CN109467558A - 1- hydrogen pyrrolizine derivative and its synthetic method and application - Google Patents

1- hydrogen pyrrolizine derivative and its synthetic method and application Download PDF

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CN109467558A
CN109467558A CN201811524268.XA CN201811524268A CN109467558A CN 109467558 A CN109467558 A CN 109467558A CN 201811524268 A CN201811524268 A CN 201811524268A CN 109467558 A CN109467558 A CN 109467558A
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unsubstituted
alkoxy
alkyl
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CN109467558B (en
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莫冬亮
邹宁
焦继文
冯钰�
潘成学
苏桂发
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Guangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention discloses a series of 1- hydrogen pyrrolizine derivatives and its synthetic method and applications.1- hydrogen pyrrolizine 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 catalyst 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 1- hydrogen pyrrolizine 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

1- hydrogen pyrrolizine derivative and its synthetic method and application
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to 1- hydrogen pyrrolizine derivative and its synthetic method and application.
Background technique
1- hydrogen pyrrolizine derivative is widely present in many natural products and drug molecule.Currently, synthesis 1- hydrogen pyrroles There are mainly two types of the methods of oxazine derivatives: one is pass through Grignard Reagent to addition, cyclisation of halogenated nitrile compounds etc. four Step reaction (J.Med.Chem.2009,52,4968；J.Org.Chem.2016,81,4112).Another method is to pass through allyl The intramolecular hydroformylation reaction (ACSCatal.2016,6,2673) of base pyrroles's aldehyde.But existing 1- hydrogen pyrroles's piperazine is similar The deficiencies of synthetic method of object is complicated there are the compatible small or experimental operating conditions of step length, substrate and functional group.
Summary of the invention
The technical problem to be solved in the present invention is to provide a series of 1- hydrogen pyrrolizine derivative of structure novels and they Synthetic method and application.
1- hydrogen pyrrolizine derivative of the present invention is compound shown in following formula (I)s or its is pharmaceutically acceptable Salt:
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 atom, C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted benzene Base；Wherein, 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 atom, cyano, C1~6Alkyl, C1~6Alkoxy or phenol oxygroup or it is unsubstituted, monosubstituted or Disubstituted phenyl, the phenylcarbonyl group or unsubstituted or mono-substituted phenyl sulfonyl replaced, or replace Amino carbonyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate formoxyl, cyano, C1~6Alkyl, alkoxy or phenol oxygroup, or replace phenylcarbonyl group, or It is unsubstituted or mono-substituted phenyl sulfonyl, or the amino carbonyl replaced；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl or C1~6Alkyl.
In above compound:
R1Further preferably unsubstituted, monosubstituted or disubstituted phenyl；
R2Further preferably unsubstituted, monosubstituted or disubstituted phenyl；
R3Further preferably hydrogen or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R4Further preferably C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R5Further preferably hydrogen atom, C1~4Alkyl or alkoxy or unsubstituted, monosubstituted or disubstituted benzene Base or C1~4Alkoxy replace phenylcarbonyl group or C1~4Alkoxy replace amino carbonyl；
R6Further preferably formoxyl, itrile group or alkoxy carbonyl, or the phenylcarbonyl group replaced.
The synthetic method of compound shown in above-mentioned formula (I), mainly comprises the steps that and takes the chemical combination as shown in following formula (II) Compound shown in object, formula (III) and catalyst are placed in organic solvent, are reacted in the presence of oxygen, and object is made Crude product；
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 atom, C1~6Alkyl or C1~6Alkoxy or unsubstituted, monosubstituted or disubstituted benzene Base；Wherein, 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 atom, cyano, C1~6Alkyl, C1~6Alkoxy or phenol oxygroup or it is unsubstituted, monosubstituted or Disubstituted phenyl, the phenylcarbonyl group or unsubstituted or mono-substituted phenyl sulfonyl replaced, or replace Amino carbonyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate formoxyl, cyano, C1~6Alkyl, alkoxy or phenol oxygroup, or replace phenylcarbonyl group, or It is unsubstituted or mono-substituted phenyl sulfonyl, or the amino carbonyl replaced；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl or C1~6Alkyl；
The catalyst is molysite and/or mantoquita.
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 be alkynes reagent, specially acetylenic acid ester, alkynes aldehyde or Acetylenic acid ketone etc. directly can commercially obtain (such as diethyl butyn, Methyl propiolate, 3- hexin -2- ketone or 2- Acraldehyde etc.).
In above-mentioned synthetic method, the molysite is preferably selected from one in ferric trichloride, trifluoromethanesulfonic acid iron and ferric acetate Kind or two or more combinations；The mantoquita is preferably selected from copper bromide, cupric iodide, copper chloride, copper sulphate, cupric acetate, nitre The combination of one or more of sour copper, copper trifluoromethanesulfcomposite, cuprous bromide, cuprous iodide and stannous chloride.Applicant In experiments it is found that being conducive to the yield for improving reaction when catalyst includes simultaneously molysite and mantoquita.
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, reaction can carry out under conditions of being heated or not heated, preferably in the item not heated It is carried out under part.When reaction is performed under heating conditions, preferable reaction temperature is less than or equal to 100 DEG C, further preferably reacts Temperature is less than or equal to 60 DEG C.Whether reaction can be used TLC tracing detection completely.According to the experience of applicant, when reaction is normal To when carrying out under the conditions of 60 DEG C, reaction time control is more suitable for temperature in 5-20h.
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 and formula shown in (III) is usually 1:1~5.For the dosage of catalyst, it is added Amount is preferably the 10-30mol% of the amount of combinations of materials shown in formula (II).
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 100:1~10:1, n-hexane and The volume ratio of ethyl acetate is preferably 100:1~10:1, and the volume ratio by petroleum ether and methanol is preferably 200:1~20:1, and two The volume ratio of chloromethanes and methanol is preferably 200:1~20:1.
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 1- hydrogen pyrrolizine derivative of structure novels and they 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 1- hydrogen pyrrole Alloxazine 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
1- hydrogen pyrrolizine derivative of the present invention is synthesized by following synthetic routes.
3aa:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=CO2Et, R6=CO2Et；
3ba:R1=4-MeOC6H4, R2=4-MeOC6H4, R3=Me, R4=Me, R5=CO2Et, R6=CO2Et；
3ca:R1=4-CF3C6H4, R2=4-CF3C6H4, R3=Me, R4=Me, R5=CO2Et, R6=CO2Et；
3da:R1=3-BrC6H4, R2=4-BrC6H4, R3=Me, R4=Me, R5=CO2Et, R6=CO2Et；
3ea:R1=Ph, R2=Ph, R3=H, R4=Ph, R5=CO2Et, R6=CO2Et；
3fa:R1=Ph, R2=Ph, R3=Et, R4=Et, R5=CO2Et, R6=CO2Et；
3ga:R1=Ph, R2=Ph, R3, R4=(CH2)4, R5=CO2Et, R6=CO2Et；
3ab:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=CO2 nBu, R6=CO2 nBu；
3ac:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=CO2CH2CH2Ph, R6=CO2CH2CH2Ph；
3ad:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=CO2CH2CH=CH2, R6=CO2CH2CH=CH2；
3ae:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=CO2Me；
3ae:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=Ph, R6=CO2Me。
By N- alkenyl α, β-unsaturation nitrone derivative 1 (0.3mmol), alkynes reagent 2 (0.4mmol), FeCl3 (0.03mmol)、CuSO4(0.06mmol) is placed in reaction tube, and 3mL 1 is added, and 2- dichloroethanes is stirred to react 5 at 25 DEG C ~20h, silica gel column chromatography separate (petrol ether/ethyl acetate=50:1~10:1, volume ratio), obtain target product 3.Different It target product and its is characterized as below:
3aa: faint yellow solid, 69mg, 76%yield；mp:147–148℃；1H NMR(400MHz,CDCl3):δ7.42 (d, J=16.8Hz, 1H), 7.33-7.29 (m, 2H), 7.27 (d, J=5.2Hz, 1H), 7.22-7.18 (m, 2H), 7.13- 7.11 (m, 5H), 6.26 (d, J=16.4Hz, 1H), 4.48 (s, 1H), 4.42 (q, J=7.2Hz, 2H), 4.35 (q, J= 7.2Hz, 2H), 2.20 (s, 3H), 1.70 (s, 3H), 1.43 (t, J=7.2Hz, 3H), 1.38 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3):δ164.9,162.5,137.9,137.4,137.2,130.2,130.1,130.0,128.9, 128.3,128.1,127.5,126.8,125.8,120.2,119.6,117.6,116.6,61.7,60.3,52.6,14.3, 14.0,11.3,10.9；IR(neat)3023,2924,2859,1725,1692,1491,1434,1384,1253,1157,966, 701cm-1；MS(ESI)m/z[M+H]+calcd for[C29H30NO4]+:456.2175；Found:456.2152. its structural formula is such as Under:
3ba: faint yellow solid, 78mg, 75%yield；mp:162–163℃；1H NMR(400MHz,CDCl3):δ7.21 (d, J=16.4Hz, 1H), 7.04 (d, J=8.8Hz, 2H), 6.96 (d, J=8.4Hz, 2H), 6.77 (d, J=8.4Hz, 2H), 6.70 (d, J=8.4Hz, 2H), 6.21 (d, J=16.8Hz, 1H), 3.69 (s, 3H), 3.68 (s, 3H), 2.11 (s, 3H), 1.62 (s, 3H), 1.35 (t, J=7.2Hz, 3H), 1.30 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3):δ 165.0,162.5,158.9,158.7,137.4,130.8,130.4,129.9,129.6,129.2,129.1,127.0, 126.9,120.0,117.5,116.7,114.3,113.8,61.7,60.2,55.2,55.1,51.8,14.3,14.0,11.3, 10.9；IR(neat)2922,2852,1731,1689,1451,1381,1252,1171,1029,965,808cm-1；MS(ESI) m/z[M+H]+calcd for[C31H34NO6]+:516.2386；Found:516.2371. its structural formula is as follows:
3ca: faint yellow solid, 59mg, 50%yield；mp 147–148℃；1H NMR(400MHz,CDCl3):δ7.50 (d, J=7.6Hz, 2H), 7.45 (d, J=16.8Hz, 1H), 7.34 (d, J=7.6Hz, 8H), 7.17 (d, J=8.0Hz, 2H), 7.09 (d, J=8.0Hz, 2H), 6.10 (d, J=16.8Hz, 1H), 4.47 (s, 1H), 4.36 (q, J=7.2Hz, 2H), 4.27 (q, J=7.2Hz, 2H), 2.10 (s, 3H), 1.61 (s, 3H), 1.36 (t, J=7.2Hz, 3H), 1.30 (t, J=6.8Hz, 3H)；13C NMR(100MHz,CDCl3):δ164.5,162.3,141.3,141.1,136.7,130.7,130.5,130.1, 129.8,129.5,128.4,128.2,126.0(q,JC-F=10.8Hz), 125.8,125.4,122.1,121.0,117.4, 116.2,62.0,60.5,52.2,14.3,14.0,11.2,10.7；IR(neat)3058,2929,2859,1720,1611, 1499,1441,1322,1159,965,679cm-1；MS(ESI)m/z[M+H]+calcd for[C31H28F6NO6]+: 592.1923；Found:592.1911. its structural formula is as follows:
3da: yellow solid, 89mg, 73%yield；mp:145–146℃.1H NMR(400MHz,CDCl3):δ7.60– 7.55 (m, 4H), 7.41-7.38 (m, 2H), 7.22-7.17 (m, 2H), 6.95 (d, J=16.0Hz, 1H), 6.92 (d, J= 16.4Hz, 1H), 4.74 (s, 1H), 4.32 (q, J=7.2Hz, 2H), 4.29 (q, J=7.2Hz, 2H), 2.09 (s, 3H), 1.71 (s, 3H), 1.30 (t, J=7.2Hz, 3H), 1.29 (t, J=6.8Hz, 3H)；13C NMR(100MHz,CDCl3):δ165.7, 160.4,137.4,136.7,133.5,133.2,131.7,131.6,129.7,129.5,128.6,128.2,126.8, 124.4,122.9,122.8,120.8,120.4,117.4,116.6,61.2,60.4,51.6,14.3,14.1,11.7,10.5； IR(neat)3046,2935,2858,1701,1603,1458,1354,1234,1109,978,698cm-1；MS(ESI)m/z[M +H]+calcdfor[C29H28Br2NO4]+:612.0385；Found:612.0378. its structural formula is as follows:
3ea: yellow solid, 89mg, 76%yield；mp:152–153℃；1H NMR(400MHz,CDCl3):δ7.49(d, J=16.8Hz, 1H), 7.40-7.36 (m, 5H), 7.29-7.25 (m, 2H), 7.22-7.18 (m, 3H), 7.15-7.13 (m, 2H), 7.10-7.06 (m, 3H), 6.30 (d, J=16.8Hz, 1H), 5.93 (s, 1H), 4.93 (s, 1H), 4.26 (q, J= 6.8Hz, 2H), 3.65 (q, J=4.8Hz, 2H), 1.27 (t, J=6.8Hz, 3H), 0.95 (t, J=7.2Hz, 3H)；13C NMR (100MHz,CDCl3):δ164.4,161.7,140.1,137.8,137.5,136.5,130.5,130.0,129.5,129.1, 128.4,128.3,128.2,127.8,127.6,127.0,126.0,125.2,121.2,119.6,117.7,117.6,61.5, 60.3,49.5,14.2,13.6；IR(neat)3053,2926,2859,1728,1651,1447,1341,1095,693cm-1； MS(ESI)m/z[M+H]+calcd for[C33H30NO4]+:504.2175；Found:504.2170. its structural formula is as follows:
3fa: faint yellow solid, 49mg, 51%yield；mp:123–124℃；1H NMR(400MHz,CDCl3):δ7.33– 7.28 ((d, J=16.8Hz, 1H), 7.25-7.21 (m, 2H), 7.18-7.11 (m, 3H), 7.08-7.04 (m, 5H), 6.23 (d, J=16.8Hz, 1H), 4.56 (s, 1H), 4.34 (q, J=6.8Hz, 2H), 4.25 (q, J=7.2Hz, 2H), 2.67-2.57 (m, 2H), 2.22-2.16 (m, 1H), 1.84-1.79 (m, 1H), 1.35 (t, J=7.2Hz, 3H), 1.30 (t, J=7.2Hz, 3H), 1.12 (t, J=7.6Hz, 3H), 0.95 (t, J=7.6Hz, 3H)；13C NMR(100MHz,CDCl3):δ164.9,162.7, 138.2,137.9,137.5,136.2,135.9,129.9,129.0,128.3,128.2,127.5,126.8,125.9, 120.3,119.6,118.2,116.5,61.8,60.3,50.2,18.7,17.9,14.3,14.2,14.0,13.6；IR (neat):3061,2934,2874,1708,1600,1555,1450,1384,1226,1177,966,697cm-1；MS(ESI) m/z[M+H]+calcd for[C31H34NO4]+:484.2488；Found:484.2478. its structural formula is as follows:
3ga: faint yellow solid, 58mg, 60%yield；mp:153-154℃；1H NMR(400MHz,CDCl3):δ7.25- 7.21 (m, 2H), 7.20-7.17 (m, 2H), 7.15-7.11 (m, 2H), 7.05 (d, J=6.8Hz, 5H), 6.22 (d, J= 16.4Hz, 1H), 4.47 (s, 1H), 4.32 (q, J=7.2Hz, 2H), 4.27 (q, J=7.2Hz, 2H), 2.64-2.52 (m, 2H), 2.14 (d, J=17.2Hz, 1H), 1.86 (d, J=17.6Hz, 1H), 1.70-1.62 (m, 2H), 1.60-1.51 (m, 2H), 1.34 (t, J=7.6Hz, 3H), 1.30 (t, J=7.2Hz, 3H)；13C NMR(100MHz,CDCl3):δ165.2, 161.8,138.5,137.9,137.0,133.9,133.4,130.1,130.0,128.4,128.0,127.4,126.9, 125.9,119.6,119.4,119.1,116.8,61.4,60.5,51.5,23.1,23.0,22.4,22.0,14.3,14.1；IR (neat)3040,2927,2855,1717,1691,1494,1231,1140,969,699cm-1；MS(ESI)m/z[M+H]+ calcdfor[C31H32NO4]+:482.2331；Found:482.2323. its structural formula is as follows:
3ab: yellow solid, 69mg, 68%yield；mp:94-95℃；1H NMR(600MHz,CDCl3):δ7.42(d,J =17.4Hz, 1H), 7.32-7.29 (m, 2H), 7.26-7.23 (m, 1H), 7.21-7.18 (m, 2H), 7.12 (d, J=6.6Hz, 5H), 6.25 (d, J=16.8Hz, 1H), 4.47 (s, 1H), 4.34-4.32 (m, 2H), 4.31-4.26 (m, 2H), 2.18 (s, 3H), 1.78-1.71 (m, 4H), 1.70 (s, 3H), 1.49-1.44 (m, 4H), 0.99 (t, J=7.8Hz, 3H), 0.97 (t, J= 7.2Hz,3H)；13C NMR(150MHz,CDCl3):δ164.8,162.7,137.9,137.3,137.2,130.2,130.0, 128.9,128.3,128.2,127.5,126.8,125.8,120.3,120.0,119.9,117.5,116.4,65.8,64.3, 52.7,30.9,30.5,19.3,19.2,13.8,13.7,11.3,10.8；IR(neat))2959,2929,2868,1725, 1625,1452,1381,1252,1165,969,696cm-1；MS(ESI)m/z[M+H]+calcd for[C33H38NO4]+: 512.2801；Found:512.2789. its structural formula is as follows:
3ac: yellow solid, 101mg, 85%yield；mp:118-119℃；1H NMR(400MHz,CDCl3):δ7.23- 7.19 (m, 5H), 7.16-7.13 (m, 6H), 7.11-7.07 (m, 5H), 7.02-7.00 (m, 5H), 6.16 (d, J=16.8Hz, 1H),4.37(s,1H),4.35-4.27(m,4H),2.94-2.88(m,4H),1.95(s,3H),1.57(s,3H)；13C NMR (100MHz,CDCl3):δ164.7,162.4,137.8,137.5,137.4,137.2,130.3,130.2,130.1,130.0, 128.9,128.8,128.5,128.4,128.3,128.1,127.5,126.8,126.6,126.5,125.9,120.1, 119.5,119.4,117.4,116.6,66.2,64.9,52.6,35.1,34.8,11.3,10.6；IR(neat)3049,2926, 2859,1638,1458,1381,1164,1078,698cm-1；MS(ESI)m/z[M+H]+calcd for[C41H38NO4]+: 608.2801；Found:608.2789. its structural formula is as follows:
3ad: faint yellow solid, 71mg, 70%yield；mp:118-119℃；1H NMR(400MHz,CDCl3):δ7.32 (d, J=16.8Hz, 1H), 7.25-7.21 (m, 2H), 7.18-7.17 (m, 1H), 7.14-7.10 (m, 2H), 7.05 (d, J= 7.2Hz, 5H), 6.18 (d, J=16.8Hz, 1H), 5.84-5.73 (m, 2H), 5.13-5.06 (m, 2H), 5.03-5.00 (m, 2H), 4.39 (s, 1H), 4.34 (t, J=6.8Hz, 2H), 4.26 (t, J=5.6Hz, 2H), 2.48-2.43 (m, 2H), 2.42- 2.38(m,2H),2.10(s,3H),1.61(s,3H)；13C NMR(100MHz,CDCl3):δ164.8,162.5,137.8, 137.4,137.2,134.1,133.7,130.3,130.1,130.0,128.9,128.3,128.2,127.5,126.8, 125.8,120.2,119.6,117.5,117.4,117.2,116.5,65.0,63.7,52.6,33.1,32.8,11.3,10.9； IR(neat)2925,2859,1705,1638,1453,1379,1166,971,698cm-1；MS(ESI)m/z[M+H]+calcd for[C31H30NO4]+:508.2488；Found:508.2479. its structural formula is as follows:
3ae: faint yellow solid, 32mg, 43%yield；mp:188-189℃；1H NMR(600MHz,CDCl3):δ7.78 (d, J=17.4Hz, 1H), 7.35 (s, 1H), 7.24-7.22 (m, 2H), 7.14-7.12 (m, 2H), 7.10-7.09 (m, 2H), 7.04-7.03 (m, 3H), 6.19 (d, J=16.8Hz, 1H), 4.46 (s, 1H), 3.78 (s, 3H), 2.10 (s, 3H), 1.65 (s, 3H)；13C NMR(150MHz,CDCl3):δ165.9,138.3,137.9,135.7,129.2,128.9,128.3,128.2, 128.1,127.3,126.5,125.8,120.6,126.5,117.5,115.2,115.1,53.3,50.8,11.2,9.3；IR(neat) 3055,2924,2854,1705,1597,1498,1444,1285,1183,970,698cm-1；MS(ESI)m/z[M+H]+calcd for[C25H24NO2]+:370.1807；Found:370.1798. its structural formula is as follows:
3af: yellow solid, 40mg, 45%yield；mp:179-180℃；1H NMR(600MHz,CDCl3):δ7.79- 7.70 (m, 2H), 7.60-7.50 (m, 4H), 7.45-7.25 (m, 6H), 7.20-7.10 (m, 4H), 6.19 (d, J=16.8Hz, 1H),4.49(s,1H),3.81(s,3H),2.12(s,3H),1.68(s,3H)；13CNMR(150MHz,CDCl3):δ164.8, 138.2,137.9,135.4,133.2,130.4,129.3,129.2,128.8,128.3,128.2,128.0,127.5, 126.9,125.7,120.9,120.4,117.3,115.4,115.1,53.9,50.5,11.4,9.2；IR(neat)3057, 2942,2855,1709,1602,1497,1454,1279,1177,971,694cm-1；MS(ESI)m/z[M+H]+calcd for [C31H28NO2]+:446.2120；Found:446.2131. its structural formula is as follows:
Embodiment 2:
1- hydrogen pyrrolizine derivative of the present invention is synthesized by following synthetic routes.
3ag:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=COCH3；
3ah:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=Ph, R6=CN；
3ai:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=H, R6=CONMe (OMe)；
3aj:R1=Ph, R2=Ph, R3=Me, R4=Me, R5=Ph, R6=4-MeC6H4SO2。
By N- alkenyl α, β-unsaturation nitrone substrate 1 (0.3mmol), alkynes reagent 2 (0.6mmol), catalyst (object The catalyst that 3ag-3aj is used is respectively ferric acetate, copper chloride, copper trifluoromethanesulfcomposite and cuprous bromide) (0.03mmol) be placed in In reaction tube, be added 3mL organic solvent (object 3ag-3aj use organic solvent be respectively benzene, hexamethylene, ether, by two The composition that six ring of oxygen and n-hexane are mixed by the volume ratio of 1:2), 3~15h, gained reaction are stirred to react at 40 DEG C Solvent is removed under reduced pressure in object, and silica gel column chromatography separates (petroleum ether/methanol=50:1~20:1, volume ratio), obtains target product 3. It different target products and its is characterized as below:
3ag: faint yellow solid, 41mg, 58%yield；mp:164-165℃；1H NMR(500MHz,CDCl3):δ7.78 (d, J=16.5Hz, 1H), 7.23-7.20 (m, 2H), 7.17 (d, J=7.0Hz, 1H), 7.13-7.08 (m, 5H), 7.02 (d, J =7.0Hz, 1H), 6.16 (d, J=16.5Hz, 1H), 4.43 (s, 1H), 2.39 (s, 3H), 2.09 (s, 3H), 1.62 (s, 3H) ；13C NMR(150MHz,CDCl3):δ194.3,138.3,137.8,136.5,129.8,129.7,128.9,128.2,128.1, 127.4,126.5,125.9,125.9,125.0,121.2,117.3,115.8,53.2,28.0,11.3,9.3；IR(neat) 3038,2921,2852,1645,1491,1446,1359,1286,1183,967,703cm-1；MS(ESI)m/z[M+H]+calcd for[C25H24NO]+:354.1858；Found:354.1849. its structural formula is as follows:
3ah: yellow solid, 58mg, 69%yield；mp:186-187℃；1H NMR(600MHz,CDCl3):δ7.53- 7.53(m,2H),7.48-7.47(m,3H),7.38-7.36(m,2H),7.31-7.29(m,1H),7.26-7.24(m,2H), 7.22-7.21 (m, 2H), 7.19-7.15 (m, 3H), 6.85 (d, J=16.8Hz, 1H), 6.72 (d, J=16.2Hz, 1H), 4.54(s,1H),1.79(s,3H),1.70(s,3H)；13C NMR(150MHz,CDCl3):δ137.5,137.4,136.7, 134.1,130.5,130.4,130.3,129.3,129.2,129.1,129.0,128.4,128.2,128.1,127.6, 127.1,125.9,118.1,117.5,117.2,94.2,51.8,12.0,11.2；IR(neat)3047,2923,2859, 2210,1637,1600,1418,1384,1159,959,697cm-1；MS(ESI)m/z[M+H]+calcd for[C30H25N2]+: 413.2018；Found:413.2010. its structural formula is as follows:
3ai: faint yellow solid, 50mg, 66%yield；mp:121–122℃；1H NMR(400MHz,CDCl3):δ7.45 (d, J=16.8Hz, 1H), 7.34-7.30 (m, 2H), 7.29 (d, J=5.2Hz, 1H), 7.23-7.16 (m, 2H), 7.15- 7.10 (m, 5H), 7.05 (s, 1H), 6.29 (d, J=16.4Hz, 1H), 4.50 (s, 1H), 3.70 (s, 3H), 2.96 (s, 3H), 2.13(s,3H),1.75(s,3H)；13C NMR(100MHz,CDCl3):δ169.6,137.8,135.4,133.7,130.0, 129.3,128.9,128.7,128.3,127.8,126.3,125.6,124.5,121.7,118.9,112.7,112.2,63.7, 47.2,38.3,19.1,16.4；IR(neat)3058,2926,2855,1720,1695,1488,1456,1381,1250, 1145,968,694cm-1；MS(ESI)m/z[M+H]+calcd for[C26H27N2O2]+:399.2073；found:399.2076. Its structural formula is as follows:
3aj: yellow solid, 74mg, 68%yield；mp:145–146℃；1H NMR(400MHz,CDCl3):δ7.82– 7.70 (m, 5H), 7.62-7.50 (m, 4H), 7.47-7.38 (m, 5H), 7.35-7.20 (m, 6H), 6.56 (d, J=16.0Hz, 1H),4.67(s,1H),2.45(s,3H),1.89(s,3H),1.70(s,3H)；13CNMR(100MHz,CDCl3):δ139.8, 138.5,137.8,135.2,133.9,133.3,130.5,130.0,129.8,129.7,129.3,129.0,128.8, 128.7,128.6,128.5,128.0,127.6,127.5,126.3,125.6,124.5,112.7,110.9,46.8,21.4, 19.6,14.8；IR(neat)3058,2924,2858,1720,1689,1494,1458,1379,1249,1109,965, 696cm-1；MS(ESI)m/z[M+H]+calcd for[C36H32NO2S]+:542.2154；Found:542.2159. its structural formula It is as follows:
Experimental example 1: 1- hydrogen pyrrolizine derivative of the present invention carries out external inhibitory activity experiment to a variety of human tumour strains:
(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 atom, 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, replace Base is C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R5Indicate hydrogen atom, cyano, C1~6Alkyl, C1~6Alkoxy or phenol oxygroup or unsubstituted, monosubstituted or two take The phenyl in generation, the phenylcarbonyl group or unsubstituted or mono-substituted phenyl sulfonyl replaced, or the ammonia replaced Base carbonyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate formoxyl, cyano, C1~6Alkyl, alkoxy or phenol oxygroup, or the phenylcarbonyl group replaced, or not Substitution or mono-substituted phenyl sulfonyl, or the amino carbonyl replaced；Wherein, substituent group C1~4Alkoxy, C1~4's Perfluoroalkyl or C1~6Alkyl.
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 atom or C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R4Indicate C1~4Alkyl or unsubstituted, monosubstituted or disubstituted phenyl；
R5Indicate hydrogen atom, C1~4Alkyl or alkoxy is unsubstituted, monosubstituted or disubstituted phenyl or C1~4 Alkoxy replace phenylcarbonyl group or C1~4Alkoxy replace amino carbonyl；
R6Indicate formoxyl, itrile group or alkoxy carbonyl, or the phenylcarbonyl group replaced.
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 catalyst are placed in organic solvent, are reacted in the presence of oxygen, system Obtain object crude product；
R5-C≡C-R6(III)；
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 atom, cyano, C1~6Alkyl, C1~6Alkoxy or phenol oxygroup or unsubstituted, monosubstituted or two take The phenyl in generation, the phenylcarbonyl group or unsubstituted or mono-substituted phenyl sulfonyl replaced, or the ammonia replaced Base carbonyl；Wherein, substituent group C1~4Alkoxy, C1~4Perfluoroalkyl, C1~6Alkyl or halogen atom；
R6Indicate formoxyl, cyano, C1~6Alkyl, alkoxy or phenol oxygroup, or the phenylcarbonyl group replaced, or not Substitution or mono-substituted phenyl sulfonyl, or the amino carbonyl replaced；Wherein, substituent group C1~4Alkoxy, C1~4's Perfluoroalkyl or C1~6Alkyl；
The catalyst is molysite and/or mantoquita.
4. synthetic method according to claim 3, it is characterised in that: the molysite is selected from ferric trichloride, trifluoro methylsulphur The combination of one or more of sour iron and ferric acetate；The mantoquita is selected from copper bromide, cupric iodide, copper chloride, sulfuric acid One or more of copper, cupric acetate, copper nitrate, copper trifluoromethanesulfcomposite, cuprous bromide, cuprous iodide and stannous chloride Combination.
5. 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.
6. synthetic method according to claim 3, it is characterised in that: reaction carries out under conditions of being heated or not heated.
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.
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