CN104016904A - Multi-substituted amidine compound as well as preparation method and application thereof - Google Patents

Multi-substituted amidine compound as well as preparation method and application thereof Download PDF

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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
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various replacements
various
benzyl
alkyl
methyl
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CN104016904B (en
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徐华栋
任杰
贾志宏
徐科
许园元
沈美华
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Shandong Xuedi Aluminum Technology Co ltd
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Changzhou University
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    • 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

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a multi-substituted amidine compound, a preparation method and an application thereof and relates to the technical field of pharmaceutical chemistry. The biological activities of the two types of amidines are also subjected to a simple test. The multi-substituted amidine compound disclosed by the invention provides an idea to design amidines drug molecules, broadens the chemical space and diversity of amidine compounds and provides a technical route for the preparation of functionalized amidine derivatives and the multi-substituted amidine compound has vast applications in the technical fields such as biochemical pharmacy and fine chemical industry.

Description

Polysubstituted amidine compound, preparation method and its usage
Technical field
The present invention relates to pharmaceutical chemistry technical field, relate to the novel amidine compound of two classes, contain preparation of described compound and uses thereof.
Background technology
Amidine is the important organic compound of a class, and amidine function has special chemistry and biological activity, is present in many natural products and drug molecule, is also applied in functional materials.Amidine, because of its unique structure, has unique character and potential use.But the amidine great majority for pharmaceutical chemistry field are simple aromatic series amidine at present, simple in structure single.Such as,
(1) two aromatic oxide 1 and 2 has anti-mycotic activity (Molecules2013,18,11250-11263; DOI:10.3390/molecules180911250).
(2) aryl two amidine positively charged ions 3 and 4 be effective DNA bonding agent (Chem.Sci., 2014,5,1901, DOI:10.1039/c3sc53317d).
(3) amidine 5 and 6 has good antiviral activity (J.Med.Chem.2014,57,759-769, DOI:10.1021/jm401492x).
These amidines are all better simply amidines, and the substituting group on nitrogen is no more than two, lacks structure diversity.Consider above shortcoming, the present invention will set forth two kinds of new complex structure amidine structures and preliminary biological activity thereof.
Summary of the invention
The object of the invention is to set forth a kind of novel polysubstituted amidine, be exactly to have invented series of new polysubstituted sulphonyl ring amidine and a series of polysubstituted open chain sulphonyl amidine specifically, and verified the biological activity that it is potential.Main purpose of the present invention is to provide chemical structure and the medical usage of this compounds.
Target compound structure of the present invention can be represented by general structure 7 and 8.7 represent polysubstituted ring-type sulphonyl amidine, and 8 represent polysubstituted chain sulphonyl amidine.
R in general formula of molecular structure 7 and 8 is the aryl (as to the stupid base of methoxyl group, acetparaminosalol phenyl, o-methoxyphenyl etc.) of various replacements, the alkyl (as benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl, substituted allyl etc.) of various replacements, is specially benzyl, to methoxy-benzyl, p-chlorobenzyl, to trifluoromethyl benzyl, to nitrobenzyl, p-methoxyphenyl, allyl group, cinnamene propyl group, carboxylic esters base allyl group, acetic acid fat base etc.; R 1for aryloxy of the alkyl (as benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl etc.) of the aryl (various substituted-phenyls, various substituted naphthyls etc.) of various replacements, various replacements, the alkoxyl group (as methoxyl group, oxyethyl group, sec.-propyl model machine, benzyloxy) of various replacements, various replacements (phenoxy group, to chlorophenoxy, to bromine phenoxy group etc.) etc., be specially phenyl, carboxylic esters base, cyclopropyl, cyclopentyl etc.; R 2for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, artyl sulfo of the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, various replacements, halogen etc. are specially methyl, cyclopropyl, formic acid fat base, benzyl, phenyl, methyl, ethyl etc.; R 3for the aryl of various replacements, the alkyl of various replacements, the alkoxyl group of various replacements, the aryloxy of various replacements, various replacement one-level amido, various replacement secondary amine etc., be specially p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, O-Nitrophenylfluorone, 2,4-dinitrophenyl, methyl, trimethyl silicon based ethyl etc.; N is 0,1,2,3 etc.
Polysubstituted ring amidine 7 is prepared according to following reaction formula (1):
Polysubstituted ring amidine 7 preparation methods, according to following step, carry out: under nitrogen protection, by a certain percentage by allyl amine alkynes 9, sulfonyl azide, alkali and mantoquita are blended in a kind of organic solvent and stir, according to substrate and specificity of reagent, temperature is controlled between certain temperature, after certain hour, stopped reaction, add water, with organic solvent ethyl acetate or dichloromethane extraction three times, organic phase is washed with saturated common salt after merging, use again anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, silica gel column chromatogram separating purification, obtain respective rings amidine 7.Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue is separated.
The structural formula of wherein said allyl amine alkynes is the aryl that wherein R is various replacements, the alkyl of various replacements, the thiazolinyl of various replacements etc., be specially benzyl, to methoxy-benzyl, p-chlorobenzyl, to trifluoromethyl benzyl, to nitrobenzyl, p-methoxyphenyl, allyl group, cinnamene propyl group, carboxylic esters base allyl group, acetic acid fat base etc.; R 1for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, artyl sulfo of the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, various replacements, halogen etc. are specially phenyl, carboxylic esters base, cyclopropyl, cyclopentyl etc.; R 2for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, artyl sulfo of the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, various replacements, halogen etc. are specially methyl, cyclopropyl, formic acid fat base, benzyl, phenyl, methyl, ethyl etc.; N is 0,1,2,3 etc.; Sulfonyl azide structural formula is R 3sO 2n 3, R wherein 3for alkyl and the aromatic base of various replacements, be specially p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, O-Nitrophenylfluorone, 2,4-dinitrophenyl, methyl, trimethyl silicon based ethyl etc.
Wherein said solvent is tetrahydrofuran (THF), toluene, methylene dichloride, trichloromethane, 1, non-polar solvent and the methyl-sulphoxides such as 2-methylene dichloride, ethyl acetate, ether, and DMF.
The mol ratio of wherein said allyl amine alkynes, sulfonyl azide, alkali, solvent and mantoquita is that 1.0:1.1:1.0:10:0.01 is between 1.0:1.1:10:100:0.1.
Wherein said sulfonyl azide is various alkyl and arylsulfonyl nitrine, alkoxyl group or amido sulfonyl azide etc.
Wherein said alkali is triethylamine, diisopropyl ethyl amine, Trimethylamine 99, trivinyl diamines, pyridine, 2,6-lutidine, 2,6-di-tert-butyl pyridine, 4-N, the mineral alkalis such as the organic basess such as N-dimethyl amine yl pyridines, N-methyl Pyrrolidine and sodium carbonate, salt of wormwood, cesium carbonate.
Wherein said mantoquita is that cuprous iodide, cuprous bromide, cuprous chloride, trifluoroacetic acid are cuprous, the cuprous cuprous acetate of trifluoromethanesulfonic acid etc.
Wherein said temperature of reaction is between-30-60 degree Celsius.
The wherein said reaction times is between 10 minutes to 5 hours.
Polysubstituted ring amidine 8 is prepared according to following reaction formula (2):
Polysubstituted ring amidine 8 preparation methods, according to following step, carry out: under nitrogen protection, by a certain percentage by alkynes 10, tertiary amine 11 sulfonyl azides, alkali and mantoquita are blended in a kind of organic solvent and stir, according to substrate and specificity of reagent, temperature is controlled between certain temperature, after certain hour, stopped reaction, add water, with organic solvent ethyl acetate or dichloromethane extraction three times, organic phase is washed with saturated common salt after merging, use again anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, silica gel column chromatogram separating purification, obtain respective rings amidine 8.Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue is separated.
The structural formula of wherein said alkynes is the aryl that wherein R is various replacements, the alkyl of various replacements, the thiazolinyl of various replacements etc., be specially benzyl, to methoxy-benzyl, p-chlorobenzyl, to trifluoromethyl benzyl, to nitrobenzyl, p-methoxyphenyl, allyl group, cinnamene propyl group, carboxylic esters base allyl group, acetic acid fat base etc.; ; The structural formula of tertiary amine is r wherein 1, R 2, R 5for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, the artyl sulfo of various replacements, is specially benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl; Sulfonyl azide structural formula is R 3sO 2n 3, R wherein 3for alkyl and the aromatic base of various replacements, be specially p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, O-Nitrophenylfluorone, 2,4-dinitrophenyl, methyl, trimethyl silicon based ethyl etc.
Wherein said solvent is tetrahydrofuran (THF), toluene, methylene dichloride, trichloromethane, 1, non-polar solvent and the methyl-sulphoxides such as 2-methylene dichloride, ethyl acetate, ether, and DMF.
The mol ratio of wherein said allyl amine alkynes, sulfonyl azide, alkali, solvent and mantoquita is that 1.0:1.1:1.0:10:0.01 is between 1.0:1.1:10:100:0.10.
Wherein said sulfonyl azide is various alkyl and arylsulfonyl nitrine, alkoxyl group and amido sulfonyl azide etc.
Wherein said mantoquita is that cuprous iodide, cuprous bromide, cuprous chloride, trifluoroacetic acid are cuprous, the cuprous cuprous acetate of trifluoromethanesulfonic acid etc.
Wherein said temperature of reaction is between-30-60 degree Celsius.
The wherein said reaction times is between 10 minutes to 5 hours.
With mtt assay, measured the restraining effect of target compound to four kinds of human cancer cell propagation.Choose SH-SY5Y (neuroblastoma cell), DU145 (prostate cancer cell), K562 (erythroleukemia cell), 4 kinds of tumour cells of MCF-7 (breast cancer cell) are test cell strain, and with a normal cell Vero (African monkey nephrocyte) in contrast, adopt mtt assay to carry out anti tumor activity in vitro evaluation to the compound of synthesized, and take blank as contrast.The tumour cell of taking the logarithm vegetative period, is centrifugally diluted to 5x104/mL with RPMI1640 or DMEM nutrient solution afterwards, is inoculated in 96 orifice plates.After 37oC overnight incubation, add the sample of different concns, then hatch 72 hours, add the MTT solution (5mg/mL) in 10uL/ hole, after 4 hours, every hole add 100uL DMSO with 37oC hatching.After 10 minutes, concussion, is placed in orifice plate on automatic microwell plate spectrophotometer, measures optical density value, and calculate half effective inhibition concentration value (IC50) by Bliss method at 570nm and 630nm place.Every group of sample carries out parallel testing 3 times.
Advantage of the present invention
1, invented the polysubstituted amidine of two class formation novelties.
2, these amidine compounds have polyfunctional group, are easy to further derivative.
3, preliminary active testing shows that this compounds has potential biological activity, is possible lead compound.
Embodiment
Below by example, the present invention is described further:
Following non-limiting example 1-3# or comparative example 1-2# are used for the present invention that explains; rather than limit the invention; in the protection domain of spirit of the present invention and claim, any modification and change that the present invention is made, all belong to protection scope of the present invention.
Raw material used in the present invention, reagent and catalyzer are by reference to pertinent literature preparation, and solvent is through purifying and refining.
Embodiment 1
Under nitrogen protection, by 1.0 mmole allyl amine alkynes 9a (R=CH 2cHCHCO 2et, R 1=H, R 2=H, n=1), 1.1 mmoles are to Methyl benzenesulfonyl nitrine, 1.0 moles of diisopropyl ethyl amines are blended in 5 milliliters of toluene, under-30 degree, add 0.01 mole of 2-thiazol formic-acid copper, be uniformly mixed, after 5 hours, add 2 milliliters of saturated ammonium chloride solutions, continue to stir 5 hours, successively use 5 ml waters, 5 milliliters of saturated common salt washings, separate organic phase and use anhydrous sodium sulfate drying, after filtration, go out organic solvent, add 1 gram of 200 order silica gel and 6 milliliters of methylene dichloride to mix, carefully steam solvent, silicagel column on residue silica gel, use ethyl acetate/petroleum ether wash-out, collect component, obtain 43% ring amidine 7a.
7a: yellow oil, 43%; 1h NMR (400MHz, CDCl 3) δ 7 .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, CDCl 3) δ 171.8,165.3,141.9,141.5,131.6,131.1,128.9,125.9,120.6,118.5,61.0,53.7,51.9,48.0,39.6,22.4,21.3,20.4,14.2, HRMS (ESI) m/z theoretical value forC 21h 29n 2o 4s +[M+H] +405.1843, measured value 405.1859.
Embodiment 2
Under nitrogen protection, by 1.0 mmole alkynes 9b 1.1 mmoles are to Methyl benzenesulfonyl nitrine, 10.0 moles of diisopropyl ethyl amines are blended in 50 milliliters of toluene, under 60 degrees Celsius, add 0.10 mole of 2-thiazol formic-acid copper, be uniformly mixed, after 10 minutes, add 2 milliliters of saturated ammonium chloride solutions, continue to stir 5 hours, successively use 5 ml waters, 5 milliliters of saturated common salt washings, separate organic phase and use anhydrous sodium sulfate drying, after filtration, go out organic solvent, add 1 gram of 200 order silica gel and 6 milliliters of methylene dichloride to mix, carefully steam solvent, silicagel column on residue silica gel, use ethyl acetate/petroleum ether wash-out, collect component, obtain 96% ring amidine 7b.
7b: 94%; 1h ?nMR (400MHz, CDCl 3) δ 7 .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, CDCl 3) δ 168.4,159.1,141.9,141.5,135.4,129.4,129.0,127.9,126.0,117.6,114.0,55.2,52.8,47.9,36.7,36.3,21.6,21.3,17.2; HRMS (ESI) m/z theoretical value C 23h 29n 2o 2s +[M+H] +413.1893, measured value 413.1892.
Following examples are all used previous reaction formula (1) method, condition and operation to carry out
Embodiment 3
7c:88%; 1h NMR (500MHz, CDCl 3) δ 7.76 (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, CDCl 3) δ 168.8,141.8,141.6,135.9,135.5,129.0,128.7,128.0,127.7,126.0,117.70,53.5,48.2,36.8,36.4,21.7,21.4,17.3; HRMS (ESI) m/z theoretical value C 22h 26n 2o 2sNa +[M+Na] +405.1607, measured value 405.1601.
Embodiment 4
7d:93%; 1h NMR (400MHz, CDCl 3) δ 7.72 (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, CDCl 3) δ 168.6,141.7,141.6,135.3,134.5,133.4,129.3,129.0,128.8,125.9,117.7,53.0,48.5,36.7,36.3,21.6,21.4,17.3; HRMS (ESI) m/z theoretical value C 22h 25n 2o 2sClNa +[M+Na] +439.1217, measured value 439.1238.
Embodiment 5
7e:95%; 1h NMR (400MHz, CDCl 3) δ 7.68 (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, CDCl 3) δ 168.9,141.8,141.5,140.1,135.3,129.8 (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 theoretical value C 23h 25f 3n 2o 2sNa +[M+Na] +473.1481, measured value 473.1469.
Embodiment 6
7f:93%; 1h NMR (400MHz, CDCl 3) δ 8.03 (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, CDCl 3) δ 168.8,147.2,143.6,142.0,141.3,135.2,129.0,128.3,125.9,123.8,117.9,53.4,49.5,36.8,36.3,21.7,21.4,17.4; HRMS (ESI) m/z theoretical value C 22h 25n 3o 4sNa +[M+Na] +450.1458, measured value 450.1482.
Embodiment 7
7g:90%; 1h NMR (400MHz, CDCl 3) δ 7.75 (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, CDCl 3) δ 169.2,167.8,141.6,141.5,135.3,128.8,125.8,117.5,61.1,52.3,50.5,36.6,35.9,21.6,21.3,17.2,13.8; HRMS (ESI) m/z theoretical value C 19h 27n 2o 4s +[M+H] +379.1686, measured value 379.1696.
Embodiment 8
7h:93%; 1h NMR (400MHz, CDCl 3) δ 7.74 (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, CDCl 3) δ 167.7,145.9,142.5,141.2,135.7,129.0,128.5,128.1,127.6,126.0,112.6,53.9,47.3,44.1,41.9,26.8,26.6,21.8,21.4,21.2; HRMS (ESI) m/z theoretical value C 24h 31n 2o 2s +[M+H] +411.2101, measured value 411.2121.
Embodiment 9
7i:93%; 1h NMR (400MHz, CDCl 3) δ 7.66 (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, CDCl 3) δ 168.8,145.6,141.8,141.5,139.5,135.9,128.9,128.7,128.4,127.9,127.8,127.6,126.0,115.7,53.4,48.2,37.2,35.1,21.4,16.9, HRMS (ESI) m/z theoretical value C 28h 31n 2o 2s +[M+H] +459.2101, measured value 459.2092.
Embodiment 10
7j:92%; 1h NMR (400MHz, CDCl 3) δ 7.70 (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, CDCl 3) δ 168.5,141.8,141.5,137.2,135.8,132.8,129.0,128.7,128.5,127.9,127.7,127.2,127.1,126.1,126.0,53.5,48.2,36.9,36.2,22.0,21.4,17.4; HRMS (ESI) m/z theoretical value C 28h 31n 2o 2s +[M+H] +459.2101, measured value 459.2122.
Embodiment 11
7k:92%; 1h NMR (400MHz, CDCl 3) δ 7.70 (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, CDCl 3) δ 171.9,165.8,141.8,141.6,135.5,131.5,129.0,128.6,128.2,127.8,126.0,121.0,61.2,54.2,52.1,48.2,39.7,22.5,21.4,20.59,14.2, HRMS (ESI) m/z theoretical value C 25h 31n 2o 4s +[M+H] +455.1999, measured value 455.2026.
Embodiment 12
7l:95%; 1h NMR (400MHz, CDCl 3) δ 7.82 (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, CDCl 3) δ 167.2,142.2,141.4,141.3,135.6,134.3,129.0,128.5,128.4,128.3,128.0,127.7,126.5,126.0,54.2,51.6,48.6,43.2,21.9,21.4,21.3; HRMS (ESI) m/z theoretical value C 28h 31n 2o 2s +[M+H] +459.2101, measured value 459.2118.
Embodiment 13
7m:42%; 1h NMR (400MHz, CDCl 3) δ 7.72 (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, CDCl 3) δ 168.7,165.5,141.7,141.5,140.6,135.3,129.0,125.9,123.2,117.7,60.5,51.1,48.9,36.7,36.2,21.6,21.3,17.2,14.2; HRMS (ESI) m/z theoretical value C 21h 29n 2o 4s +[M+H] +405.1843, measured value 405.1860.
Embodiment 14
7n:84%; 1h NMR (400MHz, CDCl 3) δ 7.77 (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, CDCl 3) δ 166.8,142.3,141.4,141.3,134.3,131.5,129.0,128.4,128.0,126.5,125.9,119.6,118.5,53.8,51.5,48.5,43.2,21.9,21.4,21.3; HRMS (ESI) m/z theoretical value C 24h 28n 2o 2sNa +[M+Na] +431.1764, measured value 431.1779.
Embodiment 15
7o:90%; 1h NMR (400MHz, CDCl 3) δ 7.75 (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, CDCl 3) δ 168.6,142.0,141.6,135.6,134.7,129.1,128.6,128.6,127.9,126.1,118.4,59.0,54.2,39.7,38.6,36.0,30.6,28.2,25.0,21.5; HRMS (ESI) m/z theoretical value C 24h 30n 2o 2sNa +[M+Na] +433.1920, measured value 433.1913.
Embodiment 16
7p:91%, 1h NMR (400MHz, CDCl 3) δ 7.83 (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, CDCl 3) δ 168.1,141.7,139.4,135.3,129.6,129.1,128.9,128.5,128.0,126.1,126.2,117.9,114.1,55.4,52.9,44.8,42.4,39.7,38.1,34.6,21.5, HRMS (ESI) m/z theoretical value C 30h 35n 2o 3s +[M+H] +503.2363, measured value 503.2349.
Embodiment 17
7q:89%; 1h NMR (400MHz, CDCl 3) δ 7.75 (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, CDCl 3) δ 169.1,141.8,141.4,136.0,135.8,134.6,134.3,132.7,130.7,129.1,128.7,128.3,127.9,127.5,126.7,126.2,117.8,54.3,49.4,46.7,41.3,32.1,21.4; HRMS (ESI) m/z theoretical value C 27h 29n 2o 2s +[M+Na] +445.1944, measured value 445.1910.
Embodiment 18
7s:96%; 1h NMR (400MHz, CDCl 3) δ 7.83 (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, CDCl 3) δ 170.9,159.3,141.8,141.3,134.8,129.7,129.1,127.2,126.2,118.0,114.1,55.3,48.1,47.2,42.1,36.0,24.3,21.5; HRMS (ESI) m/z theoretical value C 22h 27n 2o 3s +[M+H] +399.1737, measured value 399.1702.
Embodiment 19
7t:85%; 1h NMR (300MHz, CDCl 3) δ 7.84 (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, CDCl 3) δ 171.2,141.9,141.3,135.3,134.9,129.2,128.9,128.4,128.1,126.3,118.1,48.8,47.4,42.1,36.1,24.5,21.5; HRMS (ESI) m/z theoretical value C 21h 25n 2o 2s +[M+H] +369.1631, measured value 369.1629.
Embodiment 20
7u:96%; 1h NMR (400MHz, CDCl 3) δ 7.81 (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, CDCl 3) δ 171.2,142.0,141.1,134.6,133.8,133.8,129.7,129.1,128.9,126.1,118.1,, 48.0,47.5,41.9,36.0,24.4,21.5; HRMS (ESI) m/z theoretical value C 21h 23n 2o 2sClNa +[M+Na] +425.1061, measured value 425.1061.
Embodiment 21
7v:94%; 1h NMR (400MHz, CDCl 3) δ 7.79 (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, CDCl 3) δ 171.4,142.1,141.0,139.3,134.6,130.2 (q, J cF=32.4Hz), 129.2,128.5,126.2,125.7 (q, J cF=3.7Hz), 124.0 (q, J cF=270.7Hz), 118.2,48.3,47.7,41.8,36.1,24.5,21.5; HRMS (ESI) m/z theoretical value C 22h 24n 2o 2sF 3 +[M+H] +437.1505, measured value 437.1480.
Embodiment 22
7w:91%; 1h NMR (400MHz, CDCl 3) δ 8.04 (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, CDCl 3) δ 171.4,147.4,143.1,142.7,142.2,140.7,139.4,134.4,129.5,129.1,128.9,126.2,126.0,123.8,118.2,48.0,47.9,41.7,36.0,24.5,21.4,21.4; HRMS (ESI) m/z theoretical value C 21h 23n 3o 4sNa +[M+Na] +436.1301, measured value 436.1326.
Embodiment 23
7x:88%; 1h NMR (400MHz, CDCl 3) δ 7.75 (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, CDCl 3) δ 172.3,167.5,142.0,140.9,135.0,129.1,126.1,117.9,61.6,48.6,46.1,41.5,35.7,24.6,21.4,14.0, HRMS (ESI) m/z theoretical value C 18h 25n 2o 4s +[M+H] +365.1530, measured value 365.1553.
Embodiment 24
7y:86%; 1h NMR (400MHz, CDCl 3) δ 7.80 (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, CDCl 3) δ 170.9,141.7,141.5,134.9,129.1,126.1,117.9,48.0,44.0,42.1,36.0,31.3,26.6,26.4,24.5,22.5,21.4,14.0; HRMS (ESI) m/z theoretical value C 20h 31n 2o 2s +[M+H] +363.2101, measured value 363.2100.
Embodiment 25
7z:93%; 1h NMR (400MHz, CDCl 3) δ 7.77 (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, CDCl 3) δ 171.2,169.7,149.4,142.0,141.2,135.0,130.8,129.7,129.2,127.0,126.5,126.3,123.0,118.0,47.1,43.9,42.1,35.9,24.3,21.5,21.0, HRMS (ESI) m/z theoretical value C 23h 26n 2o 4sNa +[M+Na] +449.1505, measured value 449.1512.
Embodiment 26
7a ': 86%; 1h NMR (400MHz, CDCl 3) δ 7.80 (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, CDCl 3) δ 169.7,142.1,140.6,130.9,129.2,126.5,119.2,49.0,47.5,31.1,21.5,19.1; HRMS (ESI) m/z theoretical value C 14h 18n 2o 2sNa +[M+Na] +301.0981, measured value 301.0971.
Embodiment 27
7b ': 86%; 1h NMR (400MHz, CDCl 3) δ 7.80 (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, CDCl 3) δ 169.2,145.2,142.4,141.4,135.1,129.1,128.6,128.5,127.9,126.0,112.8,50.3,48.9,48.0,41.7,26.9,24.9,23.6,21.4; HRMS (ESI) m/z theoretical value C 23h 28n 2o 2sNa +[M+Na] +419.1764, measured value 419.1762.
Embodiment 28
7c ': 85%; 1h NMR (400MHz, CDCl 3) δ 7.82 (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, CDCl 3) δ 169.6,142.4,141.5,135.1,129.1,128.7,128.6,128.0,126.1,115.0,53.7,50.7,49.0,48.1,36.0,34.9,24.7,22.9,21.9,21.5; HRMS (ESI) m/z theoretical value C 25h 30n 2o 2sNa +[M+Na] +445.1920, measured value 445.1899.
Embodiment 29
7d ': 93%; 1h NMR (400MHz, CDCl 3) δ 7.89 (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, CDCl 3) δ 169.7,141.9,141.5,135.0,133.1,129.1,128.8,128.6,128.5,128.0127.6,126.6,126.2,120.5,50.0,49.0,48.9,48.7,21.5,20.9; HRMS (ESI) m/z theoretical value C 27h 29n 2o 2s +[M+H] +445.1944, measured value 445.1970.
Embodiment 30
7e ': 96%; 1h NMR (400MHz, CDCl 3) δ 7.83 (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, CDCl 3) δ 170.7,141.9,141.3,135.1,134.0,129.1,128.7,128.4,128.0,126.2,118.8,56.8,49.1,48.8,35.5,21.5,20.9,16.8,5.5, HRMS (ESI) m/z theoretical value C 23h 27n 2o 2s +[M+H] +395.1788, measured value 395.1800.
Embodiment 31
7f ': 1h NMR (400MHz, CDCl 3) δ 7.82 (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, CDCl 3) δ 171.7,171.2,142.1,140.8,135.3,134.7,129.2,128.8,128.5,128.1,126.2,117.8,61.9,59.2,48.0,41.2,36.9,28.4,21.5,14.1; HRMS (ESI) m/z theoretical value C 24h 28n 2o 4sNa +[M+Na] +463.1662, measured value 463.1650.
Embodiment 32
7g ': 1h NMR (400MHz, CDCl 3) δ 7.83 (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, CDCl 3) δ 171.8,171.7,142.2,140.8,135.3,134.7,129.2,128.9,128.6,128.2,126.3,117.9,59.0,52.7,48.0,41.2,36.9,28.5,21.5; HRMS (ESI) m/z theoretical value C 23h 26n 2o 4sNa +[M+Na] +449.1505, measured value 449.1489.
Embodiment 33
7h ': 94%; 1h NMR (400MHz, CDCl 3) δ 7.69 (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, CDCl 3) δ 169.8,157.8,141.8,140.9,134.8,131.6,129.0,126.1,124.7,118.1,113.8,55.4,50.8,42.5,36.0,24.4,21.4; HRMS (ESI) m/z theoretical value [M+H] +385.1580, measured value 385.1576.
Following examples are carried out as follows
Under nitrogen protection, substrate 9 (1mmol, 1.0 equivalents) is dissolved in to (3 milliliters) in dry tetrahydrofuran (THF), add successively respectively CuI (5mol%), diisopropyl ethyl amine (5.0 equivalent) and R ' SO 2n 3(1.1 equivalent).Reaction solution at room temperature stirs after 0.5 hour and adds saturated NH 4the Cl aqueous solution.Be extracted with ethyl acetate again three times (15 milliliters * 3 times).Merge organic phase, and with saturated common salt washing, with anhydrous sodium sulfate drying, filter away solid, concentrating under reduced pressure gained liquid.Residue silica gel chromatographic column column chromatography, the mixture of sherwood oil and ethyl acetate is made eluent.
Embodiment 34
7k ': 90%; 1h NMR (400MHz, CDCl 3) δ 7.29-7.20 (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, CDCl 3) δ 169.0,136.0,135.4,128.8,127.7,117.6,53.3,48.2,44.0,36.7,36.6,21.7,17.3; HRMS (ESI) m/z theoretical value C 16h 23n 2o 2s +[M+H] +307.1475, measured value 307.1480.
Embodiment 35
7i ': 92%; 1h NMR (400MHz, CDCl 3) δ 8.09 (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, CDCl 3) δ 169.2,150.0,149.0,135.3,135.0,128.8,127.8,127.3,127.2,123.7,118.1,53.9,48.9,36.9,21.7,17.3; HRMS (ESI) m/z theoretical value C 21h 24n 3o 4s +[M+H] +414.1482, measured value 414.1499.
Embodiment 36
7m ': 91%; 1h NMR (400MHz, CDCl 3) δ 7.72 (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, CDCl 3) δ 168.6,161.7,136.8,135.9,135.5,128.7,128.0,127.9,127.7,117.6,113.5,55.5,53.4,48.2,36.7,36.3,21.7,17.3; HRMS (ESI) m/z theoretical value C 22h 27n 2o 3s +[M+H] +399.1737, measured value 399.1756.
Embodiment 37
7n ': 90%; 1h NMR (400MHz, CDCl 3) δ 7.18-7.14 (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, CDCl 3) δ 168.6,140.3,138.7,137.8,136.1,135.6,131.3,128.6,128.0,127.6,117.6,53.3,48.1,36.7,36.6,22.8,21.7,20.9,17.3; HRMS (ESI) m/z theoretical value C 24h 31n 2o 2s +[M+H] +411.2101, measured value 411.2108.
Embodiment 38
7m ': 97%; 1h NMR (400MHz, CDCl 3) δ 7.16 (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, CDCl 3) δ 171.5,159.4,135.0,129.6,127.5,117.9,114.1,55.3,51.1,48.0,47.2,42.29,36.3,24.4,10.7 ,-1.9, HRMS (ESI) m/z theoretical value C 20h 33n 2o 3sSi +[M+H] +409.1976, measured value 409.1963.
Embodiment 39
Under nitrogen protection, by 1.0 mmole alkynes 10a 1.1 mmoles are to Methyl benzenesulfonyl nitrine, 10.0 moles of diisopropyl ethyl amines are blended in 50 milliliters of toluene, under 60 degrees Celsius, add 0.10 mole of 2-thiazol formic-acid copper, be uniformly mixed, after 10 minutes, add 2 milliliters of saturated ammonium chloride solutions, continue to stir 5 hours, successively use 5 ml waters, 5 milliliters of saturated common salt washings, separate organic phase and use anhydrous sodium sulfate drying, after filtration, go out organic solvent, add 1 gram of 200 order silica gel and 6 milliliters of methylene dichloride to mix, carefully steam solvent, silicagel column on residue silica gel, use ethyl acetate/petroleum ether wash-out, collect component, obtain 55% ring amidine 8a.
8a: yellow oil, 55%; 1h NMR (400MHz, CDCl 3) δ 7.76 (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, CDCl 3) δ 166.0,156.4,143.3,141.8,141.5,139.4,129.6,129.3,129.0,126.4,126.3,126.0,115.2,114.7,55.8,50.0,48.5,47.9,32.5,27.3,24.8,23.6,21.5,20.7,20.0,19.6; HRMS (ESI) m/z theoretical value C 28h 42n 3o 3s +[M+H] +500.2941, measured value 500.2921.
Following examples are carried out with reference to embodiment 39
Embodiment 40
8b+8c:87%; 1h NMR (400MHz, CDCl 3) δ 7.79 (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, CDCl 3) δ 166.8,143.2,141.8,141.5,141.4,139.5,129.6,129.2,129.0,129.0,128.3,127.2,126.4,126.0,126.0,57.9,56.5,53.0,49.2,47.9,37.9,32.7,31.6,31.3,27.5,27.1,26.1,21.5,21.4,21.2,20.7,20.0,20.0,16.7,13.8; 8b:HRMS (ESI) m/z theoretical value C 28h 42n 3o 2s +[M+H] +484.2992, measured value 484.3011; 8c:HRMS (ESI) m/z theoretical value C 29h 44n 3o 2s +[M+H] +498.3149, measured value 498.3169.
Embodiment 41
8d:90%; 1h NMR (400MHz, CDCl 3) δ 8.06 (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, CDCl 3) δ 165.1,147.4,143.4,142.3,140.5,131.3,129.1,128.7,128.2,126.4,125.0,123.9,119.5,52.4,50.2,21.4; HRMS (ESI) m/z theoretical value C 20h 21n 3o 4sNa +[M+Na] +422.1145, measured value 422.1167.
Embodiment 42
8e:55%; 1h NMR (400MHz, CDCl 3) δ 7.76 (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) δ 166.0,156.4,143.3,141.8,141.5,139.4,129.6,129.3,129.0,126.4,126.3,126.0,115.2,114.7,55.8,50.0,48.5,47.9,32.5,27.3,24.8,23.6,21.5,20.7,20.0,19.6; HRMS (ESI) m/z theoretical value C 28h 42n 3o 3s +[M+H] +500.2941, measured value 500.2921.
Embodiment 43
8f:36%; 1h NMR (400MHz, CDCl 3) δ 7.81 (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, CDCl 3) δ 166.6,159.4,141.6,134.4,129.8,129.1,126.1,116.4,114.5,113.6,54.8,50.4,49.2,37.9,29.8,28.9,25.0,21.5,21.0,20.3,20.0,16.7,13.8; HRMS (ESI) m/z theoretical value C 26h 38n 3o 2s +[M+H] +456.2679, measured value 456.2666.
Embodiment 44
8g:57%; 1h NMR (400MHz, CDCl 3) δ 7.80 (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, CDCl 3) δ 165.8,146.0,141.8,141.5,134.4,129.8,129.0,126.2,126.0,123.1,116.3,113.5,54.8,50.4,49.8,47.9,30.3,24.9,21.4,20.5,20.2,20.0; HRMS (ESI) m/z theoretical value C 27h 40n 3o 2s +[M+H] +470.2836, measured value 470.2810.
Experimental example
According to preceding method, compound 7a and 8a have been carried out to antitumour activity test, the results are shown in form.Result shows that compound 7a has certain antitumour activity to K562 (erythroleukemia cell); Compound 8a has obvious restraining effect to the growth of K562 (erythroleukemia cell) and MCF-7 (breast cancer cell).
Table one: 7a and the 8a active testing to four kinds of cancer cells

Claims (4)

1. polysubstituted ring-type sulphonyl amidine, its structure is as structural formula 7shown in,
，
The alkyl (as benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl, substituted allyl etc.) of the aryl that wherein R is various replacements (as to the stupid base of methoxyl group, acetparaminosalol phenyl, o-methoxyphenyl etc.), various replacements, is specially benzyl, to methoxy-benzyl, p-chlorobenzyl, to trifluoromethyl benzyl, to nitrobenzyl, p-methoxyphenyl, allyl group, cinnamene propyl group, carboxylic esters base allyl group, acetic acid fat base etc.; R 1for aryloxy of the alkyl (as benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl etc.) of the aryl (various substituted-phenyls, various substituted naphthyls etc.) of various replacements, various replacements, the alkoxyl group (as methoxyl group, oxyethyl group, sec.-propyl model machine, benzyloxy) of various replacements, various replacements (phenoxy group, to chlorophenoxy, to bromine phenoxy group etc.) etc., be specially phenyl, carboxylic esters base, cyclopropyl, cyclopentyl etc.; R 2for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, artyl sulfo of the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, various replacements, halogen etc. are specially methyl, cyclopropyl, formic acid fat base, benzyl, phenyl, methyl, ethyl etc.; R 3for the aryl of various replacements, the alkyl of various replacements, the alkoxyl group of various replacements, the aryloxy of various replacements, various replacement one-level amido, various replacement secondary amine etc., be specially p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, O-Nitrophenylfluorone, 2,4-dinitrophenyl, methyl, trimethyl silicon based ethyl etc.; N is 0,1,2,3.
2. polysubstituted chain sulphonyl amidine, its structure is as shown in structural formula 8 ,
The alkyl (as benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl, substituted allyl etc.) of the aryl that wherein R is various replacements (as to the stupid base of methoxyl group, acetparaminosalol phenyl, o-methoxyphenyl etc.), various replacements, is specially benzyl, to methoxy-benzyl, p-chlorobenzyl, to trifluoromethyl benzyl, to nitrobenzyl, p-methoxyphenyl, allyl group, cinnamene propyl group, carboxylic esters base allyl group, acetic acid fat base etc.; R 1for aryloxy of the alkyl (as benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl etc.) of the aryl (various substituted-phenyls, various substituted naphthyls etc.) of various replacements, various replacements, the alkoxyl group (as methoxyl group, oxyethyl group, sec.-propyl model machine, benzyloxy) of various replacements, various replacements (phenoxy group, to chlorophenoxy, to bromine phenoxy group etc.) etc., be specially phenyl, carboxylic esters base, cyclopropyl, cyclopentyl etc.; R 2for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, artyl sulfo of the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, various replacements, halogen etc. are specially methyl, cyclopropyl, formic acid fat base, benzyl, phenyl, methyl, ethyl etc.; R 3for the aryl of various replacements, the alkyl of various replacements, the alkoxyl group of various replacements, the aryloxy of various replacements, various replacement one-level amido, various replacement secondary amine etc., be specially p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, O-Nitrophenylfluorone, 2,4-dinitrophenyl, methyl, trimethyl silicon based ethyl etc.; N is 0,1,2,3.
3. polysubstituted ring amidine claimed in claim 1 7preparation method, carries out according to following step: under nitrogen protection, by a certain percentage by allyl amine alkynes 9, sulfonyl azide, alkali and mantoquita be blended in a kind of organic solvent and stir, according to substrate and specificity of reagent, temperature is controlled between certain temperature, after certain hour, stopped reaction, adds water, uses organic solvent ethyl acetate or dichloromethane extraction three times, organic phase is washed with saturated common salt after merging, use anhydrous sodium sulfate drying again, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, silica gel column chromatogram separating purification, obtains respective rings amidine 7; Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue is separated;
The structural formula of wherein said allyl amine alkynes is, the aryl that wherein R is various replacements, the alkyl of various replacements, the thiazolinyl of various replacements etc., be specially benzyl, to methoxy-benzyl, p-chlorobenzyl, to trifluoromethyl benzyl, to nitrobenzyl, p-methoxyphenyl, allyl group, cinnamene propyl group, carboxylic esters base allyl group, acetic acid fat base etc.; R 1for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, artyl sulfo of the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, various replacements, halogen etc. are specially phenyl, carboxylic esters base, cyclopropyl, cyclopentyl etc.; R 2for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, artyl sulfo of the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, various replacements, halogen etc. are specially methyl, cyclopropyl, formic acid fat base, benzyl, phenyl, methyl, ethyl etc.; N is 0,1,2,3 etc.; Sulfonyl azide structural formula is R 3sO 2n 3, R wherein 3for alkyl and the aromatic base of various replacements, be specially p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, O-Nitrophenylfluorone, 2,4-dinitrophenyl, methyl, trimethyl silicon based ethyl etc.;
Wherein said solvent is tetrahydrofuran (THF), toluene, methylene dichloride, trichloromethane, 1, non-polar solvent and the methyl-sulphoxides such as 2-methylene dichloride, ethyl acetate, ether, DMF;
The mol ratio of wherein said allyl amine alkynes, sulfonyl azide, alkali, solvent and mantoquita is that 1.0:1.1:1.0:10:0.01 is between 1.0:1.1:10:100:0.10;
Wherein said sulfonyl azide is various alkyl and arylsulfonyl nitrine, alkoxyl group or amido sulfonyl azide etc.;
Wherein said alkali is triethylamine, diisopropyl ethyl amine, Trimethylamine 99, trivinyl diamines, pyridine, 2,6-lutidine, 2,6-di-tert-butyl pyridine, 4-N, the mineral alkalis such as the organic basess such as N-dimethyl amine yl pyridines, N-methyl Pyrrolidine and sodium carbonate, salt of wormwood, cesium carbonate;
Wherein said mantoquita is that cuprous iodide, cuprous bromide, cuprous chloride, trifluoroacetic acid are cuprous, the cuprous cuprous acetate of trifluoromethanesulfonic acid etc.;
Wherein said temperature of reaction is between-30-60 degree Celsius;
The wherein said reaction times is between 10 minutes to 5 hours.
4. polysubstituted ring amidine claimed in claim 28 preparation methods, carry out according to following step: under nitrogen protection, by a certain percentage by alkynes 10, tertiary amine 11sulfonyl azide, alkali and mantoquita are blended in a kind of organic solvent and stir, and according to substrate and specificity of reagent, temperature is controlled between certain temperature, after certain hour, stopped reaction, adds water, uses organic solvent ethyl acetate or dichloromethane extraction three times, organic phase is washed with saturated common salt after merging, use anhydrous sodium sulfate drying again, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, silica gel column chromatogram separating purification, obtains respective rings amidine 8;
Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue is separated;
The structural formula of wherein said alkynes is, the aryl that wherein R is various replacements, the alkyl of various replacements, the thiazolinyl of various replacements etc., be specially benzyl, to methoxy-benzyl, p-chlorobenzyl, to trifluoromethyl benzyl, to nitrobenzyl, p-methoxyphenyl, allyl group, cinnamene propyl group, carboxylic esters base allyl group, acetic acid fat base etc.; ; The structural formula of tertiary amine is, wherein R 1, R 2, R 5for the aryl of various replacements, the alkoxyl group of the alkyl of various replacements, various replacements, the aryloxy of various replacements, various replacement secondary amine, the alkyl sulfenyl of various replacements, the artyl sulfo of various replacements, is specially benzyl, to methoxy-benzyl, to nitrobenzyl, methyl, ethyl, sec.-propyl, cyclohexyl, cyclopentyl, cyclopropyl; Sulfonyl azide structural formula is R 3sO 2n 3, R wherein 3for alkyl and the aromatic base of various replacements, be specially p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, O-Nitrophenylfluorone, 2,4-dinitrophenyl, methyl, trimethyl silicon based ethyl etc.;
Wherein said solvent is tetrahydrofuran (THF), toluene, methylene dichloride, trichloromethane, 1, non-polar solvent and the methyl-sulphoxides such as 2-methylene dichloride, ethyl acetate, ether, DMF;
The mol ratio of wherein said allyl amine alkynes, sulfonyl azide, alkali, solvent and mantoquita is that 1.0:1.1:1.0:10:0.01 is between 1.0:1.1:10:100:0.10;
Wherein said sulfonyl azide is various alkyl and arylsulfonyl nitrine, alkoxyl group and amido sulfonyl azide etc.;
Wherein said mantoquita is that cuprous iodide, cuprous bromide, cuprous chloride, trifluoroacetic acid are cuprous, the cuprous cuprous acetate of trifluoromethanesulfonic acid etc.;
Wherein said temperature of reaction is between-30-60 degree Celsius;
The wherein said reaction times is between 10 minutes to 5 hours.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753748A (en) * 2016-02-15 2016-07-13 灏瑰己 Synthesis method of medical intermediate sulfonyl compound
CN108117499A (en) * 2017-10-19 2018-06-05 上海应用技术大学 A kind of preparation method of α aryl amidine imine derivative
CN110627719A (en) * 2019-09-05 2019-12-31 中山大学 Cyclic amidine-based fluorescent molecule with ipsilateral push-pull electronic effect and preparation method thereof
CN111281850A (en) * 2020-03-14 2020-06-16 周琛 Analgesic pharmaceutical composition and use thereof
CN111574413A (en) * 2020-06-08 2020-08-25 杭州尚合生物医药科技有限公司 Preparation method of sulfonylamidine using 2-aminomethyl pyridine and DMF-DMA as amine source

Citations (1)

* Cited by examiner, † Cited by third party
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
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 examiner, † Cited by third party
Title
NAN LIU等: "Catalyzed Imidation of Tertiary Amines by Simple Copper Salts", 《EUR.J.ORG.CHEM.》 *
PHILIP MAGNUS等: "Reactions and Diastereoselectivity of N2-Arylsulfonyl Amidine Anions", 《J. ORG. CHEM.》 *
SHAM M.SONDHI等: "Synthesis, anticancer, and anti-inflammatory activity evaluation of methanesulfonamide and amidine derivatives of 3,4-diaryl-2-imino-4-thiazolines", 《MOLECULAR DIVERSITY》 *
SHAM M.SONDHI等: "Synthesis, anticancer, and anti-inflammatory activity evaluation of methanesulfonamide and amidine derivatives of 3,4-diaryl-2-imino-4-thiazolines", 《MOLECULAR DIVERSITY》, vol. 13, no. 3, 7 March 2009 (2009-03-07), pages 357 - 366, XP 019732293, DOI: doi:10.1007/s11030-009-9125-0 *
SUJING WANG等: "Facile synthesis of sulfonyl amidines via carbon-nitrogen bond formation mediated by FeCl3", 《CHEM.COMMUN.》 *
SUKBOK CHANG等: "Catalytic One-Pot Synthesis of Cyclic Amidines by Virtue of Tandem Reactions Involving Intramolecular Hydroamination under Mild Conditions", 《J.AM.CHEM.SOC.》 *
阿不都热合曼.乌斯曼等: "N-磺酰基环脒类化合物的合成及表征", 《合成与工艺技术》 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105753748A (en) * 2016-02-15 2016-07-13 灏瑰己 Synthesis method of medical intermediate sulfonyl compound
CN108117499A (en) * 2017-10-19 2018-06-05 上海应用技术大学 A kind of preparation method of α aryl amidine imine derivative
CN108117499B (en) * 2017-10-19 2020-10-09 上海应用技术大学 Preparation method of alpha aryl amidine imine derivative
CN110627719A (en) * 2019-09-05 2019-12-31 中山大学 Cyclic amidine-based fluorescent molecule with ipsilateral push-pull electronic effect and preparation method thereof
CN111281850A (en) * 2020-03-14 2020-06-16 周琛 Analgesic pharmaceutical composition and use thereof
CN111574413A (en) * 2020-06-08 2020-08-25 杭州尚合生物医药科技有限公司 Preparation method of sulfonylamidine using 2-aminomethyl pyridine and DMF-DMA as amine source

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