CN109678847A - Gamma lactone substituted pyridine derivative and its synthetic method and application - Google Patents

Gamma lactone substituted pyridine derivative and its synthetic method and application Download PDF

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CN109678847A
CN109678847A CN201811524279.8A CN201811524279A CN109678847A CN 109678847 A CN109678847 A CN 109678847A CN 201811524279 A CN201811524279 A CN 201811524279A CN 109678847 A CN109678847 A CN 109678847A
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unsubstituted
alkyl
replace
monosubstituted
alkoxy
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莫冬亮
廖骏一
吴鲭彦
邹宁
陈浩
苏桂发
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Guangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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Abstract

The invention discloses a series of gamma lactone substituted pyridine derivatives and its synthetic method and applications.Gamma lactone substituted pyridine derivative of the present invention has the structure as shown in following formula (I), its synthetic method are as follows: compound shown in the compound as shown in following formula (II), formula (III) and alkaline matter is taken to be placed in organic solvent, it reacts in the presence of oxygen, object crude product is made.The method of the invention is simple and easy to control, and the period is short, is not required to anhydrous and oxygen-free condition；Gained part gamma lactone substituted pyridine derivative has good anti-tumor activity.The compound difference of structure shown in the formula (I), formula (II) and formula (III) is as follows:

Description

Gamma lactone substituted pyridine derivative and its synthetic method and application
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to gamma lactone substituted pyridine derivative and its synthetic method and answers With.
Background technique
Pyridine cycle compound and gamma lactone compound are all very universal and considerable heterocyclic compounds, and Important pharmacophore in drug molecule, is important pharmacological activity unit, always by synthesis chemist and Pharmaceutical Chemist Favor.The method for constructing pyridine compounds in existing literature has: substitution is synthesized by one kettle way synthetic route under no metal Pyridine, using α, the cascade reaction sequence of beta unsaturated ketone and phosphonitrile, (equal in-situ preparation) is related to aza-Wittig, 6 π -3- nitrogen Miscellaneous triolefin electrocyclic reaction and [1,3]-hydrogen migration (Wei, H.；Li,Y.；Xiao,K.；Cheng,B.；Wang,H.；Hu,L.； Zhai,H.Org.Lett.2015.17(24):5974-5977)；The method of building lactonic ring compound, which has, utilizes 2- alkoxy carbonyl group The acid catalysis allyl reaction of allyl boronate and aldehyde occurs lactonization reaction under the conditions of TfOH and obtains interior ester products (Elford,T.-G.；Arimura,Y.；Yu,S.-H.；Hall,D-G.J.Org.Chem.2007,72(4):1276-1284.), But these existing methods cannot all synthesize the compound containing pyridine and gamma lactone simultaneously, and that there are functional group compatibilities is poor, step The deficiencies of rapid cumbersome and more complex using raw material.It has not yet to see about gamma lactone substituted pyridine derivative and its synthesis The relevant report of method.
Summary of the invention
The technical problem to be solved in the present invention is to provide the gamma lactone substituted pyridine derivatives of a kind of structure novel, and Their synthetic method and application.
Gamma lactone substituted pyridine derivative of the present invention is compound shown in following formula (I)s or it can pharmaceutically connect The salt received:
Wherein:
R1It indicates unsubstituted, monosubstituted, two replace, three replacing, four replace or five phenyl or unsubstituted that replace The unsubstituted thienyl of furyl or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4 Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R2It indicates unsubstituted, monosubstituted, two replace, three replacing, four replace or five phenyl or unsubstituted that replace The unsubstituted thienyl of furyl or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4 Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R3Indicate hydrogen, C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Its In, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Wherein, Substituent group is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen or C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace The unsubstituted thienyl of the unsubstituted furyl of phenyl or unsubstituted naphthalene；Wherein, replace Base is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R6Indicate C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace benzene The unsubstituted thienyl of the unsubstituted furyl of base or unsubstituted naphthalene；Wherein, substituent group is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom.
In above compound:
R1Further preferably unsubstituted, monosubstituted or disubstituted phenyl；
R2Further preferably unsubstituted, monosubstituted or disubstituted phenyl；
R3Further preferably hydrogen or unsubstituted, monosubstituted or disubstituted phenyl；
R4Further preferably unsubstituted, monosubstituted or disubstituted phenyl；
R5Further preferably hydrogen or unsubstituted, monosubstituted or disubstituted phenyl.
R6Further preferably unsubstituted, monosubstituted or disubstituted phenyl.
The synthetic method of compound shown in above-mentioned formula (I), mainly comprise the steps that take as Compound shown in lower formula (II), compound and alkaline matter shown in formula (III) are placed in organic solvent, the condition existing for oxygen Object crude product is made in lower reaction；
Wherein:
R1It indicates unsubstituted, monosubstituted, two replace, three replacing, four replace or five phenyl or unsubstituted that replace The unsubstituted thienyl of furyl or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4 Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R2It indicates unsubstituted, monosubstituted, two replace, three replacing, four replace or five phenyl or unsubstituted that replace The unsubstituted thienyl of furyl or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4 Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R3Indicate hydrogen, C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Its In, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Wherein, Substituent group is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen or C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace The unsubstituted thienyl of the unsubstituted furyl of phenyl or unsubstituted naphthalene；Wherein, replace Base is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R6Indicate C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace benzene The unsubstituted thienyl of the unsubstituted furyl of base or unsubstituted naphthalene；Wherein, substituent group is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom.
In above-mentioned synthetic method, R1、R2、R3、R4、R5And R6Preferential selection it is as previously described.
In above-mentioned synthetic method, compound shown in the raw material formula (II) that is related to is N- alkenyl-ɑ, β-unsaturation nitrone derivative Object can refer to existing literature (D.Kontokosta, D.S.Muller, D.L.Mo, W.H.Pace, R.A.Simpon, L.L.Anderson, Beilstein J.Org, Chem.2015,11,2097) it is synthesized, it can also free design synthetic route It is synthesized, this will not be detailed here.Compound shown in the raw material formula (III) being related to is acyl chlorides reagent, can directly from the market It is commercially available (such as phenyllacetyl chloride, 2- bromobenzene chloroacetic chloride or 4- methoxyphenylacetyl chloride).
In above-mentioned synthetic method, the organic solvent be can be selected from benzene, toluene, hexamethylene, petroleum ether, four chlorinations It is a kind of in carbon, tetrahydrofuran, ethyl acetate, acetonitrile, ether, methylene chloride, acetone, chloroform, n-hexane and dioxane Or two or more combination.When the combination for being selected as the above two above substance of organic solvent, their proportion can be Any proportion.The dosage of the organic solvent is advisable with that can dissolve the raw material participated in and reacted, it is generally the case that the formula of 1mmol (II) compound shown in is usually dissolved with the organic solvent of 3~10mL.
In above-mentioned synthetic method, the alkaline matter can be the alkaloids containing hydroxyl, or with alkalinity Amine substance etc. is preferably selected from tripotassium phosphate, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, carbonic acid Potassium, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyridine, triethylamine and N, one or more of N- diisopropyl ethyl amine Combination.When the combination for being selected as the above two above substance of alkaline matter, their proportion can be any proportion.
In above-mentioned synthetic method, reaction can carry out under conditions of ice bath, being heated or not heated, preferably in ice bath or It is carried out under conditions of not heating, the reaction of compound and alkaline matter shown in formula (III) can also be first completed under condition of ice bath After then move to and carry out under room temperature.When reaction is performed under heating conditions, preferable reaction temperature is lower than 40 DEG C.Whether reaction TLC tracing detection can be used completely.According to the experience of applicant, when reaction is when ice bath or do not heat under conditions of carry out, instead Control is more suitable in 40-60h between seasonable.
In synthetic method of the present invention, the consumption proportion of each raw material is stoichiometric ratio, in practical operation, formula (II) molar ratio of compound shown in compound, formula shown in (III) and alkaline matter is usually 1:2:1~2.
By the above method synthesize be formula (I) compound crude product, existing conventional purification process can be used to it It is purified with the purity of raising formula (I) compound.The mode for generalling use silica gel column chromatography is purified, in chromatography Eluant, eluent can be the mixed solvent consisted of petroleum ether and ethyl acetate, be also possible to be made of n-hexane and ethyl acetate Mixed solvent can also be the mixed solvent being made of petroleum ether and methanol, or be made of methylene chloride and methanol Mixed solvent.In aforementioned in the mixed solvent, the volume ratio of petroleum ether and ethyl acetate is preferably 100:1~1:1, n-hexane and second The volume ratio of acetoacetic ester is preferably 100:1~1:1, and the volume ratio by petroleum ether and methanol is preferably 100:1~10:1, dichloromethane The volume ratio of alkane and methanol is preferably 100:1~10:1.
The present invention also provides compound shown in above-mentioned formula (I) or its pharmaceutically acceptable salts in the preparation of antitumor drugs Application.
The present invention further comprises a kind of pharmaceutical composition, containing described shown in the above-mentioned formula (I) for treating upper effective dose Compound or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides a series of gamma lactone substituted pyridine derivative of structure novels and Their synthetic method.Synthetic method provided by the invention is simple and easy to control, and the period is short, is not required to anhydrous and oxygen-free condition；Gained part Gamma lactone substituted pyridine derivative has preferable anti-tumor activity, has certain potential medical value.
Specific embodiment
The present invention is described in further detail combined with specific embodiments below, content to better understand the invention, but The present invention is not limited to following embodiments.
N- alkenyl-ɑ involved in following embodiment, β-unsaturation nitrone derivative 1 are carried out referring to following synthetic routes Synthesis:
Wherein:
R1It indicates unsubstituted, monosubstituted, two replace, three replacing, four replace or five phenyl or unsubstituted that replace The unsubstituted thienyl of furyl or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4 Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R2It indicates unsubstituted, monosubstituted, two replace, three replacing, four replace or five phenyl or unsubstituted that replace The unsubstituted thienyl of furyl or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4 Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R3Indicate hydrogen, C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Its In, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Wherein, Substituent group is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom.
Specific synthetic method are as follows: by Cu (OAc)2(0.3mmol, 54mg), α, β-unsaturated oxime substrate S1 (0.3mmol) Be placed in reaction tube with ene boric acid S2 (0.9mmol), be added 3mL 1,2- dichloroethanes, at room temperature be added pyridine (3mmol, 0.24mL)；At 25 DEG C stirring 12~for 24 hours, gained reactant be added water (10mL), be extracted with dichloromethane (2 × 10mL), close And organic phase, with anhydrous sodium sulfate it is dry after filter, be removed under reduced pressure solvent, silica gel column chromatography separation (petrol ether/ethyl acetate= 10:1~1:1, volume ratio), obtain product 1 (i.e. compound N shown in formula (II)-alkenyl-ɑ, β-unsaturation nitrone derivative).
Embodiment 1
Gamma lactone substituted pyridine compound of the present invention is synthesized by following synthetic routes.
3aa:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=Ph；
3ba:R1=4-MeOC6H4, R2=4-MeOC6H4, R3=Me, R4=Me, R5=H, R6=Ph；
3ca:R1=Ph, R2=4-CF3C6H4, R3=Me, R4=Me, R5=H, R6=Ph；
3da:R1=4-CF3C6H4, R2=4-CF3C6H4, R3=Me, R4=Me, R5=H, R6=Ph；
3ea:R1=3-BrC6H4, R2=3-BrC6H4, R3=Me, R4=Me, R5=H, R6=Ph；
3fa:R1=2-BrC6H4, R2=2-BrC6H4, R3=Me, R4=Me, R5=H, R6=Ph；
3ga:R1=Ph, R2=Ph, R3=Et, R4=Ph, R5=H, R6=Ph；
3ha:R1=Ph, R2=Ph, R3,R4=(CH2)5, R5=H, R6=Ph；
3ia:R1=Ph, R2=Ph, R3=H, R4=Ph, R5=H, R6=Ph；
3ja:R1=3-MeOC6H4, R2=3-MeOC6H4, R3=Me, R4=Me, R5=H, R6=Ph；
3ka:R1=2-MeOC6H4, R2=2-MeOC6H4, R3=Me, R4=Me, R5=H, R6=Ph；
3la:R1=2- furyl, R2=2- furyl, R3=Me, R4=Me, R5=H, R6=Ph；
3ma:R1=2- thienyl, R2=2- thienyl, R3=Me, R4=Me, R5=H, R6=Ph.
By N- alkenyl-ɑ, β-unsaturation nitrone derivative 1 (0.2mmol), phenyllacetyl chloride 2 (0.4mmol), organic solvent (organic solvent that wherein object 3aa-3ga is used is tetrahydrofuran, the organic solvent that object 3ha is used for toluene with The mixed solvent that ethyl acetate is formed by the volume ratio of 1:1, the organic solvent that object 3ia-3ma is used is respectively benzene, hexamethylene Alkane, petroleum ether, acetonitrile and ether) (4mL) be placed in reaction tube, alkaline matter (wherein object 3aa-3ha is added at 0 DEG C The alkaline matter of use is triethylamine, and the alkaline matter that object 3ia-3ma is used is respectively tripotassium phosphate, hydroxide Sodium, calcium hydroxide, sodium tert-butoxide and potassium fluoride) (0.48mmol), the reaction was continued 48h.Water (10mL) extraction is added, uses dichloromethane Alkane extracts (3 × 10mL), merges organic phase, and with filtering after anhydrous sodium sulfate drying, solvent, silica gel column chromatography separation is removed under reduced pressure (petrol ether/ethyl acetate=20:1~6:1, volume ratio), obtains target product 3.It different target products and its is characterized as below:
3aa: colourless liquid, 69mg, 82%yield；1H NMR(400MHz,CDCl3):δ7.43–7.41(m,2H), 7.32-7.24 (m, 11H), 7.19-7.17 (m, 2H), 7.08 (s, 1H), 5.53 (d, J=8.0Hz, 2H), 4.38-4.33 (m, 1H),4.22–4.19(m,1H),2.56(s,3H),2.18(s,3H)；13C NMR(100MHz,CDCl3):δ175.4,158.2, 151.1,150.0,139.5,136.9,135.5,129.4,128.8,128.8,128.7,128.6,128.3,127.8, 127.7,127.6,121.6,85.1,55.5,54.5,31.9,29.7,29.6,23.5,16.1,14.1；IR(neat):2925, 1783,1710,1603,1554,1454,1385,1148,991,699cm-1；HRMS(ESI)m/z[M+H]+calcd for [C29H21NO2]+:420.1958；Found:420.1953. its structural formula is as follows:
3ba: white solid, 38mg, 39%yield, mp:83-84 DEG C；1H NMR(500MHz,CDCl3):δ7.32-7.28 (m,5H),7.20-7.18(m,2H),7.10-7.07(m,3H),6.97-6.95(m,2H),6.80-6.78(m,2H),5.47 (d, J=12.0Hz, 1H), 4.31-4.25 (m, 1H), 4.16-4.13 (m, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 2.55 (s,3H),2.19(s,3H)；13C NMR(125MHz,CDCl3):δ175.4,159.4,159.0,158.1,151.1,149.7, 135.6,131.8,130.0,129.4,128.9,128.8,128.7,127.7,121.7,114.2,113.8,85.4,55.4, 55.2,54.8,54.7,23.6,22.7,16.2,14.1；IR(neat):2963,1772,1611,1515,1291,1253, 1178,1031,803cm-1；MS(ESI)m/z[M+H]+calcd for[C31H29NO4]+:480.2169；found:480.2165. Its structural formula is as follows:
3ca: white solid, 73mg, 75%yield, mp:84-85 DEG C；1H NMR(500MHz,CDCl3):δ7.55-7.53 (m, 2H), 7.44-7.40 (m, 3H), 7.34-7.32 (m, 5H), 7.26-7.25 (m, 4H), 7.12 (s, 1H), 5.54 (d, J= 11.5Hz,1H),4.48-4.43(m,1H),4.22-4.19(m,1H),2.55(s,3H),2.19(s,3H)；13C NMR (125MHz,CDCl3):δ174.8,158.3,150.7,150.3,141.2,139.4,135.0,129.7,129.0,128.7, 128.6,128.4,128.3,128.0,127.9,125.8,121.6,84.6,55.1,54.6,23.5,16.2；IR(neat): 2960,1763,1621,1327,1168,1123,1071,1018,803,702cm-1；MS(ESI)m/z[M+H]+calcd for [C30H24F3NO2]+:488.1832；Found:488.1827. its structural formula is as follows:
3da: white solid, 64mg, 58%yield, mp:74-75 DEG C；1H NMR(400MHz,CDCl3):δ7.72–7.70 (m, 2H), 7.56-7.54 (m, 2H), 7.39-7.31 (m, 7H), 7.26-7.24 (m, 2H), 7.10 (s, 1H), 5.55 (d, J= 12.0Hz,1H),4.48–4.42(m,1H),4.22–4.19(m,1H),2.56(s,1H),2.17(s,1H)；13C NMR (125MHz,CDCl3):δ174.7,158.6,151.0,148.8,142.9,141.0,134.9,130.4,130.1,129.9, 129.5,129.1,129.0,128.6,128.3,128.0,125.8,125.8,125.4,125.4,125.1,125.0, 121.2,84.3,55.1,54.5,23.5,16.1；IR(neat):2962,1776,1620,1326,1126,847,699cm-1； HRMS(ESI)m/z[M+H]+calcd for[C31H23F6NO2]+:556.1706；Found:556.1698. its structural formula is as follows:
3ea: yellow solid, 57mg, 49%yield, mp:70-71 DEG C；1H NMR(400MHz,CDCl3):δ7.54–7.52 (m,1H),7.41(s,1H),7.35–7.31(m,5H),7.29–7.25(m,3H),7.19–7.15(m,3H),7.06(s,1H), 5.48 (d, J=8.0Hz, 1H), 4.34-4.29 (m, 1H), 4.19-4.16 (m, 1H), 2.56 (s, 3H), 2.18 (s, 3H)；13C NMR(100MHz,CDCl3):δ174.8,158.5,151.1,148.6,141.4,139.3,135.1,131.6,131.2, 131.0,130.9,130.4,129.9,129.4,128.9,128.6,127.9,127.4,126.5,122.8,122.5, 121.2,84.5,55.0,54.4,29.7,29.3,23.5,16.1；IR(neat):2923,1775,1598,1491,1154, 1010,828,699cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H23Br2NO2]+:576.0168；found: 576.0163. its structural formula is as follows:
3fa: yellow solid, 59mg, 50%yield, mp:78-79 DEG C；1H NMR(400MHz,CDCl3):δ7.55–7.53 (m,1H),7.40(s,1H),7.35–7.30(m,5H),7.29–7.26(m,3H),7.18–7.14(m,3H),7.05(s,1H), 5.48 (d, J=8.0Hz, 1H), 4.34-4.28 (m, 1H), 4.18-4.16 (m, 1H), 2.57 (s, 3H), 2.17 (s, 3H)；13C NMR(100MHz,CDCl3):δ174.7,158.6,151.0,148.5,141.5,139.2,135.0,131.4,131.2, 131.0,130.9,130.3,129.9,129.4,128.8,128.6,127.9,127.4,126.5,122.7,122.4, 121.2,84.4,55.0,54.4,29.7,29.2,23.6,16.1；IR(neat):2920,1776,1599,1490,1155, 1012,826,699cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H23Br2NO2]+:576.0168；found: 576.0164. its structural formula is as follows:
3ga: colourless liquid, 33mg, 33%yield；1H NMR(400MHz,CDCl3): δ 8.10 (d, J=8.0Hz, 2H), 7.60-7.58 (m, 1H), 7.48-7.42 (m, 7H), 7.36-7.33 (m, 3H), 7.28-7.22 (m, 9H), 5.66 (d, J= 12.0Hz, 1H), 4.34-4.29 (m, 1H), 4.22-4.19 (m, 1H), 2.69-2.63 (m, 2H), 0.74 (t, J=7.4Hz, 3H)；13C NMR(125MHz,CDCl3):δ175.4,171.2,159.5,151.8,151.6,140.8,139.6,136.8, 135.4,135.3,133.6,130.1,129.4,128.9,128.8,128.7,128.6,128.5,128.4,128.4, 128.0,127.9,127.8,127.7,122.7,85.0,55.7,54.6,31.9,31.4,30.2,29.7,22.2,14.6, 14.1；IR(neat):2935,1774,1602,1497,1152,1009,825,699cm-1；HRMS(ESI)m/z[M+H]+ calcd for[C35H29NO2]+:496.2271；Found:496.2267. its structural formula is as follows:
3ha: colourless liquid, 28mg, 31%yield；1H NMR(400MHz,CDCl3):δ7.44–7.38(m,3H), 7.32-7.26 (m, 10H), 7.23-7.18 (m, 5H), 7.06 (s, 1H), 5.52 (d, J=8.0Hz, 1H), 4.42-4.36 (m, 1H),4.22–4.19(m,1H),3.11–3.09(m,2H),2.73–2.71(m,2H),1.87–1.86(m,2H),1.75–1.73 (m,2H),1.61(s,2H)；13C NMR(100MHz,CDCl3):δ175.4,164.5,150.6,149.4,139.7,137.0, 136.0,135.5,128.8,128.8,128.7,128.3,127.9,127.7,127.7,127.6,121.8,85.2,55.2, 54.5,39.4,32.3,29.5,27.7,26.4；IR(neat):2963,1767,1624,1518,1288,1250,1176, 1031,803,695cm-1；HRMS(ESI)m/z[M+H]+calcd for[C32H29NO2]+:460.2271；found: 460.2254. its structural formula is as follows:
3ia: colourless liquid, 38mg, 34%yield；1H NMR(400MHz,CDCl3): δ 8.10 (d, J=8.0Hz, 2H), 7.61-7.58 (m, 1H), 7.47-7.42 (m, 7H), 7.36-7.33 (m, 3H), 7.28-7.21 (m, 9H), 5.65 (d, J= 12.0Hz, 1H), 4.34-4.28 (m, 1H), 4.22-4.19 (m, 1H), 2.69-2.63 (m, 2H), 0.73 (t, J=7.4Hz, 3H)；13C NMR(125MHz,CDCl3):δ175.6,171.3,158.3,151.7,151.5,142.8,138.9,136.7, 135.4,135.3,132.6,130.1,129.4,128.9,128.8,128.7,128.6,128.5,128.4,128.4, 128.0,127.9,127.8,127.7,123.7,85.0,55.8,54.6,31.9,31.4,30.2,29.7,22.2,14.6, 14.1；IR(neat):2945,1784,1612,1502,1154,1010,830,689cm-1；HRMS(ESI)m/z[M+H]+ calcd for[C35H29NO2]+:496.2271；Found:496.2268. its structural formula is as follows:
3ja: white solid, 42mg, 40%yield, mp:94-95 DEG C；1H NMR(500MHz,CDCl3):δ7.33-7.28 (m,5H),7.20-7.18(m,2H),7.10-7.06(m,3H),6.98-6.95(m,2H),6.80-6.77(m,2H),5.47 (d, J=12.0Hz, 1H), 4.30-4.25 (m, 1H), 4.16-4.13 (m, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 2.54 (s,3H),2.20(s,3H)；13C NMR(125MHz,CDCl3):δ175.4,159.4,159.0,158.1,151.1,149.7, 135.6,131.8,130.0,129.3,128.9,128.8,128.7,127.5,121.7,114.1,113.7,85.4,55.4, 55.2,54.8,54.7,23.6,22.7,16.2,14.1；IR(neat):2968,1769,1620,1514,1291,1256, 1179,1041,805cm-1；HRMS(ESI)m/z[M+H]+calcd for[C31H29NO4]+:480.2169；found: 480.2166. its structural formula is as follows:
3ka: white solid, 40mg, 39%yield, mp:84-85 DEG C；1H NMR(500MHz,CDCl3):δ7.33-7.28 (m,5H),7.20-7.18(m,2H),7.10-7.06(m,3H),6.98-6.96(m,2H),6.80-6.76(m,2H),5.48 (d, J=12.0Hz, 1H), 4.30-4.24 (m, 1H), 4.16-4.12 (m, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 2.55 (s,3H),2.22(s,3H)；13C NMR(125MHz,CDCl3):δ175.3,159.3,159.1,158.2,151.2,149.8, 135.5,131.8,130.0,129.2,128.9,128.8,128.7,127.4,121.7,114.1,113.5,85.2,55.3, 55.2,54.8,54.7,23.6,22.5,16.1,14.1；IR(neat):2970,1789,1625,1511,1300,1255, 1182,1048,805,679cm-1；MS(ESI)m/z[M+H]+calcd for[C31H29NO4]+:480.2169；found: 480.2166. its structural formula is as follows:
3la: colourless liquid, 40mg, 50%yield；1H NMR(500MHz,CDCl3):δ7.85-7.61(m,3H), 7.40-7.18(m,5H),7.13-7.10(m,2H),6.99-6.40(m,2H),6.10-6.06(m,1H),5.96(s,1H), 4.37-4.35(m,1H),3.96–3.94(m,1H),2.69(s,3H),2.34(s,3H)；13C NMR(125MHz,CDCl3):δ 174.7,156.0,154.0,142.9,141.5,137.4,136.3,135.6,134.7,129.9,128.8,128.1, 126.4,126.0,124.2,112.0,111.0,107.1,105.9,79.3,53.2,39.5,18.8,18.0；IR(neat): 2876,1673,1600,1502,1281,1251,1189,808,694cm-1；MS(ESI)m/z[M+H]+calcd for [C25H21NO4]+:400.1543；Found:400.1547. its structural formula is as follows:
3ma: colourless liquid, 40mg, 50%yield；1H NMR(500MHz,CDCl3):δ7.85-7.61(m,3H), 7.40-7.18(m,5H),7.13-7.10(m,2H),6.99-6.40(m,2H),6.10-6.06(m,1H),5.96(s,1H), 4.37-4.35(m,1H),3.96–3.94(m,1H),2.69(s,3H),2.34(s,3H)；13C NMR(125MHz,CDCl3):δ 175.7,156.0,153.8,142.7,141.4,137.3,136.4,135.5,134.8,129.8,128.7,128.2, 126.5,126.1,124.0,112.2,111.1,108.1,105.7,79.5,53.2,39.5,18.8,16.0；IR(neat): 2796,1663,1600,1507,1291,1244,1188,799,685cm-1；MS(ESI)m/z[M+H]+calcd for [C25H21NO2S2]+:432.1086；Found:432.1088. its structural formula is as follows:
Embodiment 2:
Gamma lactone substituted pyridine compound of the present invention is synthesized by following synthetic routes.
3ab:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=2-BrC6H4；
3ac:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=3-BrC6H4；
3ad:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=4-BrC6H4；
3ae:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=4-MeOC6H4；
3af:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=3-MeOC6H4；
3ag:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=2-MeOC6H4；
3ah:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=4-ClC6H4；
3ai:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=4-MeC6H4；
3aj:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=2- thienyl；
3ak:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=cyclohexyl；
3al:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=Et, R6=Ph；
3am:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=n-hexyl.
By N- alkenyl-ɑ, β-unsaturation nitrone derivative 1 (0.2mmol), phenyllacetyl chloride 2 (0.4mmol), toluene (4mL) It is placed in reaction tube, cesium carbonate (0.48mmol) is added at 25 DEG C, the reaction was continued 48h.Water (10mL) extraction is added, uses dichloro Methane extracts (3 × 10mL), merges organic phase, and with filtering after anhydrous sodium sulfate drying, solvent, silica gel column chromatography point is removed under reduced pressure From (petrol ether/ethyl acetate=20:1~6:1, volume ratio), target product 3 is obtained.Different target products and its characterization are such as Under:
3ab: yellow solid, 82mg, 82%yield, mp:59-60 DEG C；1H NMR(500MHz,CDCl3):δ7.45-7.43 (m,3H),7.41-7.40(m,1H),7.30-7.29(m,1H),7.14-7.10(m,4H),7.05-7.04(m,2H),6.94- 6.92 (m, 2H), 6.76-6.74 (m, 1H), 5.82 (s, 1H), 5.49 (d, J=9.0Hz, 1H), 4.60 (d, J=8.5Hz, 1H),2.64(s,3H),2.23(s,3H)；13C NMR(125MHz,CDCl3):δ176.3,158.6,153.1,150.3, 139.5,138.7,133.9,132.0,131.4,129.2,128.8,128.7,128.5,128.4,128.3,127.9, 127.6,127.2,126.9,125.5,120.2,84.4,51.4,50.4,23.7,16.1；IR(neat):2965,1709, 1652,1401,1241,1027,760,677cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H24BrNO2]+: 498.1063；Found:498.1060. its structural formula is as follows:
3ac: yellow solid, 78mg, 78%yield, mp:59-60 DEG C；1H NMR(500MHz,CDCl3):δ7.45-7.43 (m,3H),7.41-7.40(m,1H),7.30-7.29(m,1H),7.14-7.10(m,4H),7.05-7.04(m,2H),6.94- 6.92 (m, 2H), 6.76-6.74 (m, 1H), 5.82 (s, 1H), 5.49 (d, J=9.0Hz, 1H), 4.60 (d, J=8.5Hz, 1H),2.64(s,3H),2.23(s,3H)；13C NMR(125MHz,CDCl3):δ176.3,158.6,153.1,150.3, 139.5,138.7,133.9,132.0,131.4,129.2,128.8,128.7,128.5,128.4,128.3,127.9, 127.6,127.2,126.9,125.5,120.2,84.4,51.4,50.4,23.7,16.1；IR(neat):2969,1703, 1647,1400,1246,1024,766,687cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H24BrNO2]+: 498.1063；Found:498.1062. its structural formula is as follows:
3ad: yellow solid, 75mg, 75%yield, mp:58-59 DEG C；1H NMR(500MHz,CDCl3):δ7.46-7.43 (m,3H),7.42-7.40(m,1H),7.30-7.28(m,1H),7.14-7.10(m,4H),7.05-7.03(m,2H),6.94- 6.92 (m, 2H), 6.76-6.73 (m, 1H), 5.81 (s, 1H), 5.50 (d, J=9.0Hz, 1H), 4.60 (d, J=8.5Hz, 1H),2.61(s,3H),2.22(s,3H)；13C NMR(125MHz,CDCl3):δ176.2,158.5,153.0,150.2, 139.4,138.6,133.9,132.1,131.5,129.3,128.7,128.6,128.5,128.4,128.3,127.8, 127.6,127.1,126.8,125.6,120.1,84.5,51.4,50.4,23.7,16.1；IR(neat):2969,1723, 1650,1403,1246,1028,767,688cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H24BrNO2]+: 498.1063；Found:498.1065. its structural formula is as follows:
3ae: colourless liquid, 55mg, 61%yield；1H NMR(500MHz,CDCl3):δ7.43-7.40(m,2H), 7.29-7.24 (m, 6H), 7.21-7.17 (m, 4H), 7.08 (s, 1H), 6.87 (d, J=10.5Hz, 2H), 5.51 (d, J= 12.0Hz,1H),4.32-4.27(m,1H),4.16-4.13(m,1H),3.77(s,3H),2.56(s,3H),2.18(s,3H)；13C NMR(125MHz,CDCl3):δ175.7,159.1,158.2,151.2,139.5,137.0,129.7,129.4,128.8, 128.7,128.4,127.9,127.6,127.5,121.6,114.3,85.1,55.5,55.2,53.9,23.5,16.1；IR (neat):2963,1772,1611,1515,1291,1253,1178,1031,803,695cm-1；HRMS(ESI)m/z[M+H]+ calcd for[C30H27NO3]+:450.2064；Found:450.2057. its structural formula is as follows:
3af: colourless liquid, 52mg, 60%yield；1H NMR(500MHz,CDCl3):δ7.45-7.41(m,2H), 7.30-7.24 (m, 6H), 7.22-7.17 (m, 4H), 7.09 (s, 1H), 6.88 (d, J=10.5Hz, 2H), 5.50 (d, J= 12.0Hz,1H),4.34-4.29(m,1H),4.18-4.13(m,1H),3.79(s,3H),2.55(s,3H),2.18(s,3H)；13C NMR(125MHz,CDCl3):δ175.7,159.1,157.9,151.1,139.5,137.0,129.8,129.4,128.7, 128.6,128.4,127.9,127.6,127.5,121.4,114.3,85.1,55.5,55.1,53.9,23.5,16.0；IR (neat):2967,1770,1615,1511,1297,1253,1177,1030,806,694cm-1；HRMS(ESI)m/z[M+H]+ calcd for[C30H27NO3]+:450.2064；Found:450.2059. its structural formula is as follows:
3ag: colourless liquid, 52mg, 60%yield；1H NMR(500MHz,CDCl3):δ7.45-7.41(m,2H), 7.30-7.26 (m, 6H), 7.22-7.16 (m, 4H), 7.10 (s, 1H), 6.89 (d, J=10.5Hz, 2H), 5.51 (d, J= 12.0Hz,1H),4.34-4.28(m,1H),4.16-4.10(m,1H),3.78(s,3H),2.56(s,3H),2.19(s,3H)；13C NMR(125MHz,CDCl3):δ175.5,159.3,157.9,151.5,139.5,137.0,129.8,129.4,128.7, 128.5,128.4,127.9,127.6,127.5,122.4,115.3,85.3,55.4,55.1,53.9,23.3,16.3；IR (neat):2977,1766,1622,1512,1298,1251,1179,1019,816,687cm-1；HRMS(ESI)m/z[M+H]+ calcd for[C30H27NO3]+:450.2064；Found:450.2061. its structural formula is as follows:
3ah: liquid, 66mg, 73%yield；1H NMR(500MHz,CDCl3):δ7.46-7.43(m,3H),7.42- 7.40(m,1H),7.30-7.28(m,1H),7.14-7.10(m,4H),7.05-7.03(m,2H),6.94-6.92(m,2H), 6.76-6.73 (m, 1H), 5.81 (s, 1H), 5.50 (d, J=9.0Hz, 1H), 4.60 (d, J=8.5Hz, 1H), 2.61 (s, 3H),2.22(s,3H)；13C NMR(125MHz,CDCl3):δ176.2,158.5,153.0,150.2,139.4,138.6, 133.9,132.1,131.5,129.3,128.7,128.6,128.5,128.4,128.3,127.8,127.6,127.1, 126.8,125.6,120.1,84.5,51.4,50.4,23.7,16.1；IR(neat):2961,1713,1667,1413,1276, 1128,767,698cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H24ClNO2]+:454.1568；found: 454.1565. its structural formula is as follows:
3ai: colourless liquid, 55mg, 63%yield；1H NMR(500MHz,CDCl3):δ7.42-7.38(m,2H), 7.26-7.22 (m, 6H), 7.19-7.15 (m, 4H), 7.07 (s, 1H), 6.79 (d, J=10.5Hz, 2H), 5.47 (d, J= 12.0Hz,1H),4.32-4.26(m,1H),4.16-4.13(m,1H),2.77(s,3H),2.56(s,3H),2.18(s,3H)；13C NMR(125MHz,CDCl3):δ174.7,159.1,158.2,153.2,139.5,135.0,128.7,128.4,126.8, 126.7,126.4,124.9,124.6,124.5,121.6,114.3,85.1,55.5,55.2,53.9,23.5,16.1；IR (neat):2963,1772,1611,1515,1291,1253,1178,1031,803,695cm-1；HRMS(ESI)m/z[M+H]+ calcd for[C30H27NO2]+:434.2115；Found:434.2117. its structural formula is as follows:
3aj: colourless liquid, 48mg, 56%yield；1H NMR(500MHz,CDCl3):δ8.06-8.04(m,1H), 7.52-7.40(m,6H),7.37-7.27(m,5H),6.93–6.83(m,2H),5.96–5.94(m,1H),4.14–4.12(m, 1H),3.96–3.94(m,1H),2.53(s,3H),2.31(s,3H)；13C NMR(125MHz,CDCl3):δ173.4,157.9, 157.7,149.5,148.7,145.3,139.4,129.3,129.2,129.1,128.5,128.4,128.3,127.4, 127.3,126.2,126.1,125.9,125.1,124.9,104.9,88.7,54.2,40.1,18.6,14.3；IR(neat): 2895,1694,1604,1512,1280,1241,1155,1020,801,696cm-1；HRMS(ESI)m/z[M+H]+calcd for[C27H23NO2S]+:426.1522；Found:426.1526. its structural formula is as follows:
3ak: colourless liquid, 43mg, 51%yield；1H NMR(500MHz,CDCl3):δ8.06-8.05(m,1H), 7.52-7.41(m,5H),7.36-7.27(m,5H),5.96–5.94(m,1H),3.75–3.74(m,1H),2.66–2.65(m, 1H),2.53(s,3H),2.31(s,3H),2.06–2.05(m,1H),1.53–1.27(m,10H)；13C NMR(125MHz, CDCl3):δ178.9,157.9,157.7,149.5,139.4,139.1,129.3,129.2,129.1,128.7,128.6, 128.5,128.2,128.1,127.5,127.4,125.9,104.9,89.4,53.9,38.5,35.5,31.2,31.1,26.0, 25.8,25.7,18.6,14.3；IR(neat):2967,1762,1613,1506,1278,1247,1150,1021,800, 694cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H31NO2]+:426.2428；Found:426.2430. its structural formula It is as follows:
3al: colourless liquid, 44mg, 49%yield；1H NMR(500MHz,CDCl3):δ7.43-7.37(m,3H), 7.21-7.19 (m, 3H), 7.16-7.14 (m, 3H), 7.10-7.07 (m, 3H), 6.77-6.73 (m, 4H), 5.57 (d, J= 10.0Hz, 1H), 4.27 (d, J=10.0Hz, 1H), 2.47 (s, 3H), 2.18-2.15 (m, 2H), 2.11-2.09 (m, 3H), 1.21 (t, J=7.5Hz, 3H)；13C NMR(125MHz,CDCl3):δ178.1,157.9,151.3,150.0,139.6, 136.4,134.0,129.5,129.3,128.7,128.3,128.0,127.9,127.8,127.4,127.3,121.2,81.6, 59.3,56.3,23.9,23.4,16.1,9.1；IR(neat):2975,1764,1634,1528,1279,1247,1166, 1027,812,689cm-1；HRMS(ESI)m/z[M+H]+calcd for[C31H29NO2]+:448.2271；found: 448.2252. its structural formula is as follows:
3am: colourless liquid, 43mg, 51%yield；1H NMR(500MHz,CDCl3):δ8.06-8.05(m,1H), 7.52-7.41(m,5H),7.36-7.27(m,5H),5.96–5.94(m,1H),3.75–3.74(m,1H),2.66–2.65(m, 1H),2.53(s,3H),2.31(s,3H),1.64–1.63(m,2H),1.31–1.25(m,8H),0.88(s,3H)；13C NMR (125MHz,CDCl3):δ178.9,157.9,157.7,149.5,139.4,139.1,129.3,129.2,129.1,128.7, 128.6,128.5,128.2,128.1,127.5,127.4,125.9,104.9,89.4,53.9,31.8,29.3,27.7, 27.1,22.7,18.6,14.3,14.1；IR(neat):2977,1761,1602,1511,1278,1214,1159,1020, 831,697cm-1；HRMS(ESI)m/z[M+H]+calcd for[C29H33NO2]+:427.2506；Found:427.2509. it is tied Structure formula is as follows:
Experimental example 1: gamma lactone substituted pyridine derivative of the present invention carries out external inhibitory activity to a variety of human tumour strains Experiment:
(1) cell culture: by MGC-803, HepG-2, NCI-H460, SKOV3, T24,7702 cell culture in containing 10% The DMEM culture medium of (volume ratio) fetal calf serum and 1% (volume ratio) dual anti-(containing penicillin and streptomysin), 37 DEG C of temperature, 5%CO2And 95% air incubator in cultivate, change liquid every other day.It is passed on, is frozen after cell covers with.
(2) it plants plate: taking the cell in logarithmic growth phase, remove old culture medium, washed twice with PBS, trypsase disappears Change cell, new culture medium is added after cell rounding and terminates cell dissociation and blows and beats suspension cell, individual cells suspension is made. Suitable cell suspension is taken, a certain amount of culture medium dilution is added, is inoculated into 96 orifice plates, every 180 μ L of hole, every hole cell number is 20000-40000。
(3) dosing: being added sample to be tested in 96 orifice plates of Yu Zhongyou tumour cell, every 20 μ L of hole makes the final dense of sample Degree is 10 μM, carries out primary dcreening operation.According to being screened as a result, different concentration gradients is arranged to compound for primary dcreening operation, every group of setting 5 A multiple holes.CO is put after adding compound2Incubator culture 48h, every hole are added the MTT solution that 10 μ L are prepared, put CO2Incubator continues Cultivate 4~6h.
(4) it tests: inhaling the culture medium abandoned in 96 orifice plates, the DMSO of 100 μ L is added, put 5~10min of concussion on shaking table, make The first a ceremonial jade-ladle, used in libation of crystallization is completely dissolved.With microplate reader with the absorbing wavelength of 570nm, the reference wavelength dual wavelength of 630nm measures absorbance (OD) value calculates inhibiting rate.Inhibiting rate=(1- sample sets OD value/blank group OD value) × 100%, is calculated separately with SPSS software IC of each compound to different tumor cell lines50Value.Test result is as follows for it shown in table 1:
Table 1:

Claims (10)

1. compound shown in following formula (I)s or its pharmaceutically acceptable salt:
Wherein:
R1Indicate the phenyl or unsubstituted furans of unsubstituted, monosubstituted two substitutions, three substitutions, four substitutions or five substitutions The unsubstituted thienyl of base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4It is complete Fluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R2Indicate the phenyl or unsubstituted furans of unsubstituted, monosubstituted two substitutions, three substitutions, four substitutions or five substitutions The unsubstituted thienyl of base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4It is complete Fluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R3Indicate hydrogen, C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Wherein, it takes Dai Jiwei C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Wherein, replace Base is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen or C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace benzene The unsubstituted thienyl of the unsubstituted furyl of base or unsubstituted naphthalene；Wherein, substituent group is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R6Indicate C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace phenyl, or Person is the unsubstituted thienyl of unsubstituted furyl or unsubstituted naphthalene；Wherein, substituent group C1~4's Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom.
2. compound according to claim 1, it is characterised in that:
R1Indicate unsubstituted, monosubstituted or disubstituted phenyl；
R2Indicate unsubstituted, monosubstituted or disubstituted phenyl；
R3Indicate hydrogen or unsubstituted, monosubstituted or disubstituted phenyl；
R4Indicate unsubstituted, monosubstituted or disubstituted phenyl；
R5Indicate hydrogen or unsubstituted, monosubstituted or disubstituted phenyl.
R6Indicate unsubstituted, monosubstituted or disubstituted phenyl.
3. the synthetic method of compound described in claim 1, it is characterised in that: mainly comprise the steps that and take such as following formula (II) Compound shown in shown compound, formula (III) and alkaline matter are placed in organic solvent, are reacted in the presence of oxygen, Object crude product is made；
Wherein:
R1Indicate the phenyl or unsubstituted furans of unsubstituted, monosubstituted two substitutions, three substitutions, four substitutions or five substitutions The unsubstituted thienyl of base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4It is complete Fluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R2Indicate the phenyl or unsubstituted furans of unsubstituted, monosubstituted two substitutions, three substitutions, four substitutions or five substitutions The unsubstituted thienyl of base or unsubstituted naphthalene；Wherein, substituent group C1~4Alkoxy, C1~4It is complete Fluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R3Indicate hydrogen, C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Wherein, it takes Dai Jiwei C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R4Indicate C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted phenyl；Wherein, replace Base is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen or C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace benzene The unsubstituted thienyl of the unsubstituted furyl of base or unsubstituted naphthalene；Wherein, substituent group is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom；
R6Indicate C1~6Alkyl or it is unsubstituted, monosubstituted, two replace, three replace, four replace or five replace phenyl, or Person is the unsubstituted thienyl of unsubstituted furyl or unsubstituted naphthalene；Wherein, substituent group C1~4's Alkoxy, C1~4Perfluoroalkyl, C1~4Alkyl, cyano or halogen atom.
4. synthetic method according to claim 3, it is characterised in that: the organic solvent is selected from benzene, toluene, hexamethylene Alkane, petroleum ether, carbon tetrachloride, tetrahydrofuran, ethyl acetate, acetonitrile, ether, methylene chloride, acetone, chloroform, n-hexane With a combination of one or more in dioxane.
5. synthetic method according to claim 3, it is characterised in that: the alkaline matter is selected from tripotassium phosphate, hydrogen Sodium oxide molybdena, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, pyrrole Pyridine, triethylamine and N, the combination of one or more of N- diisopropyl ethyl amine.
6. synthetic method according to claim 3, it is characterised in that: reaction is under conditions of ice bath, being heated or not heated It carries out.
7. the synthetic method according to any one of claim 3~6, it is characterised in that: further include to object obtained The step of crude product is purified.
8. synthetic method according to claim 7, it is characterised in that: the step of purifying is that object obtained is thick Product carry out silica gel column chromatography, obtain object after purification.
9. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
10. a kind of pharmaceutical composition goes up compound described in the claim 1 of effective dose containing treatment or its is pharmaceutically acceptable Salt.
CN201811524279.8A 2018-12-13 2018-12-13 Gamma lactone substituted pyridine derivative and its synthetic method and application Pending CN109678847A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432126A (en) * 2016-09-18 2017-02-22 广西师范大学 1-oxy-2,8-diazacyclononane derivatives and synthetic method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432126A (en) * 2016-09-18 2017-02-22 广西师范大学 1-oxy-2,8-diazacyclononane derivatives and synthetic method thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JUN-YI LIAO ET AL.: "A copper-catalyzed diastereoselective O-transfer reaction of N-vinyl-α,β-unsaturated nitrones with ketenes into γ-lactones through [5 + 2] cycloaddition and N-O bond cleavage", 《GREEN CHEMISTRY》 *
SANDEEP RANA ET AL.: "Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
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Application publication date: 20190426