),2.27-2.19(m,1H),1.99-1.82(m,2H),1.72-1.63(m,2H),1.24(t,J＝7.1Hz,3H)； 13C NMR(100MHz,CDCl3)δ168.7,165.5,141.7,141.5,140.6,135.3,129.0,125.9,123.2,117.7,60.5,51.1,48.9,36.7,36.2,21.6,21.3,17.2,14.2；HRMS(ESI)m/z理论值C21H29N2O4S+[M+H]+405.1843,实测值405.1860.
实施例14
7n:84％；1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.1Hz,2H),7.41(d,J＝7.6Hz,2H),7.24(t,J＝7.6Hz,2H)；7.18-7.11(m,3H),6.15(dt,J＝17.0,10.0Hz,1H),5.57(tt,J＝16.6,6.1Hz,1H),5.20(d,J＝16.9Hz,1H),5.13(dd,J＝10.2,1.4Hz,1H),5.05-5.01(m,2H),4.67(dd,J＝9.7,4.4Hz,1H),4.21-4.16(m,1H),3.97-3.94(m,2H),3.28-3.15(m,2H),2.31(s,3H),1.81-1.77(m,2H),1.59-1.43(m,2H)；13C NMR(100MHz,CDCl3)δ166.8,142.3,141.4,141.3,134.3,131.5,129.0,128.4,128.0,126.5,125.9,119.6,118.5,53.8,51.5,48.5,43.2,21.9,21.4,21.3；HRMS(ESI)m/z理论值C24H28N2O2SNa+[M+Na]+431.1764,实测值431.1779.
实施例15
7o:90％；1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.2Hz,2H),7.19-7.14(m,5H),7.05(d,J＝6.3Hz,2H),5.72(ddd,J＝16.9,10.0,7.8Hz,1H),508-5.02(m,2H),4.63(d,J＝14.2Hz,1H),4.51(d,J＝14.2Hz,1H),3.84-3.77(m,1H),3.07(d,J＝12.9Hz,1H),2.75-2.68(m,2H),2.47-2.39(m,1H),2.31(s,3H),1.61-1.55(m,1H),1.41(dd,J＝13.9,6.3Hz,1H),0.86(s,3H),0.64(s,3H)；13C NMR(100MHz,CDCl3)δ168.6,142.0,141.6,135.6,134.7,129.1,128.6,128.6,127.9,126.1,118.4,59.0,54.2,39.7,38.6,36.0,30.6,28.2,25.0,21.5；HRMS(ESI)m/z理论值C24H30N2O2SNa+[M+Na]+433.1920,实测值433.1913.
实施例16
7p:91％；1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.2Hz,2H),7.28-7.18(m,5H),7.13(d,J＝8.6Hz,2H),7.04(d,J＝7.1Hz,2H),6.81(d,J＝8.6Hz,2H),5.78(dtd,J＝14.4,9.1,5.3Hz,1H),5.10(brs,1H),5.06(d,J＝2.4Hz,1H),4.72(d,J＝14.2Hz,1H),4.54(d,J＝14.2Hz,1H),3.83-3.81(m,1H),3.79(s,3H),3.34-3.20(m,2H),2.96-2.93(m,1H),2.68(dd,J＝13.7,5.7Hz,1H),2.39(s,3H),2.36-2.26(m,2H),2.19-2.14(m,1H),1.93-1.83(m,1H),1.39-1.32(m,1H)；13C NMR(100MHz,CDCl3)δ168.1,141.7,139.4,135.3,129.6,129.1,128.9,128.5,128.0,126.1,126.2,117.9,114.1,55.4,52.9,44.8,42.4,39.7,38.1,34.6,21.5；HRMS(ESI)m/z理论值C30H35N2O3S+[M+H]+503.2363,实测值503.2349.
实施例17
7q:89％；1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.2Hz,2H),7.28-7.21(m,5H),7.17-7.11(m,5H),7.00(d,J＝6.3Hz,1H),6.03-5.93(m,1H),5.45(t,J＝7.9,1H),5.05-4.96(m,3H),4.46(d,J＝14.6Hz,1H),4.22(ddd,J＝15.3,8.9,6.3Hz,1H),3.39(dt,J＝15.4,3.9Hz,1H),2.96(t,J＝4.8,2H),2.80(dtd,J＝21.4,14.2,7.5Hz,2H),2.34(s,3H)；13C NMR(100MHz,CDCl3)δ169.1,141.8,141.4,136.0,135.8,134.6,134.3,132.7,130.7,129.1,128.7,128.3,127.9,127.5,126.7,126.2,117.8,54.3,49.4,46.7,41.3,32.1,21.4；HRMS(ESI)m/z理论值C27H29N2O2S+[M+Na]+445.1944,实测值445.1910.
实施例18
7s:96％；1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.2Hz,2H),7.24(d,J＝8.1Hz,2H),7.08(d,J＝8.5Hz,2H),6.78(d,J＝8.6Hz,2H),5.78-5.67(m,1H),5.09-5.01(m,2H),4.47(q,J＝14.3Hz,2H),3.80-3.78(m,1H),3.77(s,3H),3.37-3.30(m,1H),3.22(t,J＝9.8Hz,1H),2.74-2.71(m,1H),2.39(s,3H),2.26(dt,J＝14.0,8.8Hz,1H),2.09-1.99(m,1H),1.88(dd,J＝12.9,7.2Hz,1H)；13C NMR(100MHz,CDCl3)δ170.9,159.3,141.8,141.3,134.8,129.7,129.1,127.2,126.2,118.0,114.1,55.3,48.1,47.2,42.1,36.0,24.3,21.5；HRMS(ESI)m/z理论值C22H27N2O3S+[M+H]+399.1737,实测值399.1702.
实施例19
7t:85％；1H NMR(300MHz,CDCl3)δ7.84(d,J＝8.3Hz,2H),7.29-7.24(m,5H),7.18-7.15(m,2H),5.75(dddd,J＝16.3,10.1,8.1,6.1Hz,1H),5.12-5.03(m,2H),4.55(d,J＝1.9Hz,2H),3.82(td,J＝9.0,2.9Hz,1H),3.37(td,J＝10.3,7.4Hz,1H),3.24(td,J＝9.0,2.9Hz,1H),2.80-2.74(m,1H),2.40(s,3H),2.33-2.19(m,1H),2.15-2.01(m,1H),1.95-1.88(m,1H)；13C NMR(100MHz,CDCl3)δ171.2,141.9,141.3,135.3,134.9,129.2,128.9,128.4,128.1,126.3,118.1,48.8,47.4,42.1,36.1,24.5,21.5；HRMS(ESI)m/z理论值C21H25N2O2S+[M+H]+369.1631,实测值369.1629.
实施例20
7u:96％；1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.2Hz,2H),7.24(t,J＝8.0Hz,4H),7.10(d,J＝8.4Hz,2H),5.79-5.68(m,1H),5.11-5.03(m,2H),4.52(d,J＝14.5Hz,1H),4.47(d,J＝14.5Hz,1H),3.80(td,J＝9.0,2.8Hz,1H),3.37(td,J＝10.2,7.4Hz,1H),3.24(t,J＝9.5Hz,1H),2.75-2.72(m,1H),2.40(s,3H),2.28(dt,J＝14.0,8.8Hz,1H),2.13-2.03(m,1H),1.92(dd,J＝13.0,7.2Hz,1H)；13C NMR(100MHz,CDCl3)δ171.2,142.0,141.1,134.6,133.8,133.8,129.7,129.1,128.9,126.1,118.1,,48.0,47.5,41.9,36.0,24.4,21.5；HRMS(ESI)m/z理论值C21H23N2O2SClNa+[M+Na]+425.1061,实测值425.1061.
实施例21
7v:94％；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.1Hz,2H),7.51(d,J＝8.0Hz,2H),7.28-7.22(m,4H),5.80-5.69(m,1H),5.11-5.04(m,2H),4.58(s,2H),3.84-3.80(m,1H),3.44-3.37(m,1H),3.26(t,J＝9.8Hz,1H),2.77-2.73(m,1H),2.40(s,3H),2.30(dt,J＝14.0,8.8Hz,1H),2.16-2.03(m,1H),1.95(dd,J＝13.0,7.2Hz,1H)；13C NMR(100MHz,CDCl3)δ171.4,142.1,141.0,139.3,134.6,130.2(q,JCF＝32.4Hz),129.2,128.5,126.2,125.7(q,JCF＝3.7Hz),124.0(q,JCF＝270.7Hz),118.2,48.3,47.7,41.8,36.1,24.5,21.5；HRMS(ESI)m/z理论值C22H24N2O2SF3 +[M+H]+437.1505,实测值437.1480.
实施例22
7w:91％；1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.7Hz,2H),7.72(d,J＝8.2Hz,2H),7.29(d,J＝8.6Hz,2H),7.20(d,J＝8.0Hz,2H),5.76-5.65(m,1H),5.08-5.01(m,2H),4.59(s,2H),3.78(td,J＝8.9,2.8Hz,1H),3.43(td,J＝10.2,7.5Hz,1H),3.28(t,J＝9.6Hz,1H),2.71-2.67(m,1H),2.36(s,3H),2.28(dt,J＝13.9,8.7Hz,1H),2.16-2.06(m,1H),1.93(dd,J＝13.1,7.2Hz,1H)；13C NMR(100MHz,CDCl3)δ171.4,147.4,143.1,142.7,142.2,140.7,139.4,134.4,129.5,129.1,128.9,126.2,126.0,123.8,118.2,48.0,47.9,41.7,36.0,24.5,21.4,21.4；HRMS(ESI)m/z理论值C21H23N3O4SNa+[M+Na]+436.1301,实测值436.1326.
实施例23
7x:88％；1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.2Hz,2H),7.20(d,J＝8.1Hz,2H),5.84-5.74(m,1H),5.12-5.07(m,2H),4.24(d,J＝17.3Hz,1H),4.11(q,J＝7.1Hz,2H),3.95(d,J＝17.3Hz,1H),3.74(td,J＝9.5,3.0Hz,1H),3.63(td,J＝10.0,7.2Hz,1H),3.35(t,J＝9.3Hz,1H),2.71-2.68(m,1H),2.36(s,3H),2.33-2.25(m,1H),2.19-2.09(m,1H),1.96(dd,J＝12.9,7.1Hz,1H),1.19(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ172.3,167.5,142.0,140.9,135.0,129.1,126.1,117.9,61.6,48.6,46.1,41.5,35.7,24.6,21.4,14.0；HRMS(ESI)m/z理论值C18H25N2O4S+[M+H]+365.1530,实测值365.1553.
实施例24
7y:86％；1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.0Hz,2H),7.22(d,J＝7.9Hz,2H),5.80-5.70(m,1H),5.10-5.05(m,2H),3.74(t,J＝7.8Hz,1H),3.51-3.38(m,2H),3.32-3.23(m,2H),2.70-2.67(m,1H),2.37(s,3H),2.31-2.23(m,1H),2.13-2.03(m,1H),1.94-1.89(m,1H),1.47-1.46(m,2H),1.21(brs,6H),0.83(t,J＝6.3Hz,3H)；13C NMR(100MHz,CDCl3)δ170.9,141.7,141.5,134.9,129.1,126.1,117.9,48.0,44.0,42.1,36.0,31.3,26.6,26.4,24.5,22.5,21.4,14.0；HRMS(ESI)m/z理论值C20H31N2O2S+[M+H]+363.2101,实测值363.2100.
实施例25
7z:93％；1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.2Hz,2H),7.29-7.25(m,1H),7.19-7.15(m,3H),7.12-7.08(m,1H),6.98(d,J＝8.0Hz,1H),5.75-5.65(m,1H),5.04-4.98(m,2H),4.54(d,J＝14.5Hz,1H),4.35(d,J＝14.5Hz,1H),3.74-3.69(m,1H),3.16(td,J＝10.3,7.3Hz,1H),3.06(t,J＝9.6Hz,1H),2.75-2.72(m,1H),2.33(s,3H),2.23-2.15(m,4H),2.02-1.92(m,1H),1.81(dd,J＝12.9,7.1Hz,1H)；13C NMR(100MHz,CDCl3)δ171.2,169.7,149.4,142.0,141.2,135.0,130.8,129.7,129.2,127.0,126.5,126.3,123.0,118.0,47.1,43.9,42.1,35.9,24.3,21.5,21.0；HRMS(ESI)m/z理论值C23H26N2O4SNa+[M+Na]+449.1505,实测值449.1512.
实施例26
7a’:86％；1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),5.70(ddt,J＝16.6,10.2,6.3Hz,1H),5.22-5.15(m,2H),4.01(d,J＝6.2Hz,2H),3.41(t,J＝7.3Hz,2H),3.07(t,J＝8.0Hz,2H),2.39(s,3H),2.04(p,J＝7.5Hz,2H)；13C NMR(100MHz,CDCl3)δ169.7,142.1,140.6,130.9,129.2,126.5,119.2,49.0,47.5,31.1,21.5,19.1；HRMS(ESI)m/z理论值C14H18N2O2SNa+[M+Na]+301.0981,实测值301.0971.
实施例27
7b’:86％；1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.2Hz,2H),7.24-7.20(m,3H),7.17-7.13(m,2H),6.98(d,J＝7.1Hz,2H),5.84(dd,J＝17.4,10.7Hz,1H),5.02(d,J＝17.4Hz,1H),4.97(d,J＝10.7Hz,1H),4.70(d,J＝14.3Hz,1H),4.33(d,J＝14.3Hz,1H),3.79-3.77(m,1H),3.36-3.29(m,1H),3.10-3.04(m,1H),2.39(s,3H),2.03-1.97(m,1H),1.28(s,3H),1.24(s,3H)；13C NMR(100MHz,CDCl3)δ169.2,145.2,142.4,141.4,135.1,129.1,128.6,128.5,127.9,126.0,112.8,50.3,48.9,48.0,41.7,26.9,24.9,23.6,21.4；HRMS(ESI)m/z理论值C23H28N2O2SNa+[M+Na]+419.1764,实测值419.1762.
实施例28
7c’:85％；1H NMR(400MHz,CDCl3)δ7.82(d,J＝7.6Hz,2H),7.24-6.98(m,5H),6.99(d,J＝7.3Hz,2H),5.65(dd,J＝17.3,10.7Hz,1H),5.05(dd,J＝31.3,14.0Hz,2H),4.73(d,J＝14.2Hz,1H),4.29(d,J＝14.2Hz,1H),3.83(d,J＝8.3Hz,1H),3.35(dd,J＝18.5,9.7Hz,1H),3.07(t,J＝9.9Hz,1H),2.40(s,3H),2.05-1.95(m,5H),1.70-1.60(m,5H)；13C NMR(125MHz,CDCl3)δ169.6,142.4,141.5,135.1,129.1,128.7,128.6,128.0,126.1,115.0,53.7,50.7,49.0,48.1,36.0,34.9,24.7,22.9,21.9,21.5；HRMS(ESI)m/z理论值C25H30N2O2SNa+[M+Na]+445.1920,实测值445.1899.
实施例29
7d’:93％；1H NMR(400MHz,CDCl3)δ7.89(d,J＝8.2Hz,2H),7.40(d,J＝7.7Hz,2H),7.32-7.28(m,2H),7.26-7.17(m,8H),5.93(dt,J＝16.9,10.1Hz,1H),5.09(dd,J＝16.9,1.1Hz,1H),5.00(dd,J＝10.1,1.6Hz,1H),4.64-4.57(m,2H),4.44(d,J＝14.3Hz,1H),4.25-4.23(m,1H),3.36-3.29(m,1H),3.22(td,J＝10.2,1.9Hz,1H),2.38(s,3H),2.02-1.86(m,2H)；13C NMR(100MHz,CDCl3)δ169.7,141.9,141.5,135.0,133.1,129.1,128.8,128.6,128.5,128.0127.6,126.6,126.2,120.5,50.0,49.0,48.9,48.7,21.5,20.9；HRMS(ESI)m/z理论值C27H29N2O2S+[M+H]+445.1944,实测值445.1970.
实施例30
7e’:96％；1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.1Hz,2H),7.26-7.23(m,5H),7.18-7.17(m,2H),5.77-5.67(m,1H),5.07(d,J＝17.0Hz,1H),4.92(d,J＝10.1Hz,1H),4.64(d,J＝14.5Hz,1H),4.52(d,J＝14.5Hz,1H),3.52(d,J＝10.2Hz,1H),3.41(t,J＝4.5Hz,1H),2.89-2.83(m,1H),2.77(d,J＝10.2Hz,1H),2.44-2.43(m,1H),2.39(s,3H),0.89(dd,J＝10.1,4.7Hz,1H),0.65-0.56(m,2H),0.52-0.48(m,1H)；13C NMR(100MHz,CDCl3)δ170.7,141.9,141.3,135.1,134.0,129.1,128.7,128.4,128.0,126.2,118.8,56.8,49.1,48.8,35.5,21.5,20.9,16.8,5.5；HRMS(ESI)m/z理论值C23H27N2O2S+[M+H]+395.1788,实测值395.1800.
实施例31
7f’:1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.2Hz,2H),7.26-7.20(m,5H),7.08-7.06(m,2H),5.82-5.72(m,1H),5.23(d,J＝14.8Hz,1H),5.08(d,J＝10.0Hz,1H),5.02(dd,J＝17.0,0.7Hz,1H),4.24-4.15(m,2H),4.07(d,J＝14.8Hz,1H),3.99(dd,J＝10.6,1.5Hz,1H),3.83-3.78(m,1H),3.04-3.01(m,1H),2.39(s,3H),2.36-2.28(m,1H),2.19-2.10(m,2H),1.27(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ171.7,171.2,142.1,140.8,135.3,134.7,129.2,128.8,128.5,128.1,126.2,117.8,61.9,59.2,48.0,41.2,36.9,28.4,21.5,14.1；HRMS(ESI)m/z理论值C24H28N2O4SNa+[M+Na]+463.1662,实测值463.1650.
实施例32
7g’:1H NMR(400MHz,CDCl3)δ7.83(d,J＝8.3Hz,2H),7.27-7.21(m,5H),7.09-7.06(m,2H),5.852-5.72(m,1H),5.24(d,J＝14.8Hz,1H),5.09(d,J＝10.0Hz,1H),5.02(dd,J＝17.0,0.9Hz,1H),4.07(d,J＝14.8Hz,1H),4.01(dd,J＝10.6,1.5Hz,1H),3.85-3.79(m,1H),3.75(s,3H),3.04-3.01(m,1H),2.41(s,3H),2.38-2.28(m,1H),2.18-2.09(m,2H)；13C NMR(100MHz,CDCl3)δ171.8,171.7,142.2,140.8,135.3,134.7,129.2,128.9,128.6,128.2,126.3,117.9,59.0,52.7,48.0,41.2,36.9,28.5,21.5；HRMS(ESI)m/z理论值C23H26N2O4SNa+[M+Na]+449.1505,实测值449.1489.
实施例33
7h’:94％；1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.2Hz,2H),7.22(d,J＝9.1Hz,2H),7.13(d,J＝8.1Hz,2H),6.75(d,J＝9.1Hz,2H),5.83-5.72(m,1H),5.11-5.03(m,2H),3.89-3.82(m,2H),3.68(s,3H),3.59(t,J＝9.6Hz,1H),2.74-2.71(m,1H),2.38(dt,J＝13.9,8.8Hz,1H),2.28(s,3H),2.21-2.10(m,1H),1.98-1.93(m,1H)；13C NMR(100MHz,CDCl3)δ169.8,157.8,141.8,140.9,134.8,131.6,129.0,126.1,124.7,118.1,113.8,55.4,50.8,42.5,36.0,24.4,21.4；HRMS(ESI)m/z理论值[M+H]+385.1580,实测值385.1576.
以下实施例按下述方法进行
在氮气保护下，将底物9(1mmol，1.0当量)溶于干燥的四氢呋喃中(3毫升),分别依次加入CuI(5mol％),二异丙基乙基胺(5.0当量)和R’SO2N3(1.1当量)。反应液在室温下搅拌0.5小时后加入饱和NH4Cl水溶液。再用乙酸乙酯萃取三次(15毫升*3次)。合并有机相，并用饱和食盐水洗，在用无水硫酸钠干燥，过滤出去固体，减压浓缩所得液体。残留物用硅胶色谱柱柱层析，石油醚和乙酸乙酯的混合物做洗脱剂。
实施例34
7k’:90％；1H NMR(400MHz,CDCl3)δ7.29-7.20(m,3H),7.18-7.16(m,2H),5.79-5.69(m,1H),5.06-5.01(m,2H),4.74(d,J＝14.6Hz,1H),4.48(d,J＝14.6Hz,1H),3.70-3.66(m,1H),3.28-3.22(m,2H),2.98-2.95(m,1H),2.88(s,3H),2.25-2.17(m,1H),1.87-1.75(m,2H),1.69-1.59(m,2H)；13C NMR(100MHz,CDCl3)δ169.0,136.0,135.4,128.8, 127.7,117.6,53.3,48.2,44.0,36.7,36.6,21.7,17.3；HRMS(ESI)m/z理论值C16H23N2O2S+[M+H]+307.1475,实测值307.1480.
实施例35
7i’:92％；1H NMR(400MHz,CDCl3)δ8.09(d,J＝8.7Hz,2H),7.88(d,J＝8.7Hz,2H),7.18-7.17(m,3H),7.01-7..00(m,2H),5.82-5.72(m,1H),5.09-5.05(m,2H),4.63(d,J＝14.7Hz,1H),4.47(d,J＝14.7Hz,1H),3.77-3.74(m,1H),3.33-3.30(m,2H),2.96-2.92(m,1H),2.31-2.22(m,1H),1.90-1.82(m,2H),1.73-1.65(m,2H)；13C NMR(100MHz,CDCl3)δ169.2,150.0,149.0,135.3,135.0,128.8,127.8,127.3,127.2,123.7,118.1,53.9,48.9,36.9,21.7,17.3；HRMS(ESI)m/z理论值C21H24N3O4S+[M+H]+414.1482,实测值414.1499.
实施例36
7m’:91％；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.9Hz,2H),7.19-7.17(m,3H),7.07-7.05(m,2H),6.78(d,J＝8.9Hz,2H),5.82-5.71(m,1H),5.06-5.01(m,2H),4.67(d,J＝14.5Hz,1H),4.46(d,J＝14.5Hz,1H),3.82-3.78(m,1H),3.73(s,3H),3.27-3.19(m,2H),2.95-2.92(m,1H),2.24-2.15(m,1H),1.84-1.77(m,2H),1.65-1.58(m,2H)；13CNMR(100MHz,CDCl3)δ168.6,161.7,136.8,135.9,135.5,128.7,128.0,127.9,127.7,117.6,113.5,55.5,53.4,48.2,36.7,36.3,21.7,17.3；HRMS(ESI)m/z理论值C22H27N2O3S+[M+H]+399.1737,实测值399.1756.
实施例37
7n’:90％；1H NMR(400MHz,CDCl3)δ7.18-7.14(m,3H),7.02-7.00(m,2H),6.78(s,2H),5.74(dtd,J＝16.3,9.2,5.1Hz,1H),5.04-5.00(m,2H),4.65(d,J＝14.4Hz,1H),4.35(d,J＝14.4Hz,1H),3.80-3.78(m,1H),3.28-3.17(m,2H),2.96-2.92(m,1H),2.53(s,6H),2.24-2.21(m,1H),2.18(s,3H),1.86-1.76(m,2H),1.66-1.57(m,2H)；13C NMR(100MHz,CDCl3)δ168.6,140.3,138.7,137.8,136.1,135.6,131.3,128.6,128.0,127.6,117.6,53.3,48.1,36.7,36.6,22.8,21.7,20.9,17.3；HRMS(ESI)m/z理论值C24H31N2O2S+[M+H]+411.2101,实测值411.2108.
实施例38
7m’:97％；1H NMR(400MHz,CDCl3)δ7.16(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),5.74(dt,J＝17.0,8.0Hz,1H),5.10(d,J＝17.0Hz,1H),5.04(d,J＝10.1Hz,1H),4.48(s,2H),3.79(s,3H),3.72(t,J＝7.8Hz,1H),3.38-3.31(m,1H),3.23(t,J＝9.9Hz,1H),3.02-2.97(m,2H),2.79-2.76(m,1H),2.30(dt,J＝14.0,8.8Hz,1H),2.12-2.01(m,1H),1.89(dd,J＝12.9,7.2Hz,1H),1.15-1.00(m,2H),0.03(s,9H)；13C NMR(100MHz,CDCl3)δ171.5,159.4,135.0,129.6,127.5,117.9,114.1,55.3,51.1,48.0,47.2,42.29,36.3,24.4,10.7,-1.9；HRMS(ESI)m/z理论值C20H33N2O3SSi+[M+H]+409.1976,实测值409.1963.
实施例39
在氮气保护下，将1.0毫摩尔炔10a1.1毫摩尔对甲基苯磺酰叠氮、10.0摩尔二异丙基乙基胺混合在50毫升甲苯中，在60摄氏度下加入0.10 摩尔2-噻唑甲酸铜，搅拌混合均匀，10分钟后，加入2毫升饱和氯化铵溶液，继续搅拌5小时，先后用5毫升水、5毫升饱和食盐水洗，分出有机相并用无水硫酸钠干燥，过滤后出去有机溶剂，加入1克200目硅胶和6毫升二氯甲烷混合均匀，小心蒸出溶剂，剩余硅胶上硅胶柱，用乙酸乙酯/石油醚洗脱，收集组分，得到55％环脒8a。
8a:黄色油状物，55％；1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.9Hz,2H),7.20(d,J＝7.8Hz,2H),6.78(d,J＝8.3Hz,2H),6.67(brs,2H),5.80-5.76(m,1H),5.15-5.08(m,2H),3.93(p,J＝6.4,1H),3.79(brs,2H),3.71(s,3H),3.45(brs,1H),3.22(brs,2H),2.87-2.85(m,2H),2.35(s,3H),1.64(brs,4H),1.27(d,J＝6.6Hz,6H),1.14(d,J＝6.4Hz,6H)；13C NMR(100MHz,CDCl3)δ166.0,156.4,143.3,141.8,141.5,139.4,129.6,129.3,129.0,126.4,126.3,126.0,115.2,114.7,55.8,50.0,48.5,47.9,32.5,27.3,24.8,23.6,21.5,20.7,20.0,19.6；HRMS(ESI)m/z理论值C28H42N3O3S+[M+H]+500.2941,实测值500.2921.
以下实施例参照实施例39进行
实施例40
8b+8c:87％；1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.5Hz,2H),7.37-7.22(m,7H),5.92(brs,1H),5.24-5.20(m,2H),4.00-3.96(m,1H),3.65(brs,2H),3.49(brs,1H),3.14(brs,2H),2.88-2.83(m,2H),2.55-2.51(m,2H),2.41(brs,1H),2.38(s,3H),1.59(brs,4H),1.43-1.40(m,2H),1.31(d,J＝6.6Hz,5H),1.20(d,J＝6.2Hz,6H),1.14-1.10(m,1H)；13C NMR(100MHz,CDCl3)δ166.8,143.2,141.8,141.5,141.4,139.5,129.6,129.2,129.0,129.0,128.3,127.2,126.4,126.0,126.0,57.9,56.5,53.0,49.2,47.9,37.9,32.7,31.6,31.3,27.5,27.1,26.1, 21.5,21.4,21.2,20.7,20.0,20.0,16.7,13.8；8b:HRMS(ESI)m/z理论值C28H42N3O2S+[M+H]+484.2992,实测值484.3011；8c:HRMS(ESI)m/z理论值C29H44N3O2S+[M+H]+498.3149,实测值498.3169.
实施例41
8d:90％；1H NMR(400MHz,CDCl3)δ8.06(m,2H),7.61(m,2H),7.30(d,J＝8.6Hz,2H),7.18(m,2H),6.66(dd,J＝17.9,12.2Hz,1H),5.75-5.62(m,3H),5.24(dd,J＝41.3,12.3Hz,2H),4.71(s,2H),4.02(d,J＝5.3Hz,2H),2.37(s,3H)；13C NMR(100MHz,CDCl3)δ165.1,147.4,143.4,142.3,140.5,131.3,129.1,128.7,128.2,126.4,125.0,123.9,119.5,52.4,50.2,21.4；HRMS(ESI)m/z理论值C20H21N3O4SNa+[M+Na]+422.1145,实测值422.1167.
实施例42
8e:55％；1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.9Hz,2H),7.20(d,J＝7.8Hz,2H),6.78(d,J＝8.3Hz,2H),6.67(brs,2H),5.80-5.76(m,1H),5.15-5.08(m,2H),3.93(p,J＝6.4,1H),3.79(brs,2H),3.71(s,3H),3.45(brs,1H),3.22(brs,2H),2.87-2.85(m,2H),2.35(s,3H),1.64(brs,4H),1.27(d,J＝6.6Hz,6H),1.14(d,J＝6.4Hz,6H)；13C NMR(100MHz,CDCl3)δ166.0,156.4,143.3,141.8,141.5,139.4,129.6,129.3,129.0,126.4,126.3,126.0,115.2,114.7,55.8,50.0,48.5,47.9,32.5,27.3,24.8,23.6,21.5,20.7,20.0,19.6；HRMS(ESI)m/z理论值C28H42N3O3S+[M+H]+500.2941,实测值500.2921.
实施例43
8f:36％；1H NMR(400MHz,CDCl3)δ7.81(d,J＝7.4Hz,2H),7.23(d,J＝7.9Hz,2H),7.02(d,J＝6.6Hz,2H),6.66(brs,2H),5.82(brs,1H),5.18-5.14(m,2H),3.89(brs,3H),3.39(brs,2H),3.27(q,J＝6.8Hz,2H),2.94-2.92(m,2H),2.39(s,3H),2.24(s,3H),1.99-1.91(m,2H),1.16(t,J＝7.0Hz,1H),1.10-1.07(m,8H)；13C NMR(100MHz,CDCl3)δ166.6,159.4,141.6,134.4,129.8,129.1,126.1,116.4,114.5,113.6,54.8,50.4,49.2,37.9,29.8,28.9,25.0,21.5,21.0,20.3,20.0,16.7,13.8；HRMS(ESI)m/z理论值C26H38N3O2S+[M+H]+456.2679,实测值456.2666.
实施例44
8g:57％；1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),7.02(d,J＝7.8Hz,2H),6.66(d,J＝7.1Hz,2H),5.86-5.79(m,1H),5.18-5.12(m,2H),3.89-3.83(m,3H),3.41-3.37(m,3H),2.93-2.89(m,2H),2.38(s,3H),2.23(s,3H),1.95-1.93(m,2H),1.27(d,J＝6.8Hz,6H),1.05(d,J＝6.4Hz,6H)；13C NMR(100MHz,CDCl3)δ165.8,146.0,141.8,141.5,134.4,129.8,129.0,126.2,126.0,123.1,116.3,113.5,54.8,50.4,49.8,47.9,30.3,24.9,21.4,20.5,20.2,20.0；HRMS(ESI)m/z理论值C27H40N3O2S+[M+H]+470.2836,实测值470.2810.
实验例
按照前述方法对化合物7a和8a进行了抗癌活性测试，结果列在一下表格中。结果表明化合物7a对K562(红白血病细胞)有一定抗癌活性；化合物8a对K562(红白血病细胞)和MCF-7(乳腺癌细胞)的生长有明显抑制作用。
表一：7a与8a对四种癌细胞的活性测试
Claims (4)
1.多取代环状磺酰脒，其结构如结构式7所示，
，
其中R为各种取代的芳基（如对甲氧基笨基、对乙酰氨基苯基、邻甲氧基苯基等）、各种取代的烷基（如苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基、取代烯丙基等），具体为苄基、对甲氧基苄基、对氯苄基、对三氟甲基苄基、对硝基苄基、对甲氧基苯基、烯丙基、肉桂烯丙基、羧酸脂基烯丙基、乙酸脂基等；R1为各种取代的芳基（各种取代苯基、各种取代萘基等）、各种取代的烷基（如苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基等）、各种取代的烷氧基（如甲氧基、乙氧基、异丙基样机、苄氧基）、各种取代的芳基氧基（苯氧基、对氯苯氧基、对溴苯氧基等）等，具体为苯基、羧酸脂基、环丙基、环戊基等；R2 为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基、卤素等，具体为甲基、环丙基、甲酸脂基、苄基、苯基、甲基、乙基等；R3为各种取代的芳基、各种取代的烷基，各种取代的烷氧基、各种取代的芳基氧基、各种取代一级胺基、各种取代二级胺基等，具体为对甲基苯基、对甲氧基苯基、对硝基苯基、邻硝基苯基、2,4-二硝基苯基、甲基、三甲基硅基乙基等； n为0, 1, 2 ,3。
2.多取代链状磺酰脒，其结构如结构式8所示，
其中R为各种取代的芳基（如对甲氧基笨基、对乙酰氨基苯基、邻甲氧基苯基等）、各种取代的烷基（如苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基、取代烯丙基等），具体为苄基、对甲氧基苄基、对氯苄基、对三氟甲基苄基、对硝基苄基、对甲氧基苯基、烯丙基、肉桂烯丙基、羧酸脂基烯丙基、乙酸脂基等；R1为各种取代的芳基（各种取代苯基、各种取代萘基等）、各种取代的烷基（如苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基等）、各种取代的烷氧基（如甲氧基、乙氧基、异丙基样机、苄氧基）、各种取代的芳基氧基（苯氧基、对氯苯氧基、对溴苯氧基等）等，具体为苯基、羧酸脂基、环丙基、环戊基等；R2 为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基、卤素等，具体为甲基、环丙基、甲酸脂基、苄基、苯基、甲基、乙基等；R3为各种取代的芳基、各种取代的烷基，各种取代的烷氧基、各种取代的芳基氧基、各种取代一级胺基、各种取代二级胺基等，具体为对甲基苯基、对甲氧基苯基、对硝基苯基、邻硝基苯基、2,4-二硝基苯基、甲基、三甲基硅基乙基等； n为0, 1, 2 ,3。
3.权利要求1所述的多取代环脒7制备方法，按照下述步骤进行：在氮气保护下，按一定比例将烯丙基胺炔9、磺酰叠氮、碱和铜盐混合在一种有机溶剂中搅拌，根据底物和试剂特性，温度控制在一定温度之间，一定时间后，停止反应，加入水，用有机溶剂乙酸乙酯或二氯甲烷萃取三遍，有机相合并后用饱和食盐水洗，再用无水硫酸钠干燥，减压蒸除溶剂，残留物用乙酸乙酯和石油醚为洗脱剂，硅胶柱色谱分离纯化，得到相应环脒7；或者反应完成后减压蒸除有机溶剂，残渣直接硅胶色谱柱分离；
其中所述烯丙基胺炔的结构式为，其中R为各种取代的芳基、各种取代的烷基、各种取代的烯基等，具体为苄基、对甲氧基苄基、对氯苄基、对三氟甲基苄基、对硝基苄基、对甲氧基苯基、烯丙基、肉桂烯丙基、羧酸脂基烯丙基、乙酸脂基等；R1为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基、卤素等，具体为苯基、羧酸脂基、环丙基、环戊基等；R2 为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基、卤素等，具体为甲基、环丙基、甲酸脂基、苄基、苯基、甲基、乙基等；n为0, 1, 2，3等；磺酰叠氮结构式为R3SO2N3，其中R3为各种取代的烷基和芳香基，具体为对甲基苯基、对甲氧基苯基、对硝基苯基、邻硝基苯基、2,4-二硝基苯基、甲基、三甲基硅基乙基等；
其中所述溶剂为四氢呋喃、甲苯、二氯甲烷、三氯甲烷、1,2-二氯甲烷、乙酸乙酯、醚等非极性溶剂和二甲亚砜，N,N-二甲基甲酰胺；
其中所述的烯丙基胺炔、磺酰叠氮、碱、溶剂和铜盐的摩尔比为1.0：1.1：1.0:10：0.01到1.0：1.1：10:100:0.10之间；
其中所述的磺酰叠氮为各种烷基和芳基磺酰叠氮、烷氧基或胺基磺酰叠氮等；
其中所述的碱为三乙胺、二异丙基乙基胺、三甲胺、三乙烯基二胺、吡啶、2,6-二甲基吡啶、2,6-二叔丁基吡啶、4-N,N-二甲基胺基吡啶、N-甲基四氢吡咯等有机碱和碳酸钠、碳酸钾、碳酸铯等无机碱；
其中所述的铜盐为碘化亚铜、溴化亚铜、氯化亚铜、三氟乙酸亚铜、三氟甲磺酸亚铜乙酸亚铜等；
其中所述反应温度在-30-60摄氏度之间；
其中所述反应时间为10分钟到5小时之间。
4.权利要求2所述的多取代环脒8制备方法，按照下述步骤进行：在氮气保护下，按一定比例将炔10、三级胺11磺酰叠氮、碱和铜盐混合在一种有机溶剂中搅拌，根据底物和试剂特性，温度控制在一定温度之间，一定时间后，停止反应，加入水，用有机溶剂乙酸乙酯或二氯甲烷萃取三遍，有机相合并后用饱和食盐水洗，再用无水硫酸钠干燥，减压蒸除溶剂，残留物用乙酸乙酯和石油醚为洗脱剂，硅胶柱色谱分离纯化，得到相应环脒8；
或者反应完成后减压蒸除有机溶剂，残渣直接硅胶色谱柱分离；
其中所述炔的结构式为，其中R为各种取代的芳基、各种取代的烷基、各种取代的烯基等，具体为苄基、对甲氧基苄基、对氯苄基、对三氟甲基苄基、对硝基苄基、对甲氧基苯基、烯丙基、肉桂烯丙基、羧酸脂基烯丙基、乙酸脂基等；；三级胺的结构式为，其中R1、R2、R5为各种取代的芳基、各种取代的烷基、各种取代的烷氧基、各种取代的芳基氧基、各种取代二级胺基、各种取代的烷基硫基、各种取代的芳基硫基，具体为苄基、对甲氧基苄基、对硝基苄基、甲基、乙基、异丙基、环己基、环戊基、环丙基；磺酰叠氮结构式为R3SO2N3，其中R3为各种取代的烷基和芳香基，具体为对甲基苯基、对甲氧基苯基、对硝基苯基、邻硝基苯基、2,4-二硝基苯基、甲基、三甲基硅基乙基等；
其中所述溶剂为四氢呋喃、甲苯、二氯甲烷、三氯甲烷、1,2-二氯甲烷、乙酸乙酯、醚等非极性溶剂和二甲亚砜，N,N-二甲基甲酰胺；
其中所述的烯丙基胺炔、磺酰叠氮、碱、溶剂和铜盐的摩尔比为1.0：1.1：1.0:10：0.01到1.0：1.1：10:100:0.10之间；
其中所述的磺酰叠氮为各种烷基和芳基磺酰叠氮、烷氧基和胺基磺酰叠氮等；
其中所述的铜盐为碘化亚铜、溴化亚铜、氯化亚铜、三氟乙酸亚铜、三氟甲磺酸亚铜乙酸亚铜等；
其中所述反应温度在-30-60摄氏度之间；
其中所述反应时间为10分钟到5小时之间。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410244556.5A CN104016904B (zh) | 2014-06-04 | 2014-06-04 | 多取代脒化合物、制备方法及其用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410244556.5A CN104016904B (zh) | 2014-06-04 | 2014-06-04 | 多取代脒化合物、制备方法及其用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104016904A true CN104016904A (zh) | 2014-09-03 |
| CN104016904B CN104016904B (zh) | 2016-11-02 |
Family
ID=51433957
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410244556.5A Active CN104016904B (zh) | 2014-06-04 | 2014-06-04 | 多取代脒化合物、制备方法及其用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104016904B (zh) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105753748A (zh) * | 2016-02-15 | 2016-07-13 | 灏瑰己 | 一种医药中间体磺酰类化合物的合成方法 |
| CN108117499A (zh) * | 2017-10-19 | 2018-06-05 | 上海应用技术大学 | 一种α芳基脒亚胺衍生物的制备方法 |
| CN110627719A (zh) * | 2019-09-05 | 2019-12-31 | 中山大学 | 一种具有同侧推拉电子效应的环脒基荧光分子及其制备方法 |
| CN111281850A (zh) * | 2020-03-14 | 2020-06-16 | 周琛 | 止痛药物组合物及其用途 |
| CN111574413A (zh) * | 2020-06-08 | 2020-08-25 | 杭州尚合生物医药科技有限公司 | 一种2-氨甲基吡啶与dmf-dma作为胺源的磺酰脒的制备方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4468403A (en) * | 1982-07-20 | 1984-08-28 | Canadian Patents & Development Limited | Analgesic substituted piperidylidene-2-sulfon(cyan)amide derivatives |
-
2014
- 2014-06-04 CN CN201410244556.5A patent/CN104016904B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4468403A (en) * | 1982-07-20 | 1984-08-28 | Canadian Patents & Development Limited | Analgesic substituted piperidylidene-2-sulfon(cyan)amide derivatives |
Non-Patent Citations (7)
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105753748A (zh) * | 2016-02-15 | 2016-07-13 | 灏瑰己 | 一种医药中间体磺酰类化合物的合成方法 |
| CN108117499A (zh) * | 2017-10-19 | 2018-06-05 | 上海应用技术大学 | 一种α芳基脒亚胺衍生物的制备方法 |
| CN108117499B (zh) * | 2017-10-19 | 2020-10-09 | 上海应用技术大学 | 一种α芳基脒亚胺衍生物的制备方法 |
| CN110627719A (zh) * | 2019-09-05 | 2019-12-31 | 中山大学 | 一种具有同侧推拉电子效应的环脒基荧光分子及其制备方法 |
| CN111281850A (zh) * | 2020-03-14 | 2020-06-16 | 周琛 | 止痛药物组合物及其用途 |
| CN111574413A (zh) * | 2020-06-08 | 2020-08-25 | 杭州尚合生物医药科技有限公司 | 一种2-氨甲基吡啶与dmf-dma作为胺源的磺酰脒的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104016904B (zh) | 2016-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104016904A (zh) | 多取代脒化合物、制备方法及其用途 | |
| CN106928117A (zh) | 一种氘代芳香类有机化合物的制备方法 | |
| Li et al. | Highly enantioselective aldol reactions catalyzed by reusable upper rim-functionalized calix [4] arene-based l-proline organocatalyst in aqueous conditions | |
| Van Buu et al. | Chiral ionic liquids derived from isosorbide: synthesis, properties and applications in asymmetric synthesis | |
| CN104744334A (zh) | 维格列汀的制备方法 | |
| EP3611163A1 (en) | High-purity isothiocyanate compound preparation method for industrial production | |
| CN104030961B (zh) | 一种多取代环脒的制备方法 | |
| EP3539968B1 (en) | Novel trityl protecting agent | |
| CN109020992B (zh) | 一种立体选择性制备β型单/双青蒿烷基醚胺马来酸盐的方法 | |
| CN113717138B (zh) | 一类氮芥类色原酮衍生物与应用 | |
| CN109053631B (zh) | 一种通过异硫氰酸酯与2-磺酰烷基苯酚合成苯并[1,3]噁嗪-2-硫酮的合成方法 | |
| CN106748949B (zh) | 一种合成α,β不饱和酰胺化合物的方法 | |
| CN105622544B (zh) | 一种n-磺酰基-3,4-二氢-2h-1,4-噻嗪的合成方法 | |
| Gautam et al. | Asymmetric synthesis of substituted NH-piperidines from chiral amines | |
| CN108530515A (zh) | 天然产物be-43547环状母核的制备方法 | |
| CN115043849B (zh) | 环内酯骨架拼接茚二酮双螺环类化合物及其制备方法及应用 | |
| CN109879832B (zh) | 一种4-烷氧基-2-芳基巯基吗啉-3,5-二酮类化合物及制备方法 | |
| Sammes et al. | Diborane reduction of penicillins: preparation of 7-deoxopenicillanic acid | |
| Enders et al. | Asymmetric Synthesis of α-Substituted β-Amino Sulfones by aza-Michael Addition/α-Alkylation | |
| Naidu et al. | A facile catalyst-free Pudovik reaction for the synthesis of α-amino phosphonates | |
| CN104610127A (zh) | 一种n-烷基-2-芳基-吲哚-3-醛的合成方法 | |
| Pirota et al. | Synthesis of tetrazole-and imidazole-based compounds: prophetic molecules made real for biological studies | |
| SU586642A1 (ru) | Производные имидазолидино-[3,2- @ ]-пиридо [2,3- @ ]-или имидазолидино-[3,2- @ ]-пиримидо-[4,5- @ ] [1,4]-тиазинов и способ их получени | |
| CN104628644A (zh) | 一种3-氮杂二环[4,1,0]庚醛及制备方法 | |
| JP5870197B2 (ja) | タキサン誘導体の製造方法 |
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 | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201119 Address after: Shandong Yuejin Road 277300 Zaozhuang City Yicheng Economic Development Zone No. 8 Patentee after: Shandong Xuedi Aluminum Technology Co.,Ltd. Address before: Gehu Lake Road Wujin District 213164 Jiangsu city of Changzhou province No. 1 Patentee before: CHANGZHOU University |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Polysubstituted amidine compound, preparation method and Application Effective date of registration: 20210625 Granted publication date: 20161102 Pledgee: Zaozhuang rural commercial bank Limited by Share Ltd. Yicheng sub branch Pledgor: Shandong Xuedi Aluminum Technology Co.,Ltd. Registration number: Y2021980005242 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220930 Granted publication date: 20161102 Pledgee: Zaozhuang rural commercial bank Limited by Share Ltd. Yicheng sub branch Pledgor: Shandong Xuedi Aluminum Technology Co.,Ltd. Registration number: Y2021980005242 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Multi substituted amidine compounds, preparation methods, and their uses Effective date of registration: 20230918 Granted publication date: 20161102 Pledgee: Zaozhuang rural commercial bank Limited by Share Ltd. Yicheng sub branch Pledgor: Shandong Xuedi Aluminum Technology Co.,Ltd. Registration number: Y2023980057072 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |